Diabetic Nephropathy - Brenner and Rector's The Kidney, 8th ed

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

CHAPTER 36. Diabetic Nephropathy

Hans-Henrik Parving Michael Mauer Eberhard Ritz

		Pathology of the Kidney in Diabetes, 1265
		Epidemiology of Microalbuminuria and Diabetic Nephropathy, 1273
		Clinical Course and Pathophysiology, 1276
		Extrarenal Complications in Diabetic Nephropathy, 1279
		Treatment, 1279
		End-Stage Renal Disease in Diabetic Patients, 1284
		Bladder Dysfunction, 1289

Persistent albuminuria (>300 mg/24 hr or 200 mg/min) is the hallmark of diabetic nephropathy, which can be diagnosed clinically if the following additional criteria are fulfilled: presence of diabetic retinopathy and the absence of clinical or laboratory evidence of other kidney or renal tract disease. This clinical definition of diabetic nephropathy is valid in both type 1 diabetes and type 2 diabetes.^[1]

During the last decade, several longi-tudinal studies have shown that raised urinary albumin excretion (based on a single measurement) below the level of clinical albuminuria (albustix), so-called microalbuminuria, strongly predicts the development of diabetic nephropathy in both type 1 and type 2 diabetes.^{[2] [3] [4]} Microalbuminuria is defined as urinary albumin excretion greater than 30 mg/24 hr (20 mg/min), and less than or equal to 300 mg/24 hr (200 mg/min), irrespective of how the urine is collected.

Nephropathy is a major cause of illness and death in diabetes. Indeed, the excess mortality of diabetes occurs mainly in proteinuric diabetic patients and results not only from end-stage renal disease (ESRD) but also from cardiovascular disease (CVD), the latter particularly in type 2 diabetic patients.^{[5] [6] [7]} Diabetic nephropathy is the single most common cause of ESRD in Europe, Japan, and United States, with diabetic patients accounting for 25% to 45% of all patients enrolled in ESRD programs.

PATHOLOGY OF THE KIDNEY IN DIABETES

This section outlines renal pathology in type 1 diabetes, followed by a comparison of the similarities and differences in renal pathology in type 2 diabetes. Taken together, diabetic nephropathology in type 1 diabetic patients is unique to this disease ( Table 36-1 ).^{[8] [9] [10]} Thickening of the glomerular basement membrane (GBM) is the first change that can be quantitated ( Fig. 36-1A and C ).^[11] Thickening of tubular basement membranes (TBMs) parallels this GBM thickening ( Fig. 36-2 ).^{[12] [13]} Afferent and efferent glomerular arteriolar hyalinosis can also be detected within 3 to 5 years after onset of diabetes or following transplantation of a normal kidney into the diabetic patient.^[14]This can eventuate in the total replacement of the smooth muscle cells of these small vessels by waxy, homogeneous, translucent-appearing periodic acid-Shiff (PAS)–positive material ( Fig. 36-3A and B ) consisting of immunoglobulins, complement, fibrinogen, albumin, and other plasma proteins.^{[15] [16]} Arteriolar hyalinosis, glomerular capillary subendothelial hyaline (hyaline caps), and capsular drops along the parietal surface of the Bowman capsule (see Fig. 36-3C ) make up the so-called exudative lesions of diabetic nephropathy. Progressive increases in the fraction of glomerular afferent and efferent arterioles occupied by extracellular matrix (ECM) and medial thickness has also been reported in young T1DM patients.^[17]

TABLE 36-1 -- Pathology of Diabetic Nephropathy in Patients with Type 1 Diabetes and Proteinuria

Always Present	Often or Usually Present	Sometimes Present
Glomerular basement membrane thickening^[*]	Kimmelstiel-Wilson nodules (nodular glomerulosclerosis)^[*]; global glomerular sclerosis; focal-segmental glomerulosclerosis, atubular glomeruli	Hyaline “exudative” lesions (subendothelial)^[†]
Tubular basement membrane thickening^[*]	Foci of tubular atrophy	Capsular drops^[†]
Mesangial expansion with predominance of increased mesangial matrix (diffuse glomerulosclerosis)^[*]		Atherosclerosis
Interstitial expansion with predominance of increased extracellular matrix material		Glomerular microaneurisms
Increased glomerular basement membrane, tubular basement membrane, and Bowman capsule staining for albumin and IgG^[*]	Afferent and efferent arteriolar hyalinosis^[*]

^*	In combination, diagnostic of diabetic nephropathy.
^†	Highly characteristic of diabetic nephropathy.



FIGURE 36-1 Electron microscopic photomicrographs of (A) normal glomerular basement membrane (GBM) on the left compared with thickened GBM from a proteinuric type 1 diabetic patient on the right, (B) normal glomerular capillary loops and mesangial zone, and (C) thickened glomerular basement membrane (GBM), mesangial expansion (predominantly with mesangial matrix), and capillary lumenal narrowing in a proteinuric type 1 diabetic patient.



FIGURE 36-2 Relationship of proximal tubular basement membrane (TBM) width and glomerular basement membrane (GBM) width in 35 type 1 diabetic patients, 25 of whom were normoalbuminuric. The hypertensive patients are represented by the open circles. r = 0.64, P < 0.001. (From Brito PL, Fioretto P, Drummond K, et al: Proximal tubular basement membrane width in insulin-dependent diabetes mellitus. Kidney Int 53:754–761, 1998.)



FIGURE 36-3 Light microscopic photomicrographs of (A) afferent and efferent arteriolar hyalinosis in a glomerulus from a type 1 diabetic patient. The glomerulus shows diffuse and nodular mesangial expansion (periodic acid—Schiff [PAS] stain), (B) a glomerular arteriole showing almost complete replacement of the smooth muscle wall by hyaline material and lumeral narrowing (PAS stain), and (C) a glomerulus with minimal mesangial expansion and a capsular drop at 3 o'clock (PAS stain).

Increases in the fraction of the volume of the glomerulus occupied by the mesangium [Vv(Mes/glom)] can be documented only after 4 to 5 years of type 1 diabetes^[11] and, in many cases, may take 15 or more years to manifest.^[18]This may be because the relationship of mesangial expansion to diabetes duration is nonlinear, with slow development earlier and more rapid development later in the disease.^[18] This mesangial expansion is primarily due to absolute and relative increases in mesangial matrix, with lesser contribu-tion from fractional increases in mesangial cell volume (see Figs. 36-1C and 36-4 [1] [4]).^[19] The first change in the volume fraction of cortex that is interstitium [Vv(Int/cortex)] is a decrease in this parameter,^[20] perhaps due to the expansion of the tubular compartment of the cortex. In contrast to the mesangium, initial interstitial expansion is primarily due to an increase in the cellular component of this renal compartment.^[21] Increase in interstitial ECM fibrillar collagen is a relatively late find-ing in this disease, which is measurable only in patients with an already esta-blished decline in glomerular filtration rate (GFR).^[21]



FIGURE 36-4 Mesangial matrix expressed as a fraction of the total mesangial (matrix/mesg) plotted against mesangial fractional volume (mesangium Vv) in long-standing type 1 diabetic patients. The normal value for matrix/mesg is approximately 0.5. Note that most diabetic patients have elevated values for matrix/mesg whether or not there is an increase in mesangium Vv (i.e., values above 0.24). (From Steffes MW, Bilous RW, Sutherland DER, Mauer SM: Cell and matrix components of the glomerular mesangium in type 1 diabetes. Diabetes 41:679–684, 1992.)

Abnormalities of the glomerular-tubular junction with focal adhesions, obstruction of the proximal tubular take-off from the glomerulus detachment of the tubule from the glomerulus (atubular glomerulus) ( Fig. 36-5A to D ) are also late disease manifestations largely restricted to patients with overt proteinuria ( Fig. 36-6 ).^[22]



FIGURE 36-5 Glomerulotubular junction (GTJ) abnormalities (GTJAs). A, Glomerulus attached to a short atrophic tubule (SAT). The arrow points to the atrophic segment. B, Glomerulus attached to a long atrophic tubule (LAT). The arrow points to the atrophic segment and tuft adhesion. C, Glomerulus attached to an atrophic tubule with no observable opening (ATNO) and a tip lesion (arrow). D, Atubular glomerulus (AG). Tubular remnants that possibly belonged to the AG. (From Najafian B, Crosson JT, Kim Y, Mauer M: Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. J Am Soc Nephrol 17:S53–S60, 2006.)*



FIGURE 36-6 Frequency of glomerulotubular junction abnormalities (GTJAs) in normoalbuminuric (NA), microalbuminuric (MA), and proteinuric (P) patients and control subjects (C). NT normal tubules; G#, number of glomeruli. (From Najafian B, Crosson JT, Kim Y, Mauer M: Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. J Am Soc Nephrol 17:S53–S60, 2006.)

These various lesions of diabetic glomerulopathy can progress at varying rates within and between type 1 diabetic patients,^{[23] [24]} and as discussed below, this is even more the case in type 2 diabetes. For example, GBM width and Vv(Mes/glom) are not highly correlated with one another; some patients have relatively marked GBM thickening without much mesangial expansion and others the converse ( Fig. 36-7 ).^{[8] [23]} Marked renal extracellular basement membrane accumulation resulting in extreme mesangial expansion and GBM thickening are present in the vast majority of type 1 diabetic patients who develop overt diabetic nephropathy manifesting as proteinuria, hypertension, and declining GFR^{[8] [23] [24]} (and see later). Ultimately, focal and global glomerulosclerosis, tubular atrophy, interstitial expansion and fibrosis, and glomerulotubular junction abnormalities (GTJA) facilitate this downward spiral.^[22]



FIGURE 36-7 Relationship between glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(Mes/glom)] in long-standing 125 Type 1 diabetic patients, 88 of whom were normoalbuminuric, 17 microalbuminuric, and 18 proteinuric. r = 0.58, p < 0.001.

The diffuse and generalized process of mesangial expansion has been termed diffuse diabetic glomerulosclerosis ( Fig. 36-8A to C ). Nodular glomerulosclerosis (Kimmelstiel-Wilson nodular lesions) represents areas of marked mesangial expansion appearing as large round fibrillar mesangial zones, with palisading of mesangial nuclei around the periphery of the nodule often with extreme compression of the adjacent glomerular capillaries ( Fig. 36-9C ). This is typically a focal and segmental change likely resulting from glomerular capillary wall detachment from a mesangial anchoring point with consequent microaneurysm formation ( Fig. 36-9A )^[25] and subsequent filling of the ballooned capillary space with mesangial matrix material ( Fig. 36-9B ). Approximately 50% of proteinuric type 1 diabetic patients have at least a few glomeruli with nodular lesions. Typically, this occurs in patients with moderate to severe diffuse diabetic glomerulosclerosis, but there are some patients with occasional nodular lesions and little diffuse mesangial expansion, suggesting that these two forms of diabetic mesangial change may, at least in part, have a different pathogenesis.



FIGURE 36-8 Light microscopic photomicrographs (periodic acid-Schiff [PAS] stain) of (A) a normal glomerulus, (B) a glomerulus from a normoalbuminuric type 1 diabetic patient with glomerular basement membrane (GBM) thickening and moderate mesangial expansion, and (C) a glomerulus from a type 1 diabetic patient with overt diabetic nephropathy and severe diffuse mesangial expansion.



FIGURE 36-9 Light microscopic photomicrographs (periodic acid-Schiff [PAS] stain) of glomeruli from type 1 diabetic patients with (A) a capillary microaneurism (mesangiolysis) at 11 o'clock, (B) nodule formation within a capillary microaneurism, (C) nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and (D) end-stage diabetic glomerular changes with nearly complete capillary closure.

As mentioned earlier, most (about two thirds) of the mesangial expansion in diabetes is due to increased mesangial matrix and one third is due to mesangial cell expansion. Thus, the mesangial matrix fraction of mesangium, as opposed to the mesangial cellular fraction, is increased in diabetic patients, often even in those in whom Vv(Mes/glom) is still within the normal range (see Fig. 36-4 ).^[19] The relative contribution of increased cell number versus cell size to the cellular component of mesangial expansion is currently unknown.

Clinical diabetic nephropathy is primarily the conse-quence of ECM accumulation, which must result from an imbalance in renal ECM dynamics whereby, over many years, the rate of ECM production exceeds the rate of removal. The accumulation of mesangial, GBM, and TBM ECM materials represents the accumulation of the intrinsic ECM components of these structures, including types IV and VI collagen, laminin, and fibronectin,^[26] and perhaps, additional ECM components not yet identified. However, not all renal ECM components change in parallel. Thus, alpha 3 and alpha 4 chains of type IV collagen increase in density in the GBM of patients with diabetic renal lesions, whereas alpha 1 and alpha 2 type IV collagen chains and type IV collagen decrease in density in the mesangium and in the subendothelial space.^{[27] [28] [29]} However, the absolute amount of these ECM components per glomerulus is increased due to the marked absolute increase in mesangial matrix material. The glomerular expression of “scar” collagen is very late in the evolution of diabetic glomerulopathy, occurring primarily in association with global glomerular sclerosis.^{[26] [27]} In the final analysis, the understanding of the nature of the ECM components that are accumulating in the mesangium, GBM, and TBM in diabetes is far from complete.^{[28] [29]}

As the disease progresses toward renal insufficiency, more glomeruli become totally sclerosed or have capillary closure in incompletely scarred glomeruli owing to massive mesangial expansion (see Fig. 36-7D ). However, an increased fraction of glomeruli may become globally sclerosed in diabetic patients without other glomeruli showing marked mesangial changes.^[30] Hørlyck and colleagues^[31] found that the distribution pattern of scarred glomeruli in type 1 diabetic patients was more often than by chance in the plane vertical to the capsule of the kidney. This suggested that glomerular scarring results, at least in part, from obstruction of medium-sized renal arteries.^[31] In fact, patients with increased numbers of globally sclerosed glomeruli have more severe arteriolar hyalinosis lesions.^[30] In general, global glomerular sclerosis and mesangial expansion are correlated in type 1 diabetic patients,^{[30] [32]} but this may be less often the case in type 2 diabetes (see later).

Podocyte number or numerical density (number/volume), or both, are reportedly reduced in both types 1 and 2 diabetic patients,^{[33] [34] [35] [36]} and these changes may be associated with albuminuria and disease progression. Podocyte detachment from GBM may be an early phenomenon in type 1 diabetes, appears to worsen with increasing albuminuria, (Toyoda M, Najafian B, Mauer M, unpublished observations), and could be responsible for podocyte loss. However, the podocyte number measurement techniques are still problematic and unstandardized and more work is needed.

When patients with at least 10 years of diabetes duration with no other selection criteria are studied by research renal biopsies, there are significant but only imprecise relationships between renal pathology and diabetic duration.^[23]This is consistent with the marked variability in both glycemia and in susceptibility to diabetic nephropathy, with some patients in renal failure after 15 years of diabetes and others without complications despite having type 1 diabetes for many decades.

Immunohistochemistry

Renal extracellular membranes, including GBM, TBM, and the Bowman capsule, demonstrate increased intensity of immunofluorescent linear staining for plasma proteins, especially albumin and immunoglobulin G (IgG).^[16]Because these changes are seen in all diabetic patients and appear unrelated to disease risk, their only clinical importance is that they not be confused with other entities, such as anti-GBM antibody disorders.

Immunohistochemical studies have also revealed decreased nephrin expression in association with decreased nephrin mRNA expression in podocytes of albuminuric diabetic patients,^{[37] [38]} opening up interesting research avenues for study of these associations^[39] and diabetic nephropathy pathogenesis.

Structural-Functional Relationships in Diabetic Nephropathy

Mesangial expansion is the major lesion of diabetic nephropathy leading to renal dysfunction in type 1 diabetes patients.^[23] Mesangial expansion out of proportion to increases in glomerular volume [i.e., increased Vv(Mes/glom)] is strongly correlated with decreased peripheral GBM filtration surface density [Sv(PGBM/glom)] ( Fig. 36-10 )^[23] and filtration surface per glomerulus (S/G) is strongly correlated with GFR in type 1 diabetes.^[40] Vv(Mes/glom) is also closely related with urinary albumin excretion rate (AER)^{[23] [24]} ( Fig. 36-11A and B ) and is a strong concomitant of hypertension.^{[23] [32]} Thus, all of the clinical manifestations of diabetic nephropathy are associated with mesangial expansion and the consequent restriction of the filtration surface. Although GBM width is also directly correlated with blood pressure (BP) and AER ( Fig. 36-12A and B ) and inversely correlated with GFR, the relationships are somewhat weaker than those seen with Vv(Mes/glom).^{[23] [24]} However, Vv(Mes/glom) and GBM width, together, explain nearly 60% of AER variability in type 1 diabetic patients with AER ranging from normoalbuminuria to proteinuria.^[24]



FIGURE 36-10 Relationship of mesangial fractional volume (% total mesangium) and filtration surface density (Sv[Peripheral Capillary/Surface]) in type 1 diabetic patients.



