Angiotensin II receptor blockade in diabetic nephropathy

The editorial by Ruddy1 reviews and emphasizes the importance of renal disease in the prognosis of the patient with type 2 diabetes mellitus. He rightly points out that the Irbesartan Diabetic Nephropathy Trial (IDNT)2 and the Reduction of End Points in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Study3 both revealed a significant decrease in the likelihood of a patient with overt clinical nephropathy reaching a doubling of serum creatinine end point (approximately halving of the baseline glomerular filtration rate) or end stage renal disease during the course of these studies. These definitive results, which indicate a significant effect of angiotensin receptor blockade in diminishing the rate of progress of renal disease in this patient population, should not be diminished by the report of the relatively modest annual decrease in creatinine clearance to which Ruddy alludes. The absolute decrease in rate of loss of renal function can be a misleading value, insofar as patients with the most advanced disease and those who are progressing most rapidly reach a study end point, are taken off the coded medication and, therefore do not contribute to the longitudinal analysis of renal function. The effect of angiotensin receptor blocking agents may be even more profound than could be concluded in these published studies. Longer follow-up may indeed reveal a greater impact on clinical course than is seen during the clinical trial. This was our experience when a follow-up study of patients who had entered the Collaborative Study Group's Captopril Trial in type 1 diabetic nephropathy was carried out. Longer term follow-up of patients who had been in this study revealed that strict blood pressure control, using the angiotensin converting enzyme inhibitor ramipril, was so effective that some patients satisfied criteria of regression and, arguably remission, during several years of follow-up, even when nephrotic range proteinuria was present at entry.4 It is important to emphasize that patients studied in the IDNT and RENAAL trials had advanced renal disease with elevated serum creatinine levels and nephrotic range proteinuria. Before the IDNT, the Collaborative Study Group carried out a pilot trial in which renal biopsies were undertaken to determine the nature of the glomerular lesion in the patient population who would ultimately satisfy the entry criteria for the IDNT. This study showed that these patients had advanced glomerular disease (Fig. 1). 5 Therefore, it is unreasonable to expect rapid resolution of the serious functional and histopathologic damage already present in the kidneys of the patients studied in IDNT and RENAAL during the limited follow-up period of a clinical trial. Observations of diabetic nephropathy in the human pancreas transplant model emphasize that resolution of the glomerular lesion is slow.6 It would seem far more important to acknowledge the results of Parving et al,7 who revealed in dramatic fashion that treatment of early type 2 diabetic nephropathy, manifest by microalbuminuria, is associated with a decrease in progression at this early stage of diabetic renal disease. These results dictate a requirement for early intervention. With respect to Ruddy's point that we need a better understanding of risk factors and other clinical determinants that impact on the results of a clinical trial, some of this information will be forthcoming in secondary analyses of these studies. The message to the prudent physician is, therefore, not merely to add one more medication to the total management required by the complex patient with type 2 diabetes mellitus. Rather, it is that there is an obligation to use angiotensin receptor blockade for renoprotection to prevent progressive type 2 diabetic nephropathy and, ultimately, renal failure. Logically the time for intervention is early in the course of the disease process.