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Searching for Genes That Matter in Acute Kidney Injury: A Systematic Review

Jonathan C. T. Lu^*, Steven G. Coca^*,, Uptal D. Patel, Lloyd Cantley^*, Chirag R. Parikh^*,; for the Translational Research Investigating Biomarkers and Endpoints for Acute Kidney Injury (TRIBE-AKI) Consortium

^* Yale University School of Medicine, New Haven, Connecticut; Clinical Epidemiology Research Center, VA Medical Center, West Haven, Connecticut; Duke University School of Medicine, Durham, North Carolina

Correspondence: Dr. Chirag Parikh, Section of Nephrology, Yale University and VAMC, 950 Campbell Avenue, Mail Code 151B, Building 35 A, Room 219, West Haven, Court 06516. Phone: 203-932-5711 Ext. 4300; Fax: 203-937-4932; E-mail: Chirag.parikh{at}yale.edu

Background and Objectives: Identifying patients who may develop acute kidney injury (AKI) remains challenging, as clinical determinants explain only a portion of individual risk. Another factor that likely affects risk is intrinsic genetic variability. Therefore, a systematic review of studies was performed that related the development or prognosis of AKI to genetic variation.

Design, setting, participants, and measurements: MEDLINE, EMBASE, HuGEnet, SCOPUS, and Web of Science were searched for articles from 1950 to Dec 2007. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality via an aggregate scoring system.

Results: The 16 included studies were of cohort or case-cohort design and investigated 35 polymorphisms in 21 genes in association with AKI. Fifteen gene-gene interactions were also investigated in four separate studies. Study populations were primarily premature infants or adults who were critically ill or postcardiac bypass patients. Among the studies, five different definitions of AKI were used. Only one polymorphism, APO E e2/e3/e4, had greater than one study showing a significant impact (P < 0.05) on AKI incidence. The mean quality score of 5.8/10 (range four to nine), heterogeneity in the studies, and the dearth of studies precluded additional meta-analysis of the results.

Conclusions: Current association studies are unable to provide definitive evidence linking genetic variation to AKI. Future success will require a narrow consensus definition of AKI, rigorous epidemiologic techniques, and a shift from a priori hypothesis-driven to genome-wide association studies.