Brenner and Rector's The Kidney, 8th ed.

CHAPTER 54. Specific Pharmacologic Approaches to Clinical Renoprotection

Gerjan Navis   Paul E. de Jong   Dick de Zeeuw

  

 

Specific Pharmacologic Intervention: A Risk Factor-Based Approach, 1848

  

 

Risk Factors for Renal Function Loss and Renoprotective Benefit of Specific Intervention, 1849

  

 

Hypertension, 1849

  

 

Glomerular Hypertension, 1852

  

 

Proteinuria, 1853

  

 

Hyperlipidemia, 1854

  

 

Pharmacologic Approaches, 1856

  

 

Antihypertensive Treatment, 1856

  

 

AT1 Receptor Blockers, 1858

  

 

Antiproteinuric Treatment, 1860

  

 

Antihyperlipemic Treatment, 1862

  

 

Genetic Factors, 1864

  

 

Pharmacogenetics, 1864

  

 

Lifestyle Factors, 1865

  

 

Smoking, 1865

  

 

Risk Factor Profile in Renal Patients, 1865

  

 

Clustering of Renal Risk Factors, 1865

  

 

Feasibility of an Integrated Approach for Cardiorenal Protection, 1866

  

 

Clinical Management, 1867

  

 

A Framework for Renoprotective Intervention, 1867

  

 

Secondary Prevention, 1868

  

 

Monitoring of Renoprotective Therapy, 1868

  

 

Optimizing Therapy Response, 1869

  

 

Protein Intake, 1870

  

 

Time Course, 1872

  

 

Individual Patient Factors in Therapy Response: New Perspective to Improve Renoprotection?, 1873

  

 

Novel Targets for Intervention, 1874

  

 

Conclusions and Future Prospects, 1874

SPECIFIC PHARMACOLOGIC INTERVENTION: A RISK FACTOR-BASED APPROACH

The number of patients with end-stage renal disease is steadily increasing worldwide, putting a heavy burden on both individual patients and society. Prevention of progressive renal damage, therefore, is a main challenge in nephrology. It has long been recognized that in many patients progressive renal function loss occurs despite absence of overt activity of the underlying renal disorder. As early as 1942, Ellis[1] suggested that hypertension is a main determinant of chronic renal function loss irrespective of the initial cause of renal damage. Since then, the hypothesis that common mechanisms account for the progressive renal function loss in many renal conditions was fueled by numerous observations. These include the renal function deterioration that occurs in many patients regardless of their initial renal disease, as well as the similarity in histopathologic abnormalities in end-stage kidneys with different underlying diseases. Moreover, the risk factors for progressive renal function loss tend to be similar for different renal disorders. Accordingly, it is assumed that progression rate is determined by three main factors: activity of the primary disease process, (mal-) adaptive alterations in the kidney, and the local and systemic sequelae of the renal disorder. [2] [3] Systemic and glomerular hypertension, proteinuria and metabolic abnormalities such as hyperlipidemia are assumed to be common mediators of glomerulosclerosis accompanied by interstitial fibrosis, the alleged final common pathway of progressive renal damage[4] as depicted in Figure 54-1 . In many renal conditions, hypertension, proteinuria, and metabolic abnormalities are simultaneously present. This clustering of risk factors is highly relevant for outcome, because many experimental and clinical data suggest that their mutual interaction accelerates progressive renal damage as well as its cardiovascular complications.

FIGURE 54-1  Simplified schedule of factors involved in progressive renal function loss, with focus on their interactions. Note the existence of several positive feedback loops, leading to a vicious circle of progressive renal damage. Shaded ovals indicate factors targeted by current pharmacologic interventions, that are discussed in the text. For sake of clarity, no attempt at completeness is made. GFR, glomerular filtration rate; AngII, angiotensin II; Aldo, aldosterone.

 

To prevent progressive renal function loss, as a matter of clinical common sense, first ongoing disease-specific factors should be eliminated. When these are accessible to intervention, such as in analgesic abuse[5] or obstructive nephropathy[6] indeed progression may be halted by their elimination. In malignant hypertension, if adequately treated, recovery of renal function may even be possible.[7] In diabetes, strict metabolic control can reverse early hyperfiltration and retard the progression of diabetic renal function loss[8] and cure of diabetes by pancreas transplantation can even lead to regression of renal structural lesions.[9]

In many renal patients, however, no disease-specific factors accessible to intervention can be identified. This prompted the development of strategies aimed at intervention with non-disease-specific, common renal risk factors to prevent progressive renal function loss. Specific intervention is available for several of those common risk factors, as depicted in Figure 54-1 . The yield of demonstrating renoprotective benefit of intervention with a certain clinical risk factor is dual. First, it allows better patient care, and second, it contributes to the evidence for a causal role of that risk factor in progressive renal function loss, thus improving pathophysiologic insights, eventually paving the way for further improvements in therapy.

The last decade witnessed substantial advances in renoprotective intervention. Major effort was put into studies evaluating the long-term renoprotective effects of pharmacologic intervention targeting blood pressure and proteinuria. Most importantly, randomized controlled trials demonstrated that reduction of blood pressure and particularly proteinuria can effectively reduce the rate of renal function loss, and thus postpone the need for renal replacement therapy. Data in diabetes demonstrated the feasibility of primary prevention of renal damage by renoprotective intervention,[10] supporting the case for possible benefits of intervention in earlier phases of the disease process.[11] Moreover, it has become increasingly clear that renal function impairment and proteinuria are potent cardiovascular risk factors,[12] not only in advanced, but also early renal failure. As a result, there is increasing emphasis on integrated approaches for the prevention of renal and cardiovascular damage[13] as apparent, for instance, from the two main outcomes of chronic kidney disease (CKD) as defined by the National Kidney Foundation. These outcomes are, first, the progressive loss of kidney function and second, development and progression of cardiovascular disease.[14] In this chapter, emphasis is placed on the prevention of progressive renal function loss.

RISK FACTORS FOR RENAL FUNCTION LOSS AND RENOPROTECTIVE BENEFIT OF SPECIFIC INTERVENTION

Hypertension

Whereas malignant hypertension has for decades been recognized to lead to rapid renal function loss, the role of less severe hypertension in progressive renal damage is less well defined. Epidemiologic data on patients entering dialysis suggest a substantial role for hypertension, hypertensive nephrosclerosis being the second most common cause of end-stage renal failure surpassed only by diabetes. Among the patients with a diagnosis of hypertensive nephrosclerosis, however, only 6% had a history of malignant hypertension, strongly suggesting a causal role for less severe hypertension in the development of end-stage renal failure.[15] Strikingly, whereas the incidence of cardiac and cerebral hypertensive end organ damage is decreasing, the number of patients entering dialysis with a diagnosis of hypertensive renal damage increases steadily, emphasizing its importance for the renal population.[16]

Morphologic studies support a role for hypertension in eliciting structural renal damage. In autopsy data in young accident victims from different countries, the prevalence of nephrosclerosis correlated with the prevalence of hypertension in the respective countries.[17] Moreover, the severity of nephrosclerosis was closely correlated to blood pressure records in autopsy series [18] [19] as well as renal biopsies in essential hypertensives.[20] In blacks with hypertensive nephrosclerosis the severity of glomerulosclerosis correlated with blood pressure.[21] Finally, in a small series of proteinuric hypertensives a primary renal disorder was present in only a minority of the patients, suggesting that the glomerular lesions in the remainder of the patients might be due to hypertension per se.[22]

Epidemiologic data support the role of blood pressure as a renal risk factor. [23] [24] Blood pressure was a strong predictor for end-stage renal failure during 16 years of follow-up in 332,544 middle-aged men in the Multiple Risk Factor Intervention Trial.[25] Remarkably, renal risk was already apparent as of a systolic blood pressure of 127 mm Hg and a diastolic blood pressure of 82 mm Hg, that is, values well within the normotensive range. In the large community-based Okinawa study, elevated and high-normal systolic and diastolic blood pressure was a predictor for end-stage renal disease in men and women.[26] Several studies point toward a specific role of systolic blood pressure, and accordingly pulse pressure,[27] and, in line, isolated systolic hypertension is associated with renal function loss in the elderly.[28]

Yet, population studies do not explain the role of blood pressure as a cause of end-stage renal failure. The prevalence of end-stage renal failure is very low, and moreover, in the above studies the rate of renal function loss was very low. For instance, in hypertensive subjects creatinine clearance fell by only 0.92 versus 0.75 mL/min/year in normotensive subjects[24] and even in subjects with evidence for renal or urinary tract disease renal function fell by only 1.1 mL/min/year. Other studies also found a well-preserved glomerular filtration rate (GFR) in hypertensives in spite of long-standing hypertension. [29] [30] [31] Yet, the age-related decline in renal blood flow was consistently more pronounced in hypertensives and even in the normotensive range effective renal blood flow is inversely related to blood pressure.[32] Apparently, however, this leads to renal function loss only in a subset of the hypertensive population.[33]

Thus, the long-term impact of blood pressure on renal function in individuals depends on the concomitant presence of other renal risk factors, specific renal susceptibility to hypertensive renal damage, or their combination. Several predictors of renal function loss were identified in hypertensive populations. These include racial factors with an increased risk in blacks, impaired glucose tolerance, increased uric acid, elevated serum creatinine, [34] [35] [36] and proteinuria.[37] In accord with experimental data,[38] the latter strongly suggests that prior renal damage is associated with enhanced susceptibility to hypertensive renal damage. Genetic factors other than ethnicity may also be involved. [39] [40] [41]

In patients with renal disease, hypertension is common, as reviewed in Chapter 42 . Its prevalence appears to increase with deteriorating renal function, amounting to some 90% of the patients entering dialysis.[42] High blood pressure is consistently associated with a poor renal outcome. In diabetic patients, the development of hypertension is closely associated with the transition of normoalbuminuria to microalbuminuria,[43] with the subsequent progression to overt proteinuria and with progressive renal function loss. [44] [45] [46] Morphologic studies in nephropathy in type 1 diabetes found an association between the severity of the renal structural lesions and blood pressure.[47] [48] In nondiabetic renal disease, high blood pressure is associated with a poor long-term renal outcome as well across a spectrum of renal disorders. [49] [50] [51] [52] Moreover, blood pressure predicted subsequent renal function loss in glomerular disorders [53] [54] as well as in adult polycystic kidney disease.[55] Considering the role of high blood pressure as the leading paradigm for explaining progressive renal function loss for many years, however, the number of studies supporting its role as an independent renal risk factor has remained relatively small for a long time. In several studies, blood pressure was not an independent determinant of renal function loss, owing to a predominant effect of proteinuria. [6] [51] [56] The relative impact of blood pressure, disease activity, and concomitant risk factors (e.g., proteinuria) on renal function loss has been proven hard to dissect[57] and may vary between different study populations.

Blood Pressure Reduction

Antihypertensive therapy has been the cornerstone of renoprotective intervention for decades. A lower blood pressure was associated with a more favorable renal outcome in diabetic as well as nondiabetic patients in many studies.[50] [52] [57] [58] [59] [60] [61] [62] [63] [64] Yet, the evidence for renoprotection provided by blood pressure reduction as such has long been debated. First, it relied mainly on studies in which both the treatment responsiveness of blood pressure and the long-term course of renal function might reflect the aggressiveness of the underlying renal condition. Moreover, several older studies failed to show a relationship between the reduction of blood pressure and progression rate. [65] [66] [67] [68] [69] [70] [71] [72] Finally, nonspecific trial-related effects such as more frequent follow-up and better patient compliance were argued to account for part of the renoprotective benefit.[73] Factors such as the obtained blood pressure level and differences in patient characteristics were suggested to account for the discrepancies.[52]

Differences in baseline proteinuria likely account for a major part of the discrepancies between studies. Landmark data from the Modification of Diet in Renal Disease (MDRD) trial showed that the renoprotective benefit of blood pressure reduction depends on the level of baseline proteinuria.[74] This prospective trial in 840 nondiabetic patients (GFR 13-55 mL/min) was designed to address the effect of a lower blood pressure target. Additional therapy included dietary protein restriction in half of the patients. For the study population as a whole, the more aggressive blood regimen resulted in a difference in mean arterial pressure (MAP) of 4.7 mm Hg which did not result in detectable additional renoprotection during the 3 years of follow-up. However, this seeming lack of renoprotective benefit was explained by an uneven distribution of renoprotective benefit over the patients. Proteinuria, diagnosis and race all affected renoprotective benefit of blood pressure reduction. [75] [76] Baseline proteinuria was the most potent determinant of the benefit of blood pressure reduction, with a greater renoprotective benefit of the lower blood pressure goal in patients with a higher baseline proteinuria ( Fig. 54-2 ).

FIGURE 54-2  Decline in glomerular filtration rate (GFR) from baseline to 3 years of follow-up, according to baseline proteinuria and blood pressure group from the MDRD study. Closed circles represent the low blood pressure target groups. Study 1 (left panel) refers to 585 patients with baseline GFR of 25-55 mL/min; study 2 (right panel) to 255 patients with baseline GFR 13-24 mL/min.  (Reproduced with permission from Klahr S, Levey AS, Beck GJ, et al: The effect of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 330:877–884, 1994.)

 

 

Interestingly, on long term follow-up the onset of renal failure, and the combined end point of renal failure or death, was significantly delayed in the low target group.[77] Power did not allow subgroup analysis here, and follow-up data on blood pressure were not available. The long term effect of a—possibly limited—period of lower blood pressure is in line with experimental data and with older data in patients with hypertensive nephrosclerosis where an initial period of aggressive blood pressure reduction was followed by improvement of long-term renal function.[78]

In diabetic nephropathy, the importance of aggressive blood pressure reduction for renal function preservation was extensively demonstrated in observational studies [62] [79] Studies in type 2 diabetes suggest that reduction of systolic pressure may be particularly relevant. [63] [65] [66] [80] Trials comparing angiotensin-converting enzyme (ACE) inhibitors with conventional antihypertensives in type 1[81] as well as type 2 diabetes[82] found that renal function loss was ameliorated more effectively in the treatment groups with the lower blood pressure, for example, the patients assigned to ACE inhibition. Whereas non-pressure-related effects of ACE inhibitors are likely to be involved in renoprotection as well, the association between blood pressure reduction and the obtained protection against renal function loss is strong, a finding corroborated by similar findings with AT1-receptor blockade. [83] [84]

Target Blood Pressure

Because there is no clear-cut threshold for pressure-associated renal risk, target blood pressure for renoprotection has long been a matter for debate. An older study in essential hypertensives found more effective stabilization of renal function by stepped care, with a blood pressure level of 129/86 mm Hg as compared with referred care with a blood pressure of 139/90 mm Hg.[35] More recently, three major trials addressed the effects of lower blood pressure targets in nondiabetic renal patients, that is, the MDRD study,[75] the AASK trial,[85] and the REIN-2 study.[86] The MDRD studied the effect of a target MAP of 92 mm Hg versus 98 mmHb (107 mmHb versus 113 mmHb in subjects older than 60 years of age) ( Fig. 54-3 ). As noted previously, baseline proteinuria was the main determinant of renoprotective benefit of lower blood pressure, with additional effects of racial factors. When baseline proteinuria was 1 to 3 g/day, a MAP of 98 mmHb (corresponding to 135/80 mmHb) provided additional renoprotection, but not when baseline proteinuria was less than 1 g/day. Moreover, when proteinuria was greater than 3 g/day, an additional benefit was found for an even lower target, that is, a MAP of 92 mmHb (125/75 mmHb).

FIGURE 54-3  Mean rate of GFR decline and achieved blood pressure level (mean arterial pressure; MAP) during follow-up in the MDRD study for patients stratified according to baseline proteinuria.  (Adapted with permission from Peterson JC, Adler S, Burkart JM, et al: For the MDRD Study group. Blood pressure control, proteinuria and the progression of renal disease. Ann Int Med 123:754–762, 1995.)

 

 

Ethnic factors affected the effects of blood pressure level. In black subjects, the difference in overall renal function loss between those assigned to the usual versus the low target level was 11.8 mL/min versus 0.3 mL/min in whites (ns), mainly due to patients with a MAP greater than 98 mmHb. However, the AASK trial, in a 3.8-year follow up in 1094 blacks with hypertensive nephrosclerosis, found no added benefit of a target MAP below 92 mmHb as compared with 102 to 107 mmHb.[6] The REIN-2 study in 338 proteinuric patients, finally, was terminated after a median follow-up of 1.6 year for “futility” because the slightly lower pressure (130/80 versus 134/82 mmHb) did not result in any effects on progression rate.[87] The discrepancies between the studies have been attributed to differences in baseline proteinuria, that was 0.53 g/day in the AASK study and 2.85 g/day in the REIN-2 study, and differences in power and duration of follow-up.[87]

For diabetic patients, the importance of a low target blood pressure for renoprotection is widely accepted. Whereas no formal trials comparing different target levels have been performed, the recommendation of a target blood pressure below 120 to 130 systolic and 80 to 85 mmHb diastolic for microalbuminuric patients[88] finds substantial support. [63] [64] [65] [89] [90]

From the available data, it was not entirely clear whether a J-curve exists for renal protection. A comparison of rate of renal function loss between several controlled studies suggested a linear relationship with mean arterial blood pressure during the study ( Fig. 54-4 ).[91]

FIGURE 54-4  Relationship between achieved blood pressure control and rate of renal function decline in different clinical trials in diabetic and non-diabetic patients.  (Adapted with permission from Bakris GL, Williams M, Dworkin L, et al: The national kidney foundation hypertension and diabetes executive committees working group. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis 36:646–661, 2000.)

 

 

More recent data, however, point toward a different impact of systolic and diastolic pressures. Systolic pressure appears to be more closely related to both renal and cardiovascular outcome than diastolic pressure. [64] [91] A meta-analysis on the determinants of the renoprotective effects of ACE-inhibitors supported the impact of systolic pressure. Moreover, the relationship between achieved systolic blood pressure and risk for renal end points depended on the level of proteinuria during the study, as shown in Figure 54-5 . In subjects with proteinuria less than 1 g/day, the relationship between blood pressure and renal risk was flat over the whole range, whereas in subjects with a proteinuria greater than 1 g/day, reduction of systolic blood pressure to values between 110 to 129 mmHb was associated with better renal outcome. Systolic values less than 110 mmHb, however, were associated with a higher renal risk.[92]

FIGURE 54-5  Meta-analysis data showing the impact of current proteinuria for the renoprotective benefit of lower systolic pressure by ACE-inhibitor versus control treatment.  (Adapted with permission from Jafar TH, Stark PC, Schmid CH, et al: Progression of kidney disease: The role of blood pressure control. Proteinuria and angiotensin-converting enzyme inhibition: A patient-level meta-analysis. Ann Int Med 139:244–252, 2003.)

 

 

Recent guidelines from the Kidney Disease Outcomes Quality Initiative (K/DOQI) initiative recommend a blood pressure level not exceeding 130/80 mmHb for renal patient[93]; this target corresponds to the level recommended to prevent cardiovascular end points in high-risk patients including renal patients[94] by the JNCVII Guidelines. The lower target blood pressures elicit the challenge of actually achieving those target pressures. This requires great effort, and most renal patients need combination therapy, as discussed later in this chapter.

Glomerular Hypertension

In healthy kidneys, glomerular pressure is well autore-gulated by the unique position of the glomerular capillaries between a preglomerular and a postglomerular resistance vessel. A series of animal studies the 1980s showed that glomerular hyperfiltration of remnant nephrons, associated with glomerular hypertrophy, occurs as a renal adaptive response to loss of functional renal mass, as discussed extensively in Chapter 25 . Briefly, it serves to maintain short-term overall GFR but appears to accelerate progressive renal damage by the exposure of the glomerular capillaries to elevated hydrostatic pressure.[95] Hyperfiltration is predominantly mediated by preglomerular vasodilation, leading to enhanced transmission of systemic blood pressure to the glomerular capillaries. The resulting impairment of autoregulation has been shown to be associated with an increased renal vulnerability to hypertensive renal damage in rats with reduced renal mass.[39] Preglomerular tone can also be reduced by a high protein intake, which may contribute to the accelerat-ing effect of high protein intake on progression of renal failure.[96]

In humans, no direct data on glomerular capillary pressure are available. Nevertheless, indirect data suggest that hyperfiltration is involved in renal function loss in several human renal conditions. Diabetic nephropathy in type 1 diabetes provides perhaps the most convincing case with its well-documented typical biphasic course with an elevated GFR and filtration fraction preceding progressive renal function loss. [97] [98] Thus, in type 1 diabetes, hyperfiltration appears to be a primary phenomenon, rather than a compensatory response to nephron loss. Morphologic studies demonstrated an association between hyperfiltration and glomerular hypertrophy in type 1 diabetes.[99]In type 2 diabetes, data are less consistent, presumbly due to the greater heterogeneity of this population. Yet early hyperfiltration [100] [101] [102] as well as glomerular hypertrophy[103] were reported in a subset of type 2 diabetes as well.

In nondiabetic renal parenchymal disease, hyperfiltration is notoriously difficult to demonstrate, because patients usually come to medical attention only after development of renal damage, and hence loss of functional renal mass. Thus hyperfiltration in remnant nephrons, if present, cannot be established because the usual methods only measure total GFR. In dedicated settings, simultaneous measurement of GFR and effective renal plasma flow nevertheless allows us to estimate filtration fraction as an index of glomerular hemodynamics not confounded by the amount of functional nephrons, but such measurements are not usually available in epidemiologic settings. Interestingly, a study in children and adolescents with adult polycystic kidney disease (APKD) suggests that hyperfiltration precedes the decline in renal function in this condition, suggesting a more generalized response to insults to the kidney.[104]Nevertheless, long-term follow-up in kidney donors indicates that, in healthy kidneys, a substantial compensatory elevation of GFR may persist for decades without inducing renal damage.[105] On the other hand, obesity—a condition associated with hyperfiltration[106]—increases the risk for long-term renal damage after uninephrectomy.[107] In line with this, a higher body mass index is associated with a larger drop in renal function after kidney donation.[108]

Fogo and associates[109] found that glomerular hypertrophy in minimal change disease predicts progression to focal glomerulosclerosis, supporting a role of glomerular hypertrophy and perhaps hyperfiltration in this condition. In essential hypertension, an elevated GFR with an elevated filtration fraction is present in a subset of newly diagnosed patients. [110] [111] Interestingly, in this population, hyperfiltration is associated with left ventricular hypertrophy, suggesting that it may reflect a generalized propensity to develop hypertensive target organ damage. Whether in essential hypertension early hyperfiltration predicts renal function loss is not yet clear.[112] In renal transplant recipients, however, a higher filtration fraction is an independent determinant of a worse graft survival,[113] supporting the relevance of glomerular hypertension as a risk factor in nondiabetic renal damage. Finally, in the general population, a biphasic pattern of GFR has been found with a striking parallel to diabetes by its association with albuminuria ( Fig. 54-6 ). A slightly elevated renal function was found in subjects with albuminuria in the high-normal range, and a lower renal function in subjects with higher rates of albumin excretion.[114]

FIGURE 54-6  Creatinine clearance in 7728 subjects from the prevention of renal and vascular endstage disease (PREVEND) cohort, according to albuminuria categories: 0 to 15, 15 to 30, 30 to 300 and greater than 300 mg/24 hours. Numbers in the bars represent the age- and gender-adjusted mean of the creatinine clearance (mL/min/1.73 m2).  (Adapted with permission from Pinto-Sietsma S-J, Janssen WMT, Hillege HJ, et al: Urinary albumin excretion is associated with renal functional abnormalities in a non-diabetic population. J Am Soc Nephrol 11:1182–1888, 2000.)

 

 

The prognostic impact of an elevated renal function in the general population, however, is uncertain. Longitudinal renal function data are under way, but interpretation in terms of clinical relevance for the moment is cumbersome, and moreover, hampered by regression to the mean.

Reduction of Glomerular Pressure

In experimental studies, the reduction of elevated glomerular capillary pressure rather than the reduction of systemic blood pressure correlates with the protection against the development of focal glomerulosclerosis in several renal conditions. [115] [116] Thus, reduction of glomerular pressure provides renoprotection in addition to reduction of systemic blood pressure. Indirect data suggest that reduction of intraglomerular hydrostatic pressure may be relevant in humans as well. In nondiabetic as well as diabetic renal disease, the early renal hemodynamic response (but not the response of systemic blood pressure) to antihypertensive therapy predicts its long-term renoprotective efficacy. A slight drop in GFR at onset of treatment—suggesting a reduction in glomeru-lar hydrostatic pressure—predicts a favorable long term course of renal function, supporting a role for reduction of glomerular pressure in long term renoprotection in humans ( Fig. 54-7 ). [117] [118]

FIGURE 54-7  Time course of glomerular filtration rate (GFR) before, during, and after withdrawal of antihypertensive therapy in renal patients. Closed circles and continuous lines are patients who initially showed a distinct fall in GFR (n = 20). Open circles and broken lines are patients in whom GFR did not fall at the start of therapy (n = 20). After withdrawal of therapy a rise in GFR occurs in patients with an initial drop only, demonstrating the functional nature of the initial drop in GFR. Interestingly, withdrawal of treatment reveals that GFR is better preserved in the patients with an initial drop.  (Reproduced wiith permission from Apperloo AJ, de Zeeuw D, de Jong PE: A short-term antihypertensive treatment induced fall in glomerular filtration rate predicts long term stability of renal function. Kidney Int 51:793–797, 1997.)

 

 

The predictive value of the early renal hemodynamic response is independent of the mode of intervention, because it occurs with ACE inhibition as well as β-blockade and, moreover, it was observed during nonpharmacologic intervention by a low protein diet.[119] Whereas these data support a role for reduction of glomerular pressure in renoprotection, alternatively, they might reflect the overall responsiveness of the renal condition to intervention and thus be an epiphenomenon. Finally, the observed relationship between renal hemodynamic response and long-term renoprotection may not be relevant in all renal conditions, because it could not be demonstrated in type 2 diabetes.[120] [121]

Proteinuria

A pathogenetic role for proteinuria in progressive renal function loss is suggested by many experimental studies with renal damage of diverse origin. In ablation models, proteinuria is closely associated with glomerular hypertension, presumably reflecting the severity of hypertension-induced renal damage. Studies in experimental nephrotic syndrome induced by puromycin-nucleoside or doxorubicin hydrochloride (Adriamycin) demonstrated that in these models, proteinuria precedes progressive glomerulosclerosis in the absence of glomerular hypertension.[122] Together with data on the tubulotoxicity of various components of proteinuric urine, these studies provide evidence that proteinuria as such can be an independent pathogenetic factor in progressive renal structural damage. In humans, the severity of proteinuria correlates well with the severity of glomerular sclerotic lesions in diverse renal conditions[123] such as IgA nephropathy,[124] pre-eclampsia,[125] diabetic nephropathy,[105] HIV nephropathy,[126] crescentic glomerulonephritis,[127] unilateral agenesis or surgical removal of renal tissue, [128] [129] reflux nephropathy,[130] and hypertensive nephropathy,[131] as reviewed elsewhere.[132] Moreover, proteinuria consistently predicts the subsequent rate of renal function loss in many renal conditions [6] [51] [133] [134] and is the best predictor of end-stage renal failure.[135] This is not only true for populations with renal conditions of diverse origin, where it might reflect differences in prognosis between different disorders, but also in homogeneous populations, for example, IgA nephropathy,[136] diabetic nephropathy, [90] [137] [138] membranous glomerulopathy, [139] [140] atherosclerotic renal disease,[141] and immune-mediated renal disease such as Wegener granulomatosis.[142] Remarkably, the association between proteinuria and progression rate is not only present in conditions in which proteinuria might reflect severity or activity of a primary glomerular disorder, but also in chronic pyelonephritis[6] and vesico-ureteral reflux. [143] [144] Thus, proteinuria, once present, is a major risk factor for progressive renal function loss across a spectrum of renal disorders. This consistent relationship fueled the hypothesis that proteinuria is a key factor in a vicious circle of non-disease-specific factors that account for progressive renal function loss.[4] Because many patients progress towards end-stage renal failure without significant proteinuria, however, its impact relative to disease-specific factors may vary between different populations. [6] [53] [145]

Less severe protein leakage, microalbuminuria, is a well-established and consistent predictor of progressive renal damage in diabetes. [146] [147] [148] [149] Therefore, it has been hypothesized that microalbuminuria might also be a determinant of progressive renal function loss in nondiabetic conditions, such as essential hypertension and age-related renal function loss, but so far, this assumption needs further substantiation.[11]

Reduction of Proteinuria

Intervention studies support a pathogenetic role of proteinuria in progressive renal function loss in experimental as well as human renal disease. In comparative studies, antihypertensive regimens associated with better reduction of proteinuria provided better renoprotection in diabetic [82] [141] [150] [151] as well as nondiabetic nephropathy. [75] [152] [153] [154] [155] This may not be limited to overt proteinuria or hypertension, because in type 2 diabetes the asssociation between reduction in albuminuria and long-term course of renal function was also present in normotensive normoalbuminuric patients.[83] The association between a reduction in proteinuria and renal prognosis is not only present with antihypertensive treatment but also for remission of proteinuria attained spontaneously, [106] [107] by immunosuppressive treatment[156] or by the nonsteroidal anti-inflammatory drug (NSAID) indomethacin.[157]Finally, more effective proteinuria reduction by a regimen of dual renin-angiotensin-aldosterone system (RAAS) blockade was associated with better long-term renal outcome, in spite of similar blood pressure reduction.[158]

Interestingly, in individual patients, the course of long-term renal function correlates with the antiproteinuric response to therapy.[159] In patients with an effective antiproteinuric response, and accordingly a lower residual proteinuria, the long-term course of renal function is more favorable than in patients with a less pronounced antiproteinuric response. [51] [83] [86] [141] [154] [160] [161] [162] [163] [164] [165] [166] [167] For clinical purposes, it is important that the correlation between reduction in proteinuria and long-term renal prognosis is already apparent early after start of therapy. This allows early distinction between patients that will benefit from the intervention and those in whom the intervention will not result in long-term renoprotection, for example, patients that need additional therapy. Of note, with the exception of the MDRD study, such a predictive value was not present for the blood pressure response, supporting an independent role of proteinuria. The predictive value is present in both diabetic and as nondiabetic patients, and appears to be independent of the severity of baseline proteinuria or albuminuria.

