Discovery could lead to much-needed kidney failure treatment

The unwanted activation of an important cell-signaling pathway may play a role in two kidney problems that are major causes of end-stage renal disease, scientists at the Albert Einstein College of Medicine of Yeshiva University have found. Their research, which opens up a novel approach for treating kidney failure, is described in the March issue of Nature Medicine. The study was led by Dr. Katalin Susztak, an assistant professor of medicine (nephrology) at Einstein.

The kidneys filter waste products from the blood and maintain the body’s fluid balance by producing urine. The filtration is carried out by numerous capillary tufts within the kidney known as glomeruli. Kidney disease occurs when glomeruli become damaged and can no longer perform their filtering function. Kidney damage may ultimately progress to end-stage renal disease, in which patients need dialysis or a kidney transplant.

The Einstein scientists focused on cells known as podocytes that line the glomeruli. Since dysfunction of podocytes cells is important in progressive kidney disease, and since a cell-signaling pathway called Notch is crucial in podocyte development, the Einstein researchers reasoned that aberrant Notch signaling might play a role in causing kidney disease.

The Notch signaling pathway plays a key role in embryonic development of humans and most other multicellular organisms. The Notch pathway tells some cells to proliferate and others to undergo programmed cell death as it profoundly affects the way tissues are organized. Faulty Notch signaling has been found in several types of cancer and in many other diseases such as multiple sclerosis.

Collectively, the observations made in the Einstein study offer strong evidence that aberrant Notch signaling is also involved in diabetic nephropathy (DNP) and focal segmental glomerulosclerosis (FSGS)—two of the major causes of end-stage renal disease. For example:

-- When comparing biopsy samples from healthy kidneys and kidneys from people with DNP and FSGS, the researchers found evidence that the Notch pathway was active in diseased but not in healthy kidneys.

-- The researchers bred a strain of mice in which they could specifically activate the Notch pathway within podocytes. Examination revealed that the podocytes in these mice underwent programmed cell death, and the mice themselves died from end-stage renal failure.

-- After inducing glomerular disease in mice by injecting them with a toxic chemical, the researchers were able to protect the rats from developing kidney disease by injecting them with a gamma secretase inhibitor—one of a class of compounds known to “shut off” the Notch pathway.

“An exciting aspect of this new work is the therapeutic implications,” according to a Nature Medicine commentary on the Einstein study written by kidney experts from the University of Michigan Medical Center. The experts noted that gamma secretase inhibitors, like the one that protected the mice from kidney disease in this study, are already in phase 1 and 2 clinical trials for treating diseases including Alzheimer’s and leukemia. The Einstein findings, they wrote, “provide some hope that researchers in the field of kidney disease can reverse the grim record of the last 20 years — during which no new therapeutic agent has been successfully implemented” for treating end-stage kidney disease.

Source: Albert Einstein College of Medicine

Related stories:

Researchers unravel key mechanism of cellular damage in aging and disease
Researchers have taken a first snapshot of how a class of highly reactive molecules inflicts cellular damage as part of aging, heart disease, stroke, cancer, diabetes, kidney disease and Alzheimer's disease to name a few. According to a study published today in the journal Cell, researchers have discovered a tool that can monitor related damage and determine the degree to which antioxidant drugs effectively combat disease.
'Statins' linked to improved survival in kidney transplant recipients
For patients receiving kidney transplants, treatment with cholesterol-lowering "statin" drugs may lead to longer survival, reports a study in the November 2008 Journal of the American Society of Nephrology (JASN).
Donor kidneys removed with single bellybutton cut
(AP) -- Brad Kaster donated a kidney to his father this week, and he barely has a scar to show for it. The kidney was removed through a single incision in his bellybutton, a surgical procedure Cleveland Clinic doctors say will reduce recovery time and leave almost no scarring.
Drug lowers body's 'set point' to control hyperparathyroidism in dialysis patients
A medication called cinacalcet—an important part of treatment to control high levels of parathyroid hormone (PTH) in patients receiving dialysis for end-stage renal disease (ESRD)—works by resetting the balance between calcium and PTH levels, according to a study in the November Journal of the American Society of Nephrology (JASN).
Combating urinary schistosomiasis: Both metrifonate and praziquantel can be used
In 2000 the World Health Organization (WHO) stopped recommending metrifonate for treating urinary schistosomiasis because the drug did not appear to be as effective as the treatment of choice, praziquantel. Now a systematic review published in the latest edition of The Cochrane Library indicates that both metrifonate and praziquantel are effective at treating the infection. The team of researchers who carried out this study suggest that metrifonate may be a valid addition to the current one-drug strategy against urinary schistosomiasis.
Turning on hormone tap could aid osteoporosis fight
A potential new drug that 'opens the taps' for the release of useful hormones could stimulate new bone growth – and may eventually bring relief to osteoporosis sufferers.
E. coli linked to beef now reported in 5 states
(AP) -- An E. coli outbreak traced to recalled beef in Michigan and Ohio has spawned cases in three other states, U.S. health officials said Tuesday.
More kidney stone disease projected due to global warming
Global warming is likely to increase the proportion of the population affected by kidney stones by expanding the higher-risk region known as the "kidney-stone belt" into neighboring states, researchers at UT Southwestern Medical Center and UT Dallas have found.

News discussion:

Medicine & Health news