Renin-Angiotensin System Blockers and Acute Kidney Injury

Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Chronic Kidney Disease

ACEIs and then ARBs had been studied extensively in the 1990s and early 2000s for their antiproteinuric and nephroprotective effects in diabetic and nondiabetic CKD. The majority of the patients who were enrolled in the clinical trials were in their adulthood, with a mean age around 50 years old. These findings are then not necessarily applicable to the majority of CKD patients attending nephrology outpatient clinics, who are in general overweight or obese, old, and affected by several comorbidities.

In more advanced CKD, data are less clear. Some years ago, a Chinese trial confirmed the nephroprotective efficacy and relative safety of ACEIs in CKD patients with serum creatinine levels of 3.1 to 5.0 mg/dL. However, the accuracy of the study was questioned by data published in duplicate reporting different sample sizes. Conversely, clinical observations indicate that some patients with advanced CKD may have an improvement in kidney function after RAS blocker withdrawal.

Similar to ACEIs, ARBs reduced the progression of type 2 diabetic nephropathy with overt proteinuria. These trial populations were much closer to that observed currently. However, the reduction in the relative risk of reaching the combined primary end point of the doubling of serum creatinine, ESRD, or death was modest (only 16% and 20% in the Irbesartan Diabetic Nephropathy Trial [IDNT] and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] study, respectively).

Although it is acknowledged that RAS blockers are nephroprotective in proteinuric nephropathies, the magnitude of the effect seems less relevant in patients without proteinuria. According to a meta-analysis, the effect of ACEIs disappears in patients with nondiabetic CKD and proteinuria <0.5 g/day. Similarly, treatment with losartan did not significantly reduce the risk of a renal event in type 2 diabetic nephropathy with baseline albuminuria less than 1.5 g/g.

In 2005 a large meta-analysis of RAS inhibitors and renal outcomes raised questions on the renal efficacy of RAS blockade. Even if ACEIs and ARBs were significantly effective, only a small reduction was seen in the risk of end-stage renal disease (ESRD) in favor of either ACEIs or ARBs (relative risk 0.87, CI 0.75–0.99; p = .04) compared with other antihypertensive drugs. These results were influenced by the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, in which there was no evidence for a greater beneficial effect of ACEIs in high-risk hypertensive patients with reduced GFR.

Considering that the progression rate of CKD seems to be very slow in subjects older than 65 years, it is then possible that the follow-up of the majority of randomized trials testing the effect of RAS inhibition may be relatively inadequate to study hypertensive kidney disease at least in Caucasians. Accordingly, a secondary analysis of the ACE Inhibition in Progressive Renal Insufficiency (AIPRI) study showed that at the start of ACEI therapy the short-term worsening of renal function was of higher magnitude in elderly patients compared with younger ones (unpublished data, Fig. 228.1 ). However, during the long-term follow-up, even the elderly patients treated with ACEIs experienced a trend toward a better GFR compared with those receiving placebo. Moreover, the initial apparent negative effect of benazepril can persist for different periods of time, being longer in the patients with slowly progressive CKD.

Anyway, this relatively scarce benefit is to be balanced with a higher risk of AKI (and hyperkalemia) in this patient population because of the older age, frailty, and high burden of cardiovascular disease. Moreover, it is becoming more often the case that patients with type 2 diabetes develop CKD without overt proteinuria.