It also appears to be independent of the mode of therapy because it was found in studies with different antihypertensive regimens as well as in populations on a single treatment regimen, and during nonpharmacologic reduction of proteinuria by a low-protein diet.[122] Animal experiments showed that the initial reduction in proteinuria also predicts long-term outcome in terms of structural glomerular and interstitial damage. [168] [169]

It has been emphasized that residual proteinuria may be even a better prognostic parameter than the initial reduction in proteinuria, and the rationale behind this is that residual proteinuria is likely to be a driving force in ongoing renal function loss.[170] At any rate, the two predictors are not mutually exclusive, but in fact correspond to a large extent, as also apparent from Figure 54-8 . The importance of recognizing the impact of residual proteinuria is that it can be used as a parameter for titration of therapy.

FIGURE 54-8  Correlation between residual proteinuria after stabilization of antiproteinuric response (X-axis, A) and rate of subsequent renal function loss (glomerular filtration rate slope, Y-axis): r = 0.62, P < 0.0004; r = 0,43, P < 0.025 in case the right side outlier is omitted, respectively. B shows the correlation between reduction in proteinuria from pre-treatment values (change proteinuria in %, X axis, lower panel) and rate of subsequent renal function loss (glomerular filtration rate slope, Y axis) in the same patients; r = 0,47, P < 0.011.  (Adapted with permission from Apperloo AJ, de Zeeuw D, de Jong PE: Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease. Kidney Int 45:S174–178, 1994.)

 

 

The consistent relationship between residual proteinuria and long-term renal prognosis demonstrates that reduction of proteinuria is a prerequisite for renoprotection. Moreover, it supports the hypothesis that proteinuria plays a causal role in progressive renal damage. Additional support is provided by the correlation between residual proteinuria during treatment and progression rate.[165] However, the evidence is not entirely conclusive. First, an alternative explanation would be that the antiproteinuric response and the course of renal function loss reflect a common underlying factor, namely severity or specific characteristics of the renal disorder. In a retrospective analysis in renal transplant recipients, pretreatment renal interstitial damage determined the antiproteinuric efficacy of ACEi.[171] In line with this concept, prospective animal data including serial renal biopsies showed that the extent of renal interstitial damage at onset of therapy, albeit mild, was associated with a worse antiproteinuric response, a larger residual proteinuria, and a worse long-term outcome.[172] Also, during maximally effective treatment (RAAS blockade and sodium restriction), residual proteinuria closely reflected the extent of renal structural damage. Second, it is hard to envisage how reduction of normoalbuminuria to even lower levels, as reported by Ravid,[83] in itself would exert renoprotection. Finally, an important piece of evidence is lacking, namely studies titrating for antiproteinuric efficacy to assess whether this would enhance renoprotection. Studies on the renoprotective effect of antihypertensives used either a fixed dose or titrated for a certain target blood pressure, and the renoprotective effect of protein restriction was also studied by standardized regimens rather than by titrating for given target.[122]Considering the consistent relationship between proteinuria reduction and renoprotection, and the absence of a J-shaped curve for proteinuria, exploration of regimens titrating for a maximal antiproteinuric effect might be a logical next step in renoprotective intervention strategies.

Hyperlipidemia

Hyperlipidemia aggravates renal damage in renal disorders of diverse origin.[172] Because dyslipidemia is common in renal disease, lipid nephrotoxicity was hypothesized to be involved in the progression of renal damage. [173] [174]This may be particularly relevant in proteinuric renal disease as proteinuria induces a distinct dyslipidemia[175] and abnormal glomerular leakage of lipoproteins elicits a sequence of intrarenal pathophysiologic processes involved in progressive glomerular and interstitial sclerosis.[176] A permissive role for prior renal damage in lipid nephrotoxicity is suggested by the limited potency of hyperlipidemia to initiate renal damage in normal kidneys in most animal models as compared with diseased kidneys [177] [178] with the exception of certain genetic models of renal damage such as the obese Zucker rat.[179] Hyperlipidemia may also affect renal prognosis indirectly, by modifying therapy response. In Adriamycin nephrosis, high pretreatment cholesterol predicted a poor antiproteinuric response to ACEi, independent of pretreatment proteinuria.[180] Whether this is due to a causal effect of hyperlipidemia on therapy response is uncertain, but these findings are well in line with an elegant study showing that statin therapy improves the responsiveness to ACE-inhibitor in a proteinuric model of therapy resistance.[181]

In humans, rare forms of primary hyperlipidemia, such as lecithin-cholesterol acyltransferase (LCAT) deficiency[182] and elevated apolipoprotein E (apo E) levels[183] were shown to elicit renal lesions, allowing to delineate the nephrotoxic potential of individual lipoproteins. On the other hand, the common forms of primary hyperlipidemia do not appear to initiate overt renal disease in normal kidneys. [184] [185] Nevertheless, a role for lipids in renal damage in the general population was supported by the Atherosclerosis Risk in Communities study, in which both low high-density lipoproteins (HDL) and high triglycerides predicted renal function loss.[186] In line with this concept, in dyslipemic men, the age-related decline in renal function was more rapid in subjects with an elevated ratio of low- to high-density cholesterol[187] in whom hypertension was simultaneously present. Morphologic data support interaction between hypertension and cholesterol, as in the AASK trial the severity of hypertensive glomerulosclerosis correlated with blood pressure and renal function as well as cholesterol.[22] A role for lipids in promoting renal damage in overt kidney disease in humans is supported by several lines of evidence. Morphologic studies in renal patients revealed glomerular deposition of lipids and of lipid-loaded macrophages in various renal disorders.[188] Mesangial accumulation of apo B and apo E was found in renal patients with diverse underlying disorders, associated with proteinuria, hyperlipidemia, and more severe mesangial hypercellularity and glomerular sclerosis.[189] In several clinical studies, hyperlipidemia is associated with a faster rate of renal function loss in renal patients. In nondiabetic nephropathy, patients with hyperlipidemia progressed at a faster rate than patients without hyperlipidemia.[190] A higher plasma cholesterol was associated with a faster progression rate in several studies. [165] [191] [192] [193] [194] The lipoprotein profile may be relevant, as elevated low-density lipoprotein (LDL) cholesterol and apo B were associated with subsequent progression rate, suggesting that nephrotoxicity relates to specific lipoproteins, possibly triglyceride-rich apo B.[195] The association between a reduced apo A-1/apo B ratio (but not total cholesterol) and progression rate is in line with the assumption of a role for specific lipoproteins.[196] In the MDRD study, controlling for the higher HDL levels in premenopausal women eliminated the difference in progression rate in favor of this subgroup.[197] In diabetic nephropathy in type 1 diabetes, the progression rate was found to be associated with higher serum cholesterol, [198] [199] [200] [201] apo B levels,[202] and TG.[203] In type 2 diabetes, an association of progression rate with serum cholesterol [124] [204] or triglycerides[205] was reported, but not all reports confirm this finding. [206] [207]

Whether the association between hyperlipidemia and progression rate reflects a causal role of lipid nephrotoxicity or, alternatively, the poor prognosis associated with proteinuria, is still uncertain as in studies reporting hyperlipidemia to be associated with a poor renal outcome proteinuria was usually more severe in hyperlipidemic patients.[193] Additional data on lipoprotein profile would be highly useful, because lipoprotein profiles can be abnormal already early in the course of renal disease, without hyperlipidemia on routine laboratory investigation.[208]

Reduction of Lipids

In experimental renal disease, pharmacologic reduction of elevated serum lipids ameliorates renal damage in different disease models. [180] [209] [210] Interestingly, in a small study in nephrotic subjects, repeat renal biopsies showed reduction of renal lipid deposition by statin treatment, also suggesting renoprotective potential of lipid intervention, by statin.[211] However, assessment of the renoprotective potential of lipid intervention is still hampered by lack of prospective studies in renal patients. Many smaller studies suggested some renoprotective potential. [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] [228] The effect on lipid profile is relatively uniform with reduction of total and LDL-cholesterol and apo B. Data on renal effects, however, were not uniform. Reduction in proteinuria was found in some studies but not in others. Time course data suggest a very gradual onset of the renoprotective action,[216] providing a possible explanation for negative results in short-term studies. Bianchi and colleagues[229] reported reduction in proteinuria and rate of renal function loss over a 1-year follow-up with atorvastatin in 56 patients with CKD. Interestingly, in proteinuric hypertensives with a normal lipid profile, a 6-month regimen of pravastatin reduced proteinuria by half, with only subtle effects on lipid profile. This effect was also present in patients on AT1-receptor blockade, indicating an added antiproteinuric potential of the statin on top of RAAS blockade.[229] However, Asselbergs and associates[230] found no effect of statin treatment on albuminuria neither as a monotherapy, nor as add-on ACE-inhibition in albuminuric subjects from the general population. On post-hoc analysis of large placebo-controlled studies, pravastatin treatment for cardiovascular conditions was associated with a modest reduction of rate of renal function loss. [231] [232] Meta-analyses support a mild antiproteinuric effect of antihyperlipidemic intervention. An older meta-analysis of 13 prospective controlled trials in 392 patients with different classes of antihyperplidemic agents supported a tendency toward proteinuria reduction by lipid reduction.[233] Two recent meta-analyses addressed the renoprotective effects of statins. Douglas and colleagues[234] analysed 15 published randomized controlled studies on various statins in 1384 patients in which albuminuria or proteinuria had been measured, with a mean duration of 24 weeks, and concluded that statins reduced albuminuria or proteinuria in 13/15 studies, with a larger effect in studies with a higher baseline proteinuria. The analysis by Sandhu and colleagues[235] included the above-mentioned studies, with additionally unpublished data and statin cross-over trials, amounting to 27 studies in 39,704 subjects, the large majority of whom were being treated for cardiovascular indications. This study corroborated the mild antiproteinuric effect and a small effect on rate of renal function loss in cardiovascular populations. Renal function decline was 1.2 mL/min/yr slower in statin users, but the authors point out that the clinical significance of this small difference in subjects without overt renal disease remains to be established, all the more so because follow-up was relatively brief, and no data on hard end points were available. Together, these data suggest that statins can potentially exert renoprotection, but this assumption needs further support from prospective long term studies including hard end points. In renal transplant recipients, statins did not affect renal function decline or graft loss over a follow-up of 5 to 6 years.[236] Whether the renal effects of statins are due to their effects on lipid profile is not established. Dissociation between effects on proteinuria and lipids has been noted in native kidneys as well as transplant recipients, [215] [239] suggesting that pleiotropic effects may at least be partially involved. There are limited data on other modes of lipid intervention. Post-hoc data from a placebo-controlled cardiovascular intervention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), showed that gemfibrozil did not affect rate of renal function loss over a 5-year period, neither in subjects with mild to moderate[237] nor in moderate to severe CKD,[238] in spite of beneficial effects on cardiovascular end points.

PHARMACOLOGIC APPROACHES

Antihypertensive Treatment

In renal patients, blood pressure reduction can be obtained by all currently available classes of antihypertensives ( Fig. 54-9 ).[239] Whether or not the choice of a particular antihypertensive matters for long-term renoprotection, independent of the obtained blood pressure reduction, has long been a matter for debate. Comparative studies as well as meta-analyses on ACEi in renal patients suggest class-specific renoprotective properties of RAAS blockade beyond blood pressure control in humans, most likely related to specific antiproteinuric effects, [158] [240] which is supported by data on the renoprotective effects of AT1 blockade. [84] [85] Accordingly, current guidelines recommend RAAS blockade as first choice antihypertensive treatment for renal patients. Nevertheless, recent data put into question the superiority of RAAS blockade, eliciting vigourous debate. As these data, however, were obtained in less-well controlled settings they do not refute the results from prior well-designed clinical trials. However, they prompt for close scrutiny and monitoring of RAAS blockade based regimens for renoprotection, to ascertain their renoprotective benefit also outside of the artificial realm of dedicated clinical investigations.

FIGURE 54-9  Meta-analysis data: unadjusted effects of different classes of antihypertensives on blood pressure in renal patients. Data are given as pooled weighted means and 95% confidence intervals for controlled and uncontrolled studies. Groups were pooled by therapy, and when there were at least two studies of each, by diabetes status.  (Reproduced with permisson from Maki DD, Ma JZ, Louis TA, Kasiske BL: Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Int Med 155:1073–1080, 1995.)

 

 

Angiotensin-Converting Enzyme Inhibitors

Animal studies from the 1980s showed that ACE inhibitors attenuate renal function loss more effectively than other antihypertensives with a similar effect on blood pressure.[118] ACE inhibitors inhibit the cleavage of angiotensin I to angiotensin II, a main effector hormone of the renin-angiotensin-aldosterone system. They also inhibit the inactivation of bradykinin and several other peptides. Hemodynamic and nonhemodynamic mechanisms are involved in their renoprotective action. The hemodynamic effects include not only a fall in blood pressure but also specific reduction of glomerular pressure by efferent vasodilation. Reduction of proteinuria (see also next paragraph), ameliorating deleterious effects of protein exposure on tubular cells, podocytes, and mesangium is assumed to be a main renoprotective mechanism.[241] Angiotensin II stimulates growth factors and inflammatory cytokines involved in various pathways of glomerular and interstitial sclerosis,[242] and induces glomerular heparanase, leading to loss of glomerular permselectivity.[172] Attenuation of these angiotensin II-driven intrarenal pathways may therefore contribute to the renoprotection. Inhibition of angiotensin II formation may not be the sole mechanism of action of ACE inhibitors. Decreased bradykinin breakdown may play a role in specific experimental models,[243] albeit not uniformly so.[244] Increased availability of smaller angiotensins such as angiotensin (1-7) may contribute to the pharmacologic efficacy, [245] [246] [247] but their impact in renal disease remains to be proved.

In humans, comparative studies found more effective attenuation of long term renal function loss by ACE inhibition versus other antihypertensives. [155] [248] Meta-analysis-data[249] support the greater renoprotective efficacy of ACE inhibition—in association with a greater reduction in blood pressure as well as proteinuria.[158] In 11 randomized controlled trials, including a total of 1860 nondiabetic patients, the relative risk for end-stage renal disease was 0.69 (95% cardiac index: 0.51–0.94) with ACE inhibition versus control antihypertensive treatment ( Fig. 54-10 ). The more effective renoprotection by ACE inhibitors was largely, but not fully, explained by the better antihypertensive and antiproteinuric effects.

FIGURE 54-10  Meta-analysis data: Blood pressure (A), urinary protein excretion (B), surivival without end-stage renal disease (C) or the combined outcome of doubling of baseline serum creatinine concentration or ESRD (D) during follow-up in patients on ACE inhibition (squares) and control regimens (circles).  (Reproduced with permission from Jafar TH, Schmid CH, Landa M, et al: For the ACE inhibition in progressive renal disease study group. Angiotensin converting enzyme inhibitors and progression of nondiabetic disease. Ann Int Med 135:73–87, 2001.)

 

 

The African American Study of Kidney Disease and Hypertension (AASK) trial, showing similar blood pressure but better renoprotection with ramipril than with amlodipine in proteinuric blacks with hypertensive nephropathy, further supports a nonpressor renoprotective effect of ACE inhibition.[86] In the recent Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 33,357 hypertensives at risk for coronary disease, however, no differences in cardiovascular and renal outcome were detected during a 4.9 year follow-up, between regimens based on lisinopril, amlodipine, and chlorthalidone, respectively, neither for the population as a whole nor after stratification for GFR.[250] The differences in population and study design with prior studies in CKD have been addressed in detail.[88] Importantly, in the ACE-inhibitor regimen, no co-treatment with diuretic was used, which is at variance with prior studies in CKD, and which is likely to have precluded an optimal therapy response, all the more so because a large proportion of the population consisted of blacks. Also, the dose of lisinopril (10 mg) may have been too low in many patients.[251] The patients were recruited from general practitioners and internists, and selected for cardiac risk. Also, it has been suggested that ACE inhibitors may not have specific renoprotective advantages for renoprotection in subjects in whom the risk for renal function loss is low. Unfortunately, no data on proteinuria, a main modulator of the specific renal benefits of RAAS blockade, were available at baseline or during follow-up. For these reasons, the data from the ALLHAT study do not refute prior data from well-documented clinical trials in renal patients. [88] [254] Accordingly, this also applies to a subsequent meta-analysis[252] that questioned the superiority of RAAS blockade for renoprotection. However, in this analysis, approximately 90% of all patients were provided by the ALLHAT study, rendering conclusions on the renal population unwarranted. Yet the ALLHAT data demonstrate that it would be naïve to assume that prescribing an ACE inhibitor will automatically result in renoprotective benefit. This notion is important, in particular considering the increasing number of patients progressing towards end-stage renal disease, as discussed in more detail later in this chapter.

Patient characteristics are relevant to the benefit of ACE inhibition; in patients with polycystic kidneys, for instance, ACE inhibition fails to reduce rate of renal function loss.[155] Overall renal risk appears to be a main determinant of the outcome of comparative studies. Studies favoring ACE inhibition tend to be the ones in which renal risk (rate of renal function loss, or baseline proteinuria) is highest. Van Essen and associates,[253] for instance, found a similar low progression rate for enalapril and atenolol (-1,92 versus -1.32 mL/min/yr), whereas Hannedouche and co-workers[248] found a difference in favour of enalapril, with a renal function loss of -3.96 mL/min/year versus -6.84 mL/min/year with β-blockade. The importance of a priori renal risk is supported by the REIN study. In patients with a proteinuria greater than 3 g/day, the benefit of ACE inhibition was already apparent after only 1 year of treatment, with a renal function loss of -6.36 mL/min/year with ramipril versus -10.56 mL/min/year in controls. Interestingly, the renoprotective benefit of ACE inhibition was proportional to baseline proteinuria,[157] as shown in Figure 54-11 . The greater advantage of ACEi over control treatment in more severely proteinuric patients was confirmed by meta-analysis data and explained by a greater absolute reduction in proteinuria.[158]

FIGURE 54-11  Rate of GFR decline (upper panel) and risk of progression of nephropathy (lower panel: combined end point: doubling of baseline serum creatinine and end-stage renal failure) for patients grouped according to baseline proteinuria, with ramipril (circles) or placebo (diamonds).  (Reproduced with permission from The GISEN group: Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and progression to terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857–1863, 1997.)



Nevertheless, patients with less severe proteinuria also benefit from ACEi, as shown by the reduction in hard end points (entry dialysis) in patients with a proteinuria of 1 to 3 g/day.[254] This benefit appears to be related to the antiproteinuric effects of the ACEi regimen, as suggested by the association between proteinuria reduction and stabilization of renal function in patients from the control group who were switched to the ACEi regimen after completion of the original study.[255] This stabilization has been argued to reflect true regression of the renal disorder and has raised hope that ACE inhibitor-based regimens will allow not only to postpone, but perhaps altogether prevent end-stage renal disease—at least in part of the patients.[256] It is of clinical importance to note that post-hoc data from the REIN study showed the largest absolute reduction in hard end points in the patients with the lowest GFR at entry.[257] The renoprotective benefits of ACE-inhibition in advanced renal disease were prospectively confirmed recently.[258]

In diabetic patients, ACE inhibition has been shown to be beneficial in all stages of renal involvement, and moreover, to be able to prevent or postpone renal involvement. In overt nephropathy, ACE inhibition attenuated long-term renal function loss in type 1 diabetes more effectively than placebo.[82] ACE inhibition attenuated the progression of incipient nephropathy (as apparent from microalbuminuria) to overt nephropathy in normotensive type 1 diabetes[259] [260] [261] independently from its effects on blood pressure[243] with a tendency for better preservation of renal function[262] and type 2 diabetes patients. [207] [263] Interestingly, ACE inhibition also appears to be able to induce regression toward normoalbuminuria in type 1 diabetic subjects with microalbuminuria.[243]

Recently, it was shown that ACE inhibition protected against the development of microalbuminuria in a large population of hypertensive, normoalbuminuric type 2 diabetic patients.[10] ACE inhibition also reduced the rate of renal function loss in relatively young, normotensive, normoalbuminuric type 2 diabetes.[83] Importantly, ACE inhibition not only reduced the risk for nephropathy but also overall mortality and cardiovascular events in diabetic patients with a high cardiovascular risk.[264] Whereas the above-mentioned data are unambiguous, the renoprotective benefit of ACE inhibition in diabetes was recently challenged by pharmacoepidemiologic data, showing that among diabetic patients reaching end-stage renal disease, subjects on ACE-inhibition were overrepresented.[265] These data are in line with pharmacoepidemiologic data from the general population, showing worse renal function in those on ACE-inhibition.[266] As the reasons for prescription were not documented in either study, however, likely these data were confounded by indication, a well-established drawback in pharmacoepidemiologic analyses on clinical end points. Likely, therefore, patients on ACE-inhibition were the ones with more risk factors for renal function loss.

ACE inhibitors are a fairly homogeneous class of drugs, apart from their kinetic properties. Nevertheless the renal effects may not necessarily be similar for all ACE inhibitors. In a meta-analyis, Maki[239] found no long-term renoprotection for lisinopril, as opposed to enalapril and captopril, suggesting differences in their renoprotective potential. A proper comparison, however, would need to consider dosage, as well as the role of modifiers of therapy response, such as volume status. Studies directly comparing the long-term renal effects of different ACE inhibitors are unlikely to become available. Data in essential hypertensives nevertheless suggest that straightforward extrapolation of renal findings from one ACE inhibitor to another is not warranted, because linopril exerted less pronounced renal hemodynamic effects than enalapril in spite of similar blood pressure effects.[267]

All in all, ACE inhibitors are particularly effective in reducing long-term renal function loss. In addition to their antihypertensive potency this is due to their antiproteinuric effects, and possibly additional renal effects. Their renoprotective potential is most readily apparent in proteinuric patients.

AT1 Receptor Blockers

Considering the importance of blockade of the RAAS for the renoprotective properties of ACE inhibtion the renoprotecive efficacy of AT1 receptor blockers can be expected to resemble those of ACE inhibition. Indeed, in animal studies as well as human studies, AT1 receptor blockade exerts all anticipated effects of RAAS blockade, such as reduction of blood pressure and renal vasodilation with a predominant effect on the efferent arteriole. [268] [269]Moreover, AT1 receptor blockade reduces proteinuria and provides renoprotection in animal models and human renal disease. [84] [85] [270] In experimental studies, some differences in renoprotective efficacy between ACE inhibitors and AT1 blockers were reported, with somewhat less extensive effects of AT1 blockade. [271] [272] It may be relevant that AT1 receptors, unlike ACE inhibitors, induce a large increase in angiotensin II level while leaving the other receptor subtype, the AT2 receptor, unblocked.[273] This receptor subtype affects processes of cell proliferation[274] and apoptosis,[275] presumably in interaction with the AT1 receptor.[276] Other possible differences could be due to impact of non-ACE angiotension II generation, or to differences in induction of ACE during treatment. In humans, few head-to-head comparisons for renoprotection are available [277] [278] that do not support clinically relevant differences. In humans, AT1 receptor blockers induce a gradual fall in in blood pressure in essential hypertension as well as in renal patients, associated with a renal hemodynamic profile similar to ACE inhibitors, [279] [280] [281] as well as an antiproteinuric effect as shown later in this chapter.

The renoprotective profile of this class was substantiated by several landmark studies, the Irbesartan Reduction in Microalbuminuria in type 2 diabetes (IRMA II),[282] the Irbesartan Diabetic Nephropathy Trial (IDNT)[85] and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Trial[84] investigating irbesartan, and losartan, respectively. The IRMA trial showed that irbesartan dose-dependently protects the hypertensive patient with type 2 diabetes from progression from the microalbuminuric state to overt nephropathy during a 2-year follow-up. The RENAAL study and the IDNT showed that AT1 blockade provided added renoprotective potential as compared with placebo plus conventional (non-ACEi, non-AT1-blocking) antihypertensives in type 2 diabetic subjects with overt nephropathy—with a significant protection as regards the rate of renal function loss, as well as development of end-stage renal disease. This leads to an estimated postponement of the need for dialysis of approximately 2 years.

Interestingly, the IDNT study also had a comparative arm with calcium channel blockers (CCBs), with an identical blood pressure, but worse renal outcome than the AT1-receptor blocker arm, the supporting nonpressor renoprotective effects of AT1 receptor blockade. Taken together, these studies indicate that in addition to the protective effect of blood pressure reduction, in this population, additional renoprotective benefit appears to be conferred by inhibiting the RAAS. This renoprotective effect again appears to be linked to the reduction of proteinuria.

Calcium Channel Blockers

CCBs are effective antihypertensives in renal patients. It is doubtful, however, whether they exert renoprotection beyond blood pressure control. CCBs are a heterogeneous class of drugs, inhibiting different types of calcium channel with a different intrarenal distribution.[283] A main distinction can be made between dihydropyridine ([DHP] e.g., nifedipine, amlodipine) and non-DHP (e.g., verapamil and diltiazem) CCBs. Differences in renal effects, ranging from protective [284] [285] to deleterious, [286] [287] [288] occur between and within different CCB subclasses in experimental studies. Differential effects on autoregulation may be involved, because nifedipine, but not non-DHPs, impairs afferent autoregulatory tone.[289] Increased transmission of systemic blood pressure to the glomerulus may thus counteract possible renoprotective effects of nifedipine, such as attenuation of glomerular hypertrophy,[290]because the severity of renal damage during nifedipine closely relates to systemic blood pressure.[251] Furthermore, non-DHP but not DHP improves glomerular membrane permeability characteristics. [291] [292] Sodium status appears to modify the efficacy of CCBs, so failure to control for sodium intake may account for differences in study outcomes, because moreover sodium status may differentially affect the renal effects of different CCBs.[293]

In humans, older studies in type 2 diabetes suggested specific renoprotective potency of the CCBs verapamil, [294] [295] [296] amlodipine,[297] and nitrendipine,[298] generally similar to ACE inhibition and better than β-blockade. In line with this idea, in hypertensive type 1 diabetes, lisinopril and DHP nisoldipine were equally effective on long-term renal function loss in a 4-year follow-up.[299] In incipient nephropathy, nitrendipine[300] and nifedipine[301] had effects similar to perindopril on blood pressure and albuminuria during a 1-year follow-up, but the renoprotective effects of nifedipine were not substantiated during longer follow-up.[302] In line with this idea, in nondiabetic patients the similar efficacy of nifedipine and captopril during 2 years of follow-up[303] was abrogated during longer follow-up, with more patients on nifedipine entering dialysis.

Of the large trials including a CCB-arm that were published in more recent years, microalbuminuria reduction with valsartan (MARVAL),[304] IDNT, AASK, Bergamo Nephrologic Diabetes Complication Trial (BENEDICT), and Ramipril Efficacy in Nephropathy (REIN)-2 [10] [85] [86] [87] did not support a specific renal effect. Only the ALLHAT study, in hypertensives selected for increased cardiac risk, noted that the amlodipine-based arm was as effective as the chlorthalidone- and lisinopril-based treatment arms.[253] However, it has been pointed out by the investigators as well as others that the ALLHAT study is invalid because of the selection of the study population and the shortcomings of treatment regimens. [88] [254]

In the MARVAL study in microalbuminuric type 2 diabetic patients, valsartan more effectively reduced albuminuria than amlodipine for a similar effect on blood pressure. In the IDNT study, in 1715 patients with nephropathy due to type 2 diabetes, in a mean follow-up of 2.6 years, irbesartan 300 mg more effectively reduced the risk for the end-stage renal disease or doubling of serum creatinine than amlodipine 10 mg with similar blood pressure.[85] The BENEDICT study evaluated the efficacy of verapamil as monotherapy and as add-on to trandolapril. This combination was based on the earlier finding that the combination of valsartan and verapamil provided a greater reduction in blood pressure and albuminuria than either agent alone in type 2 diabetes.[305] However, in the BENEDICT study, the combination had no added benefit on prevention of microaluminuria over monotherapy valsartan, and as monotherapy, verapamil had no effect.[10] In nondiabetics, both the AASK and the REIN-2 studies were stopped prematurely for lack of renoprotective benefit of the CCBs amlodipine and felodipine, respectively. In the AASK trial, ramipril provided better renoprotection than amlodipine in hypertensive nephrosclerosis in blacks at similar blood pressure and the ensuing difference in rate of renal function loss prompted to stop the trial prematurely.[86] In the REIN-2 study the added effect of felodipine on top of ramipril (2.5 or 5 mg) on blood pressure and prevention of end-stage renal function were considered “futile” at interim-analysis, which prompted to stop the study.[87]

Thus, in renal patients the available large trials favor RAAS blockade-based regimens over CCB-based regimens. Comparing CCB with placebo is usually not warranted in renal popultions, but in older subjects with systolic hypertension, active therapy with CCB nitrendipine resulted in reduction in proteinuria and serum creatinine as compared with placebo.[306] All in all, clinical renoprotection by CCB appears to be mainly related to their antihypertensive effects.

