Research Updates in Kidney and Urologic Health

Major Breakthroughs in Understanding the Molecular Basis of Kidney Disease: Surprises from Mice and Worms

Kidney research has made scientific headlines in the past few months. Three breakthroughs have emerged from studies in genetically modified mice and in the C. elegans roundworm. All three cases held surprises for investigators of kidney disease.

In one study reported in the September 1999 Nature Medicine, scientists at the National Institute of Child Health and Human Development (NICHD), the National Cancer Institute, and Baylor College of Medicine developed a mouse strain lacking the gene for a substance known as uteroglobin.

Unexpectedly, the team found that the kidneys of the genetically altered mice were malfunctioning because of deposits within the glomeruli, the kidneys' filtering apparatus. The researchers reported that the kidney problem closely mimicked a human kidney disease. "This mouse model matches the human form of IgA nephropathy very closely," said NICHD Director Duane Alexander. "It has provided us with very specific strategies for possibly determining the cause of the human condition and ultimately designing a treatment for it."

The investigators found that injecting IgA into uteroglobin-deficient mice caused abnormal deposition of IgA, fibronectin, and collagen in the animals' glomeruli, mirroring what occurs in the human disease. However, animals injected with IgA mixed with uteroglobin remained disease-free. "These results indicate that one of the essential functions of uteroglobin is to prevent abnormal IgA deposition and, consequently, IgA nephropathy in mice," said the study's senior author, Anil B. Mukherjee of NICHD. Dr. Mukherjee and collaborators next plan to compare uteroglobin levels in people who have IgA nephropathy with people who do not have the disease. If uteroglobin is found to be abnormally low in people with IgA nephropathy, treatment might involve uteroglobin supplementation.

Although encouraging, the animal research findings must be confirmed in humans. At times, animal models for disease appear promising but are later found to differ from the human conditions they were designed to imitate.

A second breakthrough, again using genetically altered mice, comes from studies of the molecule CD2AP, previously identified as critical for immune function in T cells. A team at Washington University led by Andrey Shaw created a mouse deficient in CD2AP. The researchers reported in the October 8, 1999, issue of Science that the mice had massively compromised kidney function. Further studies established that the kidney problem in the mice was very similar to congenital nephrotic syndrome, a rare human disease in which infants lose massive amounts of protein through the urine and require kidney transplantation. Last year a team of NIDDK-funded investigators led by Karl Tryggvason of the Karolinska Institute in Stockholm, Sweden, identified the gene that causes congenital nephrotic syndrome. Dubbed nephrin, the gene appears to interact with CD2AP to form critical components of the kidney filter.

The third breakthrough comes from an even more unexpected source. Studies of mutations that cause defective mating behavior in the C. elegans roundworm have helped clarify the function of polycystin, the gene product responsible for polycystic kidney disease (PKD). Described in the September 23, 1999, issue of Nature, a protein in C. elegans called lov-1 is necessary for sensory neuron function and structurally very similar to polycystin. Both proteins appear to interact to form a membrane complex critical for cell signaling.

Patient information on IgA nephropathy and PKD is available at http://kidney.niddk.nih.gov/kudiseases/a-z.asp.

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First NIH Clinical Trial for Interstitial Cystitis Begins

Oral Drugs Studied for Painful
Bladder Problem

Doctors have opened enrollment for a clinical trial of oral drugs for interstitial cystitis (IC), a persistent and often painful bladder syndrome affecting hundreds of thousands of people, mostly women.

The Interstitial Cystitis Clinical Trials Group will use pentosan polysulfate sodium (Elmiron^®) and hydroxyzine hydrochloride (Atarax^®) to treat 136 people who have IC with unremitting urinary frequency and pain or discomfort lasting at least 24 weeks.

Elmiron and Atarax were selected first for testing because patients prefer oral treatments, and studies suggest that each drug uniquely targets different aspects of IC. In some patients, Elmiron reinforces the bladder lining, usually a barrier to urine's toxicity. Elmiron is the only oral drug approved by the Food and Drug Administration for IC. Atarax is an antihistamine that reduces the activity of mast cells, connective cells that may cause bladder inflammation and pain. The two drugs may also work synergistically, leading to quicker, more potent symptom relief.

"IC leaves many people unable to cope with basic daily functions," according to Leroy M. Nyberg Jr., Ph.D., M.D., director of urology research at the National Institute of Diabetes and Digestive and Kidney Diseases, which is funding the clinical trial. "This is the first of a series of rigorous treatment trials. Our ultimate goal is to be able to recommend to physicians those therapies most likely to relieve symptoms in subgroups of patients." The cause of interstitial cystitis is unknown, and no one therapy works effectively in a large number of patients. Often mistaken for a bladder infection, IC may elude diagnosis for years.

Clinical trial participants will be divided into four groups to receive either (1) a placebo, (2) Elmiron, (3) Atarax, or (4) both active drugs for 6 to 16 months, depending on when they join. At the end of the study, doctors will compare self-reported symptom improvement between the placebo group and drug groups.

