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

CHAPTER 25. Adaptation to Nephron Loss

Maarten W. Taal   Barry M. Brenner



Structural and Functional Adaptation of the Kidney to Nephron Loss, 783



Alterations in Glomerular Physiology, 783



Mediators of the Glomerular Hemodynamic Responses to Nephron Loss, 784



Renal Hypertrophic Responses to Nephron Loss, 786



Mechanisms of Renal Hypertrophy, 788



Adaptation of Specific Tubule Functions in Response to Nephron Loss, 790



Adaptation in Proximal Tubule Solute Handling, 790



Loop of Henle and Distal Nephron, 790



Glomerulotubular Balance, 791



Sodium Excretion and Extracellular Fluid Volume Regulation, 791



Urinary Concentration and Dilution, 792



Potassium Excretion, 792



Acid-Base Regulation, 793



Calcium and Phosphate, 793



Long-Term Adverse Consequences of Adaptations to Nephron Loss, 794



Hemodynamic Factors, 794



Mechanisms of Hemodynamically Induced Injury, 795



Non-hemodynamic Factors in the Development of Nephron Injury Following Extensive Renal Mass Ablation, 797



Insights from Modifiers of Chronic Kidney Disease Progression, 802



Pharmacological Inhibition of the Renin-Angiotensin System, 802



Arterial Hypertension, 802



Dietary Protein Intake, 803



Gender, 804



Nephron Endowment, 805



Ethnicity, 805



Obesity and Metabolic Syndrome, 806



Sympathetic Nervous System, 806



Dyslipidemia, 807



Calcium and Phosphate Metabolism, 809



Anemia, 809



Tobacco Smoking, 810



Future Directions, 810

The introduction of a classification system for chronic kidney disease (CKD) by the Kidney Disease Outcomes Quality Initiative (K/DOQI) and its adoption worldwide have made a valuable contribution to raising awareness of the problem of CKD.[1] Importantly the division of the spectrum of CKD into stages has emphasized the progressive nature of CKD and facilitated the development of stage-specific strategies for slowing the progression of CKD as well as managing the complications of chronic renal failure. These developments highlight the importance of understanding the mechanisms that contribute to CKD progression in order to inform strategies for slowing such progression. Central to these mechanisms are the adaptations observed in the kidney when nephrons are lost.

The kidney's primary function of maintaining constancy of the extracellular fluid volume and composition is remarkably well preserved until late in the course of CKD. When nephrons are lost through disease or surgical ablation, those remaining or least affected undergo remarkable physiological responses resulting in hypertrophy and hyperfunction that combine to compensate for the acquired loss of renal function. Effective kidney function requires close integration of glomerular and tubular functions. Indeed, the preservation of glomerulotubular balance seen until the terminal stages of CKD is fundamental to the intact nephron hypothesis of Bricker, which essentially states that as CKD advances, kidney function is supported by a diminishing pool of functioning (or hyperfunctioning) nephrons, rather than relatively constant numbers of nephrons, each with diminishing function. This concept has important implications for the mechanisms of disease progression in CKD.

Several decades ago, clinical studies of patients with CKD established that once glomerular filtration rate (GFR) fell below a critical level, a relentless progression to end-stage renal failure inevitably ensued, even when the initial disease activity had abated. The rate of decline of GFR in a given individual followed a near constant linear relationship with time, enabling remarkably accurate predictions of the date at which end-stage renal failure would be reached and renal replacement therapy required. Among patients with diverse renal diseases, the slope of the GFR/time relationship was found to be a characteristic of individual patients rather than typical of their specific renal diseases. This observation suggested that the progressive nature of renal disease could be attributed to a final “common pathway” of mechanisms, independent of the primary cause of nephropathy.[2] Within this framework, Brenner and colleagues formulated a unifying hypothesis for renal disease progression based on the physiological adaptations observed in experimental models of CKD.[3] The central tenets of the common pathway theory state that CKD progression occurs, in general, through focal nephron loss and that the adaptive responses of surviving nephrons, although initially serving to increase single-nephron GFR and offset the overall loss in clearance, ultimately prove detrimental to the kidney. Over time, glomerulosclerosis and tubular atrophy further reduce nephron number, fueling a self-perpetuating cycle of nephron destruction culminating in uremia.

In this chapter we describe in detail the functional and structural adaptations observed in remaining nephrons following substantial reductions in functioning renal mass and the mechanisms thought to be responsible for them. We then consider how these changes may in time prove maladaptive and contribute to the progressive renal injury described above. Given the growing worldwide burden of CKD that causes substantial morbidity and mortality in individuals and threatens to overburden health care systems, it could be argued that the further elucidation of the mechanisms of CKD progression resulting in more effective interventions to slow its advance should remain among the highest priorities for nephrologists today.


Alterations in Glomerular Physiology

Glomerular hemodynamic responses to nephron loss have been studied largely in animals subjected to surgical ablation of renal mass. It was recognized several decades ago that unilateral nephrectomy in rats resulted in a rapid increase in function of the remaining kidney, detectable 3 days after nephrectomy, such that the GFR achieved a maximum of 70% to 85% of the previous 2-kidney value after 2 to 3 weeks. As no new nephrons are formed in mature rodents, the observed rise in GFR represents an increase in the filtration rate of remaining nephrons.

Detailed study of glomerular hemodynamics was facilitated by the identification of a rat strain, Munich-Wistar, which is unique in bearing glomeruli on the kidney surface. This allowed micropuncture of the glomerulus and direct measurement of intraglomerular pressures as well as sampling of blood from afferent and efferent arterioles. These techniques made possible the study of mechanisms underlying the compensatory rise in GFR after renal mass ablation. Increases in whole kidney GFR at 2 to 4 weeks after unilateral nephrectomy were attributable to an increase in single nephron GFR (SNGFR) averaging 83%, achieved in large part by a rise in glomerular plasma flow rate (QA), which in turn, resulted from dilation of both afferent and efferent arterioles. Although systemic blood pressure was not elevated, glomerular capillary hydraulic pressure (PGC) and the glomerular transcapillary pressure difference (DP) were increased significantly post uninephrectomy, accounting for an estimated 25% of the rise in SNGFR.[4] The glomerular ultrafiltration coefficient, Kf (the product of glomerular hydraulic permeability and surface area available for filtration), was unaltered at this stage but may become elevated later.[5]

With more extensive nephron loss, even greater compensatory increases in SNGFR were observed. In Munich-Wistar rats studied 7 days after unilateral nephrectomy and infarction of 5/6 of the contralateral kidney, SNGFR in the remnant was more than double that of 2-kidney controls. This increment was again attributable to large increases in QA, and a substantial rise in PGC. Efferent and afferent arteriolar resistances were reduced to half or less of control values but the decrease in afferent arteriolar resistance was proportionately greater, accounting for the observed rise in PGC.[6] Comparison of renal infarction versus surgical excision models of 5/6 nephrectomy subsequently found that changes in arteriolar resistance were similar but that PGC was significantly more elevated in the infarction model, indicating that glomerular transmission of elevated systemic blood pressure (absent in the surgical excision model) also contributes to the increase in PGC.[7] Changes in Kf after extensive renal mass ablation appear to be time-dependent, with a decrease reported at 2 weeks after surgery,[8] and an increase at 4 weeks.[9] Further studies indicated that glomerular hemodynamic responses to nephron loss seem to be similar between the superficial cortical and juxtamedullary nephrons.[10] The rise in SNGFR associated with renal mass ablation is often referred to as glomerular hyperfiltration and the elevated PGC is termed glomerular hypertension. Together these terms encompass the central concepts underlying the hemodynamic adaptations in the remnant kidney.

Glomerular hemodynamic adaptations to nephron loss may show interspecies variation. In dogs, increases in SNGFR observed 4 weeks after 3/4 or 7/8 nephrectomy were attributable largely to increases in QA and Kf. In contrast to the findings in rodents, DP was only modestly elevated. After ablation of 7/8 of their renal mass, dogs developed a significant rise in PGC independent of arterial pressure, again as a result of relatively greater relaxation of afferent versus efferent arterioles.[11]

In humans, the effects of nephron loss on the physiology of the remnant kidney have been studied mainly in healthy individuals undergoing donor nephrectomy for kidney transplantation. Inulin clearance studies of the earliest kidney donors revealed that total GFR in the donor's remaining kidney had increased to 65% to 70% of the previous 2-kidney value by 1 week post nephrectomy. A meta-analysis of data from 48 studies that included 2988 living kidney donors, estimated that GFR decreased, on average, by only 17 ml/min after uninephrectomy.[12] These observations imply that single kidney GFR (and therefore also the average SNGFR) increases by 30% to 40% after uninephrectomy in humans. There is currently no method for estimating SNGFR or PGC in vivo and more detailed assessments of glomerular hemodynamics in humans have thus not yet been possible.

Mediators of the Glomerular Hemodynamic Responses to Nephron Loss

The factors that are sensed after renal mass ablation and serve as signals to initiate the adjustments in glomerular hemodynamics responsible for the increase in remnant kidney GFR remain to be identified. However, the effector mechanisms have been studied extensively and the hemodynamic changes can be attributed to the net effects of complex interactions of several factors, each having specific, and sometimes opposing actions on the various determinants of glomerular ultrafiltration. Several vasoactive substances, including angiotensin II (AII), aldosterone, natriuretic peptides (NP), endothelins (ET) eicosanoids and bradykinin, have been implicated. Moreover, sustained increases in SNGFR also require resetting of the autoregulatory mechanisms that normally govern GFR and renal plasma flow (RPF).

Renin-Angiotensin-Aldosterone System

Angiotensin II appears to play a critical role in the development of glomerular capillary hypertension following renal ablation and may also contribute to changes in Kf. Acute infusion of AII in normal rats results in a rise in PGC, due to a greater increase in efferent than afferent resistance, and reductions in QA and Kf. [13] [14] Chronic administration of AII for 8 weeks resulted in systemic hypertension, lowered single kidney GFR and, with the exception of Kf, elicited similar glomerular hemodynamic changes to those observed after acute infusion in both normal and uninephrectomized rats.[5] The importance of the influence of endogenous AII on glomerular hemodynamics in remnant kidneys was revealed by studies with pharmacological inhibitors of the renin-angiotensin system (RAS). Chronic treatment of 5/6 nephrectomized rats with either an angiotensin-converting enzyme inhibitor (ACEI) [15] [16] or angiotensin II (subtype 1) receptor antagonist (AT1RA) [17] [18] results in normalization of PGC through reduction in systemic blood pressure and dilatation of both afferent and efferent arterioles. SNGFR, however, remains elevated due to an increase in Kf. Furthermore, acute infusion of an ACEI or saralasin, a peptide analogue receptor antagonist of AII, was found to normalize PGC in 5/6 nephrectomized rats through efferent arteriolar dilatation, without affecting mean arterial pressure (MAP). [8] [19] It is unclear why these findings could not be confirmed with the AT1RA, losartan.[20]

These effects of RAS inhibition imply that there is increased local activity of endogenous AII, yet plasma renin levels show only a transient increase following 5/6 nephrectomy. [7] [21] This suggests differential regulation of the systemic versus intrarenal RAS and that AII is formed locally. Renin mRNA and protein levels are both increased in glomeruli adjacent to the infarction scar in 5/6 nephrectomized rats. [22] [23] [24] Furthermore renal renin mRNA levels are increased at day 3 and 7 after renal mass ablation by infarction but not when renal mass is excised surgically, suggesting that renal infarction activates the RAS by creating a margin of ischemic tissue around the organizing infarct and explaining the greater severity of hypertension as well as glomerulosclerosis associated with the infarction model.[7] Detailed studies of intrarenal AII levels following 5/6 nephrectomy achieved by infarction have confirmed these findings by showing higher AII levels in the peri-infarct portion of the kidney than the intact portion at all time points.[21] On the other hand, the studies also showed that the rise in intrarenal AII following 5/6 nephrectomy was transient. Whereas AII levels in the peri-infarct portion were elevated compared to sham-operated controls at 2 weeks after surgery, they were not statistically different at 5 or 7 weeks. In the intact portion of the remnant kidney, AII levels were similar to controls at 2 and 5 weeks and were lower at 7 weeks.[21] Sustained increases in intrarenal AII levels are therefore not required to maintain the hypertension and progressive renal injury characteristic of this model. Nevertheless, subsequent studies have shown that the renoprotective effects of ACEI and AT1RA treatment are associated with a reduction in intrarenal AII levels in both the peri-infarct and intact portions of the remnant kidney.[25] In contrast, treatment with the dihydropyridine calcium antagonist, nifedipine, did not reduce proteinuria despite lowering blood pressure to the same levels as the RAS antagonists, and was associated with an increase in intrarenal AII.[25] Thus intrarenal AII appears to play a central role in the pathogenesis of hypertension and renal injury in this model even in the absence of sustained increases in AII levels. Further research is required to fully explain these findings. It could be argued that apparently normal intrarenal AII levels are inappropriately high in the context of the hypertension and extracellular fluid (ECF) volume expansion in these animals or that the average intrarenal AII-levels measured may have failed to detect important local elevations of AII.

Recently attention has focused on the potential role of aldosterone in progressive renal injury. In addition to evidence that aldosterone may exert profibrotic effects in the kidney (see later), recent observations suggest that it may also have important glomerular hemodynamic effects. Previous observations that the deoxycorticosterone-salt model of hypertension is associated with glomerular capillary hypertension prompted detailed studies of microperfused rabbit afferent and efferent arterioles that found dose-dependent constriction of both arterioles in response to nanomolar concentrations of aldosterone, with greater sensitivity observed in efferent arterioles.[26] These effects were not inhibited by spironolactone and were still present with albumin-bound aldosterone, indicating that they may be mediated by specific membrane receptors rather than the intracellular receptors responsible for most of the actions of aldosterone. Interestingly aldosterone may also counteract rabbit afferent arteriolar vasoconstriction via an NO-dependent pathway, an action that would also increase PGC. [27] [28]


Endothelins are potent vasoconstrictor peptides that act via at least two receptor subtypes, ETA and ETB. ET receptors have been identified throughout the body and are most abundant in the lungs and kidneys. ETA receptors are primarily located on vascular smooth muscle cells and mediate vasoconstriction as well as cellular proliferation. ETB receptors are expressed on vascular endothelial and renal epithelial cells and appear to play a role as clearance receptors as well as mediating endothelium-dependent vasodilation via NO. [29] [30] [31] Renal production of endothelins is increased after 5/6 nephrectomy, raising the possibility that they may also contribute to the observed glomerular hemodynamic adaptations. [32] [33] Acute and chronic infusion of endothelin elicits dose-dependent reductions in RPF and GFR in normal rats. [34] [35] [36] [37] Despite some differences that were likely due to differences in experimental conditions and endothelin dose, most studies have reported greater increases in efferent than afferent arteriolar resistance resulting in an increase in PGC. The ultrafiltration coefficient (Kf) was significantly reduced and thus SNGFR was unchanged or was decreased. [38] [39] [40] [41] On the other hand, blockade of endogenous endothelin actions in normal rats results in a large fall in PGC due mainly to a rise in afferent arteriolar resistance indicating that endogenous endothelin causes tonic dilation of the afferent arteriole via ETB receptors in normal rats.[42] The potential interaction between endothelins and other vasoactive molecules is illustrated by observations that chronic infusion of AII results in increased production of endothelin[43] and that endothelin-1 transgenic mice are not hypertensive but evidence induction of inducible nitric oxide synthase (iNOS) resulting in increased NO production as a probable counter-regulatory mechanism to maintain normal blood pressure.[44] Furthermore some of the glomerular hemodynamic effects of endothelin appear to be modulated by prostaglandins.[41] Detailed micropuncture studies to elucidate the role of endothelins in remnant kidney hemodynamics have not yet been published. These studies should be facilitated by the ongoing development of specific ETA and ETB receptor antagonists.

Natriuretic Peptides

Atrial natriuretic peptide (ANP) and other structurally related natriuretic peptides (NP), mediate, in large part, the functional adaptations in tubular sodium reabsorption that maintain sodium excretion in 5/6 nephrectomized rats[45]but also exert important hemodynamic effects. Circulating ANP levels are elevated in 5/6 nephrectomized rats and acute administration of a NP antagonist elicited profound decreases in GFR and RPF in 5/6 nephrectomized rats on high salt (but not low salt diet), indicating that NP play an important role in the observed hemodynamic responses to 5/6 nephrectomy.[46] Further insights into the renal hemodynamic effects of NP were gained from observations in normal rats infused with a synthetic ANP. Whole kidney and single nephron GFR increased by approximately 20% due entirely to a rise PGC, resulting from significant afferent arteriolar dilatation and efferent arteriolar constriction.[47] In the experiments discussed earlier, some residual elevation in remnant kidney GFR appeared to persist even after the NP system was suppressed by sodium restriction or a NP receptor antagonist, suggesting that factors other than NP make contributions to glomerular hyperfiltration following renal mass ablation. The potential interaction between NP and other vasoactive molecules is illustrated by the observation that ANP infusion in normal rats induced an increase in renal nitric oxide synthase activity.[48]


Eicosanoids, another family of potent vasoactive molecules present in abundance in the kidney, may also play a role in mediating glomerular hyperfiltration. Urinary excretion per nephron of both vasodilator and vasoconstrictor prostaglandins is increased in rats and rabbits after renal mass ablation. [49] [50] [51] Infusion of PGE2, PGI2, or 6-keto PGE1 into the renal artery elicits significant renal vasodilatation.[52] Whereas acute inhibition of prostaglandin synthesis by infusion of the cyclooxygenase (COX) inhibitor, indomethacin, had no effect on GFR or glomerular hemodynamics in normal rats, indomethacin lowered both SNGFR and QA after 3/4 or 5/6 nephrectomy. [49] [50] On the other hand, chronic treatment with a selective COX-2 inhibitor attenuated the systemic and glomerular hypertension observed in 5/6 nephrectomized rats but had no effect on GFR.[53] The relative effects of prostaglandin synthesis inhibitors on afferent and efferent arterioles may vary with time post nephrectomy. Afferent arteriolar constriction was the predominant finding reported at 24 hours post surgery, whereas constriction of both afferent and efferent arterioles was observed at 3 to 4 weeks. [49] [50] Some contribution of thromboxanes to glomerular hemodynamic adjustments after 5/6 nephrectomized rats is suggested by the increase in GFR seen after acute infusion of a selective thromboxane synthesis inhibitor.[51] Thus different eicosanoids appear to exert opposite effects but the general impression is that the combined effects of vasodilator prostaglandins outweigh those of the vasoconstrictors. This interaction is illustrated by the observation that perfusion of isolated glomeruli with bradykinin resulted in vasodilation of the efferent arteriole that was completely blocked by a indomethacin but that this blockade was reversed by a specific antagonist of 20-hydroxyeicosatetraenoic acid (20-HETE), a vasocontrictor eicosanoid, indicating that the glomerulus produced both vasodilator and vasoconstrictor eicosanoids.[54]

Nitric Oxide

The extremely short half-life of nitric oxide (NO) precludes direct measurement of NO levels or administration of exogenous NO in experimental models. The actions of NO have thus been inferred from experiments with inhibitors of nitric oxide synthase (NOS). Intravenous infusion of NOS inhibitors results in systemic and renal vasoconstriction as well as a reduction in GFR in normal rats. [55] [56] Thus, NO appears to exert a tonic effect on the physiological maintenance of systemic blood pressure and renal perfusion under resting conditions. It is unclear, however, whether NO plays a specific role in the adaptive hemodynamic changes that follow renal mass ablation. Indeed, renal expression of nitric oxide synthase and renal NO generation are reduced in 5/6 nephrectomized rats, whereas systemic production of NO is increased. [57] [58] Mean arterial pressure and renal vascular resistance increased whereas RBF and GFR decreased to a similar extent after acute infusion of an endothelial NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA), irrespective of whether given to normal rats or 3 to 4 weeks after unilateral or 5/6 nephrectomy.[56] Chronic NOS inhibition with L-NAME produced elevations in systemic blood pressure and PGC in 5/6 nephrectomized rats without affecting GFR[59] whereas chronic treatment with aminoguanidine, an inhibitor of inducible NOS, had no effect on GFR, RPF, or PGC.[58] On the other hand, renal NOS expression and activity are increased early after unilateral nephrectomy and pretreatment of rats with a subpressor dose of nitro-L-arginine methyl ester (L-NAME) prevents the early increase in RBF and decrease in renal vascular resistance usually observed after unilateral nephrectomy. [60] [61] It therefore appears that NO plays a role in early hemodynamic adaptations to nephron loss resulting in an increase in RBF but in the longer term NO retains a tonic influence on systemic and renal hemodynamics without being a specific determinant of the adaptive changes in glomerular hemodynamics.


Bradykinin is a potent vasodilatory peptide that is elevated in the remnant kidney[21] and may therefore contribute to hemodynamic adaptations after nephron loss. Acute and chronic infusion of bradykinin results in increased RPF but has no effect on GFR. [62] [63] Micropuncture studies in intact animals are lacking but studies of isolated perfused afferent arterioles have shown that bradykinin induces a biphasic response with vasodilation at low concentrations and vasconstriction at higher concentrations. Both effects appear to be mediated by products of COX.[64] Similar experiments with efferent arterioles found dose-dependent vasodilation (no biphasic response) that was dependent on cytochrome P450 metabolites but independent of COX products or NO.[65] When glomeruli were perfused with bradykinin, vasodilation of efferent arterioles was again observed but was inhibited by a COX inhibitor indicating that bradykinin induces glomerular production of COX metabolites (prostaglandins) that also contribute to efferent arteriolar dilation.[54] Further studies are required to elucidate the role of bradykinin after nephron loss.