β-Blockers

Experimental data on β-blockade as a mode of renoprotection are almost entirely lacking because β-blockers fail to reduce blood pressure in rats. In humans, on the other hand, the antihypertensive efficacy of β-blockers is well documented. Moreover, in essential hypertension β-blockade not only reduces blood pressure but also reduces mortality. For these reasons, these drugs are among the first-line drugs for uncomplicated hypertension, as recommended by current guidelines. In patients with cardioavascular comorbidity, the indication of β-blockade is considered compelling.[96] In renal patients, β-blockers effectively reduce blood pressure. By virtue of this long-standing experience, in comparative studies on the renoprotective potential of newer classes of drugs, β-blockers often are part of the so-called “conventional” antihypertensive regimen, mostly in combination with diuretics. No studies are available supporting specific renoprotection by β-blocker-based antihypertensive treatment. β-blockers were less effective than ACE inhibition in long-term renoprotection in nondiabetic patients [251] [307] as well as in black type 2 diabetes patients.[300] However, other well-controlled studies found a similar rate of renal function loss with β-blockers and ACE inhibition in diabetic [308] [309] [310] as well as nondiabetic patients.[256] β-blockers, therefore, likely are useful in long-term renoprotection by virtue of their effect on blood pressure, or, in subjects with concomitant heart failure, by preventing cardiac deterioration.

Diuretics

In essential hypertension, diuretics not only reduce blood pressure but also mortality from cardiovascular causes. In spite of concerns about their metabolic effects, diuretics are first-line therapy in hypertension according to current guidelines.[96] In most renal patients, diuretics are required for effective blood pressure control, and accordingly, diuretics are part of the therapeutic regimen in many studies. Yet, it has been argued that, suprisingly, their long-term renoprotective effect in humans has not been established.[311] Retrospective data in hypertensive renal patients suggested that diuretics may be associated with more rapid renal function loss,[50] and prospective data in elderly hypertensive patients did not support long-term renoprotection.[310] Experimental data suggest that diuretic treatment may lack renoprotective effects in specific models of experimental renal disease,[312] as opposed to dietary sodium restriction.[313] Whereas this issue deserves further exploration, for the moment, diuretics are indispensable in renoprotective intervention, considering the importance of control of volume status and blood pressure in patients with overt renal disease. This is illustrated by data from Buter and colleagues,[314] in which the poor therapeutic efficacy of ACE inhibition during high sodium intake was restored by adding hydrochlorothiazide. In the ALLHAT study, chlorthalidone-based treatment was one of the treatment arms, and the lack of differences in outcome with the lisinopril- or amlodipine-based regimens has been taken to support the rationale for diuretics as a first line of therapy.[253] However, as discussed previously in this chapter, the impact of this study for patients with overt renal disease is limited.[88]

Whether different diuretics are equivalent for renoprotection is unknown. Aldosterone blockade, by spironolactone has been in use for diuretic treatment in particular in cirrosis and in heart failure for a long time already. Interest in aldosterone blockade for renoprotection has been around for a long time[315] as reviewed recently, and was boosted in recent years by the finding of specific cardioprotective effects.[316] In animal experiments, aldosterone blockade exerted renoprotection, also in models in which it did not affect blood pressure.[317] In a recent study in diabetic nephropathy, monotherapy spironolactone reduced blood pressure similar to cilazapril, with, remarkably, a larger reduction in albuminuria with a small added effect of the combination on albuminuria.[318] Likewise, in hypertensive subjects, the more selective aldosterone blocker eplerenone reduced blood pressure similarly to enalapril, with a larger reduction in albuminuria,[319] and its blood pressure effects were similar to those of amlodipine with a better effect on albuminuria.[320] These data point toward specific renoprotective effects of aldosterone blockade as a monotherapy and as add-on on top of RAAS blockade, as also discussed later in this chapter.

Antiproteinuric Treatment

Reduction of proteinuria can be obtained by pharmacologic treatment, by dietary intervention and by their combination. Pharmacologic measures to reduce proteinuria can be symptomatic, for example, aimed at reduction of proteinuria as such, or causal, that is, aimed at intervention of the underlying condition. Minimal change disease is the typical example in which a causal approach (i.e., steroid therapy) is undisputedly the first-choice therapy, because a total and often permanent remission can be obtained. This may also apply to the related condition of glomerular tip lesion. For other conditions, such as focal glomerulosclerosis and membranous glomerulopathy, the results of causal therapy are less equivocal, and both causal and symptomatic regimens have been recommended. Conditions initially responsive to causal approaches, such as immunologically mediated glomerular disorders, may become unresponsive when the renal disorder takes a chronic course. Such an altered therapy responsiveness presumably reflects a shift in the determinants of renal damage, with a decreased impact of the primary disease-specific factors. Causal therapy usually involves potent immunosuppresive regimens. Thus, a careful work-up, including renal morphologic data, an assessment of the prior course of the disease and of circulating parameters of disease activity is required to estimate the potential therapeutic benefit of a causal approach for the individual patient. Causal therapeutic regimens are discussed extensively in Chapters 30 and 31 .

For many proteinuric patients, a causal approach is not available, or does not exert the hoped-for benefit. For these patients symptomatic antiproteinuric therapy is warranted. Pharmacologic treatment can elicit a symptomatic reduction of proteinuria by lowering systemic blood pressure and by class-specific renal effects.

ACE inhibitors consistently reduce albuminuria and proteinuria more effectively than conventional antihyperten-sive treatment even when the effect on blood pressure is similar, [321] [322] [323] as already illustrated in Figure 54-10 . The antiproteinuric effect may be partly due to the lower systemic and glomerular pressure. However, the antiproteinuric effect is more gradual than the hemodynamic effects,[324] suggesting that gradual improvement of glomerular permselectivity contributes to the reduction in proteinuria as well.[325] In diabetic patients, an antiproteinuric effect as well as preservation of renal structural characteristics[326] was found in the absence of an effect on blood pressure, supporting specific renal effects as well.[327] The antiproteinuric effect of ACE inhibitors is present across virtually the whole spectrum of renal disorders, with a greater absolute reduction in subjects with a higher baseline proteinuria.

AT1 receptor blockers have been shown to reduce albuminuria and proteinuria in numerous studies, as summarized later in this chapter. [82] [84] [328] [329] [330] [331] [332] [333] [334] [335] [336] [337] [338] [339] [340]

Their mechanism of antiproteinuric action largely parallels that of ACE inhibition, with a contribution of blood pressure as well as glomerular pressure. Moreover, AT1 blockade restores the structural integrity of the glomerular basement membrane, decreasing heparanase and restoring glomerular heparan sulfate expression, as shown by experimental data.[172] The latter may explain the gradual onset of the antiproteinuric effect. The absolute reduction in proteinuria, as apparent from Figure 54-12 , is largest in patients with the highest pretreatment proteinuria, in accord with similar findings with ACEi. The magnitude of the antiproteinuric response is more or less similar to ACE inhibition, provided adequate doses are given. This holds true when comparing groups of patients on the two different regimens, but, moreover, also for individual patients, the responses to ACE inhibition and AT1 receptor blockade are strongly correlated, as illustrated in Figure 54-13 , summarizing data in diabetic and nondiabetic patients.[341]

FIGURE 54-12  The antiproteinuric effect of AT1 receptor blockade in different studies in diabetic and nondiabetic patients. The albuminuria data from Anderson and colleagues were converted to proteinuria using the formula from the authors (prot = 1.4 × alb). The albumin/creatinine data from Brenner and co-workers were converting to proteinuria/24 h using a formula from the authors (prot = 8.658 × [alb (mg)/creat (mg)] 0.793).  (Adapted with permission from de Zeeuw D, Navis GJ: Optimizing the RAAS intervention treatment strategy in diabetic and non-diabetic nephropathy: the potential of exploring the mechanisms of response variability. In Mogensen CE [ed]: Diabetic Nephropathy in Type 2 Diabetes. London, Science Press, 2002, pp 103-116.)

 

 

FIGURE 54-13  The antiproteinuric effect of the angiotensin converting enzyme inhibitor enalapril and the AT1-receptor blocker losartan administered in the same patient. A close correlation is observed between the effect of the two interventions in the same patient, in nondiabetic (non-diabetic renal disease [NDRD], triangles) and diabetic proteinuria (insulin-dependent diabetes mellitus [IDDM], circles).  (Adapted with permission from Bos H, Andersen S, Rossing P, et al: The role of patient factors in therapy resistance to antiproteinuric intervention in non-diabetic and diabetic nephropathy. Kidney Int 75:S32–S37, 2000.)

 

 

This may reflect RAAS blockade as their common mechanism of action, but it could also implicate that responsiveness to antiproteinuric therapy is an individual characteristic. Evidence for renal responsiveness as an individual characteristic is discussed in more detail later in this chapter. Just two head-to-head comparisons are available for long term effects on proteinuria and renoprotection, both in type 2 diabetes. Lacourciere[271] found similar reduction in blood pressure and proteinuria for enalapril and losartan during a 1-year treatment period in incipient nephropathy. Recently, the Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study found similar a similar rate of renal function loss over a 5-year follow-up, as well as similar blood pressure and albuminuria with telmisartan 80 mg/d compared with enalapril 20 mg/d in 250 subjects with early nephropathy.[278] However, the power to detect differences was low in particular due to a high drop-out rate.

Renin inhibition reduces proteinuria. Whereas clinical application of older representative of this class of drugs has previously been hampered by their poor bioavailability, their antiproteinuric effect supports the assumption that blockade of the RAAS as such provides a mechanism of proteinuria reduction.[342] A study on the long-term renoprotective effects of the new renin-inhibitor aliskiren[343] is currently under way.

Calcium Channel Blockers

CCBs can reduce proteinuria, with differences in renal effects between DHP CCB and non-DHP CCB. The latter were reported to reduce proteinuria diabetes similar to ACE inhibitors[344] and better than β-blockers,[345] in several studies in type 2 diabetes, as also summarized above. DHP CCBs by contrast are less effective in reducing proteinuria for a given reduction in blood pressure, and can even increase proteinuria. [346] [347] This is particularly apparent when no effective blood pressure control is obtained, probably by impairment of autoregulatory afferent vascular tone induced by this subclass of CCBs. Yet, an attenuation of albuminuria during long-term treatment with nifedipine, similar to ACE inhibition, has also been reported.[348] In nondiabetic patients, the reduction in proteinuria by verapamil (-12%) was reported to be less than with trandolapril (-51%).[349] Because verapamil did not reduce blood pressure, the data suggest that reduction of blood pressure was a prerequisite for an antiproteinuric effect. In line with this idea, in the BENEDICT trial in type 2 diabetics verapamil did not affect blood pressure and albuminuria, neither as a monotherapy nor as add-on on ACE inhibition.[10] In the AASK trial, ramipril provided better proteinuria reduction than amlodipine at similar blood pressure levels, and the ensuing difference in rate of renal function loss prompted to stop the trial.[86] As discussed previously, antiproteinuric properties have been described with CCBs, but apparently this potential of CCBs does not translate into long term renoprotective benefit, as shown by recent large trials including hard end points in type 2 diabetes and nondiabetic renal disease, the IDNT, AASK, BENEDICT, and REIN-2. [10] [85] [86] [87] The ALLHAT data are somewhat at variance with those studies, but this trial does not allow assessment of antiproteinuric and renoprotective efficacy by lack of data on baseline proteinuria.[253]

The effect of β-blockers on proteinuria varies between different studies and tends to be small. [350] [351] [352] Pooled data from comparative studies indicate a slight reduction in proteinuria that appears to be related to the obtained fall in blood pressure. [242] [326] [327]

As to diuretics, few controlled data on the effects of thiazide and loop diuretics as a monotherapy are available. One study found a reduction in albuminuria with indapamide in type 2 diabetes,[353] but others found no effects with hydrochlorothiazide[354] and chlorthalidone.[355] Yet, it is well established, however, that diuretics potentiate the antiproteinuric effect of RAAS blockade. Aldosterone blockade, on the other hand, may offer specific renoprotective effects, as has become clear recently. [356] [357] This may partly relate to the diuretic effect with consequently a lower blood pressure, but several studies found antiproteinuric effects of spironolactone and eplerenone independent from blood pressure control as well, as reviewed recently.[319] Interestingly, spironolactone appears to have added antiproteinuric efficacy on top of ACE inhibition or AT1 receptor blockade (and cotreatment with loop diuretics or thiazide) in humans.[358] In this respect, it may also be relevant that the so-called aldosterone escape during RAAS blockade is associated with ongoing renal function loss in diabetic subjects, providing a rationale for added aldosterone blockade for more effective renoprotection.[359] Recent experimental data, interestingly, show that aldosterone blockade may even have the potential to induce remission of glomerular lesions.[360] Of note, in renal patients the combination RAAS blockade with aldosterone blockade requires close consideration of safety, in particular because of risk for hyperkalemia.

The number of controlled studies on the effect of other antihypertensives on proteinuria is very limited as well. No effect on proteinuria was found with α-methyldopa in overt proteinuria.[361] The α-blocker doxazosine was reported to reduce microalbuminuria in essential hypertensives.[362] Monoxidine, a selective imidazoline antagonist, reduces sympathetic nerve activity and blood pressure in patients with renal failure, when added to RAAS blockade.[363]Nonhypotensive doses of moxonidine reduced proteinuria and glomerulosclerosis in the remnant kidney model,[364] and reduced albuminuria in type 1 diabetic subjects.[365]

NSAIDs reduce proteinuria without affecting blood pressure. The antiproteinuric efficacy of different NSAIDs is proportional to their effect on renal prostaglandin production.[366] The reduction in proteinuria by NSAIDs is associated with a reduction in GFR that is presumed to reflect reduced glomerular hydrostatic pressure, due to afferent vasoconstriction. In animal studies, selective COX-2 inhibition reduced proteinuria and provided renoprotection.[367] Like NSAIDs, however, they can induce a decrease in GFR, sodium retention and a rise in blood pressure.[368] Preliminary data in humans suggest an antiproteinuric effect, but further clinical development has been hampered by concerns about cardiovascular toxicity.

Combination Therapy

When combining agents with a different mechanism of action, an additive effect may be anticipated. In addition, pharmacologic treatment of proteinuria should be combined with dietary measures to obtain the full therapeutic benefit. The options for combination treatment for proteinuria reduction are discussed later in this chapter.

Antihyperlipemic Treatment

The dyslipidemia in renal patients is highly variable and may vary with the underlying renal disorder, in particular the presence of proteinuria, as well as prior abnormalities of lipid profile, for instance associated with metabolic syndrome or diabetes. Therefore, an individual approach tailored to the specific abnormalities in lipid profile is required for the renal patient. Similar to nonrenal patients, dietary intervention combined with pharmacologic therapy is the cornerstone of lipid correction. Importantly, in proteinuric patients, reduction of proteinuria exerts a lipid-lowering effect as well. Based on the high cardiovascular risk in renal patients, aggressive lipid intervention, aimed at reduction of LDL, is recommended in current guidelines.[369] It was recognized at the time that no sufficient data were available on cardiovascular outcome of lipid intervention in renal patients, one of the reasons being that patients with advanced renal disease were usually excluded for trials. Data from the Dialysis Outcomes and Practice Pattern Study (DOPPS) initiative[370] and the U.S. Renal Data Registry (USRDR)[371] showing lower mortality supported the cardiovascular benefits of statins in dialysis patients, and prospective data from the Assessment of Lescol in Renal Transplantation (ALERT) study support their cardiovascular benefit in transplant recipients, [372] [373] but unexpectedly, in the prospective four-dimensional study in diabetic dialysis patients, atorvastatin did not improve cardiovascular outcome, in spite of a reduction in LDL.[374] This led to questioning the validity of extrapolating data from cardiovascular populations to renal patients, but the effects could also be attributed to too-advanced cardiovascular damage in this specific population. A subsequent meta-analysis in patients with moderate to devere renal insufficiency showed a reduction of cardiac events by fluvastatin[375] with a larger benefit in subjects with more severe renal function impairment, supporting the assumption that lipid intervention with statins can be of therapeutic benefit in renal patients. However, firm prospective data are still lacking. The effect of statin intervention (combined with cholesterol absorption inhibitor ezetimide) on cardiovascular and renal protection in advanced CKD, therefore, is the subject of the large SHARP study.[376]

HMG-CoA reductase inhibitors effectively reduce total cholesterol, LDL-cholesterol, apo B and triglycerides in renal patients with and without proteinuria, and in patients on dialysis.[377] The effect on HDL cholesterol appears to be variable between patients. As a result, the slight increase in HDL cholesterol that is noted in several studies more often than not lacks statistical significance. [216] [217] [223] [378] Pooled data[379] nevertheless support improved HDL during statin in renal patients. The discrepancies as to HDL may also be due to differential effects on HDL subtypes, because Warwick and colleagues[380] found unchanged total HDL and HDL3, associated with an increase in HDL2. Of note, Lp(a) levels are not affected by HMG-CoA reductase inhibitors, either in nonrenal patients[381] or in patients with diabetic nephropathy. [382] [383] [384] On the whole, HMG-CoA inhibitors appear to be better tolerated than other pharmacologic interventions. The observation of rosuvastatin-induced proteinuria raised concern on possible renal toxicity of statins. However, this was shown to be due to dose-dependent inhibition of receptor-mediated endocytosis of proteins in the proximal tubular cells,[385] and it has been speculated that this may even be a renoprotective mechanism.[386] At any rate, HMG-CoA reductase inhibitors are considered safe,[387] also in advanced renal disease.[380]

Fibric acid derivatives appear to be the most effective agents for reduction of triglycerides in renal patients. Their efficacy in reducing total and LDL-cholesterol, however, appears to be limited. The efficacy of bile sequestrants on total and LDL cholesterol is variable. Of note, these agents appear to increase triglyceride levels in proteinuric patients. The latter is in accord with findings in other populations and limits their use in patients with high triglycerides. Fibrate treatment, however, was associated with elevation in serum creatinine in 5.9% of the patients versus 2.8% on placebo in the VA-HIT study, a primary cardiovascular population that included 690 individuals with moderate renal failure. These increases in creatinine were attributed to myocyte toxicity rather than an effect on renal function.[240] In nonrenal patients, the new nicotinic acid derivative acipimox was shown to be a useful adjunctive to HMG-CoA reductase inhibition because combination therapy was shown to reduce Lp(a) levels.[388] Data on the efficacy and safety of this combination in renal patients are still lacking.

Importantly, symptomatic antiproteinuric treatment leads to improvement of lipid profile.[389] The effect appears to be proportional to the efficacy of proteinuria reduction and is independent of the mode of proteinuria reduction, as it was observed with ACE-inhibition, [390] [391] [392] [393] AT1 receptor blockade,[394] and indomethacin ( Fig. 54-14 ).[395]

FIGURE 54-14  Summary of relationship between reduction in proteinuria and reduction in total cholesterol (mean values per study) during antiproteinuric treatment in nondiabetic patients in different studies. 1, ACE-inhibitor; 2, low protein diet; 3, AT1 receptor blockade; 4, NSAID. (Adapted with permission from Vogt L, Laverman GD, Dullaart RPF, Navis GJ: Lipid management in proteinuric patients. Nephrol Dial Transplant 19:5–8, 2004.)

 

 

Interestingly, unlike statin treatment, reduction of proteinuria is also associated with a reduction in Lp(a) proportional to the reduction in proteinuria, [394] [396] which may be relevant to the reduction of cardiovascular risk.

In patients with proteinuria due to diabetic nephropathy, hyperlipidemia may not only be related to the proteinuric state but also to metabolic abnormalities inherent to the impaired glucose tolerance, or to primary lipid abnormalities predisposing to the development of diabetic nephropathy. In diabetic patients, Hebert and colleagues[397] found that remission of nephrotic range proteinuria (from 5 to 0.9 g/day) in eight type 1 diabetes patients led to a reduction in total cholesterol, whereas no effect on cholesterol occurred in patients (n = 95) in whom proteinuria remained in the nephrotic range (n = 95; from 6.2 to 5.1 g/day). In type 2 diabetes patients, a reduction of proteinuria from 6.8 to 1.7 g/day, achieved by lisinopril plus verapamil resulted in a reduction of total cholesterol from 7.6 mmol/L to 6.5 mmol/L.[348] In this study, the smaller reductions of proteinuria by monotherapy lisinopril (to 2.5 g/day) or verapamil (to 2.9 g/day) did not alter total cholesterol. In type 2 diabetes with albuminuria in the nonnephrotic range, ACE inhibition appears to reduce albuminuria without effect on cholesterol, [398] [399] although a slight reduction in cholesterol has been reported in one study.[400] Dual blockade of the RAAS, finally, was associated with an improved lipid profile as well.[401] Taken together, the data in diabetic patients seems to implicate that reduction of proteinuria needs to be substantial in order to exert an effect on total cholesterol. However, in microalbuminuric type 1 diabetes, reduction of albuminuria by losartan was associated with a slight decrease in total, VLDL and LDL cholesterol and apo B levels, without effect on Lp(a).[402] Clearly, more data are needed to better explore this issue. Moreover, the effects of proteinuria reduction on specific lipoproteins remains to be explored altogether.

Genetic Factors

Until recently, the relevance of genetic factors for renal disease was largely limited to single-gene renal disorders with Mendelian inheritance. Several lines of evidence support a role for genetic factors in multifactorial renal conditions as well. These include animal data on genetic differences in the susceptibility to progressive renal damage,[403] familial clustering of diabetic nephropathy[404] in humans, and the association of several renal disorders (i.e., membranous glomerulopathy,[405] IgA nephropathy,[406] and focal segmental sclerosis[407] with distinct HLA patterns). A role for genetic factors in modifying renal prognosis was also suggested by the remarkably constant individual rate of renal function loss versus the large interindividual differences in progression rate, even among subjects with the same disorder,[408] and by ethnic differences in renal risk. [15] [409]

The recent advances in molecular genetics provided great potential to elucidate the genetic basis of complex traits like progressive renal damage,[410] its complications, and therapy response, respectively. The potential of hypothesis-free approaches to discover completely novel genes for renal damage is large, and can uncover new pathways for renal damage, and thus new molecular targets for therapy. It is becoming increasingly clear that the strategies that were fruitful in single-gene disorders are not invariably suitable to unravel complex traits as well, and that additional strategies are needed. The importance of independent confirmation for results from genetic association studies has been pointed out by many, and in this respect, currently, several large scale collaborations are being established to provide the necessary infrastructure for such endeavours, also in the renal community.[411] However, genetic and environmental diversity can preclude confirmation also for genuine genetic effects, and it would be naïve to expect breakthroughs from epidemiologic sources only, impressive as the large networks may be. Functional studies, addressing the physiologic and pathophysiologic effects of variation in known and novel genes are definitely required. These can provide better insights into the biology of renal damage, and provide new targets for therapy.

The complexity of these issues is well illustrated by the gradual progress in understanding the role of the ACE insertion/deletion (I/D) polymorphism in renal damage. ACE (I/D) polymorphism is a frequently occurring polymorphism, that is, a determinant of circulating[412] and tissue[413] ACE levels, also in the kidney[414] ACE levels. As such, it was one of the first candidate genes for renal damage, with moreover a plausible mechanism of action, namely increased availability of angiotensin II. The latter is supported by enhanced responses to angiotensin I in isolated human blood vessels[415] and by increased in vivo responses of blood pressure,[416] renal vascular resistance, and aldosterone to angiotensin I in DD homozygotes, healthy subjects,[417] and type 1 diabetics.[418] An association between DD genotype and progressive renal function loss was reported in renal disorders of diverse origin,[419] IgA nephropathy, [420] [421] diabetic nephropathy, [422] [423] APKD,[424] renal transplantation,[425] and hypertensive nephrosc-lerosis. [40] [41] [42] [426] Yet, many conflicting data were reported, which may reflect methodologic flaws[427] as well as biologic heterogeneity. Meta-analyses nevertheless support a role for the DD genotype as a renal risk factor. [428] [429] Animal data, showing that renal susceptibility to exogenously inflicted damage is predicted by higher renal (but not circulating) ACE activity measured before disease induction, support a pathophysiologic role for the elevated renal ACE levels.[430]

Pharmacogenetics

An effect of genetic factors on therapy response has long been recognized. Genetic factors were known to account for differences in drug metabolism such as slow versus rapid acetylation of hydralazine and isoniazid.[431] More recently, the developments in genetics allowed the interest to be expanded into pharmacodynamics as well. Several genetic polymorphisms are associated with individual differences in therapeutic benefit from, for instance, diuretic therapy[432] and prevention of coronary restenosis by statins.[433] These developments may provide a basis to design individual treatment strategies by identifying responders and nonresponders before therapy,[434] by risk stratification, or by identification of new targets for intervention. However, the response to pharmacologic intervention is complex and drug response is definitely a complex phenotype. Variations in pathophysiologic factors as well as in compensatory responses—subject to polygenic regulation as well as environmental factors—all are relevant to the eventual therapeutic benefit.

The case of ACE genotype again well illustrates this complexity. The higher ACE levels in DD genotype suggest that these subjects might either be particularly susceptible to ACE inhibition, or would require higher doses ACEi, or would particularly benefit from AT1 blockade (i.e., circumventing the higher ACE levels). The latter assumption, however, was refuted.[435] The relationship between ACE genotype and response to ACE inhibition was tested in several post-hoc analyses with conflicting results. The responses of blood pressure and proteinuria in DD genotype were reported to be better, similar, or worse than in ID and II genotype. [425] [436] [437] [438] [439] [440] In diabetes, the data appear slightly more consistent, with a worse outcome of treatment in the DD genotype.[441] Differences in genetic or environmental background, gene-gene interaction, gene-environment interaction, interaction with gender,[442] or a combination may be involved in the discrepancies. Interaction with sodium intake may be relevant as high sodium intake appeared to evoke differences in the responses of blood pressure and proteinuria to ACEi between patients with different ACE (I/D) genotypes with a poor response on high sodium in DD genotype only.[443] Prospective data support gene-environment interaction between ACE genotype and sodium status, because the increased responses of blood pressure and aldosterone to angiotensin I that occurred in DD homozygotes during liberal sodium could be annihilated by sodium restriction in the same subjects.[421] Thus, sodium restriction might provide a strategy to ameliorate the unfavorable phenotype in ACE gene polymorphism. Preliminary, prospective data in healthy volunteers support the assumption that sodium restriction can be used to circumvent the DD-associated resistance to therapy,[444] but this requires further substantiation, in particular in renal patients. If volume loading elicits the unfavorable phenotype in DD genotype, one might expect expect gene-gene interaction with genes relevant to volume status, such as α-adducin polymorphism. Indeed, ACE (I/D) genotype and α-adducin genotype exert a synergistic effect on the response to volume expansion in humans.[445]

These data demonstrate that the impact of genetic variation can fruitfully be studied starting from logical physiologic hypotheses. Better insights in the genetic determinants of therapy response is required. It would be important to determine the relative importance of genetic versus phenotypic response determinants, and to identify (phenotypic or genetic) contextual factors that allow specific candidate genes to modulate therapy response, to be able to include genetic factors in strategies for individualized therapy[446] as a strategy to improve overall outcome. Modifiable environmental factors such as sodium intake are of specific interest to overcome adverse effects of a specific genetic make-up on therapy response.

Lifestyle Factors

Obesity

Massive obesity has long been known to be associated with focal glomerulosclerosis.[447] Less extreme obesity is increasingly recognized as a renal risk factor in diverse conditions, that is, after uninephrectomy,[109] in patients with IgA nephritis,[448] and in renal transplant recipients. [449] [450] Moreover, studies in the general population demonstrated an association between body mass index (BMI) and long-term risk for end-stage renal disease. [451] [452] The mechanism underlying renal damage in obesity is presumably multifactorial, and may partly relate to its clustering with hypertension, insulin resistance or diabetes mellitus, with lipid abnormalities, and with a generalized inflammatory state. The epidemiologic association between a central body fat distribution and renal function,[453] as well as the long-term renal risk of metabolic syndrome,[454] suggests that not only weight excess, but particularly the associated insulin resistance, is involved in the effects on the kidney. Weight excess, moreover, is associated with glomerular hyperfiltration and elevated filtration fraction that can occur independently from hypertension or glucose intolerance, and that may well contribute to the increased renal risk,[455] as reviewed recently.[456] Increased RAAS activity may play a role in obesity-associated glomerular hyperfiltration, as suggested by elevated circulating RAAS parameters in obesity,[457] and by the association between BMI and the renal hemodynamic response to RAAS blockade in nondiabetic as well as diabetic subjects. [458] [459] Specific obesity-related mechanisms, related to leptin and adiponectin, are currently under investigation.[460] High sodium intake was reported to steepen the independent association between BMI and albuminuria on cross-sectional analysis in the general population,[461] suggesting that volume excess potentiates the renal risks of obesity. This assumption finds support in recent data showing that dietary sodium restriction annihilates the association between BMI and glomerular hyperfiltration in healthy young adults.[462] Earlier studies also suggest interaction with sodium intake,[463] but the mechanism requires further exploration.

The association between BMI and an unfavorable renal hemodynamic profile is not limited to overt obesity, as shown in healthy kidney donors with a BMI not exceeding 30 kg/m2 [464] and in transplant recipients.[454] Thus, in line with recent epidemiologic data,[456] the effects of weight excess may be much more widespread than assumed thus far, which warrants focus on this emerging renal risk factor for the years to come.

Weight loss ameliorates the renal abnormalities. In morbidly obese, proteinuric patients with diverse glomerular disorders reduction in BMI from 37.1 to 32.6 by a hypocaloric diet reduced proteinuria (2.9 to 0.4 g/day), proportional to weight loss. This was similar to the efficacy of captopril in control obese patients without weight reduction.[465] Subsequent studies confirmed these findings in nondiabetic and diabetic patients. [466] [467] Also, weight reduction by bariatric surgery ameliorates the hyperfiltration profile.[468] The renal effects of intervention in weight excess in less extreme obesity have not been investigated so far, and studies on the long-term consequences of interventions in body weight are lacking altogether. Whereas for renal patients it may seem logical to correct morbid weight excess, nevertheless, the benefits and risks of pursuing a BMI within the normal range are poorly defined. In particular, in advanced renal failure, maintenance of adequate nutritional status is important to be considered as well.

