Abstract
Diabetic nephropathy is the leading cause of kidney failure in adults. In the United States, approximately half of patients initiating dialysis have diabetes mellitus, and most of these have type 2 diabetes. Patients with youth-onset type 2 diabetes exhibit a particularly high risk of progressive diabetic nephropathy after a relative short duration of disease. Mortality among patients with diabetic nephropathy is high, with cardiovascular diseases predominating. Once overt diabetic nephropathy is present, kidney failure can often be postponed, but in most instances not prevented, by effective antihypertensive treatment and careful glycemic control. Accordingly, there has been intensive research into pathophysiologic mechanisms of diabetic kidney injury, predictors of risk for diabetic nephropathy, and early intervention strategies. In this review, we summarize the epidemiologic and mechanistic data on diabetic nephropathy, provide an overview of previous and current clinical trials, review treatments, and discuss future directions.
Keywords
diabetic nephropathy, diabetic kidney disease, elevated albumin excretion, hyperfiltration, impaired GFR, rapid GFR decline, ESRD, type 1 diabetes, type 2 diabetes
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in adults. In the United States, approximately half of patients initiating dialysis have diabetes mellitus, and most of these have type 2 diabetes. Patients with youth-onset type 2 diabetes, as shown in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, exhibit a particularly high risk of progressive diabetic nephropathy after a relatively short duration of disease. Mortality among patients with diabetic nephropathy is high, with cardiovascular diseases predominating. Once overt diabetic nephropathy is present, kidney failure can often be postponed, but in most instances not prevented, by effective antihypertensive treatment and careful glycemic control. Accordingly, there has been intensive research into the pathophysiologic mechanisms of diabetic kidney injury, predictors of risk for diabetic nephropathy, and early intervention strategies.
The classic terminology used to describe different states of urinary albumin excretion includes normoalbuminuria, microalbuminuria, and macroalbuminuria (or “overt proteinuria”). Normoalbuminuria is typically defined as urinary albumin excretion rate (UAER) less than 20 µg/min or urinary albumin to creatinine ratio (UACR) less than 30 mg/g (or 30 mg/day). Microalbuminuria is defined as UAER between 20 and 200 µg/min or UACR between 30 and 300 mg/g (30 to 300 mg/day) and macroalbuminuria as UAER greater than 200 µg/min or UACR greater than 300 mg/g (>300 mg/day). Updated guidelines now use the terms “moderately increased albuminuria” rather than microalbuminuria and “severely increased albuminuria” instead of macroalbuminuria. To promote internal validity, the authors of this chapter decided to use the classic terminology of albumin excretion (normoalbuminuria, microalbuminuria, and macroalbuminuria), unless the data of the original studies were reported differently.
Pathophysiology
The pathophysiology underlying diabetic nephropathy is complex and remains incompletely understood. While other important modulating factors may contribute, the long-term deleterious impacts of hyperglycemia and insulin resistance are central to the development and progression of diabetic nephropathy. Studies in both type 1 and type 2 diabetes have shown that improved glycemic control can reduce the risk of developing diabetic nephropathy. Moreover, the development of the earliest diabetic kidney lesions can be slowed or prevented by strict glycemic control, as was demonstrated in a randomized trial in type 1 diabetic kidney transplant recipients. Similarly, intensive insulin treatment decreases the progression rates of glomerular lesions in patients with type 1 diabetes and microalbuminuria. Finally, established diabetic glomerular lesions in the native kidneys of patients with type 1 diabetes regress with prolonged normalization of glycemic levels after successful pancreas transplantation. In summary, these studies strongly suggest that hyperglycemia is necessary for the development and maintenance of diabetic nephropathy because correction of hyperglycemia allows expression of reparative mechanisms that facilitate healing of the original diabetic glomerular injury.
Hemodynamic mechanisms, including hyperfiltration, likely play a significant role in the pathogenesis of diabetic nephropathy through neurohormonal (e.g., renin-angiotensin–aldosterone system activation) and tubular (e.g., tubuloglomerular feedback) pathways. However, patients with other causes of hyperfiltration, such as unilateral nephrectomy, do not typically develop nephropathy. Furthermore, it is unlikely that all patients with diabetes and hyperfiltration develop diabetic kidney disease. Therefore glomerular hyperfiltration alone cannot fully explain the genesis of the early lesions of diabetic nephropathy. However, previous studies and clinical observations suggest that hemodynamic factors are important in modulating both the initiation of nephropathy and also the rate of progression of diabetic lesions that are already well established. Studies in adults with type 1 diabetes have also demonstrated that hyperfiltration is associated with a greater risk of experiencing rapid glomerular filtration rate (GFR) decline (>3 mL/min/1.73 m 2 /year or >3.3%/year) with resultant reduced GFR (<60 mL/min/1.73 m 2 ). It is worth noting that the presence of reduced GFR in normoalbuminuric patients with type 1 diabetes is associated with more severe glomerular lesions, and these patients may be at increased risk of further progression.
