Researchers conducted a literature review to assess current evidence of drug class combinations and their association with the development of acute kidney injury (AKI). The full findings are published in the Annals of Pharmacotherapy .

The team searched MEDLINE and Embase databases for citations with at least 1 drug-combination. Each study was evaluated according to the GRADE criteria. No standardized definition of AKI was used. A total of 151 citations were evaluated for full-text review, with 121 citations meeting the inclusion criteria. Of the 76 unique drug class combinations identified, 56 were considered very low quality, 12 were considered low quality, 8 were of moderate quality, and none were considered high quality. 

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) + diuretics was noted in the most citations (n=10). Furosemide was the most commonly evaluated diuretic; indomethacin was the most commonly evaluated NSAID. The data showed a 1.24-fold increase in AKI, with serum creatinine >1.6mg/dL in the furosemide group. 

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The combination of NSAIDs, diuretics, and renin-angiotensin system (RAAS) agents was cited in 6 studies. The data showed a 31% higher rate of AKI in patients receiving triple therapy vs diuretic therapy only. 

The combination of statins and macrolides was cited in 3 studies. The evaluated drugs included atorvastatin, simvastatin, or lovastatin compared in combination with either clarithromycin/erythromycin (CYP3A4 inhibitors) or azithromycin. The data showed a 1.78 relative risk for AKI, with and increase in serum creatinine of 1.11 mg/dL in patients in the CYP3A4 inhibitors group.

Other evaluated combinations and relative risk values (if applicable) were: calcium channel blockers + clarithromycin (odds ratio 0.98); eplerenone + loop diuretics (renal function decline in the eplerenone group); gentamicin + polygeline 3.5% (2.5-fold increase in relative risk with dual therapy); vancomycin + piperacillin/tazobactam (2.5-fold more likely); statins + calcium channel blockers (odds ratio 1.94); gentamicin + cephalosporins; NSAID + RAAS agents; statins + fenofibrates; simvastatin + cyclosporine; methotrexate + NSAIDs; cyclosporine + ciprofloxacin (4-fold rise in serum creatinine); and diuretics + RAAS agents.

The study highlights a lack of well-designed studies addressing drug class combination-associated AKI. NSAIDs + diuretics with or without additional renin-angiotensin aldosterone agents demonstrated the strongest level of evidence. Findings from this review may lead to “additional scrutiny about combining certain individual nephrotoxic drugs and stresses the need to further investigate drug combinations associated with AKI,” the authors concluded.

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1. Rivosecchi RM, Kellum JA, Dasta JF, et al. Drug Class Combination–Associated Acute Kidney Injury. Ann Pharmacother 2016 Jul 7. doi:10.1177/1060028016657839. [Epub ahead of print]

This article originally appeared on MPR