Adjustments in Renal Autoregulatory Mechanisms

After extensive renal mass ablation, there is a marked readjustment of the autoregulatory mechanisms that control RPF and GFR. [66] [67] The role of myogenic mechanisms is uncertain but detailed studies of afferent arteriolar myogenic responses suggest that the primary role of the myogenic response is to protect the glomerulus from elevations in systolic blood pressure.[68] The tubuloglomerular feedback system is reset after renal mass ablation to permit and sustain the elevations in SNGFR and PGC described earlier. [69] [70] Resetting appears to occur as early as 20 minutes after unilateral nephrectomy,[71] in proportion to the extent of renal ablation. The adjustments observed after uninephrectomy are of lesser magnitudes than those seen after 5/6 nephrectomy.[69]

Interaction of Multiple Factors

As is readily appreciated from the earlier discussion, the adjustments in glomerular hemodynamics seen after renal mass ablation represent the net effect of several endogenous vasoactive factors. Natriuretic peptides and vasodilator prostaglandins dilate the preglomerular vessels whereas bradykinin dilates both afferent and efferent arterioles. On the other hand AII, vasoconstrictor prostaglandins, and possibly endothelins constrict both afferent and efferent arterioles with a greater effect on the latter. A net fall in preglomerular vascular resistance is observed and efferent arteriolar resistance decreases to a lesser extent. Together with transmission of a greater proportion of the raised systemic blood pressure to the glomerular capillary network, these alterations in microvascular resistances result in the observed elevations in QA, PGC, DP, and SNGFR ( Table 25-1 ). The importance of multiple vasoactive factors is illustrated by the observation that treatment of 5/6 nephrectomized rats with omapatrilat, an inhibitor of both angiotensin-converting enzyme and neutral endopeptidase that results in reduced AII production as well as increased NP and bradykinin levels, lowered PGC more than angiotensin-converting enzyme inhibition alone.[72] The complexity of factors involved is further illustrated by observations that other molecules involved in the modulation of progressive renal injury may exert hemodynamic effects by influencing the mediators discussed earlier. Acute infusion of hepatocyte growth factor (HGF) has been shown to induce a decline in blood pressure and GFR, an effect that is mediated by a short-term increase in endothelin-1 production.[73] In isolated perfused preparations, platelet-activating factor (PAF) at picomolar concentrations has been shown to induce glomerular production of NO, resulting in dilation of preconstricted efferent arterioles whereas at nanomolar concentrations, PAF constricts efferent arterioles through local release of COX metabolites.[74] The potential role of other recently identified vasoactive molecules such as urotensin II remains to be elucidated.[75]

TABLE 25-1   -- Hemodynamic Effects of Vasoactive Molecules Mediating Glomerular Hemodynamic Adaptations after Partial Renal Mass Ablation










Angiotensin II [5] [13] [14] [15] [16] [17] [18] [19]



Aldosterone [26] [27] [28]







Endothelins [34] [35] [36] [37] [38] [39] [40] [41] [42]


Natriuretic peptides [46] [47]


Prostaglandins [49] [50] [51] [52] [53] [54]

Bradykinin [62] [63] [64] [65]






Observed changes after partial renal ablation [6] [7]


↑ ↓


PGC, glomerular capillary hydraulic pressure; QA, glomerular plasma flow rate; Kf, glomerular ultrafiltration coefficient; SNGFR, single nephron GFR; RPF, renal plasma flow; GFR, glomerular filtration rate.




Renal Hypertrophic Responses to Nephron Loss

The notion that a single kidney enlarges to compensate for the loss of its partner has been entertained since antiquity. Aristotle (384–322 BC) noted that a single kidney was able to sustain life in animals, and that such kidneys were enlarged. In preparation for the first human nephrectomy in 1869 a German surgeon, Gustav Simon, uninephrectomized dogs and noted a 1.5-fold increase in the size of the remaining kidney at 20 days.[76] Compensatory renal hypertrophy has been studied in a variety of species including toads, mice, rats, guinea-pigs, rabbits, cats, dogs, pigs, and baboons. The majority of experimental work has been conducted on rodents subjected to uninephrectomy, but hypertrophic responses have also been studied in response to unilateral ureteric obstruction or after nephrotoxin administration.[77]

Whole-Kidney Hypertrophic Responses

Among the earliest responses to unilateral nephrectomy are biochemical changes that precede cell growth. Increased incorporation of choline, a precursor of cell membrane phospholipid, has been detected as early as 5 minutes and increased choline kinase activity, at 2 hours after nephrectomy. Activity of ornithine decarboxylase, the enzyme catalyzing the first step of polyamine synthesis, is elevated at 45 to 120 minutes and polyamine levels peak at 1 to 2 days post nephrectomy. Early alterations in mRNA metabolism have also been observed. Although there is no change in the half-life or cytoplasmic distribution of mRNA, a near 25% increase in the fraction of newly synthesized poly(A)-deficient mRNA occurs within 1 hour of uninephrectomy and total RNA synthesis in the kidney increases by 25% to 100% relative to that in the liver. Ribosomal RNA synthesis is increased by 40% to 50% at 6 hours. The rate of protein synthesis is increased at 2 hours and is nearly doubled at 3 hours. Data on cyclic nucleotide levels, which are thought to affect cell growth and proliferation, are conflicting. Some studies report elevated levels of cGMP in the remaining kidney as early as 10 minutes after surgery, whereas others have found no consistent changes in cAMP or cGMP levels.[77] Genome-wide analysis of gene expression using cDNA microarrays in remaining rat kidneys up to 72 hours after uninephrectomy has revealed the dominant response to be suppression of genes responsible for inhibition of growth and apoptosis.[78]

Early biochemical changes are followed by a period of rapid growth. DNA synthesis is increased at 24 hours and increased numbers of mitotic figures are evident at 28 to 36 hours. Both reach a maximum increase of 5-fold to 10-fold at 40 to 72 hours. In rats, kidney weight is increased at 48 to 72 hours after uninephrectomy and achieves a 30% to 40% gain at 2 to 3 weeks ( Fig. 25-1 ). [61] [77] As nephron number is fixed shortly before birth in most species, this gain in kidney weight is attributable to increased nephron size. Growth is thought to occur largely through cell hypertrophy, accounting for 80% of the increase in renal mass seen in adult rats and, to a lesser extent, through hyperplasia. Hypertrophy is achieved largely through regulation of the G1 cell cycle kinase (cell cycle-dependent mechanism).[79] Renal mass continues to rise for 1 to 2 months until a 40% to 50% increase is achieved. The degree of compensatory growth is a function of the extent of renal ablation. Uninephrectomy has been shown to provoke an 81% increase of residual renal mass at 4 weeks compared to an increase of 168% after 70% renal ablation. Normal controls gained 31% in kidney weight over the same period. Age diminishes renal hypertrophic responses: after uninephrectomy, greater increases in kidney weight and more extensive hyperplasia was observed in 5-day-old versus 55-day-old rats and aging rats exhibited gains in kidney weight of only one third to three quarters of those seen in younger controls.[77]



FIGURE 25-1  Rate of compensatory renal growth after unilateral nephrectomy (circles) and ureter ligation (squares).  (Reproduced with permission from Dicker SE, Shirley DG: Compensatory hypertrophy of the contralateral kidney after unilateral ureteral ligation. J Physiol (Lond) 220:199–210, 1972.)




In humans, assessment of renal hypertrophy after nephrectomy is dependent on radiological studies. Ultrasound studies have reported increases of 19% to 100% in kidney volume[80] and in computed tomography studies, an increase of 30% to 53% in renal cross-sectional area. [81] [82] The relatively small number of subjects included, wide variation in the time intervals between nephrectomy and assessment of renal size, and differing indications for nephrectomy make interpretation of these results difficult.

Glomerular Enlargement

The principal morphometric change observed in glomeruli after uninephrectomy is an increase in volume. Glomerular enlargement appears to parallel whole-kidney growth and has been detected as early as 4 days after surgery.[83]The degree of enlargement of superficial and juxtamedullary glomeruli is similar. Proportionally similar increases in number and size of all cell types occur, with preservation of the relative volumes of different glomerular cells.[77]There is consensus that glomerular capillaries increase in length and number (i.e., more branching) but most studies show that diameter or cross-sectional surface area of the glomerular capillaries remains constant or increases only minimally. [84] [85] Transplantation of hypertrophied kidneys into uninephrectomized recipients has demonstrated regression of glomerular hypertrophy within 3 weeks, yet the increase in capillary length was maintained.[85]

Glomerular hypertrophy, as evidenced by elevated RNA/DNA and protein/DNA ratios as well as by increased glomerular volume (VG) on electron microscopy, has been detected at 2 days after 5/6 nephrectomy.[86] The initial increase in VG was due, almost entirely, to increases in visceral epithelial cell volume, whereas at 14 days the increase in VG was largely accounted for by mesangial matrix expansion. Although several studies report glomerular capillary lengthening after 5/6 nephrectomy, few have detected any increase in cross-sectional area or diameter of the glomerular capillaries. [87] [88] [89] [90] These observations should, however, be considered in the light of important technical considerations. In vitro perfusion of isolated glomeruli demonstrates that VG increases as perfusion pressure is raised through physiological and pathophysiological ranges. Moreover, glomerular capillary “compliance” in these studies was a function of the baseline VG and glomeruli obtained from remnant kidneys post 5/6 nephrectomy had a higher compliance than those from control animals.[91] These findings have two important implications. First, although glomerular pressures are only minimally elevated after uninephrectomy, the glomerular capillary hypertension associated with more extensive renal ablation is likely to contribute significantly to the increase in VG. Second, estimates of VG in tissues that have not been perfusion-fixed at the appropriate blood pressure should be interpreted with caution. Direct comparison of VG in perfusion-fixed versus immersion-fixed kidney from the same rats yielded estimates of VG in immersion-fixed samples that were 61% lower than those from perfusion-fixed kidneys.[92]

Mechanisms of Renal Hypertrophy

Despite more than a century of research that has identified a large number of mediators or modulators of renal hypertrophy, the identities of the specific factors that regulate hypertrophy and the stimuli to which these factors respond remain elusive. Renal innervation does not appear to play a role as kidneys transplanted into bilaterally nephrectomized rats exhibit the same degree of hypertrophy after 3 weeks as kidneys remaining after uninephrectomy.[93] The absence of any reduction in renal hypertrophy when rats are treated with an ACEI after uninephrectomy indicates that the renin-angiotensin system also does not play a major role.[94] Several hypotheses have been advanced to account for the observed changes that are associated with renal hypertrophy and have been discussed in detail in other publications [76] [77] but are summarized below. Currently, however, none is able to explain satisfactorily all of the reported observations.

Solute Load

The notion that hypertrophy after uninephrectomy is stimulated by the need for the remaining kidney to excrete larger amounts of metabolic waste products, necessitating more excretory “work”, was proposed by Sacerdotti in 1896. Subsequently, it became apparent that urea excretion is largely a function of glomerular filtration, whereas the main energy-requiring function of the renal tubules is reabsorption of filtered electrolytes (principally sodium) and water. The hypothesis was therefore modified to view hypertrophy as a response to the increased demand for water and solute reclamation imposed by increased SNGFR (solute load hypothesis). Several lines of evidence support the concepts underlying the “solute load hypothesis”. After uninephrectomy RBF increased by 8% in the remaining kidney and preceded hypertrophy but treatment with a subpressor dose of the NOS inhibitor L-NAME prevented the rise in RBF and substantially attenuated increases in renal weight as well as glomerular and proximal tubule area at 7 days post nephrectomy.[61] In the remnant kidney, proximal tubule sodium absorption increases in parallel with GFR (glomerulotubular balance) and tubules continue to display enhanced fluid reabsorption in vitro, implying that the adaptive changes are intrinsic to the tubular epithelial cells. In chronic glomerulonephritis, a lesion characterized by marked heterogeneity in SNGFR, there is preservation of the SNGFR to proximal fluid reabsorption ratio and a close correlation between glomerular and proximal tubule hypertrophy. Moreover, sustained increases in GFR in the absence of renal mass ablation result in renal hypertrophy in some conditions, including pregnancy (in some but not all studies) and diabetes mellitus.[76]

On the other hand, experimental maneuvers dissociating renal solute load from hypertrophy appear to contradict the solute load hypothesis. Total diversion of urine from one kidney into the peritoneum by ureteroperitoneostomy is associated with an increase in GFR in the contralateral kidney of similar magnitude to that seen after uninephrectomy, but no increase in renal mass or mitotic activity. In another example, potassium depletion results in renal hypertrophy without any increase in GFR. Moreover, the findings that some of the early biochemical changes associated with hypertrophy precede increases in glomerular filtration or sodium reabsorption, argue against a causal association of hypertrophy and increased solute load. It is, however, possible to offer alternative explanations for each of the observations discussed earlier. Despite these conflicting data, there is nevertheless considerable evidence of an association between glomerular filtration rate and proximal tubule hypertrophy that may play a role in stimulating renal growth in the remnant kidney.[76]

Renotropic Factors

Failure of the “solute load hypothesis” to explain all of the experimental data has led others to propose instead that the primary stimulus for renal hypertrophy is a change in renal mass and that renal growth is under the control of specific growth and/or inhibitory factors. Evidence in support of this theory is derived from three types of experiment. In the first, a stable connection is established between the extracellular space and microcirculation of two animals (parabiosis) and the effects of renal mass ablation in one animal are assessed in the intact kidneys of its partner. Despite some inconsistencies due to variations in methodology these experiments generally found that uninephrectomy in one animal resulted in hypertrophy of the contralateral kidney and, to a lesser extent, of both kidneys of the parabiotic partner. Bilateral nephrectomy in one partner or triple nephrectomy produced incremental degrees of hypertrophy in the remaining kidney(s). Furthermore, the hypertrophy was rapidly reversed following cessation of cross circulation.[76]

A second strategy has been to inject serum or plasma from uninephrectomized animals into intact subjects and then assess renal hypertrophy by radiolabeled thymidine uptake or mitotic count. Although studies using single small intraperitoneal or subcutaneous doses were negative, the administration of repeated, large doses by intraperitoneal or intravenous routes elicited renal hypertrophy in most.[76]

The data that most consistently support the existence of a renotropic factor are derived from in vitro experiments in which renal tissues are incubated in the presence or absence of plasma or serum from rats subjected to renal mass ablation. Evidence for hypertrophy has generally been assessed by incorporation of radiolabelled thymidine or uridine into DNA or RNA, respectively. In general these experiments have shown increased uptake of radiolabeled nucleotides after incubation with serum from uninephrectomized animals. This effect appears to organ specific, but not species specific. That a tissue factor produced by kidneys and up-regulated after nephrectomy may be required for the activity of a circulating “renotropin”, is suggested by experiments in which kidney extract from rats taken 20 hours after uninephrectomy, in the presence of normal rat serum, was found to stimulate 3H thymidine incorporation in normal renal cortex but addition of the same extract in the absence of the serum tended to depress 3H thymidine uptake. Serum taken from bilaterally nephrectomized animals lacks renotropic effects but these can be restored after dialysis of the serum, suggesting the presence of renotropin inhibitory factors that accumulate in the absence of renal function. Although the specific identity of renotropin remains elusive, several lines of evidence suggest that it is a small protein. Retention of activity after ultrafiltration, dialysis and removal of albumin from serum implies that renotropin is a molecule of 12 kDa to 25 kDa with no significant binding to albumin. [76] [77]

Several hypotheses have been advanced to reconcile the earlier observed effects and operation of a putative renotropic system. It has variously been proposed that (1) renotropin is a circulating substance normally catabolized or excreted by the kidneys, (2) renal growth is regulated by a specific renotropin-producing tissue that is inhibited by a factor produced by normal kidneys, (3) renal growth is tonically inhibited by a substance produced by normal kidneys, a decrease in the levels of which induces an enzyme in the renal cortex that cleaves a circulating precursor of renotropin to produce the active molecule. [76] [77]

Endocrine Effects

Several of the major endocrine systems influence renal growth but each lacks selective effects on the kidney. There is little evidence that any of these systems represent the specific mediators of compensatory renal hypertrophy. Whereas early experiments suggested that hypophysectomy inhibits compensatory hypertrophy after uninephrectomy, later studies that controlled for the reduction in renal mass that usually accompanies hypopituitarism, found a degree of hypertrophy comparable to that seen in normal rats. Nevertheless, specific renotropic activity has been identified in a sub-fraction of ovine pituitary extract associated with a lutropin-like substance. [76] [77] Uninephrectomy is accompanied by a transient increase in the pulsatile release of growth hormone (GH) in male but not female rats suggesting a role for this hormone in the early phase of hypertrophy in males.[95] When the increase in GH was prevented by administration of an antagonist to GH-releasing factor or the effects of GH are blocked by a GH-receptor blocker, renal hypertrophy is significantly attenuated. [96] [97] Adrenal hormones appear to play little role in renal hypertrophy. Adrenalectomy does not inhibit compensatory growth after uninephrectomy. Whereas renal weight relative to body weight is reduced in hypothyroidism and increased by excess thyroid hormone, compensatory hypertrophy still occurs in thyroidectomized rats. Progesterone and estradiol in excess or ovariectomy have little effect on renal weight, but testosterone appears to play a role, as evidenced by a fall in kidney/body weight after orchidectomy and an increase in kidney weight with excess testosterone. Whereas orchidectomy does not inhibit hypertrophy after uninephrectomy, exogenous testosterone did increase the degree of hypertrophy observed, in some, but not all studies. [76] [77]

Growth Factors

Of the numerous growth factors and their receptors that have been localized in the kidney, at least four are associated with renal hypertrophy. [98] [99] Several lines of evidence suggest a role for insulin-like growth factor-I (IGF-1). Renal IGF-1 levels were elevated at 1 to 5 days after uninephrectomy and started to decline within days in some [100] [101] but not all studies.[102] In one study the level of renal IGF-1 expression was significantly correlated with the extent of renal mass ablation.[103] On the other hand, Shohat and colleagues found an increase in serum IGF-1 levels only at 10 days post nephrectomy, which was still present on day 60.[100] That IGF-1 may be induced independent of GH in the setting of renal hypertrophy is illustrated by preservation of the increase in renal IGF-1 in hypophysectomized[104] and GH-deficient rats.[105] Other molecules related to IGF function are also up-regulated: renal IGF-1 receptor gene expression was increased twofold to fourfold in female rats after uninephrectomy[95]; IGF-1 binding protein mRNA was up-regulated in the remnant kidney at 2 weeks after 5/6 nephrectomy[106]; analysis of the genome-wide transcriptional response to unilateral nephrectomy identified IGF-2 binding protein was one of the few activated genes.[78] Further evidence suggests that IGF-1 may in turn promote production of vascular endothelial growth factor (VEGF), suggesting that VEGF may be a down-stream mediator of IGF-1 effects, at least in the pathogenesis of diabetic retinopathy.[107] That VEGF is important for compensatory renal hypertrophy is confirmed by the observation that treatment of mice with VEGF antibodies after uninephrectomy completely prevented glomerular hypertrophy and inhibited renal growth at 7 days.[101] Epidermal growth factor (EGF) in the remaining kidney is increased on day 1 in mice[108] and by day 5 in rats.[109] In addition, EGF has been shown to induce IGF-I mRNA production in collecting duct cells in vitro, suggesting the existence of a local paracrine system.[110] Increased mRNA levels for both hepatocyte growth factor (HGF) and its receptor, c-met, have been demonstrated in the remaining kidney as early as 6 hours after uninephrectomy. [111] [112] In another study the rise in HGF message was found to be non-specific, occurring in both liver and kidney, and also in sham-operated rats, whereas the increase in mRNA for c-met was specific for the outer renal medulla.[113] Despite these associations, the timing of the changes in growth factor levels remains unclear. Whereas some investigators report early increases, [108] [114] several others report changes only at time points when significant hypertrophy is already present, thus failing to provide convincing evidence that they represent the proximal effectors in a renotropic system. [100] [109]

Failure to identify a specific “renotropin” to date has led some to suggest instead that renal hypertrophy occurs as a result of increased sensitivity of renal cells to prevailing levels of growth promoting factors. This enhanced sensitivity, it is argued, may result from changes in the intracellular environment brought about by responses to increased glomerular filtration such as the increase in Na+/H+ exchange seen in proximal tubule cells after renal mass reduction.[76] As can readily be appreciated from the earlier discussion, many factors have been associated with compensatory renal hypertrophy but a unifying hypothesis that adequately accounts for them all remains elusive. It is likely that multiple pathways are involved. Some factors appear to control normal renal growth and may have a permissive or modulating role in compensatory hypertrophy, whereas others act as specific mediators of the dynamic processes that follow a reduction in renal mass.


As noted earlier, the bulk of the increase in renal mass following uninephrectomy is due to hypertrophy of the proximal nephron. The more distal nephron segments also enlarge, but to a lesser extent. In uninephrectomized rats, the proximal convoluted tubule is increased on average by 17% in luminal diameter and 35% in length, yielding a 96% increase in total volume; the distal convoluted tubule is enlarged by 12% in luminal diameter and 17% in length, yielding a 25% increase in total volume.[115] Maintenance of homeostasis for various solutes in the face of a declining GFR requires highly integrated responses from each tubule segment. Whereas some solutes including creatinine and urea are chiefly cleared by glomerular filtration and therefore rise gradually in plasma with declining GFR, for others, the tubule solute handling adapts so that plasma levels remain constant, virtually until end-stage renal failure is reached ( Fig. 25-2 ).



