Diabetic Nephropathy

Diabetic nephropathy is the single most common cause of chronic renal failure in the United States, accounting for 45% of patients receiving renal replacement therapy, and is a rapidly growing problem worldwide. The dramatic increase in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity, metabolic syndrome, and Type 2 diabetes mellitus.

Approximately 40% of patients with Types 1 or 2 diabetes develop nephropathy, but due to the higher prevalence of Type 2 diabetes (90%) compared to Type 1 (10%), the majority of patients with diabetic nephropathy have Type 2 disease. Renal lesions are more common in African-American, Native American, Polynesian, and Maori populations.

Risk factors for the development of diabetic nephropathy :include hyperglycemia, hypertension, dyslipidemia, smoking, a family history of diabetic nephropathy, and gene polymorphisms affecting the activity of the renin-angiotensin-aldosterone axis.

Within 1–2 years after the onset of clinical diabetes, morphologic changes appear in the kidney. Thickening of the GBM is a sensitive indicator for the presence of diabetes but correlates poorly with the presence or absence of clinically significant nephropathy. The composition of the GBM is altered notably with a loss of heparan sulfate moieties that form the negatively charged filtration barrier. This change results in increased filtration of serum proteins into the urine, predominately negatively charged albumin. The expansion of the mesangium due to the accumulation of extracellular matrix correlates with the clinical manifestations of diabetic nephropathy. This expansion in mesangial matrix can be associated with the development of mesangial sclerosis. Some patients also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules.

 Immunofluorescence microscopy often reveals the nonspecific deposition of IgG (at times in a linear pattern) or complement staining without immune deposits on electron microscopy. Prominent vascular changes are frequently seen with hyaline and hypertensive arteriosclerosis. This is associated with varying degrees of chronic glomerulosclerosis and tubulointerstitial changes. Renal biopsies from patients with Types 1 and 2 diabetes are largely indistinguishable.
These pathologic changes are the result of a number of postulated factors. Multiple lines of evidence support an important role for increases in glomerular capillary pressure (intraglomerular hypertension) in alterations in renal structure and function. Direct effects of hyperglycemia on the actin cytoskeleton of renal mesangial and vascular smooth-muscle cells as well as diabetes-associated changes in circulating factors such as atrial naturetic factor, angiotensin II, and insulin-like growth factor (IGF) may account for this. Sustained glomerular hypertension increases matrix production, alterations in the GBM with disruption in the filtration barrier (and hence proteinuria) and glomerulosclerosis. A number of factors have also been identified which alter matrix production, including the accumulation of advanced glycosylation end products, circulating factors including growth hormone, IGF-I, angiotensin II, connective tissues growth factor, TGF-, and dyslipidemia.

The natural history of diabetic nephropathy in patients with Types 1 and 2 diabetes is similar. However, since the onset of Type 1 diabetes is readily identifiable and the onset of Type 2 diabetes is not, a patient newly diagnosed with Type 2 diabetes may have renal disease for many years before nephropathy is discovered and presents as advanced diabetic nephropathy. At the onset of diabetes, renal hypertrophy and glomerular hyperfiltration are present. The degree of glomerular hyperfiltration correlates with the subsequent risk of clinically significant nephropathy. In the approximately 40% of patients with diabetes who develop diabetic nephropathy, the earliest manifestation is an increase in albuminuria detected by sensitive radioimmunoassay. Albuminuria in the range of 30–300 mg/24 h is called microalbuminuria.

In patients with Types 1 or 2 diabetes, microalbuminuria appears 5–10 years after the onset of diabetes. It is currently recommended to test patients with Type 1 disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter, and, because the time of onset of Type 2 diabetes is often unknown, to test Type 2 patients at the time of diagnosis of diabetes and yearly thereafter.
Patients with small rises in albuminuria increase their levels of urinary albumin excretion, typically reaching dipstick positive levels of proteinuria (>300 mg albuminuria) 5–10 years after the onset of early albuminuria.

 Microalbuminuria is a potent risk factor for cardiovascular events and death in patients with Type 2 diabetes. Many patients with Type 2 diabetes and microalbuminuria succumb to cardiovascular events before they progress to proteinuria or renal failure. Proteinuria in frank diabetic nephropathy can be variable, ranging from 500 mg to 25 g/24 h, and is often associated with nephrotic syndrome. More than 90% of patients with Type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopathy in Type 1 patients with proteinuria should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with Type 2 diabetes with nephropathy have diabetic retinopathy. There is a highly significant correlation between the presence of retinopathy and the presence of Kimmelstiel-Wilson nodules . Also, characteristically, patients with advanced diabetic nephropathy have normal to enlarged kidneys, in contrast to other glomerular diseases where kidney size is usually decreased. Using the above epidemiologic and clinical data, and in the absence of other clinical or serologic data suggesting another disease, diabetic nephropathy is usually diagnosed without a renal biopsy.

After the onset of proteinuria >500 mg/24 h, renal function inexorably declines, with 50% of patients reaching renal failure in 5–10 years; thus, from the earliest stages of microalbuminuria, it usually takes 10–20 years to reach end-stage renal disease. Hypertension may predict which patients develop diabetic nephropathy, as the presence of hypertension accelerates the rate of decline in renal function. Once renal failure appears, however, survival on dialysis is far shorter for patients with diabetes compared to other dialysis patients; some diabetics do better clinically if they are started on dialysis before they reach advanced renal failure. Survival is best for patients with Type 1 diabetes who receive a transplant from a living related donor. 
Good evidence supports the benefits of blood sugar and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy. In patients with Type 1 diabetes, intensive control of blood sugar clearly prevents the development or progression of diabetic nephropathy. The evidence in patients with Type 2 disease, although less compelling, also supports intensive control of blood sugar. Controlling systemic blood pressure to levels of 130/80 mmHg or less decreases renal and cardiovascular adverse events in this high-risk population. The vast majority of patients with diabetic nephropathy require three or more antihypertensive drugs to achieve this goal. Drugs that inhibit the renin-angiotensin system, independent of their effects on systemic blood pressure, have been repeatedly shown to slow the progression of diabetic nephropathy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration) stages, independent of any effect they may have on systemic blood pressure.

Since angiotensin II increases efferent arteriolar resistance and, hence, glomerular capillary pressure, one key mechanism for the efficacy of ACE inhibitors or angiotensin receptor blockers (ARBs) is reducing glomerular hypertension. Patients with Type 1 diabetes for 5 years who develop albuminuria or declining renal function should be treated with ACE inhibitors. Patients with Type 2 diabetes and microalbuminuria or proteinuria may be treated with ACE inhibitors or ARBs.