Diabetic Nephropathy

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Chapter 28

Diabetic Nephropathy

It is estimated that more than 500,000 Americans have end-stage renal disease (ESRD).1 In the United States, nearly half of patients entering ESRD programs in 2006 had diabetes (about 90% had type 2 diabetes).1 The much higher prevalence of type 2 diabetes accounts at least in part for the greater contribution of these patients to ESRD incidence. Diabetic nephropathy (DN) develops in 15% to 35% of type 1 diabetic patients, with a peak in the incidence around 15 to 20 years of diabetes.2 Studies in type 2 diabetic patients from Western Europe3 and in Pima Indians from Arizona4 show nephropathy rates similar to or higher than those of type 1 diabetic patients. There are data suggesting that the incidence of DN among patients with type 1 diabetes may be declining over time. Studies in Pima Indians showed a continuous increase in the incidence of proteinuria as well as an increase in the incidence of ESRD between 1967 and 1994, with a decline in the ESRD rates between 1995 and 2002.5 Studies from Sweden6 and Denmark7 reported a 50% to 60% decline in the incidence of proteinuria among patients with type 1 diabetes in the last decades. Thus, the cumulative incidence of proteinuria after 20 to 25 years of type 1 diabetes fell from about 30% in patients whose diabetes was diagnosed in the 1960s to about 13% in those whose diabetes was diagnosed after 1970. However, while the incidence of ESRD declined between 1998 and 2002 among patients with type 1 diabetes, it increased 5% per year among European and European-descent patients with type 2 diabetes.8 Moreover, after adjusting for population growth, the ESRD incidence in the United States is over 35% higher than a decade ago, and the explanation for this increase is unclear.9

The annual cost of caring for these patients in the United States alone exceeds $10 billion, accounting for more than 24% of Medicare costs. Moreover, costs can be 25% greater in ESRD patients with diabetes than in patients without diabetes.10 Once overt DN, manifested as proteinuria and decreased glomerular filtration rate (GFR), is present, ESRD can be postponed but in most instances not prevented by effective antihypertensive treatment11,12 or glycemic control.13 The mortality rate of patients with DN is high, and a marked increase in cardiovascular risk accounts for more than half of the increased mortality among these patients and for much of the 5-year survival rate of less than 20% among diabetic patients on chronic dialysis.

