Genetic Markers Could Help Identify Hospital Patients at Risk for AKI

/kidneynews/6_12/1/graphic/1f1.jpg

Researchers have isolated several genetic markers that could help identify individuals at risk for acute kidney injury (AKI) in the hospital setting (1). Results from the study presented at ASN Kidney Week 2014 in Philadelphia, PA, offer new clues about the pathogenesis of AKI. The findings could eventually lead to potential therapeutic interventions to help prevent kidney failure and premature death in thousands of patients who undergo cardiovascular surgery or other hospital interventions each year. Currently, AKI affects one in five hospitalized patients worldwide.

Collaborators from Yale University, Vanderbilt University, and the University of Western Ontario wanted to determine if they could identify patients who may have a higher genetic risk for developing AKI in the hospital. Doing so could uncover novel pathways that could be targeted for therapeutic interventions, said senior author Chirag R. Parikh, MD, PhD, FASN of Yale.

Investigators in this multicenter study weren’t alone in their clinical suspicion that some individuals could have a genetic predisposition for developing AKI in the hospital setting. “What is clear is that patients of similar age and health status can have drastically different kidney outcomes after a potential insult like cardiopulmonary bypass surgery,” said Benjamin Humphreys, MD, PhD, FASN, of Brigham and Women’s Hospital and Director of the Harvard Stem Cell Institute Kidney Group in Boston. “Many patients do just fine, but others develop AKI. The absence of obvious clinical factors to explain these divergent outcomes suggests a role for genetic predisposition.”

Until recently, analysis methods limited the scope of genetic AKI studies. “The putative genetic components of AKI have until recent years been mainly investigated by hypothesis-driven research (of candidate genes),” Parikh said. “But technological progress in genotyping has opened the possibilities toward hypothesis-generating genomic screens and novel opportunities to explore polygenetic perspectives, now spanning a wide array of possible analyses falling under the term Genome-Wide Association Study (GWAS).”

With GWAS scientists can analyze genetic variants in multiple individuals to determine if a disease or trait is linked to any single-nucleotide polymorphisms (SNPs). The method has been utilized to investigate numerous disease conditions from chronic kidney disease to cardiovascular disease to cancer. According to Parikh, it provides an excellent approach to discover genetic factors in a population because of the high number of recombinant events the population represents.

Using GWAS methods, the investigators analyzed data from patients at risk for AKI in the hospital setting—760 adults with AKI and 669 adult controls who underwent surgery or received care in the intensive care unit (ICU)—to determine if any SNPs were associated with the development of AKI. The study population was selected from the surgical ICU (TRIBE-AKI study) and the medical ICU (VALID ICU cohort). AKI was defined as a rise in creatinine of 0.3 mg/dL or 50 percent from baseline for at least two days.

After genotyping a total of 992,895 SNPs, the researchers identified six clusters of three or more SNPs on six different chromosomes that are associated with a patient’s risk of developing AKI. Among these clusters, four (SOX2-OT, IL33, RAB20, and TAOK1) are intronic (not coding information for protein synthesis) and the remaining 2 are intergenic (involving more than one gene). “All six SNP clusters are protective against AKI, with odds ratios ranging from 0.55 to 0.72,” said Parikh.

Brigham and Women’s Humphreys found the results very intriguing and noted that they could certainly lead to a better understanding of AKI pathophysiology. “Most of the SNP clusters identified appear to protect against AKI,” he said. “Understanding how certain gene variants confer renal protection could lead to new therapeutic strategies as well as new risk prediction tools.”

“AKI is a heterogeneous disease and genetic studies need to be continued to fully capture the host risk,” Dr. Parikh emphasized. “It is recommended that sequencing can be used as a complement to GWAS, to obtain a better map of the genetic variants in GWAS-significant genes or well-established candidate genes.”

Although it was a relatively small study by GWAS standards, the results are promising, Humphreys said. “They clearly call for a much larger analysis to rigorously evaluate the association of these candidate SNPs with risk of AKI.”

Parikh agreed, adding that “further collaborative research is required utilizing larger cohorts to confirm these findings and identify candidate genes that are mechanistically linked to pathogenesis of AKI.”

This study was supported by the National Institutes of Health R01HL085757 and P30 DK079310 O’Brien Kidney Center Grant.

Reference

1. 

Zhao B, et al. Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Conferring Risk for Acute Kidney Injury. J Am Soc Nephrol 25 (Suppl); 2014:7A.