Diabetic Nephropathy
DEFINITION AND CAUSES
Diabetic nephropathy (DN) is typically defined by macroalbuminuria—that is, a urinary albumin excretion of more than 300 mg in a 24-hour collection—or macroalbuminuria and abnormal renal function as represented by an abnormality in serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR). Clinically, diabetic nephropathy is characterized by a progressive increase in proteinuria and decline in GFR, hypertension, and a high risk of cardiovascular morbidity and mortality.
PREVALENCE AND RISK FACTORS
Diabetes has become the primary cause of end-stage renal disease (ESRD) in the United States, and the incidence of type 2 diabetes mellitus continues to grow in the United States and worldwide. Approximately 44% of new patients entering dialysis in the United States are diabetics. Early diagnosis of diabetes and early intervention are critical in preventing the normal progression to renal failure seen in many type 1 and a significant percentage of type 2 diabetics.
In the United States, approximately 20.8 million people, or 7.0% of the population, are estimated to have diabetes, with a growing incidence. Roughly one third of this population, 6.2 million, is estimated to be undiagnosed with type 2 diabetes. The prevalence of diabetes is higher in certain racial and ethnic groups, affecting approximately 13% of African Americans, 9.5% of Hispanics, and 15% of Native Americans, primarily with type 2 diabetes.1,2 Approximately 20% to 30% of all diabetics will develop evidence of nephropathy, although a higher percentage of type 1 patients progress to ESRD.
PATHOPHYSIOLOGY AND NATURAL HISTORY
The common progression from microalbuminuria to overt nephropathy has led many to consider microalbuminuria to define early or incipient nephropathy. Renal disease is suspected to be secondary to diabetes in the clinical setting of long-standing diabetes. This is supported by the history of diabetic retinopathy, particularly in type 1 diabetics, in whom there is a strong correlation. The natural history of diabetic nephropathy is a process that progresses gradually over years.
Early diabetes is heralded by glomerular hyperfiltration and an increase in GFR. This is believed to be related to increased cell growth and expansion in the kidneys, possibly mediated by hyperglycemia itself. Microalbuminuria typically occurs after 5 years in type 1 diabetes. Overt nephropathy, with urinary protein excretion higher than 300 mg/day, often develops after 10 to 15 years. ESRD develops in 50% of type 1 diabetics, with overt nephropathy within 10 years.
Type 2 diabetes has a more variable course. Patients often present at diagnosis with microalbuminuria because of delays in diagnosis and other factors affecting protein excretion. Fewer patients with microalbuminuria progress to advanced renal disease. Without intervention, approximately 30% progress to overt nephropathy and, after 20 years of nephropathy, approximately 20% develop ESRD. Because of the high prevalence of type 2 compared with type 1 diabetes, however, most diabetics on dialysis are type 2 diabetics.
Long-standing hyperglycemia is known to be a significant risk factor for the development of diabetic nephropathy. Hyperglycemia may directly result in mesangial expansion and injury by an increase in the mesangial cell glucose concentration. The glomerular mesangium expands initially by cell proliferation and then by cell hypertrophy. Increased mesangial stretch and pressure can stimulate this expansion, as can high glucose levels. Transforming growth factor β (TGF-β) is particularly important in the mediation of expansion and later fibrosis via the stimulation of collagen and fibronectin. Glucose can also bind reversibly and eventually irreversibly to proteins in the kidneys and circulation to form advanced glycosylation end products (AGEs). AGEs can form complex cross-links over years of hyperglycemia and can contribute to renal damage by stimulation of growth and fibrotic factors via receptors for AGEs. In addition, mediators of proliferation and expansion, including platelet-derived growth factor, TGF-β, and vascular endothelial growth factor (VEGF) that are elevated in diabetic nephropathy can contribute to further renal and microvascular complications.
Proteinuria, a marker and potential contributor to renal injury, accompanies diabetic nephropathy. Increased glomerular permeability will allow plasma proteins to escape into the urine. Some of these proteins will be taken up by the proximal tubular cells, which can initiate an inflammatory response that contributes to interstitial scarring eventually leading to fibrosis. Tubulointerstitial fibrosis is seen in advanced stages of diabetic nephropathy and is a better predictor of renal failure than glomerular sclerosis. Hyperglycemia, angiotensin II, TGF-β, and likely proteinuria itself all play roles in stimulating this fibrosis. There is an epithelial-mesenchymal transition that takes place in the tubules, with proximal tubular cell conversion to fibroblast-like cells. These cells can then migrate into the interstitium and produce collagen and fibronectin.
In diabetic nephropathy, the activation of the local renin-angiotensin system occurs in the proximal tubular epithelial cells, mesangial cells, and podocytes. Angiotensin II (ATII) itself contributes to the progression of diabetic nephropathy. ATII is stimulated in diabetes despite the high-volume state typically seen with the disease, and the intrarenal level of ATII is typically high, even in the face of lower systemic concentrations. ATII preferentially constricts the efferent arteriole in the glomerulus, leading to higher glomerular capillary pressures. In addition to its hemodynamic effects, ATII also stimulates renal growth and fibrosis through ATII type 1 receptors, which secondarily upregulate TGF-β and other growth factors.
Control of hypertension has clearly shown to be an important and powerful intervention in decreasing the progression of diabetic nephropathy. In diabetics who have disordered autoregulation at the level of the kidney, systemic hypertension can contribute to endothelial injury. Human studies of type 2 diabetics have shown that blood pressure lowering, regardless of the agent used, retards the onset and progression of diabetic nephropathy. In animal studies, the degree and severity of the diabetic nephropathy were strongly linked to systemic blood pressure.