FIGURE 36-11 A, Correlation between mesangial fractional volume (Vv[Mes/glom]) and albumin excretion rate (AER) in 124 patients with type 1 diabetes. ◆ = normoalbuminuric patients; □=microalbuminuric patients; ▵=proteinuric patients. r = 0.75; P < 0.001. B, Vv(Mes/glom) in 88 normoalbuminuric (NA), 17 microalbuminuric (MA), and 19 proteinuric (P) patients with type 1 diabetes. The hatched area represents the mean±2 SD in a group of 76 age-matched normal control subjects. All groups are different from control subjects. (From Caramori ML, Kim Y, Huang C, et al: Cellular basis of diabetic nephropathy: 1. Study design and renal structural functional relationships in patients with long-standing type 1 diabetes. Diabetes 51:506–513, 2002.)



FIGURE 36-12 A, Correlation between glomerular basement membrane (GBM) width and albumin excretion rate (AER) in 124 patients with Type 1 diabetes. ◆ = normoalbuminuric patients; □=microalbuminuric patients; ▵=proteinuric patients. r = 0.62, p < 0.001. B, GBM width in 88 normoalbuminuric (NA), 17 microalbuminuric (MA), and 19 proteinuric (P) patients with type 1 diabetes. The hatched area represents the mean±2 SD in a group of 76 age-matched normal control subjects. All groups are different from control subjects. (From Caramori ML, Kim Y, Huang C, et al: Cellular basis of diabetic nephropathy: 1. Study design and renal structural functional relationships in patients with long-standing type 1 diabetes. Diabetes 51:506–513, 2002.)

As noted earlier, decreased glomerular podocyte number and detachment has been related to glomerular permeability alterations in diabetes. In addition, changes in podocyte shape, including increases in foot process width and decreases in filtration slit-length density, correlate with AER increases in type 1 diabetic patients.^{[34] [41] [42]}

Also, heparin sulfate proteoglycans, presumably an epithelial cell product important in glomerular charge-based permselectivity, is decreased in density in the lamina rara externa in proportion to the increase in AER in type 1 diabetic patients.^[43] Whether the addition of podocyte cell structural variables would reduce the residual unexplained variability in AER or GFR in diabetic nephropathy (see later) has not yet been tested. If true, this would support the idea that podocyte alterations contribute to proteinuria and renal insufficiency. Moreover, confirmation that reduced podocyte number predicts diabetic nephropathy development or progression^[44] would add further credence to the importance of this cell in this disease.

The total peripheral capillary filtration surface is directly correlated with GFR across the spectrum from hyperfiltration to renal insufficiency.^{[40] [45] [46]} Nonetheless, as already noted, diabetic glomerulopathy structural parameters, examined in linear regression models, explain only a minority of GFR variability in type 1 diabetic patients.^[24] Percent global sclerosis^[30] and interstitial expansion^[10] are also linearly correlated with the clinical manifestations of diabetic nephropathy and are, to some extent, independent predictors of renal dysfunction and hypertension in type 1 diabetes. In fact, some have argued that renal dysfunction in diabetes is primarily consequent to interstitial rather than glomerular lesions.^{[47] [48] [49]} However, the conclusion that the interstitium is more closely related to renal dysfunction in diabetes than glomerular changes has derived from studies in which most, if not all, patients already have elevated serum creatinine values and in which the interstitium is carefully measured but the glomerular structure is only subjectively estimated.^{[47] [48] [49]} In fact, during most of the natural history of diabetic nephropathy, glomerular parameters are more important determinants of renal dysfunction, whereas interstitial changes may become a stronger determinant of the rate of progression from established renal insufficiency to terminal uremia.^[50]Furthermore, as mentioned earlier, in the first decade of diabetes, Vv(Int/cortex) is decreased^[20] whereas Vv(Mes/glom) and GBM width are already increased. Moreover, early interstitial expansion in type 1 diabetes is mainly due to expansion of the cellular component of this compartment and increased interstitial fibrillar collagen is seen in patients whose GFR is already reduced.^[21] These and other findings suggest that the interstitial and glomerular changes of diabetes have somewhat different pathogenetic mechanisms and that advancing interstitial fibrosis generally follows the glomerular processes in type 1 diabetes.

Through much of the natural history of diabetic nephropathy, lesions develop in complete clinical silence. When microalbuminuria and proteinuria initially manifest, lesions are often far advanced and loss of GFR may then progress relatively rapidly toward ESRD. This typical clinical story is best mirrored by nonlinear analyses of structural-functional relationships.^[22] Using piecewise regression models, glomerular structural variables alone [Vv(Mes/glom), GBM width, and total filtration surface per glomerulus or TFS] explained 95% of variability in AER ranging from normoalbuminuria to proteinuria, thus leaving little room for improvement by adding nonglomerular structural variables to this model. These same glomerular structures, however, explained only 78% of GFR variability, and this increased to 92% with the addition of indices of glomerular tubular junction abnormalities and Vv(Int/cortex).^[22]

In summary, most of the AER and GFR changes in type 1 diabetes are explained by diabetic glomerulopathy changes and these structural-functional relationships are largely driven by more advanced lesions, whereas structure is highly variable (from virtually none to moderate severity) in patients without functional abnormalities.

Microalbuminuria and Renal Structure

As discussed elsewhere in this chapter, persistent microalbuminuria is a predictor of the development of clinical nephropathy, whereas the absence of microalbuminuria in long-standing type 1 diabetic patients indicates a lower nephropathy risk. Proteinuria in type 1 diabetes of 10 or more years' duration is typically associated with advanced diabetic glomerular pathology.^{[23] [24]} Therefore, one might reason that microalbuminuria is associated with underlying renal structural changes that are predictive of the ultimate progression of this pathology. However, the relationship of renal structural changes to these low levels of albuminuria (i.e., normal or microalbuminuria) is complex and incompletely understood. Normoalbuminuric patients with a mean of 20 years' type 1 diabetes, as a group, have increased GBM width and Vv(Mes/glom).^{[24] [51]} The structural parameters within this group vary from within the normal range to advanced abnormalities that overlap with patients with microalbuminuria and proteinuria (see Figs. 36-11B and 36-12B [11] [12]).^{[24] [51]} Patients with microalbuminuria AER (20–200 mg/min) have, on average, even greater GBM and mesangial expansion, with almost no values in the normal range, but these values overlap with those of normoalbuminuric and proteinuric patients (see Figs. 36-11B and 36-12B [11] [12]).^{[24] [51]}The incidence of hypertension and reduced GFR is greater in patients with microalbuminuria.^{[24] [51]} Thus, microalbuminuria is a marker of more advanced lesions as well as other functional disturbances.^{[24] [51]} Studies suggest that greater GBM width in baseline biopsies of normoalbuminuric patients is predictive of later clinical progression to microalbuminuria.^[51] Furthermore, microalbuminuric patients with greater GBM width are more likely to progress to proteinuria.^[52] Some normoalbuminuric long-standing type 1 diabetic patients, particularly women with retinopathy or hypertension, have reduced GFR, and this is associated with worse diabetic glomerulopathy lesions.^{[53] [54] [55]} Thus, increased AER is not always the initial clinical indicator of diabetic nephropathy, and GFR measurements may be indicated in normoalbuminuric female patients with the above characteristics.

Risk Factors for Nephropathy May Be Intrinsic to the Kidney

Nondiabetic members of identical twin pairs discordant for type 1 diabetes have glomerular structure within the normal range.^[12] In every pair studied, the diabetic twin had higher values for GBM and TBM width and Vv(Mes/glom) than the nondiabetic twin. Several diabetic twins had values for GBM width and Vv(Mes/glom) that were within the range of normal and had “lesions” only in comparison with their nondiabetic twin,^[12] whereas others had more severe lesions. Thus, given sufficient duration, probably all type 1 diabetic patients have structural changes that are similar in their direction but vary markedly between individuals in the rate at which these lesions develop.

There is a growing body of information, discussed elsewhere in this chapter, that supports the view that, in addition to glycemia as a risk factor, genetic variables confer susceptibility or resistance to diabetic nephropathy. This is also suggested by the marked variability in the rate of development of kidney lesions of diabetic nephropathy in transplanted kidneys, despite the fact that the recipients all had ESRD secondary to diabetic nephropathy.^[56] This variability, only partially explained by glycemic control, argues for genetically determined renal tissue responses as important in determining nephropathy clinical outcomes.^[56]

Glomerular volume and number could be structural determinants of nephropathy risk. Mean glomerular volumes were higher in patients developing diabetic nephropathy after 25 years of type 1 diabetes compared with a group that developed nephropathy after only 15 years.^[57] These studies suggest that as mesangial expansion develops, glomerular volume increases (the studies of Østerby and colleagues^[45] support this view) and argue that patients who are unable to respond to mesangial expansion with glomerular enlargement will more quickly develop overt nephropathy than those whose glomeruli enlarge to provide compensatory preservation of glomerular filtration surface. The number of glomeruli per kidney can vary markedly among normal individuals and among diabetic patients,^{[58] [59]} and it has been suggested that fewer glomeruli per kidney could be a risk factor for diabetic nephropathy.^[60]However, studies of type 1 diabetic transplant recipients indicate that having a single kidney does not result in accelerated lesion development compared to having two kidneys^[56] (see also Chang S, Caramori ML, Moriya R, Mauer M, unpublished results). Diabetic patients with advanced renal failure have reduced numbers of glomeruli, but this likely results from resorption of sclerotic glomeruli.^[59] If reduced glomerular number were a risk factor, it would be predicted that proteinuric patients without advanced renal failure would have fewer glomeruli, but this was not the case.^[59] Although probably not important in the genesis of diabetic nephropathology, reduced glomerular number could be associated with more rapid progression to ESRD once advanced lesions and overt diabetic nephropathy had developed.

Comparisons of Nephropathy in Type 1 and Type 2 Diabetes

Renal pathology and structural-functional relationships have been less well studied in type 2 diabetic patients, despite the fact that 80% or more of diabetic ESRD patients have type 2 diabetes. Proteinuric white Danish type 2 diabetic patients were reported to have structural changes similar to proteinuric type 1 diabetic patients, and the severity of these changes was strongly correlated with the subsequent rate of decline of GFR.^[61] However, this report also described greater heterogeneity in glomerular structure in these type 2 patients than these authors had seen in type 1 patients, with some type 2 proteinuric patients having little or no diabetic glomerulopathy.^[61] A study of 52 microalbuminuric and proteinuric northern Italian type 2 diabetic patients biopsied for clinical reasons defined three general groups of abnormalities.^[62] About one third of the patients had changes similar to those typically seen in patients with type 1 diabetes. One third had a marked increase in the percentage of globally sclerosed glomeruli associated with severe tubulointerstitial lesions, whereas nonsclerosed glomeruli showed only mild diabetic changes. In the third group, there were typical changes of diabetic glomerulopathy and superimposed changes of proliferative glomerulonephritis, membranous nephropathy, and so on.^[62] In another Danish study, three fourths of proteinuric type 2 diabetic patients had diabetic nephropathology,^[63] but one fourth had a variety of nondiabetic glomerulopathies, including “minimal lesions,” glomerulonephritis, mixed diabetic and glomerulonephritis changes, or chronic glomerulonephritis. All patients with proteinuria and diabetic retinopathy had diabetic nephropathy; only 40% of patients without retinopathy had diabetic nephropathy.^[63] A British study found similar results.^[64] It is very likely that these high incidences of diagnosis other than or in addition to diabetic nephropathy represent a significant selection bias, because many patients in these studies had clinical indications for kidney biopsies, many because of atypical clinical presentations or findings. In fact, the likelihood of finding nondiabetic disease among type 2 diabetic patients is highly influenced by a center's clinical indications for renal biopsy in type 2 diabetic patients.^[65] In fact, when renal biopsies are performed for research and not for diagnostic purposes, definable renal diseases other than secondary to diabetes, are distinctly uncommon.^[65] However, only a minority of type 2 albuminuric patients in this study had findings typical of type 1 patients (about 30%), whereas others had either minimal abnormalities (about 30%) or glomerulosclerotic, vascular and/or tubulointerstitial lesions that were disproportionally severe relative to the diabetic glomerulopathy lesions (about 40%).^[66]

Structural-Functional Relationships in Type 2 Diabetic Nephropathy

Renal structural-functional relationships in Japanese type 2 diabetic patients were initially reported to be similar to those in type 1 patients.^[67] However, a more recent study indicated greater heterogeneity in Japanese type 2 diabetic patients, with some microalbuminuric and proteinuric patients having normal glomerular structural parameters.^[68] Østerby and co-workers found less advanced glomerular changes in type 2 versus type 1 diabetic patients with similar AERs.^[60] However, the type 1 patients had lower GFR levels than type 2 patients with similar AERs.^[61] These findings could reflect much larger glomerular volumes in the type 2 patients, with associated preservation of filtration surface. In fact, GFR and filtration surface per glomerulus were correlated in these patients.^[61] Also, the explanation for the proteinuria in these type 2 patients was, at least in part, unexplained. Vv(Mes/glom) increased progressively from early to long-term diabetes, with clinical findings ranging from normoalbuminuria, to microalbuminuria, to clinical nephropathy^[34] in Pima Indian type 2 diabetic patients. Global glomerular sclerosis correlated inversely with GFR in these patients.^[34] These authors also suggested, as noted earlier, that glomerular podocyte loss was related to proteinuria in these patients, although this was not seen in microalbuminuric patients (see earlier).

The less precise correlation between glomerular structure and renal function in type 2 versus type 1 diabetic patients may be related to the more complex patterns of renal injury seen in type 2 diabetic patients (see earlier).^[66] These considerations are relevant to prognosis, in that the patients with more typical diabetic glomerulopathy electron microscopic morphometric findings of mesangial expansion were more likely to have progressive loss of GFR over the next 4 years of follow-up.^[69] This was confirmed in a study of proteinuric Danish type 2 diabetic patients in which those with light microscopic changes of diabetic glomerulopathy had much more rapid decline in GFR over a median of 7.7 years of follow-up.^[63]

In summary, it appears that renal structural changes in type 2 diabetes are more heterogeneous and diabetic glomerulopathy lesions are less severe than in type 1 patients with similar albuminuria levels. Approximately 40% of the patients show atypical renal injury patterns, and these patterns are associated with higher body mass index and less diabetic retinopathy.^[66] Further cross-sectional and longitudinal studies in type 2 diabetic patients are required before these complexities can be better understood.

It is possible that the atypical manifestations of renal injury in type 2 diabetes could be related to the pathogenesis of type 2 diabetes per se. Thus, obesity, hypertension, increased plasma triglyceride levels, decreased high-density lipoprotein cholesterol concentrations, and accelerated atherosclerosis accompany hyperglycemia in many type 2 diabetic patients in what Reaven termed syndrome X and is now often referred to as the metabolic syndrome.^[70]Renal dysfunction in the metabolic syndrome could be the consequence of hypertensive nephrosclerosis, hyperlipidemic renal vascular atherosclerosis, renal hypoperfusion due to congestive heart failure, or the synergistic effects of these multiple factors, which could clinically simulate nephropathy in type 2 diabetes. The increased risk of clinical renal disease in certain populations, such as black, Native American, or Hispanic patients, could represent variability in the renal consequence of one or more of these pathogenetic influences. For example, there are differences in the renal structural consequences of hypertension in black and white patients.^[71]

Other Renal Disorders in Diabetic Patients

It has been reported that renal disorders such as nil lesion nephrotic syndrome^[72] and membranous nephropathy^[73] occur with greater frequency in type 1 diabetic patients than among nondiabetic persons. In fact, when biopsied for research purposes only and not for clinical indications, fewer than 1% of type 1 patients with 10 or more years of diabetes and fewer than 4% of those with proteinuria and long diabetes duration will have conditions other than, or in addition to, diabetic nephropathy (M. Mauer, personal observations). As already discussed, proteinuric type 2 diabetic patients without retinopathy may have a high incidence of atypical renal biopsies or other diseases. Proteinuria in type 1 diabetic patients with less than 10 years of diabetes duration or type 2 diabetic patients without retinopathy should be thoroughly evaluated for other renal diseases and renal biopsy for diagnosis and prognosis should be strongly considered.

