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Abstract

Marble almost 30 yrs ago pointed out that retinopathy increases monotonically with duration of insulin treatment whereas nephropathy reaches a plateau involving 30-40% of patients. Only some patients are at specific risk. He believed that glycemic state and familial factors contributed. The remarkable success of ACE inhibition and ARB's in delaying nephropathy provided clues on pathogenesis. Do genes governing the renin system contribute? Some studies have so indicated. This is the situation in which “intermediate phenotype can provide a bridge between the gene on the one hand and disease expression on the other”. We selected renal vascular response to captopril as that phenotype. Type 1 diabetics at risk of nephropathy show an enhanced renal vasodilator response, which correlates with risk factors including glycemic control, filtration status, and with ACE gene polymorphisms. Similar principles apply to Type 2 diabetes, but obesity and ethnicity make a major contribution. This has long been recognized as a low-renin state: How can one reconcile the effectiveness of ACE inhibition and ARB's with a low-renin state? Evidence suggests that the low PRA is misleading as the intrarenal RAS is activated: The low PRA reflects excessive intrarenal AngII levels. The RAS represents a final common pathway for contributions from glycemic control, genetic polymorphisms, obesity, ethnicity, and prior renal injury. Diabetic nephropathy is one of the few diseases in which effective treatment saves money. The more that we spend on treatment, the more money we save. The past 10 yrs brought extraordinary advances; the next 10 promise even more.

ACE inhibition, angiotensin receptor blockade, glycemic control, genes
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© American Journal of Hypertension, Ltd. 2002
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