Systemic blood pressure levels and a lack of normal nocturnal blood pressure dipping may both be implicated in the progression and genesis of diabetic nephropathy. Supporting this hypothesis is the association between intensive blood pressure control and decreased rates of progression from normoalbuminuria to microalbuminuria, and from microalbuminuria to overt proteinuria, in both normotensive and hypertensive patients with type 2 diabetes.
Studies on human genetics offer important mechanistic insights into complex traits such as diabetic nephropathy. A genetic predisposition to diabetic nephropathy is suggested in multiple cross-sectional studies in type 1 and type 2 diabetic siblings concordant for diabetes. Importantly, diabetic sibling pairs who are concordant for diabetic nephropathy risk are also highly concordant for diabetic glomerulopathy lesions, and this risk is in part independent of glycemia. Novel loci associated with albuminuria were identified by genome-wide association study (GWAS) meta-analysis of albuminuria traits in the general population. An association between protein coding gene for cubilin (CUBN) and albuminuria was demonstrated, and gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. While there are ongoing searches for genetic loci related to diabetic nephropathy susceptibility through genomic scanning and candidate gene approaches, the search for specific variants that confer predisposition to diabetic nephropathy remains relatively unrewarding. GWAS is a promising approach to improve discovery of risk variants associated with diabetic nephropathy, as reflected by ongoing multinational efforts to compile a GWAS resource of more than 25,000 participants with diabetes, defined according to nephropathy status.
Diabetic nephropathy is characterized not only by glomerular disease but also by tubulointerstitial injury. While glomerular changes have received more attention than tubulointerstitial changes in diabetic kidney disease research, tubular injury may be more closely associated with kidney function than glomerular injury. Tubular proteinuria predates microalbuminuria in youths with type 1 diabetes, suggesting that tubular damage may occur earlier than glomerular injury in the course of diabetic nephropathy. Tubular changes associated with diabetic nephropathy include basement membrane thickening, tubular hypertrophy, epithelial–mesenchymal transition, glycogen accumulation, and interstitial inflammation. Basement membrane thickening and tubular hypertrophy are mainly related to extracellular matrix (ECM) accumulation, which reflects an imbalance between ECM synthesis and degradation, is the principal cause of mesangial expansion, and contributes to expansion of the interstitium late in the disease. Several mechanisms have been proposed to explain the link between hyperglycemia and ECM accumulation. These include increased levels of tumor growth factor (TGF)-β; activation of protein kinase C, which stimulates ECM production through the cyclic adenosine monophosphate (cAMP), pathway; increased advanced glycation end products; and increased activity of aldose reductase, leading to accumulation of sorbitol. There is also growing evidence that oxidative stress is increased in diabetes and is also related to diabetic nephropathy, mediated through altered nitric oxide production and action, and endothelial dysfunction. Importantly, many factors associated with diabetic nephropathy may act through both hemodynamic and nonhemodynamic pathways. For example, angiotensin II increases intraglomerular pressure and hyperfiltration and also increases the production of injurious mediators such as protein kinase C. Intraglomerular hypertension, whether a consequence of angiotensin II, other neurohormones, or tubular factors, is associated with increased glomerular wall tension and shear stress, leading to the activation of proinflammatory and profibrotic pathways.
Glycocalyx dysfunction has recently attracted attention as a potential mediator of both diabetic glomerulopathy and tubulopathy. The glycocalyx is a polysaccharide gel that covers the luminal surface of the endothelium, thereby acting as a filtration barrier and regulator of endothelial vascular function. Under exposure to hyperglycemic conditions, the glycocalyx is modified, leading to exposure of heparan sulfate domains that allow chemokine binding, inflammation, and result in glycocalyx degradation. Albuminuria is likely to at least in part occur as a consequence disruption of the glycocalyx. The presence of overlapping and interrelated injurious pathways that promote diabetic nephropathy highlight the need for a multifaceted therapeutic approach, as outlined in this chapter.