Natural History of Diabetic Nephropathy

Type 1 Diabetes

For simplicity, the course of renal involvement in type 1 diabetes can be roughly divided into five stages (Table 28-1). Stage 1, present at diagnosis, is that of renal hypertrophy-hyperfunction. At this stage, patients at risk and not at risk of DN currently cannot be clearly separated. Genetic factors associated with predisposition to or protection from DN (see Genetic Predisposition) could, in the future, add to prediction of risk during this period. Although some studies1417 and a recent meta-analysis18 suggest that the presence of GFR above the normal range (glomerular hyperfiltration) is a risk factor for DN, this remains controversial and does not fit with data showing that more than 65% of young type 1 diabetic subjects have increased GFR.19 Most studies addressing this issue evaluated cohorts of patients with average diabetes duration of a decade or so. In an inception cohort study of patients with adult-onset type 1 diabetes within 6 months of diabetes diagnosis, higher than normal levels of albumin excretion rate (AER), blood pressure, hemoglobin A1c, male sex, and shorter stature were significant independent (albeit imprecise) predictors of microalbuminuria development over 18 years of follow-up, while GFR was noncontributory. Stage 2 is characterized by the presence of glomerular lesions in patients with normal albumin excretion rate and normal blood pressure levels. Preliminary studies suggest that normoalbuminuric patients with more severe glomerular lesions are at increased risk of progression.20 Further, patients with type 1 diabetes, normoalbuminuric at baseline, with greater increase in DN lesions over the subsequent 5 years, have greater increases in AER over that time (Kukla, Caramori, and Mauer, unpublished observations). Decreased normal nocturnal blood pressure decline (dipping) and increased nocturnal systolic blood pressure in 24-hour blood pressure monitoring may be an early indicator of DN risk, preceding the development of persistent microalbuminuria.21 The presence of persistent microalbuminuria with at least 2 of 3 consecutive values between 20-200 µg/min for 30-300 mg/g of creative defines stage 3. This typically occurs after 5 or more years of type 1 diabetes, but microalbuminuria may be present earlier, particularly during adolescence and in patients with poor glycemic control and high-normal blood pressure levels, and may be more frequent and less prognostic in daytime urine samples due to postural proteinuria, especially in adolescents (Mauer, unpublished observations). Compared to normoalbuminuric patients, patients with persistent microalbuminuria are at three- to fourfold increased risk of progression to proteinuria and ESRD.22 Current studies indicate that about 20% to 45% of microalbuminuric type 1 diabetic patients will progress to proteinuria after about 10 years of follow-up, while 20% to 25% will return to normoalbuminuric levels, and the rest will remain microalbuminuric, at least over the subsequent 6 to 10 years.2226 Of note, studies conducted 2 to 3 decades ago estimated that about 80% of type 1 diabetic microalbuminuric patients would progress to proteinuria over the next 10 years.2729 The differences in progression rates may be related to overestimation of risk in these earlier small post hoc studies, differing definitions of microalbuminuria, improved prognosis due to advancements in treatment, or some combination of these factors. Alternatively, the natural history of DN may have changed over the past decades. At stage 3, glomerular lesions are generally more serious than in the previous ones. GFR is usually normal and stable or slowly declining during this stage, and recent data suggest that the subset with microalbuminuria and declining GFR may be at particularly high risk of progression.30 Blood pressure levels tend to increase, and hypertension is not uncommon. Some patients also have hypercholesterolemia and hypertriglyceridemia, along with increased fibrinogen, von Willebrand factor, and prorenin levels. Other microvascular (diabetic retinopathy and neuropathy) and macrovascular (coronary artery disease and stroke) complications are also more common. Stage 4 is defined by the presence of overt proteinuria [AER > 200 µg/min or 300 mg/24 hour or albumin/creatinine ratio (ACR) > 300 mg/g]. Proteinuria typically develops only after 10 to 20 years of type 1 diabetes. Patients with proteinuria at shorter type 1 diabetes duration deserve a clinical renal biopsy. However, microalbuminuria or proteinuria may be present at diagnosis in patients with type 2 diabetes where onset of diabetes may go undetected for many years or because the increased urinary protein is of another pathogenesis in patients with minimal or atypical DN lesions. GFR is often reduced, and hypertension and dyslipidemia are very common. Retinopathy and peripheral and autonomic neuropathy are present in most patients, and if retinopathy is absent, this should call the diagnosis of DN into question. The risk for cardiovascular events is extremely high, and asymptomatic myocardial ischemia is frequent. Without treatment, GFR declines about 14 mL/min/yr in type 1 diabetic patients with proteinuria and hypertension. Progression to ESRD (stage 5) will occur 5 to 15 years after the development of proteinuria.

Table 28-1

Stages of Diabetic Nephropathy

image

ESRD, End-stage renal disease; GFR, glomerular filtration rate.

Modified from Caramori ML, Mauer M: Pathogenesis and pathophysiology of diabetic nephropathy. In Greenberg A, Cheung AK, Coffman TM, et al (eds): Primer on kidney diseases, ed 4, Philadelphia, 2005, Saunders, pp 241–248.

Type 2 Diabetes

As already noted, diabetes duration is usually not precisely known. At diagnosis, about 10% of type 2 diabetic patients have nephropathy, 20% retinopathy, 70% hypertension, and 60% dyslipidemia. Interestingly, in studies of Pima Indians where type 2 diabetes onset is much more precisely known and the age of onset is much younger than in most other type 2 diabetes cohorts, the course of diabetic kidney disease is very similar to that of type 1 diabetic patients. Overall, in patients with type 1 and type 2 diabetes, the rate of progression from microalbuminuria to proteinuria is similar to that of type 1 diabetic patients, around 30% after 10 years of follow-up.31,32 Thus, the Steno 2 study reported that 31% of initially microalbuminuric type 2 diabetic patients progressed to proteinuria, while the same proportion (31%) of patients became normoalbuminuric, and 38% remained microalbuminuric after about 8 years of follow-up.32 Moreover, those who were normoalbuminuric at follow-up had a lower rate of GFR decline (2.3 mL/min/yr) compared to patients who remained microalbuminuric (3.7 mL/min/yr; P = 0.03) or who progressed to proteinuria (5.4 mL/min/yr; P < 0.001).32 GFR decline may be more variable in type 2 than in type 1 diabetes. Microalbuminuric type 2 diabetic patients with GFR decline usually have more advanced typical diabetic glomerulopathy lesions and worse metabolic control,33 while those with mild or atypical lesions have no significant GFR decline over nearly 5 years of follow-up. The above categories are general, and progression is highly variable and often nonlinear. The expression and natural history of these overlapping stages may be influenced by complex genetic, environmental, and treatment interactions that may greatly affect progression and outcome. Thus, the scheme presented here is only a useful general guide, but it cannot be considered an accurate map of the course of individual patients.

