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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 ?g/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.

SUBMITTER: Palevsky PM

PROVIDER: S-EPMC5108193 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Palevsky Paul M PM Zhang Jane H JH Seliger Stephen L SL Emanuele Nicholas N Fried Linda F LF

Clinical journal of the American Society of Nephrology : CJASN 20160927 11

<h4>Background and objectives</h4>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.<h4>Design, setting, participants, & measurements</h4>In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care w ...[more]

PMID: 27679519

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Project description:Background and objectivesHow to best medically manage patients who survived hospitalized AKI is unclear. Use of renin-angiotensin system blockers in this setting may increase risk of recurrent AKI.Design, setting, participants, & measurementsThis is a cohort study of 10,242 members of an integrated health care delivery system in Northern California who experienced AKI and survived a hospitalization between January 1, 2006 and December 31, 2013. All study participants did not have prior heart failure or use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) up to 5 years prior. New receipt and time-updated exposure of ACE-Is/ARBs was identified on the basis of dispensed prescriptions found in outpatient health plan pharmacy databases. The main outcome of interest was subsequent episode of hospitalized AKI after discharge from an initial index hospitalization complicated by AKI. Recurrent AKI episode was defined using acute changes in serum creatinine concentrations. Marginal structural models were used to adjust for baseline and potential time-dependent confounders.ResultsForty-seven percent of the study population had a documented eGFR<60 ml/min per 1.73 m2 or documented proteinuria before hospitalization. With a median of 3 (interquartile range, 1-5) years of follow-up, 1853 (18%) patients initiated use of ACE-Is/ARBs and 2124 (21%) patients experienced recurrent AKI. Crude rate of recurrent AKI was 6.1 (95% confidence interval [95% CI], 5.9 to 6.4) per 100 person-years off ACE-Is/ARBs and 5.7 (95% CI, 4.9 to 6.5) per 100 person-years on ACE-Is/ARBs. In marginal structural causal inference models that adjusted for baseline and potential time-dependent confounders, exposure to ACE-I/ARB use was not associated with higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.12).ConclusionsIn this study of AKI survivors without heart failure, new use of ACE-I/ARB therapy was not independently associated with increased risk of recurrent hospitalized AKI.

Project description:ObjectiveTo compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy.DesignSystematic review and meta-analysis.Data sourcesPubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012.Study selectionRandomised controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long term efficacy (≥ 1 year) or safety events (≥ 4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure.Results33 randomised controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79).ConclusionAlthough dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.

Project description:BackgroundPrognostic biomarkers that predict the severity of AKI at an early time point are needed. Urinary angiotensinogen was recently identified as a prognostic AKI biomarker. The study hypothesis is that urinary renin could also predict AKI severity and that in combination angiotensinogen and renin would be a strong predictor of prognosis at the time of AKI diagnosis.Design, setting, participants, & measurementsIn this multicenter, retrospective cohort study, urine was obtained from 204 patients who developed AKI after cardiac surgery from August 2008 to June 1, 2012. All patients were classified as having Acute Kidney Injury Network (AKIN) stage 1 disease by serum creatinine criteria at the time of sample collection. Urine output was not used for staging. Urinary angiotensinogen and renin were measured, and the area under the receiver-operating characteristic curve (AUC) was used to test for prediction of progression to AKIN stage 3 or in-hospital 30-day mortality. These biomarkers were added stepwise to a clinical model, and improvement in prognostic predictive performance was evaluated by category free net reclassification improvement (cfNRI) and chi-squared automatic interaction detection (CHAID).ResultsBoth the urinary angiotensinogen-to-creatinine ratio (uAnCR; AUC, 0.75; 95% confidence interval [CI], 0.65 to 0.85) and the urinary renin-to-creatinine ratio (uRenCR; AUC, 0.70; 95% CI, 0.57 to 0.83) predicted AKIN stage 3 or death. Addition of uAnCR to a clinical model substantially improved prediction of the outcome (AUC, 0.85; cfNRI, 0.673), augmenting sensitivity and specificity. Further addition of uRenCR increased the sensitivity of the model (cfNRI(events), 0.44). CHAID produced a highly accurate model (AUC, 0.91) and identified the combination of uAnCR >337.89 ng/mg and uRenCR >893.41 pg/mg as the strongest predictors (positive predictive value, 80.4%; negative predictive value, 90.7%; accuracy, 90.2%).ConclusionThe combination of urinary angiotensinogen and renin predicts progression to very severe disease in patients with early AKI after cardiac surgery.

Dataset Information

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

Publications

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

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