FIGURE 25-2  Representative patterns of adaptation for different types of solutes in body fluids in chronic renal failure. Pattern A: rise in serum concentration with each permanent reduction in GFR (e.g., creatinine); Pattern B: rise in serum concentration only after GFR falls below a critical value due to adaptive increases in tubular secretion (e.g., phosphate); Pattern C: serum concentration remains normal through almost entire period of progression of renal failure (e.g., sodium).  (Modified from Bricker NS, Fine L: In Brenner BM, Rector FC (eds): The Kidney, 2nd ed. Philadelphia, WB Saunders, 1981.)


Adaptation in Proximal Tubule Solute Handling

In renal ablation models, as with the increase in remnant kidney SNGFR, the extent to which proximal tubule enlarges is inversely proportional to the remnant kidney mass. Proximal tubule enlargement is associated with an increase in proximal fluid reabsorption. In studies of both animals and humans with reduced renal mass, the increase in proximal fluid reabsorption observed was found to be proportional both to the increase in remnant kidney GFR and the increase in tubular volume.[116] Similarly, in proximal tubules isolated from remnant kidneys, the observed increase in transtubular fluid flux was proportional to the increases in size and protein content of the tubule epithelial cells.[117] [118] Folding of the basolateral membrane of the proximal tubule epithelium was also found to increase, resulting in augmentation of the basolateral surface area, in proportion to the increase in cell volume.[119] This increase in surface area was accompanied by an increase in activity of Na-K-ATPase, the membrane pump that generates the main driving force for proximal tubule solute transport.[119]

Increases in proximal tubule size and surface area are not, however, the only determinants of increased transport activity in this nephron segment. Fluid reabsorption in isolated proximal tubule segments increases within 24 hours of nephrectomy (i.e., when GFR is already increasing, but well before significant hypertrophy occurs), implying an intrinsic tubular epithelial cell adaptation to nephron loss.[120] This observation also raises the possibility that the increases in proximal fluid reabsorption occurring in response to nephron loss are driven by the increase in SNGFR and further implies that the increased reabsorptive load could stimulate hypertrophy. [76] [77] As solute reclamation is an energy-requiring process, it is not surprising that in uninephrectomized rabbits, the increase in proximal tubule volume was accompanied by a proportional increase in mitochondrial volume.[121] The observation that the increase in renal mass is outstripped by the rise in GFR in models of progressive nephron loss implies that renal energy consumption per unit of remnant renal mass increases as renal function declines.[115]

The rise in SNGFR that occurs in the remnant kidney presents increased loads of glucose, amino acids, and other solutes that would normally be reabsorbed entirely in the proximal tubule, provided the maximal transport capacity was not exceeded. Maximal proximal tubular reabsorptive capacities for glucose and amino acids have been shown to increase in proportion to tubule mass after partial renal ablation.[122] Some metabolic functions of proximal tubules are also augmented in the remnant kidney, so as to maintain adequate plasma levels of important metabolites including citrulline, arginine, and serine.[123] Other proximal tubule functions, however, are not adjusted in proportion to proximal tubule mass: fractional phosphate reabsorption is decreased whereas ammoniagenesis increases. [122] [124] [125] These adaptations are appropriate homeostatic responses that permit continued excretion of daily phosphate and acid loads, respectively, as the number of functioning nephrons declines.

Loop of Henle and Distal Nephron

Although there is little change in cross-sectional area in the thick ascending limb of the loop of Henle, fluid reabsorption in this segment also increases in proportion to SNGFR.[115] In contrast, both the distal tubule and the cortical collecting duct enlarge in response to nephron loss.[115] Unlike the proximal tubule, however, where the increased reabsorptive capacity is chiefly due to increased tubule dimensions, the increased reabsorptive capacity observed in the distal segments is far greater than would be expected for the corresponding increase in tubule volume, implying a major adaptive increase in active solute transport.[115] Levels of mRNA for the Na+/myo-inositol cotransporter (SMIT) and Na+/Cl-/betaine-gamma-amino-n-butyric acid transporter (BGT-1) are increased in the cortex and outer medulla of remnant kidneys from 5/6 nephrectomized rats.[126] Likewise, potassium secretion by the distal nephron increases in compensation for nephron loss, facilitated by an increased basolateral surface area of cortical collecting duct principal cells and an increase in Na-K-ATPase activity. [127] [128]

Glomerulotubular Balance

Micropuncture studies have confirmed that proximal fluid reabsorption remains proportional to glomerular filtration over a wide range of SNGFR in both glomerular and tubulointerstitial diseases. [129] [130] This glomerulotubular balance is critical to the physiological integrity of remnant nephron function and hence extracellular fluid homeostasis. Compensatory increases in SNGFR in surviving nephrons must be accompanied by similar increases in proximal tubular solute and water reabsorption, so as to avoid overwhelming the distal nephron transport capacity and disrupting its regulation of the volume and composition of the final urine. Conversely, reductions in SNGFR in damaged nephrons must be matched by similar reductions in proximal fluid reabsorption so as to maintain adequate solute and water delivery to the distal tubule, again permitting excretion of urine of appropriate volume and composition.

Glomerulotubular balance is maintained as follows: the degree of single nephron hyperfiltration occurring as a consequence of nephron loss determines the passive Starling forces operating in the post-glomerular microcirculation, which in turn, govern net trans-tubular solute reabsorption.[131] Increases in SNGFR associated with an increased filtration fraction result in elevated post-glomerular capillary protein concentrations, which determine nonlinear increases in oncotic pressure, PE, the major determinant of peritubular capillary reabsorptive force (Pr). Reductions in SNGFR, in contrast, result in a lowered peritubular oncotic pressure, thereby reducing Pr. Thus, SNGFR and proximal fluid reabsorption remain in direct proportion to one another. Prevention of hyperfiltration by dietary protein restriction has been shown to abrogate the increase in proximal fluid reabsorption in the remnant kidney, underscoring the dependence of proximal tubular function on the level of glomerular filtration.[131] In the remnant kidney of rats subjected to extensive renal mass ablation, absolute fluid reabsorption was found to be markedly increased in proximal portions of both superficial and juxtamedullary nephrons, yet fluid delivery to the more distal segments of the nephron was also somewhat increased.[132] In the setting of nephron loss, sodium reabsorption by the loop of Henle has been shown to remain proportional to sodium delivery to that segment, indicating preservation of tubulo-tubular balance, a mechanism that maintains appropriate distal solute and water delivery in the face of progressive nephron loss. Until the adaptive capacities of these mechanisms are finally exhausted, the operation of glomerulotubular balance and tubulotubular balance ensures that the distal tubule mechanisms that determine final urine composition are not overwhelmed by unregulated distal delivery of water and solute.[133] In keeping with these physiological observations, morphologic studies have shown that within the same kidney, nephrons associated with damaged glomeruli are usually atrophic and presumably hypofunctioning, whereas those associated with healthier glomeruli are usually hypertrophic and hyperfunctioning.[134]

In order to maintain homeostasis in the face of continued food and water intake, specific mechanisms that enhance single nephron water and solute excretion must come into play, in addition to the adjustments in SNGFR and tubular reabsorption that occur in response to nephron loss. These mechanisms are not unique to the setting of renal insufficiency, however, and are also engaged when the normal kidney is challenged to excrete extraordinary loads of solute and water. In general, the adaptive physiology of the chronically injured kidney is adequate to preserve homeostasis for many solutes under baseline conditions, but the adaptive capacity may easily become overwhelmed by fluctuations in fluid intake and especially by increases in electrolyte and acid loads. Patients with chronic renal failure are therefore susceptible to develop volume overload, volume loss, hyperkalemia, and acidosis when the excretory capacity of the kidney is challenged by relatively modest increases in excretory demands.

Sodium Excretion and Extracellular Fluid Volume Regulation

In chronic renal failure, ECF volume is often maintained very close to normal until end-stage is reached.[135] This remarkable feat is accomplished by an increase in fractional sodium excretion (FENa) in inverse proportion to the decline in GFR.[136] Many studies have been carried out in an attempt to identify which nephron segments are responsible for the decrease in sodium reabsorption: micropuncture studies in uninephrectomized rats have shown that tubule fluid transit times, as well as the half-time for reabsorption of a stationary saline droplet in the proximal tubule lumen, were not different from controls[115]; in remnant kidneys of rats receiving high, normal, or low sodium diets, absolute sodium reabsorption was found to increase, but fractional sodium and fluid reabsorption were found to decrease in all groups[137]; micropuncture studies in dogs and rats have failed to detect significant reductions in fractional proximal tubule fluid and sodium reabsorption[138]; distal sodium delivery was found to be markedly increased in the rat remnant kidney[137]; increased solute transport activity has been demonstrated in distal tubule of uninephrectomized rats[115]; under conditions of hydropenia and salt loading, sodium reabsorption by the medullary collecting duct of the rat remnant kidney was markedly reduced.[139] Taken together, these data suggest that proximal fractional reabsorption remains largely unchanged, and that in the setting of renal insufficiency, adjustments in sodium excretion occur predominantly in the loop and distal nephron segments.[140]

In addition to load-dependent tubular adaptations in sodium handling, sodium excretion is also modulated by hormonal influences. Levels of natriuretic peptides (NP) are elevated in chronic renal failure as a result of reduced clearance and in response to alterations in sodium and volume status. [46] [141] In rats with extensive renal mass ablation, plasma atrial natriuretic peptide (ANP) levels may be restored toward normal levels by dietary sodium restriction, but, in response to increases in sodium intake, they rise progressively along with sodium excretion.[142] The notion that ANP plays an important role in mediating adaptive changes in sodium excretion in the setting of renal ablation is confirmed by observations that administration of a NP receptor antagonist reduced both FENa and GFR in 5/6 nephrectomized rats receiving either normal or high salt diets, but did not alter these variables in rats fed low salt diets.[143] Significantly, NP not only modulate sodium excretion but may also contribute to the attendant glomerular hyperfiltration, and thereby further exacerbate renal injury (see earlier).

Systemic hypertension has also been proposed by Guyton and associates as a contributor to the increase in FENa observed with renal insufficiency.[144] Their hypothesis states that a constant sodium intake in the face of a reduced number of functioning nephrons leads to positive sodium balance as a result of reduced excretory capacity. Positive sodium balance leads to an increase in ECF volume and a rise in systemic blood pressure that, in turn, leads to an increase in FENa and re-establishes the steady state. In support of this hypothesis, salt intake has been shown to be critical to the development of hypertension in subtotally nephrectomized dogs[145] and uremic patients have been found to exhibit marked sodium retention when treated with vasodilating antihypertensive agents.[146] On the other hand, a lowered salt intake in 5/6 nephrectomized rats does not prevent the development of systemic hypertension,[89] suggesting that sodium excretion and hypertension are not always interdependent in the setting of extensive renal mass ablation. Sodium conservation, on the other hand, is also impaired with renal insufficiency and, in response to an acute reduction in sodium intake most patients were unable to reduce sodium excretion below 20 to 30 mEq/day.[147] The “salt-losing” tendency associated with CKD appears to be dependent on the salt load per nephron and may therefore be reversible with adequate dietary sodium restriction. Other factors modulating FENa in the setting of renal insufficiency include changes in sympathetic nervous system activity, aldosterone, prostaglandins, and parathyroid hormone levels. [140] [148] Sodium homeo-stasis and volume regulation are discussed in further detail in Chapters 5 and 12 .

Urinary Concentration and Dilution

Extracellular fluid homeostasis is usually well maintained until renal insufficiency is far advanced, when the ability of the kidney to excrete a volume load becomes significantly reduced.[140] Normal generation of solute-free water is about 12 mL per 100 mL of GFR, and is dependent on dilution of tubule fluid in the thick ascending limb, maintenance of low water permeability in the distal nephron segments in the absence of antidiuretic hormone (ADH), and decreased hypertonicity of the medullary interstitium during water diuresis. Although the single nephron capacity to excrete free water per milliliter of GFR is not reduced in patients with advanced renal disease,[149] the absolute reduction in GFR reduces the overall capacity of the kidney to excrete a water load. Patients with chronic renal failure therefore cannot adequately dilute their urine, and are prone to water intoxication and hyponatremia. Hypothetically, in addition to excretion of the equivalent of 2 L of “isotonic urine” per day (obligatory excretion of 600 mOsm/d), normal kidneys, with a GFR of 150 L/d, can excrete up to 18 L of free water, whereas failing kidneys, with a GFR of 15 L/d, can only excrete about 1.8 L of free water per day. The minimum urinary osmolality achievable by normal kidneys would therefore approach 30 mOsm/L (600 mOsm/20 L) whereas that of diseased kidneys would be 160 mOsm/L (600 mOsm/3.8 L).

Urinary concentration is also impaired in renal insufficiency. Normal urinary concentration requires preservation of the countercurrent mechanism in order to maintain hypertonicity of the medullary interstitium and normal water transport across the distal nephron segments in response to ADH. Maximal urinary osmolality in normal subjects is about 1200 mOsm/L. As GFR decreases, however, maximal urinary osmolality falls, and with a GFR of 15 mL/min is reduced to about 400 mOsm/L.[150] A normal individual can therefore excrete the obligatory daily 600 mOsm in as little as 0.5 L of urine, whereas the patient with a GFR of 15 mL/min can excrete the same load in a minimum of 1.5 L. Part of the defect in urinary concentration observed in renal injury may be attributed to the high solute load imposed per surviving nephron. In patients with chronic renal insufficiency, however, the osmotic effect of urea was shown to be inadequate to account fully for the reduction in maximal urine concentration, indicating that factors other than osmotic diuresis contribute to reduction in urinary concentrating ability in these patients.[150] Furthermore, in patients with chronic primary glomerulonephritis, reduction in urine concentrating capacity was found to correlate significantly with the degree of medullary fibrosis on renal biopsy,[151] suggesting that disruption of the medullary architecture, with the consequent loss of medullary hypertonicity, may result in disproportionate impairment of urinary concentrating ability at any given level of GFR. Consistent with this observation, patients with primary tubulointerstitial injury (e.g., analgesic nephropathy and sickle cell disease) have markedly impaired urinary concentrating abilities, even early in the course of their illness. [150] [152] [153] Similarly, in animal experiments, surgical exposure of the renal papilla in intact hydropenic rats was found to lead to reduction in urinary osmolality because of the accompanying alterations in vasa recta flow and ensuing washout of medullary solutes.[154] Interestingly, similar exposure of papillae in rats with remnant kidneys did not affect urinary osmolality, presumably because medullary solute washout had already occurred due to the adaptive responses to nephron loss. Urinary concentration also depends on water reabsorption in the distal nephron segments of the remnant nephron. Reduction in water reabsorption may be the result of several mechanisms in the failing kidney. Defective cyclic AMP-mediated response to ADH may render the cortical collecting duct resistant to the effects of ADH, resulting in increased water delivery to the papillary collecting duct.[155] Urinary osmolality is inversely proportional to fractional water delivery to the papillary collecting duct in 5/6 nephrectomized rats, despite an increase in absolute water reabsorption per functioning collecting tubule when compared with controls.[154] Patients with renal insufficiency are therefore prone to volume depletion in the presence of water deprivation or impaired thirst mechanisms. More commonly, the inability to concentrate urine becomes manifest as nocturia, which develops as renal function deteriorates. Urinary concentrating and diluting mechanisms are discussed in further detail in Chapters 9 and 13 .

Potassium Excretion

In order to maintain potassium homeostasis in the face of continued dietary intake and a reduced number of functioning nephrons, potassium excretion per nephron must increase. In both normal and diseased kidneys, almost all of the filtered potassium is reabsorbed in the proximal tubule and loop of Henle. Potassium excretion is therefore determined predominantly by distal secretion,[140] although a reduction in potassium reabsorption by the loop of Henle has been shown to contribute to increased potassium excretion in rats with reduced renal mass.[156] In both normal and partially nephrectomized dogs, urinary potassium excretion was found to correlate directly with serum potassium concentration.[157] Similarly, in intact and uninephrectomized rats, net potassium secretion in the distal convoluted tubule occurred only during potassium infusion, whereas potassium secretion by cortical collecting tubules (CCT) occurred under all conditions, and was greater after uninephrectomy.[158] Other studies have confirmed that the CCT is an important site of potassium secretion in the remnant kidney. [127] [139] Secretion of potassium by CCT isolated from remnant kidneys of rabbits fed normal or high potassium diets, was shown to persist in vitro, and to be directly related to the dietary potassium content,[127] indicating an intrinsic tubular adaptation to potassium load. This adaptation was absent in CCT from rabbits in which dietary potassium had been reduced in proportion to the amount of renal mass lost. In addition to variation with dietary potassium load, the increase in potassium secretion by remnant CCT was also found to correlate with plasma aldosterone levels, but not with intracellular potassium concentration or Na-K-ATPase activity.[127] In contrast, however, others have reported an increase in cortical and outer medullary Na-K-ATPase activity in homogenates from rat remnant kidneys that was abrogated when potassium intake was reduced in proportion to the reduction in GFR.[159] Finally, the frequent occurrence of hyperkalemia in patients with chronic renal insufficiency after treatment with an aldosterone antagonist or an ACEI, suggests that “normal” aldosterone levels are required to maintain adequate potassium excretion in this population.[160] In general therefore, the increase in potassium secretion by surviving nephrons appears to be predominantly determined by the rise plasma potassium after potassium ingestion, and by intrinsic tubular adaptation to the increased filtered potassium load. [157] [158] In both dogs and patients with chronic renal insufficiency, however, the kaliuretic response to an oral potassium load is attenuated compared to normals despite higher serum potassium levels. [157] [161] The eventual, complete excretion of a potassium load, therefore, occurs at the expense of a sustained increase in serum potassium. Control of potassium excretion is discussed further in Chapters 5 and 15 .

Acid-Base Regulation

Reduction of GFR in patients with chronic kidney disease is associated with the development of systemic metabolic acidosis, due to a reduction in serum bicarbonate concentration. Normal acid-base balance requires reabsorption of filtered bicarbonate, excretion of titratable acid, ammonia generation, and acidification of tubular luminal fluid by the distal nephron.[140] In chronic kidney disease, acidosis develops as a result of varying degrees of impairment in each of these processes.[162]

Reduction in renal ammonia synthesis is the greatest limitation to acid excretion in CKD. Low serum bicarbonate levels result in maintenance of acid urine, which stimulates proximal tubule ammoniagenesis and also protonates ammonia resulting in its entrapment as ammonium in the tubule lumen. Net ammonia production per hypertrophied proximal tubule has been shown to increase in response to nephron loss.[155] With decreasing GFR, however, this increase becomes inadequate to compensate for further nephron loss, and absolute ammonia excretion falls.[125] In addition, disruption of the tubulo-medullary ammonium concentration gradient as a result of structural injury may impair ammonia trapping and therefore reduce ammonium excretion.[125] Bicarbonate reabsorption by the nephron occurs predominantly in association with sodium reclamation in the proximal tubule and is dependent on generation of a proton gradient in the distal nephron. Conflicting data with respect to bicarbonate reabsorption in remnant kidneys may reflect species differences. In dogs with remnant kidneys, bicarbonate reabsorption was increased at both proximal and distal micropuncture sampling sites compared to intact controls.[163] In contrast, bicarbonate reabsorption per unit GFR is reduced in both humans and rats with CKD[140] and some patients with renal insufficiency demonstrate bicarbonate wasting until serum bicarbonate drops below 20 mEq/L.[164] Bicarbonate reabsorption is also reduced in the setting of hyperkalemia, increased extracellular fluid volume, and hyperparathyroidism, all of which may be present in patients with chronic renal insufficiency. [165] [166] [167] Distal urinary acidification tends to be relatively well preserved in patients with CKD and urinary pH, although higher than in normal individuals with experimental acidosis, is usually about 5.[168] Urinary excretion of titratable acid is also generally well preserved in the setting of nephron loss, as a consequence of increased fractional phosphate excretion. [122] [125] As renal failure progresses, acid excretion becomes more dependent on excretion of titratable acid. Renal acidification mechanisms are discussed more comprehensively in Chapters 7 and 14 .

