A surprising source for a kidney disease. A new CUMC study suggests antibodies generated in response to gut inflammation travel to the kidney (in photo) where they cause a common kidney disease. Image: Ali Gharavi.
IgA nephropathy occurs when IgA antibodies—which normally help the body fight infection—lodge in the kidney’s tiny filtering units, where they cause inflammation and scarring. Over time, the kidney malfunctions, and more than 20 percent of patients eventually experience kidney failure and require a transplant.
But why the antibodies accrue in the kidney, and where they come from, were not well understood.
To learn more, Drs. Kiryluk and Gharavi, in collaboration with Richard Lifton, MD, PhD, of Yale, enrolled more than 35 medical centers worldwide to search the genomes of 20,000 individuals for genetic risk factors for IgA nephropathy. The search uncovered 15 regions of the genome associated with the disease, and surprisingly, all of the regions were associated with the intestine.
“This study really changes our perspective on IgA nephropathy,” says Dr. Gharavi, who is a professor of medicine at Columbia University College of Physicians & Surgeons and chief of nephrology at NewYork-Presbyterian/Columbia University Medical Center.
“This suggests that IgA nephropathy is an inflammatory disease involving, or perhaps initiated in, the intestine.
“Each one of the 15 genetic susceptibility regions we identified harbors a gene that is involved in the maintenance or protection of the mucosal lining of the intestine,” he says. “This suggests that IgA nephropathy is an inflammatory disease involving, or perhaps initiated in, the intestine. It’s not simply an intrinsic disease of the kidney.”
Dr. Gharavi says treatment strategies for the disease may be found in current treatments for inflammatory bowel disease, which shares some genetic risk factors with IgA nephropathy, or may be developed by targeting the genetic risk factors identified in the study.
“This study also explains why IgA nephropathy is more common in Asian and Asian-American populations than in people of European or African descent,” says Dr. Kiryluk, assistant professor of medicine (nephrology) and the study’s first author.
“We noticed that the frequency of the 15 genetic risk factors mirrored the worldwide distribution of the disease. The genetic risk factors were more common in Asian populations, which have the highest incidence of the disease, and least common in African populations, which have the lowest incidence. In fact, some genetic risk factors are so common in Asian populations that they are “fixed,” or present in every person.”
The observed geographic pattern suggested that the genes that increase the risk of developing IgA nephropathy might also be beneficial in some way. So Dr. Gharavi and his colleagues compared the distribution of various environmental factors with the frequency of the genetic risk factors.
The strongest correlation was with the diversity of parasitic worms (called helminthes), which often infest the intestine. This strongly suggests that the genetic risk factors common in Asian populations may represent protective adaptations against intestinal worm infestations.
“Because they are protective against worms, they were enriched in populations in East Asia, where we know helminth infections are particularly common and still are a significant cause of infant mortality,” Dr. Gharavi says.
“Connecting the disease with a pathogen is very helpful. Now we can go back and look at the pathways that fight intestinal worm infection to see if we can find ways to fight IgA nephropathy.”
The findings were published online Oct. 12 in Nature Genetics.
This study and its researchers were supported by the NIH (R01DK082753, R01DK095510, K23DK090207, R03DK099564, R21DK098531); the Center for Glomerular Diseases at Columbia University; the Howard Hughes Medical Institute; the American Society of Nephrology; the American Heart Association (13GRNT14680075); the joint Italian Ministry of Health and NIH “Ricerca Finalizzata”; Fondazione Malattie Renali nel Bambino; and InterOmics (PB05 MIUR-CNR Italian Flagship Project).
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