For example, large long-term clinical trials have demonstrated that improved blood glucose34,35 and blood pressure control, perhaps especially with renin-angiotensin system blockers,12,36,37 slows the progression of DN in proteinuric patients with already substantially reduced GFR. Indeed, the natural history of DN may have changed after the results of these trials were available to the scientific community and to patients. This has led to the publication of revised treatment guidelines by several entities recommending stricter glycemic and blood pressure control for patients with diabetes. Although in the past it was believed that once DN was present the decline of renal function was inexorable, it is now clear that this may not always be the case.12,36,37 Finally, the demonstration that prolonged euglycemia leads to reversal of established DN lesions in patients with type 1 diabetes38 contradicts the long-held belief that these lesions are irreversible.

Kidney Structure in Diabetes

DN manifests as a constellation of structural changes unique to this disease (Table 28-2).3941 Subtle thickening of the glomerular basement membrane (GBM) is the initial quantifiable change (Fig. 28-1A and C), and this is paralleled by thickening of tubular basement membranes (TBM) (Fig. 28-2).42,43 Afferent and efferent glomerular arteriolar hyalinosis can be present within 3 to 5 years of diabetes onset.44 Involvement of both vessels is virtually pathognomonic of diabetes, and these changes can progress to total replacement of the smooth muscle cells of these small vessels by hyaline, a waxy, homogeneous, stained-glass appearing, periodic acid Shiff (PAS)-positive material (Fig. 28-3A and B).45 These arteriolar lesions, along with glomerular capillary subendothelial hyaline and capsular drops (hyaline caps) along the parietal surface of the Bowman capsule (see Fig. 28-3C), constitute the exudative lesions of DN.

Table 28-2

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)* Afferent and efferent arteriolar hyalinosis* Atherosclerosis
Interstitial expansion with predominance of increased extracellular matrix material   Glomerular microaneurysms
Increased glomerular basement membrane, tubular basement membrane, and Bowman’s capsule staining for albumin and IgG*    

*In combination, diagnostic of diabetic nephropathy.

Highly characteristic of diabetic nephropathy.

From Parving H-H, Mauer M, Ritz E: Diabetic nephropathy. In Brenner BM (ed): Brenner & Rector’s the kidney, ed 7, Philadelphia, 2004, Saunders, pp 1777–1818.

Increases in the fraction of the glomerulus occupied by the mesangium, or mesangial fractional volume [Vv(Mes/glom)], may be measurable after only 4 to 5 years of type 1 diabetes,46 but in most cases, it may take 10 or more years to increase into the abnormal range.47 Mesangial expansion in diabetes mainly results from the accumulation of mesangial matrix material and less from the expansion of the cellular component of the mesangium (see Fig. 28-1C; Fig. 28-4).48 The cortical interstitium is the space between renal tubules, glomeruli, and blood vessels. As a fraction of cortical volume, interstitium [Vv(Int/cortex)] is initially decreased early in type 1 diabetes, perhaps due to expansion of the tubular compartment, which is 85% of the cortex. Moderate increases in Vv(Int/cortex) are primarily due to expansion of the cellular component of the interstitium, the initial explanation for interstitial expansion in type 1 diabetes, whereas increased interstitial fibrillar collagen comes later, with more marked interstitial expansion and in association with already reduced GFR.49

Abnormalities of the junction of the glomerulus with its tubule, with obstruction of the proximal tubular take-off from the glomerulus and, in the extreme, complete detachment of the tubule from the glomerulus (atubular glomerulus) (Fig. 28-5A to D) occur late in the disease and, in type 1 diabetes, is largely restricted to patients with overt proteinuria (Fig. 28-6).50