Calcium and Phosphate

Derangements of calcium and phosphate metabolism occurring with renal insufficiency are not only the result of impaired urinary excretion of these solutes, but also of associated abnormalities in vitamin D metabolism and parathyroid hormone (PTH) secretion. With progressive renal dysfunction,1-hydroxylation of vitamin D by the kidney decreases; calcium absorption from the gut decreases; serum calcium tends to decrease; serum phosphate tends to increase; PTH secretion increases. In response to increased PTH, calcium is mobilized from bone, renal phosphate excretion is enhanced, and the steady state becomes re-established, with secondary hyperparathyroidism as the “trade-off”.[169] In CKD, serum phosphate does not increase until GFR falls below 20 ml/min, and phosphate balance is maintained predominantly by an increase in fractional phosphate excretion.[170] With moderate renal insufficiency, therefore, filtered phosphate is not greatly increased and the increase in phosphate excretion must be achieved by a reduction in phosphate reabsorption per nephron.[171] With more severe reductions in GFR, however, phosphate excretion is maintained by an increase in serum phosphate as well as reduced reabsorption per nephron. Sodium-dependent phosphate transport measured in proximal tubular brush border membrane vesicles prepared from the remnant kidneys of dogs was shown to be decreased when compared to that in vesicles derived from normal dogs.[122] Interestingly, however, this decrease was abolished if the partially nephrectomized dog had also undergone parathyroidectomy, indicating that PTH plays an important role in proximal tubular adaptation to phosphate excretion. Studies of isolated proximal tubules from eu-parathyroid uremic rabbits showed a reduction in net phosphate flux per unit of reabsorptive surface area, and an increase in sensitivity to PTH.[124] The authors postulated that the number of PTH receptors per tubule must increase in the remnant kidney, concomitant with tubular hypertrophy. The levels of mRNA encoding the sodium coupled phosphate transporter, NaPi-2 are reduced by approximately 50% in remnant kidneys from 5/6 nephrectomized rats.[172] In contrast, tubules from hyperparathyroid uremic rabbits demonstrated reduced PTH sensitivity, consistent with down-regulation or persistent occupancy of the PTH receptors. On the other hand, studies in animals with reduced renal mass subjected to parathyroidectomy have shown that fractional excretion of phosphate remains inversely proportional to the reduction in GFR,[173] indicating that phosphate excretion is not entirely dependent on the presence of PTH. Whereas most of the reduction in phosphate reabsorption is achieved in the proximal tubule, there is also some evidence of increased fractional phosphate excretion by the distal tubule in uremic dogs and rats.[174] As kidney failure advances, renal 1-hydroxylation of vitamin D decreases, and as a result, calcium absorption from the gut is reduced.[175] In renal failure, fractional intestinal calcium absorption is inversely proportional to blood urea nitrogen.[175] Calcium excretion, on the other hand, varies widely in patients with renal disease, probably due to differences in diet, heterogeneity of vitamin D production, and predominance of glomerular versus tubulointerstitial injury.[176] In normal individuals, calcium excretion is mediated by suppression of PTH-induced reabsorption in the distal nephron, and by suppression of PTH-independent mechanisms in the thick ascending limb. In patients with CKD, fractional calcium excretion remains unchanged until GFR falls below 25 mL/min, when fractional excretion increases due to the obligatory solute diuresis.[140] Absolute calcium excretion, however, remains low. Hypocalciuria in patients with chronic renal insufficiency has been shown to be due, in part, to the attendant hyperparathyroidism.[177] Similar findings were obtained in rats with reduced renal mass, in which parathyroidectomy resulted in increased calcium excretion compared to non-parathyroidectomized controls.[178] Renal calcium clearance is increased in patients with tubulointerstitial disease and in rats with surgical papillectomy, suggesting that regulation of calcium reabsorption depends on intact medullary structures, and that regulation of calcium excretion may be largely modulated by the distal nephron segments.[140] The potential contribution of calcium and phosphate to renal disease progression are discussed later. Calcium and phosphate metabolism are also discussed in greater detail in Chapters 5 and 16 .


The functional and structural adaptations to nephron loss described earlier may be regarded as a beneficial response that minimizes the resultant loss of total GFR. It has been appreciated for several decades, however, that rats subjected to partial nephrectomy subsequently develop hypertension, albuminuria, and progressive renal failure. Detailed histopathological studies in rat remnant kidneys after 5/6 nephrectomy revealed mesangial accumulation of hyaline material that progressively encroached on capillary lumina, obliterating Bowman's space and finally resulting in global sclerosis of the glomerulus. These findings, together with the observation that sclerosed glomeruli are a common finding in human CKD of diverse etiologies, led to the hypothesis that glomerular hyperfiltration ultimately results in damage to remaining glomeruli and contributes to a vicious cycle of progressive nephron loss. The 5/6 nephrectomy model has been extensively studied and considerable progress has been made in elucidating how the physiological adaptations of remaining nephrons that initially permit greatly augmented function per nephron, ultimately produce a complex series of adverse effects that eventuate in progressive renal injury and an inexorable decline in function.[6]

Hemodynamic Factors

As early as 1 week after extensive renal mass ablation, glomerular hyperfiltration and glomerular capillary hypertension were associated with morphological changes, including visceral epithelial cell cytoplasmic attenuation, protein reabsorption droplets and foot process fusion, mesangial expansion and focal lifting of endothelial cells from the basement membrane.[6] Evidence that these morphological changes were a consequence of the glomerular hemodynamic alterations was provided by studies in rats fed a low protein diet after 5/6 nephrectomy. This intervention prevented the hemodynamic changes, effectively normalizing QA, PGC, and SNGFR, and abrogated the structural lesions observed in rats on standard diet.[6] Similar findings were subsequently described in a variety of animal models of CKD, including diabetic nephropathy [179] [180] and deoxycorticosterone (DOCA)-salt hypertension.[181] Together, these observations led Brenner and colleagues to propose that the hemodynamic adaptations following renal mass ablation ultimately prove injurious to glomeruli and initiate processes that eventuate in glomerulosclerosis. The resulting obliteration of further glomeruli would induce hyperfiltration in remaining, less affected glomeruli, thereby establishing a vicious cycle of progressive nephron loss. These mechanisms constituted a “common pathway” for renal damage that could account for the inexorable progression of CKD, regardless of the cause of the initial renal injury.[3] The hypothesis also explained the finding of both atrophic and hypertrophic nephrons typically encountered in chronically diseased kidneys. Further evidence supportive of the “hyperfiltration hypothesis” was gleaned from the study of experimental diabetic nephropathy in which glomerular hyperfiltration was also found to be a forerunner of glomerular pathology. [6] [180] Maneuvers such as unilateral nephrectomy, which exacerbates hyperfiltration in the remaining kidney, were also found to exacerbate diabetic renal injury.[182]Furthermore, when the kidney was shielded from elevated perfusion pressure and from glomerular capillary hypertension by creating unilateral renal artery stenosis, the ipsilateral kidney was protected against the development of diabetic injury, which progressed unabated in the contralateral kidney.[183] In addition, when glomerular hyperfiltration was reversed in 5/6 nephrectomized rats by transplantation of an isogeneic kidney, hypertension and proteinuria were ameliorated, and glomerular injury was limited.[184] Similarly, augmenting renal mass in the Fisher➙Lewis rat transplant model normalized PGC and greatly reduced the development of chronic renal allograft injury. [185] [186]Direct evidence that similar mechanisms may operate in human kidneys is derived from a study of 14 patients with solitary kidneys who had undergone varying degrees of partial nephrectomy of the remaining kidney for malignancy.[187] Before renal sparing surgery, proteinuria was absent in all patients. Although serum creatinine remained stable after an initial rise of 50% in 12 patients, the two patients subjected to the most extensive nephrectomy (75% and 67%, respectively) developed progressive renal failure and required long-term dialysis. Moreover, among the remaining patients, seven developed proteinuria, the levels of which were inversely related to the amount of renal tissue preserved. Renal biopsy specimens in four patients with moderate to severe proteinuria showed FSGS,[187] which later morphometric analysis revealed to involve virtually all glomeruli examined.[188]

The importance of glomerular hemodynamic factors in the development of progressive renal injury was further illustrated by studies that reported dramatic protective effects against the development of glomerulosclerosis after chronic inhibition of the RAS with either ACEI or AT1RA treatment in 5/6 nephrectomized rats. [15] [16] [17] [18] Micropuncture studies showed that like the low protein diet, the renoprotective effects of RAS inhibition were associated with near normalization of the PGC, yet, in contrast to the effects of dietary protein restriction, SNGFR remained elevated.[189] This suggested that glomerular capillary hypertension, rather than hyperfiltration per se, was the key factor in the initiation and progression of glomerular injury. Confirmation of this view came from an experiment in which rats were treated with a combination of reserpine, hydralazine, and hydrochlorothiazide (“triple therapy”) to lower arterial pressure to levels similar to those obtained with an ACEI. In contrast to the glomerular hemodynamic effects of the ACEI, however, triple therapy did not alleviate glomerular hypertension or proteinuria and glomerular injury progressed unabated [16] [17] ( Fig. 25-3 ). Interestingly, within the context of pharmacological inhibition of the RAS, the level to which systemic blood pressure is reduced remains a critical determinant of the extent of the renal protection conferred.[190] The effectiveness of both ACEI and AT1RA in lowering glomerular pressure and ameliorating glomerular injury has since been observed in several other animal models of chronic kidney disease, including diabetic nephropathy, [179] [191] [192] hypertensive renal disease, [193] [194] experimental chronic renal allograft failure (a model that lacks systemic hypertension but exhibits glomerular capillary hypertension), [195] [196] [197] age-related glomerulosclerosis, [198] [199] and obesity-related glomerulosclerosis.[200] It is noteworthy that the phase of transition from an acute, nonhypertensive experimental injury induced by PAN administration, to a chronic nephropathy characterized by proteinuria and glomerulosclerosis, is also associated with the development of glomerular capillary hypertension.[201] That similar mechanisms are relevant in human CKD progression has been strongly suggested by the results of clinical trials showing substantial renoprotective effects with ACEI and AT1RA treatment. [202] [203] [204] [205] [206] The importance of glomerular capillary hypertension has been further illustrated by studies of the effects of Omapatrilat, a vasopeptidase inhibitor. Micropuncture studies after 5/6 nephrectomy showed even greater lowering of PGC with Omapatrilat than with ACEI treatment, despite equivalent effects on systemic blood pressure. In subsequent chronic studies, Omapatrilat produced more effective renoprotection than the ACEI.[72] Thus, among the determinants of glomerular hyperfiltration, glomerular capillary hypertension has been identified as a critical factor in the initiation and progression of glomerular injury.



FIGURE 25-3  Proteinuria levels following 5/6 nephrectomy in untreated rats (NX) versus treatment with triple therapy (reserpine, hydralazine, and hydrochlorothiazide—TRx), (NX + TRx), or enalapril (NX + ACEI). Despite equivalent levels of blood pressure control, enalapril therapy almost completely prevented proteinuria and glomerulosclerosis whereas triple therapy afforded no renoprotection.  (Reproduced with permission from Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77:1993–2000, 1986.) *P < 0.05 versus untreated controls.




Mechanisms of Hemodynamically Induced Injury

Mechanical Stress

Several mechanisms have been proposed whereby elevated PGC may result in glomerular cell injury. Experiments in isolated perfused rat glomeruli have reported significant increases in glomerular volume with increases in perfusion pressure over the normal and relevant abnormal range.[91] These increases in wall tension and glomerular volume can be predicted to result in stretching of glomerular cells. Experimental evidence suggests that such stretching may have adverse consequences for all three major cell types in the glomerulus. Furthermore, recent advances in the study of cellular responses to mechanical stress raise the possibility that glomerular hyperperfusion may also promote the development of glomerulosclerosis through more subtle and complex pathways that induce profibrotic phenotypic alterations in glomerular cells.[207]

Endothelial Cells

The vascular endothelium serves multiple complex functions including acting as a dynamic barrier to leukocytes and plasma proteins, secretion of vasoactive factors (prostacyclin, NO, and endothelin), conversion of AI to AII, and expression of cell adhesion molecules. It is also the first cellular structure in the kidney that encounters the mechanical forces imparted by glomerular hyperperfusion. After 5/6 nephrectomy, endothelial cells are activated or injured, resulting in detachment and exposure of the basement membrane. This in turn may induce platelet aggregation, deposition of fibrin, and intracapillary microthrombus formation. [6] [208] It has been recognized for some time that segmental glomerulosclerosis is associated with focal obliteration of capillary loops[209] and that interstitial fibrosis is associated with loss of peritubular capillaries.[210] Recently it has been shown that this loss of capillaries in the remnant kidney is associated with a decrease in endothelial cell proliferation and reduced constitutive expression of vascular endothelial growth factor (VEGF) by podocytes and renal tubule cells as well as increased expression of the anti-angiogenic factor, thrombospondin-1, by the renal interstitium.[211] Because VEGF is an important endothelial cell angiogenic, survival, and trophic factor, these findings suggest that capillary loss may be in part due to failure of recovery from hemodynamically mediated endothelial cell injury. Furthermore, short-term treatment of rats with VEGF ameliorated both glomerular and peritubular capillary loss after 5/6 nephrectomy.[212] This preservation of capillaries was associated with a trend toward less glomerulosclerosis and significantly less interstitial deposition of type III collagen, as well as better preservation of renal function. Long-term studies are required to evaluate further the potential benefit of improving renal angiogenesis in the setting of progressive renal injury.

Endothelial cells bear numerous receptors that allow them to detect and respond to changes in mechanical forces. Thus exposure of endothelial cells to changes in shear stress, cyclic stretch, or pulsatile barostress that result from glomerular hyperperfusion may induce changes in expression of genes involved in inflammation, cell cycle control, apoptosis, thrombosis, and oxidative stress.[213] The in vitro responses of endothelial cells to mechanical forces have largely been studied in the context of vascular remodeling and atherosclerosis but it can readily be appreciated that similar responses may impact on the development of inflammation and fibrosis within the remnant kidney. Of particular interest are observations that shear stress can stimulate endothelial expression of adhesion molecules[214] and proinflammatory cytokines.[215] It is clear from the earlier discussion why biomechanical activation has been described as an “emerging paradigm” in endothelial cell biology[216] but further studies focusing on glomerular endothelial responses to mechanical stress are required to elucidate the role of such mechanisms in progressive renal injury.

Mesangial Cells

Mesangial cells are closely associated with the capillaries in the glomerulus and are therefore also exposed to mechanical forces. Evidence from in vitro studies indicates that mesangial cells respond to changes in these mechanical forces in ways that may promote inflammation and fibrosis. Subjecting mesangial cells to cyclical stretch or strain has been shown to induce proliferation[217] and synthesis of extracellular matrix constituents. [218] [219] Cyclical stretch also stimulates synthesis of intercellular cell adhesion molecule (ICAM)-1,[220] monocyte chemoattractant protein (MCP)-1,[220] transforming growth factor (TGF)-b,[221] and its receptor[222] as well as connective tissue growth factor (CTGF).[223] Cyclical stretch also activates the RAS in cultured mesangial cells[224] and AII in turn may induce TGF-β synthesis.[225] Mesangial cells cultured at ambient pressures of 50 mm Hg to 60 mm Hg (i.e., levels corresponding to glomerular capillary hypertension) also show enhanced synthesis and secretion of extracellular matrix when compared with cells grown at “normal” pressures of 40 mm Hg to 50 mm Hg.[226] Exposure of mesangial cells to barostress, achieved by culture under increased barometric pressure, stimulates expression of cytokines including platelet derived growth factor (PDGF)-B[227] and MCP-1.[228] Transduction of mechanical forces by mesangial cells has been associated with tyrosine phosphorylation[229] and protein kinase C-induced increases in S-6 kinase activity.[230]


A growing body of evidence attests to the importance of podocyte injury in a variety of renal diseases and in CKD progression.[231] Podocytes display morphological evidence of injury as early as 1 week after 5/6 nephrectomy[6]and 6 months after uninephrectomy.[232] Increased numbers of podocytes have been observed in the urine from rats after 5/6 nephrectomy and in human CKD.[231] In 5/6 nephrectomized rats the number of podocytes correlated with the severity of proteinuria as well as mean arterial blood pressure, suggesting that podocyte loss may contribute to CKD progression.[233] The importance of podocyte injury in CKD progression is further supported by the observation that amelioration of glomerular damage in 5/6 nephrectomized rats treated with 1,25-dihydroxyvitamin D3 is associated with preservation of podocyte number as well as prevention of podocyte hypertrophy and injury.[234] It has been proposed that progressive loss of podocytes results in adhesions between exposed areas of glomerular basement membrane and parietal epithelial cells. Formation of adhesions between the glomerular tuft and Bowman's capsule in turn allows misdirection of protein-rich glomerular filtrate into the interstitium where it provokes inflammation that further contributes to nephron loss.[235] As podocytes are attached to the outer aspect of the glomerular basement membrane it is reasonable to expect that they would be exposed to increased mechanical forces resulting from glomerular hypertension. Confirmation that podocytes respond to such physical forces is derived from several in vitro experiments that examined podocyte responses to stretching. Activation of a voltage-sensitive potassium channels was observed in response to stretching of the podocyte cell membrane[236] and culture of podocytes under constant stretch inhibited podocyte proliferation.[237] Exposure to cyclical stretching that mimics pulsatile strain within the glomerulus has been shown to cause reorganization of the actin cytoskeleton,[238] up-regulation of COX-2 and E-prostanoid 4 receptor expression[239] as well as podocyte hypertrophy.[240] In another experiment cyclical stretching of podocytes was associated with increased production of AII and TGF-β as well as up-regulation of angiotensin subtype 1 receptors resulting in increased AII-dependent apoptosis.[241] Taken together these data suggest that stretch-induced podocyte injury is a further mechanism whereby glomerular hypertension contributes to glomerular injury.

Cellular Infiltration in Remnant Kidneys

Despite the lack of an obvious immune stimulus, an inflammatory cell infiltrate composed predominantly of macrophages and smaller numbers of lymphocytes is observed in remnant kidneys after 5/6 nephrectomy.[242] As discussed earlier it is possible that the glomerular hemodynamic adaptations to nephron loss may provoke an inflammatory cell response through the effects of mechanical forces on endothelial and mesangial cells. Thus up-regulation of renal endothelial adhesion molecules may facilitate egress of leukocytes from the circulation into the mesangium, where they may participate in further renal injury. The recruited cellular infiltrate may constitute an abundant source of potent pleiotropic cytokine products that in turn influence other infiltrating leukocytes, dendritic cells, and kidney cells, stimulating cell proliferation, elaboration of extracellular matrix components, and increased endothelial adhesiveness.[243] Evidence is now emerging that these proposed mechanisms, based largely on in vitro observations, are indeed relevant in vivo. In the 2-kidney, 1-clip model of renovascular hypertension, up-regulated expression of adhesion molecules and TGF-β as well as cell infiltration is observed only in the non-clipped kidney that is exposed to the hypertensive perfusion pressure. [244] [245] In the 5/6 nephrectomy model, coordinated up-regulation of a variety of cell adhesion molecules, cytokines, and growth factors in association with macrophage infiltration has been observed at time points that precede the development of severe glomerulosclerosis. [246] [247]Furthermore, the renoprotection afforded by ACEI or AT1RA treatment in this model was associated with inhibition of cytokine up-regulation and prevention of renal infiltration by macrophages. [247] [248]

Several lines of evidence suggest that this cellular infiltrate contributes to renal injury and is not merely a consequence of it. In one study, multiple linear regression analysis identified glomerular macrophage infiltration in the remnant kidney as a major determinant of mesangial matrix expansion and adhesion formation between Bowman's capsule and glomerular tufts.[242] Furthermore, depletion of leukocytes in rats by irradiation delayed the onset of glomerular injury after renal ablative surgery.[249] Several studies have reported amelioration of the cellular infiltrate and renal injury in the 5/6 nephrectomy model following treatment with the immunosuppressive agent, mycofenolate mofetil. [250] [251] [252] [253] One study found that mycophenolate also lowers PGC, which may account for some of its renoprotective effects.[254] Interestingly, the anti-inflammatory agent, nitroflurbiprofen, which is also a NO donor, has a modest effect to ameliorate remnant kidney injury following 5/6 nephrectomy.[255]

Infiltrating macrophages, although present in the glomeruli of remnant kidney, are chiefly distributed in the tubulointerstitial regions, [242] [247] suggesting that they play a role in the development of the tubulointerstitial fibrosis that accompanies glomerulosclerosis. Further analysis of the cellular infiltrate has also identified mast cells in close proximity to areas of tubulointerstitial fibrosis.[256] It is possible that interstitial infiltrates are recruited as the result of tubulointerstitial cell activation by the downstream effects of cytokines released in the glomeruli. Alternatively it has been proposed that excessive uptake of filtered proteins by tubule epithelial cells stimulates expression of cell adhesion and chemoattractant molecules that recruit macrophages and other monocytic cells to tubulointerstitial areas.[257] The chemokine receptor CCR-1 has been shown to be important in interstitial but not glomerular recruitment of leukocytes. Treatment with a non-peptide CCR-1 antagonist has been shown to reduce interstitial macrophage infiltration and ameliorate interstitial fibrosis in the unilateral ureteric obstruction (UUO) model but data are still lacking in the 5/6 nephrectomy model.[258] Furthermore, antagonism of MCP-1 signaling through gene therapy-induced production of a mutant form of MCP-1 by skeletal muscle resulted in reduced interstitial macrophage infiltration and amelioration of interstitial fibrosis in mice after UUO.[259] Finally, overexpression of the anti-inflammatory cytokine interleukin-10 in rats using an adeno-associated virus serotype 1 vector system was associated with reduced interstitial infiltration and lower levels of MCP-1, RANTES, IFN-g, and IL-2 expression after 5/6 nephrectomy as well as attenuation of proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis.[260] The identification of renal tubule cells expressing α-smooth muscle actin after 5/6 nephrectomy has raised the possibility that tubule cells may undergo transdiffrentiation to a myofibrobast phenotype that contributes to interstitial fibrosis.[261]Furthermore, the renoprotection observed with mycophenolate treatment in 5/6 nephrectomized rats is associated with reductions in interstitial myofibroblast infiltration and collagen type III deposition.[262]

The importance of inflammatory factors acting “downstream” from the hemodynamic changes in the common pathway mechanisms of CKD progression has further been demonstrated by studies using a peroxisome proliferator-activated receptor g (PPARg) receptor agonist.[263] These compounds are primarily used as antidiabetic agents that reduce insulin resistance in type 2 diabetes mellitus. The PPARg receptor is a member of the nuclear receptor superfamily of transcriptional factors and in vitro studies suggest that PPARg receptor agonists may have a wide range of effects including modulation of adipocyte differentiation, macrophage function, and activation of other transcription factors.[263] Rats treated with a PPARg receptor agonist after 5/6 nephrectomy evidenced significant attenuation of the proteinuria and glomerulosclerosis observed in untreated rats, despite the failure of treatment to lower blood pressure. This renoprotection was observed in association with marked reductions in glomerular cell proliferation, glomerular macrophage infiltration, and renal expression of PAI-1 as well as TGF-b.[263] The authors speculate that some of these effects may have resulted from the known actions of PPARg receptor activation to antagonize the activities of the transcription factors AP-1 and NF-kB.

