Diabetes mellitus is a major cause of renal morbidity and mortality and diabetic nephropathy is one of the leading causes of chronic kidney failure in the United States. End - stage kidney disease occurs in as many as 30% of insulin-dependent type I diabetics and accounts for 20% of deaths in patients younger than 40 years. By far the most common lesions involve the glomeruli and are associated clinicallyh with three glomerular syndromes, including non nephrotic proteinuria, nephrotic syndrome, and chronic renal failure. However, diabetes also affects the arterioles, causing arteriolar sclerosis; increases susceptibility to the development of pyelonephritis, and particularly papillary necrosis; and causes a variety of tubular lesions. The term diabetic nephropathy is applied to the conglomerate of lesions that often occur concurrently in the diabetic kidney.

Proteinuria, sometimes in the nephrotic range occurs in about 50% of both type 1 and type 2 diabetics. It is usually discovered 12 to 22 years after the clinical appearance of diabetes and (particularly in type 1 diabetics) often heralds the progressive development of chronic renal failure ending in death or end stage disease within a period of 4 to 5 years. The morphologic changes in the glomeruli include (1)capillary basement membrane thickening (2) diffuse diabetic glomerulosclerosis, and (3) nodular glomerulosclerosis.

The pathogenesis of diabetic glomerulosclerosis is intimately linked with that og generalized diabetic microangiopathy.

The bulk of evidence suggests that diabetic glomerulosclerosis is caused by the metabolic defect that is the insulin deficiency or the resultant hyperglycemia or some other aspects of glucose intolerance.

Biochemical alterations in diabetic GBM are significant and include increased amount and synthesis of collagen type IV and fibronectin and decreased synthesis of proteoglycan heparan sulfate.

Nonenzymatic glycosylation of proteins, known to occur in diabetics and giving rise to advanced glycosylation and products, may contribute to the glomerulopathy. The mechanisms by which advanced glycosylation end products cause their effects.

One hypothesis implicates hemodynamic changes in the initiation or progression of diabetic glomerulosclerosis. It is well known that early onset type I diabetics have an increased GFR increased glomerular filtration area increased glomerular capilary pressure and glomerular hypertrophy . Hemodynamic alterations and glomerular hypertrophy also occur in experimental streptozotocin induced diabetes in rats, in which they are associated with proteinuria and can be reversed by diabetic control. It has been speculated that the subsequent morphologic alterations in the mesangium are somehow influenced by the glomerular hypertrophy and hemodynamic changes, akin to the adaptive responses to ablation of renal mass.

To sum up, two processes seem to play a role in the fullyu developed diabetic glomerular lesions: a metabolic defect possibly linked to advanced glycosylation and products, that accounts for the thickened GBM and increased mesangial matrix that occur in all patients; and hemodynamic effects associated with glomerular hypertrophy which leads to glomerulosclerosis in about 40% of patients.

Clinical Course

The clinical manifestations of diabetic glomerulosclerosis are linked to those of diabetes. The increased GFR typical of early onset type 1 diabetics is associated with microalbuminuria defined as urinary albumin excretion of 30 to 300 mg/day of albumin. Microalbuminuria and increased GFR are important predictors of future overt diabetic nephropathy in these patients. Overt proteinuria then develops which may be mild and asymptomatic initially but gradually increased to nephrotic levels in some patients. This is followed by progressive loss GFR leading to end stage renal failure within a period of 5 years.

Systemic hypertension may precede the development proteinuria and renal insufficiency. Indeed the risk of renal disease in type 1 diabetics is associated with a genetic predisposition to hypertension, possibility related to polymorphisms in the genes encoding proteins of the renin angiotension system. Hypertension in turn increases the susceptibility to developing diabetic nephropathy in the presence of poor hyperglycemic control.

Although the prevalence of protenuria is comparable in type 1 and type 2 diabetics, the lesions are more heterogeneous and less predictable in type 2 diabetics. Indeed 20 to 50% of type 2 patients undergoing renal biopsy have other glomerular diseases (eg., membranous glomerulonephritis). End stage renal disease results in only 10% to 20% of patients with type 2 diabetes.