Pathology
Type 1 Diabetes
In patients with type 1 diabetes, glomerular lesions can appear within a few years after diabetes onset. The same time frame is present when a normal kidney is transplanted into a patient with diabetes. The changes in kidney structure caused by diabetes are specific, creating a pattern not seen in any other disease, and the severity of these diabetic lesions is related to the functional disturbances of the clinical kidney disease, as well as to diabetes duration, glycemic control, and genetic factors. However, the relationship between the duration of type 1 diabetes and extent of glomerular pathology is not precise. This is consistent with the marked variability in susceptibility to this disorder, such that some patients may develop kidney failure after having diabetes for 15 years, whereas others escape kidney complications despite having type 1 diabetes for decades.
Light Microscopy
Kidney hypertrophy is the earliest structural change in type 1 diabetes but is not reflected in any specific light microscopic changes. In many patients, glomerular structure remains normal or near normal even after decades of diabetes, whereas others develop progressive diffuse mesangial expansion, seen mainly as increased periodic acid–Schiff (PAS)-positive ECM mesangial material. In about 40% to 50% of patients developing proteinuria, there are areas of extreme mesangial expansion called Kimmelstiel-Wilson nodules (nodular mesangial expansion). Mesangial cell nuclei in these nodules are palisaded around masses of mesangial matrix material with compression of surrounding capillary lumina. Nodules are thought to result from earlier glomerular capillary microaneurysm formation. Notably, about half of patients with severe diabetic nephropathy do not have these nodular lesions; therefore, although Kimmelstiel-Wilson nodules are diagnostic of diabetic nephropathy, they are not necessary for severe kidney disease to develop.
Early changes often include arteriolar hyalinosis lesions involving replacement of the smooth muscle cells of afferent and efferent arterioles with PAS-positive waxy, homogeneous material ( Fig. 26.1 ). The severity of these lesions is directly related to the frequency of global glomerulosclerosis, perhaps as the result of glomerular ischemia. Glomerular basement membrane (GBM) and tubular basement membrane (TBM) thickening may be seen with light microscopy, although they are more easily seen with electron microscopy. In addition, tubular glomeruli and glomerulotubular junction abnormalities are present in proteinuric patients with type 1 diabetes and may be important in the progressive loss of GFR in diabetic nephropathy. Finally, usually quite late in the disease, tubular atrophy and interstitial fibrosis occur.
Immunofluorescence
Diabetes is characterized by increased linear staining of the GBM, TBM, and Bowman capsule, especially for immunoglobulin G (mainly IgG4) and albumin. Although this staining can only be removed by strong acid conditions, consistent with strong ionic binding, the intensity of staining is not related to the severity of the underlying lesions.
Electron Microscopy
The first measurable change observed in diabetic nephropathy is thickening of the GBM, which can be detected as early as 1.5 to 2.5 years after onset of type 1 diabetes ( Fig. 26.2 ). TBM thickening is also seen and parallels GBM thickening. A measurable increase in the relative area of the mesangium begins by 4 to 5 years, with the proportion of the glomerular volume that is mesangium increasing from about 20% (normal) to about 40% when proteinuria begins, and to 60% to 80% in patients with stage 3 chronic kidney disease (CKD). Immunohistochemical studies indicate that these changes in mesangium, GBM, and TBM represent expansion of the intrinsic ECM components at these sites, most likely including types IV and VI collagen, laminin, and fibronectin.
Qualitative and quantitative changes in the renal interstitium are observed in patients with various kidney diseases. Interstitial fibrosis is characterized by an increase in ECM proteins and cellularity. Preliminary studies suggest that the pathogenesis of interstitial changes in diabetic nephropathy is different from the changes that occur in the mesangial matrix, GBM, and TBM. Whereas for all but the later stages of diabetic nephropathy, GBM, TBM, and mesangial matrix changes represent the accumulation of basement membrane ECM material, early interstitial expansion is largely a result of cellular alterations, and only later, when GFR is already compromised, is interstitial expansion associated with increased interstitial fibrillar collagen and peritubular capillary loss. Consistent with most kidney diseases affecting the glomeruli, the fraction of GBM covered by intact, nondetached foot processes is lower in proteinuric patients with diabetes, when compared with either control subjects or individuals with type 1 diabetes with low levels of albuminuria. Moreover, the fraction of the glomerular capillary luminal surface covered by fenestrated endothelium is reduced in all stages of diabetic nephropathy, with increasing severity in normoalbuminuric, microalbuminuric, and overtly proteinuric patients with type 1 diabetes, respectively, as compared with controls.
