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Research Shows Hypertension-Associated Kidney Disease May Be Misnamed

WINSTON-SALEM, N.C. – Doctors have long believed that high blood pressure directly caused kidney damage. However, new research out of Wake Forest University Baptist Medical Center suggests that it may be the other way around, with kidney impairment generating high blood pressure in many patients.

The discovery of a kidney failure gene suggests that “hypertension-associated kidney disease” may be an outdated term, said Barry I. Freedman, M.D., in articles published recently in Kidney International and the American Journal of Nephrology. Freedman is the John H. Felts III Professor and Chief of the Section on Nephrology at Wake Forest Baptist, which is ranked among the nation’s top 50 services for kidney disease by U.S. News & World Report.

Freedman’s research team, along with colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), the National Cancer Institute (NCI), and the NIDDK-sponsored Family Investigation of Nephropathy and Diabetes (FIND) Study, contributed to the identification of the MYH9 gene underlying several common forms of kidney failure in African-Americans. This significant genetic discovery was first announced in September 2008 by the NIDDK and the NIH. Freedman’s work extended the genetic association to include hypertension-associated end-stage renal disease (ESRD), the second most common reported cause of ESRD in the U.S. His research team previously had identified strong familial clustering of hypertension-associated kidney disease and suggested the existence of a kidney failure gene.

“Identifying the MYH9 gene was an important breakthrough in our understanding of factors initiating kidney disease,” said Thomas D. DuBose, M.D., Tinsley Harrison Professor and Chair of the Department of Internal Medicine at Wake Forest University School of Medicine. “Since ESRD affects African-Americans disproportionally compared to Caucasian Americans, there is hope that genetic screening for MYH9 in high-risk populations will help identify individuals at risk for chronic kidney disease and lead to the discovery of biomarkers of chronic kidney disease that may signify risk at earlier stages. Such knowledge would allow initiation of protective therapy to slow progression of kidney disease or possibly protect from development of kidney disease.”

Variants in the MYH9 gene contribute to approximately 70 percent of non-diabetic kidney disease in African-Americans, said Freedman. These new data strongly suggest that hypertension (high blood pressure) may be the result of a primary kidney disease, not the cause of the kidney disease. Nephrologists agree that elevated systemic blood pressure worsens all forms of chronic kidney disease and speeds progression toward end-stage kidney disease with the need for dialysis. However, the evidence suggesting that mild to moderate hypertension directly causes kidney damage is weaker, said Freedman. Relatively few African-Americans or European Americans with high blood pressure and initially normal kidney function will develop progressive kidney disease.

Nearly 30 percent of Americans who begin renal replacement therapy – dialysis – are considered to have hypertensive nephrosclerosis, but this is a vague diagnosis, Freedman said. Nephrosclerosis is a kidney disorder in which the kidney’s small arteries and arterioles are damaged. The diagnosis is most commonly applied to African-Americans with hypertension and kidney disease in the absence of other causes of kidney failure, such as diabetes.

Compared to European Americans, African-Americans who live in the southeastern United States have up to 20-fold greater risk for developing ESRD attributed to hypertension. The increased frequency and severity of high blood pressure in African-Americans do not fully account for their excess rates of hypertensive kidney failure. Importantly, lowering blood pressure to usual or lower levels does not seem to slow the progression of kidney disease in hypertensive African-Americans. Despite this and other evidence, the concept that hypertension frequently causes kidney disease has stuck – until now.

“With this new genetic finding, we can look at this disease in a different light,” said Freedman. “A major susceptibility gene associated with a structural unit in the kidney has been identified and associated with kidney failure in African-Americans labeled as having hypertension-associated kidney failure. It is clear that environmental factors are also required to initiate kidney disease, since not all individuals carrying the risk versions of the MYH9 gene develop kidney failure. It is likely that studying MYH9 gene variants will lead us toward new diagnostic tests to allow pre-symptomatic detection of high-risk individuals and suggest novel strategies to preserve renal function.”

Freedman participated in a group press conference about the discovery of this gene variant and its applications held at the American Society of Nephrology (ASN) meeting in Philadelphia. Co-researchers on the study were Carl Langefeld, Ph.D., Jasmin Divers, Ph.D., and Donald Bowden, Ph.D., of Wake Forest. These results will be featured on the Kidney International website with an upcoming podcast.

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Media Relations Contacts: Annette Porter, aporter@wfubmc.edu, (336) 716-2416; or Bonnie Davis, bdavis@wfubmc.edu.

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