Effect of renin–angiotensin–aldosterone system blockade in adults with diabetes mellitus and advanced chronic kidney disease not on dialysis: a systematic review and meta-analysis

Abstract

The presumed superiority of renin-angiotensin-aldosterone system (RAAS)-blocking agents over other antihypertensive agents in patients with diabetes to delay development of end-stage kidney disease (ESKD) has recently been challenged. In addition, there is ongoing uncertainty whether RAAS-blocking agents reduce mortality and/or delay ESKD in patients with diabetes and chronic kidney disease (CKD) stages 3-5. In this subgroup, there might be an expedited need for renal replacement therapy (RRT) when RAAS-blocking agents are used. We conducted a meta-analysis of randomized controlled trials (RCTs) of at least 6-months duration in adult patients with diabetes who also have non-dialysis CKD stages 3-5. RCTs comparing single RAAS-blocking agents to placebo or alternative antihypertensive agents were included. Outcomes of interest were all-cause mortality, cardiovascular morbidity, progression of renal function, ESKD and adverse events. A total of nine trials (n = 9797 participants with CKD stages 3-5) fit our inclusion criteria. There was no difference between the RAAS group and control group regarding all-cause mortality {relative risk [RR] = 0.97 [95% confidence interval (CI) 0.85-1.10]}, cardiovascular mortality [RR = 1.03 (95% CI 0.75-1.41)] and adverse events [RR = 1.05 (95% CI 0.89-1.25)]. There was a trend for a favourable effect for non-fatal cardiovascular events [RR = 0.90 (95% CI 0.81-1.00)] and a lower risk of the composite endpoint need for RRT/doubling of serum creatinine [RR = 0.81 (95% CI 0.70-0.92)] in the RAAS-blocking agents group versus the control group. We found evidence that in patients with diabetes mellitus and CKD stages 3-5, treatment with RAAS-blocking agents did not result in a clear survival advantage. The effect on renal outcomes did depend on the selected outcome measure. However, we did not find evidence that the use of RAAS-blocking agents expedited the need for RRT in patients with CKD stages 3-5.

ACE Inhibitor Benefit to Kidney and Cardiovascular Outcomes for Patients with Non-Dialysis Chronic Kidney Disease Stages 3–5: A Network Meta-Analysis of Randomised Clinical Trials

“…Several published meta-analyses and systematic reviews evaluated the effects of RAS blockers on CKD patients [9,[15][16][17][18][19][20][21]. One network meta-analysis that included 119 RCTs comprising 64,768 participants, mostly with chronic kidney disease, showed that ACEIs or ARBs could reduce the risks of kidney failure and cardiovascular events.…”

“…To date, there is little information available with regard to patients with CKD3-5 and diabetes mellitus. A previous pair-wise meta-analysis including nine trials, conducted in non-dialysis diabetic patients (n = 9797 participants) with CKD stages 3-5, found that RAAS-blocking agents could lower the risk of renal replacement therapy/doubling of serum creatinine, but had no beneficial effect on all-cause mortality and cardiovascular mortality events compared to placebo or other antihypertensive agents [15]. However, most of these effects were attributed to only three trials which used a head-to-head comparison between these two types of agents [15].…”

“…A previous pair-wise meta-analysis including nine trials, conducted in non-dialysis diabetic patients (n = 9797 participants) with CKD stages 3-5, found that RAAS-blocking agents could lower the risk of renal replacement therapy/doubling of serum creatinine, but had no beneficial effect on all-cause mortality and cardiovascular mortality events compared to placebo or other antihypertensive agents [15]. However, most of these effects were attributed to only three trials which used a head-to-head comparison between these two types of agents [15]. According to our subgroup analyses for patients with diabetes, only ARBs had significant superiority over placebo in preventing the occurrence of kidney events, ranking in the top position with highest SUCRA probability.…”

American Indian chronic Renal insufficiency cohort study (AI-CRIC study)

“…Many previous studies demonstrated the relationship between diabetes, obesity, and hypertension in persons with chronic kidney disease. RAASI treatment correlates with subsequent reduction in the rate of ESKD [49,50]. The prevalence of hypertension in CKD varies by race, etiology of CKD and GFR [5].…”

Assessment of the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in peritoneal dialysis patients: a systematic review and meta-analysis on clinical trials

“…Most nephrologists prescribe ACEIs and ARBs to preserve renal function in early-stage CKD patients [28]. Several meta-analyses [8,29] and RCTs [7,[30][31][32][33][34][35] have reported that ACEIs and ARBs have beneficial effects on the total mortality and the progression to ESKD regardless of the CKD stage and the presence of diabetes. However, recent studies [36,37] revealed that increased creatinine or decreased GFR after the initiation of RASIs correlated with worse renal outcome in predialysis CKD patients.…”