Taken together these findings strongly support the hypothesis that in addition to direct glomerular cell injury, glomerular hemodynamic adaptations to nephron loss provoke a complex series of proiflammatory and profibrotic responses that further contribute to renal damage. Treatments that antagonize the mediators of these responses may therefore be of benefit in slowing the rate of progression of CKD.

Non-hemodynamic Factors in the Development of Nephron Injury Following Extensive Renal Mass Ablation

The weight of evidence in support of the hypothesis that glomerular hemodynamic adaptations are central to progressive renal injury does not exclude the possibility that the kidney may also be affected by a variety of factors not directly attributable to hemodynamic changes. These non-hemodynamic factors have been extensively studied in recent years and may offer new therapeutic targets for future renoprotective interventions.

Transforming Growth Factor-β

TGF-β is associated with chronic fibrotic states throughout the body, including CKD.[264] In vitro TGF-β elicits overproduction of extracellular matrix constituents by mesangial cells and its expression is increased in several experimental models of renal disease including diabetic nephropathy,[265] anti-Thy-1 glomerulonephritis,[266] Adriamycin-induced nephropathy,[267] and chronic allograft nephropathy[268] as well as in human glomerulonephritis,[269] [270] HIV nephropathy,[271] diabetic nephropathy,[272] and chronic allograft nephropathy.[273] The role of TGF-β in renal fibrosis is further illustrated by experiments in which transfection of the gene for TGF-β into one renal artery produced ipsilateral renal fibrosis.[274] In 5/6 nephrectomized rats a twofold to threefold increase in remnant kidney mRNA levels for TGF-β was observed and in situ hybridization revealed elevations in TGF-β mRNA throughout glomeruli, tubules, and interstitium. Treatment with an ACEI or an AT1RA resulted in substantial renal protection and prevented up-regulation of TGF-β. [247] [248] Furthermore, in rats treated with an ACEI or an AT1RA the extent of glomerulosclerosis correlated closely with remnant kidney TGF-β mRNA levels.[190] Several interventions that inhibit the effects of TGF-β have been shown to afford renoprotection in animal models of renal disease: transfection of the gene for decorin, a naturally occurring inhibitor of TGFb, into skeletal muscle limited the progression of renal injury in anti Thy-1 glomerulonephritis[275]; administration of anti-TGF-β antibodies to salt-loaded Dahl-salt sensitive rats ameliorated the hypertension, proteinuria, glomerulosclerosis, and interstitial fibrosis typical of this model[276]; treatment with Tranilast [n-(3,4-dimethoxycin-namoyl) anthranilic acid; Pharm Chemical, Shanghai Lansheng Corporation, Shanghai, China], an inhibitor of TGF-β–induced extracellular matrix production, significantly reduced albuminuria, macrophage infiltration, glomerulosclerosis, and interstitial fibrosis in 5/6 nephrectomized rats[277]; transfer of an inducible gene for Smad 7, which blocks TGF-β signaling by inhibiting Smad 2/3 activation, inhibited proteinuria, fibrosis, and myofibroblast accumulation after 5/6 nephrectomy[278]; two weeks of treatment with a polyamide compound designed to suppress transcription of the TGF-β gene, significantly reduced proteinuria and prevented up-regulation of TGF-β, connective tissue growth factor (CTGF), collagen type 1 α1, and fibronectin mRNA in the renal cortex as well as suppressing urinary TGF-β excretion and staining for TGF-β by immunofluorescence in salt-loaded Dahl-salt sensitive rats.[279] Another fibrogenic molecule, CTGF, has also been observed to be overexpressed in kidney biopsies from patients with a variety of renal diseases.[280] The specific induction of CTGF expression by exogenous TGF-β in mesangial cells [223] [281] and fibroblasts,[282] together with the finding that blocking antibodies to TGF-β inhibited increased CTGF expression in mesangial cells exposed to high glucose concentrations,[281] suggests that CTGF may serve as a downstream mediator of the profibrotic effects of TGF-β.[283]

Angiotensin II

As discussed earlier, AII plays a central role in the glomerular hemodynamic adaptations observed after renal mass ablation. Angiotensin subtype 1 receptors are, however, distributed on many cell types within the kidney including mesangial, glomerular epithelial, endothelial, tubule epithelial and vascular smooth muscle cells suggesting multiple potential actions of AII within the kidney.[284] Experimental studies have revealed several non-hemodynamic effects of AII that may be important in CKD progression ( Fig. 25-4 ): in isolated, perfused kidneys, infusion of AII results in loss of glomerular size permselectivity and proteinuria, an effect that has been attributed to both hemodynamic effects of AII resulting in elevations in PGC, and a direct effect of AII on glomerular permselectivity.[285] Furthermore, overexpression of angiotensin subtype 1 receptors on podocytes resulted in albuminuria and focal segmental glomerulosclerosis in the absence of hypertension in transgenic rats.[286] In vitro AII has been shown to stimulate mesangial cell proliferation and induce expression of TGF-β, resulting in increased synthesis of extracellular matrix (ECM).[225] In vivo, transfection of rat kidneys with human genes for renin and angiotensinogen, resulted in glomerular ECM expansion within 7 days.[287] AII also stimulates production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells and vascular smooth muscle cells [288] [289] [290] and may therefore further increase accumulation of ECM through inhibition of ECM breakdown by matrix metalloproteinases that require conversion to an active form by plasmin. Other reports indicate that AII may directly induce the transcription of a variety of cell adhesion molecules and cytokines as well as activating the transcription factor, NF-kB [291] [292] [293] and directly stimulating monocyte activation.[294] AII infusion provoked up-regulation of COX-2 expression in rats that was not dependent on blood pressure elevation[295] and 5/6 nephrectomized rats evidenced AII-dependent up-regulation of interstitial COX-2 expression.[296] Finally, AII may have fibrogenic effects via mineralocorticoids (see later). Interestingly AII may also have antifibrotic effects via the angiotensin subtype 2 receptor (AT2). AII appears to up-regulate AT2 receptor expression via an AT2 receptor-dependent mechanism after 5/6 nephrectomy and treatment with an AT2 receptor antagonist exacerbates renal damage.[297] Furthermore overexpression AT2receptors in transgenic mice was associated with reduced albuminuria as well as decreased glomerular expression of platelet derived growth factor-βB chain and TGF-β after 5/6 nephrectomy.[298]



FIGURE 25-4  Scheme depicting the central role of angiotensin II, through hemodynamic and non-hemodynamic effects, in the pathogenesis of progressive renal injury and fibrosis following nephron loss. ECM, extracellular matrix; mf, macrophage; PAI-1, plasminogen activator inhibitor-1; PGC, glomerular capillary hydraulic pressure; TGF-b, transforming growth factor-β.  (Reproduced and revised with permission from Taal MW, Brenner BM: Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists. Kidney Int 57:1803–1817, 2000.)





Observations that aldosterone stimulates collagen synthesis in the myocardium and that spironolactone treatment affords survival benefit in addition to that achieved with ACEI alone in heart failure patients[299] gave impetus to studies investigating the potential role of aldosterone in renal fibrosis. In the remnant kidney model, adrenal hypertrophy and markedly elevated plasma aldosterone levels have been reported. Furthermore, administration of exogenous aldosterone during inhibition of the RAS with combination ACEI and AT1RA therapy in the 5/6 nephrectomy model negates the renal protective effects of the latter.[300] Further evidence of the role of aldosterone was provided by experiments in which rats subjected to adrenelectomy after 5/6 nephrectomy received replacement glucocorticoid but not mineralocorticoid therapy, resulting in less severe renal injury than rats with intact adrenal glands.[301] Mechanisms whereby aldosterone may contribute to renal damage include hemodynamic effects (see earlier), mesangial cell proliferation,[302] and reactive oxygen species production[303] as well as increased production of PAI-1, [304] [305] TGF-β,[306] and CTGF. [307] [308] Early experimental use of aldosterone receptor blockers in 5/6 nephrectomized rats yielded only modest renoprotective effects [300] [309] but one study has found significant amelioration of glomerulosclerosis in 5/6 nephrectomized rats treated with spironolactone, alone or in combination with triple antihypertensive therapy or an AT1RA.[304] In some rats spironolactone was associated with apparent regression of glomerulosclerosis. Furthermore the observed renoprotection was associated with inhibition of renal cortex mRNA levels for PAI-1.[304] Spironolactone has also been shown to ameliorate renal damage in other experimental models including diabetic nephropathy,[307] radiation nephritis,[310] and stroke-prone hypertension.[311] Several small clinical trials have reported renoprotective benefits associated with spironolactone or other aldosterone receptor blockers, generally in combination with ACEI treatment.[312] In the largest study to date (reported only in abstract form) treatment of patients with type 2 diabetes and microalbuminuria with the aldosterone receptor blocker, eplerenone, was associated with greater reduction in albuminuria than ACEI treatment (62% versus 45%) and combination ACEI and eplerenone treatment resulted in an even greater reduction (74%).[313]

Hepatocyte Growth Factor

Investigations have shed light on the role of HGF as a potential anti-fibrotic factor in CKD. Initial studies focused on the property of HGF to ameliorate tubule cell injury in models of renal ischemia [314] [315] but studies in models of CKD suggest that HGF may also ameliorate chronic renal injury through its mitogenic, motogenic, morphogenic, and anti-apoptotic actions.[316] As discussed earlier, HGF is up-regulated in the remaining kidney after uninephrectomy and may play a role in compensatory renal hypertrophy.[111] Further studies have confirmed that HGF and its receptor, c-met, are also up-regulated in the remnant kidney after 5/6 nephrectomy.[317] Furthermore, blockade of HGF action with anti-HGF antibodies resulted in a more rapid decline in GFR and more severe renal fibrosis that was associated with increased ECM accumulation and a greater number of myofibroblasts in the interstitium and tubules. Moreover, in vitro studies revealed that HGF decreased ECM accumulation in proximal tubule cell cultures by increasing expression of collagenases such as matrix metalloproteinase-9 (MMP-9) and decreasing the expression of the endogenous inhibitors of MMPs, tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), and TIMP-2.[317] Multiple experiments have confirmed the renoprotective effects of HGF: the renoprotective effects of ACEI and AT1RA treatment are associated with increased renal expression on HGF mRNA[318]; treatment with anti-HGF antibodies resulted in increased TGF-β levels in a mouse model of chronic glomerulonephritis[319]; HGF treatment ameliorated the progression of chronic allograft nephropathy in a renal transplant model[320]; HGF blocked the TGF-β induced transdifferentiation of tubule epithelial cells to myofibroblasts[321]; exogenous HGF administration[321] or HGF over-expression[322] blocked myofibroblast activation and prevented interstitial fibrosis in the unilateral ureteric obstruction model; HGF gene transfer into skeletal muscle ameliorated glomerulosclerosis and interstitial fibrosis after 5/6 nephrectomy[323]; HGF treatment suppressed CTGF expression and attenuated renal fibrosis after 5/6 nephrectomy.[324] In contrast, other studies have reported adverse renal effects associated with excess HGF exposure: transgenic mice that over-expressed HGF developed progressive renal disease characterized by tubular hypertrophy, glomerulosclerosis, and cyst formation[325] and HGF administration resulted in more rapid deterioration of creatinine clearance as well as increased albuminuria in obese db diabetic mice.[326] Available evidence thus suggests that HGF may play a role in ameliorating chronic renal injury but inappropriate or excessive exposure to HGF may have adverse renal effects.

Bone Morphogenetic Protein-7

Bone morphogenetic protein (BMP)-7, also termed osteogenic protein-1, is a bone morphogen involved in embryonic development and tissue repair. Preliminary evidence suggests that BMP-7 may also play a role in renal repair. BMP-7 is down-regulated after acute renal ischaemia,[327] early in the course of experimental diabetes[328] and after 5/6 nephrectomy.[329] Furthermore administration of exogenous BMP-7 increased tubular regeneration after 5/6 nephrectomy,[329] attenuated interstitial inflammation and fibrosis after UUO,[330] and ameliorated glomerulosclerosis in rats with diabetic nephropathy.[331] In vitro experiments have identified several potential renoprotective effects attributable to BMP-7 including inhibition of proinflammatory cytokine as well as endothelin expression in tubule cells exposed to TNF-α,[332] reversal of renal tubule epithelial to mesenchymal cell transdifferentiation,[333]and antagonism of the fibrogenic effects of TGF-β in mesangial cells.[334] The renoprotective effect is further illustrated by the observation that expression of a transgene for BMP-7 in podocytes and proximal renal tubule cells was associated with prevention of podocyte drop-out as well as amelioration of albuminuria, glomerulosclerosis, and interstitial fibrosis after induction of diabetes.[335] Further experiments are required to evaluate the potential renoprotective effects of chronic BMP-7 administration after 5/6 nephrectomy.


The consistent observation of renal and in particular glomerular hypertrophy after renal mass reduction has prompted investigators to propose that processes involved in, or resulting from hypertrophy may contribute to progressive renal injury in CKD.[336] The well-documented observation that renal and glomerular hypertrophy precede the development of diabetic nephropathy and the finding of a positive association between glomerular size and early sclerosis in rats subjected to renal mass ablation[337] further suggests that hypertrophy may play a direct role in pathogenesis of glomerulosclerosis. Several clinical observations also support an association between glomerular hypertrophy and renal injury. Oligomeganephronia, a rare congenital condition in which nephron number 25% of normal or less, is characterized by marked hypertrophy of the remaining glomeruli and development of proteinuria and renal failure in adolescence, with FSGS as the typical renal biopsy finding.[338] In children with minimal change disease, a glomerulopathy generally associated with spontaneous remission and lack of progression to renal failure, investigators noted an association between glomerular size and the risk of developing FSGS and renal failure.[339]

Two forms of intervention have been employed in an attempt to interrupt the development of glomerular hypertrophy after renal mass reduction and thereby assess its role in renal disease progression. Rats subjected to 5/6 nephrectomy were compared to rats in which 2/3 of the left kidney was infarcted and the right ureter drained into the peritoneal cavity (an intervention that apparently results in decreased renal clearance without compensatory renal hypertrophy). Micropuncture studies confirmed similar degrees of eleva-tion of PGC and SNGFR in both models. At 4 weeks, however, the maximal planar area of the glomerulus was significantly less and glomerular injury, as assessed by sclerosis index, significantly reduced in ureteroperitoneostomized rats versus 5/6 nephrectomized controls. Accordingly, the authors concluded that glomerular hypertrophy was more important than glomerular capillary hypertension in the progression of glomerular injury in this model.[336] Dietary sodium restriction has also been utilized to inhibit renal hypertrophy after 5/6 nephrectomy. Although sodium restriction had no effect on glomerular hemodynamics, glomerular volume was significantly reduced in 5/6 nephrectomized rats fed low versus normal sodium diets. Moreover, urinary protein excretion was lower and glomerulosclerosis was less severe in rats on restricted sodium intake.[89] These findings were extended by another study in which the effect of sodium restriction in preventing glomerular hypertrophy and ameliorating glomerular injury was confirmed, but that also found that these benefits were overcome by administration of an androgen that stimulated glomerular hypertrophy despite sodium restriction. Glomerular hemodynamics were similar among the groups.[340]

Glomerular hypertrophy may contribute to glomerulosclerosis through a number of different mechanisms. According to the Law of Laplace, the increase in glomerular volume could result in an increase in capillary wall tension only if the capillary wall diameter was also increased. Cyclic stretch would then exert stress capable of damaging epithelial, mesangial, and endothelial cells as described earlier. Alternatively, glomerulosclerosis may be viewed as a maladaptive growth response following loss of renal mass and resulting in excessive mesangial proliferation and extracellular matrix production.[336] In the past there has tended to be a dichotomy of viewpoints regarding the relative importance of hemodynamic factors or hypertrophy in the pathogenesis of glomerulosclerosis. [336] [341] Proponents of the “hypertrophy hypothesis” pointed out that in some experiments a disassociation between glomerular hemodynamic changes and glomerulosclerosis has been observed and that in one study, antihypertensive therapy was renoprotective without lowering PGC.[336] On the other hand, those favoring the “hemodynamic hypothesis” noted that treatment with an ACEI[16] or AT1RA[18] in 5/6 nephrectomized rats resulted in renoprotection without preventing renal or glomerular hypertrophy and that many of the studies purporting to show a positive association between glomerular hypertrophy and sclerosis failed to report glomerular hemodynamic data. Furthermore, rats subjected to ureteroperitoneostomy developed significantly more glomerulosclerosis than sham-operated controls despite a lack of increase in glomerular size.[341] Several other observations suggests that hemodynamic factors override the potential role of hypertrophy in progressive renal damage: the renoprotection achieved after 5/6 nephrectomy by low protein diet (associated with prevention of glomerular hypertrophy) can be reversed by treatment with calcium channel blockers that inhibit renal autoregulation but have no effect on glomerular size[342]; comparison of rats subjected to 5/6 nephrectomy by excision versus infarction of 2/3 of the remaining kidney shows similar increases in glomerular volume but the infarction model is associated with more severe glomerular hypertension and glomerulosclerosis.[7] A growing appreciation of the complexity of the multiple adaptations that follow nephron loss has facilitated the development of a consensus view that continues to regard raised glomerular capillary pressure as a central factor in initiating glomerulosclerosis but also acknowledges that glomerular hypertrophy and other pathogenetic mechanisms may act in concert with hemodynamic factors in a complex interplay that even-tuates in a vicious cycle of progressive renal damage ( Fig. 25-5 ). [207] [343]



FIGURE 25-5  Scheme hypothesizing the interaction of hemodynamic and non-hemodynamic factors in the “common pathway” of mechanisms contributing to progressive nephron loss in chronic renal disease. PGC, glomerular capillary hydraulic pressure; SNGFR, single nephron glomerular filtration rate.  (Reproduced from Mackenzie HS, Taal MW, Luyckx VA: In Brenner BM (ed): The Kidney, 6th ed. Philadelphia, WB Saunders, 2000.)


Altered Glomerular Permselectivity to Proteins

Abnormal excretion of protein in the urine is the hallmark of experimental and clinical glomerular disease. Whereas immune complex deposition and resulting inflammation account for abnormal permeability of the glomerular filtration barrier to proteins in glomerulonephritis, studies in rats subjected to extensive renal ablation have shown loss of glomerular barrier function to proteins of similar molecular size, yet in the apparent absence of primary immune-mediated renal injury or inflammatory response. Sieving studies using dextrans and other macromolecules in rats 7 or 14 days after 5/6 nephrectomy revealed loss of both size and charge-selectivity of the glomerular filtration barrier. Ultrastructural examination of the remnant kidneys revealed detachment of glomerular endothelial cells and visceral epithelial cells from the glomerular basement membrane. In addition, protein reabsorption droplets and attenuation of cytoplasm resulting in bleb formation was observed in podocytes. The authors concluded that the altered permselectivity may be due, in part, to separation of endothelial cells from the glomerular basement membrane allowing access of macromolecules and, in part, to loss of anionic sites in the lamina rara externa resulting in both loss of charge-selectivity and detachment of podocytes.[344] A direct role for AII in modulating glomerular capillary permselectivity is suggested by the observation of marked increases in urinary protein excretion during infusion of AII in normal rats. Although some investigators have attributed this to a direct effect of AII on the cellular components of the glomerular filtration barrier, resulting in opening of interendothelial junctions and epithelial cell disruption, others have shown that the increase in proteinuria may be accounted for almost completely by the associated hemodynamic changes, principally a reduction in QA and an increase in filtration fraction.[345] On the other hand, the notion that AII may mediate changes in glomerular permselectivity independent of its effects on glomerular hemodynamics is supported by studies in an isolated perfused rat kidney preparation in which infusion of AII augmented urinary protein excretion and enhanced the clearance of tracer macromolecules independent of any change in filtration fraction.[285]

Proteinuria, long considered simply a marker of glomerular injury, has also been implicated as an effector of injury processes involved in renal disease progression, especially those resulting in tubulointerstitial fibrosis.[346] In rats with aminonucleoside-induced nephrotic syndrome the proteinuric phase of the disease was associated with an acute interstitial nephritis, the intensity of which correlated closely with the severity of the proteinuria.[257] Furthermore, in an overload proteinuria model induced by daily intraperitoneal administration of bovine serum albumin to uninephrectomized rats, proximal tubule cell injury and interstitial infiltration of macrophages and lymphocytes were evident after 1 week.[347] The severity of the proteinuria showed a positive correlation with the intensity of the infiltrate. At 4 weeks, focal areas of chronic interstitial inflammation were noted.[347] A causative association between excessive proteinuria and interstitial inflammation has been suggested by in vitro studies of proximal tubule epithelial cells cultured in media supplemented with high concentrations of albumin, immunoglobulin (Ig) G, or transferrin. Cellular uptake of these proteins was observed to increase secretion of endothelin-1,[348] MCP-1,[349] RANTES,[350] interleukin-8,[351] and fractaline.[352] Electrophoretic mobility shift assay of cell nucleus extracts revealed intense activation of the transcription factor NF-kB that was dependent on the concentration of protein in the medium.[350] Furthermore, the liberation of these molecules was noted to be predominantly from the basolateral aspect of the cells. This would be in keeping with secretion into the renal interstitium in vivo, thereby contributing to the development of tubulo-interstitial inflammation and fibrosis. Exposure of tubule cells to albumin has also been shown to result in increased levels of intracellular reactive oxygen species and activation of the signal transducer and activator of transcription (STAT) signaling pathway.[353] The STAT pathway in turn mediates a variety of cellular responses including proliferation and induction of cytokines as well as growth factors. Preliminary evidence suggests that exposure of tubule cells to albumin may also induce apoptosis.[354] Other experiments have found apoptosis in tubule cells exposed to high molecular weight plasma proteins but not smaller proteins.[355] Despite this evidence, other investigators have raised important concerns regarding the interpretation of these observations.[356] They point out that the concentrations of plasma proteins used in vitro were non-physiological and far exceeded those observed in proximal tubule fluid from experimental models of nephrotic syndrome. Furthermore many of the experiments were performed in cells that were routinely cultured in the presence of high concentrations of protein (serum) that may significantly alter their phenotype. Finally, not all investigators have been able to confirm the observations. In particular some have found proliferative or profibrotic responses when proximal tubule cells are exposed to serum or serum fractions, but no response after exposure to purified forms of albumin or transferrin, suggesting that factors other than albumin or transferrin may be involved. [357] [358] Thus uncertainty remains regarding the potential tubulotoxic effect of filtered plasma proteins in proteinuric CKD and the specific identity of filtered molecules that may contribute to kidney damage.[356]

