Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade

Abstract

Background and objectives: The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI.

Design, setting, participants, & measurements: In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m², and urinary albumin excretion of at least 300 μg/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events.

Results: The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98).

Conclusions: Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Keywords: Albumins; Ambulatory Care; Arm; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Lisinopril; Losartan; Nephrons; Renin-Angiotensin System; Veterans; acute kidney injury; angiotensin converting enzyme inhibitor; angiotensin receptor blocker; chronic kidney disease; creatinine; diabetes mellitus; diabetic nephropathy; glomerular filtration rate; proteinuria; renin angiotensin system; risk factors.

Figure 1.

Kaplan–Meier plots of the cumulative percentage of patients with an initial episode of AKI. The primary study end point was the first occurrence of change in the eGFR (a decline of ≥30 ml/min per 1.73 m² body surface area if the initial eGFR was ≥60 ml/min per 1.73 m² or a decline of ≥50% baseline eGFR if the baseline eGFR was <60 ml/min per 1.73 m²), ESRD, or death. P value was calculated using a stratified log rank test. 95% CI, 95% confidence interval.

Figure 2.

Kaplan–Meier plots of the cumulative percentage of patients developing the primary study end point (Prim Endpt) of death, end-stage renal disease or decline in eGFR after the initial episode of AKI. P value was calculated using a stratified log rank test. 95% CI, 95% confidence interval.