Drug Class Combination–Associated Acute Kidney Injury

Objective: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). Data Sources: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication)." Study Selection and Data Extraction: Inclusion criteria were the following: English language, full-text availability, and at least I drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. Data Synthesis: Out of 1952 total citations, 144 were assessed for full-text review with 118 citations (6%) meeting final inclusion criteria. The selected citations produced 117 drug-drug combinations, with 74 unique drug class combinations. Overall, 56 combinations (75.7%) were considered very low quality. Eleven combinations (14.9%) were considered low quality. There were seven (9.5%) combinations of moderate quality, while no combination was considered high quality. The three most frequently evaluated drug classes were calcineurin inhibitors, statins, and non-steroidal anti-inflammatory drugs (NSAIDs). The combination of NSAIDs and diuretics (moderate quality) was reported in 10 citations, including a randomized control trial demonstrating a 12.4 fold increased rate of AKI in the combination group. Conclusions: Our study demonstrates a lack of well-designed studies addressing drug class combination associated AKI. The combination of non-steroidal anti-inflammatory drugs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest grade level and overall quality of evidence. Despite its limitations, this review highlights the effects of combining nephrotoxic drug classes, and the clinician should evaluate for less nephrotoxic therapeutic alternatives.