Diabetic Nephropathy Lesions Are Reversible

Mesangial expansion after 7 months of diabetes reversed within 2 months after normoglycemia was induced by islet transplantation in streptozotocin diabetic rats.^[74] Thus, it was disappointing that no improvement in diabetic nephropathy lesions in their native kidneys was found after 5 years of normoglycemia following successful pancreatic transplantation^[75] in type 1 patients with diabetes duration of approximately 20 years. However, after 10 years of normoglycemia, these same patients had marked reversal of diabetic glomerulopathy lesions. Thus, GBM and TBM width were reduced at 10 years compared with the baseline and 5-year values, with several patients having measures at 10 years that had returned to the normal range ( Fig. 36-13A and B ).^[76] Similar results were obtained with Vv(Mes/glom), primarily due to a marked decrease in mesangial matrix fractional volume (see Fig. 36-13C and D ). Remarkable glomerular architectural remodeling was seen by light microscopy, including the complete disappearance of Kimmelstiel-Wilson nodular lesions ( Fig. 36-14A to C ).^[76] The reason for the long delay in this reversal process is not understood and could include cell memory for the diabetic state, the slow process of replacement of glycated by nonglycated ECM, or other yet undetermined processes. Regardless of the mechanism, relevant renal or circulating cells must be able to recognize the abnormal ECM environment and to initiate and sustain a state of imbalance in which the rate of ECM removal exceeds that of ECM production. This is clearly not the normal situation because throughout adult life, GBM width and mesangial matrix remain quite constant consistent, with balanced ECM production and removal.^[77] More recently, remodeling and healing in the tubulointerstitium has been demonstrated in these same patients.^[78] These studies demonstrated reduction in total cortical interstitial collagen remarkable potential for healing of kidney tissue damaged by longstanding diabetes.^[74] Whether healing can be induced by treatments other than cure of the diabetic state is currently unknown.



FIGURE 36-13 (A-D) Thickness of the glomerular basement membrane (GBM), thickness of the tubular basement membrane (TBM), mesangial fractional volume, and mesangial-matrix fractional volume at baseline, and 5 and 10 years after pancreas transplantation. The shaded area represents the normal ranges obtained in the 66 age- and sex-matched normal controls (means±2 SD). Data for individual patients are connected by lines. (From Fioretto P, Steffes MW, Sutherland DER, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75, 1998.)



FIGURE 36-14 Light microscopic photomicrographs (periodic acid-Schiff [PAS] stain) of renal biopsy specimens obtained before and after pancreas transplantation from a 33-year-old woman with type 1 diabetes of 17 years' duration at the time of transplantation. A, Typical glomerulus from the baseline biopsy specimen, which is characterized by diffuse and nodular (Kimmelstiel-Wilson) diabetic glomerulopathy. B, Typical glomerulus 5 years after transplantation with persistence of the diffuse and nodular lesions. C, Typical glomerulus 10 years after transplantation, with marked resolution of diffuse and nodular mesangial lesions and more open glomerular capillary lumina. (From Fioretto P, Steffes MW, Sutherland DER, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75, 1998.)

EPIDEMIOLOGY OF MICROALBUMINURIA AND DIABETIC NEPHROPATHY

Prevalence and Incidence

Table 36-2 displays the prevalence, incidence, and cumulative incidence of abnormally elevated urinary albumin excretion in type 1 and type 2 diabetes. The overall prevalence of micro- and macroalbuminuria is around 30% to 35% in both types of diabetes. However, the range in prevalence of diabetic nephropathy is much wider in patients with type 2 diabetes. This is mainly explained by ethnic differences. The highest prevalence is found in Native Americans, followed by Asian patients, Mexican Americans, Black Americans, and European white patients.^[79] It should be stressed that a good agreement has been documented between the clinic and population based studies. The cumulative incidence of persistent proteinuria in type 1 diabetic patients diagnosed before 1942 was about 40% to 50% after a 25- to 30-year duration, but it has declined to 15% to 30% in type 1 diabetic patients diagnosed after 1953.^{[2] [80]}This so-called calendar effect has unfortunately not been seen in European white type 2 diabetic patients. The reason for the declining cumulative incidence of proteinuria in type 1 diabetic patients is unknown, but improved diabetes care and control have been suggested,^[81] in addition to a general decline in non-diabetic glomerulopathies.

TABLE 36-2 -- Prevalence, Incidence, and Cumulative Incidence of Microalbuminuria and Nephropathy in Diabetes^[*]

	Clinic based		Population based
	Type 1	Type 2	Type 2
Prevalence (%) of: Microalbuminuira^{[82] [87] [476] [477]}	13 (9–20)	25 (13–27)	20 (17–21)
Macroalbuminuria^{[2] [82] [476]}	15 (8–22)	14 (5–48)	16 (9–46)
Incidence of macroalbuminuria (%/yr),^[6]	1.2 (0–3)	1.5 (1–2)	-
Cumulative incidence of macroalbuminuria (%/25 yr)^{[2] [6] [478]}	31 (28–34)	28 (25–31)	-
Cholesterol^{[132] [133] [499]}	+	+
Presence of retinopathy^{[61] [132] [133] [165] [500]}	+	+
Use of oral contraceptive^[499]	+	?
Inflammation^{[119] [502] [503]}	+	+
Adiponectin^[502]	+	+
Nocturnal hypertension^[503]	+	+

+, present; -, not present; ?, no relevant information; F, female; IDDM, insulin-dependent diabetes mellitus; M, male.

^*	Median and range indicated.

Diabetic nephropathy rarely develops before 10 years' duration of type 1 diabetes, whereas approximately 3% of newly diagnosed type 2 diabetic patients have overt nephropathy.^[82] The incidence peak (3%/year) is usually found between 10 to 20 years of diabetes; thereafter a progressive decline in incidence takes place. Thus, the risk of developing diabetic nephropathy for a normoalbuminuric patient with a diabetes duration of greater than 30 years is reduced.^[83] This changing pattern of risk indicates that the magnitude of exposure to diabetes is not sufficient to explain the development of diabetic nephropathy, and suggests that only a subset of patients are susceptible to kidney complications.

Microalbuminuria Predicts Nephropathy

The type 1 diabetic subpopulation at risk may now be identified fairly accurately by the detection of microalbuminuria.^[3] Several longitudinal studies have shown that microalbuminuria, strongly (predictive power of 80%) predicts the development of diabetic nephropathy in type 1 diabetic patients.^{[84] [85]}

Type 1 diabetic patients with microalbuminuria have a median risk ratio of 21 for developing diabetic nephropathy, whereas the risk ratio for developing diabetic nephropathy range, from 4.4 to 21 (median 8.5) in microalbuminuric type 2 diabetic patients.^[86] In addition to microalbuminuria, several other risk factors or markers for the development of diabetic nephropathy have been documented or suggested, as discussed in details later ( Table 36-3 ).

TABLE 36-3 -- Risk Factors/Markers for Development of Diabetic Nephropathy in Type 1 and Type 2 Diabetic Patients

Risk Factors/Markers	Type 1	Type 2
Normoalbuminuria (above median)^{[132] [133] [479]}	+	+
Microalbuminuria^{[83] [141] [480] [481] [482]}	+	+
Sex^{[5] [82]}	M > F	M > F
Familial clustering^{[467] [483] [484] [485]}	+	+
Predisposition to arterial hypertension^{[159] [160] [161]}	+/-	+
Increased sodium/lithium counter transport^{[159] [160] [486] [487] [488] [489] [490] [491]}	+/-	-
Ethnic conditions^{[79] [492]}	+	+
Onset of IDDM before 20 years of age^{[5] [83]}	+	?
Glycemic control^{[3] [4] [129] [482] [493]}	+	+
Hyperfiltration^{[128] [129] [130] [131]}	+/-	+/-
Prorenin^{[494] [495] [496] [497]}	+	?
Smoking^{[175] [498]}	+	+

Prognosis in Microalbuminuria

A recent meta-analysis has demonstrated that microalbuminuria is a strong predictor of total and cardiovascular mortality and cardiovascular morbidity in diabetic patients.^[87] Accordingly microalbuminuria predicts coronary and peri-pheral vascular disease and death from CVD in the general nondiabetic population.^{[88] [89]} The mechanisms linking microalbuminuria and death from CVD are poorly understood. Microalbuminuria has been proposed as a marker of widespread endothelial dysfunction that might predispose to enhanced penetrations in the arterial wall of atherogenic lipoprotein particles^[90] and a marker of established CVD.^[91] Also, microalbuminuria is associated with excess of well known and potential cardiovascular risk factors.^[91] Elevated BP, dyslipoproteinemia, increased platelet aggregability; endothelial dysfunction, insulin resistance, and hyperinsulinemia have been demonstrated in microalbuminuric diabetic patients, as previously reviewed.^{[3] [84] [87]} Autonomic neuropathy, which is also associated with microalbuminuria predicts death (often sudden) from CVD in diabetic patients.^{[92] [93] [94]} Whereas the prevalence of coronary heart disease (CHD) based on Minnesota-coded electrocardiogram (ECG) is not increased in microalbuminuric type 2 patients.^[82] Echocardiographic studies have revealed impaired diastolic function and cardiac hypertrophy in microalbuminuric type 1 and type 2 patients.^{[95] [96] [97]} Left ventricular hypertrophy predisposes the individual to ischemic heart disease, ventricular arrythmia, sudden death, and heart failure.^[98] Recently, we have demonstrated that high N-terminal probrain matriuretic peptide is a major risk marker for CVD in type 2 diabetes with microalbuminuria.^[99]

Prognosis in Diabetic Nephropathy

In a cohort of 1030 type 1 diabetic patients diagnosed between 1933 and 1952, patients not developing proteinuria had a low and constant relative mortality, whereas patients with proteinuria on average had a 40 times higher relative mortality.^[5] Type 1 diabetic patients with proteinuria showed the characteristic bell-shaped relationship between diabetes duration/age and relative mortality of 110 in women and 80 in men in the age range of 34 to 38 years. Several other studies have confirmed the poor prognosis in type 1 diabetic patients suffering from diabetic nephropathy, as reviewed by Borch-Johnsen.^[5] In three early studies that described the natural course of diabetic nephropathy in type 1 diabetic patients, the cumulative death rate 10 years after onset of nephropathy ranged from 50% to 77%, as reviewed by Parving.^{[84] [85]} The 50% figure is a minimum value because the study included only death due to ESRD.

The overall decrease in relative mortality from 1933 to 1972 was 40% and is partly explained by the decrease in the cumulative incidence of proteinuria. Unfortunately this calendar effect is not seen in proteinuric type 2 diabetic patients, and subsequently, no improved prognosis has been reported.^[6] However, the prognostic importance of proteinuria in type 2 diabetic patients is considerably less than in type 1 diabetes. Proteinuria confers a 3.5 times higher risk of death, and the concommitant presence of arterial hypertension increases this relative risk to 7 in Pima Indians with type 2 diabetes.^[100] European type 2 diabetic patients with proteinuria have a fourfold excess of premature death compared with patients without proteinuria.^[101] The cumulative death rate 10 years after onset of abnormally elevated urinary albumin excretion in European Type 2 diabetic patients was 70% compared with 45% in normoalbuminuric type 2 diabetic patients.^[102]

ESRD is the major cause of death, accounting for the mortality rate of 59% to 66% in type 1 diabetic patients suffering from nephropathy.^[5] The cumulative incidence of ESRD 10 years after onset of proteinuria in proteinuric type 1 diabetic patients is 50%, as compared with 3% to 11% in proteinuric European type 2 diabetic patients and 65% in proteinuric Pima Indians with type 2 diabetes. However, renal insufficiency was defined as a serum creatinine of 2.0 mg/dL in the Pima study. Ninety-seven percent of the excess mortality associated with type 2 diabetes in this population is found in patients with proteinuria: 16% of deaths were ascribed to ESRD, whereas 22% were due to CVD.^[100] CVD is also a major cause of death (15% to 25%) in type 1 diabetic patients with nephropathy, despite the relatively low age at death.^[5] Borch-Johnsen and associates^[103] studied a cohort of 2890 type 1 diabetic patients and demonstrated that the relative mortality from CVD was 37 times higher in proteinuric type 1 diabetic patients compared with the general population. Abnormalities in well-established cardiovascular risk factors alone cannot account for this finding. Based on the RENAAL (Reduction of End Points in NIDDM with the Angiotensin II Antagonist Losartan) study, we have shown that type 2 diabetic patients with diabetic retinopathy have a poor prognosis.^[104]Several studies have shown abnormally raised levels of serum apolipoprotein (a) to be an independent risk factor for premature ischemic heart disease in nondiabetic subjects. However, studies in type 1 and type 2 diabetic patients suffering from diabetic nephropathy have yielded conflicting results.^{[105] [106] [107] [108]} Most studies have demonstrated that a familial predisposition to CVD is present in type 1 diabetic patients with diabetic nephropathy.^{[109] [110] [111]} Increased left ventricular hypertrophy, an established CVD risk factor, and a decrease in diastolic function occur early in the course of diabetic nephropathy.^{[94] [112] [113]} Left ventricular hypertrophy is a well-established risk factor for CVD. Recently, it has been demonstrated that cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.^{[93] [94]} Increased plasma homocysteine concentration is also a CVD risk factor and predicts mortality in type 2 diabetic patients with albuminuria.^[114] We demonstrated that increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time, and are strongly and independently associated with risk of death in type 2 diabetes.^[115] Tarnow and co-workers.^{[116] [117]} have demonstrated that elevated circulating N-terminal probrain natriuretic peptide is a new independent predictor of the excess overall and cardiovascular mortality in proteinuric type 1 and type 2 diabetic patients without symptoms of heart failure. In addition, several new circulating biomarkers of cardiovascular risk in diabetic nephropathy has been identified, for example, symmetric dimethylarginine^[118] and mannose-binding lectin.^[119] Finally, it should be mentioned that reduced kidney function is a cardiovascular risk factor.^{[120] [121]}

CLINICAL COURSE AND PATHOPHYSIOLOGY

A preclinical phase consisting of a normo- and a microalbuminuric stage and a clinical phase characterized by albuminuria are well documented in both type 1 and type 2 diabetic patients.

Normoalbuminuria

Approximately one third of type 1 diabetic patients will have a GFR higher than the upper normal range of age matched healthy nondiabetic subjects.^[122] The degree of hyperfiltration is less in type 2 diabetic patients^{[123] [124]} and reported lacking in some studies.^[125] The GFR elevation is particularly pronounced in newly diagnosed diabetic patients and during other intervals with poor metabolic control. Intensified insulin treatment and near-normal blood glucose control reduce GFR toward normal levels after a period of days to weeks in both type 1 and type 2 diabetic patients.^[123] Additional metabolites, vasoactive hormones, and increased kidney and glomerular size have been suggested as mediators of hyperfiltration in diabetes, as reviewed by Mogensen.^[122] Four factors regulate GFR. First, the glomerular plasma flow influences the mean ultrafiltration pressure and thereby GFR. Enhanced renal plasma flow has been demonstrated in type 1 and type 2 diabetic patients with elevated GFR.^[123] Second, the systemic oncotic pressure, which is reported to be normal as calculated from plasma protein concentrations. The third determinant of GFR is the glomerular transcapillary hydraulic pressure difference, which cannot be measured in humans. However, the demonstrated increase in filtration fraction is compatible with enhanced transglomerular hydraulic pressure difference. The last determinant of GFR is the glomerular ultrafiltration coefficient, Kf, which is determined by the product of the hydraulic conductance of the glomerular capillary and the glomerular capillary surface area available for filtration. Total glomerular capillary surface area is clearly increased already at the onset of human diabetes.