Smoking

An increasing body of evidence indicates that cigarette smoking is associated with an increased rate of renal function loss,[469] both in overt renal disease and in the general population. [470] [471] The effect appears to be particularly prominent in diabetic nephropathy, but it is also apparent in nondiabetic renal disease. Obviously, the most important intervention measure is to quit smoking. Physical inactivity also is a predictor for renal function loss; whereas the effects are largely mediated by hypertension and glucose intolerance, there is an independent effect as well.[474]

RISK FACTOR PROFILE IN RENAL PATIENTS

Clustering of Renal Risk Factors

In most renal patients, several risk factors are simultaneously present. Proteinuria in particular clusters with hypertension as well as with hyperlipidemia, in nondiabetic [167] [472] and diabetic nephropathy.[46] The clustering may partly be due to causal links between the risk factors, and partly reflect common causes, such as the severity of the underlying disorder. Both hypertension and proteinuria may be related to the underlying renal disorder, but aggravation of proteinuria by higher blood pressure, or pressor effects of proteinuria-associated sodium retention may also be involved. A causal link is also involved in clustering between proteinuria and hyperlipidemia. These associations are clinically important in view of their synergism in the eventual effects on renal damage. Proteinuria not only enhances the susceptibility to hypertensive renal damage but also appears to enhance lipid-associated renal structural damage. [180] [181]

Concordance of Renal and Cardiovascular Risk Factors

The close association between renal and cardiovascular damage is increasingly recognized.[13] On epidemiologic analysis, renal and cardiovascular damage cluster in cohorts selected for renal disease or cardiovascular disease, respectively, as well as general population-based cohorts.[12] Renal function impairment is a consistent cardiovascular risk factor in populations with renal or cardiovascular disease. [473] [474] [475] [476] Causality may be involved as renal function impairment elicits many cardiovascular risk factors, such as hypertension, sodium retention, dysplipidemia, oxidative stress, phosphate retention, hyperuricemia, anemia, and so forth. The other way around, most cardiovascular disorders are associated with renal function impairment, such as myocardial infarction,[477] heart failure,[477] peripheral vascular disease,[478] and electrocardiogram abnormalities.[204] Again, causality may be involved as cardiovascular damage exposes the kidney to several insults, such as reduced cardiac output and renal perfusion, neurohumoral activation, and effects of endothelial dysfunction and atherosclerosis on the renal vasculature. Moreover, concordance in progression of renal and cardiac dysfunction over time was reported in several populations. For instance, among 439 patients with type 1 diabetes and nephropathy,[202] mortality was two- to threefold higher in patients with rapid renal function loss as compared with those with less renal function loss. In a recent study in patients with left ventricular systolic dysfunction, mortality was highest in those with rapid renal function deterioration.[479] Remarkably, even a brief and transient decrease in renal function, as observed after thoracic surgery, is associated with increased long-term mortality.[480]

So kidney-derived risk factors can affect the cardiovascular system and vice versa, raising the possibility of a vicious circle of progressive mutual end organ damage. In addition, common risk factors and pathways may affect the kidney and cardiovascular system simultaneously, as also suggested by morphologic correspondence between atherosclerosis and glomerulosclerosis.[481] Cardiovascular risk in renal patients can partly be attributed to risk factors also present in other populations, that is, hypertension, hyperlipidemia, being overweight, diabetes, anemia, and smoking, but renal function impairment and proteinuria are prominently and independently involved as the main risk factors. Proteinuria and albuminuria, in particular, are highly potent cardiovascular risk factors. In nephrotic range proteinuria, the risk for myocardial infarction was increased five- to sixfold.[482] The high prevalence of established cardiovascular risk factors in proteinuric patients is presumably involved.[483] Hyperlipidemia is usually proportional to the severity of proteinuria, with a particularly atherogenic lipid profile by elevation of the highly atherogenic Lp(a).[484] Endothelial dysfunction may contribute to the enhanced cardiovascular risk in proteinuria, because distinct endothelial function impairment is present in proteinuric as compared with nonproteinuric renal patients.[485]Interestingly, reduction of proteinuria by ACEi was associated with a reduction of von Willebrand factor, which may indicate reversibility of proteinuria-associated endothelial dysfunction.[486] Moreover, in vitro data suggest a role for hypoalbuminemia, as albumin ameliorates the vasculotoxic effects of oxidized LDL.[487]

Cardiovascular risk is not only increased in patients with overt proteinuria but also in microalbuminuric diabetic and nondiabetic subjects,[488] eliciting the hypothesis that microalbuminuria is a marker of generalized endothelial dysfunction.[489] An unfavorable metabolic risk factor profile was reported in microalbuminuric essential hypertensives, [490] [491] as well as microalbuminuric subjects from the general population,[492] demonstrating that clustering of cardiovascular risk factors is not limited to overt renal disease or nephrotic range proteinuria, or both. Thus, on a population-basis, its health impact may be considerably larger than previously suspected, as underscored by the impact of microalbuminuria on mortality in the general population.[12]

Feasibility of an Integrated Approach for Cardiorenal Protection

Both renoprotection and reduction of cardiovascular risk are therapeutic targets in the management of renal patients. The concordance of risk factors for renal and cardiovascular damage suggests that intervention in the common risk factors may potentially reduce both cardiovascular and renal risk. Moreover, because both proteinuria and renal function impairment are powerful cardiovascular risk factors, it could be argued that effective renoprotection could provide cardiovascular protection as well, and the other way around, preservation of cardiac function could protect the kidney!

The feasibility of a single intervention to reduce cardiorenal risk poses a major advantage in establishing an integrated approach for overall risk reduction. Considering the prominent role of RAAS blockade in cardiovascular prevention, RAAS blockade would be the most logical dual-purpose intervention. Data from the Heart Outcomes Prevention Evaluation (HOPE) and the MICRO-HOPE studies, showing reduction of renal as well as cardiovascular risk by ramipril 10 mg in patients at high cardiovascular risk,[267] substantiate the potential of such an approach, although data from the Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study, in diabetic patients failed to confirm these results with a low (2.5 mg) dose of ramipril.[493] The RENAAL trial showed protection against heart failure along with renoprotection by AT1 receptor blockade, without an effect, however, on overall cardiovascular morbidity and mortality.[84] In an interesting parallel with the predictive effect of proteinuria reduction for renoprotection, the reduction in proteinuria by intervention also predicted the cardiovascular benefit of intervention,[494] as illustrated in Figure 54-15 .

FIGURE 54-15  Composite figure showing the correspondence of cardiovascular and renal risk reduction in relation to antiproteinuric effect in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Kaplan-Meier curves of risk for cardiovascular end points (left panel) and end-stage renal disease (right panel), according to change in proteinuria at 6 months from baseline.  (Adapted with permission from de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65:2309–2320, 2004.)

 

 

In line with this concept, in the LIFE study, reduction in albuminuria predicted protection against cardiovascular events in hypertensive patients with left ventricular hypertrophy.[495] Accordingly, it was proposed that—analogous to renoprotection—reduction of albuminuria could be a target for cardiovascular protection as well. [233] [498] Whereas the avenue of combined renal and cardiovascular protection is highly promising, many unanswered questions remain. For instance, it is unknown whether that the optimal regimens to reduce renal and cardiovascular risk, respectively, are similar with respect to the preferred class of drug, optimal dose, and target blood pressure for risk reduction. Moreover, focus on common risk factors should not lead to neglect of organ-specific pathways of damage, and of differences in driving forces for end-organ damage between different populations, as illustrated by the unanticipated lack of benefit of statins in the four-dimensional study in diabetic dialysis patients.[378] At any rate, the importance of an integrated approach for the improvement of renal and cardiovascular prevention is undisputed.[13]

CLINICAL MANAGEMENT

A Framework for Renoprotective Intervention

In spite of the substantial advancements in renoprotective intervention, the number of patients requiring renal replacement therapy increases worldwide. A further increase is anticipated, based on the increasing incidence of type 2 diabetes as well as the aging population. Many pharmacologic agents of proven renal and cardiovascular potency are available currently, and moreover, lifestyle interventions (diet, smoking) are available that can provide additional benefit. To turn these options into an optimal therapeutic benefit is the major challenge for the next decades. It requires not only knowledge on the most appropriate therapeutic measures for intervention but also strategies to ensure appropriate implementation of such therapeutic measures in subjects at risk. The latter requires awareness of the risk, as well as implementation of the targets recommended by current guidelines. It has been pointed out that much is to be gained by better compliance with recommended treatment targets, because even among patients with advanced renal disease under supervision of a nephrologist, undertreatment is common.[496] Considering the insiduous course of renal disease, moreover, better early detection strategies for patients at risk for progressive renal damage are needed. This needs to be accompanied by better risk stratification, because renoprotection requires aggressive and costly therapy for many years, if not throughout life. Proper risk stratification is therefore needed to be able to assign treatment to patients likely to benefit, thus alleviating the burden of treatment in those at a low risk, and improving cost-effectiveness of the intervention. A framework for renoprotective intervention is given in Table 54-1 .


TABLE 54-1   -- Framework for Renoprotective Intervention

Identify patients at risk for renal function loss

Establish individual overall risk profile

Intervention: pharmacologic and nonpharmacologic measures for overall risk reduction

Monitor therapeutic efficacy: blood pressure and proteinuria

Adapt and optimize therapy on an individual basis

If therapy resistant: consider causes and circumvention

 

 

 

Early Detection and Prevention

Because renal function damage is often asymptomatic, many renal patients come to medical attention only after renal damage is well established. This could suggest that for renal disease, early prevention is impracticable. However, diabetes and hypertension are by far the most frequent causes of end-stage renal disease, suggesting that focus on these populations may allow early prevention. Indeed, in diabetes, early intervention has been shown to be feasible, beneficial to the patient, and cost effective.[497] However, in hypertension, so far no intervention studies are available that demonstrate renoprotective benefit of intervention, likely due to the fact that renal failure develops in only a small minority of the hypertensive population. Therefore, better identification of subjects with an increased risk for renal damage would be important. This is all the more so, because most subjects with CKD are not aware of their condition.[498] Therefore, screening strategies for renal risk are currently being investigated.[11]

Early Prevention in Diabetes

In diabetes, increasing evidence supports the efficacy of early prevention of nephropathy. In type 1 diabetes, both improved glycemic control[8] and aggressive blood pressure control are effective for primary prevention.[499] In type 2 diabetes, primary prevention was obtained by ACE inhibition in normotensive[83] and in hypertensive normoalbuminuric subjects[10] and by intensified glycemic control.[500] AT1 receptor blockade prevented against progression from microalbuminuria to overt albuminuria[286] In normotensive normoalbuminuric type 1 diabetes, ACEi reduced albuminuria.[501] However, the prognostic significance of normoalbuminuria is unknown and data on the effect on renal function decline are to be awaited.[502]

In the natural history of diabetes, nephropathy is preceded by appearance of low levels of albumin in the urine accompanied by a slight rise in blood pressure within the so-called normotensive range, as discussed in Chapter 36 . Microalbuminuria, defined as an excretion rate of 30 to 300 mg/day or 20 to 200 mg/min is a strong predictor of subsequent progression to overt nephropathy in diabetes. [149] [150] [151] The different definitions of microalbuminuria, screening procedures, confounding factors, and confirmatory procedures have been reviewed elsewhere.[90] In spite of such differences, microalbuminuria stands out as a first prognostic sign that should guide the start and subseqent monitoring of renoprotective intervention. [90] [503] Accordingly, screening for microalbuminuria is a main recommendation for prevention of nephropathy in diabetes. [90] [504] [505] [507]

When microalbuminuria occurs, pharmacologic intervention is mandatory [90] [508] irrespective of blood pressure.[243] In type 2 diabetes, hypertension is often present before albuminuria occurs. Obviously this warrants intervention; data from the BENEDICT study showed that ACE inhibition can effectively reduce onset of albuminuria.[10] RAAS blockade by ACE inhibition or AT1 receptor blockade is recommended as a first line of therapy. Whether there are advantages of one class over the other is uncertain. Most studies in type 1 diabetes were done with ACE inhibitor, and most studies in type 2 diabetes were done with AT1 receptor blockade. Two available comparisons between ACE inhibition and AT1 blockade do not support a clinically relevant difference over a 1- and a 5-year follow-up, respectively, [281] [282] but their power to detect a difference was limited. Of note, in type 2 diabetes, during similar rigorous blood pressure control, regimens based on β-blocker and ACE-inhibitor provided a similar reduction of renal and cardiovascular risk, suggesting that class differences become less relevant during strict blood pressure control.[314] In type 1 diabetes, the importance of rigourous blood pressure control, rather than class-specific drug properties, has also been emphasized.[506] Monitoring of therapy should include albuminuria and blood pressure, aiming at stabilization and eventually reduction of microalbuminuria and blood pressure less than 120 to 30/85 to 80 mmHb. If therapy response is insufficient for blood pressure or albuminuria, therapy should be up-titrated. A diuretic is needed in most patients. In addition, the dose of the RAAS blocker should be increased, and dual blockade considered. Adjunct therapy should entail strict glycemic control. Whether dietary protein restriction contributes to prevention of nephropathy in microalbuminuric diabetics has not been established. Primary prevention should also address overall cardiovascular risk factors, in particular in type 2 diabetes.

Primary Prevention of Renal Function Loss in Nondiabetics

Among nondiabetics, hypertension is the main cause of renal failure, but for individual patients, the risk for renal damage is low. The main intervention is blood pressure reduction. Placebo-controlled evidence for improvement of mortality is only available for β-blockade and diuretics, but more recent data found a low mortality rate with ACE inhibitors and CCBs as well.[507] ACE inhibition was more effective for renoprotection than CCBs in proteinuric blacks with hypertensive nephropathy,[86] but in the absence of overt renal disease or proteinuria there is no evidence for a renal advantage of a particular class of antihypertensives.[508] The ALLHAT data in essential hypertensives at high risk for cardiac disease, albeit much criticized, are in line with this assumption.[253] Accordingly, in uncomplicated hypertension as a first line of therapy, ACE inhibitors, CCBs, diuretics, α-blockers, and AT1 receptor blockers can be used. For individual patients, the choice can be guided by (contra-) indications from co-morbidity, such as coronary artery disease, heart failure, peripheral vascular disease, gout, and chronic obstructive pulmonary disease.

Microalbuminuria is a marker of increased cardiovascular risk in nondiabetic subjects[12] and thus can serve to identify patients who will benefit from intensive treatment of blood pressure and associated risk factors, such as hyperlipidemia. Interestingly, it has recently been shown that screening and subsequent treatment of microalbuminuria with an ACE inhibitor in the general population is effective, as well as cost effective in the prevention of vascular events.[509] Whether this also holds true for prevention of renal function loss is not yet known. It is anticipated that screening for albuminuria in nondiabetics in the short term will be mainly effective for cardiovascular risk, and that only on long-term specific renal benefits will become apparent.[11]

Secondary Prevention

In patients with established renal disease, first, primary causal factors for ongoing renal damage, if present, should be eliminated as effectively as possible. Such factors include obstructive uropathy, urinary tract infections and analgesic abuse, and poor glycemic control in diabetic patients.

In established renal disease, the renal benefit of rigorous blood pressure control is supported by many studies, and reduction of blood pressure to below 130/80 mmHb is recommended. Based on observational studies a similar low blood pressure level has been recommended for patients with diabetic nephropathy. [90] [503] [507] For proteinuric patients target blood pressure should be even lower, that is, 125/75 mmHb. Achievement of such low blood pressure levels in renal patients was shown to be feasible as well as safe.[510]

The MDRD data highlighted the importance of proteinuria to should guide therapy. Even if blood pressure is in the so-called “normotensive” range, presence of proteinuria should prompt institution of therapy. Considering the consistent predictive value of proteinuria reduction for subsequent renoprotection, not only reduction of blood pressure, but also reduction of proteinuria should be a main target of renoprotective intervention. Consequently, proteinuria as well as blood pressure should be monitored as discussed below.

Whereas all currently available antihypertensives reduce blood pressure in renal patients, the proven renoprotective efficacy of RAAS blockade renders ACE-inhibitors or AT1 receptor blockers first choice agents in patients with overt renal disease, in particular in those with proteinuria. In patients without proteinuria, notably those with polycystic kidneys and tubulointerstitial disease, other classes of drugs, such as β-blockers and CCBs may also be used as first-line drugs. Cardiovascular co-morbidity can provide additional considerations. Impaired sodium excretion with volume overload is common in renal patients. Accordingly, for optimal blood pressure control in renal patients correction of volume status by dietary sodium restriction or diuretics or both is crucial, as discussed later. Whereas diuretics are often required as adjunct therapy in renal patients, their renoprotective efficacy has not been well established. [49] [508]

In addition to dietary sodium restriction, in subjects with overt proteinuria adjunct therapy should preferably entail dietary protein restriction.[511] Adherence to the diet is important to obtain the renoprotective benefit.[512] In obese patients, weight loss can effectively reduce proteinuria, and correction of overweight should be considered, taking into consideration maintenance of adequate nutritional status. Additional measures in renal patients should entail control of prevalent cardiorenal risk factors. The main measures are discontinuation of smoking and control of hyperlipidemia. In proteinuric patients, reduction of proteinuria, by pharmacologic intervention supplemented by restriction of dietary protein and cholesterol, is a prerequisite for improvement of lipoprotein profile including reduction of Lp(a). Yet, in many renal patients, specific antihyperlipidemic therapy is required. HMG-CoA reductase inhibitors are effective for this purpose and may be combined with fibric acid derivates in patients with high triglycerides. The combination with newer nicotinic acid derivatives yielded promising results in nonrenal patients, affording reduction of Lp(a), but data in renal patients are not yet available.

Monitoring of Renoprotective Therapy

Usually chronic renal function loss takes years or decades to lead to end-stage renal failure. Monitoring of rate of renal function loss is cumbersome, owing to the protracted course of the disease and to the limitations of creatinine-based renal function monitoring.[513] The MDRD data showed that tubular creatinine secretion is affected by diagnosis, class of antihypertensive drug, and diet, underlining the importance of GFR measurements by clearance of specific tracers.[514] Even with specific tracers, however, the intratest variability of GFR measurement is considerable,[515] eliciting the need of large study populations or prolonged follow-up or both. Reduction of the intra- and intertest coefficient of variation for GFR by correcting for voiding errors, substantially reduces the error of the slope of GFR decline.[516] Frequent measurements can further improve the accuracy of GFR slope calculations, thus alleviating the need for large populations in clinical trials.

A slight reduction in GFR at onset of antihypertensive therapy predicts a better long-term renoprotection. [120] [121] This reduction presumably reflects a functional decrease in glomerular capillary pressure that is favorable in the long run. In the MDRD study, onset of dietary protein restriction was associated with a slight initial GFR drop as well. In clinical trials, therefore, comparison of GFR slopes should preferably be based on the GFR slope as of the end of titration of the regimen under study. For individual patients, a drop in GFR at onset of treatment can thus be considered a favorable prognostic sign, provided that it is modest and not progressive. However, when the drop in GFR is substantial or the clinical condition compatible with renal artery stenosis, it is important to exclude renal artery stenosis, in particular when the treatment includes ACE inhibition or AT1 receptor blockade.

In individual patients, even with sophisticated and frequent measurements, the rate of GFR decline is usually too slow to monitor and titrate renoprotective therapy. Titration on intermediate parameters predicting future renal function loss provides a feasible alternative. Whereas obviously blood pressure should be monitored, proteinuria (or albuminuria) is the best predictor of future renal function loss[517] and thus reflects the renoprotective efficacy of the regimen. Proteinuria, therefore, can guide adjustment of therapy. Whereas it can be inferred that titration for reduction of proteinuria results in better long-term renoprotection, so far, no controlled studies have addressed this issue.

As valuable as proteinuria may be as a noninvasive predictor of progression, it remains important to realize that intermediate parameters provide just an indirect reflection of organ damage, and can dissociate from the actual status of organ damage. In recent animal experiments, for instance, the correlation between proteinuria and glomerular damage was consistently maintained during ACE inhibition. However, during potentiation of proteinuria reduction by low sodium, proteinuria dissociated from the interstitial damage, that was progressive despite effective proteinuria reduction.[518] This implies that progressive interstitial damage can go unnoticed during renoprotective treatment, despite reduction of the noninvasive markers proteinuria and blood pressure. Whereas, for obvious reasons, there are no data to substantiate such a dissociation in humans, these data prompt for caution in the interpretation of intermediate parameters, and underline the need for hard end point studies, as well as better noninvasive markers.

Optimizing Therapy Response

Despite the recent advancements, chronic renal disease is still essentially a progressive condition, as reflected by the increasing number of patients entering dialysis. For better prevention of end-stage renal failure, several strategies are needed, including early identification of patients at risk for progressive renal function loss, monitoring of therapy response, and optimization of renoprotective intervention by an integrated regimen of pharmacologic and nonpharmacologic measures.

It is of great clinical importance that long-term renoprotective efficacy, and possibly also the cardioprotective efficacy, can be predicted from the antiproteinuric effect of therapy. Thus, proteinuria can serve as an intermediate parameter that allows proper adjustment of therapy. Several dietary and pharmacologic measures are available to that purpose that can (and usually need to) be applied simultaneously. A stepped approach to optimize therapy response in summarized in Table 54-2 .


TABLE 54-2   -- Circumvention of Treatment Resistance in Renoprotective Intervention by RAAS Blockade

General measures

Check, and if necessary, improve compliance

Dietary measures

Restrict dietary sodium to 50 mEq/day

Restrict dietary protein in proteinuric patients

Pursue weight loss in excessively obese

Pharmacological measures

Consider dose-response for proteinuria separately

Add diuretic

Add other antihypertensive if BP above target

Consider dual blockade if proteinuria persists

Consider higher dose of RAAS blockade if proteinuria persist

Add indomethacin if proteinuria persists

 

BP, blood pressure; RAAS, renin-angiotensin-aldosterone system.

 

 

 

Sodium Status

Some extent of volume expansion is present in most renal patients, in particular in advanced renal failure[519] and in proteinuric patients. In specific patient categories, such as blacks, microalbuminuric diabetic patients, and obese subjects, impaired sodium handling may be an early phenomenon. [494] [520] Blood pressure is often sodium sensitive in renal patients, and sodium restriction or diuretic therapy or both are usually required for effective blood pressure control. Sodium overload is not only associated with a higher blood pressure but also with specific renal effects. In experimental renal disease, sodium overload induces glomerular hypertrophy by hemodynamic as well as direct, nonhemo-dynamic growth-promoting effects. [521] [522] In hypertension, high sodium intake is associated with increased glomerular protein leakage[523] and, in susceptible individuals, renal vasoconstriction and elevated filtration fraction. [494] [524]

Sodium status is a main determinant of the efficacy of antihypertensive therapy. The role of volume factors in resistance to older antihypertensives that tended to induce sodium retention is well established. However, also for classes of drugs that do not induce sodium retention themselves, volume status affects therapy response. This particularly applies to all RAAS-blocking drugs: that is, ACE inhibitors,[525] AT1-receptor blockers,[526] their combination,[527]and renin-inhibitors.[528] Sodium restriction enhances the effects of ACE-inhibition on blood pressure, renal hemodynamics, and proteinuria. Importantly, it raises the top of the dose response, that is, during sodium depletion a larger maximum response can be obtained, so sodium restriction can be used to enhance the treatment response and not just to obtain a response at lower dosages. [171] [529] A rise in sodium intake from 50 to 200 mEq/day annihilated the antiproteinuric effect of ACE inhibition almost completely, with less prominent blunting of the blood pressure response.[365] Cross-sectional data demonstrating a correlation between antiproteinuric efficacy of ACE inhibition and urinary sodium excretion in nondiabetic as well as diabetic nephropathy support these intervention data.[530] Blunting of the effect of ACE inhibition during liberal sodium intake could be overcome by adding hydrochlorothiazide (Fig. 54-16 ).[318]

FIGURE 54-16  Effect of sodium status on the responses of proteinuria (bars) and blood pressure (mean arterial pressure: MAP, lines) to ACE inhibition. The left panel shows the effect of ACE inhibition as compared with pretreatment values during low- and high-salt diet, with an almost complete blunting of the antiproteinuric effect during high salt. The right panel shows the effect of a shift from a low- to a high-salt intake during chronic ACE inhibition, with subsequent addition of hydrochlorothiazide (hct).  (Adapted with permission from Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D: Efficacy and variability of the antiproteinuric effect of lisinopril. Kidney Int 36:272–279, 1989 and Buter H, Hemmelder MH, Navis GJ, et al: Blunting of the antiproteinuric efficicay of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 13:1682–1685, 1998.)

 

 

The effect of sodium status on antiproteinuric effect may relate to its concomitant effects on blood pressure, but specific tissue effects may be important as well. In rats, high sodium intake induces a rise in renal ACE.[531] In line with this, high sodium impairs the inhibition of angiotensin I conversion in the vascular wall by ACE inhibitor.[532] Studies on responses to angiotensin I and II during different sodium intake suggest that high sodium may increase tissue ACE in human as well.[421]

For CCBs, the interaction with sodium status appears more heterogeneous. In essential hypertension, CCBs were less effective during low sodium diet. [533] [534] However, this may not similarly apply to renal patients. Sodium restriction was required for an optimal antiproteinuric response to the non-DHP diltiazem (but not for nifedipine) [534] [535] in type 2 diabetes. This may be a specific renal interaction because high sodium intake blunted the antiproteinuric effect without affecting blood pressure.

It is not completely clear whether the renoprotective effect of diuretics is equivalent to dietary sodium restriction. Animal data suggest sodium restriction exerts more effective renoprotection than diuretic therapy[318] but similar data in humans are lacking. Recent studies showed added effects of spironolactone, when added to RAAS blockade (against a background of loopdiuretic or thiazide) on proteinuria,[362] that may partly relate to its diuretic effect.

Protein Intake

The renoprotective potential of dietary protein restriction has been extensively evaluated in experimental animals and in humans, as reviewed in Chapter 25 . In addition, protein intake can modulate the antiproteinuric effect of ACE inhibition. A rise in protein intake from 0.3 to 1 g/kg/day in enalapril-treated patients led to a rise in proteinuria from 1.7 to 3 g/day.[536] In moderately severe proteinuria (7.4 g/day), restriction of protein intake from a calculated value of 1.31 to 0.81 g/kg/day reduced proteinuria to 6.3 g/day, with a further reduction to 3.4 g/day after adding lisinopril.[396] In severe proteinuria, during lisinopril, protein restriction from 1.3 to 0.87 g/kg/day reduced proteinuria from 8.8 to 5.9 g/day. Thus, ACE inhibition and protein restriction had additive effects on proteinuria. No additive effects were observed for blood pressure and renal hemodynamics. In patients with less severe proteinuria, no data are available.

Dose Titration for Proteinuria

Considering the importance of proteinuria, surprisingly few data were available on dose response for proteinuria for ACE inhibitors or AT1 receptor blockers until recently, and recommended doses were mainly based on dose response for blood pressure. It is increasingly recognized, however, that dose-response curves for blood pressure and proteinuria are not necessarily similar. Nonhypotensive doses of ACE inhibitor can reduce proteinuria, [174] [537]and a progressive antiproteinuric effect with doses up to 20 mg/day lisinopril was found in normotensive subjects with IgA nephropathy in whom the maximum reduction of blood pressure occurred at 5 mg/day.[538] Because proteinuria reduction is an independent treatment target, these data prompted several studies addressing the antiproteinuric potential of doses of ACEi higher than needed for optimal blood pressure reduction.

Laverman and associates[539] as well as Ruggenenti and colleagues[540] report progressive reduction in proteinuria with increasing doses of 10, 20, and 40 mg/day lisinopril in nondiabetic nephropathy, with also a slightly lower blood pressure. No plateau phase was obtained for antiproteinuric response, suggesting that the maximally effective dose for proteinuria might even be higher. At the highest dose, no added effect of AT1 blockade was observed. For AT1-receptor blockade, recent studies with candesartan[541] and telmisartan[542] respectively, found an optimal antiproteinuric effect at higher doses than the maximal blood pressure response in nondiabetic and diabetic nephropathy. [344] [543] Increasing antiproteinuric effects were found with up to 96 mg for candesartan[544] (although well-controlled titration in diabetes found 16 mg/day the optimal dose),[545] 80 mg twice daily for telmisartan, and 900 mg for irbesartan. Of note, the responses of blood pressure and proteinuria were not always concordant, and in subjects with normal blood pressure, a better antiproteinuric effect could often be obtained by higher doses that did not, or only slightly affected blood pressure.[546]

For a balanced view of the renoprotective potential of supramaximal doses of ACE inhibitor or AT1 receptor blockade, the benefits of high-dose monotherapy ACE inhibitor or AT1 receptor blockade should be weighed against those of dual blockade of the RAAS (see next section), and of combination regimens. Moreover, tolerability and toxicity need consideration. Adverse effects in general are usually dose related. The adverse renal effects of captopril early after its introduction were related to excessive high doses.[547] In a small feasibility study, aggressive titration for proteinuria with lisinopril against a background of AT1 blockade and diuretic was associated with a relatively poor tolerability.[548] No data on hard end points are currently available to support dose-recommendations for long-term renoprotection. So, the intermediate targets blood pressure control plus optimal reduction of proteinuria should guide titration of therapy. If proteinuria persists despite good blood pressure control, current evidence supports a dose increase although it may not be invariably effective.