Several lines of evidence suggest that proteins other than albumin or immunoglobulin may indeed play a role in the progression of chronic nephropathies. It has been proposed that free fatty acids (FFA) bound to albumin may play an important role provoking a proinflammatory response in tubule cells. In one experiment albumin-βound fatty acids stimulated macrophage chemotactic activity whereas delipidated albumin did not.[359] Albumin-βound FFA has also been shown to activate peroxisome proliferator activated-receptors (PPAR)-γ and induce apoptosis in proximal tubule cells.[360] HDL and LDL have been identified in the urine, renal interstitium and tubule cells in renal biopsies of patients with nephrotic syndrome. In vitro, cultured human proximal tubule epithelial cells take up LDL and HDL.[361] Oxidized LDL may cause tubular cell injury and exposure of tubular epithelial cells to HDL is associated with increased synthesis of endothelin-1. [361] [362] A role has also been proposed for other compounds bound to filtered proteins such as IGF-1, which has been detected in increased amounts in the proximal tubular fluid of rats with adriamycin nephrosis. Proximal tubule cells cultured in the presence of proximal tubular fluid from nephrotic rats exhibit enhanced cell proliferation and increased secretion of type I and type IV collagen. Both effects were inhibited by neutralizing IGF-1 receptor antibodies.[363] Other growth factors in plasma including HGF and TFG-β may also appear in glomerular ultrafiltrate with proteinuria and exert effects on tubule cells.[364] Furthermore cytokines produced in injured glomeruli may have downstream proinflammatory effects. Whereas complement components are normally absent from tubular fluid, C3 and C5b-9 neoantigen were observed along the luminal border of tubule epithelial cells in the protein overload proteinuria model. To examine the role of filtered complement in renal injury, rats with puromycin aminonucleoside nephrosis were subjected to complement depletion with cobra venom factor or inhibition of complement activation by administration of soluble recombinant human complement receptor type 1, before the onset of proteinuria. In control rats, proximal tubular degeneration, interstitial leukocyte infiltrate, and renal impairment (as assessed by inulin and para-aminohippurate (PAH) clearances) occurred at 7 days, together with positive staining for C3 and C5b-9 along the proximal tubule brush border. Both interventions were associated with significantly less tubulointerstitial pathology and greater clearance of PAH but not inulin, whereas the severity of the proteinuria was unaffected, suggesting that filtered complement plays a significant role in the tubulointerstitial injury associated with proteinuria.[365] A more selective approach, using recombinant complement inhibitory molecules targeted to proximal tubule cells with carrier antibodies to brush border antigen resulted in significant reduction of interstitial fibrosis in the same model.[366]

In experimental models of proteinuric renal disease, filtered proteins have also been found to accumulate in the glomerular mesangium344 and may therefore contribute to glomerular as well as tubulointerstitial injury. Further support for this notion is derived from a meta-analysis of 57 studies of experimental CKD that found a consistent positive correlation between the severity of proteinuria and the extent of glomerulosclerosis.[367] Lipoproteins, in particular, accumulate in the glomeruli of patients with glomerulonephritis. [368] [369] Furthermore, low density lipoprotein (LDL) stimulates mesangial cells to proliferate in vitro [370] [371] and enhances mesangial cell synthesis of the extracellular matrix protein, fibronectin.[372] LDL exposure is also associated with increased mesangial cell mRNA levels for MCP-1,[372] and PDGF.[371] Oxidation of LDL by mesangial cells or macrophages may enhance its toxicity.[370] Thus, accumulation of proteins in the mesangium may stimulate a number of different mechanisms that contribute to glomerulosclerosis.

The relevance of these findings to the processes occurring in vivo has been borne out by studies in rats. In the protein-overload model, the development of proteinuria at 1 week was associated with significant increases in TGF-β at both protein and mRNA levels, in interstitial as well as proximal tubule cells.[347] Similarly, renal cortical mRNA levels encoding the macrophage chemoattractant, osteopontin, were increased on day 4 and immunofluorescence localized increased osteopontin staining to cortical tubules at day 7. MCP-1 and osteopontin mRNA and protein levels were elevated at 2 and 3 weeks. Furthermore, a significant effect of proteinuria on molecules involved in ECM protein turnover was observed. Although mRNA levels for various renal matrix proteins were variable, staining for the proteins in the cortical interstitium increased progressively. Levels of mRNA for the protease inhibitors plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were elevated at 2 weeks, at which time significant renal fibrosis was present.[347] Gene expression profiling has identified over 100 genes that are up-regulated in the proximal tubule cells of mice exposed to overload proteinuria.[373] Consistent with the hypothesis that protein-βound FFA are important, rats receiving FFA-replete bovine serum albumin (BSA) developed more severe tubulointerstitial injury and more extensive macrophage infiltration than those receiving FFA-depleted BSA. [374] [375] In other models of proteinuric renal disease including 5/6 nephrectomy and passive Heymann nephritis, accumulation of albumin and IgG by proximal tubule cells occurred before infiltration of the interstitium by macrophages and MHC-II positive mononuclear cells. The infiltrates localized to areas where proximal tubule cells stained positive for intracellular IgG, or where luminal casts were present. Furthermore, proximal tubule cells that stained positive for IgG also showed evidence of increased osteopontin production.[376] The IgG staining in proximal tubule cells was subsequently associated with peritubular accumulation of macrophages and α-smooth muscle actin positive cells as well as up-regulation of TFG-β mRNA in the tubular and infiltrating cells.[377] The importance of inflammatory factors in the development of interstitial fibrosis is illustrated by the observation that treatment of rats with experimental membranous nephropathy with rapamycin was associated with reduced expression of profibrotic and proinflammatory genes as well as amelioration of interstitial inflammation and fibrosis.[378] Further studies in the 5/6 nephrectomy model have suggested that tubulo-interstitial injury may play an important role in the decline of GFR, especially in the late stages of progressive renal injury.[379] By examining serial sections of remnant kidneys, the investigators were able to show that in association with a doubling in serum creatinine, there was a substantial increase in the proportion of glomeruli no longer connected to glomeruli (atubular glomeruli) or connected to atrophic tubules. The majority of these glomeruli were not globally sclerosed, implying that the tubular injury was responsible for the final loss of function in these glomeruli. The authors speculate that the absorption of excess filtered protein may play an important role in this tubular injury.[379] Finally evidence is accumulating of the role of proteinuria in the development of interstitial damage in human CKD. Among 215 patients with CKD, urine albumin to creatinine ratio (ACR) correlated with urinary MCP-1 levels and interstitial macrophage numbers. Furthermore urine ACR and interstitial macrophage number independently predicted renal survival.[380]

Establishing a cause-effect relationship between proteinuria and renal damage in humans is difficult but several clinical studies provide evidence in support of this notion. A meta-analysis of 17 clinical studies of CKD revealed a positive correlation between the severity of proteinuria and the extent of biopsy-proven glomerulosclerosis.[367] Observations from the Modification of Diet in Renal Disease (MDRD) trial also suggest that proteinuria is an independent determinant of CKD progression: greater levels of baseline proteinuria were strongly associated with more rapid declines in GFR; reduction of proteinuria, independent of reduction in blood pressure, was associated with lesser rates of decline in GFR. Furthermore, the degree of benefit achieved by lowering blood pressure below usual target levels, was highly dependent on the level of baseline proteinuria.[381] The severity of proteinuria at baseline has been shown to be the most important independent predictor of renal outcomes in randomized trials of ACEI or AT1RA treatment in diabetic nephropathy[382] and non-diabetic CKD.[203] Furthermore the percentage reduction in proteinuria over the first 3 to 6 months as well as the absolute level of proteinuria at 3 or 6 months are strong independent predictors of the subsequent rate of decline in GFR among patients with diabetic nephropathy[382] and non-diabetic CKD.[383] A meta-analysis that included data from 1860 patients with non-diabetic CKD confirmed these findings and showed that during antihypertensive treatment, the current level of proteinuria was a powerful predictor of the combined end point of doubling of baseline serum creatinine or onset of ESRD (relative risk 5.56 for each 1.0 g/day of proteinuria).[384] Taken together, the evidence from experimental and clinical studies provides support for the hypothesis that impaired glomerular permselectivity results in excessive filtration of proteins and/or protein-βound molecules that contribute to kidney damage but many questions regarding the tubulotoxic potential of filtered plasma proteins and the identity of the specific molecules involved remain unanswered. Despite these uncertainties, the close association between the severity of proteinuria and renal prognosis implies that reduction of proteinuria should be regarded as an important independent therapeutic goal in clinical strategies seeking to slow the rate of progression of CKD.


Pharmacological Inhibition of the Renin-Angiotensin System

Experimental evidence showing a central role for AII in mechanisms of CKD progression through hemodynamic and non-hemodynamic effects has been borne out in randomized clinical trails of ACEI and AT1RA treatment in patients with all forms of CKD. ACEI treatment has been shown to be renoprotective in patients with microalbuminuria and type 2 diabetes mellitus,[385] type 1 diabetes and overt nephropathy,[202] as well as non-diabetic CKD.[203] [206] [386] [387] Treatment with an AT1RA affords renoprotection in patients with type 2 diabetes and microalbuminuria[388] or overt nephropathy. [204] [205] Furthermore at least one large randomized study has reported additional renoprotective benefit among patients with non-diabetic CKD who received combination ACEI and AT1RA treatment versus monotherapy.[389] Evidence is also accumulating that AT1RA treatment at doses higher than previously recommended affords additional renoprotection.[390] One meta-analysis has called into question the importance of RAS inhibition[391] but it should be noted that this study was dominated by data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) study, which found no difference in fatal coronary heart disease or non-fatal myocardial infarction among hypertensive patients with at least one cardiovascular risk factor randomized to treatment with a thiazide diuretic, a calcium channel blocker or an ACEI.[392] In a post hoc analysis there was also no difference in the secondary outcome of ESRD or >50% decrement in GFR but patients with serum creatinine >2 mg/dl were specifically excluded resulting in only a minority of patients (5662 of 33,357) having renal disease (estimated GFR < 60 ml/min/1.73 m2). Furthermore, there was no assessment of proteinuria.[393] Thus inclusion of the ALLHAT data was inappropriate and significantly affected the results of the meta-analysis.[394] Other meta-analyses that did not include ALLHAT data have shown significant renoprotective benefit in patients receiving ACEI treatment. [395] [396] In summary there is now evidence from multiple randomized trials showing significant renoprotection associated with pharmacological inhibition of the RAS in a wide variety of forms of CKD, confirming that AII is a critical mediator of mechanisms of CKD progression in humans and providing support for the consensus that RAS inhibition should be central to treatment strategies for slowing CKD progression.[397] The role of RAS inhibitor treatment in achieving optimal renoprotection is discussed further in Chapter 54 .

Arterial Hypertension

Malignant hypertension frequently leads to renal injury, but whether or not less severe forms of hypertension cause “hypertensive nephrosclerosis” remains a subject of debate. [398] [399] An increased risk of developing progressive renal failure with higher levels of blood pressure has been observed in several population-βased studies [400] [401] [402] [403] and is exemplified by findings from the Multiple Risk Factors Intervention Trial (MRFIT).[404] In a population of 332,544 men there was a strong, graded relationship between blood pressure and the risk of developing or dying with ESRD over a 15- to 17-year follow-up period. Renal function was not assessed at screening or during follow-up, however, so it is not possible to establish with any certainty whether higher blood pressure initiated renal disease or accelerated a nephropathy that was already present. In one study the importance of hypertension as a risk factor for ESRD was further illustrated by the observation that lowering systolic blood pressure by 20 mm Hg reduced the risk of ESRD by two thirds.[401] Even small increases in blood pressure, below the threshold usually used to define hypertension, are associated with an increased risk of ESRD. [400] [402] [405] Hypertension has also been identified as a risk factor for developing albuminuria or renal impairment among patients with type 2 diabetes mellitus.[406]

Whereas the role of hypertension in initiating renal disease requires further clarification, there is clear evidence that hypertension accelerates the rate of progression of preexisting renal disease, most likely through transmission of raised hydraulic blood pressure to the glomerulus resulting in exacerbation of glomerular capillary hypertension associated with nephron loss.[2] Among patients with diabetic nephropathy and non-diabetic CKD, the initiation of antihypertensive therapy results in significant reductions in rates of GFR decline implying that hypertension, an almost universal consequence of impaired renal function, also contributes to the progression of CKD.[407] The potential impact of hypertension on the kidney is exemplified by case reports of patients with unilateral renal artery stenosis who manifested diabetic nephropathy or focal segmental glomerulosclerosis only in the non-stenotic kidney, and not in the stenotic side that was shielded from the hypertension. [408] [409] Uncertainty remains, however, as to what level of blood pressure lowering is required to achieve optimal renoprotection. Several randomized trials have sought to resolve this issue. In the Modification of Diet in Renal Disease (MDRD) study patients with predominantly non-diabetic CKD were randomized to a target MAP of <92 mm Hg (equivalent to <125/75 mm Hg) versus <107 mm Hg (equivalent to 140/90 mm Hg). Whereas there was no difference between the overall rate of change in GFR during a mean of 2.2 years follow-up, patients randomized to the low blood pressure target evidenced an early rapid decrease in GFR, likely due to associated renal hemodynamic effects, which obscured a later significantly slower rate of GFR decline. Furthermore the effect of blood pressure control was strongly modulated by the severity of proteinuria. Among patients with >3 g/day of proteinuria at baseline, randomization to the low blood pressure target was associated with a significantly slower rate of GFR decline.[410] Secondary analysis also revealed significant correlations between the rate of GFR decline and achieved blood pressure, an effect that was more marked among those with greater baseline proteinuria.[411] In study 1 (patients with GFR of 25-55 ml/min/1.73 m2), rates of GFR decline increased above a MAP of 98 mm Hg among patients with baseline proteinuria of 0.25–3.0 g/day, and above 92 mm Hg in those with baseline proteinuria >3.0 g/day. In study 2 (patients with GFR of 13-24 ml/min/m2), higher achieved blood pressure was associated with greater rates of GFR decline at all levels among patients with baseline proteinuria >1 g/day ( Fig. 25-6 ). That the benefits of lower blood pressure may become evident only over a longer period is illustrated by the observation that further follow-up (mean 6.6 years) of patients from the MDRD study revealed a significant reduction in the risk of ESRD (adjusted HR 0.68; 95%CI 0.57–0.82) or a combined end point of ESRD or death (adjusted HR 0.77; 95%CI 0.65–0.91) among patients randomized to the low blood pressure target even though treatment and blood pressure data were not available beyond the 2.2 years of the original trial.[412] In the African American Study of Kidney Disease and Hypertension (AASK) no significant difference in the rate of GFR decline was observed between patients randomized to a MAP goals of ≤92 mm Hg versus 102 mm Hg to 107 mm Hg. It should be noted, however, that patients in AASK generally had low levels of baseline proteinuria (mean urine protein 0.38–0.63 g/day).[387] Thus the MDRD and AASK study results support the notion that lower blood pressure targets afford additional renoprotection in patients with more severe proteinuria. Because not all the patients in the MDRD study received ACEI treatment, it remained unclear to what extent the level of blood pressure attained is important in CKD patients receiving ACEI or AT1RA treatment. Experimental studies have found systolic blood pressure to be a major determinant of glomerular injury in rats receiving either ACEI or AT1RA treatment.[190] [413] Moreover among patients with type 1 diabetes and established nephropathy receiving ACEI treatment, randomization to a low (MAP < 92 mm Hg) versus “usual” (MAP = 100–107 mm Hg) blood pressure target was associated with significantly lower levels of proteinuria after 2 years, although there was no significant difference in GFR decline.[414] On the other hand intensive blood pressure control was not associated with significantly improved renal function among patients with autosomal dominant polycystic kidney disease but, by the authors' own admission, the study may not have had adequate statistical power to detect such a difference.[415] Furthermore, additional blood pressure reduction with a calcium channel blocker in patients with non-diabetic CKD on ACEI treatment failed to produce additional renoprotection but the degree of additional blood pressure reduction was modest (4.1/2.8 mm Hg) and may have been insufficient to improve outcomes in patients already receiving optimal ACEI therapy.[416] On the other hand, secondary analysis of data from the Irbesartan Diabetic Nephropathy Trial (IDNT) did show greater renoprotection among patients who achieved lower blood pressure targets such that achieved systolic blood pressure (SBP) >149 mm Hg was associated with a 2.2-fold increased risk of developing ESRD or a doubling of serum creatinine versus achieved SBP < 134 mm Hg.[417] Importantly, the relationship between improved outcomes and lower achieved SBP persisted among those patients treated with irbesartan. A note of caution from this study was the observation that achieved SBP < 120 mm Hg was associated with increased all-cause mortality and no further improvement in renal outcomes.[417] Whereas the results of randomized trials comparing “low” and “usual” blood pressure targets among CKD patients have not yielded unequivocal results, the overall picture is one of lower blood pressure targets being associated with more effective renoprotection among those with more severe proteinuria. These observations have led to a consensus that blood pressure should be lowered to <130/80 mm Hg in all patients with CKD.[397] Available evidence also supports a somewhat lower target blood pressure of <125/75 mm Hg for patients with significant proteinuria (>1 g/day). [411] [417]



FIGURE 25-6  The interaction of blood pressure reduction and proteinuria at baseline on the rate of decline in glomerular filtration rate.  (Reproduced with permission from Peterson JC, Adler S, Burkart JM, et al: Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 123:754–762, 1995.)