Type 2 Diabetes
Glomerular and tubular structures in type 2 diabetes are less well studied but overall seem more heterogeneous than those observed in type 1 diabetes. Between 30% and 50% of patients with type 2 diabetes who have clinical features of diabetic nephropathy have typical changes of diabetic nephropathy, including diffuse and nodular mesangial expansion and arteriolar hyalinosis ( Fig. 26.3 ). Notably some patients, despite the presence of albuminuria, have absent or only mild diabetic glomerulopathy, whereas others have disproportionately severe tubular and interstitial abnormalities and/or vascular lesions and/or an increased number of globally sclerosed glomeruli. Patients with type 2 diabetes with microalbuminuria more frequently have morphometric glomerular structural measures in the normal range on electron microscopy and less severe lesions compared with patients with type 1 diabetes and microalbuminuria or overt proteinuria. Interestingly, Pima Indians with type 2 diabetes, a high-risk population for ESRD, have lesions more typical of those seen in type 1 diabetes.
It is unclear why some studies show more structural heterogeneity in type 2 than in type 1 diabetes, whereas others do not. Regardless, the rate of kidney disease progression in type 2 diabetes is related, at least in part, to the severity of the classic changes of diabetic glomerulopathy. Although there are reports that patients with type 2 diabetes have an increased incidence of nondiabetic lesions, such as proliferative glomerulonephritis and membranous nephropathy, this likely reflects biopsies more often being performed in patients with atypical clinical features. When biopsies are performed for research purposes, the incidence of other definable kidney diseases is very low (<5%). It is also noteworthy that a significant proportion of patients with type 2 diabetes exhibit an accelerated GFR decline in the absence of albuminuria. Although this phenotype is not yet completely understood, it has been suggested that this may reflect a predominance of microvascular disease rather than glomerular disease, thereby attenuating albuminuria risk. GFR reduction in the absence of albuminuria highlights the need to identify alternate biomarkers that better capture early diabetic nephropathy risk.
Structural-Functional Relationships in Diabetic Nephropathy
Kidney disease progression rates vary greatly among individuals with diabetes. Patients with type 1 diabetes and patients with proteinuria who are biopsied for research purposes always have advanced glomerular lesions and usually have vascular, tubular, and interstitial lesions as well. There is considerable overlap in glomerular structural changes between long-standing normoalbuminuric and microalbuminuric patients, as some normoalbuminuric patients with long-standing type 1 diabetes can have quite advanced kidney lesions, whereas many patients with longstanding diabetes and normoalbuminuria have structural measurements within the normal range.
Ultimately expansion of the mesangium, mainly resulting from ECM accumulation, reduces or even obliterates the glomerular capillary luminal space, decreasing the glomerular filtration surface and therefore decreasing the GFR. Accordingly, the fraction of the glomerulus occupied by mesangium correlates with both GFR and albuminuria in patients with type 1 diabetes, reflecting in part the inverse relationship between mesangial expansion and total peripheral GBM filtration surface per glomerulus. GBM thickness is also directly related to the albumin excretion rate. Finally, the extent of global glomerulosclerosis and interstitial expansion are correlated with the clinical manifestations of diabetic nephropathy (proteinuria, hypertension, and declining GFR).
In patients with type 1 diabetes, glomerular, tubular, interstitial, and vascular lesions tend to progress more or less in parallel, whereas in patients with type 2 diabetes, this often is not the case. Current evidence suggests that, among type 2 diabetes patients with microalbuminuria, those patients with typical diabetic glomerulopathy have a higher risk of progressive GFR loss than those with lesser degrees of glomerular changes. A remarkably high frequency of glomerular tubular junction abnormalities can be observed in proteinuric type 1 diabetic patients. Most of these abnormalities are associated with tuft adhesions to Bowman capsule at or near the glomerular tubular junction (tip lesions). The frequency and severity of these lesions (as well as the presence of completely atubular glomeruli) predict GFR loss.
The data on structural-functional relationships in type 2 diabetes are less abundant. In several small studies, morphometric measures of diabetic glomerulopathy correlated with kidney function parameters similar to those observed in type 1 diabetes, although there seems to be a subset of patients who have normal glomerular structure despite persistent albuminuria. Overall, the relationships between kidney function and glomerular structure are less precise in patients with type 2 diabetes. It is important to note that the rate of GFR decline significantly correlates with the severity of diabetic glomerulopathy lesions. Thus kidney lesions different from those typical of diabetic glomerulopathy should be considered when investigating the nature of abnormal levels of albuminuria in type 2 diabetes. These lesions include changes in the structure of renal tubules, interstitium, arterioles, and podocytes. For example, Pima Indians with type 2 diabetes and proteinuria have fewer podocytes per glomerulus than those without nephropathy, and, in this population, a lower number of podocytes per glomerulus at baseline was the strongest predictor of greater increases in albuminuria and of progression to overt nephropathy in microalbuminuric patients. These results suggest that changes in podocyte structure and density occur early in diabetic nephropathy and might contribute to increasing albuminuria in these patients. More biopsy data are needed in people with type 1 and type 2 diabetes to better characterize DKD and rule out non-diabetes-related nephropathy.