The fact that most types 1 and 2 diabetics do not develop diabetic nephropathy (DN) suggests that other factors may be involved. Genetic factors clearly play a role in the predisposition to diabetic nephropathy in family members who have DN, and linkage to specific areas on the human genome is evolving. The theory of a reduction in nephron number at birth indicates that individuals born with a reduced number of glomeruli may be predisposed to subsequent renal injury and progressive nephropathy. This has been shown in animal studies in which the mother was exposed to hyperglycemia at the time of pregnancy. If this linkage is true in humans, that would have important implications concerning the role of maternal factors in the eventual development of kidney disease.3
SIGNS AND SYMPTOMS
Early signs and symptoms of kidney disease in patients with diabetes are typically unusual. However, a vast array of signs and symptoms listed below may manifest when kidney disease has progressed:4
The differential diagnosis of diabetic nephropathy is vast, but it includes the following in a patient with known diabetes mellitus:
DIAGNOSIS
Laboratory Tests
In screening for diabetic nephropathy, we recommend early testing for glucose intolerance and diabetes to identify patients who are at risk for developing microalbuminuria, particularly if they have other risks for type 2 diabetes, such as hypertension, lipid abnormalities, or central obesity. As noted, approximately one third of type 2 diabetics are believed to be undiagnosed. Once the diagnosis of diabetes has been made, we routinely check urinary protein levels only to guide therapy and prognosis.
It is not uncommon to find microalbuminuria or macroalbuminuria in a type 2 diabetic at or soon after the initial diagnosis of diabetes. This may be because the patient has had undiagnosed diabetes for many years, or it may relate to the contributions of hypertension or other processes that may cause proteinuria independently of diabetes, such as small-vessel atherosclerosis. Microalbuminuria is now recognized as an independent cardiac risk factor, even in the absence of diabetes. Screening for microalbuminuria in nondiabetics may have important implications for cardiac risk, and should lead to instituting some of the same therapies as those used for diabetic nephropathy (Table 1).
Imaging Studies
A renal ultrasound is typically obtained to observe for kidney size. In the early stages of diabetic nephropathy, kidney size may be enlarged from hyperfiltration. With progressive kidney disease from diabetes, the kidneys diminish in size from glomerulosclerosis. In addition, a renal ultrasound can assess for hyperechogenicity that suggests chronic kidney disease and can assist in ruling out obstruction.
Diagnostic Procedures
Frequently, the question is raised as to whether proteinuria is from diabetes or from a primary renal disease. Suspicion may arise in patients with significant proteinuria without a long history of diabetes or without other signs of end-organ damage, such as retinopathy or neuropathy. Although the presence of retinopathy supports a diabetic source of proteinuria, the lack of diabetic retinopathy does not rule out diabetic nephropathy, particularly in type 2 diabetics.
Patients with diabetes can develop nephrotic-range proteinuria (higher than 3.5 g/24 hr), but typically only after long-standing diabetes. A bland urine sediment supports the diagnosis of diabetes, although it is not uncommon to have some microscopic hematuria with advanced diabetic nephropathy. The presentation of an acute nephrotic syndrome, rapidly rising urinary protein level, or rapidly declining GFR should lead to consideration of renal biopsy. The finding of red cell or white cell casts in the urine should also suggest a biopsy. Renal biopsy findings consistent with diabetic nephropathy in the early stages are mesangial expansion and glomerular basement membrane thickening. Eventual progression of diabetic nephropathy can lead to nodular glomerulosclerosis, also referred to as Kimmelstiel-Wilson disease.
Often, a patient will present without available history and may be frankly nephrotic in the face of long-standing diabetes. In cases of uncertainty such as this, it is not wrong to consider a renal biopsy, because the finding of a primary glomerular disease could potentially change the course of management.
Staging
Table 2 Stages of Chronic Kidney Disease
| Stage | Description | GFR (mL/min) |
|---|---|---|
| 1 | Kidney damage with normal or raised GFR | ≥90 |
| 2 | Kidney damage with mild decrease in GFR | 60-89 |
| 3 | Moderate decrease in GFR | 30-59 |
| 4 | Severe decrease in GFR | 15-29 |
| 5 | Kidney Failure | <15 |
GFR, glomerular filtration rate.
From National Kidney Foundation: GFR, 2008. Available at http://www.kidney.org/professionals/KLS/gfr.cfm#20.
Summary
TREATMENT
Lifestyle Modification
One keystone in the prevention and management of diabetic nephropathy is tight glycemic control. In the Diabetes Control and Complications Trial, type 1 diabetics were randomized to intensive or conventional insulin treatments and followed for an average of 6.5 years.5 Average hemoglobin A1c (HbA1c) values were 7.2% versus 9.2%. There was a 39% risk reduction in the development of microalbuminuria and a 54% reduction in the development of macroalbuminuria in the intensive treatment group.
In the UK Prospective Diabetes Study (UKPDS), 3867 patients with newly diagnosed type 2 diabetes were randomized to oral or insulin therapy versus dietary control and followed for 11 years.6 The difference in HbA1c was 7.0% versus 7.9%. After 9 years, there was a significant risk reduction in the intensive group, with a relative risk of 0.76 for the development of microalbuminuria.
The complete correction of hyperglycemia with pancreatic transplantation in type 1 diabetics has led to a dramatic resolution in glomerular and tubular expansion and fibrosis over time.7 With a drop in HbA1c from an average of 8.7% to 5.5% in eight transplanted patients, there was a significant reduction in basement membrane thickening and mesangial expansion on repeat biopsies over time. Even glomerular sclerosis appeared to resolve, showing that renal fibrosis may be reversible, although it took 10 years after transplantation to see these significant changes.
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