Studies in insulin-treated experimental diabetic rats have revealed hyperfiltration, hyperperfusion, enhanced glomerular capillary hydraulic measure, reduced proximal tubular pressure, unchanged systemic oncotic pressure, and unchanged or slightly elevated Kf.^[126] Several studies suggest that insulin-like growth factor I plays a major role in the initiation of renal and glomerular growth in diabetic animals, as reviewed by Flyvbjerg.^[127]

Longitudinal studies suggest that hyperfiltration is a risk factor for the subsequent increase in urinary albumin excretion and the development of diabetic nephropathy in type 1 diabetic patients,^{[128] [129]} but conflicting results have also been reported.^[130] The prognostic significance of hyperfiltration in type 2 diabetic patients is still debated.^[131] Six prospective cohort studies investigating normoalbuminuric type 1 and type 2 diabetic patients for 4 to 10 years, revealed that minimal elevation of urinary albumin excretion, poor glycemic control, hyperfiltration, elevated arterial BP, retinopathy, and smoking contribute to the development of persistent microalbuminuria and overt diabetic nephropathy.^{[129] [132] [133] [134] [135] [136]} Because several of those risk factors are modifiable, intervention is feasible, as discussed later.

Microalbuminuria

In 1969, Keen and colleagues^[137] demonstrated elevated urinary albumin excretion in newly diagnosed type 2 diabetes. This abnormal but subclinical albumin excretion rate has been termed microalbuminuria, and it can be normalized by improved glycemic control. In addition to hyperglycemia, many other factors can induce microalbuminuria in diabetic patients such as hypertension, massive obesity, heavy exercise, various acute or chronic illnesses, and cardiac failure.^{[138] [139]} Furthermore, the day-to-day variation in urinary albumin excretion rate is high (30% to 50%). Consequently, more than one urine sample is needed to determine whether an individual patient has persistent microalbuminuria. Urinary albumin excretion within the microalbuminuric range (30 mg to 300 mg/24 hr) in at least two out of three consecutive nonketotic sterile urine samples is the generally accepted definition of persistent microalbuminuria. Persistent microalbuminuria has not been detected in type 1 diabetic children younger than 12 years and is exceptional in the first 5 years of diabetes.^[140] The annual rate of raise of urinary albumin excretion is about 20% in both type 2 diabetes^[141] and type 1 diabetic patients with persistent microalbuminuria.^[142]

The excretion of albumin in the urine is determined by the amount filtered across the glomerular capillary barrier and the amount reabsorbed by the tubular cells. A normal urinary β2-microglobulin excretion rate in microalbuminuria suggests that albumin derives from enhanced glomerular leakage rather than from reduced tubular reabsorption of protein. The transglomerular passage of macromolecules is governed by the size- and charge-selective properties of the glomerular capillary membrane and hemodynamic forces operating across the capillary wall. Alterations in glomerular pressure and flow influence both the diffusive and the convicting driving forces for transglomerular passage of proteins. Studies using renal clearance of endogenous plasma proteins or dextrans have not detected a simple size-selective defect.^{[143] [144] [145]} Determination of IgG/IgG₄ ratio suggests that loss of glomerular charge selectivity precedes or accompanies the formation of new glomerular macromolecular pathways in the development of diabetic nephropathy.^[143] Reduction in the negatively charged moieties of the glomerular capillary wall, particularly sialic acid and heparan sulfate have been suggested.^[91] but not confirmed.^{[43] [146]} Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney.^[147] Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and progression of diabetic kidney disease.^{[34] [148] [149] [150]} Filtration fraction is presumed to reflect the glomerular hydraulic pressure, and microalbuminuric Type 1 diabetic patients have elevated filtration both at rest and during exercise compared to normal controls. A close correlation between filtration fraction and urinary albumin excretion has been demonstrated as well. The demonstration that microalbuminuria diminishes promptly with acute reduction in arterial BP argues for reversible hemodynamic factors to play an important role in the pathogenesis of microalbuminuria. Imanishi and associates^[151] have demonstrated that glomerular hypertension is present in type 2 diabetic patients with early nephropathy and closely correlated with increased urinary albumin excretion. In addition, it should be mentioned that increased pressure has been demonstrated in the nail fold capillaries of microalbuminuric type 1 diabetic patients.^[152]

GFR measured with the single injection ⁵¹Cr-EDTA plasma clearance method or the renal clearance of inulin is normal or slightly elevated in type 1 diabetic patients with microalbuminuria. Prospective studies have demonstrated that GFR remains stable at normal or supranormal levels for at least 5 years if clinical nephropathy does not develop.^[153] Nephromegaly is still present and even more pronounced in microalbuminuric as compared with that of normoalbuminuric type 1 diabetic patients.^[154]

Changes in tubular function take place early in diabetes and are related to the degree of glycemic control. The proximal tubular reabsorption of fluid, sodium, and glucose is enhanced.^[155] This process could diminish distal sodium delivery and thereby stimulate a tubuloglomerular feedback-mediated enhancement of GFR. A direct effect of insulin increasing distal sodium reabsorption has also been demonstrated.^{[155] [156]} The consequences of these alterations in tubular transport for overall kidney function are unknown.

Several studies have demonstrated BP elevation in children and adults with Type 1 diabetes and microalbuminuria.^{[84] [85]} The prevalence of arterial hypertension (JNC-V criteria=140/90 mm Hg) in adult type 1 diabetic patients increases with albuminuria, being 42%, 52%, and 79% in subjects with normo-, micro-, and macroalbuminuria, respectively.^[157] The prevalence of hypertension in type 2 diabetes (mean age 60 years) was higher: 71%, 90%, and 93% in the normo-, micro-, and macroalbuminuric group, respectively.^{[82] [157]} A genetic predisposition to hypertension in type 1 diabetic patients developing diabetic nephropathy has been suggested,^[158] but other studies did not confirm the concept.^{[159] [160]} Recently, we have confirmed the original finding by applying 24-hour BP measuring in a large group of parents to type 1 diabetic patients with and without diabetic nephropathy.^[161] In addition, the cumulative incidence of hypertension was higher among parents of proteinuric patients, with a shift toward younger age at onset of hypertension in this group. However, the difference in prevalence of parental hypertension was not evident using office BP measurements. Several studies have reported that sodium and water retention play a dominant role in the initiation and maintenance of systemic hypertension in microalbuminuria and diabetic nephropathy, whereas the contribution of the renin-angiotensin-aldosterone system is smaller.^[162]

Diabetic Nephropathy

Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hr), a relentless decline in GFR, raised arterial BP, and enhanced cardiovascular morbidity and mortality.^{[84] [85]} Although albuminuria is the first sign, peripheral edema is the first symptom of diabetic nephropathy. Fluid retention is frequently observed early in the course of this kidney disease, that is, at a stage with well preserved renal function and only slight reduction in serum albumin. A recent study suggests that capillary hypertension, increased capillary surface area, and reduced capillary reflection coefficient for plasma proteins contribute to the edema formation, whereas the wash-down of subcutaneous interstitial protein tends to prevent the progressive edema formation in diabetic nephropathy.^{[163] [164]}

Most studies dealing with the natural history of diabetic nephropathy have demonstrated a relentless, often linear but highly variable rate of decline in GFR ranging from 2 to 20 mL/min/y, mean 12 mL/min/y.^{[3] [84] [85]} Type 2 diabetic patients suffering from nephropathy display the same degree of loss in filtration power and in variability of GFR.^{[165] [166]} Morphologic studies in both type 1 and type 2 diabetic patients have demonstrated a close inverse correlation between the degree of glomerular and tubulointerstitial lesions on one side and the GFR level on the other side, as discussed in details previously. Myers and co-workers^{[167] [168]} have demonstrated a reduction in the number of restrictive pores leading to loss of ultrafiltration capacity (Kf) and impairment of glomerular barrier size-selectivity leading to progressive albuminuria and IgG-uria in diabetic nephropathy. Furthermore, the extent to which ultrafiltration capacity is impaired appears to be related to the magnitude of the defect in the barrier size-selectivity. A defect in the glomerular barrier size-selectivity has also been demonstrated in type 2 diabetic patients with diabetic nephropathy.^[169] The reduction in renal plasma flow is proportional to the reduction in GFR (filtration fraction unchanged), and the impact on GFR is partially offset by the diminished systemic colloid osmotic pressure.

Several putative promoters of progression in kidney function have been studied in type 1 diabetes^{[170] [171] [172] [173] [174]} and type 2 diabetic^{[165] [175] [176]} patients with nephropathy ( Fig. 36-15 ). A close correlation between BP and the rate of decline in GFR has been documented in type 1 and type 2 diabetic patients.^{[50] [172] [174] [175] [177] [178] [179]} This suggests that systemic BP accelerates the progression of diabetic nephropathy. Previously, the adverse impact of systemic hypertension on renal function and structure was thought to be mediated through vasoconstriction and arteriolar nephrosclerosis.^[180] However, evidence from rat models shows that systemic hypertension is transmitted to the single glomerulus in such a way as to lead to hyperperfusion and increased capillary pressure.^[181] Intraglomerular hypertension has also been documented directly in streptozotocin diabetic rats^[181] and estimated to prevail in human diabetes particularly complicated by kidney disease.^[151] Impaired or abolished renal autoregulation of GFR and RPF as demonstated in type 1 and type 2 diabetic patients with nephropathy will contribute to increase vulnerability to hypertension or ischemic injuries of glomerular capillaries.^[182] Defective autoregulation of GFR has been demonstrated in streptozotocin diabetic rats during hyperglycemia,^[183] by contrast studies in man with Type 2 diabetes revealed no impact of glycemic control of GFR autoregulation.^[184] Originally, Remuzzi and Bertani^[185] suggested that proteinuria itself may contribute to renal damage. Type 1 diabetic patients with diabetic nephropathy and nephrotic range proteinuria (>3 g/24 hr) had the worst prognosis. Several observational studies and treatment trials have confirmed and extended the above-mentioned findings to also include subnephrotic range proteinuria.^{[50] [100] [177] [186]}



FIGURE 36-15 Putative promoters for progression of diabetic nephropathy.

For many years, it was believed that once albuminuria had become persistent, then glycemic control had lost its beneficial impact on kidney function and structure. Consequently, the concept of “point of no return” was advocated by many investigators as reviewed by Parving.^[84] This misconception was based on studies with few patients applying inappropriate methods for monitoring kidney function (serum creatinine) and glycemic control (random blood glucose). Several more recent studies dealing with large number of type 1 diabetic patients have documented the important impact of glycemic control on progression of diabetic nephropathy.^{[177] [179] [186]} In contrast, most of the studies dealing with proteinuric type 2 diabetic patients have failed to demonstrate any significant impact,^{[164] [165] [187]} with two exceptions.^{[175] [188]} Nearly all studies in type 1 and type 2 diabetic patients have demonstrated a correlation between serum cholesterol concentration and progression of diabetic nephropathy, at least in univariate analysis,^{[164] [165] [172] [174] [175] [177] [178] [179]} and some have failed to demonstrate cholesterol as an independent risk factor in multiple regression analysis.

Dietary protein restriction retards the progression of renal disease in virtually every experimental animal model tested.^[180] Surprisingly, all major observational studies in type 1 and type 2 diabetic patients with diabetic nephropathy have failed to demonstrate an impact of dietary protein intake on the rate of decline in GFR.^{[164] [165] [166] [177] [178] [179]} Some but not all studies suggest that smoking may act as a progression promoter in both type 1 and type 2 diabetic patients with proteinuria^{[189] [190]}; however, some larger, long-term studies have not been able to confirm that.^{[175] [191]}

The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE/ID) is strongly associated with the level of circulating ACE and increased risk of CHD in nondiabetic and diabetic patients.^{[192] [193]} The plasma ACE level in DD subjects is about twice that of II subjects with ID subjects having intermediate levels.^[194] Yoshida and colleagues^[195] followed 168 proteinuric type 2 diabetic patients during 10 years. Analysis of the clinical course of the three ACE genotypes revealed that the majority (95%) of the patients with the DD genotype progressed to ESRD within 10 years. Moreover, the DD genotype appeared to increase mortality once dialysis was initiated. Three observational studies have confirmed that the D-allele was a deleterious effect on kidney function.^{[196] [197] [198]} Finally, more severe diabetic glomerulopathy lesions have been documented both during the development and the progression of renal disease in type 2 diabetic patients with the D allele.^[199] Furthermore, microalbuminuric type 1 patients carrying the D allele have an increased progression of diabetic glomerulopathy, a finding based on renal biopsies taken at baseline and after 26 to 48 months of follow-up.^[200] Based on a large, double-blind randomized study (RENAAL) comparing the renoprotective effects of losartan versus placebo on top of conventional BP lowering drug in proteinuric type 2 diabetic patients, we demonstrated that the D allele of the ACE gene had a harmfull impact on doubling of baseline creatinine concentration, ESRD, or death.^[201] The impact was more pronounced in the white and the Asian patient group than the black and Hispanic groups. The beneficial effects of losartan were greatest in the ACE/DD group and intermediate in the ID group for nearly all endpoints, a trend suggesting a quantitative interaction between treatment and ACE genotype on progression of renal diasease. Such interaction was most significant for the risk reductiton of the ESRD end-point.^[201]

We showed an accelerated initial and sustained loss of GFR during ACE inhibitor treatment of albuminuric type 1 patients homozygous for the DD polymorphism of the ACE gene.^[202] The DD genotype independently influenced the sustained rate of decline in GFR or, in other words acted as a progression promoter. Three other studies have demonstrated that the D allele is a risk factor for an accelerated course of diabetic nephropathy in patients with type 1 diabetes.^{[203] [204] [205]} A potential contribution from other candidate genes in relation to the renin-angiontensin system has been suggested.^[205]

Pregnancy in women with diabetic nephropathy is accompanied by an increase in complications such as hypertension and proteinuria and by increases in prematurity and fetal loss. The impact of pregnancy on long-term course of renal function in women with diabetic nephropathy has not been clarified until most recently. Our study suggests that pregnancy has no adverse long-term impact on kidney function and survival in type 1 diabetic patients with well-preserved kidney function (serum creatinine at start of pregnancy < 100 mmol/L) suffering from diabetic nephropathy.^[204]

Nondiabetic glomerulopathy is very seldom in proteinuric type 1 diabetic patients, whereas this condition is common in proteinuric type 2 diabetic patients without retinopathy.^[206] A prevalence of biopsies with normal glomerular structure or nondiabetic kidney diseases of approximately 30% was demonstrated. Furthermore, a more rapid decline in GFR and a progressive rise in albuminuria in type 2 diabetic patients with diabetic glomerulopathy compared with type 2 diabetic patients without this condition has been demonstrated.^{[63] [207]}

Systemic BP elevation to a hypertensive level is an early and frequent phenomenon in diabetic nephropathy.^{[82] [84] [85]} Furthermore, nocturnal BP elevation (‘non-dippers’) occurs more frequently in type 1 and type 2 diabetic patients with nephropathy.^{[208] [209]} Exaggerated BP response to exercise has also been reported in long-standing IDDM patients with microangiopathy. Finally, the increase in glomerular pressure consequent to nephron adaption may be accentuated with concomitant diabetes, as suggested in animal studies.^[210]

EXTRARENAL COMPLICATIONS IN DIABETIC NEPHROPATHY

Diabetic retinopathy is present in virtually all type 1 diabetic patients with nephropathy, whereas only 50% to 60% of proteinuric type 2 diabetic patients suffer from retinopathy.^[82] Absence of retinopathy should require further investigation for nondiabetic glomerulopathies.^[1] Blindness due to severe proliferative retinopathy or maculopathy is approximately 5 times greater in type 1 and type 2 diabetic patients with nephropathy compared with normoalbuminuric patients.^[82] Macroangiopathy, for example, stroke, carotid artery stenosis, CHD, and peripheral vascular disease, are 2 to 5 times more common in nephropathic patients.^[82]

Peripheral neuropathy is present in almost all patients with advanced nephropathy. Foot ulcers with sepsis leading to amputation occur frequently (>25%), probably due to a combination of neural and arterial disease. Autonomic neuropathy may be asymptomatic and simply manifest as abnormal cardiovascular reflexes, or it may result in debilitating symptoms. Nearly all patients suffering from nephropathy have grossly abnormal autonomic function test.^[93]

TREATMENT

The major therapeutic interventions that have been investigated include near-normal blood glucose control, antihypertensive treatment, lipid lowering, and restriction of dietary proteins. The impact of these three treatment modalities on progression from: normo- to microalbuminuria (primary prevention), microalbuminuria to diabetic nephropathy (secondary prevention), and diabetic nephropathy to ESRD are described and discussed.

