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Kidney Disease

New Therapeutic Strategy in Chronic Kidney Disease

Chronic kidney disease (CKD) affects at least one in four Americans who are older than 60 and can significantly shorten lifespan. Yet the few available drugs for CKD can only modestly delay the disease’s progress towards kidney failure. Now, however, a team led by researchers at the Perelman School of Medicine at the University of Pennsylvania has found an aspect of CKD’s development that points to a promising new therapeutic strategy.

A release from the university quotes says Katalin Susztak, MD, PhD, an associate professor of Medicine in the Renal Electrolyte and Hypertension Division, as saying, “We found that a defect in energy production in affected kidney cells plays a key role in CKD development. Restoring the energy supply in these cells largely prevented signs of CKD in mouse models.”

In the study, published online in December 2014 advance of the print edition of “Nature Medicine”, Susztak and colleagues focused on a central feature of CKD: the “fibrosis” process. This is a pathological response to chronic kidney stress that includes an abnormal buildup of fibrous collagen, a loss of capillaries, a die-off of important kidney cells called tubular epithelial cells, and other changes that progressively reduce a kidney’s ability to filter the blood properly.

The researchers compared the patterns of gene activity in fibrotic and normal human kidney tissue samples. They found abnormal patterns in gene networks linked to inflammation and sharp drops in activity in gene networks that support energy metabolism in the fibrotic samples.

The fact that inflammation is a factor in CKD was already well known, so Susztak and her colleagues aimed their investigation at two types of energy metabolism—glucose oxidation and fatty acid oxidation — that seemed markedly reduced in the fibrotic samples.

“What we found is that the tubular epithelial cells preferentially use fatty acid oxidation as their energy source in normal conditions,” Susztak says. “Even when fatty acid metabolism drops in the context of CKD, these cells don’t switch to burning glucose for energy.”

Susztak’s team examined several mouse models of kidney fibrosis, and again found strikingly lower activity in genes that support fatty acid metabolism. The researchers also found strong hints that the loss of cellular fuel is a driver of the fibrosis process. In mouse models, the drop in fatty acid metabolism preceded the signs of fibrosis. In human tubular epithelial cells, artificially reducing fatty acid metabolism quickly brought about fibrosis-like signs, including the buildup of fat molecules (unspent fuel) and the deaths of many affected cells.

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