Dietary Protein Intake

Increased dietary protein intake and intravenous protein loading in animals or humans with intact kidneys are associated with increases in renal mass, renal blood flow, and GFR, as well as a decrease in renal vascular resistance. The magnitude of the increases in GFR and renal blood flow in response to a protein load is a function of renal reserve. In patients with renal insufficiency some studies have shown that the percentage increase in GFR in response to a protein meal is reduced in those with a lower baseline GFR. [418] [419] In contrast, a study comparing the renal response to an oral protein load in patients with moderate and advanced renal failure found a similar percent increase in GFR over baseline in both groups, demonstrating that even with advanced renal disease, some renal reserve is still present and that elevated intake of dietary protein may have undesirable effects on glomerular hemodynamics at all levels of renal function.[420]

To understand the mechanisms whereby protein loading acutely augments renal function, various components of protein diets have been examined individually: administration of equivalent quantities of urea, sulfate, acid, and vegetable protein to dogs or humans all failed to reproduce a meat protein-induced rise in GFR. [421] [422] [423] In contrast, feeding or infusion of mixed or individual amino acids (e.g., glycine, L-arginine) was shown to effect increases in GFR of similar magnitude to those seen with meat ingestion. [424] [425] Micropuncture experiments demonstrated that amino acid infusion resulted in increases in glomerular plasma flow and transcapillary hydraulic pressure difference, thereby raising SNGFR without affecting the ultrafiltration coefficient.[424] Interestingly, however, perfusion of the isolated kidney with an amino acid mixture resulted in only a modest increase in GFR.[426]Taken together, these observations suggest that amino acids themselves do not have a major direct effect on renal hemodynamics, but their effects appear to be mediated by an intermediate compound generated only in the intact organism. Glucagon, the secretion of which is stimulated by protein feeding, has been proposed as such a mediator. GFR and renal blood flow increase in response to glucagon infusion in dogs.[425] Furthermore, administration of the glucagon antagonist, somatostatin, consistently blocks amino acid-induced augmentation in renal function both in humans and rats. [424] [427] Large protein meals are also rich in minerals, potassium, phosphate, and acids. Indeed, after feeding a protein meal to dogs, the excretions of sodium, potassium, phosphorus, and urea were found to increase in parallel to the increase in GFR.[421] On the other hand, sodium chloride reabsorption in the proximal tubule and loop of Henle was found to be increased in rats maintained on a high protein diet.[428] As result, less sodium and chloride would be delivered to the macula densa, thereby inhibiting tubulo-glomerular feedback and adding a further stimulus to renal hyperemia. Because dietary protein does not affect systemic blood pressure,[424] other factors have been suggested to contribute to the renal hemodynamic changes following a protein load. Administration of the nitric oxide inhibitor L-NMMA or non-steroidal anti-inflammatory agents have been shown to blunt the renal hyperemic response to an oral protein load in both rats and humans, invoking a role for nitric oxide and prostaglandins. [428] [429] In addition, AII and endothelin have been proposed as mediators of protein-induced renal injury as low protein diets have been shown to reduce renal endothelin-1, endothelin receptors A and B, and AT1receptor mRNA expression in PAN-injected and normal rats. [430] [431]

It has been proposed that the augmented renal function induced by dietary protein may be an evolutionary adaptation of the kidney to the intermittent heavy protein intake of the hunter-gatherer.[3] Renal hyperfunction following a protein load would serve to facilitate excretion of the waste products of protein catabolism and other dietary components thereby achieving homeostasis in the face of an abrupt increase in consumption in times of nutritional plenty; the subsequent decline of GFR to baseline during the intervals between meals would then favor mechanisms suited to conservation of fluid and electrolytes in times of scarcity. Persistent renal hyperfunction due to continuous excessive protein intake, however, leads to renal injury in experimental models. Laboratory animals with intact kidneys and ingesting food ad libitum become proteinuric and develop glomerulosclerosis with age. [3] [131] [432] This progression was significantly attenuated by feeding animals on alternate days only.[131] Furthermore, aging rats fed a high protein diet ad libitum showed marked acceleration and increased severity of renal injury compared to rats receiving a normal protein diet, whereas rats fed a low protein diet were protected from renal injury.[432] Similarly, in diabetic rats, progression of nephropathy was markedly accelerated in the setting of a high protein diet and substantially attenuated by a low protein diet.[180] In this study, kidney weight in high-protein-fed diabetic rats was significantly greater than in diabetic rats receiving normal protein diets, suggesting that protein-induced renal hypertrophy may itself contribute to acceleration of renal functional deterioration. As discussed earlier, the renoprotective effects of dietary protein restriction in experimental animals are associated with virtual normalization of PGCand SNGFR.[6]

Despite unambiguous evidence from experimental studies, confirmation of a beneficial effect of protein restriction in clinical trials has proved elusive. Following the publication of several smaller studies that generally suggested a beneficial effect from protein restriction but that suffered from deficiencies in design or patient compliance, a large, multicenter, randomized study, the MDRD study, was conducted to resolve the issue.[410] Five hundred eighty-five patients with moderate chronic renal failure (GFR = 25–55 ml/min/1.73 m2) were randomized to “usual” (1.3 g/kg/day) or “low” (0.58 g/kg/day) protein diet (study 1) and 255 patients with severe chronic renal failure (GFR = 13–24 ml/min/1.73 m2) to “low” (0.58 g/kg/day) or “very low” (0.28 g/kg/day) protein diet. All causes of CKD were included but patients with diabetes mellitus requiring insulin therapy were excluded. Patients were also assigned to different levels of blood pressure control. After a mean of 2.2 years follow-up, the primary analysis revealed no difference in the mean rate of GFR decline in study 1, and only a trend toward a slower rate of decline in the “very low” protein group in study 2. Secondary analyses of the MDRD data, however, revealed that dietary protein restriction probably did achieve beneficial effects. In study 1 “low” protein diet was associated with an initial reduction in GFR that likely resulted from the functional effects of decreased protein intake and not from loss of nephrons. This initial reduction in GFR obscured a later reduction in the rate of GFR decline that was evident after 4 months in the “low” protein group and that may have resulted in more robust evidence of renoprotection had follow-up been continued for a longer period.[433] Despite inconclusive findings in several of the individual studies, three meta-analyses have each concluded that dietary protein restriction is associated with a reduced risk of ESRD (odds ratio of 0.62 and 0.67, respectively) [434] [435] as well as a modest reduction in the rate of estimated GFR decline (0.53 ml/min/year).[436] Whereas the renoprotective benefit of dietary protein restriction in humans appears modest, such dietary restriction is associated with other benefits including improvement in acidosis as well as reduction in phosphorus and potassium load. Thus comprehensive dietary intervention with a moderate restriction in dietary protein intake should remain an important part of the treatment of patients with CKD.[437] The interaction of diet and kidney disease is discussed further in Chapter 53 .


Laboratory studies indicate that male animals appear to be at greater risk of developing renal disease and of disease progression than females. Age-associated glomerulosclerosis is much more pronounced in male than in female rats and it is notable that the male propensity for age-related glomerulosclerosis can be prevented by castration.[438] This gender difference was found to be independent of PGC or glomerular hypertrophy, suggesting a role for the sex hormones as modulators of renal injury. Ovariectomy, on the other hand, had no effect on the development of glomerular injury seen in non-ovariectomized female rats, implying that the presence of androgens, and not the lack of estrogens promotes renal injury. [438] [439] By contrast, in the hypercholesterolemic Imai rat the development of spontaneous glomerulosclerosis in males can be significantly reduced by castration, or by administration of exogenous estrogens. [440] [441] These data again suggest an important role for androgens in the development of renal injury, and raise the possibility that estrogens may to some extent counteract the adverse effects of androgens. In an apparently conflicting observation, female Nagase analbuminemic rats develop renal injury of greater severity than males, a characteristic that is ameliorated by ovariectomy.[442] These rats may be unique, however, in that triglyceride levels, which are higher in females, may have an independent and overriding effect on renal disease propensity. Glomerulosclerosis also develops to a significantly greater extent in male versus female rats subjected to extensive renal ablation.[443] This difference was independent of blood pressure and glomerular hypertrophy, but the degree of glomerulosclerosis and the extent of mesangial expansion each were found to correlate significantly with an increased expression of glomerular procollagen α1(IV) mRNA in males. Similarly, in aging Munich-Wistar rats, glomerular metalloproteinase activity was found to decrease with age in males but not in females or castrated rats, suggesting that suppression of metalloproteinase activity by androgens could account for the gender difference in disease susceptibility.[444] Finally, estrogens, but not androgens possess anti-oxidant activity and have been shown to inhibit mesangial cell LDL oxidation,[445] a property that may contribute to renoprotection.

Clinical studies suggest that humans also evidence a gender difference with respect to CKD progression. Data from the United States Renal Data System show a substantially higher incidence of ESRD among males (413/million population in 2003) versus females (280/million population)[446] and several studies have reported worse renal outcomes in males. In a Japanese community-βased mass screening program the risk of developing ESRD (if baseline serum creatinine was greater than 1.2 mg/dl for males or 1 mg/dl for females) was almost 50% higher in men than in women.[447] In a large population-βased study in the United States, male gender was associated with a significantly increased risk of ESRD or death associated with CKD.[402] Similarly, in France, studies of factors influencing development of ESRD in patients with moderate and severe renal disease found that disease progression was accelerated in males versus females, especially in those with chronic glomerulonephritis or ADPKD. Furthermore, the effect of hypertension as a risk factor for CKD progression appeared to be greater in males. [448] [449] Other studies of patients with established CKD have reported a lower risk of ESRD among female patients with CKD stage 3[450] and a shorter time to renal replacement therapy among male patients with CKD stage 4 and 5.[451] One meta-analysis of 68 studies that included 11,345 patients with CKD reported a higher rate of decline in renal function in men[452] but another meta-analysis of individual patient data from 11 randomized trials evaluating the efficacy of ACEI treatment in CKD did not show an increased risk of doubling of serum creatinine or ESRD, or ESRD alone among men.[453] On the contrary, after adjustment for baseline variables including blood pressure and urinary protein excretion women evidenced a significantly higher risk of these end points than men.[453] One limitation of these studies is that the menopausal status of the women was often not documented. In general, the prevalence of hypertension and uncontrolled hypertension is higher among men; men tend to consume more protein than women; the prevalence of dyslipidemias is greater in men than premenopausal women. All of these factors may contribute to the increased severity of renal disease observed in men but they do not explain all of the differences. [454] [455] The role of gender in kidney disease is extensively reviewed in Chapter 20 .

Nephron Endowment

Experimental and clinical studies have shown that the number of nephrons per kidney is variable and may be influenced by several factors during development in utero. Furthermore low nephron endowment predisposes individuals to CKD. It has been proposed that reduced nephron endowment results in an increase in single nephron GFR and therefore a reduction in renal reserve.[456] Whereas the glomerular hemodynamic changes associated with mild-moderate congenital nephron deficiencies may not in themselves be sufficient to provoke renal injury, they could be predicted to compound the effects of an acquired nephron loss and predispose the individual to progressive renal damage. Thus CKD should be viewed as a “multi-hit” process in which the first “hit” may be reduced nephron endowment.[457] Nephron endowment is discussed in detail in Chapter 19 .


African Americans comprise only 12.4% of the total U.S. population but account for 30.8% of the U.S. ESRD population.[458] In the age group from 20 to 44 years, there are 18 African Americans for every white patient with ESRD.[459] The reasons for this obvious discrepancy are complex and include both social and biological factors. [460] [461] Interestingly, data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study show a lower prevalence of estimated GFR 50-59 ml/min/1.73 m2 among Africa American versus white subjects but a higher prevalence of estimated GFR 10-19 ml/min/1.73 m2 suggesting that African Americans have a lower risk of developing CKD but a higher risk of progression of CKD to ESRD.[462]

African Americans appear to be more susceptible to focal and segmental glomerulosclerosis (FSGS). One retrospective analysis of 340 routine kidney biopsies detected a significantly higher prevalence of FSGS and a significantly lower prevalence of membranous glomerulonephritis, IgA, and immunotactoid nephropathies among black versus white patients.[463] Similarly, among pediatric transplant recipients a higher proportion of African American and Hispanic children had FSGS as a primary diagnosis versus whites.[464] The same investigators found that despite similar treatment modalities and similar durations of nephrotic syndrome, black children with FSGS reached ESRD almost twice as frequently as white children.[464]

More significant in terms of patient numbers and morbidity, however, are the racial discrepancies in the incidence of ESRD due to hypertensive and diabetic nephropathies. Among hypertensive patients undergoing treatment, the risk of decline in renal function in black patients was found to be almost twice that of whites.[465] This finding of increased risk persisted after controlling for the effects of diabetes, blood pressure levels, heart failure, and male gender. Similarly, in the MRFIT trial, despite similar levels of blood pressure control in black versus white men, renal function deteriorated more rapidly in the black men.[466] MDRD study data showed the prevalence of hypertension to be higher in blacks versus whites among patients with CKD, despite a higher mean GFR in the black patients.[455] Hypertensive patients were found to have had more rapid progression of renal disease prior to entry into the study, suggesting that the higher prevalence of hypertension in black patients is likely to be a significant contributor to accelerated progression of CKD. On the other hand both higher mean arterial pressure and black race were independent predictors of a faster decline in GFR in the MDRD study.[467] In a large community- based epidemiological study, black patients were found to have a 5.6 times higher unadjusted incidence of hypertensive ESRD with respect to the entire study population.[468] This increased incidence was directly related to the prevalence of hypertension, severe hypertension, and diabetes in the study population, and inversely related to age at diagnosis of hypertension and socioeconomic status. After adjustment for these factors the risk of hypertensive ESRD remained 4.5 times greater among blacks compared to whites, providing further evidence that black patients have an increased susceptibility to renal disease beyond that attributable to their increased prevalence of hypertension and diabetes. Salt-sensitive hypertension, in particular, is more prevalent in the black population than in the white population.[469] Comparing renal responses to a high sodium intake in salt-sensitive versus salt-resistant patients, renal blood flow was found to decrease in the face of an increased filtration fraction (implying an increased PGC) in salt-sensitive patients whereas the converse occurred in salt-resistant patients.[398] These observations are consistent with the notion that salt loading injures the glomerulus through glomerular capillary hypertension and that salt-sensitive individuals, and blacks in particular, are at added risk of this form of injury. The incidence of ESRD due to diabetic nephropathy is fourfold higher among African Americans than among white Americans.[458] It is notable that after controlling for the higher prevalence of diabetes and hypertension as well as age, socioeconomic status, and access to health care, the excess incidence of ESRD due to diabetes in blacks versus whites was confined to type 2 diabetics.[470] Among type 1 diabetics, blacks were not found to be at higher risk than whites. Indeed, the majority of blacks with diabetic ESRD (77%) had type 2 diabetes whereas the majority of whites with diabetic ESRD (58%) had type 1 diabetes.[471]Black race was also found to be associated with a threefold higher risk of early renal function decline (increase in serum creatinine of ≤0.4 mg/dl) among adults with diabetes.[472]

Several potential factors contributing to the different prevalence and severity of renal disease among population groups have been analyzed. Adjustment for socioeconomic factors reduces, but does not eliminate the increased risk of African Americans to develop ESRD. [458] [461] [472] African Americans have lower birth weights than their white counterparts and may therefore have programmed or genetically determined deficits in nephron number, rendering them more susceptible to hypertension and subsequent ESRD. [473] [474] Finally, 40% of African-American patients with hypertensive ESRD and 35% with type 2 diabetes associated ESRD have first-, second-, or third-degree relatives with ESRD implying a strong familial susceptibility to ESRD and therefore a genetic predisposition.[475] Other ethnic groups including Asians, [406] [476] Hispanics,[477] Native Americans,[478] Mexican Americans,[479]and Australian Aboriginals[480] have also been found to be at increased risk of developing CKD and ESRD.

Obesity and Metabolic Syndrome

Obesity may directly cause a glomerulopathy characterized by proteinuria and histological features of focal and segmental glomerulosclerosis[481] but it is likely that it also exacerbates progression of other forms of CKD. Micropuncture studies have confirmed that obesity is another cause of glomerular hypertension and hyperfiltration that may contribute to the progression of CKD. [482] [483] Detailed investigation of adipocyte function has revealed that they are not merely storage cells but produce a variety of hormones and proinflammatory molecules that may contribute to progressive renal damage.[484] In humans severe obesity is associated with increased renal plasma flow, glomerular hyperfiltration, and albuminuria, abnormalities that are reversed by weight loss.[485] Several large population-βased studies have identified obesity as a risk factor for developing CKD [403] [486] and one study has found a progressive increase in relative risk of developing ESRD associated with increasing body mass index (BMI) (RR 3.57; CI 3.05–4.18 for BMI 30.0–34.9 kg/m2 versus BMI 18.5–24.9 kg/m2) among 320,252 subjects with no evidence of CKD at initial screening.[487] The metabolic syndrome (insulin resistance) defined by the presence of abdominal obesity, dyslipidemia, hypertension, and fasting hyperglycemia is also associated with an increased risk of developing CKD. Analysis of the Third National Health and Nutrition Examination Survey (NHANES) data revealed a significantly increased risk of CKD and microalbuminuria in subjects with the metabolic syndrome as well as a progressive increase in risk associated with the number of components of the metabolic syndrome present.[488] Furthermore, a longitudinal study of 10,096 patients without diabetes or CKD at baseline identified metabolic syndrome as an independent risk factor for the development of CKD over 9 years (adjusted OR 1.43; 95%CI 1.18–1.73). Again there was a progressive increase in risk associated with the number of traits of the metabolic syndrome present (OR 1.13; 95%CI 0.89–1.45 for one trait versus OR 2.45; 95%CI 1.32–4.54 for five traits).[489] Patient hip-waist ratio, a marker insulin resistance, was independently associated with impaired renal function even in lean individuals (BMI < 25 kg/m2) among a population-βased cohort of 7676 subjects.[490] The effect of obesity on progression in cohorts of patients with established CKD is less well documented. In one study increased BMI was an independent predictor CKD progression among 162 patients with IgA Nephropathy.[491] On the other hand, obesity may be less relevant to progression in more advanced stages of CKD as evidenced by the observation that BMI was unrelated to the risk of ESRD among a cohort of patients with CKD stage 4 and 5.[451]

Sympathetic Nervous System

Overactivity of the sympathetic nervous system has been observed in patients with CKD and several lines of evidence suggest that this may be another factor that contributes to progressive renal injury.[492] The kidneys are richly supplied with afferent sensory and efferent sympathetic innervation and may therefore act as both a source and target of sympathetic activation. That the former is true is suggested by a study that compared postganglionic sympathetic nerve activity (SNA) measured via microelectrodes in the peroneal nerve in normal individuals and hemodialysis patients subdivided into those who retained their native kidneys and those who had undergone bilateral nephrectomy.[493] SNA was 2.5 times higher in non-nephrectomized dialysis patients compared to both normals and nephrectomized patients, in whom SNA was similar. Furthermore, increased SNA was associated with increased vascular tone and mean arterial blood pressure in non-nephrectomized patients. SNA did not vary as a function of age, blood pressure, antihypertensive agents, or body fluid status. The authors speculated that intrarenal accumulation of uremic compounds stimulates renal afferent nerves via chemoreceptors, leading to reflex activation of efferent sympathetic nerves and increased SNA. Other studies, however, have observed increased SNA in the absence of uremia in patients with renovascular disease,[494] hypertensive ADPKD,[495] and non-diabetic CKD[496] or increased noradrenaline secretion in patients with nephrotic syndrome[497] and ADPKD. [495] [498] Furthemore, correction of uremia by renal transplantation does not abrogate the increased SNA.[499] Interestingly, investigation of eight living kidney donors found no increase in SNA after donor nephrectomy, suggesting that the rise in SNA is related to renal damage rather than nephron loss.[496] Together, these findings suggest that a variety of forms of renal injury may provoke increased SNA and that uremia is not required for this response.

Evidence from experimental studies indicates that sympathetic overactivity resulting from renal disease may also accelerate renal injury. Ablation of afferent sensory signals from the kidneys by bilateral dorsal rhizotomy in 5/6 nephrectomized rats prevented the expected rise in systemic blood pressure, attenuated the rise in serum creatinine, and reduced the severity of glomerulosclerosis in the remnant kidneys when compared with sham rhizotomized controls.[500] To further investigate whether these benefits were solely attributable to the prevention of hypertension, 5/6 nephrectomized rats were treated with non-hypotensive doses of the sympatholytic drug moxonidine.[501]Despite the lack of effect on blood pressure, moxonidine treatment was associated with lower levels of proteinuria and less severe glomerulosclerosis than untreated rats. In a similar study, 5/6 nephrectomized rats were treated the α-blocker, phenoxybenzamine, the β-blocker, metoprolol, or a combination.[502] As in the previous study, the doses used did not lower blood pressure, but all three treatments significantly lowered albuminuria and almost normalized the reductions in capillary length density (an index of glomerular capillary obliteration) and podocyte number. Metoprolol and combination therapy significantly lowered the glomerulosclerosis index versus untreated controls. Taken together, these results indicate that increased SNA accelerates renal injury independent of its effect on blood pressure, and that the adverse effects are not mediated by sympathetic cotransmitters but by catecholamines. Furthermore, sympathetic nerve overactivity has been proposed to contribute to the development of tubulointerstitial injury by reducing of peritubular capillary perfusion to the extent that tubular and interstitial ischemia result.[503]

Preliminary evidence suggests that sympathetic overactivity may also be important in the progression of human CKD. Among patients with type 1 diabetes mellitus and proteinuria, evidence of parasympathetic dysfunction (that permits unopposed sympathetic tone) was associated with an increase in serum creatinine over the next 12 months.[504] Furthermore, among 15 normotensive type 1 diabetics, 3 weeks' treatment moxonidine significantly lowered albumin excretion rates without affecting blood pressure.[505] In other studies, chronic treatment with an ACEI or AT1RA, of proven benefit in renoprotection, was associated with a reduction in sympathetic overactivity. [506] [507] In contrast, treatment with amlodipine was associated with increased SNA. Because ACEIs and AT1RAs do not readily enter the CNS, it is possible that RAS inhibition modulates neurotransmitter release in the kidney and reduces afferent signaling. Several questions remain to be answered regarding the role of increased SNA in CKD progression. Whereas the renoprotective effects of sympatholytic drugs appear to be independent of effects on systemic blood pressure, it is as yet unknown what effect they have on glomerular hemodynamics. Further studies are also required to determine the extent to which chronic inhibition of sympathetic overactivity may be beneficial in a variety of forms of human CKD and whether or not this benefit is additive to that derived from ACEI treatment.


Moorhead and colleagues advanced the hypothesis that abnormalities in lipid metabolism may contribute to the progression of CKD.[508] Glomerular injury, accompanied by an alteration in basement membrane permeability, was envisaged as the initiator of a vicious cycle of hyperlipidemia and progressive glomerular injury. They proposed that urinary losses of albumin and lipoprotein lipase activators result in an increase in circulating low-density lipoproteins (LDL), which in turn bind to the glomerular basement membrane further impairing its permselectivity; filtered lipoproteins accumulate in the mesangium, stimulating extracellular matrix synthesis and mesangial cell proliferation; filtered LDL is taken up and metabolized by the tubules, leading to cell injury and interstitial disease. Notably, this hypothesis did not propose hyperlipidemia as an initiating factor in renal injury, but rather as a participant in a self-sustaining mechanism of disease progression.

