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New Drug developed to counter kidney disease
Changes to a key protein amplified its natural ability to counter kidney disease, according to a study published today by researchers at UAB in the journal Nature Medicine.
When healthy, the kidneys filter blood, divert waste into urine and return useful proteins to the bloodstream.
Diabetes, high blood pressure and cancer damage the kidneys; but nothing hastens kidney failure like proteinuria, where proteins get past damaged filters, enter the urine and cause scarring in the tubules carrying it.
In the current study, researchers demonstrated for the first time that the body tries to counter proteinuria by making more of a protein called Angiopoietin-like 4 or Angptl4, but that a second pathway interferes.
Specifically, Angptl4 takes part in two competing feedback loops: one in which worsening proteinuria triggers greater Angptl4 production, and a second where rising Angptl4 levels soon shut down Angptl4 production.
The second loop restrains the first, which may explain why people with severe proteinuria make just three times as much Angptl4 as people with healthy kidneys, instead of 30 times as much.
Based on their new understanding, the team engineered a version of Angptl4 that still counters proteinuria, but can no longer engage the pathway where it slows its own production.
When injected into rats bred to serve as models of human kidney diseases, the mutant protein, freed of its normal constraints, reduced proteinuria by 60 percent.
“We’re making progress toward the first evidence-based therapy designed specifically for a major category of kidney disease,” said Sumant Singh Chugh, M.D., director of the UAB Glomerular Disease Therapeutics Laboratory and corresponding author of the study.
“If successful, it would improve many lives and hopefully raise awareness that kidney disease is underway in 26 million Americans.”
In 2010, kidney failure caused 91,000 deaths, with another 179,000 people living with kidney transplants and 415,000 more on dialysis.
Nearly 10 times as many patients are now treated for kidney failure as were in 1980, with the “silence” surrounding the epidemic explained by the disease’s lack of symptoms until severe and the inability of available drugs to prevent kidney failure. There is also currently no treatment designed to counter proteinuria.
A thin cross section of a kidney biopsy from a patient with collapsing glomerulopathy, a damaging version of the rare, genetic disease called focal segmental glomerulosclerosis that drives kidney failure. Capillaries in the kidneys of these patients collapse, setting blood proteins free that cause scarring in the surrounding tissue.
“All classes of drugs used to treat kidney disease today — from high blood pressure meds to steroids — were developed decades ago for use against other diseases, with some actually toxic to the kidneys, because we have nothing better,” said Chugh, also a professor in the Division of Nephrology within the Department of Medicine, part of the UAB School of Medicine. “Our lab is focused on preventing damage to the blood-filtering clusters of capillaries called glomeruli that causes proteinuria in many patients.”
UAB News Service