Combination Therapy

Combining drugs with different mechanisms of action can exert additive effects. Rational combination therapy can target different pathways, as well as different levels within a single pathway. Most renal patients require combination of different antihypertensives for effective blood pressure control. This is illustrated in Figure 54-17 , summarizing the number of antihypertensives needed to obtain target pressure in clinical trials, amounting to an average of three different drugs.[91]

FIGURE 54-17  Average number of antihypertensives needed to achieve lower blood pressure goals in the available trials that randomized for lower blood pressure targets.  (Adapted with permission from Bakris GL, Williams M, Dworkin L, et al: The national kidney foundation hypertension and diabetes executive committees working group. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis 36:646–661, 2000.)

 

 

Several combinations may provide specific renoprotection, as judged from their effect on proteinuria, and moreover, for dual RAAS blockade, an effect on hard end points was demonstrated as well.[161]

First, as outlined previously, during RAAS blockade, diuretics overcome the effects of high sodium intake on blood pressure and proteinuria. Next, RAAS blockade with the NSAID indomethacin exerts an additive effect on proteinuria without affecting blood pressure. [399] [549] Monitoring of renal function and serum potassium is warranted when using this combination,[550] because it induces a substantial fall in GFR, in particular during volume depletion. The reduction of GFR correlates to the reduction of proteinuria, and reflects functional reduction of filtration pressure, because it is reversible after withdrawal of indomethacin. Hyperkalemia can ensue owing to the combined effects of a drop in GFR, decreased aldosterone levels, and direct tubular effects of indomethacin: this may prompt dietary potassium restriction or treatment with resin exchangers. Finally, the sodium-retaining effects of indomethacin warrant control of sodium status as this may offset the beneficial effects. Obviously, this combination should only be used in experienced hands. Whether selective COX-2 inhibitors will turn out to have a similar profile remains to be established.

Experimental and human data in type 2 diabetes and nondiabetic proteinuria suggested an additive renoprotective effect of ACE inhibitors and non-DHP CCBs. [348] [353] [551] However, the large BENEDICT trial, in type 2 diabetes did not show an added long-term benefit for prevention of nephropathy in type 2 diabetes over ACE-inhibitor monotherapy.[10]

The RAAS cascade has several internal feedback loops. Accordingly, blockade at a single level elicits compensatory responses at other levels, providing a rationale for blocking the RAAS at different levels simultaneously. ACE inhibitors have been combined with AT1 receptor blockers, [552] [553] [554] renin inhibitors,[555] and with aldosterone blockade.[362] In renal populations, combined therapy with ACE-inhibitor and AT1 receptor blocker exerted a more effective antiproteinuric response than either monotherapy, in diabetic nephropathy as well as nondiabetic nephropathy. [543] [556] [557] [558] Moreover, recent data from the Combination Treatment of Angiotensin-II Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) study showed that dual blockade by trandolapril 3 mg daily and losartan 100 mg daily, in nondiabetic patients was more effective than either monotherapy on hard end points[161] supporting the importance of dual blockade as a future strategy. Moreover, this study supports a specific renal effect of the dual blockade, because the better effects on proteinuria and renal function loss were obtained at similar blood pressure ( Fig. 54-18 ).[559]

FIGURE 54-18  Data from the COOPERATE trial, showing blood pressure-independent antiproteinuric effects of dual renin-angiotensin-aldosterone system blockade.  (Adapted with permission from Nakao N, Yoshimura A, Morita H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease [COOPERATE]: A randomised controlled trial. Lancet 361:117–124, 2003.)



Yet, added effects are not uniformly reported.[560] Dose considerations are relevant because several studies applied submaximal doses, [561] [562] with the rationale of possible fewer side effects of the separate drugs. Thus, the efficacy of dual blockade could be due to more effective RAAS blockade as such, and might also have been obtained with a higher dose of either drug. For maximal proteinuria reduction, however, it would also be relevant to assess whether dual blockade, at optimal doses of both drugs, would result in further reduction of proteinuria. Agarwal[560] and Laverman[546] considered the dose issue, and show that adding a relatively low-dose losartan to an adequate dose of lisinopril (40 mg) did not improve efficacy, as shown in Figure 54-19 . Adding lisinopril to an optimal antiproteinuric dose of losartan, however, further reduced proteinuria. Relative potency of the agents as well as dose may thus determine added effects.

FIGURE 54-19  Antiproteinuric effect of increasing doses of lisinopril followed by dual renin-angiotensin-aldosterone system blockade by adding losartan to the maximally effective dose of lisinopril (left panel), as well as increasing doses of losartan followed by combined therapy with lisinopril added to the maximally effective dose losartan.  (Adapted from Laverman GD, Navis G, Henning RH, et al: Dual renin-angiotensin system blockade at optimal doses for proteinuria. Kidney Int 62:1020–1025, 2002.)

 

 

Interestinly, Jacobsen and colleagues[563] recently showed that adding irbesartan to 40 mg enalapril, the maximally recommended dose, resulted in a further reduction in blood pressure and a corresponding decrease in albuminuria, supporting the added potential at higher doses as well. It should be noted that dual blockade was associated with a slight drop in hemoglobin, attributed to the effects of intensive RAAS blockade on EPO-production.

The above-mentioned data suggest that the eventual potency of dual blockade for renoprotection is larger than that for monotherapy and should be further explored as a strategy to improve renoprotection. Optimal dosing schedules, also relative to other optimizing measures such as volume control, as well as the potential of simultaneously blocking even more levels in the RAAS (aldosterone, renin), have to be explored further. Finally, it would be important to consider whether dual RAAS blockade might improve therapy response in individuals resistant to monotherapy. So far, no human studies addressed this issue, but animal data show that resistance to ACE inhibition is not circumvented by combined therapy at adequate dose, nor by supramaximal dosing ACE inhibition.[564] This could suggest that the potential of maximal RAAS blockade to overcome therapy resistance is limited and that multidrug regimens, with combined intervention in different pathways of renal damage, should be explored to further improve renoprotection. Animal data suggest a role for combination with statins, as statin restored responsiveness to ACE-inhibition in rats with severe, therapy-resistant renal disease,[184] for mycophenolate mofetil,[565] or adrenergic blockade. [367] [368] [369] Data on the effect of statins on top of RAAS blockade in humans are currently under way.[380]

Time Course

In nondiabetic patients the reduction of proteinuria takes several weeks to achieve its maximum, which should be considered when titrating for optimal reduction of proteinuria. In microalbuminuric type 1 diabetes, on the other hand, the time course of albuminuria reduction parallels blood pressure reduction, with maximum responses already in the first week of treatment,[566] which may reflect the greater renal impact of blood pressure in these patients. The lack of similar data on other antihypertensives, or in diabetics with overt nephropathy for the moment precludes to recommend a fixed schedule for the time course of titration steps. The diurnal pattern of therapy-response also shows dissociation between reduction of blood pressure and proteinuria. Whereas chronic treatment by either the long-acting ACE inhibitor trandolapril or the renin-inhibitor remikiren exerted effective blood pressure control during 24 hours, proteinuria was only reduced during daytime.[567] The mechanism underlying nocturnal resistance to proteinuria reduction, and its impact on long-term renal prognosis are not yet clear. Because it occurs with long-acting agents, pharmacodynamic factors are likely. Whether an alternative dosing schedule, with dosing in the evening, can improve antiproteinuric efficacy should be awaited.

INDIVIDUAL PATIENT FACTORS IN THERAPY RESPONSE: NEW PERSPECTIVE TO IMPROVE RENOPROTECTION?

For improvement of therapy response, so far, we focused on options proven to be effective at the group level. However, for almost any intervention, within-group differences in response by far exceed the differences between treatment groups, be they different classes of drugs, different doses, diet, or combinations of these. Thus, for most interventions providing evidence-based renoprotection at group level, therapeutic efficacy is insufficient in a substantial proportion of the patients. This may be one of the reasons underlying the paradox between the advances in renoprotection shown in clinical trials, and the increasing number of patients entering dialysis. Focus on individual differences in response, therefore, may allow new perspectives for improvement of renoprotection.

Studies in essential hypertension, applying different interventions in individual patients by a rotation schedule, showed that the blood pressure response to different classes of antihypertensives is individually determined.[568] Renal responsiveness to antihypertensive therapy is individually determined as well. For RAAS blockade, the renal vasodilator response varies greatly between patients. Studying the same patient twice, after an intervention that increases the mean response, reveals the individual pattern of responsiveness.[569] The renal response to ACE inhibition in essential hypertension ( Fig. 54-20 , left panel) is potentiated by dietary sodium restriction[570] but this does not affect the ranking of the patients. Data in type 1 diabetes (see Fig. 54-20 , right panel) show that shifting from ACE inhibition to AT1 blockade does not alter the individual ranking either.[571] Thus, the range of responses is large, and neither potentiation of the response by low sodium nor shift to another class of RAAS-blockade allows poor responders to catch up with good responders.

FIGURE 54-20  Individual responses of effective renal plasma flow to renin-angiotensin-aldosterone system-blockade in essential hypertension (left panel) and IDDM (right panel). Regression lines (continuous) and lines of identity (dotted) are also given. It shows that between-patient differences persist when the patient is studied a second time, irrespective of whether the other intervention leaves the overall magnitude of the response unchanged (right panel), or when the overall response is potentiated (left panel).  (Adapted from Navis G, de Jong P, Donker AJ, et al: Diuretic effects of angiotensin-converting enzyme inhibition: comparison of low and liberal sodium diet in hypertensive patients. J Cardiovasc Pharmacol 9:743–748, 1987 and Lansang MC, Price DA, Laffel LM, et al: Renal vascular responses to captopril and to candesartan in patients with type 1 diabetes mellitus. Kidney Int 59:1432–1438, 2001.)

 

 

Importantly, the response to antiproteinuric intervention is invidually determined as well, as already mentioned earlier.[345] Both ACE inhibition and AT1 blockade are effective at group level, but individual responses can range from a 100% reduction in proteinuria to lack of response. Importantly, neither the switch from ACE inhibition to AT1 receptor blockade, nor higher doses could allow poor responders to catch up with good responders.[547] Because the individual antiproteinuric response pattern was similar after the switch to an NSAID, it appears to be a true individual characteristic, rather than a reflection of the RAAS dependency of proteinuria. Moreover, other measures that improve antiproteinuric response at group level (i.e., protein restriction and diuretic) do not make poor responders catch up either,[572] as shown for added diuretic in Figure 54-21 . It should also be noted, however, that the greatest absolute benefit of the added diuretic is observed in the subjects at the highest risk. Recently, moreover, these short-term findings in humans were corroborated by animal data on long-term renal outcome[573] so there is no reason for therapeutic nihilism!

FIGURE 54-21  Individual data on residual proteinuria during monotherapy ACEi during high sodium (X-axis) as well as after addition of the diuretic hydrochlorothiazide (Y-axis). Regression line (continuous line) and line of identity (dotted line) are given as well.  (Adapted from Buter H, Hemmelder MH, Navis GJ, et al: Blunting of the antiproteinuric efficicay of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 13:1682–1685, 1998 and Laverman GD, de Zeeuw D, Navis GJ: Between-patient differences in response to renoprotective intervention: The clue towards improvement of renoprotection? Editorial review. J Renin Angiotensin Aldosterone Syst 2:205–213, 2002.)

 

 

Thus, individual factors are main determinants of the response to renoprotective intervention. Unravelling the mechanisms underlying differences in therapy response is important to develop strategies to overcome therapy resistance. Disease-specific factors may be relevant, as suggested by the lack of benefit by ACEi in polycystic kidney disease [75] [155] and tubulointerstitial disease.[155] However, large response differences occur between patients with the same renal condition as well. The extent of pretreatment renal interstitial damage may be involved, as suggested by retrospective data in transplant recipients,[174] and prospective animal data.[172] If prospectively confirmed in humans, this would support the case for starting treatment as early as possible![574]

Race,[575] familial factors, and body mass index [462] [463] have been reported to affect the response to RAAS blockade[576] at least in some studies, although the race effect was not confirmed for the RENAAL study,[577] but lack of data prevents a solid conclusion on these issues. As to ACE inhibition, individual differences in aldosterone escape may be relevant in resistance to renoprotective benefit,[363] possibly related to ACE (I/D) genotype[578] and sodium status,[421] supporting a role for aldosterone blockade. As discussed previously, [436] [437] identification of genetic response determinants may affect choice and intensity of therapy, by early identification of patients unlikely to get long-term benefit. Moreover, it can help to unravel the underlying mechanisms, the intermediate phenotypes, and interaction with environmental factors,[421] which is even more important as a prerequisite to develop rational pharmacologic approaches to overcome therapy resistance.

NOVEL TARGETS FOR INTERVENTION

In spite of the advances in renoprotection over the past decades, in many patients, aggressive intervention eventually does not prevent end-stage renal disease, and the cardiovascular complications of renal damage. This prompts the development of novel intervention strategies, aimed at intervention in relevant pathways that are not (sufficiently) addressed by the current intervention strategies, for renal as well as cardiovascular protection.

Several novel approaches are currently under investigation in clinical trials. A lower hemoglobin levels predicts long-term renal function loss, [579] [580] and is a potent cardiovascular risk factor as well. Whereas the use of erythropoietin for treatment of anemia in advanced renal failure is well established, the effects of early intervention on long term renal function and its complications are unknown. This is currently addressed in the trial to reduce cardiovascular events with aranesp therapy study.[581]

The use of vitamin D is also well established in advanced renal failure, to control the complications of disturbed calcium-phospate balance. Interestingly, paracalcitol, a recently developed vitamin D compound tested for its effects on secondary hyperparathyroidism, was found to reduce proteinuria in renal patients,[582] which prompts further exploration of its renoprotective potency.

Distorted integrity of the glomerular basement membrane with loss of anionic sites, as well as changes in extracellular matrix contibute to proteinuria and progressive renal function loss. These changes are characterized (among others) by loss of glycosaminoglycans (GAGs) and heparan sulphates. Administration of heparin and other GAGs, prevented albuminuria and preserved glomerular basement membrane integrity in experimental animals and oral treatment with GAG sulodexine reduced micro- and macroalbuminuria in diabetic patients,[583] prompting its further investigation in an ongoing large trial.

CONCLUSIONS AND FUTURE PROSPECTS

Major advancements mark the prevention of progressive renal function loss over the past decade. It is well established now that hard end points can be reduced by reduction of blood pressure and proteinuria. RAAS blockade-based therapy is particularly effective in diabetic as well as nondiabetic renal disease, and accordingly, is first-choice therapy for renoprotection. Its superiority over other antihypertensives is not apparent only in early intervention in nondiabetic hypertensives. Substantial evidence supports reduction of proteinuria as a treatment target for renoprotection. Interestingly, reduction of proteinuria and albuminuria predict cardiovascular protection as well, so reduction of glomerular protein leakage can guide integrated strategies for renal and cardioavascular protection. Data in diabetes have shown the feasibilily and benefits of early intervention by monitoring and targeting albuminuria. The potential of a similar strategy for nondiabetic subjects is currently under investigation.

Despite all progress, however, in many patients chronic renal failure is still a progressive condition. Several complementary strategies have been proposed to improve overall outcome. Titrating for antiproteinuric effect is a logic next step for long-term renoprotection. Higher doses, as well as dual RAAS blockade can be used to this purpose, with appropriate adjunct dietary measures. Both high-dose and dual blockade appear to afford renoprotection in excess of blood pressure effects. Further exploration of the renoprotective effects of aldosterone blockade may further enhance the potency of RAAS blockade-based therapy. The added value of antihyperlipemic treatment by statins on top of reduction of blood pressure and proteinuria is currently under investigation. Moreover, the effect of interventions in additional pathways (erythropoietin, GAGs, and so forth) is under study, under the plausible assumption that optimal renoprotection will eventually require sophisticated combination regimens targeting different pathways of damage.

Identification of patients likely to benefit from such an aggressive approach is warranted. Importantly, glomerular protein leakange not only predicts renal risk but also the benefit of intervention. Further elucidation of individual determinants of renal risk, and responsiveness to therapy may allow new perspectives to improve renal prognosis.

References

1. Ellis A: Natural history of Bright's disease; Clinical, histological and experimental observations. The vicious circle in Bright's disease.  Lancet  1942; i:72-76.

2. Klahr S, Schreiner G, Ichikawa I: The progression of renal disease.  N Engl J Med  1988; 318:1657-1666.

3. Narins RG, Cortes P: The role of dietary protein restriction in progressive azotemia. Editorial.  N Engl J Med  1994; 330:929-930.

4. Remuzzi G, Bertani T: Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?.  Kidney Int  1990; 38:384-394.

5. Hauser AC, Derfler K, Balcke P: Progression of renal insufficiency in analgesical nephropathy: Impact of drug abuse.  J Clin Epidemiol  1991; 44:53-56.

6. Williams PS, Fass G, Bone JM: Renal pathology and proteinuria determine progression in untreated mild/moderate chronic renal failure.  Q J Med  1988; 67:343-354.

7. Isles GC, McLay A, Boulton-Jones JM: Recovery in malignant hypertension presenting as acute renal failure.  Q J Med  1984; 212:439-452.

8. Diabetes Control and Complications Trial Research Group : The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med  1993; 329:977-986.

9. Fioretto P, Steffes MW, Sutherland DE, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation.  N Engl J Med  1998; 339:69-75.

10. Ruggenenti P, Fassi A, Ilieva AP, et al: Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes.  N Engl J Med  2004; 351:1941-1951.

11. de Jong PE, Curhan GC: Screening, monitoring and treatment of albuminuria, public health perspectives.  J Am Soc Nephrol  2006; 17:2120-2126.

12. Hillege HL, Fidler V, et al: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in the general population.  Circulation  2002; 106:1777-1782.

13. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a factor for development of cardiovascular disease. A statement from the AHA Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology and Epidemiology and Prevention.  Circulation  2003; 108:2154-2169.

14. Levey AS, Coresh J, Balk E, et al: National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification and stratification.  Ann Int Med  2003; 139:137-147.

15. Perneger TV, Whelton PK, Klag ML: History of hypertension in patients treated for end-stage renal disease.  J Hypertens  1997; 15:451-456.

16.   US Renal Data System. USRDS 2003 Annual Data Report: Atlas of end stage renal disease in the United States. Bethesda Md. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

17. Tracy RE, Malcom GR, Oalmann MC, et al: Renal microvascular features of hypertension in Japan, Guatemala and the United States.  Arch Pathol Lab Med  1992; 16:50-55.

18. Tracy RE, Tabares Toca V: Nephrosclerosis and blood pressure. I. Rising and falling patterns in lengthy records.  Lab Invest  1974; 34:20-29.

19. Tracy RE, Velez-Duran M, Heigle T, Oalmann MC: Two variants of nephrosclerosis separately related to age and blood pressure.  Am J Pathol  1988; 131:270-282.

20. Katafuchi R, Takebayashi S: Morphometric and functional correlations in benign nephrosclerosis.  Clin Nephrol  1987; 28:238-243.

21. Fogo A, Breyer JA, Smith MC, et al: The AASK pilot Study Investigators: Accuracy of diagnosis of hypertensive nephrosclerosis in African Americans: A report from the African American Study of Kidney Disease (AASK) Trial.  Kidney Int  1997;244-252.

22. Harvey JM, Howie AJ, Lee SJ, et al: Renal biopsy findings in hypertensive patients with proteinuria.  Lancet  1992; 340:1435-1436.

23. Lindeman RD, Tobin J, Shock NW: Association between blood pressure and the rate of decline in renal function with age.  Kidney Int  1984; 26:861-868.

24. Perneger TV, Nieto FJ, Whelton PK, et al: A prospective study of blood pressure and serum creatinine. Results from the “Clue” study and the ARIC study.  JAMA  1993; 269:488-493.

25. Klag MJ, Whelton PK, Randall BL, et al: Blood pressure and end stage renal disease in men.  N Engl J Med  1996; 334:13-18.

26. Tozawa M, Iseki K, Iseki C, et al: Influence of smoking and obesity on the development of proteinuria.  Kidney Int  2002; 62:956-962.

27. He J, Whelton PK: Elevated systolic blood pressure as a risk factor for cardiovascular and renal disease.  J Hypertens  1999; 17:S7-S13.

28. Young JH, Klag MJ, Muntner P, et al: Blood pressure and decline in kidney function: Findings from the Systolic Hypertension in the Elderly Program (SHEP).  J Am Soc Nephrol  2002; 13:2776-2782.

29. Schmieder RE, Schachtinger H, Messerli FH: Accelerated decline in renal perfusion with aging in essential hypertension.  Hypertension  1994; 23:351-357.

30. London GM, Safar ME, Sassard JE, et al: Renal and systemic hemodynamics in sustained essential hypertension.  Hypertension  1984; 6:743-754.

31. Fliser D, Franek E, Joest M, et al: Renal function in the elderly: Impact of hypertension and cardiac function.  Kidney Int  1997; 51:1196-1204.

32. Kimura G, London GM, Safar ME, et al: Glomerular hypertension in renovascular hypertensive patients.  Kidney Int  1991; 39:966-972.

33. Walker WG, Neaton JD, Cutler JA, et al: Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial.  JAMA  1992; 268:3085-3091.

34. Shulman NB, Ford CE, Hall WD, et al: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function.  Hypertension  1989; 13:80-93.

35. Perry Jr HM, Miller JP, Fornoff JR, et al: Early predictors of 15-year end-stage renal disease in hypertensive patients.  Hypertension  1995; 25:587-594.

36. Walker WG, Neaton JD, Cutler JA, et al: Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial.  JAMA  1992; 268:3085-3091.

37. Peterson JC, Adler S, Burkart JM, et al: For the MDRD Study group. Blood pressure control, proteinuria and the progression of renal disease.  Ann Int Med  1995; 123:754-762.

38. Bidani AK, Schwartz MM, Lewis EJ: Renal autoregulation and vulnerability to hypertensive injury in remnant kidney.  Am J Physiol  1987; 252:F1003-F1010.

39. Kario K, Kanai N, Nishiuma S, et al: Hypertensive nephropathy and the gene for angiotensin-converting enzyme.  Arterioscler Thromb Vasc Biol  1997; 17:252-256.

40. Pontremoli R, Sofia A, Tirotta A, et al: The deletion polymorphism of the angiotensin converting enzyme gene is associated with target organ damage in essential hypertension.  J Am Soc Nephrol  1996; 7:2550-2558.

41. Mallamaci F, Zuccala A, Zoccali C, et al: The deletion polymorphism of the angiotensin- converting enzyme is associated with nephroangiosclerosis.  Am J Hypertens  2000; 13:433-437.

42. Brown MA, Whitworth JA: Hypertension in human renal disease.  J Hypertens  1992; 10:701-712.

43. Poulsen PL, Hansen KW, Mogensen CE: Ambulatory blood pressure in the transition from normo to microalbumnuria: A longitudinal study in IDDM.  Diabetes  1994; 43:1248-1253.

44. Hasslacher C, Ritz E, Terpstra J, et al: Natural history of nephropathy in type I diabetes.  Hypertension  1985; 7:II74-II78.

45. Mogensen CE, Christensen CK: Blood pressure changes and renal function in incipient and overt diabetic nephropathy.  Hypertension  1985; 7:II64-II73.

46. Rossing P, Hommel E, Smidt U, Parving H-H: Impact of blood pressure and albuminuria on the progression of diabetic nephropathy in IDDM patients.  Diabetes  1993; 42:715-719.

47. Harris RD, Steffes MW, Bilous RW, et al: Global glomerular sclerosis and glomerular arteriolar hyalinosis in insulin dependent diabetes.  Kidney Int  1991; 40:107-114.

48. Mauer SM, Sutherland DER, Steffes MW: Relationship of blood pressure to nephropathology in insulin-dependent diabetes mellitus.  Kidney Int  1992; 41:736-740.

49. Brazy PC, Fitzwilliam JF: Progressive renal disease: Role of race and antihypertensive medications.  Kidney Int  1990; 37:1113-1119.

50. Locatelli F, Marcelli D, Comelli M, et al: Proteinuria and blood pressure as causal components of progression to end-stage renal failure.  Nephrol Dial Transplant  1996; 11:461-467.

51. Oldrizzi L, Rugiu C, de Biase V, Maschio G: The place of hypertension among the risk factors for renal function in chronic renal failure.  Am J Kidney Dis  1993; 21:S119-S123.

52. Wight JP, Salzano S, Brown CB, El Nahas AM: Natural history of chronic renal failure: A reappraisal.  Nephrol Dial Transplant  1992; 7:379-383.

53. Orofino L, Quereda C, Lamas S, et al: Hypertension in primary chronic glomerulonephritis: An analysis of 288 biopsied patients.  Nephron  1987; 45:22-26.

54. Rambausek M, Rhien C, Waldherr R, et al: Hypertension in chronic idiopathic glomerulonephritis: An analysis of 311 biopsied patients.  Eur J Clin Invest  1989; 19:176-180.

55. Gonzalo A, Gallego A, Rivera M, et al: Influence of hypertension on early renal insufficiency in autosomal dominant polycystic kidney disease.  Nephron  1996; 72:225-230.

56. Stenvinkel P, Alvestrand A, Bergström J: Factors influencing progression in patients with chronic renal failure.  J Int Med  1989; 226:183-188.

57. Walker WG: Hypertension-related renal injury: A major contributor to end stage renal disease.  Am J Kidney Dis  1993; 22:164-173.

58. Alvestrand A, Gutierrez A, Bucht H, Bergström J: Reduction of blood pressure retards the progression of chronic renal failure in man.  Nephrol Dial Transplant  1988; 3:624-631.

59. Hannedouche TH, Albouze G, Chauveau PH, et al: Effects of blood pressure and antihypertensive treatment on progression of advanced renal failure.  Am J Kidney Dis  1993; 21:31-137.

60. Mogensen CE: Long term antihypertensive treatment inhibiting progression of diabetic nephropathy.  Br Med J  1982; 285:685-689.

61. Parving H-H, Andersen AR, Smidt UM, Svendsen PA: Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy.  Lancet  1983; i:1175-1179.

62. Bakris GL, Weir MR, Shahinfar S, et al: Effects of blood pressure level on progression of diabetic nephropathy: Results from the RENAAL study.  Arch Int Med  2003; 163:1555-1565.

63. Pohl MA, Blumenthal S, Cordonnier DJ, et al: Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcome in the Irbesartan Diabetic Nephropathy Trial: Clinical implications and limitations.  J Am Soc Nephrol  2005; 16:3027-3037.

64. Rossing K, Christensen PK, Hovind P, et al: Progression of nephropathy in type 2 diabetic patients.  Kidney Int  2004; 66:1596-1605.

65. Pohl JF, Thurston H, Swales JD: Hypertension with renal impairment. Influence of intensive therapy.  Q J Med  1974; 43:569-581.

66. Mitchell HC, Graham RM, Pettinger WA: Renal function during long term treatment of hypertension with minoxidil. Comparison of benign and malignant hypertension.  Ann Int Med  1980; 93:676-681.

67. Oldrizzi L, Rugio C, Maschio G: Hypertension and progression of renal failure in patients on protein-restricted diet.  Contrib Nephrol  1987; 54:134-143.In Maschio G, Campese VM, Valvo M, Oldrizzi L (eds)

68. Vetter K, Lindenau K, Kripki F, Frohling PT: Influence of hypertension on the rate of progression of chronic renal failure.  Scand J Urol Nephrol  1988; 108:21-23.

69. Shimamatsu K, Onoyama K, Harada A, Kumagai H: Effect of blood pressure on the progression rate of renal impairment in chronic glomerulonephritis.  J Clin Hypertens  1985; 5:239-244.

70. Hannedouche T, Chauveau P, Fehrat A, et al: Effect of moderate protein restriction on the rate of renal function loss in chronic renal failure.  Kidney Int  1989; 27:S91-S95.

71. Madhavan S, Stockwell D, Cohen H, Alderman MH: Renal function during antihypertensive treatment.  Lancet  1995; 345:749-751.

72. Alberti D, Locatelli F, Graziani G, et al: Hypertension and chronic renal insufficieny: The experience of the Northern Italian Cooperative Study Group.  Am J Kidney Dis  1993; 21:124-130.

73. Bergström J, Alvestrand A, Bucht H, Gutierrez A: Progression of chronic renal failure in man is retarded with more frequent clinical follow-ups and blood pressure control.  Clin Nephrol  1986; 25:1-6.

74. Klahr S, Levey AS, Beck GJ, et al: The effect of dietary protein restriction and blood pressure control on the progression of chronic renal disease.  N Engl J Med  1994; 330:877-884.

75. Peterson JC, Adler S, Burkart JM, et al: For the MDRD Study group. Blood pressure control, proteinuria and the progression of renal disease.  Ann Int Med  1995; 123:754-762.

76. Hebert LA, Kusek JA, Green T, et al: For the MDRD study group. Effects of blood pressure control on progressive renal disease in blacks and whites.  Hypertension  1997; 30:428-435.

77. Sarnak ML, Greene T, Wang X, et al: The effect of a lower target blood pressure on the progression of kidney disease: Long term follow-up of the Modification of Diet in Renal Disease Study.  Ann Int Med  2005; 142:342-351.

78. Pettinger WA, Lee HC, Reisch J, Mitchell HC: Long term improvement in renal function after short term strict blood pressure control hypertensive nephrosclerosis.  Hypertension  1989; 13:766-772.

79. Parving H-H, Andersen AR, Smidt UM, et al: Effect of antihypertensive treatment on kidney function in diabetic nephropathy.  Br Med J  1987; 294:1443-1447.

80. Pohl MA, Blumenthal S, Cordonnier DJ, et al: Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcome in the Irbesartan Diabetic Nephropathy Trial: Clinical implications and limitations.  J Am Soc Nephrol  2005; 16:3027-3037.

81. Lewis EJ, Hunsicker LG, Bain RP, et al: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy.  N Engl J Med  1993; 329:1456-1462.

82. Ravid M, Brosh D, Levi Z, et al: Use of enalapril to attentuate decline in renal function in normotensive normo-albuminuric patients with type 2 diabetes mellitus.  Ann Int Med  1998; 128:983-988.

83. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with Type 2 diabetes and nephropathy.  N Engl J Med  2001; 345:861-869.

84. Lewis EJ, Hunsicker LG, Clarke WR, et al: Collaborative study group. Renoprotective effects of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.  N Engl J Med  2001; 345:851-860.

85. Wright JT, Bakris G, Greene T, et al: African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial.  JAMA  2002; 288:421-2431.

86. Ruggenenti P, Perna A, Loriga G, et al: Blood pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2) multi-centre randomised controlled trial.  Lancet  2005; 365:939-946.

87. Levey AS: Which antihypertensive agents in chronic kidney disease?.  Ann Intern Med  2006; 144:213-215.

88. Mogensen CE, Keane WF, Bennett PH, et al: Prevention of diabetic renal disease with special reference to microalbuminuria.  Lancet  1995; 346:1080-1084.

89. Bakris GL, Williams M, Dworkin L, et al: The national kidney foundation hypertension and diabetes executive committees working group. Preserving renal function in adults with hypertension and diabetes: A consensus approach.  Am J Kidney Dis  2000; 36:646-661.

90. Parving H-H, Smidt UM, Hommel E, et al: Effective antihypertensive therapy postpones renal insufficiency in diabetic nephropathy.  Am J Kidney Dis  1993; 22:188-195.

91. Berl T, Hunsicker LG, Lewis JB, et al: The Collaborative Study Group. Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.  J Am Soc Nephrol  2005; 16:2170-2179.

92. Jafar TH, Stark PC, Schmid CH, et al: Progression of kidney disease: The role of blood pressure control. Proteinuria and angiotensin-converting enzyme inhibition: A patient-level meta-analysis.  Ann Int Med  2003; 139:244-252.

93. Kidney Disease Outcome Quality Initiative (K/DOQI): K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.  Am J Kidney Dis  2004; 43:S1-S290.

94. Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: The JNC-& report.  JAMA  2003; 289:2560-2572.

95. Hostetter TH, Olson JL, Rennke HG, et al: Hyperfiltration in remnant nephrons. A potentially adverse response to renal ablation.  Am J Physiol  1981; 241:F83-F85.

96. Zatz R, Meyer TW, Rennke HG, Brenner BM: Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy.  Proc Natl Acad Sci USA  1985; 82:5963-5967.

97. Mogensen CE, Hansen KW, Nielsen S, et al: Monitoring diabetic nephropathy: Glomerular filtration rate and abnormal albuminuria in diabetic renal disease: Reproducibility, progression, and efficacy of antihypertensive intervention.  Am J Kidney Dis  1993; 22:174-187.

98. Parving H-H, Kastrup H, Smidt UM, et al: Impaired autoregulation of glomerular filtration rate in type I (insulin-dependent) diabetic patients with nephropathy.  Diabetologia  1984; 27:547-552.

99. Hirose K, Tsuchida H, Osterby R, Gundersen HJ: A strong correlation between glomerular filtration rate and filtration surface in diabetic kidney hyperfunction.  Lab Invest  1980; 43:434-437.

100. Vedel P, Obel J, Nielsen FS, et al: Glomerular hyperfiltration in microalbuminuric NIDDM patients.  Diabetologia  1996; 39:1584-1589.

101. Nowack R, Raum E, Blum W, Ritz E: Renal hemodynamics in recent onset type II diabetes.  Am J Kidney Dis  1992; 20:342-347.

102. Vora JP, Dolben J, Dean JD, et al: Renal hemodynamics in newly presenting non-insulin dependent diabetes meliitus.  Kidney Int  1992; 41:829-835.

103. Gambara V, Mecca G, Remuzzi G, Bertani T: Heterogeneous nature of renal lesions in type II diabetes.  J Am Soc Nephrol  1993; 3:1458-1466.

104. Wong H, Vivian L, Weiler G, et al: Patients with autosomal dominant polycystic kidney disease hyperfiltrate early in their disease.  Am J Kidney Dis  2004; 43:624-628.

105. Talseth T, Fauchald P, Skrede S, et al: Long-term blood pressure and renal function in kidney donors.  Kidney Int  1986; 29:1072-1076.

106. Anastasio P, Spitali L, Frangiosa A, et al: Glomerular filtration rate in severely overweight normotensive humans.  Am J Kidney Dis  2000; 35:1144-1148.

107. Praga M, Hernandez E, Herrero JC, et al: Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy.  Kidney Int  2000; 58:2111-2118.

108. Rook M, Hofker S, van Son WJ, et al: Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after kidney donation.  Am J Transplant  2006; 6:1653-1659.

109. Fogo A, Hawkins EP, Berry PL, et al: Glomerular hypertrophy in minimal change predicts subsequent pogression to focal glomerular sclerosis.  Kidney Int  1990; 38:115-123.

110. du Cailar G, Ribstein J, Mimran A: Glomerular hyperfiltration and left ventricular mass in mild never-treated essential hypertension.  J Hypertens  1991; 9:S158-S159.

111. Schmieder RE, Messerli FH, Garavaglia G, Nunez B: Glomerular hyperfiltration indicates early target organ damage in essential hypertension.  JAMA  1990; 264:2775-2780.

112. Schmieder RE, Veelken R, Gatzka CD, et al: Predictors for hypertensive nephropathy: Results of a 6-year follow-up study.  J Hypertens  1995; 13:357-365.

113. Bosma RJ, Kwakernaak AJ, Homan van der Heide JJ, et al: Body mass index and glomerular hyperfiltration in renal transplant recipients: cross-sectional analysis and long-term inpact.  Am J Transplant  2007; 7:645-652.

114. Pinto-Sietsma S-J, Janssen WMT, Hillege HJ, et al: Urinary albumin excretion is associated with renal functional abnormalities in a non-diabetic population.  J Am Soc Nephrol  2000; 11:1182-1888.

115. Anderson SA, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in rats.  J Clin Invest  1986; 77:1993-2000.

116. Dworkin LD, Grosser M, Feiner HD, et al: Renal vascular effects of antihypertensive therapy in uninephrectomized spontaneously hypertensive rats.  Kidney Int  1989; 35:790-798.

117. Apperloo AJ, de Zeeuw D, de Jong PE: A short-term antihypertensive treatment induced fall in glomerular filtration rate predicts long term stability of renal function.  Kidney Int  1997; 51:793-797.

118. Hansen HP, Rossing P, Tarnow L, et al: Increased glomerular filtration rate after withdrawal of antihypertensive therapy.  Kidney Int  1995; 47:1726-1731.

119. El Nahas AM, Masters-Thomas A, Brady SA, et al: Selective effect of low protein diets in chronic renal diseases.  Br Med J  1984; 289:1337-1341.

120. Hansen HP, Nielsen FS, Rossing P, et al: Kidney function after withdrawal of long-term antihypertensive therapy in diabetic nephropathy.  Kidney Int  1997; 52:S49-S53.

121. Ravid M, Savin H, Jurtin I, et al: Long term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients.  Ann Int Med  1993; 118:577-581.

122. Fogo A, Yoshida Y, Glick AD, et al: Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis.  J Clin Invest  1988; 82:322-330.

123. Howie AJ, Lee SJ, Green NJ, et al: Different clinicalopathologic types of segmental sclerosing glomerular lesions in adults.  Nephrol Dial Transplant  1993; 8:590-599.

124. Kroker BP, Dawson DV, Sanfilipppo F: IgA nephropathy. Correlation of clinical and histologic features.  Lab Invest  1983; 48:19-24.

125. Nagai Y, Arai H, Washisawa Y, et al: FGS-like lesions in pre-ecclampsia.  Clin Nephrol  1991; 36:134-140.

126. D'Agati V, Suh J, Carbone L, et al: Pathology of HIV associated nephropathy: A detailed morphologic and comparative study.  Kidney Int  1989; 35:1358-1370.

127. Ferrario F, Tadros MT, Napodano P, et al: Critic reevaluation of 41 cases of “idiopathic” crescentic glomerulonephritis.  Clin Nephrol  1994; 41:1-9.

128. Novick AC, Gephardt G, Guz B, et al: Long term follow-up after partial removal of a solitary kidney.  N Engl J Med  1991; 325:1059-1062.

129. Kiprov DD, Colvin RB, McCluskey RT: Focal and segmental glomerulosclerosis and proteinuria associated with unilateral agenesis.  Lab Invest  1982; 46:275-281.

130. El Khatib MT, Becker GJ, Kincaid-Smith P: Morphologic aspects of reflux nephropathy.  Kidney Int  1987; 32:261-266.

131. Harvey JM, Howie AJ, Lee SJ, et al: Renal biopsy findings in hypertensive patients with proteinuria.  Lancet  1992; 340:1435-1436.

132. Perna A, Remuzzi G: Abnormal permeability to proteins and glomerular lesions: A meta-analysis of experimental and clinical studies.  Am J Kidney Dis  1996; 27:34-41.

133. Mallick NP, Short CD, Hunt LP: How far since Ellis?.  Nephron  1987; 46:113-124.

134. Samuelsson O, Wilhelmsen L, Elmfeldt D, et al: Predictors of cardiovascular morbidity in treated hypertension: Results from the primary preventive trial in Göteborg, Sweden.  J Hypertens  1985; 3:167-176.

135. Ruggenenti P, Perna A, Mosconi L, et al: For the GISEN group. Urinary protein excretion rate is the best predictor of ESRF in non-diabetic proteinuric chronic nephropathies.  Kidney Int  1998; 53:1209-1216.

136. Beukhof JR, Kardaun O, Schaafsma W, et al: Toward individual prognosis of IgA nephropathy.  Kidney Int  1986; 29:549-556.

137. Breyer JA, Bain RP, Evans JK, et al: The colloborative study group. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy.  Kidney Int  1996; 50:1651-1658.

138. de Zeeuw D, Remuzzi G, Parving HH, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL.  Kidney Int  2004; 65:2309-2320.

139. Donadio Jr JV, Torres VE, Velosa JA, et al: Idiopathic membranous glomerulopathy: The natural history of untreated patients.  Kidney Int  1988; 33:708-715.

140. Hunt LP, Short CD, Mallick NP: Prognostic indicators in patients presenting with nephrotic syndrome.  Kidney Int  1988; 34:382-388.

141. Halimi J-M, Ribstein J, Du Cailar G, et al: Albuminuria predicts renal functional outcome after intervention in atheromatous renovascular disease.  J Hypertens  1995; 13:1335-1342.

142. Franssen CFM, Stegeman CA, Oost-Kort W, et al: Determinants of renal outcome in anti-myeloperoxidase-associated crescentic glomerulonephritis.  J Am Soc Nephrol  1998; 9:1915-1923.

143. Kincaid-Smith P, Becker G: Reflux nephropathy and chronic atrophic glomerulonephritis: A review.  J Infectious Dis  1978; 138:774-780.

144. Zuchelli P, Gaggi R: Reflux nephropathy in adults.  Nephron  1991; 57:2-9.

145. Jungers P, Hannedouche T, Itakura Y, et al: Progression to end-stage renal failure in non-diabetic kidney diseases: a multivariate analysis of determinant factors.  Nephrol Dial Transplant  1995; 10:1353-1360.

146. Parving HH, Oxenbøll B, Svendsen PA, et al: Early detection of patients at risk of developing diabetic nephropathy.  Acta Endocrinol (Copenh)  1982; 100:550-555.

147. Viberti GC, Hill RD, Jarrett RJ, et al: Microalbuminuria as a predictor of clinical nephropathy in insulin dependent diabetes mellitus.  Lancet  1982; i:1430-1432.

148. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients.  N Engl J Med  1984; 311:89-93.

149. Mathiesen ER, Oxenbøll B, Johansen K, et al: Incipient nephropathy in Type I (insulin dependent) diabetes.  Diabetologia  1984; 26:406-410.

150. Bjorck S, Mulec H, Jonson SA, et al: Contrasting effects of enalapril and metoprolol on proteinuria in diabetic nephropathy.  Br Med J  1990; 300:904-907.

151. Atkins RC, Briganti EM, Lewis JB, et al: Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy.  Am J Kidney Dis  2005; 45:281-287.

152. Maschio G, Alberti D, Janin G, et al: Effect of the angiotensin converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency.  N Engl J Med  1996; 334:939-945.

153. Kamper AL, Strandgaard S, Leyssac PP: Effect of enalapril on progression of chronic renal failure.  Am J Hypertension  1992; 5:423-430.

154. The GISEN group : Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and progression to terminal renal failure in proteinuric, non-diabetic nephropathy.  Lancet  1997; 349:1857-1863.

155. Jafar TH, Schmid CH, Landa M, et al: For the ACE inhibition in progressive renal disease study group. Angiotensin converting enzyme inhibitors and progression of nondiabetic disease.  Ann Int Med  2001; 135:73-87.

156. Idelson BA, Smithlime N, Smith GW, Harrington JT: Prognosis in steroid treated idiopathic nephrotic syndrome.  Ann Int Med  1977; 137:891-896.

157. Vriesendorp R, Donker AJM, de Zeeuw D: Effects of non-steroidal anti-inflammatory drugs on proteinuria.  Am J Med  1986; 81:84-93.

158. Nakao N, Yoshimura A, Morita H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial.  Lancet  2003; 361:117-124.

159. Wapstra FH, Navis GJ, de Jong PE, de Zeeuw D: Short term and long term antiproteinuric response to inhibition of renin angiotensin axis in patients with non-diabetic renal disease; Prediction of GFR decline.  Exp Nephrol  1996; 4:47-52.

160. El Nahas AM, Masters-Thomas A, Brady SA, et al: Selective effect of low protein diets in chronic renal diseases.  Br Med J  1984; 289:1337-1341.

161. Praga M, Hernández E, Montoyo C, et al: Long-term beneficial effects of angiotensin-converting enzyme inhibition with nephrotic proteinuria.  Am J Kidney Dis  1992; 20:240-248.

162. Apperloo AJ, de Zeeuw D, de Jong PE: Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease.  Kidney Int  1994; 45:S174-S178.

163. The GISEN Group : Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.  Lancet  1997; 349:1857-1863.

164. Peterson JC, Adler S, Burkart JM, et al: MDRD Study group. Blood pressure control, proteinuria and the progression of renal disease.  Ann Int Med  1995; 123:754-762.

165. Kamper A-L, Strandgaard S, Leyssac PP: Late outcome of a controlled trial of enalapril treatment in progressive chronic renal failure. Hard end-points and influence of proteinuria.  Nephrol Dial Transplant  1995; 10:1182-1188.

166. Rossing P, Hommel E, Smidt UM, Parving H-H: Reduction in albuminuria predicts diminished progression in diabetic nephropathy.  Kidney Int  1994; 45:S145-S149.

167. Rossing P, Hommel E, Smidt UM, Parving H-H: Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment.  Diabetologia  1994; 37:511-516.

168. Wapstra FH, van Goor H, Navis GJ, et al: Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis.  Clin Sci  1996; 90:393-401.

169. Kramer AB, Laverman GD, van Goor H, et al: Interindividual differences in antiproteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pre-treatment renal damage.  J Pathol  2003; 201:160-167.

170. Ruggenenti P, Perna A, Remuzzi G: Retarding progression of chronic renal disease: The neglected issue of residual proteinuria.  Kidney Int  2003; 63:2254-2261.

171. Lufft V, Kliem V, Hamkens A, et al: Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage.  Clin Transplant  1998; 12:409-415.

172. Kasiske BL, O'Donnell MP, Schmits PG, et al: Renal injury of diet-induced hypercholesterolemia in rats.  Kidney Int  1990; 37:880-891.

173. Keane WF, Kasiske B, O'Donnell MP, Kin Y: The role of altered lipid metabolism in the progression of renal disease.  Am J Kidney Dis  1991; 17:S38-S42.

174. Moorhead JF: Lipids and pathogenesis of kidney disease.  Am J Kidney Dis  1991; 17:65-70.

175. Joven J, Villabona C, Vilella Masana L, et al: Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome.  N Engl J Med  1990; 323:579-584.

176. Keane WF, Raij L: Relationship among altered glomerular barrier permselectivity, angiotensin II and mesangial uptake of macromolecules.  Lab Invest  1985; 53:599-604.

177. Kasiske DL, O'Donnell MP, Schmitz PC, et al: Effects of reduced renal mass on tissue lipids and renal injury in hyperlipemic rats.  Kidney Int  1989; 35:40-47.

178. de Boer E, Navis GJ, Tiebosch ATM, et al: Systemic factors are involved in the pathogenesis of proteinuria-induced glomerulosclerosis in adriamycin nephrotic rats.  J Am Soc Nephrol  1999; 10:2359-2366.

179. Kasiske BL, O'Donnell MP, Cleary MP, Keane WF: Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats.  Kidney Int  1990; 33:667-672.

180. Bos H, de Jong PE, de Zeeuw D, Navis GJ: Do severe systemic sequelae of proteinuria modulate the antiproteinuric response to chronic ACE-inhibition?.  Nephrol Dial Transplant  2002; 17:793-797.

181. Zoja C, Corna D, Rottoli D, et al: Effect of combining ACE inhibitor and statin in severe experimental nephropathy.  Kidney Int  2000; 61:1635-1645.

182. Ohta Y, Yamamoto S, Tsuchida H, et al: Nephropathy of familial lecithin-cholesterol acyl transferase deficiency: Report of a case.  Am J Kidney Dis  1986; 7:41-46.

183. Saito T, Sato H, Kudo K, et al: Lipoprotein glomerulopathy: Glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia.  Am J Kidney Dis  1989; 13:148-153.

184. Keane WF, St Peter JV, Kasiske BL: Is the aggressive mangement of hyperlipidemia in nephrotic syndrome mandatory?.  Kidney Int  1992; 42:S134-S141.

185. Smellie WSA, Warwick GL: Primary hyperlipidemia is not associated with increased urinary albumin excretion.  Nephrol Dial Transplant  1991; 6:398-401.

186. Muntner P, Coresh J, Smith C, et al: Plasma lipids and risk of developing renal dysfunction: The Atherosclerosis Risk in Communities Study.  Kidney Int  2000; 58:293-301.

187. Manttari M, Alikoski T, Manninine V: Effects of hypertension and dyslipidemia on the decline in renal function.  Hypertension  1995; 26:670-675.

188. Lee HS, Lee JS, Koh HI, Ko KW: Intraglomerular lipid deposition in routine biopsies.  Clin Nephrol  1991; 36:67-75.

189. Sato H, Suzuki S, Kobayshi H, et al: Immunohistochemic localization of apolipoproteins in the glomeruli in renal disease: Specifically apoB and apoE.  Clin Nephrol  1991; 36:127-133.

190. Maschio G, Oldrizzi L, Rugiu C, et al: Factors affecting progression of renal failure in patients on long term dietary protein restriction.  Kidney Int  1987; 32:S49-S52.

191. Samuelsson O, Aurell M, Knight-Gibson C, et al: Apolipoprotein-B containing lipoproteins and the progression of renal insuffiency.  Nephron  1993; 63:279-285.

192. Ravid M, Brosh D, Ravid-Safran D, et al: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia.  Arch Intern Med  1998; 158:998-1004.

193. Appel GB, Radakrishnan J, Avram MM, et al: RENAAL-study: Analysis of metabolic parameters as predictors of risk in the RENAAL study.  Diabetes Care  2003; 23:1402-1407.

194. Samuelsson O, Mulec H, Knight-Gibson C, et al: Lipoprotein abnormalities are associated with an increased rate of renal insufficiency.  Nephrol Dial Transplant  1997; 12:1908-1915.

195. Attman P-O, Samuelsson O, Alaupovic P: Progression of renal failure; Role of apoB-containing lipoproteins.  Kidney Int  1997; 52:98-101.

196. Capelli P, Evangelista M, Bonomini M, et al: Lipids and the progression of chronic renal failure.  Nephron  1992; 62:31-35.

197. Coggins CH, Breyer Lewis JH, Caggiula AW, et al: Differences between women and men with chronic renal disease.  Nephrol Dial Transplant  1998; 13:1430-1437.

198. Parving H-H, Rossing P, Hommel E, Smidt UM: Angiotensin converting enzyme inhibition in diabetic nephropathy: Ten years experience.  Am J Kidney Dis  1995; 26:99-107.

199. Krolewski AS, Warram JH, Christlieb AR: Hypercholesterolemia. A determinant of renal function loss and deaths in IDDM patients with nephropathy.  Kidney Int  1994; 45:S125-S131.

200. Mulec H, Johnson S-A, Björck S: Relation between serum cholesterol and diabetic nephropathy.  Lancet  1990; 335:1536-1538.

201. Breyer JA, Bain RP, Evans JK, et al: The colloborative study group. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy.  Kidney Int  1996; 50:1651-1658.

202. Mulec H, Johnsen SA, Wiklund O, Björck S: Cholesterol: A renal risk factor in diabetic nephropathy?.  Am J Kidney Dis  1993; 22:196-201.

203. Hadjadj S, Duly-Bouhanick B, Bekherraz A, et al: Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes.  Diabetes Metab  2004; 30:43-51.

204. Ravid M, Savin H, Jurtin I, et al: Long term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients.  Ann Int Med  1993; 118:577-581.

205. Hasslacher C, Bostedt-Kiesel A, Kempe HP, Wahl P: Effect of metabolic factors and blood pressure on kidney function in proteinuric Type 2 (non-insulin-dependent) diabetic patients.  Diabetologia  1995; 36:1051-1056.

206. Jerums G, Allen TJ, Salamandris C, et al: Relationship of progressively increasing albuminuria to apolipoprotein (a) and blood pressure in type 2 (non-insulin dependent) diabetic patients.  Diabetologia  1993; 36:1037-1044.

207. Yokota C, Kimura G, Inenaga T, Kawano Y: Risk factors for progression of diabetic nephropathy.  Am J Nephrol  1995; 15:488-492.

208. Samuelsson O, Attman P-O, Knight-Gibson C, et al: Lipoprotein abnormalities without hyperlipidemia in moderate renal insufficiency.  Nephrol Dial Transplant  1994; 9:1580-1585.

209. Diamond JR, Hanchak NA, McCarter MD, Karnovsky MJ: Cholestyramine resin ameliorates chronic aminonucleoside nephrosis.  Am J Clin Nutr  1990; 51:606-611.

210. Sato H, Suzuki S, Ueno M, et al: Localization of apolipoprotein (a) and B-100 in various renal diseases.  Kidney Int  1993; 43:430-435.

211. Gheith OA, Sobh MA, Mohamed Kel-S, et al: Impact of treatment of dyslipidemia on renal function, fat deposits and scarring in patients with persistent nephrotic syndrome.  Nephron  2002; 91:612-619.

212. Rabelink AJ, Hené RJ, Erkelens DW, et al: Partial remission of nephrotic syndrome in patients on long term simvastatin.  Lancet  1990; 335:1045-1046.

213. Rayner BL, Byrne MJ, van Zyl Smit R: A prospective clinical trial comparing the treatment of idiopathic membranous nephropathy and nephrotic syndrome with simvastatin and diet, versus diet alone.  Clin Nephrol  1996; 46:219-224.

214. Chan PCK, Robinson JD, Yeung WC, et al: Lovastatin therapy in glomerulopnephritis patients with hyperlipidemia and heavy proteinuria.  Nephrol Dial Transplant  1992; 7:93-99.

215. Neverov NI, Kaysen GA, Tareyeva IE: Effect of lipid-lowering therapy on the progression of renal disease in nondiabetic nephrotic patients.  Contrib Nephrol  1997; 120:68-78.In Keane WF, Hörl WH, Kasiske BL (eds): Lipids and the Kidney

216. Warwick GL, Packard CJ, Murray L, et al: Effect of simvastatin on plasma lipid and lipoprotein concentration and low-density lipoprotein metabolism in the nephrotic syndrome.  Clin Sci  1992; 82:701-708.

217. Martins Prata M, Nogueira AC, Reimao Pinto J, et al: Long- term effect of lovastatin on lipoprotein profile in patients with primary nephrotic syndrome.  Clin Nephrol  1994; 41:277-283.

218. Kasiske BL, Velosa JA, Halstenson CE, et al: The effects of lovastatin in hyperlipemic patients with the nephrotic syndrome.  Am J Kidney Dis  1990; 15:8-15.

219. Golper TA, Illingwirth DR, Morris CD, Bennett WM: Lovastatin in the treatment of multifactorial hyperlipidemia associated with proteinuria.  Am J Kidney Dis  1989; 13:312-320.

220. Thomas ME, Harris KPG, Ramaswamy C, et al: Simvastatin for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.  Kidney Int  1993; 44:1124-1129.

221. Shoyi J, Nishizawa Y, Toyokawa A, et al: Decreased albuminuria by pravastatin in hyperlipidemic diabetics.  Nephron  1991; 59:664-665.

222. Nielsen S, Schmitz O, Møller N, et al: Renal function and insulin sensitivity during simvastatin treatment in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria.  Diabetologia  1993; 36:1079-1086.

223. Biesenbach G, Zagornik J: Lovastatin in the treatment of hypercholesterolemia in nephrotic syndrome due to diabetic nephropathy stage IV-V.  Clin Nephrol  1992; 37:274-279.

224. Hommel E, Andersen P, Gall M, et al: Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy.  Diabetologia  1992; 35:447-451.

225. Lam KSL, Cheng IKP, Janus ED, Pang RWC: Cholesterol lowering therapy may retard the progression of diabetic nephropathy.  Diabetologia  1995; 38:604-609.

226. Lee T-M, Su S-F, Tsai C-H: Effect of pravastatin on proteinuria in patients with well-controlled hypertension.  Hypertension  2002; 40:67-73.

227. Zhang A, Vertommen J, van Gaal L, de Leeuw I: Effects of pravastatin on lipid levels, in vitro oxidizability of non-HDL lipoproteins and microalbuminuria in IDDM.  Diabetes Res Clin Pract  1995; 29:189-194.

228. Tonolo G, Ciccarese M, Brizzi P, et al: Reduction of albumin excretion rate in normotensive micro-albuminuric type 2 diabetic patients during long-term simvastatin treatment.  Diabetes Care  1997; 20:1891-1895.

229. Bianchi S, Bigazzi R, Caiazza A, Campese VM: A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.  Am J Kidney Dis  2003; 41:565-570.

230. Asselbergs FW, Diercks GR, Hillege JL, et al: Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria.  Circulation  2004; 110:2809-2816.

231. Tonelli M, Moye L, Sacks FM, et al: Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.  J Am Soc Nephrol  2003; 14:1605-1613.

232. Tonelli M, Isles C, Craven T, et al: Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease.  Circulation  2005; 112:171-178.

233. Fried LF, Orchard TJ, Kasiske B: Effect of lipid reduction on the progression of renal disease: A meta-analysis.  Kidney Int  2001; 59:260-269.

234. Douglas K, O'Malley PG, Jackson JL: Meta-analysis: The effect of statins on albuminuria.  Ann Int Med  2006; 145:117-125.

235. Sandhu S, Wiebe N, Fried LF, Tonelli M: Statins for improving renal outcomes: A meta-analysis.  J Am Soc Nephrol  2006; 17:2006-2016.

236. Fellstrom B, Holdaas H, Jardine AG, et al: Assessment of Lescol in Renal Transplantation study investigators. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial.  Kidney Int  2004; 66:1549-1555.

237. Tonelli M, Collins D, Robins S, et al: Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) Investigators. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency.  Kidney Int  2004; 66:1123-1130.

238. Tonelli M, Collins D, Robins S, et al: Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease.  Am J Kidney Dis  2004; 44:832-839.

239. Maki DD, Ma JZ, Louis TA, Kasiske BL: Long-term effects of antihypertensive agents on proteinuria and renal function.  Arch Int Med  1995; 155:1073-1080.

240. The ACE inhibitors in Diabetic Nephropathy Group : Should all patients with type 1 diabetes mellitus and micro-albuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data.  Ann Int Med  2001; 134:370-379.

241. Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.  J Clin Invest  2006; 116:288-296.

242. Wolf G: Angiotensin as a renal growth promoting factor.  Adv Exp Med Biol  1995; 377:225-236.

243. Kon V, Fogo A, Ichikawa I: Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition.  Kidney Int  1993; 44:545-550.

244. Wapstra FH, Navis GJ, de Jong PE, et al: Chronic angiotensin II-infusion, but not bradykinin blockade abolishes the antiproteinuric response to ACE-inhibition in established adriamycin nephrosis.  J Am Soc Nephrol  2000; 11:490-496.

245. Iyer SN, Chappell MC, Averill DB, et al: Vasodepressor actions of angiotensin (1-7) unmasked during combined treatment with lisinopril and losartan.  Hypertension  1998; 31:699-705.

246. Luque M, Martin P, Martell N, et al: Effects of captopril related to increased levels of prostacyclin and angiotensin (1-7) in essential hypertension.  J Hyp  1996; 14:799-805.

247. Kocks MJ, Lely AT, Boomsma F, et al: G. Sodium status and angiotensin-converting enzyme inhibition: Effects on plasma angiotensin-(1-7) in healthy man.  J Hypertens  2005; 3:597-602.

248. Hannedouche T, Landais P, Goldfarb B, et al: Randomised controlled trial of enalapril and beta-blockers in non-diabetic chronic renal failure.  Br Med J  1994; 309:833-837.

249. Giatras I, Lau J, Levey A: For the Angiotensin Converting Enzyme Inhibition and Progressive Renal Disease Study Group. Effect of angiotensin converting enzyme inhibitors on the progression of nondiabetic renal disease: A meta-analysis of randomized trials.  Ann Int Med  1997; 127:337-345.

250. Rahman M, Pressel S, Davis BR, et al: Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker versus a diuretic: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).  Arch Intern Med  2005; 165:936-946.

251. Rossing P, Parving H-H, de Zeeuw D: Renoprotection by blocking the RAAS in diabetic nephropathy-Fact or fiction?.  Nephrol Dial Transplant  2006; 21:2354-2357.