Glycemic Control

Primary Prevention

Strict metabolic control achieved by insulin treatment or islet cell transplantation normalizes hyperfiltration, hyperperfusion, and glomerular capillary hypertension, and reduces the rate of increase in urinary albumin excretion in experimental diabetic animals.^[84] The treatment also mitigates the development of diabetic glomerulopathy, whereas the glomerular enlargement remains unaffected. Risk factors for progression from normoalbuminuria to micro- and macroalbuminuria have been identified ( Table 36-4 ). Short-term near-normal blood glucose control in normoalbuminuric type 1 diabetic patients reduces GFR, RPF, urinary AER, and the enlarged kidney. Increased kidney size is associated with an exaggerated renal response to amino acid infusion, and studies suggest that both abnormalities can be corrected by 3 weeks of intensified insulin treatment.^[211] A meta-analysis of long-term (8 to 60 months) intensive blood glucose control has documented a beneficial effect on the progression from normo- to microalbuminuria in type 1 diabetic patients.^[212] The odds ratio for progressing from normo- to microalbuminuria ranged from 0.22 to 0.40 in the intensified treated groups. A worsening of diabetic retinopathy was observed during the initial months of intensive therapy, but in the longer term, the rate of deterioration was slower than it was in the conventional treated type 1 diabetic patients.^[213] Side effects are a major concern with intensive therapy, and the frequency of severe hypoglycemia and diabetic ketoacidosis were greater in several studies.^[212] In the DCCT trial,^[214] intensive therapy reduced the occurrence of microalbuminuria by 39% (95% confidence interval [CI], 21 to 52), and that of albuminuria by 54% (95% CI, 19 to 74), when analyzing the two cohorts combined. Despite this, however, 16% in the primary prevention and 26% in the secondary prevention cohort developed microalbuminuria during the 9 years of intensive treatment. This clearly documents that we need additional treatment modalities in order to avoid or reduce the burden of diabetic nephropathy.

TABLE 36-4 -- RENAAL and IDNT Results Comparison of Primary Composite End Point and Components

Composite End Point	Risk Reduction (% [95% CI])
	Losartan vs. Placebo (80)	Irbesartan versus Placebo (81)	Irbesartan versus Amlodipine (81)	Amlodipine versus Placebo (81)
DsCr, ESRD, Death	16 (2, 28)	20 (3, 34)	23 (7, 37)	- 4 (14, - 25)
DsCr	25 (8, 39)	33 (13, 48)	37 (19, 52)	- 6 (16, - 35)
ESRD	28 (11, 42)	23 (- 3, 43)	23 (- 3, 43)	0 (- 32, 24)
Death	- 2 (- 27, 19)	8 (- 31, 23)	- 4 (23, - 40)	12 (- 19, 34)
ESRD or death	20 (5, 32)	—	—	—

CI, confidence interval; DsCr, doubling of serum creatinine; RENAAL, Reduction of End Points in NIDDM with the Angiotensin II Antagonist Losartan Study; IDNT, Irbesartan Diabetic Nephropathy Trial.

A much smaller study with a design similar to the DCCT in Japanese type 2 diabetic patients also showed a beneficial effect on progression of normoalbuminuria to micro- and macroalbuminuria.^[215] This study has been confirmed and extended by the United Kingdom Prospective Diabetes Study (UKPDS) data documenting a progressive beneficial effect of intensive metabolic control on the development of microalbuminuria and overt proteinuria.^[216]

Secondary Prevention

Several modifiable risk factors (level of urinary albumin excretion, HbA_1c, smoking, BP, and serum cholesterol concentration) for progression from microalbuminuria to overt diabetic nephropathy has been identified in clinical trials and observational studies of type 1 and type 2 diabetic patients.^{[3] [4] [141] [217] [218] [219] [220]}

The renal impact of intensive diabetic treatment versus conventional diabetic treatment on the progression or regression of microalbuminuria in type 1 diabetic patients has shown conflicting outcome, as reviewed by Parving.^[84]These disappointing results might partly be due to the relatively short length of the follow-up period, because the UKPDS study with 15 years of follow-up documented a progressive beneficial effect with time on the development of proteinuria and a twofold increase in plasma creatinine.^[216] Furthermore, pancreatic transplantation can reverse glomerulopathy in patients with type 1 diabetes and normo- (N = 3) or microalbuminria (N = 4), but reversal requires more than 5 years of normoglycemia.^[76] Recently, we demonstrated that intensified multifactorial intervention (pharmacologic therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria) in patients with type 2 diabetes and microalbuminuria substantially slows progression to nephropathy, retinopathy, and autonomic neuropathy.^{[92] [221]}

Nephropathy

The impact of improved metabolic control on progression of kidney function in type 1 diabetic patients with nephropathy has been disappointing. The rate of decline in GFR and the increase in proteinuria and in systemic BP were not affected by improved glycemic control. However, it should be stressed that none of the trials were randomized and the number of patients investigated was small. In contrast, most major prospective observational studies have indicated an important role for glycemic control in the progression of diabetic nephropathy, as discussed earlier.^{[84] [177] [179] [186]}

Blood Pressure Control

Primary Prevention

Originally, Zatz and co-workers^[222] showed that prevention of glomerular capillary hypertension in normotensive insulin-treated streptozotocin diabetic rats effectively protects against the subsequent development of proteinuria and focal and segmental glomerular structural lesions. Other studies confirmed the beneficial effect of ACE-inhibition in uninephrectomised rats made diabetic by streptozotocin. Anderson and associates^{[223] [224]} have demonstrated that antihypertensive therapy slows the development of diabetic glomerulopathy but that ACE-inhibitors affords superior long-term protection compared with triple therapy with reserpine, hydralazine, and hydrochlorothiazide or a calcium channel blocker (nifedipine). Recent observations are consistent with the concept that glomerular hypertension is a major factor in the pathogenesis of experimental diabetic glomerulopathy, and indicates that lowering of systemic BP without concommitant reduction of glomerular capillary pressure may be insufficient to prevent glomerular injury.^{[223] [224] [225]} Lowering of systemic BP by ACE inhibitors or conventional antihypertensive treatment affords significant renoprotection in spontaneously hypertensive streptozotocin diabetic rats.^[226] No specific benefit of ACE inhibition was observed in this hypertensive model in contrast to the above-mentioned normotensive models. Three randomized placebo-controlled trials in normotensive type 1 and type 2 diabetic patients with normal albumin excretion rate have suggested a beneficial effect on the development of microalbuminuria.^{[227] [228] [229]}In contrast to these three studies, which were carried out as placebo-controlled trials, the literature contains three new studies comparing the effect of ACE inhibitors versus a long-acting dihydropyridine calcium antagonist^{[230] [231]}or b blockade^[232] in hypertensive type 2 diabetic patients with normoalbuminuria. All three studies reported a similar beneficial renoprotective effect of BP reduction with and without ACE inhibition. Furthermore, the UKPDS study reported that by 6 years, a smaller proportion of patients in the group under tight BP control had developed microalbuminuria and a 29% reduction in risk (P < 0.009), with a nonsignificant 39% reduction in the risk for proteinuria (P = 0.061).^[232] Beneficial effects of aggressive BP control in normotensive (BP < 160/90 mm Hg) type 2 diabetic patients on albuminuria, retinopathy, and incidence of stroke have recently been demonstrated.^[233] The results were the same whether enalapril or nisoldipine were used as the initial BP-lowering drug. Originally, the EUCLID study group^[234] demonstrated a significant beneficial effect of ACE inhibition on progression of diabetic retinopathy and development of proliferative retinopathy in type 1 diabetic patients. The BENEDICT study has demonstrated that ACE inhibition decreases the incidence of microalbuminuria in hypertensive type 2 diabetic patients with normoalbuminuria. The effect of verapamil alone was similar to that of placebo.^[235]

Secondary Prevention

A meta-analysis of 12 trials in 698 type 1 diabetic patients with microalbuminuria who were followed for at least 1 year has revealed that ACE inhibitors reduced the risk of progression to macroalbuminuria compared with that of the placebo group (odds ratio 0.38 [95% CI, 0.25 to 0.57]).^[236] Regression to normoalbuminuria was 3 times greater than in the patients receiving placebo. At 2 years, the urinary albumin excretion rate was 50% lower in patients taking ACE inhibitors than in those receiving placebo. Furthermore, we showed that the beneficial effect of ACE inhibitors on preventing progression from microalbuminrua to overt nephropathy is long lasting (8 years' duration) and, more important, it is associated with preservation of normal GFR.^[237] Recent data from a doubleblind randomized study lasting 3 years show that long-acting dihydropyridine calcium antagonists are as effective as ACE inhibitors in delaying the occurrence of macroalbuminuria in normotensive patients with type 1 diabetes with persistent microalbuminuria.^[238] Finally, agents blocking the effect of the rennin-angiotensis system (RAS) have a beneficial impact on glomerula structural changes in type 1 and type 2 diabetic patients with early diabetic glomerulopathy.^{[239] [240] [241]}

Recently, Borch-Johnsen and colleagues^[142] analyzed the cost-benefit of screening and antihypertensive treatment of early renal disease indicated by microalbuminuria in type 1 diabetic patients. The authors reached the conclusions that screening and intervention programs are likely to have life-saving effects and lead to considerable economic savings.

The impact of ACE inhibition in microalbuminuric type 2 diabetic patients has also been evaluated. A randomized study^[242] of diabetic patients with microalbuminuria treated with perindopril or nifedipine for 12 months was conducted. Both treatments significantly reduced mean arterial BP and urinary albumin excretion rate. Unfortunately, the study dealt with a heterogeneous group of hypertensive or normotensive type 1 or type 2 diabetic patients. Ravid and co-workers^[141] have conducted a double-blind randomized study in 94 normotensive microalbuminuric non-insulin-dependent diabetes mellitus (NIDDM) patients receiving enalapril or placebo for 5 years. The kidney function remained stable, and only 12% of the patients in the actively treated group developed diabetic nephropathy, whereas the kidney function declined by 13%, and 42% of the patients receiving placebo developed nephropathy. These data have been confirmed.^{[219] [220] [233] [243]}

Antihypertensive treatment has a renoprotective effect in hypertensive patients with type 2 diabetes and microalbuminuria.^{[221] [229] [230] [231] [232] [244] [245] [246] [247] [248] [249]} There has been conflicting evidence regarding the existence of a specific renoprotective effect—that is, a beneficial effect on kidney function beyond the hypotensive effect—of agents that block the RAS in patients with type 2 diabetes and microalbuminuria.^{[221] [229] [230] [231] [232] [244] [245] [246] [247] [248] [249]} The inconclusive nature of the previous evidence may have been due in part to the small size of the patient groups studied and the short duration of antihypertensive treatment in most previous trials. An exception is the long-lasting UKPDS, which suggested the equivalence of a β-blocker and an angiotensin-I-converting enzyme inhibitor.^[232] Therefore we evaluated the renoprotective effect of an angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria, called the IRMA 2 trial.^[250]

A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized double-blind, placebo-controlled study of irbesartan at a dose of either 150 mg daily or 300 mg daily and were followed for 2 years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater 200 mg/min and at least 30% higher than the baseline level. The baseline characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2%) and 19 patients of the 195 patients in the 150-mg group (9.7%) reached the primary end-point, as compared with 30 of the 201 patients on placebo (14.9%) (hazard ratio 0.30 [95% CI, 0.14 to 0.61; P < 0.001] and 0.61 [95% CI, 0.34 to 1.08; P = 0.08] for the two irbesartan groups, respectively) ( Fig. 36-16 ). The average BP during the course the study was 144/83 mm Hg in the placebo group, and 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P = 0.004 for the comparison of systolic BP between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P = 0.02). The IRMA 2 study demonstrated that irbesartan is renoprotective independent of its BP-lowering effect in patients with type 2 diabetes and microalbuminuria. In a substudy of IRMA 2, irbesartan was found to be renoprotective independent of its beneficial effect in lowering 24-hour BP.^[251] In another substudy, we showed a persistent reduction of microalbuminuria after withdrawal of all antihypertensive treatment suggesting that the 300 mg irbesartan dose daily confers long-term renoprotection.^[252] Remission to normoalbuminuria was more common in the Irbeartan-treated patients compared with those treated with placebo.^[250] The importance of this finding is a slower decrease in GFR, as demonstrated in the STENO-2 study.^[253] Recently, we have demonstrated an enhanced renoprotective effects of ultrahigh doses of irbesartan (900 mg daily) in patients with type 2 diabetes and microalbuminuria.^[254] Finally, we have demonstrated cost-effectiveness of early irbesartan treatment versus placebo in addition to standard conventional BP-lowering treatment.^[255] Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the STENO-2 study, we evaluated the effect on cardiovascular and microvascular diseases of an intensified, targeted, multifactorial intervention comprising behavior modification and polypharmacologic therapy aimed at several modifiable risk factors (hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of CVD with aspirin) in patients with type 2 diabetes and microalbuminrua; we compared this approach with a conventional interntion involving multiple risk factors.^[92]Patients receiving intensive therapy had a significantly lower risk of CVD (hazard ratio, 0.47; 95% CI, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95% CI, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95% CI, 0.21 to 0.86) and autonomic neuropathy (hazard ratio, 0.37; 95% CI, 0.18 to 0.79). In conclusion, a target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50%.



FIGURE 36-16 Probability of progression to diabetic nephropathy during treatment with irbesartan 150 mg daily (— —), 300 mg daily (- - - -) or placebo (solid line) in hypertensive type 2 diabetic patients with persistent microalbuminuria. The difference between placebo and irbesartan 150 mg daily was not significant (P = 0.08 by log-rank test) but significant when compared with irbesartan 300 mg daily (P < 0.001 by log-rank test).

In 1995, a consensus report on the detection, prevention, and treatment of diabetic nephropathy with special reference to microalbuminuria was published.^[256] Improved blood glucose control (HbA_1c below 7.5%–8%), and treatment with ACEI is recommended. Based on the trials mentioned earlier and later with angiotensin II receptor blockers (ARBs), the American Diabetes Association now recommends: “In hypertensive Type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARB's are the initial agents of choice.”^[257]

Nephropathy

From a clinical point of view, the ability to predict long-term effects on kidney function of a recently initiated treatment modality, for example, antihypertensive therapy, would be of great value because this could allow for early identifica-tion of patients in need of an intensified or alternative therapeutic regimen. In two prospective studies dealing with conventional antihypertensive treatment and ACEI, we found that the initial reduction in albuminuria (surrogate end point) predicted a beneficial long-term treatment effect on rate of decline in GFR in diabetic nephropathy (principal end point).^{[258] [259]} These findings have been confirmed and extended.^{[179] [260]} Furthermore, similar findings have been demonstrated in nondiabetic nephropathies.^{[261] [262]}

The antiproteinuric effect of ACEI in patients with diabetic nephropathy varies considerably. Individual differences in the RAS may influence this variation. Therefore, we tested the potential role of an insertion (I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric responsiveness in an observational follow-up study of young hypertensive Type 1 diabetic patients with diabetic nephropathy.^[263] Our data showed that Type 1 diabetic patients with II genotype are particularly susceptible to commonly advocated renoprotective treatment. Recently, the EUCLID Study Group^[264] demonstrated that urinary albumin excretion rate during lisinopril treatment was 57% lower in the II group, 19% lower in the ID group, and 19% higher in the DD group as compared with that of the group treated with placebo. Furthermore, the polymorphism of the ACE gene predicts therapeutic efficacy of ACEI against progression of nephropathy in type 2 diabetic patients.^[198] All previous observational studies in diabetic and nondiabetic nephropathies have demonstrated that the deletion polymorphism of the ACE gene, particularly the DD, genotype is a risk factor for an accelerated loss of kidney function.^{[196] [197] [202] [203] [265] [266] [267] [268] [269] [270]} Furthermore, the ACE deletion polymorphism reduces the long-term beneficial effect of ACE inhibition on progression of diabetic and nondiabetic kidney disease.^{[202] [268]} These findings suggest that the DD genotype patient should be offered more aggressive ACEI or treatment with ARBs or dual blockade of the RAS.