The lesions of diabetic glomerulopathy also progress at varying rates within individual patients.51,52 A given patient may have relatively marked GBM thickening with less advanced mesangial expansion or vice versa (Fig. 28-7).39,51 However, both abnormalities are advanced in the majority of type 1 diabetic patients who develop clinical DN manifesting as proteinuria, hypertension, and declining GFR39,51,52 (see later). In addition to these classic diabetic glomerulopathy lesions (GBM and TBM thickening and mesangial expansion), focal and global glomerulosclerosis, tubular atrophy, interstitial expansion and fibrosis, and glomerulotubular junction abnormalities contribute to the progressive GFR loss which culminates in ESRD.50

Mesangial expansion, occurring relatively evenly in most glomeruli, has been termed diffuse diabetic glomerulosclerosis (Fig. 28-8A to C). Kimmelstiel-Wilson nodular lesions are large round fibrillar areas of mesangial expansion with palisading of mesangial nuclei around the periphery of the nodule, often with extreme compression of the adjacent glomerular capillaries (Fig. 28-9C). These nodules result from glomerular capillary microaneurysm formation (see Fig. 28-9A)53 and subsequent filling of the expanded capillary space with mesangial matrix (see Fig. 28-9B). About half of proteinuric type 1 diabetic patients have some nodular lesions, typically on a background of diffuse diabetic glomerulosclerosis (Fioretto and Mauer, unpublished observations). In the end, clinical DN largely results from marked extracellular matrix (ECM) accumulation whereby over many years, the rate of ECM production exceeds the rate of removal. The ECM that accumulates in mesangium, GBM and TBM is made up of the normal ECM constituents of these sites, including (primarily) types IV and VI collagen, laminin, and fibronectin54 and perhaps additional ECM components not yet identified. “Scar” collagens (mainly collagens I and II) are seen only very late in the diabetic glomerulopathy process, primarily associated with global glomerular sclerosis or developing in the center of nodular lesions.54,55 Understanding the processes that result in ECM accumulation in the mesangium, GBM, and TBM in diabetes is incomplete.56,57 Glomeruli may become globally sclerosed in diabetic patients without other diabetic changes,58 especially in type 2 diabetes (see later). In type 1 diabetic patients, there is a relationship between the severity of arteriolar hyalinosis lesions and the number of globally sclerosed glomeruli, with greater frequency of scarred glomeruli in the plane vertical to the kidney capsule, suggesting that glomerulosclerosis could also be caused by occlusion of medium-sized renal arteries.59 As renal insufficiency progresses, there are increasing numbers of totally scarred glomeruli, glomeruli with capillary closure due to massive mesangial expansion (see Fig. 28-9D), or atubular glomeruli (i.e., glomeruli that are nonfunctioning because they are detached from their tubules (see later).

Numbers of glomerular podocytes are reportedly reduced in patients with type 1 and 2 diabetes,60-63 especially in association with albuminuria and disease progression. This may be at least in part due to increased podocyte detachment from the GBM.64 However, more work is needed to further document and understand these potentially important podocyte abnormalities.

Structural-Functional Relationships in Diabetic Nephropathy

Mesangial expansion is the major cause of GFR loss in type 1 diabetic patients.51 Increase in Vv(Mes/glom) is strongly inversely correlated with filtration surface (Fig. 28-10) per glomerulus which in turn is strongly directly correlated with GFR in type 1 diabetes.65 Mesangial fractional volume is also directly correlated with AER51,52 (Fig. 28-11A and B) and systemic blood pressure.51,66 The relationships of GBM width with these clinical manifestations of diabetic kidney disease are also important but are somewhat weaker than those for mesangial changes.51,52 However, mesangial and GBM changes together explain most of the AER variability in type 1 diabetes, ranging from normoalbuminuria to proteinuria.52

As mentioned, decreased podocyte number and detachment are related to albuminuria. Increases in podocyte foot process width also correlate with AER increases in type 1 diabetic patients.61,67,68 If podocyte number or shape changes are early predictors of DN risk,69 this would support an important pathogenetic role for this key glomerular cell in this disease.