Several lines of experimental evidence confirm the association between dyslipidemia and renal injury. Both intact and uninephrectomized rats with dietary-induced hypercholesterolemia developed more extensive glomerulosclerosis than their normocholesterolemic controls, and the severity of glomerulosclerosis correlated with serum cholesterol levels[509]; aging female Nagase analbuminemic rats (NAR) have endogenous hypertriglyceridemia and hypercholesterolemia and develop proteinuria and glomerulosclerosis by 9 and 18 months of age respectively whereas male NAR have lower lipid levels and have no glomerulosclerosis by 22 months of age.[442] Interestingly, ovariectomy in female NAR lowers triglyceride levels and reduces their renal injury. In seeming contradiction, however, young and aging male Sprague-Dawley rats developed more extensive glomerulosclerosis than age and sex matched NAR, despite increased cholesterol levels in the NAR.[510] Triglyceride levels, however, were lower in the NAR, again suggesting an independent role for triglycerides in lipid-mediated renal injury. Whereas data regarding the role of lipids in initiating renal disease are conflicting, several studies support the notion that dyslipidemia may promote renal damage. Cholesterol feeding has been shown to exacerbate glomerulosclerosis in uninephrectomized rats, pre-diabetic rabbits, rats with puromycin aminonucleoside nephropathy (PAN), and in the unclipped kidney of rats with two kidney, one clip (2-K,1C) hypertension. When hypertension and dyslipidemia are superimposed, a synergistic effect that dramatically accelerates renal functional deterioration is observed. [511] [512]

In humans, the extent of the role of lipids in initiation and progression of renal disease remains unclear. At autopsy, a highly significant correlation was found between the presence of systemic atherosclerosis and the percentage of sclerotic glomeruli in normal individuals, fostering speculation that the development of glomerulosclerosis may be analogous to that of atherosclerosis.[513] A study designed to identify the clinical correlates of hypertensive ESRD found a strong association between atherosclerosis and hypertensive ESRD among older white patients.[514] Furthermore, dyslipidemia has been identified in several large studies as a risk factor for subsequent development of CKD in apparently healthy individuals. [403] [515] [516] The common forms of primary hypercholesterolemia are not associated with an increased incidence of renal disease in the general population but renal injury has been described in association with rare inherited disorders of lipoprotein metabolism. [517] [518]

Whereas primary lipid-mediated renal injury is rare among patients with CKD, the latter is frequently accompanied by elevations in serum lipids, as a result of urinary loss of albumin and lipoprotein lipase activators, defective clearance of triglycerides, modification of LDL by advanced glycation end products, reduced plasma oncotic pressure, adverse effects of medication, and underlying systemic diseases. [519] [520] Among a cohort of adult patients with CKD, the most frequent lipid abnormalities noted were hypertriglyceridemia, low high density lipoprotein (HDL), and increased apolipoprotein levels.[521] Furthermore, in a study of 631 routine renal biopsies, lipid deposits were detected in non-sclerotic glomeruli in 8.4% of kidneys and staining for apo B was positive in approximately one quarter of biopsies, suggesting that lipid deposition is not infrequent in diverse renal diseases.[368] Several epidemiological studies have found a strong association between CKD progression and dyslipidemia: in the MDRD study, low serum HDL cholesterol was found to be an independent predictor of more rapid rates of decline in GFR[522]; elevated total cholesterol, LDL-cholesterol, and apo B have been found to correlate strongly with GFR decline in CKD patients[523]; hypercholesterolemia was shown to be a predictor of loss of renal function in type 1 and type 2 diabetics [524] [525]; among non-diabetic patients CKD advanced more rapidly in patients with hypercholesterolemia and hypertriglyceridemia, independent of blood pressure control[526]; among patients with IgA nephropathy hypertriglyceridemia was independently predictive of progression.[527] Not all studies confirm these findings, however: in the Multiple Risk Factor Intervention Trial (MRFIT), dyslipidemias were not associated with a decline in renal function[466]; in a retrospective analysis of patients with nephrotic syndrome, hypercholesterolemia at diagnosis was not found to be a predictor of renal disease progression.[528] In the latter study, however, both progressors and non-progressors had markedly elevated serum cholesterol levels that may have confounded the analysis. Interpretation of these data is complicated by the fact that in patients with renal insufficiency, dyslipidemias do not occur in isolation and are associated with other factors that also affect renal disease progression including hypertension, hyperglycemia, and proteinuria. Levels of serum cholesterol and triglycerides have been found to correlate with blood pressure and circulating AII levels in type 1 and type 2 diabetics with renal disease and to rise with increasing proteinuria in patients with nephrotic syndrome.[518]

The possible mechanisms whereby hyperlipidemia may contribute to renal injury have not been fully elucidated. Cholesterol feeding has been associated with an increase in mesangial lipid content,[509] glomerular macrophages, and TGF-β as well as fibronectin mRNA levels. [529] [530] Furthermore, reduction of glomerular macrophages by whole-βody X-irradiation in the setting of nephrotic syndrome, significantly reduced albuminuria without affecting serum lipids, indicating that macrophages play a central role in hyperlipidemic glomerular injury.[530] Mesangial cells express receptors for LDL and uptake is stimulated by vasoconstrictor and mitogenic peptides such as endothelin-1 and PDGF.[371] Metabolism of LDL by mesangial cells leads to increased synthesis of fibronectin and MCP-1, which may contribute to mesangial matrix expansion and recruitment of circulating macrophage/monocytes into the glomerulus.[372] Moreover, triglyceride-rich lipoproteins (very low density lipoprotein, VLDL, and intermediate density lipoprotein, IDL) induce mesangial cell proliferation and elaboration of IL-6, PDGF, and TGF-β in vitro.[531]Mesangial cells, macrophages, and renal tubule cells all have the capacity to oxidize LDL via formation of reactive oxygen species, a step that may be inhibited by antioxidants and HDL. [361] [532] [533] Oxidized LDL may induce dose-dependent mesangial cell proliferation or mesangial cell death as well as production of TNF-α, eicosanoids, monocyte chemotaxins, and glomerular vasoconstriction. These pathways, together with free radicals generated during LDL oxidation, may each contribute to renal inflammation and injury. [531] [532] Hyperlipidemia is also associated with elevated PGC, raising the possibility of a further pathway to glomerulosclerosis via hemodynamic injury.[509]The elevated PGC appears to be mediated, in part, by an increase in renal vascular resistance that occurs in the context of increased plasma viscosity. In diabetic patients, circulating AII levels have been found to correlate with serum cholesterol[534] and both oxidized LDL and lipoprotein(a) have been shown to stimulate renin production by juxtaglomerular cells in vitro.[533] Moreover, oxidized LDL has been found to reduce nitric oxide synthesis by endothelial cells[533] raising the possibility that alterations in activity of the renin angiotensin system and nitric oxide metabolism could also contribute to the increase in PGC observed with hyperlipidemia.

It would follow that if hyperlipidemia exacerbates renal injury, interventions designed to lower serum lipids should ameliorate disease progression. Treatment with a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or clofibric acid in the obese Zucker rat (a strain with endogenous hyperlipidemia and spontaneous glomerulosclerosis) and 5/6 nephrectomized rats (which develop hyperlipidemia secondary to renal insufficiency), resulted in lowering of serum lipid levels, reduction in albuminuria, reduction in mesangial cell DNA synthesis, and attenuation of glomerulosclerosis, despite a lack of effect on either systemic blood pressure or PGC. [9] [535] In rats in the nephrotic phase of PAN, HMG-CoA reductase inhibitor treatment resulted in reduction of albuminuria and serum cholesterol, reduction of MCP-1 mRNA expression, and a 77% reduction in glomerular macrophage accumulation.[536] The HMG-CoA reductase inhibitors may therefore exert beneficial effects on renal disease progression, not only by a reducing serum lipid levels, but also by inhibiting mesangial cell proliferation and mechanisms for the recruitment of macrophages due to decreased expression of chemotactic factors and cell adhesion molecules.[537] Cholesterol-fed rats with PAN treated with the antioxidants probucol or vitamin E showed significant reductions in proteinuria and glomerulosclerosis compared to untreated controls.[538] Furthermore, plasma VLDL and LDL from the treated animals were less susceptible to in vitro oxidation and less renal lipid peroxidation was evident, implying that lipid peroxidation plays an important role in renal injury associated with hyperlipidemia. In some clinical studies, dietary or pharmacological lowering of serum lipids has also been associated with a reduction in proteinuria and lower rates of decline in renal function but other studies have failed to demonstrate significant beneficial effects of lipid-lowering therapy on proteinuria or decline of renal function, despite adequate therapeutic reductions in serum lipids. A meta-analysis of 13 small studies that included both diabetic and non-diabetic renal disease found that lipid-lowering therapy significantly reduced the rate of decline in GFR (mean reduction of 1.9 ml/min/year).[539] The results of large clinical trials of lipid lowering therapies in patients with CKD are still awaited. Several secondary analyses of data from clinical trials suggest that lipid-lowering therapy may slow progression in human CKD but these data should be interpreted with caution. Secondary analysis of data from a randomized trial of pravastatin treatment for patients with a history of myocardial infarction found that pravastatin slowed the rate of GFR decline in patients with estimated GFR < 40 ml/min/1.73 m2, an effect that was also more pronounced in those with proteinuria.[540] Similarly, patients with previous cardiovascular disease or diabetes randomized to simvastatin treatment in the Heart Protection Study evidenced a smaller increase in serum creatinine than those who received placebo.[541] In a placebo-controlled open-label study, atorvastatin treatment in patients with CKD, proteinuria, and hypercholesterolemia was associated with preservation of creatinine clearance whereas those receiving placebo evidenced a significant decline.[542] Whereas these renoprotective effects were associated with cholesterol lowering it is possible that they may also be due to the direct pleiotropic effects of HMG-CoA reductase inhibitors. This notion is further supported by the observation that lipid lowering with fibrates was not associated with preservation of renal function, [543] [544] although one study did show reduced progression to microalbuminuria among type 2 diabetics receiving fenofibrate.[545]

Calcium and Phosphate Metabolism

As is the case with many of the adaptations that follow nephron loss, evidence is accumulating that alterations in calcium and phosphate metabolism may also contribute to progressive renal damage. A retrospective analysis of 15 patients with non-progressing CKD (GFR 27-70 mL/min, observed for up to 17 years) revealed that the single feature common to all these patients was an enhanced capacity to excrete phosphate when compared to patients with similar GFR but progressive renal disease.[546] In all of the non-progressors, serum phosphate and calcium remained within normal limits without use of phosphate binders, calcium supplementation, or vitamin D. It is not yet clear which factor is most important but evidence suggests that hyperphosphatemia, renal calcium deposition, hyperparathyroidism, and activated vitamin D deficiency may each play a role.


Uninephrectomized rats receiving a high phosphate diet (1%) developed renal calcium and phosphate deposition and tubulointerstitial injury within 5 weeks of nephrectomy.[171] Similar changes were observed in a proportion of intact rats fed a 2% phosphate diet. Phosphate excess, therefore, does appear to have some intrinsic nephrotoxicity that is enhanced in the setting of reduced nephron number. A high phosphate diet has also been associated with the development of parathyroid hyperplasia and hyperparathyroidism in remnant kidney rats.[547] Conversely, in both animals and humans with renal insufficiency, dietary phosphate restriction or treatment with oral phosphate binders has been associated with reductions in proteinuria and glomerulosclerosis and attenuation of disease progression as well as prevention of hyperparathyroidism. [548] [549] [550] [551] Dietary phosphate restriction, however, almost inevitably also imposes dietary protein restriction. It is therefore not clear whether the benefit was derived directly from reduced phosphate intake or indirectly from protein restriction. One study in humans has reported additional renoprotection when phosphate restriction was superimposed on protein restriction.[552]

Renal Calcium Deposition

Calcium-phosphate deposition is a frequent histologic finding in end-stage kidney biopsies, irrespective of the underlying cause of renal failure. [175] [553] Calcium levels in end-stage kidneys have been found to be approximately nine times greater than levels in control kidneys.[553] Histologically, deposits were seen in cortical tubule cells, basement membranes, and the interstitium. [553] [554] Furthermore, the severity of renal parenchymal calcification has been found to correlate with the degree of renal dysfunction, implicating calcium-phosphate deposition in disease progression. [548] [555] To determine whether the calcium deposits observed in end-stage kidneys precede or follow renal parenchymal fibrosis, rats with reduced renal mass were maintained on a high phosphate diet, thus ensuring a high calcium-phosphate product. A subgroup was treated with 3-phosphocitrate, an inhibitor of calcium-phosphate deposition.[555] Treatment with 3-phosphocitrate led to a significant reduction in renal injury compared to controls, indicating that calcium-phosphate deposition within the kidney occurs during the evolution of renal injury and may exacerbate nephron loss. Calcium deposition in the renal parenchyma is associated with ultrastructural evidence of mitochondrial disorganization and calcium accumulation[554] and may therefore contribute to renal injury via uncoupling of mitochondrial respiration and generation of reactive oxygen species.[556] Mitochondrial calcium deposition was reduced by dietary protein restriction or calcium channel blocker therapy. [554] [556] Other potential roles for cellular calcium in renal disease progression include effects on vascular smooth muscle tone, mesangial cell contractility, cell growth and proliferation, extracellular matrix synthesis, and immune cell modulation.[557]


Podocytes express a unique transcript of parathyroid hormone (PTH) receptor and PTH has been shown to have several effects on the kidney including decreasing SNGFR (without change in QA, PGC, or DP), lowering Kf as well as stimulating renin production.[551] Furthermore, increased PTH levels may exacerbate renal damage through effects on blood pressure,[558] glucose intolerance, and lipid metabolism. [559] [560] Two experimental studies have provided evidence that PTH may contribute to CKD progression. In the first parathyroidectomy was shown to improve survival, reduce the increased renal mass as well as renal calcium content, and attenuate the rise in serum creatinine observed in 5/6 nephrectomized rats fed high protein diet.[561] In the other, calcimimetic treatment and parathyroidectomy after 5/6 nephrectomy each abrogated tubulointerstitial fibrosis and glomerulosclerosis.[562]Interpretation of these data are, however, complicated by the observation in the latter study that both interventions also lowered blood pressure.

Activated Vitamin D Deficiency

It is perhaps not surprising that vitamin D, normally 1-hydroxylated in the kidney and therefore deficient in CKD, has several potentially beneficial effects on the kidney. In experimental studies 1,25 (OH)2D3 has been shown to inhibit proliferation of mesangial as well as tubule cells, inhibit renal hypertrophy after uninephrectomy,[563] and inhibit renin expression.[551] Several experiments have reported amelioration of renal damage in rats treated with 1,25 (OH)2D3 or vitamin D analogue after 5/6 nephrectomy. [564] [565] Interestingly, a further study found that 1,25 (OH)2D3 treatment also preserved podocyte number, volume, and structure after 5/6 nephrectomy.[234] To date controlled trials examining the effect of 1,25 (OH)2D3 treatment on human CKD are not available.


Anemia is a frequent consequence of CKD but may also influence its progression. Both acute and chronic anemias are associated with reversible increases in renal vascular resistance and a normal or reduced filtration fraction in animals and humans. Conversely, an increase in hematocrit is associated with an increase in filtration fraction. Thus hematocrit may influence renal hemodynamics and thereby affect the rate of progression of CKD. The effects of anemia on glomerular hemodynamics have been studied in rats subjected to 5/6 nephrectomy, DOCA-salt hypertension, and diabetes. [566] [567] [568] Irrespective of the model, anemia was associated with significant amelioration of glomerulosclerosis and consistently associated with reduction in PGC. Reduced PGC arose predominantly through reductions in efferent arteriolar resistance in rats with renal ablation, lowered systolic blood pressure in DOCA-salt rats and increased afferent arteriolar resistance in diabetic rats. Similarly, in the MWF/Ztm rat, which develops spontaneous glomerulosclerosis with age, anemia induced by dietary iron deficiency was associated with lower blood pressure, reduced urinary protein excretion and less extensive glomerulosclerosis compared with controls fed diet of normal iron content.[569] In contrast, however, prevention of anemia by administration of erythropoietin to remnant kidney rats in order to maintain a normal hematocrit, resulted in increased systemic and glomerular blood pressures and markedly increased glomerulosclerosis.[566]

Despite the apparently favorable hemodynamic effects of anemia in experimental models of CKD, humans studies suggest that anemia may in fact accelerate CKD progression. In patients with inherited hemoglobinopathies, chronic anemia is associated with glomerular hyperfiltration that eventuates in proteinuria, hypertension, and ESRD. [570] [571] Furthermore, reduced hemoglobin was an independent predictor of increased risk of developing ESRD among patients with diabetic nephropathy in the RENAAL trial.[572] Several longitudinal studies of patients with other forms of CKD have identified lower hemoglobin as a risk factor for progression. [573] [574] Further confirmation that anemia has an adverse effect of CKD progression is derived from two small randomized studies that have reported renoprotective benefit when anemia is corrected with erythropoietin. Among non-diabetic patients with serum creatinine 2 mg/dL to 6 mg/dL early treatment (started when hemoglobin <11.6 g/dL) with erythropoietin alpha was associated with a 60% reduction in the risk of doubling serum creatinine, ESRD, or death versus delayed treatment (started when hemoglobin <9.0 g/dL)[575] and in patients with serum creatinine 2 mg/dL to 4 mg/dL and hematocrit <30%, erythropoietin treatment was associated with significantly improved renal survival.[576] On the other hand, two other studies that had effect on left ventricular mass as their primary end point, found no effect of high versus low hemoglobin target on rate of decline in GFR [577] [578] and one study reported a more rapid progression to ESRD among erythropoietin-treated patients randomized to a high (13.0–15.0 g/dL) versus a low (10.5–11.5 g/dL) hemoglobin target.[579]

The reasons for the apparent contradiction between the beneficial hemodynamic effects of anemia in experimental models and the identification of anemia as a risk factor for CKD progression in clinical studies, are unknown. It is possible that the benefit of the hemodynamic effects is outweighed by other factors such as increased renal hypoxia and ROS formation that may contribute to progressive renal damage. Issues related to the treatment of anemia in CKD are discussed further in Chapter 55 .

Tobacco Smoking

Smoking produces acute sympathetic nervous system activation resulting in tachycardia and an increase in systolic blood pressure of up to 21 mm Hg.[580] Vasoconstriction occurs in several vascular beds, including the kidneys. Among healthy, non-smoking volunteers, acute exposure to cigarette smoke caused an 11% increase in renovascular resistance accompanied by a 15% reduction in GFR and an 18% decrease in filtration fraction. These effects appear to be mediated, at least in part, by nicotine because similar responses were observed after chewing nicotine gum.[581] Furthermore the renal hemodynamic effects of smoking can be blocked by pre-treatment with a β-blocker, indicating that β-adrenergic stimulation is also involved.[582] The effects of chronic smoking on the normal kidney are less well defined. Renal plasma flow but not GFR is reduced in chronic smokers and plasma endothelin levels are elevated. In one population-βased study, chronic smoking was associated with a small increase in creatinine clearance, implying that smoking may cause glomerular hyperfiltration.[583] That these functional abnormalities may result in structural changes to blood vessels is suggested by the observation of abnormal intrarenal vasculature in smokers. [584] [585] Moreover epidemiological studies have found smoking to be an important predictor of albuminuria in the general population. [583] [586] In one study, heavy smoking (>20 cigarettes/day) was associated with a relative risk for albuminuria of 1.92.[586] Furthermore, in other epidemiological studies, smoking has been identified as a significant risk factor for renal impairment [403] [587] [588] and the development of ESRD.[402]

Whereas more studies are required to elucidate the effects of smoking on healthy kidneys, a growing body of evidence attests to the role smoking as an important risk factor for disease progression in a variety of forms of CKD. The first published studies focused on diabetic nephropathy. Among type 1 diabetics smoking has been found to be significant a risk factor for the development of microalbuminuria and overt nephropathy. [589] [590] Furthermore, smoking was associated with more rapid progression from microalbuminuria to overt nephropathy[591] and with almost double the rate of decline in GFR in non-smokers.[592] Similar observations have been made among type 2 diabetics. [593] [594] [595] Several studies have also reported associations between smoking and accelerated CKD progression among non-diabetic forms of CKD. Among men with ADPKD or IgA nephropathy, a dose-dependent association between smoking and ESRD was observed, with an odds ratio of 5.8 for those with >15 pack years versus <5 pack years.[596] The median time to ESRD was almost halved in smokers versus non-smokers in patients with lupus nephritis.[597] Among 295 patients with a primary glomerulonephritis, those with a serum creatinine >1.7 mg/dl were significantly more likely to be smokers than those with normal creatinine.[598] Similarly, among 73 patients with primary renal disease, the rate of decline in GFR was doubled in heavy smokers versus non-smokers.[599] Finally, smoking was the most powerful predictor of a rise in serum creatinine among patients with severe essential hypertension.[600]

Mechanisms whereby cigarette smoking may result in renal injury include are the subject of ongoing research but are thought to include sympathetic nervous system activation, glomerular capillary hypertension, endothelial cell injury, and direct tubulotoxocity.[601] Among patients with CKD the hemodynamic effects were variable, but smoking was associated with a consistent increase in albumin/creatinine excretion.[581] Analysis of urine from both smokers and non-smokers has revealed significantly higher excretions of thromboxane- and prostacycline-derived products in smokers.[602] The authors suggest that increased synthesis of thromboxanes and prostacyclines may have pathologic importance for vascular injury given the biologic effects of these compounds on platelets and smooth muscle cells. An important role for sympathetic nervous system activation was suggested by a recent experimental study in which sympathetic denervation abrogated renal injury induced by exposure to cigarette smoke condensate.[603] A growing body of evidence thus supports the notion that the kidney is yet another organ that is adversely affected by smoking. Preliminary studies indicate that smoking cessation is therefore another intervention that may contribute to slowing the rate of progression of CKD.[604]


The development of pharmacological inhibitors of the RAS provided powerful and incisive tools to explore renal hemodynamic and other associated adaptations in the setting of progressive renal injury. These physiological insights paved the way for clinical studies that have now provided clear evidence for the use of ACEI and AT1RA treatment as the mainstay of renoprotective strategies. Nevertheless, these studies have shown at best a halving of the rate of CKD progression. Ongoing research involving cell biology and molecular cloning as well as genomics and proteomics continues to yield novel insights into the mechanisms of progressive renal injury that promise to direct researchers to potential new molecular targets for renoprotective interventions. The development of the means to specifically inhibit molecular targets may provide new forms of therapy for those with CKD and enable physicians to realize the ultimate goal of achieving remission of progressive renal injury in the majority of patients and even regression of renal damage in some.


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