Reversal of Diabetic Nephropathy Lesions
The lesions of diabetic nephropathy have long been considered irreversible. Theoretically, if reversal were possible, this would happen in the setting of long-term normoglycemia. Interestingly, in pancreas transplant recipients, the lesions of diabetic nephropathy were unaffected after 5 years of normoglycemia but reversed in all patients by 10 years posttransplant, with a remarkable amelioration of glomerular structure abnormalities evident by light microscopy, including total disappearance of Kimmelstiel-Wilson nodular lesions. The long time necessary for these diabetic lesions to disappear is consistent with their slow rate of development. The understanding of the molecular and cellular mechanisms involved in these repair processes could provide new directions for the treatment of diabetic nephropathy.
Medical Management of Diabetes
Both kidney and cardiovascular morbidity and mortality are increased in patients with type 2 diabetes, particularly in those with nephropathy. Accordingly, treatment goals in these individuals focus on slowing the rate of GFR decline and delaying the onset of kidney failure, as well as primary and secondary prevention of cardiovascular disease. This is mainly done by targeting multiple kidney and cardiovascular risk factors, such as hyperglycemia, hypertension, and dyslipidemia ( Fig. 26.4 ). Targeting albuminuria is of specific interest for kidney protection, although not all therapies that reduce albuminuria lead to kidney or cardiovascular benefits. The remainder of this chapter reviews traditional therapeutic options to decrease the risk of kidney and cardiovascular morbidity and mortality, as well as novel risk factors for diabetic nephropathy that may provide insight into new drug targets and possibilities for new therapeutic interventions.
Traditional Therapeutic Strategies for Diabetic Nephropathy
Glycemic Control
Rationale
Poor glycemic control, as reflected by higher hemoglobin A1c (HbA1c) levels, is associated with markedly worse kidney and cardiovascular outcomes in observational studies of patients with type 1 and type 2 diabetes, and targeting HbA1c values lower than 7% may delay the progression of diabetic kidney disease, including development of microalbuminuria and overt nephropathy. In patients with type 1 diabetes, the benefit of intensive glucose control in the prevention of microvascular complications (specifically retinopathy or microalbuminuria) was demonstrated in the diabetes control and complications trial (DCCT), where long-term follow-up showed a significant reduction in the risk of developing reduced GFR among individuals who were treated intensively earlier in the course of diabetes. In type 2 diabetes, the United Kingdom prospective diabetes study (UKPDS) and ADVANCE-ON documented the benefit of intensive glucose targeting on microvascular complications. Of note, although most studies of type 2 diabetes have shown a benefit in kidney outcomes, multiple trials failed to show a benefit of intensive glycemic control on mortality and cardiovascular disease, with some trials actually showing increased mortality with intensive control. In contrast with this older literature, more recent trials such as the Empagliflozin-Reduce Excess Glucose Outcome (EMPA-REG OUTCOME) trial and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study demonstrate a significant reduction in cardiovascular endpoints (and kidney outcomes; EMPA-REG OUTCOME), even though HbA1c lowering effects were modest. This suggests a predominance of nonglycemic mechanisms leading to cardiorenal damage, although the underlying pathways require further study. Accordingly, a careful individualized approach is required when assigning glycemic targets in individuals with diabetes and kidney disease.
Medications of Choice
In principle, one uses the same drugs for glycemic control in patients with diabetes with and without kidney disease until late stage 3 CKD ( Table 26.1 ). There is controversy regarding metformin use in advanced CKD, with some guidelines recommending that use be restricted to those with serum creatinine ≤1.5 mg/dL (133 µmol/L) in men and 1.4 mg/dL (124 µmol/L) in women, because of an increased risk for life-threatening lactic acidosis. However, in practice many patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m 2 receive metformin without any problem. Although it is unlikely to occur, a randomized controlled trial assessing the efficacy and safety of metformin in patients with more advanced CKD is warranted, as metformin is an excellent glucose-lowering agent for many patients. Of note, metformin should be temporarily discontinued before surgery or administration of contrast media and during episodes of acute, significant illness.
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