Although glomerular capillary filtration surface is directly correlated with GFR in type 1 diabetes,65,70,71 linear regression models only partially explain GFR variability in these patients.52 Global sclerosis58 and interstitial expansion41 are additional independent predictors of GFR loss. However, the conclusion that the interstitium is more important than glomerular changes in diabetes came from studies where most patients were in advanced stages of kidney failure.7274 At these advanced stages, when serum creatinine is already clearly elevated, especially if above 2 mg/dL, interstitial changes are common to most chronic renal diseases and are not specific to diabetes. During most of the natural history of DN, glomerular parameters are more important determinants of renal dysfunction. Moreover, as already discussed, early interstitial expansion in type 1 diabetes is mainly due to expansion of its cellular component, and increased interstitial fibrillar (scar) collagen is primarily seen in patients whose GFR is reduced,56 while glomerular ECM changes are due to accumulation of basement membrane components. Thus, the interstitial and glomerular changes of diabetes probably have different pathogenetic mechanisms.

Through many years of the natural history of DN, lesions develop without detectable clinical or laboratory abnormalities. Often, when microalbuminuria initially manifests, lesions are far advanced. Once proteinuria is present in type 1 diabetes, GFR loss typically progresses relatively rapidly toward ESRD. This nonlinear clinical course is best reflected by nonlinear analyses of structural-functional relationships.50 Using piecewise linear regression instead of simple linear models, glomerular structural variables alone explained 95% of variability in AER. These glomerular structures, mesangial fractional volume, GBM width and filtration surface density, however, explained less than 80% of GFR variability. This increased to more than 90% with the addition of measures of glomerular tubular junction abnormalities and interstitial expansion.50

In summary, most of the renal functional abnormalities in type 1 diabetes are explained by diabetic glomerulopathy. Structure is highly variable in patients without functional abnormalities. Structural-functional relationships are largely driven by more advanced lesions.

Microalbuminuria and Renal Structure

Persistent microalbuminuria antedates clinical nephropathy, whereas normoalbuminuria in longstanding type 1 diabetic patients predicts lower nephropathy risk. However, the relationship of renal structural changes to low levels of albuminuria (i.e., normal to microalbuminuria) is far from simple. As a group, normoalbuminuric longstanding type 1 diabetic patients have diabetic glomerulopathy lesions.52,75 Their structural measurements range from normal to pathology overlapping in severity with microalbuminuric and proteinuric patients (see Fig. 28-11B; Fig. 28-12B).52,75 Increased GBM width predicts progression to microalbuminuria and proteinuria.75,76 Microalbuminuric patients have on average even more severe lesions, with few type 1 diabetic patients having renal structural measures still within the normal range (see Fig. 28-11B and Fig. 28-12B).52,75 Hypertension and reduced GFR are also more frequent in these patients, so microalbuminuria is a marker of more advanced lesions and other functional disturbances.52,75 However, reduced GFR may be present in normoalbuminuric longstanding type 1 diabetic patients. This is more frequent in females with retinopathy and/or hypertension and is associated with advanced glomerulopathy lesions.23,77,78 Microalbuminuria may not be the first indicator of DN, and careful GFR and blood pressure measurements are needed, especially in female patients with the described characteristics.

Normal identical twins of type 1 diabetic patients have normal renal structure.42 Diabetic twins have greater GBM and TBM width and mesangial fractional volume than their nondiabetic twin, albeit sometimes still within the normal range despite many years of diabetes.42 Over time, all type 1 diabetic patients appear to develop some structural changes of DN, but the rate may be so slow that the lesions would be undetectable except by comparison with their nondiabetic twin and would not lead to clinical disease. There is also striking variability in the rate at which lesions develop in kidneys transplanted into type 1 diabetic patients who all had ESRD secondary to DN.75 This cannot be fully explained by glycemia and suggests genetically determined renal tissue susceptibility.75

Interestingly, studies of type 1 diabetic transplant recipients indicate that having a single kidney does not appear to accelerate the rate of development of DN lesions, arguing against reduced nephron number as a risk factor.79 In fact, proteinuric diabetic patients without advanced renal failure have normal numbers of glomeruli.80 However, reduced glomerular number could be associated with faster GFR decline once overt DN develops.

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