Recent advances in management of type 2 diabetes and nephropathy: lessons from the RENAAL study

Diabetic nephropathy has become the single most important cause of end-stage renal disease (ESRD) worldwide. Strategies to slow the rate of loss of renal function in these patients recently have been developed. The renin-angiotensin-aldosterone system has proven to be an important target for intervention.

The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a randomized, double-blind, multinational, clinical trial that studied 1,513 patients with type 2 diabetes and nephropathy for a mean of 3.4 years. Patients were administered either losartan or placebo, each in addition to conventional antihypertensive therapy, with dosage adjustments as necessary to achieve a target blood pressure of less than 140/less than 90 mm Hg.

The study showed a significant benefit of losartan, beyond the effects of lowering blood pressure, on the primary composite end point of doubling serum creatinine level, ESRD, or death (-16%; P = 0.02). Losartan reduced the incidence of serum creatinine level doubling (-25%; P = 0.006) and ESRD (-28%; P = 0.002), but had no effect on rate of death. The composite end point of cardiovascular morbidity and mortality was similar in the two groups. The rate of first hospitalization for heart failure was reduced in the losartan group (-32%; P = 0.005), as was proteinuria (-35%; P < 0.001). The RENAAL study also provided the opportunity to evaluate risk factors that predict ESRD in patients with type 2 diabetes in whom blood pressure was aggressively treated. In our multivariate model, four independent risk factors, proteinuria (most important), serum creatinine level, hypoalbuminemia, and anemia, were identified that predicted the development of ESRD.

Proteinuria is the single most powerful predictor of ESRD in patients with type 2 diabetes and nephropathy. Thus, it is imperative that it be assessed in all patients with type 2 diabetes to identify those at risk for progressive renal disease. The routine availability of the urinary albumin-creatinine ratio as a diagnostic test provides an important opportunity to further improve the prognosis of individuals with type 2 diabetes and nephropathy.