Mechanisms of diabetic renal and cardiovascular disease.

The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain to be established. However, there is now evidence that renal disease clusters in families and that genetic factors are of central importance in determining liability. A predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Genetically controlled hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. This suggestion derives from the observation that the fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first sign of renal damage is the appearance of microalbuminuria and of a small elevation in arterial pressure, changes associated with significant mesangial expansion. Microalbuminuria is associated with abnormalities of lipoprotein profiles possibly as a consequence of insulin-resistance-induced hyperinsulinemia. It could be postulated that the environmental changes brought about by diabetes lead in susceptible individuals to increased systemic and intraglomerular pressure on the one hand and mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities would further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered of reduction in renal function, more hypertension, more proteinuria, more glomerular obsolence, more hyperlipidemia and eventually end-stage renal failure or premature cardiovascular death.