252. Casas JP, Chua W, Loukogeorgakis S, et al: Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis.  Lancet  2005; 366:2026-2033.

253. van Essen GG, Apperloo AJ, Rensma PL, et al: Are ACE inhibitors superior to beta-blockers in retarding progressive function decline?.  Kidney Int  1997; 52:S58-S62.

254. Ruggenenti P, Perna A, Gherardi G, et al: For the GISEN group. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria.  Lancet  1999; 354:359-364.

255. Ruggenenti P, Perna A, Benini R: For the GISEN group. In chronic nephropathies prolonged ACE inhibition can induce remission: Dynamics of time-dependent changes in GFR.  J Am Soc Nephrol  1999; 10:997-1006.

256. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal diseases.  Lancet  2001; 357:1601-1608.

257. Ruggenenti P, Perna A, Remuzzi G: For the GISEN group. ACE inhibitors to prevent end-stage renal disease: When to start and why possibly never to stop: A post-hoc analysis of the REIN trial results.  J Am Soc Nephrol  2001; 12:2832-2837.

258. Hou FF, Zhang X, Zhang GH, et al: Efficacy and safety of benazepril for advanced chronic renal insufficiency.  N Engl J Med  2006; 354:131-140.

259. Viberti GC, Mogensen CE, Groop LC, Pauls JF: For the European Microalbuminuria Captopril Study Group. Effect of captopril on the progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.  JAMA  1994; 271:275-279.

260. Laffel LMB, McGill JB, Gans DJ: For the North American Microalbuminuria Study Group. The beneficial effect of angiotensin converting enzyme inhibition with captopril on diabetic nephropathy in normotoensive IIDM patients with microalbuminuria.  Am J Med  1995; 99:497-504.

261. The Microalbuminuria Captopril Study Group : Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria.  Diabetologia  1996; 39:587-593.

262. Mathiesen ER, Hommel E, Giese J, Parving H-H: Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria.  Br Med J  1991; 303:81-87.

263. Ravid M, Lang R, Rachmani R, Lishner M: Long-term renoprotective effect of angiotensin converting enzyme inhibition in non-insulin dependent diabetes mellitus.  Arch Int Med  1996; 156:286-289.

264. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE and MICRO-HOPE study; Heart Outcomes Prevention Evaluation Study Investigators.  Lancet  2000; 355:253-259.

265. Suissa S, Hutchinson T, Brophy JM, et al: ACE-inhibitor use and the long-term risk of renal failure in diabetes.  Kidney Int  2006; 69:913-919.

266. Monster TB, de Jong PE, de Jong-van den Berg LT: Drug-induced renal function impairment: a population-based survey.  Pharmacoepidemiol Drug Saf  2003; 12:135-143.

267. Apperloo AJ, de Zeeuw D, de Jong PE: Discordant effects of enalapril and lisinopril on systemic and renal hemodynamics.  Clin Pharmacol Ther  1994; 56:647-658.

268. Keiser JA, Bjork FA, Hodges JC, Taylor DG: Renal hemodynamic and excretory responses to PD 123319 and Losartan, nonpeptide AT1 and AT2 subtype specific angiotensin II ligands.  J Pharmacol Exp Ther  1992; 262:1154-1160.

269. Remuzzi A, Fassi A, Sangalli F, et al: Prevention of renal injury in diabetic MWF rats by angiotensin II antagonism.  Exp Nephrol  1998; 6:28-38.

270. Remuzzi A, Malanchine B, Battaglia C, et al: Comparison of the effects of angiotensin converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats.  Exp Nephrol  1996; 4:19-25.

271. Morrisey JJ, Klahr S: Differential effects of ACE and AT1 receptor inhibition on chemoattractant and 84adhesion molecules.  Am J Physiol  1998; 274:F580-F586.

272. Klahr S, Morrissey JJ: Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring.  Kidney Int  1997; 63:S111-S114.

273. Chung O, Unger T: Unopposed stimulation of the angiotensin AT2 receptor in the kidney.  Nephrol Dial Transplant  1998; 13:537-540.

274. Stoll M, Steckelings UM, Paul M, et al: The angiotensin II AT2 receptor mediates inhibition of cell proliferation in coronary endothelial cells.  J Clin Invest  1995; 95:651-657.

275. Yamada T, Horiuchi M, Dzau VJ: Angiotensin II type 2 receptor mediates programmed cell death.  Proc Natl Acad Sci  1996; 93:156-160.

276. Nakajima M, Hutchinson HG, Fujinaga M, et al: The angiotensin II subtype 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: Gain-of-function study using gene transfer.  Proc Natl Acad Sci USA  1995; 92:10663-10667.

277. Lacourciere Y, Belanger A, Godin C, et al: Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy.  Kidney Int A  2000; 8:762-769.

278. Barnett AH, Bain SC, Bouter P, et al: Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.  N Engl J Med  2004; 351:1952-1961.

279. Gansevoort RT, de Zeeuw D, de Jong PE: Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system?.  Kidney Int  1994; 45:861-867.

280. Buter H, Navis GJ, de Zeeuw D, et al: Renal hemodynamic effects of candesartan in impaired and normal renal function.  Kidney Int  1997; 52:S185-S187.

281. Burnier M, Roch-Ramel F, Brunner HR: Renal effects of angiotensin II receptor blockade in normotensive subjects.  Kidney Int  1996; 49:1787-1790.

282. Parving H-H, Lehnert H, Brochner-Mortensen J, et al: For the Irbesartan in patients with type II diabetes and microalbuminuria study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type II diabetes.  N Engl J Med  2001; 345:870-879.

283. Tarif N, Bakris G: Preservation of renal function; The spectrum of effects by calcium channel blockers.  Nephrol Dial Transplant  1997; 12:2244-2250.

284. Goligorsky MS, Chaimovits C, Rapoport J, et al: Calcium metabolism in uremic nephrocalcinosis: Preventive effect of verapamil.  Kidney Int  1985; 27:774-779.

285. Harris DCH, Hammond WS, Burke TJ, Schrier RW: Verapamil protects against progression of experimental chronic renal failure.  Kidney Int  1987; 31:41-46.

286. Jackson B, Johnston CI: The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: Effect of treatment with an angiotensin converting enzyme inhibitor or a calcium inhibitor.  J Hypertens  1988; 6:495-501.

287. Brunner FP, Thiel G, Hermle M, et al: Long term enalapril and verapamil in rats with reduced renal mass.  Kidney Int  1989; 36:969-977.

288. Jyothirmayi GN, Reddi AS: Effect of diltiazem on glomerular heparan sulfate and albuminuria in diabetic rats.  Hypertension  1993; 21:795-802.

289. Griffin KA, Picken MM, Bidani AK: Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys.  J Clin Invest  1995; 96:793-800.

290. Dworkin LD, Benstein JA, Parker M, et al: Calcium antagonists and converting enzyme inhibitors reduce renal injury by different mechanisms.  Kidney Int  1993; 43:808-814.

291. Bakris GL, Smith AC: Effects of sodium intake on albumin excretion in patients with diabetic nephroapthy treated with long-acting calcium antagonists.  Ann Int Med  1996; 125:201-203.

292. Anderson SA, Rennke HG, Brenner BM, et al: Nifedipine versus fosinopril in uninpehrectomized rats.  Kidney Int  1992; 41:817-891.

293. Bakris GL, Weir ML: Salt intake and reductions in arterial pressure: Is there a direct link?.  Am J Hyperten  1996; 9:200S-206S.

294. Bakris GL, Copley JB, Vicknair N, et al: Calcium channel blockers versus other antihypertensives on progression of NIDDM associated nephropathy.  Kidney Int  1996; 50:1641-1650.

295. Bakris GL, Copley JB, Vicknair N, et al: Calcium channel blockers versus other antihypertensives on progression of NIDDM associated nephropathy.  Kidney Int  1996; 50:1641-1650.

296. Bakris GL, Mangrum A, Copley JB, et al: Calcium channel or beta-blockade on progression of diabetic renal disease in African-American.  Hypertension  1997; 29:773-780.

297. Velussi M, Brocco E, Frigato F, et al: Effects of cilazapril and amlopdipine on kidney function in hypertensive NIDDM.  Diabetes  1996; 45:216-222.

298. Fogari R, Zoppi A, Corradi L, et al: Long term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function.  J Hum Hypertens  1999; 13:47-53.

299. Tarnow L, Rossing P, Jensen C, et al: Long term renoprotective benefit of nisoldipine and lisinopril in type 1 diabetic nephropathy.  Diabetes Care  2000; 23:1725-1730.

300. Kopf D, Schmitiz H, Beyer J, et al: A double-blind study of perindopril and nitrendipine in incipient diabetic nephropathy.  Diabetes Nutr Metab  2001; 14:245-252.

301. Jerums G, Allen TJ, Tsalamandris C, Cooper ME: Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy.  Kidney Int  1992; 41:904-911.

302. Jerums G, Allen TJ, Campbell DJ, et al: Long term comparison between perindopril and nifedipine in normotensive patients with type 1 diabetes and microalbuminuria.  Am J Kidney Dis  2001; 37:890-899.

303. Zucchelli P, Zuccala A, Borghi M, et al: Long term comparison between captopril and nifedipine in the progression of renal insufficiency.  Kidney Int  1992; 42:452-458.

304. Viberti GC, Wheeldon NM: Microalbuminuria reduction with Valsartan (MARVAL) Study investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus.  Circulation  2002; 106:672-678.

305. Bakris GL, Weir MR, deQuattro V, McMahon FG: Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.  Kidney Int  1998; 54:1283-1289.

306. Voyaki SM, Staessen JA, Thijs L, et al: Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.  J Hypertens  2001; 19:511-519.

307. Rekola A, Bergstrand A, Bucht H: Deterioration rate in IgA nephropathy: Comparison of a converting enzyme inhibitor and beta-blocking agents.  Nephron  1991; 59:57-60.

308. Nielsen FS, Rossing P, Gall MA, et al: Long term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.  Diabetes  1997; 46:1182-1188.

309. Elving LD, Wetzels JFM, van Lier HJJ, et al: Captopril and atenolol are equally effective in retarding progression of diabetic nephropathy.  Diabetologia  1994; 37:604-609.

310. UK Prospective Diabetes Study Group : Efficacy of atenolol and enalapril in reducing risk of macrovascular and microvascular complications in type 2 diabetes UKPDS 39.  Br Med J  1998; 317:713-720.

311. Susic D, Frohlich ED: Nephroprotective effect of antihypertensive drugs in essential hypertension.  J Hypertens  1998; 16:555-567.

312. Ono H, Ono Y, Frohlich ED: Hydrochlorothiazide exacerbates nitric oxide blockade nephrosclerosis with glomerular hypertension in spontaneously hypertensive rats.  J Hypertens  1996; 14:823-828.

313. Benstein JA, Feiner HD, Parker M, Dworkin LD: Superiority of salt restriction over diuretics in reducing renal hypertrophy and injury in uninephrectomized SHR.  Am J Physiol  1990; 258:F1675-F1681.

314. Buter H, Hemmelder MH, Navis GJ, et al: Blunting of the antiproteinuric efficicay of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide.  Nephrol Dial Transplant  1998; 13:1682-1685.

315. Ponda MP, Hostetter TH: Aldosterone antagonism in chronic kidney disease.  Clin J Am Soc Nephrol  2006; 1:668-677.

316. Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Stduy Investigators.  N Engl J Med  1999; 341:709-717.

317. Rocha R, Chander PN, Zuckerman A, et al: Role of aldosterone in renal vascular injury instroke-prone hypertensive rats.  Hypertension  1998; 31:451-458.

318. Rachmani R, Slavachevsky I, Amit M, et al: The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: A randomized controlled study.  Diabet Med  2004; 21:471-475.

319. Williams GH, Burgess E, Kolloch RE, et al: Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension.  Am J Cardiol  2004; 93:990-996.

320. White WB, Duprez D, St Hillaire R, et al: Effects of the selective aldosterone blocker eplerenone versus the calcoum antagonist amlodipine in systolic hypertension.  Hypertension  2003; 41:1021-1026.

321. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D: Reduction of proteinuria by angiotensin converting enzyme inhibition.  Kidney Int  1987; 32:78-83.

322. Weidmann P, Schneider M, Böhlen L: Therapeutic efficacy of different antihypertensive drugs in human diabetic nephropathy: An updated meta-analysis.  Nephrol Dial Transplant  1995; 10:39-45.

323. Kasiske BL, Kalil RSN, Ma JZ, et al: Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis.  Ann Int Med  1993; 118:129-138.

324. Gansevoort RT, de Zeeuw D, de Jong PE: Dissociation between the course of the hemodynamic and antiproteinuric effects of Angiotensin-I Converting Enzyme inhibition.  Kidney Int  1993; 44:579-584.

325. Remuzzi A, Pertitucci E, Ruggenenti P, et al: Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy.  Kidney Int  1991; 39:1267-1273.

326. Nankervis A, Nicholls K, Kilmartin G, et al: Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: A 3-year placebo-controlled study.  Metabolism  1998; 47:12-15.

327. Rudberg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive Type I (insulin-dependent) diabetic patients irrespective of its hypotensive effect.  Diabetologia  1990; 33:470-476.

328. de Zeeuw D, Navis GJ: Optimizing the RAAS intervention treatment strategy in diabetic and non-diabetic nephropathy: the potential of exploring the mechanisms of response variability.   In: Mogensen CE, ed. Diabetic Nephropathy in Type 2 Diabetes,  London: Science Press; 2002:103-116.

329. Schulz E, Beck J, Pedersen EB, et al: Tolerability and antihypertensive efficacy of losartan versus captopril in patients with mild to moderate hypertension and impaired renal function: A randomized, double-blind, parallel study.  Clin Drug Invest  2000; 19:183-194.

330. Fernandez-Andrade C, Russo D, Iversen B, et al: Comparison of losartan and amlodipine in renally impaired hypertensive patients.  Kidney Int  1998; 54(Suppl. 68):S120-S124.

331. Caruso D, D'isanto F, Del Piano C, Caruso G: Losartan versus amlodipine in double blind study in hypertensive patients with diabetic nephropathy.  J Human Hypertens  1999; 13:S5-S7.

332. Calvino J, Lens XM, Romero R, Sanchez GD: Long-term anti-proteinuric effect of Losartan in renal transplant recipients treated for hypertension.  Nephrol Dial Transplant  2000; 15:82-86.

333. DelCastillo D, Campistol JM, Guirado L, et al: Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients.  Kidney Int  1998; 54:S135-S139.

334. Hadjigavriel M, Kyriakides G: Efficacy and safety of losartan in renal transplant recipients.  Transplant Proc  1999; 31:3300-3301.

335. Holgado R, Del Castillo D: Angiotensin II type I (AT1) receptor antagonists in the treatment of hypertension after renal transplantation.  Nephrol Dial Transplant  2001; 16:1-4.

336. Mora-Macia J, Cases A, Calero F, Barcelo P: Effect of angiotensin II receptor blockade on renal disease progression in patients with non-diabetic chronic renal failure.  Nephrol Dial Transplant  2001; 16:1-3.

337. Campistol JM, Inigo P, Jimenez W, et al: Losartan decreases plasma levels of TGF-beta 1 in transplant patients with chronic allograft nephropathy.  Kidney Int  1999; 56:714-719.

338. Holdaas H, Hartmann A, Berg KJ, et al: Renal effects of losartan and amlodipine in hypertensive patients with non-diabetic nephropathy.  Nephrol Dial Transplant  1998; 13:3096-3102.

339. Schiller A, Ivan V, Gluhovschi G, et al: Short-term therapy with AII receptor blocker losartan. Cardiac and renal effects in patients with essential hypertension and hypertension of glomerular origin.  Nephrol Dial Transplant  1999; 14:A63.

340. Andersen S, Rossing P, Juhl TR, et al: Optimal dose for losartan in renoprotection in diabetic nephropathy.  Nephrol Dial Transplant  2002; 17:1413-1418.

341. Bos H, Andersen S, Rossing P, et al: The role of patient factors in therapy resistance to antiproteinuric intervention in non-diabetic and diabetic nephropathy.  Kidney Int  2000; 75:S32-S37.

342. van Paassen P, de Zeeuw D, Navis GJ, et al: Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function.  Nephrol Dial Transplant  2000; 15:637-643.

343. Pilz B, Shagdarsuren E, Wellner M, et al: Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats.  Hypertension  2005; 46:569-576.

344. Bakris GL, Barnhill BW, Sadler R: Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection.  Kidney Int  1992; 41:912-919.

345. Slataper R, Vicknair N, Sadler R, Bakris GL: Comparative effects of different antihypertensive treatments on progression of diabetic renal disease.  Arch Int Med  1993; 153:973-980.

346. Mimran A, Insua A, Ribstein J, et al: Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.  J Hypertens  1988; 6:919-923.

347. Demarie BK, Bakris GL: Effect of different calcium antagonists on proteinuria associated with diabetes mellitus.  Ann Int Med  1990; 113:987-988.

348. Melbourne Diabetic Nephropathy Study Group : Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria.  Br Med J  1992; 302:210-216.

349. Hemmelder MH, de Zeeuw D, de Jong PE: Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease.  Nephrol Dial Transplant  1999; 14:98-104.

350. Apperloo AJ, de Zeeuw D, Sluiter HE, de Jong PE: Differential effects of enalapril and atenolol on proteinuria and renal hemodynamics in non-diabetic renal disease.  Br Med J  1991; 303:821-824.

351. Björk S, Mulec H, Johnson SA, et al: Renal protective effect of enalapril in diabetic nephropathy.  Br Med J  1992; 304:339-343.

352. Erley CM, Harrere U, Krämer BK, Risler T: Renal hemodynamics and reduction of proteinuria by a vasodilating beta-blocker versus and ACE inhibitor.  Kidney Int  1992; 41:1297-1303.

353. Flack JR, Molyneaux L, Willey K, Yue DK: Regression of microalbuminuria: Results of a controlled study, indapamide versus captopril.  J Cardiovasc Pharmacol  1993; 22:75-77.

354. Hallab M, Gallois Y, Chatellier G, et al: Comparison of reduction in microalbuminuria by enalapril and hydrochlorothiazide in normotensive patients with insulin dependent diabetes mellitus.  Br Med J  1993; 306:175-182.

355. Stornello M, Valvo EV, Scapatello L: Comparative effects of enalapril, atenolol and chlorthaliidone on blood pressure and kidney function of diabetic patients affected by arterial hypertension and persistent proteinuria.  Nephron  1991; 58:52-57.

356. Chrysostomou A, Pedagogos E, MacGregor L, et al: Double-blind placebo-controlled study on the effect of aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long term angiotensin-converting enzyme inhibitor therapy with or without angiotensin II receptor blocker.  Clin J Am Soc Nephrol  2006; 1:256-262.

357. Sato A, Hayashi K, Naruse M, Saruta T: Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension  2003; 41:64-68.

358. Schjoedt KJ, Rossing K, Juhl TR, et al: Beneficial impact of spironolactone in diabetic nephropathy.  Kidney Int  2005; 68:2829-2836.

359. Schjoedt KJ, Andersen S, Rossing P, et al: Aldosterone escape during blockade of the renin-angiotensin aldosterone system is associated with enhanced decline in glomerular filtration rate.  Diabetologia  2004; 47:1936-1939.

360. Aldigier JC, Kanjanbuch T, Ma L-J, et al: Regression of existing glomerulosclerosis by inhibition of aldosterone.  J Am Soc Nephrol  2005; 16:3306-3314.

361. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D: Efficacy and variability of the antiproteinuric effect of lisinopril.  Kidney Int  1989; 36:272-279.

362. Erley CM, Haefele U, Heyne N, et al: Microalbuminuria in essential hyperten-sion. Reduction by different antihypertensive drugs.  Hypertension  1993; 21:810-815.

363. Neumann J, Ligtenberg G, Oey L, et al: Monoxidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure.  J Am Soc Nephrol  2004; 15:2902-2907.

364. Amann K, Rump LC, Simonaviciene A, et al: Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nehretomized rats.  J Am Soc Nephrol  2000; 11:1469-1478.

365. Strojek K, Grzeszczak W, Gorska J, et al: Lower of micro-albuminuria in diabetic aptients by a sympaticoplegic agent: Novel approach to prevent progression of diabetic nephropathy?.  J Am Soc Nephrol  2001; 12:602-605.

366. Vriesendorp R, Donker AJM, de Zeeuw D: Effects of non-steroidal anti-inflammatory drugs on proteinuria.  Am J Med  1986; 81:84-93.

367. Wang JL, Cheng HF, Shappell S, et al: A selective cyclooxygenase-2 inhibitor decreases proteinuria and retards progressive renal injury in rats.  Kidney Int  2000; 57:2334-2342.

368. Brater DC, Harris C, Redfern JS, et al: Renal effects of COX-2-selective inhibitors.  Am J Nephrol  2001; 21:1-15.

369. National Kidney Foundation: K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease.  Am J Kidney Dis  2003; 41:S1-S92.

370. Mason NA, Bailie GR, Satayathum S, et al: HMG-coenzyme a reductase inhibitor use is associated with mortality reduction in hemodialysis patients.  Am J Kidney Dis  2005; 45:119-126.

371. Seliger SL, Weiss NS, Gillen DL, et al: HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients.  Kidney Int  2002; 61:297-304.

372. Holdaas H, Fellstrom B, Jardine AG, et al: Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial.  Lancet  2003; 361:2024-2031.

373. Holdaas H, Fellstrom B, Cole E, et al: Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: The ALERT extension study.  Am J Transplant  2005; 5:2929-2936.

374. Wanner C, Krane V, Marz W, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med  2005; 353:238-248.

375. Holdaas H, Wanner C, Abletshauser C, et al: The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: A pooled analysis of double-blind, randomized trials.  Int J Cardiol  2007; 117:64-74.

376. Landray M, Baigent C, Leaper C, et al: The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: A randomized controlled study of the biochemic safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD.  Am J Kidney Dis  2006; 47:385-395.

377. Naveenathan SD, Pansini F, Strippoli FM: Statins in patients with chronic kidney disease: evidence form systematic reviews and randomized clinical trials.  PloS Med  2006; 3:615-618.

378. Rabelink A, Erkelens D, Hené R, et al: Effect of simvastatin and cholestyramine on lipoprotein profile in hyperlipidemia of nephrotic syndrome.  Lancet  1988; ii:1335-1337.

379. Massy ZA, Ma JZ, Louis TA, Kasiske BL: Lipid lowering therapy in patients with renal disease.  Kidney Int  1995; 48:188-198.

380. Warwick GL, Packard CJ, Murray L, et al: Effect of simvastatin on plasma lipid and lipoprotein concentration and low-density lipoprtoein metabolism in the nephrotic syndrome.  Cli Sci  1992; 82:701-708.

381. Kostner GM, Gavish D, Leopold B, et al: HMG-CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.  Circulation  1989; 80:1313-1319.

382. Lam KSL, Cheng IKP, Janus ED, et al: Cholesterol lowering therapy may retard the progression of diabetic nephropathy.  Diabetologia  1995; 38:604-609.

383. Hommel E, Andersen P, Gall M, et al: Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy.  Diabetologia  1992; 35:447-451.

384. Shoyi J, Nishizawa Y, Toyokawa A, et al: Decreased albuminuria by pravastatin in hyperlipidemic diabetics.  Nephron  1991; 59:664-665.

385. Verhulst A, D'Haese P, de Broe M: Inhibitors of HMG-CoA reductase reduce receptor mediated endocytosis in human kidney proximal tubular cells.  J Am Soc Nephrol  2004; 15:2249-2257.

386. Agarwal R: Statin induce proteinuria: Renal injury or protection?.  J Am Soc Nephrol  2004; 15:502-2503.

387. Kasiske BL, Wanner C, O'Neill WC: National Lipid Association Statin Safety Task Force Kidney Expert Panel. An assessment of statin safety by nephrologists.  Am J Cardiol  2006; 97:82C-85C.

388. Hoogerbrugge N, Jansen H, de Heide L, et al: The additional effects of acipimox to simvastatin in the tretament of combined hyperlipidemia.  J Int Med  1997; 241:151-155.

389. Vogt L, Laverman GD, Dullaart RPF, Navis GJ: Lipid management in proteinuric patients.  Nephrol Dial Transplant  2004; 19:5-8.

390. Gansevoort RT, Heeg JE, Dikkeschei FD, et al: Symptomatic antiproteinuric treatment decreases serum lipoprotein (a) concentration in patients with glomerular proteinuria.  Nephrol Dial Transplant  1994; 9:244-250.

391. Praga M, Hernandez E, Montoyo C, et al: Long term beneficial effects of angiotensin converting enzyme inhibition in patients with nephrotic syndrome.  Am J Kidney Dis  1992; 20:240-248.

392. Gansevoort RT, de Zeeuw D, de Jong PE: Additive antiproteinuric effect of ACE-inhibition and a low protein diet in human renal disease.  Nephrol Dial Transplant  1995; 10:497-504.

393. Ruggenenti P, Mise N, Pisoni R, et al: Diverse effects of increasing doses on lipid abnormalities in chronic nephropathies.  Circulation  2003; 107:586-592.

394. de Zeeuw D, Gansevoort RT, de Jong PE: Angiotensin II antagonism improves the lipoprotein profile in patients with nephrotic syndrome.  J Hypertens  1995; 13:S53-S58.

395. Heeg JE, de Jong PE, Vriesendorp R, de Zeeuw D: Additive antiproteinuric effect of the NSAID indomethacin and the ACE-inhibitor lisinopril.  Am J Nephrol  1990; 10:S94-S97.

396. Keilani T, Schlueter WA, Levin ML, Batlle DC: Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin converting enzyme inhibitor.  Ann Int Med  1993; 118:246-254.

397. Hebert LA, Bain RP, Verme D, et al: Remission of nephrotic range proteinuria in type I diabetics.  Kidney Int  1994; 46:1688-1693.

398. Nielsen FS, Rossing P, Gall M-A, et al: Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.  Diabetes  1994; 43:1108-1113.

399. Romero R, Salinas I, Lucas A, et al: Renal function changes in microalbuminuric normotensive type II diabetic patients treated with angiotensin converting enzyme inhibitors.  Diabetes Care  1993; 16:597-600.

400. Ravid M, Neumann L, Lishener M: Plasma lipids and the progression of nephropathy in diabetes mellitus type II. Effect of ACE inhibitors.  Kidney Int  1995; 47:907-910.

401. Jacobsen P, Parving HH: Beneficial impact on cardiovascular risk factors by dual blockade of the renin-angiotensin system in diabetic nephropathy.  Kidney Int  2004; 92:S108-S110.

402. Buter H, van Tol A, Navis GJ, et al: Angiotensin II receptor antagonist treatment lowers plasma total and very low plus low density lipoprotein cholesterol in Type 1 diabetic patients with albuminuria without affecting plasma cholesterol esterification and cholesteryl ester transfer.  Diabetic Med  2000; 17:550-552.

403. Grond J, Beukers JYB, Schilthuis MS, et al: Analysis of renal structural and functional features in two rat strains with a different susceptibility to glomerular slcerosis.  Lab Invest  1986; 54:77-83.

404. Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy.  N Engl J Med  1989; 320:1161-1165.

405. Klouda PT, Manos J, Acheson EJ, et al: Strong association between idiopathic membranous glomerulopathy and HLA-DRW3.  Lancet  1979; ii:770-771.

406. Egido J, Julian BA, Wyatt RJ: Genetic factors in primary IgA nephropathy.  Nephrol Dial Transplant  1987; 2:134-142.

407. Glicklich D, Haskell L, Senitzer D, Weis RA: Possible genetic predisposition to idiopathic focal and segmental glomerulosclerosis.  Am J Kidney Dis  1988; 12:26-30.

408. Mitch WE, Buffington G, Lemaan J, Walser M: Progression of renal failure: A simple method of estimation.  Lancet  1976; ii:1326-1331.

409. Pazanias M, Eastwood JB, MacRae KD, Phillips ME: Racial origin and primary renal diagnosis in 771 patients with end stage renal disease.  Nephrol Dial Transplant  1991; 6:931-935.

410. Korstanje R, DiPetrillo K: Unraveling the genetics of chronic kidney disease using animal models.  Am J Physiol Renal Physiol  2004; 287:F347-F352.

411. Brenchley PE, Lindholm B, Dekker FW, Navis GJ: Translating knowledge of the human genome into clinical practice in nephrology dialysis and transplantation: The Renal Genome Network (ReGeNet).  Nephrol Dial Transplant  2006; 21:2775-2779.

412. Rigat B, Hubert C, Alhenc Gelas F, et al: An insertion/deletion polymorphism in the angiotensin converting enzyme gene accounting for half of the variance of serum enzyme levels.  J Clin Invest  1990; 86:1343-1346.

413. Danser JAH, Schalekamp MADH, Bax WA, et al: Angiotensin converting enzyme in the human heart. Effect of the deletion/insertion polymorphism.  Circulation  1995; 92:1387-1388.

414. Mizuiri S, Yoshikawa H, Tanegashima M, et al: Renal ACE immunohistochemic localization in NIDDM patients with nephropathy.  Am J Kidney Dis  1998; 31:301-307.

415. Buikema H, Pinto YM, Rooks G, et al: The deletion polymorphism of the angiotensin converting enzyme gene is related to phenoptypic differences in human arteries.  Eur Heart J  1996; 17:787-794.

416. Ueda S, Elliot HL, Morton JJ, Connel JM: Enhanced pressor response to angiotensin I in normtensive men with the deletion genotype (DD) for angiotensin-converting-enzyme.  Hypertension  1995; 25:1266-1269.