In an attempt to overcome this interaction, we evaluated the short- and long-term renoprotective effect in diabetic nephropathy of losartan in type 1 diabetic patients' homozygous for either the insertion or the deletion allele.^{[271] [272]}Our data suggest that ARB offers similar short- and long-term renoprotective and BP-lowering effects in albuminuric hypertensive type 1 diabetic patients with the ACE II and DD genotypes. Data from the RENAAL study mentioned before indicates that proteinuric type 2 diabetic patients with D allele of the ACE gene have an unfavorable renal prognosis that can be mitigated and even improved by losartan.^[201] Head-to-head comparisons of ACEI versus ARB suggest similar ability to reduce albuminuria and BP in diabetic patients with elevated urinary albumin excretion.^{[273] [274] [275]}

These results indicate that the reduction in albuminuria and BP induced by ACE inhibition is primarily caused by interference with the RAS. Because reduction of proteinuria is a prerequisite for successful long-term renoprotection, we investigated whether individual patient factors are determinants of antiproteinuric efficacy.^[276] The study suggests that patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs. Furthermore, in dose escalation studies of different ARBs, we have demonstrated that the optimal renoprotective dose of losartan is 100 mg daily, 16 mg daily for candesartan,^{[277] [278]} and 900 mg daily for irbesartan.^[254] Unfortunately we do not know the optimal renoprotective dose of the various ACE inhibitors. However, short-term studies suggest that the combination of ACEI and ARBs may offer additional renal and cardiovascular protection in diabetic patients with elevated albumin excretion rate.^{[279] [280] [281] [282] [283] [284] [285]} Recently, Nakao and associates^[286] performed a long-term (4 years' duration) double-blind randomized study of 263 nondiabetic renal disease patients in Japan. Patients were randomly assigned ARB (losartan 100 mg daily), ACEI (Trandolapril 3 mg daily), or a combination of both drugs at equivalent doses. By the end of follow-up, 22.5% of the losartan-treated patients, 23.3% of the Trandolapril treated patients and 11.4% in the combination group had reached the combined end point of doubling of the baseline serum creatinin concentration or ESRD (log-rank, test P = 0.02). In accordance, animal studies suggest that low-dose dual blockade of RAS achieves more important reduction in kidney tissue angiotensin II activity as compared with high doses of captopril or losartan.^[287] In addition, it should be mentioned that ARBs reduce BP without adversely altering the ability to autoregulate GFR in diabetic patients.^[288] In recent years, it has become clear that aldosterone should be considered a hormone with widespread unfavorable effects on the vasculature, the heart, and the kidneys.^{[289] [290]} We have demonstrated that elevated plasma aldosterone during long-term treatment with losartan is associated with an enhanced decline in GFR in type 1 diabetic patients with diabetic nephropathy.^[291] Consequentlly, aldosterone blockade could be considered in patients with suboptimal renoprotection during RAS blockade. Short-term studies in type 1 and type 2 proteinuric diabetic patients have demonstrated that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and BP.^{[292] [293] [294]}

Initiation of antihypertensive treatment usually induces an initial drop in GFR that is 3 to 5 times higher per unit of time than during the sustained treatment period.^[295] This phenomenon occurs with conventional antihypertensive treatment, with β-blockers, and diuretics, and when ACE inhibitors are used. Whether this initial phenomenon is reversible (hemodynamic) or irreversible (structural damage) after prolonged antihypertensive treatment has recently been investigated: In Type 1 patients suffering from diabetic nephropathy, our results render some support to the hypothesis that the faster initial decline in GFR is due to a functional (hemodynamic) effect of antihypertensive treatment that does not attenuate over time, whereas the subsequent slower decline reflects the beneficial effect on progression of nephropathy.^[295] A similar effect has been demonstrated in nondiabetic glomerulopathies.^[296] In contrast, our results suggest that the faster initial decline in GFR after initiating antihypertensive therapy in hypertensive type 2 patients with diabetic nephropathy is due to an irreversible effect.^[297]

In 1982, Mogensen described a beneficial effect of long-term antihypertensive treatment in five hypertensive men with type 1 diabetes and nephropathy.^{[297] [298]} Our prospective study initiated in 1976 has demonstrated that early and aggressive antihypertensive treatment reduces albuminuria and the rate of decline in GFR in young men and women with type 1 diabetes an nephropathy.^{[299] [300] [301]} Figure 36-17 illustrates the mean value for arterial BP, GFR, and albuminuria in nine patients receiving long-term (>9 years) treatment with metoprolol, furosemide, and hydralazine.^[301] Note that the data are consistent with a time-dependent renoprotective effect of antihypertensive treatment that in the long term might lead to regression of the disease (ΔGFR = 1 mL/min/y), at least in some patients. The same progressive benefit ΔGFR with time has been demonstrated on in nondiabetic renal diseases.^[302]Regression of kidney disease (ΔGFR = 1 mL/min/y) has been documented in a sizable fraction (22%) of type 1 patients receiving aggressive antihypertensive therapy for diabetic nephropathy.^[303] Remission of proteinuria for at least 1 year (proteinuria=1 g/24 hr) has been described in patients with type 1 diabetes participating in the Captopril Collaborative study.^[304] Eight of 108 patients experienced remission during long-term follow-up.^[304] We confirmed and extended these findings in a long-term prospective observational study of 321 patients with type 1 diabetes and nephropathy.^[305] The remission group, not surprisingly, is characterized by slow progression of diabetic nephropathy and an improved cardiovascular risk profile. More important, our prospective study suggests that remission of nephrotic range albuminuria in type 1 and type 2 diabetic patients, induced by aggressive antihypertensive treatment with and without ACE inhibitors, is associated with a slower progression in diabetic nephropathy and a substantially improved survival.^{[306] [307]}



FIGURE 36-17 Average course of mean arterial blood pressure, glomerular filtration rate (GFR), and albumin before (Υ) and during (λ) long-term effective antihypertensive treatment on nine type I patients suffering from diabetic nephropathy. (From Parving H-H, Rossing P, Hommel E, Smidt UM: Angiotensin converting enzyme inhibition in diabetic nephropathy: ten years' experience. Am J Kidney Dis 26:99–107, 1995, with permission.)

In 1992, Björck and co-workers suggested that ACE inhibitors in diabetic nephropathy confer renoprotection, for example, a beneficial effect on renal function and structure above and beyond that expected from the BP-lowering effect alone.^[308] Their investigation was a prospective, open, randomized study lasting for 2.2 years in patients with type 1 diabetes. In 1993, The Captopril Collaborative Study Group demonstrated a significant risk reduction for doubling of serum creatinine concentrations in patients with type 1 diabetes and nephropathy who received Captopril (48%; 95% CI, 16% to 69%).^[309] In comparison, the placebo-treated patients received conventional antihypertensive treatment excluding calcium channel blockers. We recently reported that long-term treatment (4 years' duration) with an ACE inhibitor or a long-acting dihydropyridine calcium antagonist has similar beneficial effects on progression of diabetic nephropathy in hypertensive patients with type 1 diabetes.^[310]

Thus, interruption of the RAS slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2 diabetes as reviewed by Parving.^[84] Against this background, two large multinational, double-blind, randomized placebo-controlled trials with ARBs were carried out in comparable populations of hypertensive patients with type 2 diabetes, proteinuria, and elevated serum creatinine levels.^{[311] [312]} In both trials, the primary outcome was the composite of a doubling of the base-line serum creatinine concentration, ESRD, or death. A comparison of the benefits obtained in the RENAAL study versus the IDNT (Irbesartan Diabetic Nephropathy Trial) is shown in Table 36-4 . Side effects were minimal, and less than 2% of the patients had to stop ARB because of severe hyperkalemia. The number of sudden deaths in the different groups was alike. The two landmark studies lead to the following conclusion: “Losartan and irbesartan conferred significant renal benefits in patients with Type 2 diabetes and nephropathy. This protection is independent of the reduction in BP it causes. The ARBs are generally safe and well tolerated.” A recent meta-analysis of IRMA 2^[250] and the two above-mentioned ARB trials^{[311] [312]} revealed a significant risk reduction (15%) of cardiovascular events as compared with the control groups.^[313] Based on the three above-mentioned outcome trials with ARBs, the American Diabetes Association now recommends: “In hypertensive Type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARB's are the initial agents of choice.”^[257]

Early studies describing the prognosis of overt diabetic nephropathy observed a median survival of 5 to 7 years after the onset of persistent proteinuria. End-stage renal failure was the primary cause of death in 66% of patients. When deaths attributed only to ESRD were considered, the median survival time was 10 years. All this was before patients were offered antihypertensive therapy.^[84] Long-term antihypertensive therapy was evaluated prospectively in 45 type 1 diabetic patients who developed overt diabetic nephropathy between 1974 and 1978. Ten years after onset of diabetic nephropathy, the cumulative death rate was 18% and the median survival was more than 16 years.^{[314] [315]}We went on to examine whether antihypertensive therapy also improved survival in an unselected cohort of 263 patients with diabetic nephropathy followed for up to 20 years, and observed a median survival of 13.9 years; only 35% of patients died because of end-stage renal failure (serum creatinine > 500 mmol/L).^[316] Fortunately, survival continues to improve, and we recently showed a median survival rate of 21 years after onset of diabetic nephropathy^[317]( Fig. 36-18 ).



FIGURE 36-18 Cumulative death rate from onset of diabetic nephropathy in type 1 diabetic patients during the natural history of diabetic nephropathy (red line, n = 45, Knowles^[472]; yellow line, n = 360, Andersen et al^[473]) compared with patients who had effective antihypertensive treatment (orange line, n = 45, Parving et al^[315]; black line, n = 263, Rossing et al^[101]; green line, n = 199, Astrup et al^[317]).

The first information on progression based on a randomized, double-blind placebo-controlled antihypertensive treatment trial was presented by the Collaborative Study Group of Angiotensin Converting Enzyme Inhibition with captopril in diabetic nephropathy.^[309] This study lasting on average 2.7 years demonstrated a risk reduction of 61% (95% CI 26% to 80%, P = 0.002) in the subgroup of 102 patients with baseline serum creatinine concentration greater than 133 mmol/L and 46% (P = 0.14) in the 307 patients with serum creatinine concentration at baseline below 133 mmol/L for the occurrence of death or progression to dialysis or transplantation in type 1 diabetic patients treated with captopril versus placebo. An economic analysis of the use of captopril in diabetic nephropathy revealed that ACEI will provide significant savings in the health care costs.^[318]

In conclusion, the prognosis of type 1 diabetic patients suffering from diabetic nephropathy has improved during the past decade, largely because of effective antihypertensive treatment with conventional drugs (b-blockers, diuretics) and ACE inhibitors. Unfortunately, scanty information on this important issue is available in type 2 diabetic patients with diabetic nephropathy.

Lipid Lowering

The renoprotective effect of HMGCoA reductase inhibitors in patients with type 1 or type 2 diabetes with micro- or macroalbuminuria appears to be highly variable.^[120] However, all nine studies are of short duration dealing with small number of patients and only evaluating the surrogate end point: urinary albumin excretion. Large long-term double-blind, randomized trials with hard end points, for example, doubling of serum creatinine or ESRD, are urgently needed.

Dietary Protein Restriction

Short-term studies in normoalbuminuric, microalbuminuric, and macroalbuminuric type 1 diabetic patients have shown that a low-protein diet (0.6–0.8 g/kg/d) reduces urinary albumin excretion and hyperfiltration, independently of changes in glucose control and BP.^{[319] [320]} Longer term trials in type 1 patients with diabetic nephropathy suggest that protein restriction reduces the progression of kidney function,^{[321] [322]} but the interpretation has been challenged.^{[323] [324]} Pedrini and colleagues^[325] performed a meta-analysis and concluded that dietary protein restriction effectively slows the progression of diabetic renal disease, but the conclusion has been disputed.^{[326] [327]}Most recently, we reported a 4-year prospective, controlled trial with concealed randomization comparing the effects of a low-protein diet with a usual protein diet in 82 type 1 diabetic patients with progressive diabetic nephropathy.^[328] ESRD or death occurred in 27% of patients on a usual protein diet as compared with 10% on low-protein diet (log-rank test P = 0.04). The relative risk of ESRD or death was 0.23 (0.07–0.72) for patients assigned to a low-protein diet, after an adjustment at baseline for the presence of CVD at baseline.

END-STAGE RENAL DISEASE IN DIABETIC PATIENTS

Epidemiology

Diabetic nephropathy has become the leading cause of ESRD in most Western countries.^[329] According to the 2005 report of the U.S. Renal Data System (www.usrds.org), diabetes as a comorbid condition was reported in 44.8% of incident ESRD patients in the United States (4.3% type 1, 40.5% type 2). In Europe, the proportion of diabetics varied considerably between countries. In 1999, on average, 117 diabetics per million population per year developed ESRD; the proportion was stable for those younger than 45 years but rose by 2.2% per year in the age group 45 to 64 years and by 7% among those 65 to 74 years.^{[330] [331]} Registry figures tend to underestimate the renal burden of diabetes; we found that diabetes as a comorbid condition was present in no less than 48.9% of patients admitted for renal replacement therapy in Heidelberg.^[332] Clinical features of classic Kimmelstiel-Wilson disease were found in only 60%, however. Atypical presentation consistent with ischemic nephropathy, that is, shrunken kidneys with no major proteinuria, accounted for 13%, and known primary renal disease (e.g., polycystic disease, analgesic nephropathy, glomerulonephritis) with superimposed diabetes accounted for 27% of the cases. Survival of the diabetic patient on hemodialysis (HD) is reduced whether or not diabetic or primary nondiabetic renal disease accounts for ESRD.^[333] In the Heidelberg series, diabetes had not been diagnosed at the time of admission in 11% of these patients, presumably because the patients had lost weight secondary to anorexia, thus self-correcting hyperglycemia. This may explain why apparent de novo diabetes commonly develops in patients on dialysis^[334]; patients with diabetic nephropathy may completely lose hyperglycemia after weight loss because of uremia and regain weight after refeeding on dialysis.

The diabetic patient with ESRD has several options for renal replacement therapy:

	1.	Transplantation (kidney only, simultaneous pancreas plus kidney, pancreas after kidney).
	2.	HD.
	3.	Continuous ambulatory peritoneal dialysis (CAPD).

There is consensus that today medical rehabilitation and survival are best after transplantation,^[335] particularly after transplantation of pancreas plus kidney.^[336] The results of CAPD and HD are inferior to transplantation but comparable between CAPD and HD.

Management of the Patient with Advanced Renal Failure

The diabetic patient with advanced renal failure has usually a much higher burden of microvascular and macrovascular complications ( Table 36-5 ) than the diabetic patient without or with the early stages of diabetic nephropathy. The morbidity of these diabetic patients with advanced renal failure is usually more severe than that of the average patient seen in the diabetes outpatient clinic. The diabetic patient with advanced renal impairment, even if he or she is asymptomatic, must therefore be monitored at regular intervals for timely detection of these complications (opthalmologic examination at half-yearly intervals, cardiac and angiologic status yearly, foot inspection at each visit).

TABLE 36-5 -- Major Microvascular and Macrovascular Complications in Patients with Diabetic Nephropathy

Microvascular complications

		Retinopathy
		Polyneuropathy including autonomic neuropathy (gastroparesis, diarrhea/obstipation, detrusor paresis, painless myocardial ischemia, erectile dysfunction; supine hypertension/orthostatic hypotension)

Macrovascular complications

		Coronary heart disease, left ventricular hypertrophy, congestive heart failure
		Cerebrovascular complications (stroke)
		Peripheral artery occlusive disease

Mixed complications diabetic foot (neuropathic, vascular)

The physician in charge of a diabetic patient with impaired renal function has to face a spectrum of therapeutic challenges, which are listed in Table 36-6 . The most vexing clinical problems are related to CHD and autonomic polyneuropathy.

TABLE 36-6 -- Frequent Therapeutic Challenges in the Diabetic Patient with Renal Failure

Hypertension (blood pressure amplitude, circadian rhythm)

Hypervolemia

Glycemic control (insulin half-life, cumulation of oral hypoglycemic agents)

Malnutrition

Bacterial infections (diabetic foot)

Timely creation of vascular access

Hypertension

At any given level of GFR, BP tends to be higher in diabetic compared with nondiabetic patients with renal failure. Because of their beneficial effect on cardiovascular complications^[337] and progression,^{[311] [312] [338] [339]} ACE inhibitors or ARBs are obligatory unless there are absolute or relative contraindications, for example, an acute major increase in serum creatinine (e.g., renal artery stenosis, hypovolemia) or hyperkalemia resistant to corrective maneuvers (such as loop diuretics, dietary potassium restriction, or correction of metabolic acidosis). Because of their marked propensity to retain salt, patients with diabetic nephropathy have a tendency to develop hypervolemia and edema.^[340] Therefore, dietary salt restriction and the use of loop diuretics are usually indicated. At least in monotherapy, thiazides are not sufficient once GFR is below 30 to 50 mL/min. When the creatinine concentration is elevated, multidrug antihypertensive therapy is usually necessary to normalize BP with, on average, three to five antihypertensive agents. In these patients, hypertension is also characterized by a high BP amplitude (as a result of increased aortic stiffness) and by an attenuated night-time decrease in BP, which in itself is a potent risk predictor.^{[341] [342]}

Glucose Control

On the one hand, renal failure causes, among other problems, insulin resistance by accumulation of a (hypothetical) circulating factor interfering with the action of insulin. As a result, there is a tendency to develop impaired glucose tolerance and hyperglycemia. Insulin resistance is improved after the start of dialysis.

