Renoprotection by blocking the RAAS in diabetic nephropathy—fact or fiction?

Abstract

Diabetic nephropathy is characterized by proteinuria, blood pressure elevation, a relentless decline in renal function and a high risk of cardiovascular disease. In 1992, based on clinical studies, it was suggested that angiotensin-converting enzyme inhibitors (ACEIs) offer renoprotection in diabetic nephropathy—i.e. an effect protecting the kidney function above and beyond what was offered by similar blood pressure reduction with other antihypertensive agents [1]. This study was conducted in type 1 diabetic patients with moderately impaired renal function. The finding was confirmed and extended by the Collaborative Study Group [2] in a study with a median follow-up, 3 years; range, 1.8–4.8, demonstrating that in type 1 diabetic patients, ACEIs were associated with a 50% [95% confidence intervals (CI) 18–70] reduced risk of dialysis/transplantation or death. Subsequently blockade of the renin–angiotensin system (RAS) was investigated in type 2 diabetic patients using angiotensin II receptor blockers (ARB), and a renoprotective effect was again demonstrated, compared with placebo (standard antihypertensive therapy) in hypertensive microalbuminuric type 2 diabetic patients in the IRMA 2 trial lasting 2 years, where a 70% reduction in the progression to overt nephropathy was observed in patients receiving the maximal dose of irbesartan 300 mg daily [3]. Again, this effect was shown to be present beyond the bloodpressure-lowering effect of ARB-intervention. This was further substantiated in a substudy, in which it was documented that there was no difference in 24-h blood pressure in patients treated with ARB or standard antihypertensive therapy [4]. In patients with type 2 diabetes and overt diabetic nephropathy, the IDNT study with a mean follow-up time of 2.6 years demonstrated a significant 20% reduction in the development of the combined endpoint doubling of S-creatinine, end-stage renal disease (ESRD) or death in the patients treated with irbesartan compared with placebo (standard antihypertensive therapy), and 23% risk reduction compared with the calcium channel blocker amlodipine [5]. It should be stressed that, particularly in comparison with the amlodipine arm, the systemic blood pressure was completely identical. The RENAAL study with a mean follow-up time of 3.4 years (range, 2.3–4.6) similarly demonstrated that ARB losartan could significantly reduce the development of doubling of creatinine, ESRD and death by 16% compared with standard antihypertensive therapy [6]. Following these studies, FDA and EMEA approved irbesartan and losartan for renoprotection in diabetic patients (beyond blood pressure). Clinical guidelines recommended the use of inhibition of the RAS for prevention of diabetic nephropathy and ESRD. Despite all this evidence, the renoprotective effects of RAS blockade in diabetic nephropathy have recently been questioned on several occasions. In this article, we critically assess three recent publications that have challenged the specific renoprotective role of ACEI/ARBs in proteinuric diabetic patients suffering from diabetic kidney disease. We will not discuss the role of ACE inhibition or ARB in non-proteinuric kidney diseases in diabetic patients.