417. van der Kleij FGH, de Jong PE, de Zeeuw D, Navis GJ: Enhanced responses of blood pressure, renal function and aldosterone to angiotensin I in DD genotype are blunted by low sodium intake.  J Am Soc Nephrol  2002; 13:1025-1033.

418. Luik PT, Hoogenberg KH, van der Kleij FGH, et al: The influence of ACE (I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive normoalbuminuric type I diabetes mellitus.  Diabetologia  2003; 46:1131-1139.

419. van Essen GG, Rensma PL, de Zeeuw D, et al: Association between angiotensin-converting enzyme gene polymorphism and failure of renoprotective therapy.  Lancet  1996; 347:94-95.

420. Harden PN, Geddes C, Rowe PA, et al: Polymorphism in angiotensin converting enzyme gene and progression of IgA nephropathy.  Lancet  1995; 345:1540-1542.

421. Yoshida H, Kuriyama S, Atsumi Y, et al: Role of the deletion polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.  J Clin Invest  1995; 96:2162-2169.

422. Parving H-H, Jacobsen P, Tarnow L, et al: Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: Observational follow-up study.  Br Med J  1996; 313:591-594.

423. Yoshida H, Kuriyama S, Atsumi Y, et al: Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus.  Kidney Int  1996; 50:657-664.

424. Baboolal K, Ravine D, Daniels J, et al: Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease.  Kidney Int  1997; 52:607-613.

425. Broekroelofs J, Stegeman CA, Navis GJ, et al: Is donor or recipient ACE genotype associated with long-term graft survival after renal transplantation?.  J Am Soc Nephrol  1998; 9:2075-2081.

426. Fernandez-Llama P, Poch E, Oriola J, et al: Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis.  Kidney Int  1998; 53:1743-1747.

427. Boonstra AH, de Jong PE, de Zeeuw D, Navis GJ: Genetic markers for angII in renal disease.  Semin Nephrol  2001; 21:580-592.

428. Staessen JA, Wang JG, Ginocchio G, et al: The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk.  J Hypertens  1997; 15:1579-1592.

429. Ng DP, Tai BC, Koh D, et al: Angiotensin I converting enzyme insertion/deletion polymorphsims and its assocoation with diabetic nephropathy: A meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects.  Diabetologia  2005; 48:1008-1018.

430. Rook M, Lely AT, Kramer AB, et al: Individual differences in renal ACE activity in healthy rats predict susceptibility to adriamycin-induced renal damage.  Nephrol Dial Transplant  2005; 20:59-64.

431. Veseij ES, Penno MB: Assessment of methods to identify sources of interindividual pharmacokinetic variations.  Clin Pharmacol  1983; 8:378-409.

432. Cusi D, Barlassina C, Azzani T, et al: Polymorphism of alpha-adducin and salt-sensitivity in patients with essential hypertension.  Lancet  1997; 349:1353-1357.

433. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al: The role of a common variant of the cholersteryl ester transfer protein gene in the progression of coroanry atherosclerosis. The Regression Growth Evaluation Statin Study Group.  N Engl J Med  1998; 338:86-93.

434. Marshall A: Laying the foundations of personalized medicine.  Nature Biothechnol  1997; 15:954-957.

435. Andersen S, Tarnow L, Cambien F, et al: Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype.  Kidney Int  2002; 62:192-198.

436. Moriyama T, Kitamara H, Ochi S, et al: Association of angiotensin I converting enzyme gene polymorphism with susceptibility to antiproteinuric effect of angiotensin I converting enzyme inhibitors in patients with proteinuria.  J Am Soc Nephrol  1995; 6:1674-1678.

437. Jacobsen P, Rossing K, Rossing P, et al: Angiotensin-converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy.  Kidney Int  1998; 53:1002-1006.

438. van der Kleij FGH, Navis GJ, Gansevoort RT, et al: ACE genotype does not determine the short term renal response to ACE inhibition in proteinuric patients.  Nephrol Dial Transplant  1997; 12:42-46.

439. Penno G, Chaturvaedi N, Talmud PJ, et al: EUCLID study group. Effect of angiotensin converting enzyme (ACE) gene polymorphism on progression of enal disease and the influence of ACE inhibition in IDDM patients.  Diabetes  1998; 47:1507-1511.

440. Perna A, Ruggenenti P, Testa A: For the GISEN group. ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies.  Kidney Int  2000; 57:274-281.

441. So WY, Ma RCW, Ozaki R, et al: Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients: Interaction with ACE insertion-deletion polymorphism.  Kidney Int  2006; 69:1438-1443.

442. Ruggenenti P, Perna A, Zoccali C, et al: For the GISEN group. Chronic proteinuric nephropathies II. Outcomes and response to treatment in a prospective cohort of 352 patients: Differences between men and women in relation to the ACE gene polymorphism.  J Am Soc Nephrol  2000; 11:88-96.

443. van der Kleij FGH, Schmidt A, Navis GJ, et al: ACE I/D polymorphism and short term response to ACE inhibition: Effect of sodium status.  Kidney Int  1997; 63:S23-S26.

444. Lely AT, Visser F, Kocks MJA, et al: Selective blunting of blood pressure response to ACE inhibition by high sodium in ACE DD genotype in healthy men.  J Am Soc Nephrol  2005; 16:182A.

445. Barlassina C, Schork N, Manunta P, et al: Synergistic effect of apha-adducin and ACE genes in causing blood pressure changes with body sodium and volume expansion.  Kidney Int  2000; 57:1083-1090.

446. Jacobsen PK, Tarnow L, Parving H-H: Time to consier ACE insertion/deletion genotypes and indivdiual renoprotective treatment in diabetic nephropathy?.  Kidney Int  2006; 69:1293-1295.

447. Kambham N, Markowitz GS, Valeri AM, et al: Obesity-related glomerulopathy: An emerging epidemic.  Kidney Int  2001; 59:1498-1509.

448. Bonnet F, Deprele C, Sassolas A, et al: Excessive body weight as a new independent risk factor for clinical and pathologic progression in primary IgA nephritis.  Am J Kidney Dis  2001; 37:720-724.

449. Meier-Kriesche HU, Arndorfer JA, Kaplan B: The impact of body mass index on renal transplant outcomes: A significant independent risk factor for graft failure and patient death.  Transplantation  2002; 15:70-74.

450. Kwakernaak AJ, Tent H, Rook M, et al: Renal hemodynamics in overweight and obesity: pathogenetic factors and targets for intervention.  Expert Rev Endocrinol Metab  2007; 2:539-552.

451. Iseki K, Ikemiya Y, Kinjo K, et al: Body mass index and the risk of development of end-stage renal disease in a screened cohort.  Kidney Int  2004; 65:1870-1876.

452. Ejerblad E, Fored CM, Lindblad P, et al: Obesity and risk for chronic renal failure.  J Am Soc Nephrol  2006; 17:1695-1702.

453. Pinto-Sietsma SJ, Navis GJ, Janssen WM, et al: A central fat distribution is related to renal function impairment, even in lean subjects.  Am J Kidney Dis  2003; 41:733-741.

454. Chen J, Muntner P, Hamm LL, et al: The metabolic syndrome and chronic kidney disease in US adults.  Ann Int Med  2004; 140:167-674.

455. Ribstein J, Du Cailar G, Mimran A: Combined renal effects of overweight and hypertension.  Hypertension  1995; 26:610-615.

456. Bosma RJ, Krikken JA, Homan van der Heide JJ, et al: Obesity and renal hemodynamics.  Contrib Nephrol  2006; 151:184-202.

457. Engeli S, Bohnke J, Gorzelniak K, et al: Weight loss and the renin-angiotensin-aldosterone system.  Hypertension  2005; 45:356-362.

458. Ahmed SB, Fisher ND, Stevanovic R, et al: Body mass index and angiotensin-dependent control of the renal circulation in healthy humans.  Hypertension  2005; 46:1316-1320.

459. Price DA, Lansang MC, Osei SY, et al: Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.  Diabet Med  2002; 19:858-861.

460. Wolf G, Chen S, Cheol Han D, Ziadeh FN: Leptin and renal disease.  Am J Kidney Dis  2002; 39:1-11.

461. Verhave JC, Hillege HL, Burgerhof JG, et al: The PREVEND study group. Sodium intake affects urinary albumin excretion especially in overweight subjects.  J Intern Med  2004; 256:324-330.

462. Krikken JA, Lely AT, Bakker SJL, et al: The effect of a shift in sodium intake on renal hemodynamics is determined by body mass index in healthy young men.  Kidney Int  2007; 71:260-265.

463. Porter L, Hollenberg NK: Obesity, salt intake and renal perfusion in healthy humans.  Hypertension  1998; 32:144-148.

464. Bosma RJ, Homan van der Heide JJ, Oosterop EJ, et al: Body mass index is associated with renal hemodynamics in non-obese healthy subjects.  Kidney Int  2004; 65:259-265.

465. Praga M, Hernandez E, Andres A, et al: Effects of body weight loss and captopril treatment on proteinuria associated with obesity.  Nephron  1995; 70:35-41.

466. Morales E, Valero MA, Leon M, et al: Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies.  Am J Kidney Dis  2003; 41:319-327.

467. Saiki A, Nagayama D, Ohhira M, et al: Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy.  Int J Obes  2005; 29:1115-1120.

468. Chagnac A, Weinstein T, Herman M, et al: The effects of weight loss on renal function in patients with severe obesity.  J Am Soc Nephrol  2003; 14:1480-1486.

469. Orth SR, Ritz E, Schrier RW: The renal risks of smoking.  Kidney Int  1997; 51:1669-1677.

470. Stengel B, Tarver-Carr ME, Powe NR, et al: Lifestyle factors, obesity and the risk for chronic kidney disease.  Epidemiology  2003; 14:479-487.

471. Tozawa M, Iseki K, Iseki C, et al: Influence of smoking and obesity on the development of proteinuria.  Kidney Int  2002; 62:956-962.

472. Kuster S, Mehls O, Seidel C, Ritz E: Blood pressure in minimal change and other types of nephrotic syndrome.  Am J Nephrol  1990; 10:76-80.

473. Hillege HL, van Gilst WH, van Veldhuisen DJ, et al: CATS Randomized Trial. Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: The CATS randomized trial.  Eur Heart J  2003; 24:412-420.

474. Ritz E, Koch M: Morbidity and mortality due to hypertension in patients with renal failure.  Am J Kidney Dis  1993; 21:113-118.

475. Anavekar NS, McMurray JJ, Velazquez EJ, et al: Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.  N Engl J Med  2004; 351:1285-1295.

476. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.  N Engl J Med  2004; 351:1296-1305.

477. Hillege HL, Nitsch D, Pfeffer MA, et al: Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators.  Circulation  2006; 113:671-678.

478. Mui KW, Sleeswijk M, van den Hout H, et al: Incidental renal artery stenosis is an independent predictor of mortality in patients with peripheral vascular disease.  J Am Soc Nephrol  2006; 17:2069-2074.

479. Khan NA, Ma I, Thompson CR, et al: Kidney function and mortality among patients with left ventricular systolic dysfunction.  J Am Soc Nephrol  2006; 17:244-253.

480. Loef BG, Epema AH, Smilde TD, et al: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival.  J Am Soc Nephrol  2005; 16:195-200.

481. Diamond JR: Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis.  Kidney Int  1991; 31:S29-S34.

482. Ordonez JD, Hiatt RA, Killebrew EJ, Fireman BH: The increased risk of coronary heart disease associated with the nephrotic syndrome.  Kidney Int  1993; 44:638-642.

483. Radhakrishan J, Appel AS, Valeri A, Appel GB: The nephrotic syndrome, lipids and risk factors for cardiovascular disease.  Am J Kidney Dis  1993; 22:135-142.

484. Wanner C, Rader D, Bartens W, et al: Elevated plasma lipoprotein (a) in patients with the nephrotic syndrome.  Ann Intern Med  1993; 119:263-269.

485. Stroes ESG, Joles JA, Chang PC, et al: Impaired endothelial function in patients with nephrotic range proteinuria.  Kidney Int  1995; 48:544-550.

486. Hernandez E, Toledo T, Alamo C, et al: Elevation of von Willebrand factor levels in patients with IgA nephropathy: Effect of ACE inhibition.  Am J Kidney Dis  1997; 30:397-403.

487. Vuong TD, de Kimpe S, de Roos R, et al: Albumin restores lysophosphatidylcholine induced inhibition of vasodilation in rat aorta.  Kidney Int  2001; 60:1088-1096.

488. Yudkin JS, Forrest RD, Jackson CA: Microalbuminuria as predictor of vascular disease in non-diabetic subjects.  Lancet  1988; ii:530-533.

489. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, et al: Albuminuria reflects widespread vascular damage.  Diabetologia  1989; 32:219-226.

490. Bigazzi R, Bianchi S, Baldari D, et al: Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors.  Hypertension  1994; 23:195-199.

491. Bianchi S, Bigazzi R, Valtriani C, et al: Elevated serum insulin levels in patients with essential hypertension and microalbuminuria.  Hypertension  1994; 23:681-687.

492. Verhave JC, Hillege HL, Burgerhof JG, et al: The PREVEND Study Group. The association between atherosclerotic risk factors and renal function in the general population.  Kidney Int  2005; 67:1967-1973.

493. Marre M, Lievre M, Chatellier G, et al: DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: Randomised, double blind, placebo controlled trial (the DIABHYCAR study).  Br Med J  2004; 328:495.

494. de Zeeuw D, Remuzzi G, Parving HH, et al: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy.  Circulation  2004; 110:921-927.

495. Ibsen H, Olsen MH, Wachtell K, et al: Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: Losartan intervention for endpoint reduction in hypertension study.  Hypertension  2005; 45:198-202.

496. De Nicola L, Minutolo R, Chiodini P, et al: TArget Blood Pressure LEvels in Chronic Kidney Disease (TABLE in CKD) Study Group. Global approach to cardiovascular risk in chronic kidney disease: reality and opportunities for intervention.  Kidney Int  2006; 69:538-545.

497. Palmer AJ, Annemans L, Roze S, et al: Cost-effectiveness of early irbesartan treatment versus control (standard antihypertensive medications excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease.  Diabetes Care  2004; 27:1897-1903.

498. Coresh J, Byrd-Holt D, Astor BC, et al: Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000.  J Am Soc Nephrol  2005; 16:180-188.

499. Parving H-H: The use of antihypertensive agents in prevention and treatment of diabetic nephropathy.  Curr Opin Nephrol Hypertension  1994; 3:292-300.

500. Kawazu S, Tomomo S, Shimizu M, et al: The relationship between early diabetic nephropathy and control of plasma glucose in non-insulin dependent diabetes mellitus. The effect of glycemic control on the development and progression of diabetic nephropathy in an 8-year follow-up.  J Diabetes Complications  1994; 8:13-17.

501. Euclid Study Group : Randomized placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria.  Lancet  1997; 349:1787-1792.

502. Wang PH: When should ACE inhibitors be given to normotensive patients with IDDM.  Lancet  1997; 349:1782-1783.

503. American Diabetes Association : Diabetic nephropathy. Position Statement.  Diabetes Care  1997; 20:S24-S27.

504. Bennett PH, Haffner S, Kasiske BL, et al: Screening and management of microalbuminuria in patients with diabetes mellitus: Recommendations of the scientific advisory board of the National Kidney Foundation from an ad hoc committee of the council on diabetes mellitus of the National Kidney Foundation.  Am J Kidney Dis  1995; 25:107-112.

505. Mogensen CE: Management of early nephropathy in diabetic patients: With emphasis on microalbuminuria.  Annu Rev Med  1995; 46:79-94.

506. Parving HH, Jacobsen P, Rossing K, et al: Benefits of long-term antihypertensive treatment on prognosis in diabetic nephropathy.  Kidney Int  1996; 49:1778-1782.

507. Hansson L, Zanchetti A, Carruthers SG, et al: Effects of internsive blood pressure lowering and low-dose aspirin in patients with hypertension. Results of the Hypertension Optimal Treatment (HOT) randomised trial.  Lancet  1998; 351:1755-1763.

508. Susic D, Frohlich ED: Nephroprotective effect of antihypertensive drugs in essential hypertension.  J Hypertens  1998; 16:555-567.

509. Atthobari J, Asselbergs FW, Boersma C, et al: PREVEND IT Study Group. Cost-effectiveness of screening for albuminuria with subsequent fosinopril treatment to prevent cardiovascular events: A pharmacoeconomic analysis linked to the prevention of renal and vascular endstage disease (PREVEND) study and the prevention of renal and vascular endstage disease intervention trial (PREVEND IT).  Clin Ther  2006; 28:432-444.

510. Lazarus JM, Bourgoignie JJ, Buckalew VM, et al: The MDRD Study Group. Achievement and safety of a low blood pressure goal in chronic renal disease.  Hypertension  1997; 29:641-650.

511. Pedrini MT, Levey AS, Lau J, et al: The effect of dietary protein restriction on the progression of diabetic and non-diabetic renal diseases: A meta-analysis.  Ann Int Med  1996; 124:627-632.

512. Levey AS, Adler S, Caggiula AW, et al: The MDRD Study Group. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study.  Am J Kidney Dis  1996; 27:652-663.

513. Walser MM, Drew HH, LaFrance LD: Creatinine measurements often yield false estimates in chronic renal failure.  Kidney Int  1988; 34:412-418.

514. MDRD Study Group : Effects of diet and antihypertensive therapy on creatinine clearance and serum creatinine concentration in the Modification of Diet in Renal Disease Study.  J Am Soc Nephrol  1996; 4:556-565.

515. Levey AS, Green T, Schluchter MD, et al: Glomerular filtration rate in clinical trials.  J Am Soc Nephrol  1993; 4:1159-1171.

516. Apperloo AJ, de Zeeuw D, de Jong PE: Precision of GFR determinations for long term slope calculations is improved by simultaneous infusion of 125I-iothalamate and 131I-Hippuran.  J Am Soc Nephrol  1996; 7:567-572.

517. Mathiesen ER, Feldt-Rasmussen B, Hommel E, et al: Stable glomerular filtration rate in normotensive IDDM patients with stable microalbuminuria.  Diabetes Care  1997; 20:286-289.

518. Hamming I, Navis G, Kocks MJA, et al: ACE inhibition has adverse renal effects during dietary sodium restriction in proteinuric and healthy rats.  J Pathol  2006; 209:129-139.

519. Koomans HA, Roos JC, Boer P, et al: Salt sensitivity of blood pressure in chronic renal failure. Evidence for renal control of body fluid volume distribution.  Hypertension  1982; 4:190-192.

520. Strojek K, Grzeszczak W, Lacha B, et al: Increased prevalence of salt sensititivy of blood pressure in IDDM with and without microalbuminuria.  Diabetologia  1995; 38:1443-1448.

521. Dworkin LD, Benstein JA, Tolbert E, Feiner HD: Salt restriction inhibits renal growth and stabilizes renal injury in rats with established renal disease.  J Am Soc Nephrol  1996; 7:437-442.

522. Allen TJ, Waldron MJ, Casley D, et al: Salt restriction reduces hyperfiltration, renal enlargement and albuminuria in experimental diabetes.  Diabetes  1997; 46:19-24.

523. Weir MR, Dengel DR, Behrens MT, Goldberg AP: Salt induced increases in systolic pressure affect renal hemodynamics.  Hypertension  1995; 25:1339-1344.

524. van Paassen P, de Zeeuw D, Navis GJ, de Jong PE: Does the renin-angiotensin system determine the renal and systemic hemodynamic response to sodium in patients with essential hypertension?.  Hypertension  1996; 27:202-205.

525. Navis GJ, Jong PE, de Donker AJM, et al: Moderate sodium restriction in hypertensive subjects: Renal effects of ACE-inhibition.  Kidney Int  1987; 31:815-819.

526. Burnier M, Rutschman B, Nussberger J, et al: Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.  Hypertension  1993; 22:339-347.

527. Esnault VLM, Ekhlas AMR, Delcroix C, et al: Diuretic and enhanced sodium restriction results in improved antiproteinuric response to RAS blocking agents.  J Am Soc Nephrol  2005; 16:474-481.

528. Denolle T, Luo P, Guyene TT, et al: Acute effects of a pseudo-tetrapeptideas renin-inhibitor on blood pressure and renin-angiotensin system of sodium repleted and sodium depleted patients.  Arzneimittelforschung  1993; 43:255-259.

529. Philipp T, Letzel H, Arens HJ: Dose-finding study of candesartan cilexetil plus hydrochlorothiazide in patients with mild to moderate hypertension.  J Hum Hypertens  1997; 11:S67-S68.

530. Jerums G, Allen TJ, Tsalamandris C, Cooper ME: Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy.  Kidney Int  1992; 41:904-911.

531. Vogt L, Kocks MJA, Laverman GD, Navis GJ: Renoprotection by blockade of the renin-angiotensin-aldosterone system in diabetic and non-diabetic kidney disease.  Minerva Medica  2004; 95:395-409.

532. Kocks MJA, Gschwend S, Buikema H, et al: High dietary sodium blunts effects of ACE inhibition on vascular angiotensin I to angiotensin II conversion in rats.  J Cardiovasc Pharmacol  2003; 42:601-606.

533. Morgan T, Anderson A, Wilson D, et al: Paradoxic effect of sodium restriction on blood pressure in people on slow-channel calcium blocking drugs.  Lancet  1986; i:793.

534. Weinberger MH: The relationship of sodium balance and concomitant diuretic therapy to blood pressure response with calcium channel entry blockers.  Am J Med  1991; 90:15S-20S.

535. Weir MR: The influence of dietary salt on the antiproteinuric effect of calcium channel blockers.  Am J Kidney Dis  1997; 29:800-805.

536. Ruilope LM, Casal MC, Praga M, et al: Additive antiproteinuric effect of converting enzyme inhibition and a low protein intake.  J Am Soc Nephrol  1992; 3:1307-1311.

537. Rudberg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive type 1 (insulin-dependent) diabetic patients irrespective of its hypotensive effect.  Diabetologia  1990; 33:470-476.

538. Palla R, Panichi V, Finato V, et al: Effect of increasing doese of lisinopril on proteinuria of normotensive patients with IgA nephropathy and normal renal function.  Int J Clin Pharmacol Res  1994; 14:35-43.

539. Laverman GD, Navis GJ, Henning RH, et al: Dual renin-angiotensin system blockade at optimal doses for proteinuria.  Kidney Int  2002; 62:1020-1025.

540. Ruggenenti P, Mise N, Pisoni R, et al: Diverse effects of increasing doses on lipid abnormalities in chronic nephropathies.  Circulation  2003; 107:586-592.

541. Schmieder RE, Klingbeil AU, Fleischmann EH, et al: Additional antiproteinuric effect of ultrahigh dose candesartan: A double-blind, randomized, prospective study.  J Am Soc Nephrol  2005; 16:3038-3045.

542. Aranda P, Segura J, Ruilope LM, et al: Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies.  Am J Kidney Dis  2005; 46:1074-1079.

543. Rossing K, Schjoedt KJ, Jensen BR, et al: Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.  Kidney Int  2005; 68:1190-1198.

544. Weinberg MS, Weinberg AJ, Cord R, Zappe DH: The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein secretion.  J Renin Angiotensin Aldosterone Syst  2001; 2:S196-S198.

545. Rossing K, Christensen PK, Hansen BV, et al: Optimal dose of candesartan for renoprotection in type2 diabetic patients with nephropahty: A double-blind randomized cross-over study.  Diabetes Care  2003; 26:150-155.

546. Laverman GD, Andersen S, Rossing P, et al: Renoprotection with and without blood pressure reduction.  Kidney Int  2005; 94:S54-S59.

547. Hoorntje SJ, Kallenberg CG, Weening JJ, et al: Immune-complex glomerulopathy in patients treated with captopril.  Lancet  1980; 1:1212-1215.

548. Vogt L, Navis G, de Zeeuw D: Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: a feasible strategy?.  J Am Soc Nephrol  2005; 16:S53-S57.

549. Perico N, Remuzzi A, Sangalli F, et al: The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.  J Am Soc Nephrol  1998; 9:2308-2317.

550. Navis GJ, Faber HJ, de Zeeuw D, de Jong PE: ACE-inhibitors and the kidney: A risk-benefit assessment.  Drug Safety  1996; 15:200-211.

551. Bakris GL, Griffin KA, Picken MM, Bidani AK: Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury.  J Hypertension  1997; 15:1181-1185.

552. Azizi M, Chatelier G, Guyene TT, et al: Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives.  Circulation  1995; 92:825-834.

553. Richer C, Bruneval P, Menard J, Giudicelli JF: Additive effects of enalapril and losartan in (mRen-2) 27 transgenic rats.  Hypertension  1998; 31:692-698.

554. Jacobsen P, Andersen S, Jensen BR, et al: Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.  J Am Soc Nephrol  2003; 14:992-999.

555. Fossa AA, Weinberg LJ, Barber RL, et al: Synergistic effect on reduction in blood pressure with co-administration of the renin-inhibitor CP 80,794, and the angiotensin converting enzyme inhibitor captopril.  J Cardiovascular Pharmacol  1992; 20:75-82.

556. Mogensen CE, Neldam S, Tikkanen I, et al: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study.  Br Med J  2000; 321:1440-1444.

557. Russo D, Pisani A, Balletta MM, et al: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy.  Am J Kidney Dis  1999; 33:851-856.

558. Russo D, Minutolo R, Pisana A, et al: Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.  Am J Kidney Dis  2001; 38:18-25.

559. Nakao N, Seno H, Kasuga H, et al: Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.  Am J Nephrol  2004; 24:543-548.

560. Agarwal R: Add-on angiotensin receptor blockade with maximized ACE-inhibition.  Kidney Int  2001; 59:2282-2289.

561. Mogensen CE, Neldam S, Tikkanen I, et al: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: The candesartan and lisinopril microalbuminuria (CALM) study.  Br Med J  2000; 9:1440-1444.

562. Rutkowski P, Tylicki L, Renke M, et al: Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.  Am J Kidney Dis  2004; 43:260-268.

563. Jacobsen P, Andersen S, Rossing K, et al: Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.  Kidney Int  2003; 63:1874-1880.

564. Bos H, Henning RH, de Jong PE, et al: Addition of AT1 receptor blockade fails to overcome resistance to ACE inhibition in adriamycin nephrosis.  Kidney Int  2002; 61:473-480.

565. Remuzzi G, Zoja C, Gagliardini E, et al: Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals.  J Am Soc Nephrol  1999; 10:1542-1549.

566. Buter H, Navis GJ, Dullaart RPF, et al: Time course of the antiproteinuric and renal haemodynamic responses to losartan in micro-albuminuric IDDM.  Nephrol Dial Transplant  2001; 16:771-775.

567. Buter H, Hemmelder M, van Paassen P, et al: Is the reduction of proteinuria by RAAS blockade less effective during the night?.  Nephrol Dial Transplant  1997; 12:53-56.

568. Dickerson JEC, Hingorani AD, Ashby MJ, et al: Optimisation of antihypertensive treatment by crossover rotation of four major classes.  Lancet  1999; 353:2008-2013.

569. Navis G, de Jong P, Donker AJ, et al: Diuretic effects of angiotensin-converting enzyme inhibition: comparison of low and liberal sodium diet in hypertensive patients.  J Cardiovasc Pharmacol  1987; 9:743-748.

570. Navis GJ, de Jong PE, Donker AJM, et al: Moderate sodium restriction in hypertensive subjects: Renal effects of ACE-inhibition.  Kidney Int  1987; 31:815-819.

571. Lansang MC, Price DA, Laffel LM, et al: Renal vascular responses to captopril and to candesartan in patients with type 1 diabetes mellitus.  Kidney Int  2001; 59:1432-1438.

572. Laverman GD, de Zeeuw D, Navis GJ: Between-patient differences in response to renoprotective intervention: The clue towards improvement of renoprotection? Editorial review.  J Renin Angiotensin Aldosterone Syst  2002; 2:205-213.

573. Kramer AB, Bos H, van Goor H, et al: Sodium intake modifies the negative prognostic value of renal damage prior to treatment with ACE-inhibitors on proteinuria induced by adriamycin.  Nephron Physiol  2006; 103:43-52.

574. de Jong PE, Brenner BM: From secondary to primary prevention of progressive renal disease: The case for screening for albuminuria.  Kidney Int  2004; 66:2109-2118.

575. Weir MR, Saunders E: Differing mechanisms of action of angiotensin converting enzyme inhibition in black and white hypertensive patients.  Hypertension  1995; 26:124-130.

576. Hollenberg NK, Anzalone DA, Falkner B, et al: Familial factors in the antihypertensive response to lisinopril.  Am J Hypertens  2000; 14:218-223.

577. de Zeeuw D, Ramjit D, Zhang Z, et al: Renal risk and renoprotection among ethnic groups with type 2 diabetic nephropathy: A post hoc analysis of RENAAL.  Kidney Int  2006; 69:1675-1682.

578. Schjoedt KJ, Jacobsen P, Rossing K: Dual blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy: The role of aldosterone.  Horm Metab Res  2005; 37:4-8.

579. Iseki K, Ikemiya Y, Iseki C, et al: Haematocrit and the risk of developing end-stage renal disease.  Nephrol Dial Transplant  2003; 18:899-905.

580. Keane WF, Brenner BM, de Zeeuw D, et al: RENAAL Study Investigators. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL study.  Kidney Int  2003; 63:1499-1507.

581. Mix TC, Brenner RM, Cooper ME, et al: Rationale-Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): Evolving the management of cardiovascular risk in patients with chronic kidney disease.  Am Heart J  2005; 149:408-413.

582. Agarwal R, Acharya M, Tian J, et al: Antiproteinuric effect of oral paricalcitol in chronic kidney disease.  Kidney Int  2005; 68:2823-2828.

583. Gambaro G, Kinalska I, Oksa A, et al: Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: The Di.N.A.S. randomized trial.  J Am Soc Nephrol  2002; 13:1615-1625.