On the other hand, the half-life of insulin is prolonged, causing a tendency to develop hypoglycemic episodes. This risk is further compounded by anorexia and by accumulation of most sulfonylurea compounds (with the exception of gliquidone or glimepiride). Glinides and glitazones do not accumulate.

It follows that as the result of these opposing influences glycemia is difficult to predict, and thus, close monitoring of plasma glucose concentrations is advisable. There is an increasing trend to use short-acting insulins more liberally in these patients, particularly during intercurrent illness (infections, surgery), and insulin treatment is also useful to combat catabolism and malnutrition.

Malnutrition

Patients are often severely catabolic and are predisposed to develop malnutrition, particularly during periods of intercurrent illness and fasting, but also from ill-advised recommendation of protein-restricted diets, particularly when these anorectic patients concomitantly reduce energy intake. Malnutrition is a potent independent predictor of mortality,^[343] and its presence justifies an early start of renal replacement treatment. Anorectic obese patients with type 2 diabetes and advanced renal failure often undergo massive weight loss, leading to normalization of fasting and even postloading glycemia. The diagnosis of Kimmelstiel-Wilson disease then requires documentation of retinopathy or renal biopsy. Wasting with low muscle mass is an important cause why physicians misjudge the severity of renal failure, because at any given level of GFR, serum creatinine concentrations are then spuriously low. This contributes to dosing errors of drugs, which accumulate in renal failure and may also contribute to the belated start of renal replacement therapy. It is advisable to measure or estimate GFR (Cockcroft-Gault or MDRD formula) in cases of doubt.

Acute and “Acute-on-Chronic” Renal Failure

Multimorbid diabetic patients with nephropathy are particularly prone to develop acute renal failure (ARF), very often when serum creatinine is already elevated (“acute on chronic”). In the Heidelberg program, 27% of patients with ARF had diabetes.^[332] The most common causes were emergency cardiologic interventions involving administration of radiocontrast, septicemia, low cardiac output, and shock. The high susceptibility of the kidney to ischemic injury, at least in experimental diabetes, may be a contributory factor.^[344] It is of note that in the intensive care unit, strict glycemic control reduces the risk of ARF even in nondiabetic patients.^[345] Frequently, ARF necessitates HD culminating in irreversible chronic renal failure. This mode of presentation as irreversible ARF has a particularly poor prognosis.^[346] Prevention of radiocontrast-induced ARF necessitates adequate hydration of the patient with saline as well as temporary interruption of diuretics treatment.^[347]

Vascular Access

Timely creation of vascular access is of overriding importance. It should be considered when the GFR is approximately 20 to 25 mL/min. Although venous runoff problems are not unusual (venous occlusion from prior injections, infusions, or infections, as well as hypoplasia of veins, particularly in elderly female diabetics), inadequate arterial inflow is increasingly recognized as the major cause of fistula malfunction.^[348] If distal arteries are severely sclerotic, anastomosis at a more proximal level may be necessary. Use of native vessels is clearly the first choice and results of grafts are definitely inferior.^[349] It is often necessary to create an upper arm native arteriovenous fistula^{[349] [350] [351]} or use more sophisticated approaches.^[352] Arteriosclerosis of arm arteries not only jeopardizes fistula flow but also predisposes to the steal phenomenon with ensuing finger gangrene.^[353]

Anemia

In diabetic patients with renal failure compared with nondiabetic patients, anemia is more frequent and more severe at any given level of GFR.^[354] The major cause of anemia is an inappropriate response of the plasma erythropoietin (EPO) concentration to anemia. Inhibition of the RAS may be an additional factor. In patients whose serum creatinine is still normal, the EPO concentration predicts the future rate of loss of GFR.^[355] There had been some concern that correction of anemia by EPO accelerated the rate of loss of GFR, but this has not been confirmed.^[355a] There is no controlled evidence concerning the effect of reversal of anemia by EPO on diabetic end-organ damage. Although EPO is a retinal proangiogenic factor in diabetes,^[356] uncontrolled observations show some improvement of diabetic retinopathy after administration of EPO,^[357] which is in line with experimental observations on a protective role of EPO in retinal ischemia^[358] and diabetic polyneuropathy.^[359] Because congestive heart failure is such a frequent complication of diabetic patients with renal failure,^[360] it is of interest that in nondiabetic patients, correction of anemia by EPO improves heart function.^[361]

Initiation of Renal Replacement Therapy

Many nephrologists would agree that renal replacement therapy should be started earlier than in nondiabetic patients at an eGFR of approximately 15 mL/min. An even earlier start may be justified when hypervolemia and BP become uncontrollable, when the patient is anorectic and cachectic, and when the patient vomits as the combined result of uremia and gastroparesis.

Hemodialysis

In recent years, survival of diabetic patients on HD has tended to improve.^[330] Astonishingly high survival rates, for example, 50% at 5 years in dialysed diabetic patients, have been reported from East Asia. To a large extent, these differences between countries may reflect the frequency of cardiovascular death in the background populations.

Intradialytic and Interdialytic Blood Pressure

Diabetic patients receiving dialysis tend to be more hypertensive than dialyzed nondiabetic patients. In diabetic patients, BP is exquisitely volume dependent. The problem is compounded by the fact that patients are predisposed to intradialytic hypotension, so that it is difficult to reach the target “dry weight” by ultrafiltration. Nevertheless, reduced dietary salt intake and ultrafiltration may permit control of hypertension without medication, but most patients need antihypertensive drugs. The main causes of intradialytic hypotension are, on the one hand, disturbed counterregulation (autonomous polyneuropathy) and, on the other hand, disturbed left ventricular compliance so that cardiac output decreases abruptly when left ventricular filling pressure diminishes during ultrafiltration.^[362] One or more of the following approaches are useful to avoid intradialytic hypotension: long dialysis sessions, omission of antihypertensive agents immediately before dialysis sessions, controlled ultrafiltration, and to a minor extent, also correction of anemia by EPO therapy. If nothing works, however, alternative treatment modalities, such as hemofiltration and CAPD, should be considered. Intradialytic hypotension increases the risk of cardiac death by a factor of three.^[333] It also prediposes to myocardial ischemia, arrhythmia, deterioration of maculopathy, and particularly in the elderly, nonthrombotic mesenteric infarction.

Pulse pressure and impaired elasticity, as well as calcification of central arteries, are major predictors of death and of cardiovascular events in nonuremic patients. They are also significant predictors of death in nondiabetic patients, but for uncertain reasons, not in diabetic patients on HD.^[363]

Cardiovascular Problems

Why is survival of diabetic patients on HD (and CAPD) inferior compared with that of nondiabetic patients? According to a Canadian study,^[364] 31% of diabetic patients on HD died from cardiovascular causes. Cardiovascular mortality accounted for 59% of overall deaths in diabetic patients compared with 14% in nondiabetic controls.

Stack and Bloembergen^[360] examined the prevalence of CHD in a national random sample of patients entering renal replacement programs and noted that the prevalence of CHD was significantly higher in diabetic compared with nondiabetic patients, the difference between the two groups even exceeding that observed between sexes.

Diabetic patients are at a greater risk of acquiring CHD in the predialytic phase. The odds ratio of developing new CVD was 5.35 for diabetic patients with established kidney disease who were not yet on dialysis.^[365] This explains the high prevalence of cardiovascular complications when diabetic patients enter dialysis programs. The rate of onset of ischemic heart disease was strikingly and significantly higher in diabetic patients compared with nondiabetic patients on HD.^{[361] [365] [366]}

The diabetic patient is also at higher risk when coronary complications supervene. When myocardial infarction develops, short-term and long-term survival are very poor in all HD patients, but poorest in the diabetic patient on HD: 62.3% versus 55.4% in the nondiabetic patient after 1 year and 93.3% versus 86.9% after 5 years.^[366] Diabetic patients are also more prone to develop cardiac arrest during dialysis sessions^[367] and more likely to die from sudden death in the dialysis interval. These complications are presumably not fully explained by the severity of stenosing coronary lesions. Undoubtedly, however, in dialyzed diabetic patients, coronary calcification is more pronounced^[368]and complex triple-vessel lesions are more frequent. In agreement with our experience, Varghese and colleagues^[369] found triple-vessel lesions in 27% of diabetic compared with 12% of nondiabetic patients. Nevertheless, the impact of ischemic heart disease is presumably amplified by further frequently coexisting cardiac abnormalities such as congestive heart failure, left ventricular hypertrophy, and disturbed sympathetic innervation,^{[371] [372]} as well as fibrosis of the heart and microvessel disease with diminished coronary reserve and deranged cardiomyocyte metabolism with reduced ischemia tolerance.^[372] Such functional abnormalities, particularly insufficient NO-dependent vasodilator reserve and deranged sympathetic innervation, have been documented even in the earliest stages of diabetes.^[373] They are also present in dialyzed diabetic patients.^[370]

Therapeutic challenges are prevention in the asymptomatic patient and intervention in the symptomatic patient. With respect to prevention, unfortunately, little evidence-based information is available. Observational studies suggest that good glycemic control in patients entering dialysis programs^[374] or patients on dialysis^[375] reduces overall and cardiovascular mortality. It is also sensible to reduce afterload (BP control) and preload (hypervolemia). Despite the evidence of benefit from statin therapy in diabetic patients without renal failure^[376] and in nondiabetic patients with renal failure but not on dialysis,^[377] the four-dimensional study did not find a reduction of cardiac events by atorvastatin in dialysed type 2 diabetic patients.^[378] Diabetic patients with renal failure are characterized by premature and more pronounced anemia so that timely and effective treatment with recombinant human EPO is advisable, although there is no controlled evidence of cardiovascular benefit.^[379] If one can extrapolate the results of the Heart Outcomes Prevention Evaluation^[337] study and the losartan Intervention for Endpoint Reduction in Hypertension study^[380] to ESRD, pharmacologic blockade of the RAS using ACE inhibitors or ARBs is indicated and safe,^[381] even in patients with advanced renal failure. In view of the importance of disturbed sympathetic innervation,^[382] it is surprising that β-blockers are only sparingly administered to dialyzed diabetic patients, although better survival on β-blockers has been shown in observational studies^[383] and substantially better survival with carvedilol in dialyzed patients has been documented in a controlled interventional study.^[384]

In a very small series of diabetic patients with symptomatic CHD, active intervention, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG), was superior to medical treatment alone,^[385]and in another series, 15% of the surgically managed patients had reached a cardiovascular end point after 8.4 months of follow-up compared with 77% of the medically managed group.^[386] Because patients often fail to complain of pain, and because screening tests such as exercise ECG and thallium scintigraphy are notoriously poor predictors, one should resort directly to coronary angiography if there is any suspicion of CHD.

No dogmatic statements concerning type of intervention are possible in the absence of evidence from controlled prospective studies. Retrospective interventional studies^{[387] [388] [389]} have consistently shown more adverse outcomes in diabetic patients compared with nondiabetic patients treated either with CABG or PTCA. After PTCA, the coronary reocclusion rate had been devastating in the past, for example, in some series, 70% at 1 year, even in nondiabetic HD patients. Results have considerably improved in recent years. More recent series suggest markedly better outcomes after PTCA plus stenting compared with PTCA alone,^[389] but the frequency of diffuse three-vessel disease with heavy calcification in dialysed diabetic patients remains a major problem.^[390] A recent retrospective analysis of dialysed diabetics suggested that CABG using internal mammary grafts (but not CABG using venous grafts) yielded superior outcome compared with PTCA with or without stenting.^[388] In view of the fact that renal failure per se aggravates insulin resistance^[391] and that in uremia, insulin-mediated glucose uptake of the heart is reduced,^[392] normalization of blood glucose by insulin and glucose infusion is particularly important in uremic patients with diabetes and ischemic heart disease.

Metabolic Control

Dialysis partially reverses insulin resistance so that insulin requirements often become less than before dialysis. Even patients with type 1 diabetes may occasionally lose their need for insulin, at least transiently, on institution of HD. In other patients, however, insulin requirements increase, presumably because anorexia is reversed so that appetite and food consumption increase. It is most convenient to use dialysates that contain glucose, usually about 200 mg/mL. This allows insulin to be administered at the usual times of day, reduces the risk of hyperglycemic or hypoglycemic episodes, and causes fewer hypotensive episodes.^[393]

Adequate control of glycemia is important because hyperglycemia causes thirst, high fluid intake, and hypovolemia, as well as an osmotic shift of water and K⁺ from the intracellular to the extracellular space. This leads to circulatory congestion and hyperkalemia. Diabetics with poor glucose control are also more susceptible to infection. Finally, in dialyzed diabetic patients, hyperglycemia definitely increases the risk of death, mainly from CVD.^[375]

Assessment of glycemic control using HbA_1c is confounded by carbamylation of hemoglobin, by altered red blood cell survival, and by assay interference from uremia.^[394] HbA_1c values above 7.5% cause modest overestimation of hyperglycemia in diabetic patients with ESRD.

Diminished insulin-mediated glucose uptake, that is, insulin resistance, has been noted in the hearts of uremic animals,^[392] and this is presumably one factor causing reduced ischemia tolerance of the heart. In view of the high cardiac risk and the benefit from intensive insulin therapy in critically ill patients,^[395] insulin should presumably be administered more generously in diabetic patients with renal failure. This might also be beneficial in the control of catabolism and malnutrition.

Malnutrition

Because of anorexia and prolonged habituation to dietary restriction, the dietary intake of energy (30–35 kcal/kg/d) and protein (1.3 g/kg/d) intake often falls short of the recommended target in diabetic patients on HD. By x-ray absorptiometry, Okuno and co-workers documented a decrease in body fat mass in diabetic compared to nondiabetic patients.^[395a] This is particularly undesirable because malnutrition is a potent predictor of death. It is of concern that indicators of malnutrition and microinflammation are more commonly found in diabetic patients.^[396] Surprisingly, conventional indicators of malnutrition are not predictive of survival in diabetic patients, however.^[397]

Miscellaneous

In the past, visual prognosis in dialyzed diabetics was extremely poor and a high proportion of patients were blind after several months. Despite the use of heparin (which in the past had been accused as a culprit), de novo amaurosis on HD has become very rare.

On average, hyperparathyroidism tends to be much less pronounced in diabetic patients compared to nondiabetic patients on HD.

Amputation

At the start of HD, 16% of diabetic patients have undergone amputation, most above-the-ankle amputation.^[398] The distinction between neuropathic and vascular foot lesions is crucial to improve outcomes, because the treatment of the two conditions is different.^{[400] [401]} The presence of diabetic foot lesions is one of the most powerful predictors of survival in dialysed diabetic patients, possibly as a result of the associated microinflammatory state.^[399]

Peritoneal Dialysis

CAPD is not the most common treatment modality. According to the U.S. Renal Data System in 2003, 41,940 incident diabetic patients were treated with HD, 2,808 with CAPD, and 367 with renal transplantation. The proportion of diabetic patients treated by CAPD varies greatly between countries, illustrating that selection of treatment modalities is also strongly influenced by logistics and reimbursement policies and not only by medical considerations. There are very good a priori reasons to offer initially CAPD treatment to diabetic patients. In diabetic patients with ESRD, forearm vessels are often sclerosed, so that it is not possible to create a fistula. The alternative of HD through intravenous catheters (instead of arteriovenous fistulas or grafts) yields unsatisfactory long-term results because blood flow is low and the risk of infection is high. Long-term dialysis through catheter was identified as one major predictor of poor patient survival on HD.^[400]

There are additional reasons for offering PD as the initial mode of renal replacement therapy to the diabetic patient. According to Heaf and co-workers, during the first 2 years, survival is better for patients treated with CAPD compared to HD, and this was also true for diabetic patients^[401] except for the very elderly.^[402]

A survival advantage is no longer demonstrable beyond the second year (presumably because by then residual renal function has decayed). Moreover, CAPD provides slow and sustained ultrafiltration without rapid fluctuations of fluid volumes and electrolyte concentrations, features that are advantageous for BP control and prevention of heart failure.

