To RAS or Not to RAS ? The Evidence for and Cautions with Renin‐Angiotensin System Inhibition in Patients with Diabetic Kidney Disease

Substantial morbidity, mortality, and costs are associated with progressive diabetic kidney disease (DKD). A goal of Healthy People 2020 is to reduce kidney disease attributable to diabetes mellitus and increase the proportion of patients who receive agents that interrupt the renin-angiotensin system (RAS), such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). The mechanisms that contribute to progressive loss of kidney function in patients with diabetes are disrupted by inhibition of the RAS. ACEIs, ARBs and direct renin inhibitors (DRIs) all reduce the effect of angiotensin II, yet each works through a different mechanism and displays properties that may or may not be replicated by the others. As single agents, RAS inhibitors and blockers have been shown to slow the rate of progression of DKD and to reduce new cases of end-stage renal disease in various subsets of patients with diabetes and proteinuria (e.g., albuminuria). However, even with contemporary use of ACEIs, ARBs, and, more recently, DRIs, the burden of kidney disease remains high. Thus investigators sought to explore the utility of combining agents (e.g., dual RAS therapy) in various regimens for cardiovascular and kidney end points. Recent data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) studies suggest that kidney-related outcomes (composite of dialysis initiation, doubling serum creatinine concentration, or death) were increased with ACEI plus ARB or DRI plus ARB combinations. Consequently, dual therapy should not be routinely prescribed in patients with diabetes until further data become available from other future studies. This review provides an introduction to DKD and a rationale for using RAS inhibition; discusses screening, detection, and monitoring of patients with DKD; and summarizes results from meta-analyses and critical reviews and from recent large randomized controlled studies published since the meta-analyses or reviews. Finally, we suggest a clinical approach for using RAS agents in patients with DKD.