Regarding Dr. Mandal's first statement, when we calculated creatinine clearance with the Cockcroft-Gault formula (which corrects for inaccuracy of urine collection), it decreased 3.3% in the losartan group and increased 2.7% in the placebo group; this difference was not statistically significant. Furthermore, as is known from previous long-term, large-scale studies, creatinine clearance stabilizes after prolonged treatment with ACE inhibitors or angiotensin-receptor antagonists (1-3). These agents have been shown to reduce the decline in GFR and to preserve kidney function.

We agree that control of blood glucose is the most important factor in reducing the development and progression of diabetic nephropathy. However, since the difference in glycosylated hemoglobin levels between our 2 study groups was not statistically significant, our data do not suggest that the slightly lower glycosylated hemoglobin level in the placebo group is responsible for the observed stable creatinine clearance.

Also, many studies have shown that strict blood pressure control delays the onset and progression of kidney disease. Although the study by Schrier and colleagues is interesting, accumulating evidence from several well-conducted, large-scale studies suggests that ACE inhibitors and angiotensin-receptor antagonists have specific additive renal protective effects above the reduction in blood pressure in patients with type 1 or type 2 diabetes, with or without hypertension.

Since many factors contribute to diabetic kidney damage, prevention and treatment should also target multiple factors. In our opinion, agents inhibiting the renin-angiotensin system have been shown to be renoprotective and are very likely to have an additive effect in reducing kidney damage combined with strict blood glucose and blood pressure control. In addition, for renal disease, albuminuria is also a strong and independent risk factor for cardiovascular morbidity and mortality (4, 5). Reducing urinary albumin excretion might reduce cardiovascular disease and death.

The statements of Drs. Kario and Shimada are also very interesting. Blood pressure in our study patients was measured between 8:00 a.m. and 12:00 noon. Since we did not use ambulatory blood pressure monitoring, we cannot exclude the possibility that a reduction of nocturnal or specific morning blood pressure associated with losartan helped reduce urinary albumin excretion rate.