An interesting concept has been proposed by Van Biesen and colleagues.^[403] Patients who started on CAPD and who were transferred to HD after residual renal function had decayed had better long-term survival than patients who started on HD and remained on HD throughout. As a potential explanation, it has been proposed that an early start on CAPD prevents the organ damage that accumulates in the terminal stage of uremia. Survival of patients who had remained on CAPD for more than 48 months was inferior compared with patients on HD, presumably because CAPD is no longer sufficiently effective when residual renal function has gone, at least in heavier patients. It is also relevant that CAPD treatment presents no surgical contraindications to renal transplantation.

In the past, an idea had been advanced that seems a priori attractive—to administer insulin by injection into the CAPD fluid with the goal of providing insulin via the “physiologic” portal route. Unfortunately, there are practical problems: uncertainty of dosage because insulin binds to the surface of dialysis bags and tubing^[404] and is degraded by insulinases in the peritoneum.^[405] Moreover, the rate of absorption from the peritoneal cavity shows large interindividual variation. There is no firm evidence that the procedure permits better control of glycemia or dyslipidemia.^[406] As a result, most nephrologists no longer use this approach.

Although protein is lost across the peritoneal membrane, the main nutritional problem is gain of glucose and calories because high glucose concentrations in the dialysate are necessary for osmotic removal of excess body fluid. This leads to weight gain and obesity. Daily glucose absorption is 100 to 150 g, because a CAPD patient is exposed to 3 to 7 tons of fluid containing 50 to 175 kg of glucose per year. The use of glucose-containing fluids has another interesting disadvantage. Heat sterilization of glucose under acid conditions creates highly reactive glucose degradation products (GDPs) such as methylglyoxal, glyoxal, formaldehyde, 3-deoxyglucosone, and 3,4-dideoxyglucosone-3-ene.^[407] GDPs are cytotoxic and also lead to the formation of advanced glycation end products. Even in nondiabetic patients on CAPD, deposits of advanced glycation end products are found in the peritoneal membrane. They trigger fibrogenesis and neoangiogenesis presumably by interaction with RAGE, the receptor for AGE.^[408] The products also enter the systemic circulation presumably contributing to systemic microinflammation.^[409] These findings led to the snappy but misleading term “local diabetes mellitus.”^[410] Heat sterilization of two-compartment bags circumvents the generation of toxic GDPs. In prospective studies, CAPD fluid produced with this technique of sterilization was much less toxic than conventional CAPD fluid despite the high glucose concentration in the CAPD fluid.^[411]

Transplantation

Kidney Transplantation

There is consensus that medical rehabilitation of the diabetic patient with uremia is best after transplantation.^[335] Survival of the diabetic patient with a kidney graft is worse compared with a nondiabetic patient with a kidney graft. Nevertheless, because survival of the diabetic patient is so much poorer on dialysis, the percent gain in life expectancy of the diabetic patient with a graft, compared with the dialyzed diabetic patient on the waiting list, is much greater than in the nondiabetic patient. The higher mortality of the diabetic with a kidney graft is mainly due to complications resulting from preexisting vascular disease, left ventricular hypertrophy, and post-transplant hypertension.^[412] Wolfe and colleagues^[335] calculated an adjusted relative risk of death in transplant recipients, compared with patients on the waiting list; it was 0.27 in patients with diabetes and 0.39 in patients with glomerulonephritis. Obviously, the perioperative risk is higher in diabetic than in nondiabetic patients, but nevertheless, in diabetic patients, the predicted survival on the waiting list was 8 years and, after transplantation, 19 years. At present, the majority of diabetic patients receiving a transplant have type 1 diabetes, although graft and patient survival are impressive in carefully selected type 2 diabetic patients without macrovascular complications who had received kidney grafts.^[413] Diabetic patients must be subjected to rigorous pretransplantation evaluation, which in most centers, includes routine coronary angiography. As an alternative, Manske and colleagues have devised an algorithm to identify the diabetic patient who should receive screening tests before transplantation.^[414] Patients should also be examined by Doppler sonography of pelvic arteries and, if necessary, angiography, to avoid placement of a renal allograft into an iliac artery with compromised arterial flow at risk of ischemia of the extremity and amputation. Preemptive transplantation, that is, transplantation before initiation of dialysis, provides some modest long-term benefit.^[415]

Kidney-Plus-Pancreas Transplantation

Despite great excitement over the seminal double transplantation performed by Kelly and co-workers^[416] in Minneapolis, the results of simultaneous pancreas and kidney transplantation (SPK) had remained disappointing for a long time. The breakthrough came with the introduction of calcineurin inhibitors and low-steroid protocols. In an impressively large single-center experience, Becker and co-workers^[336] showed that survival of patients with SPK approached that of patients who underwent transplantation for nondiabetic renal disease and was clearly superior to diabetic recipients of living donor kidney grafts and particularly of cadaver kidney grafts. The 10-year Kaplan-Meier estimate of patient survival was 82% in 215 SPK versus 71% in 111 live donor kidney graft recipients. The annual mortality rate was 1.5% for SPK recipients, 3.65% for living donor kidney graft recipients, and 6.27% for cadaver donor kidney graft recipients. Reversibility of established microvascular complications after SPK is minor at best, with the important exception of autonomic polyneuropathy,^[417] particularly improved cardiorespiratory reflexes,^[418] and some improvement in nerve conduction.^[419] Further benefits include improved gastric and bladder function,^[371] as well as superior quality of life, better metabolic control, and improved survival^[336] so that today, SPK should be the preferred treatment for the type 1 diabetic who meets the selection criteria. There is an increasing tendency for early or even preemptive SPK.^[415] Because graft outcome is progressively more adverse with increasing time spent on HD,^[420] the latter strategy is sensible. In the United States, diabetics younger than 55 years of age are usually considered for SPK when GFR has become less than 40 mL/min, whereas in Europe, the criteria are more conservative, requiring a GFR of less than 20 mL/min.^[421] Exclusion criteria are, among others, active smoking, morbid obesity, uncorrected CVD, and so on. Clear indications for pancreas transplantation in nonuremic diabetic patients have not been established so far.

Pancreas-After-Kidney Transplantation

An alternative strategy must be considered in the diabetic patient who has a live kidney donor: in a first step, the living donor kidney is transplanted, and subsequently, once stable renal function is achieved (GFR > 50 mL/min), a cadaver donor pancreas is transplanted. The outcomes are satisfactory.^[422]

Transplantation of pancreas segments obtained from living donors is still an experimental procedure.^[423]

Procedure and Management

Today the preferred SPK technique is enteric drainage. Bladder drainage has been increasingly abandoned because of mucosal irritation, development of strictures, bicarbonate wasting with metabolic acidosis, recurrent urinary tract infections (UTIs), and reflux pancreatitis.

Oral glucose tolerance normalizes unless the graft is damaged by ischemia or by subclinical rejection related to HLA-DR mismatch.^[424] Most investigators find either normalization of insulin sensitivity^[425] or some impairment of insulin-stimulated nonoxidative glucose metabolism^[426] with hepatic insulin resistance^[427] possibly related to insulin delivery into the systemic circulation (as opposed to physiologic delivery into the portal circulation).^{[430] [431]}Impressive normalization of lipoprotein lipase activity and of the lipid spectrum have also been reported consistent with reduced atherogenic risk.^[430]

An interesting issue is whether graft rejection affects kidney and pancreatic grafts in parallel. Although this is mostly so (permitting use of renal function as a surrogate marker of rejection in the pancreas), it is by no means obligatory. Nevertheless because episodes of isolated rejections of the pancreas are rare monitoring the kidney graft is the usual procedure. The pancreatic graft can be directly monitored by duplex sonography, if necessary. Pancreas graft biopsy is used to distinguish graft pancreatitis from immune injury to the graft. Pancreas grafts are usually lost because of alloimmunity reactions, but in rare cases graft loss resulting from destruction by autoimmume mechanisms has been described.^[431] Recurrence of autoimmune inflammation (insulitis) in the recipient with lymphocytic infiltration and selective loss of insulin-producing beta cells (while glucagon, somatostatin, and pancreatic polypeptide-secreting cells were spared) were often seen in the pioneering era when segmental pancreatic grafts were exchanged between monozygotic twins. Today this has become rare, presumably because immunosuppression keeps autoimmunity under control. Rejection of the pancreas responds poorly to steroid treatment. Its treatment should always include T cell antibodies.

In the past an immunosuppression protocol based on tacrolimus and mycophenolate mofetil (MMF) was used as the standard in most centers around the world. In 72% of patients treated with this combination it is possible to withdraw steroids within the first year after SPK.^[432] Novel induction strategies and steroid-free maintenance regimens are currently under investigation.^[433]

Islet Cell Transplantation

Although advanced procedures such as transplantation of stem cells or precursor cells, transplantation of encapsulated islet cells, islet xenotransplants, and insulin gene therapy are still beyond the horizon, islet cell transplantation has so far yielded some interesting, but not yet satisfactory, results. According to the last available registry report, in 2002 439 patients had received islet cell transplants worldwide, mainly in eight major centers. Patient survival was 79%, and 14% of patients were off insulin, but measurable C peptide values greater than 0.5 ng/mL as evidence of residual islet function were noted in 45% of patients. Minor intraportal insulin secretion may be relevant because it may normalize hepatic glucose production.^[434] This field had gotten a major boost with the observations of Shapiro and co-workers who reported successful islet transplantation achieving insulin independence in seven consecutive patients using a steroid-free immunosuppression regimen consisting of sirolimus, tacrolimus, and taclizumab.^[435] Such early success was confirmed by others. Five years after transplantation, however, insulin independence was achieved in only 10%, a result inferior to whole pancreas allotransplantation.^[436]

Diabetes in Nondiabetic Solid Organ Graft Recipients

An increasingly serious problem of solid organ transplantation, including renal transplantation, is the de novo appearance of diabetes in graft recipients who had no diabetes at the time of transplantation. In Spain this was seen in 17.4%^[437] and in the US in up to 21% at 10 years.^[438] De novo diabetes is presumably the result of several factors: the diabetogenic action of calcineurin inhibitors, particularly tacrolimus, and steroids as well as the unmasking of diabetes after rapid weight gain in individuals genetically predisposed to diabetes mellitus. Predictors of de novo diabetes are a family history of diabetes, age, obesity, hepatitis C, treatment with tacrolimus.^{[439] [440] [441]}Complications include increased cardiovascular events^[440] and even delayed graft loss from allograft diabetic nephropathy.^[441]

BLADDER DYSFUNCTION

Bladder dysfunction as a sequela of autonomous diabetic polyneuropathy is frequent in diabetic patients, leading to straining, hesitancy, and the sensation of incomplete emptying of the bladder, in males combined with erectile dysfunction.^[442] Disabling symptoms are rare, however (with the exception of the frail elderly).

Because of its association with autonomous polyneuropathy, it is not surprising that bladder dysfunction is frequently associated with postural hypotension, gastroparesis, constipation, and nocturnal diarrhea.

In classic cases, cystometry shows increased bladder volume at first desire to void and increased maximal bladder capacity associated with decreased detrusor contractility.^[443] These abnormalities appear very early in the course of the disease.^[444] Bladder dysfunction is of interest in two respects. First, it has often been stated that cystopathy is related to progression when supposedly an element of obstructive uropathy is superimposed on diabetic nephropathy. Torffvit,^[445] however, failed to note any relation to progression. Second, and possibly more important, cystopathy with residual volume after voiding renders eradication of UTIs difficult.

Some studies have shown that diabetic cystopathy is not the most common urodynamic finding in patients with diabetes mellitus and voiding dysfunction^[446] underlining the necessity of careful urodynamic studies in the symptomatic patient. Kaplan and co-workers^[446] found bladder outlet obstruction in 36% of male diabetic patients with voiding dysfunction. This observation is in agreement with the finding of Menendez and colleagues^[447] who evaluated the urodynamic changes in IDDM patients with ESRD. Abnormal urodynamic findings were found in 84% of patients: the bladder was hypersensitive in 39% and hyposensitive in 30% of the cases. Evaluation of somatosensory evoked potentials of tibial and pudendal nerve and of the bulbocavernosus reflex has been shown to discriminate between symptomatic and asymptomatic diabetic patients.^[448] Acute decompensation may be provoked by anticholinergics. Starer and Libow^[449] examined diabetic patients who were incontinent. Cystometry showed involuntary contractions in 61% of patients, normal voluntary contractions in 13%, and subnormal or absent contractions in 26%. This study again shows that classic urinary retention secondary to autonomic neuropathy is not the most common cause of urinary incontinence in the diabetic.

Urinary Tract Infection

For a long time it had been controversial whether the frequency of bacteriuria is higher in diabetic patients, but there has never been any doubt that symptomatic UTIs are more severe and more aggressive.

The hypothesis of a higher prevalence of UTI in diabetes goes back to the studies of Vejlsgaard^[450] who noted a higher frequency of bacteriuria, that is, of greater than 10⁵ colony-forming units per milliliters urine in female (18.8% vs. 7.9% in control), but not in male diabetics. Such UTI was mostly asymptomatic (33%). A higher prevalence of UTI was also found in pregnant diabetic patients and was related to the presence of retinopathy, presumably as a surrogate marker for autonomous polyneuropathy.

The results of prospective studies remained controversial. A higher prevalence in diabetic women was noted by Balasoiu^[451] and Zhanel and their associates,^[452] but not by Brauner and co-workers.^[453] A recent 4 year prospective study in a cohort of diabetic and nondiabetic women showed, however, that the incidence of UTIs as well as asymptomatic bacteriuria was twice as high in diabetic compared to nondiabetic women: The risk was higher in women on insulin and with longer duration of diabetes.^[454] UTIs may also pose problems after renal transplantation.^[455]

Virulence factors in Escherichia coli isolated from diabetic women with asymptomatic bacteriuria did not differ from those in nondiabetic women^[456] and the spectrum of bacterial isolates as well as the resistance rates to antibiotics did not differ between diabetic and nondiabetic individuals.^{[459] [460]} A recent study found, however, that UTI were predictive of later hospitalization because of symptomatic UTI.^[459]

Symptomatic UTIs definitely run a more aggressive course in diabetic patients. Recent studies show that by multivariate analysis diabetes and poor glycemic control are independent factors associated with upper urinary tract involvement.^[460] UTIs in diabetes may also lead to complications, such as prostatic abscess, emphysematous cystitis and pyelonephritis,^[461] intrarenal abscess formation, renal carbuncle^[462] and penile necrosis (Fournier disease).^{[464] [465]} One particular complication is renal papillary necrosis: it had been known since the 19th century and was rediscovered in the 1930s.^[464] In 1969 the large autopsy series of Ditscherlein^[465] still documented papillary necrosis in approximately 10% of 400 diabetic patients. This has not been confirmed in our more recent autopsy series.^[466] Among hundreds of diabetic patients in our unit, clinical evidence of this complication was found only once. There may be a secular trend of diminishing incidence, possibly related to earlier and more frequent administration of antibiotics. Papillary necrosis should be suspected in diabetic patients with UTI and septicemia, renal colic, hematuria, or obstructive uropathy.

Extrarenal bacterial metastases are common in patients with UTI and septicemia, particularly UTI with methicillin-resistant staphylococci: e.g., endophthalmitis,^[467] spondylitis, iliopsoas abscess formation and others.

In community-acquired UTI, the predominant microbe is E. coli, but Klebsiella is more frequently found in diabetic patients than in control subjects^[468]; exotic microbes such as Pasteurella multocida; staphylococci, including methicillin-resistant staphylococci; and fungi, particularly Candida,^{[471] [472] [473]} may also be found.

The reasons for the potentially higher frequency and the definitely higher severity of UTI in diabetes are not known, but may include more favorable conditions for bacterial growth (glucosuria), defective neutrophil function, increased adherence to uroepithelial cells and impaired bladder evacuation (detrusor paresis).

As to the management of UTI, no clear benefits of antibiotic treatment have been demonstrated for treatment of asymptomatic bacteriuria in diabetic patients. Community-acquired symptomatic lower UTI may be managed with trimethoprim, trimethoprim with sulfamethoxazole, or gyrase inhibitors. For nosocomially acquired UTI, sensitivity tests and sensitivity-directed antibiotic intervention are necessary. Invasive candiduria can be managed with amphotericin by irragation or systemic administration of fungicidal substances.

References

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