"If the results are promising, we want to study more patients over a longer time. This would allow us to gather more solid information about the therapies and how we can help patients," says Nyberg. "And we are exploring other possible treatments to evaluate in subsequent trials."

J. Richard Landis, Ph.D., at the University of Pennsylvania School of Medicine in Philadelphia, is coordinating data collection and analysis.

Note: A fact sheet on IC is at http://kidney.niddk.nih.gov/kudiseases/a-z.asp.
A list of centers and doctors is below and at
www.niddk.nih.gov/patient/ic.htm.

Interstitial Cystitis Clinical Trials Group

Maryland
John Warren, M.D.
University of Maryland, Baltimore
410–706–7560

Massachusetts
Grannum R. Sant, M.D.
Tufts University School of Medicine
New England Medical Center, Boston
617–636–7956

Michigan
Ananias C. Diokno, M.D.
William Beaumont Hospital, Royal Oak
248–551–0387

David Burks, M.D.
Henry Ford Hospital, Detroit
313–916–2075

New York
Edward M. Messing, M.D.
University of Rochester, Rochester
716–275–3345

Oklahoma
Daniel J. Culkin, M.D.
University of Oklahoma, Oklahoma City
405–271–6900

Pennsylvania
Alan J. Wein, M.D.
University of Pennsylvania, Philadelphia
Marilou Foy, R.N., C.C.R.C.
215–349–5874

Kristine E. Whitmore, M.D.
Graduate Hospital, Philadelphia
Marilou Foy, R.N., C.C.R.C.
215–349–5874

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Clinical Trials Will Test Tolerance Induction in Transplantation

Researchers from the National Naval Medical Center, the Walter Reed Army Medical Center, and the National Institutes of Health (NIH) have begun testing new methods to prevent the rejection of transplanted and health-restoring organs and tissues. Initiated in 1999, the program aims to develop methods that eliminate or greatly reduce the need for chronic immunosuppression in transplantation. Studies will also explore ways of identifying patients who may need far less immunosuppression than is currently prescribed. The investigators are particularly interested in techniques that reeducate the cells that trigger immune activation and the eventual rejection of transplanted tissue.

The first clinical study applying tolerance induction therapy involves patients receiving a kidney transplant for end-stage renal disease. More than 12,000 kidney transplants are performed yearly in the United States. Of these, 70 percent are from cadavers. Immunosuppressive agents are used to prevent rejection but may be accompanied by significant side effects such as infection, cardiovascular disease, and death. Many grafts are lost—1-year graft survival for cadaveric kidneys is approximately 87 percent, and 10-year survival is about 32 percent. Although living-related transplants do better than cadaveric kidneys, the 10-year graft survival is only about 54 percent.

Affordability is also an issue. Some kidney transplant patients may have trouble paying for immunosuppressive medication after the first 3 years, when their Medicare coverage expires. Investigators hope that paying for medications will no longer be a problem if this research program successfully eliminates or reduces the need for immunosuppressive medications.

In a second study, researchers are transplanting islet cells in people with diabetes caused by a pancreatectomy or with clearly documented (by genetic testing) maturity onset diabetes of youth (MODY). Islets are isolated by an expert team from the University of Miami together with the NIH Department of Transfusion Medicine. The islets are then infused via a tube inserted through the skin into the liver's portal vein. If this trial shows that tolerance induction methods can prevent the immune system from rejecting transplanted islets, the study will be expanded to determine whether people with type 1 diabetes may also benefit.

The trials are being conducted at the NIH Organ/Tissue Transplant Research Center, which opened in May 1999. Located in the NIH Clinical Center in Bethesda, Maryland, the Center is a collaborative project of the NIH, the Walter Reed Army Medical Center, the Naval Medical Research Center, and the Diabetes Research Institute at the University of Miami. The site includes a state-of-the-art clinical transplant ward, operating facility, and outpatient clinic designed for the study of new drugs or techniques that may improve the success of organ and tissue transplants.

Enrollment is still open for clinical trials involving patients with renal failure who need a kidney or kidney-pancreas transplant, or patients with diabetes in need of a pancreatic islet transplant. Trials involving patients who already have been transplanted are planned as well. If you are interested in joining one of these clinical studies, please call the NIH Clinical Center's Patient Recruitment and Public Liaison Office at 800–411–1222.

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Conference Will Launch New Healthy People Report with First-Ever Chronic Kidney Disease Chapter

NIDDK will celebrate the release of the first chronic kidney disease chapter in Healthy People 2010 at the conference Partnerships for Health in the New Millennium, to be held January 24–28, 2000, in Washington, DC.

Join the celebration, show your support, and offer suggestions for achieving and tracking progress toward chapter objectives at the session “Preventing Chronic Kidney Disease.” We will discuss scientific background, specific objectives, and current and future challenges to improving the Nation’s kidney health in the first decade of the new millennium.

The Healthy People report reviews the best science available to identify the most significant preventable threats to public health, establish national goals for improving health, and focus public and private sector efforts. Federal and State agencies and local communities measure progress in their programs in relation to Healthy People objectives.

For more information and conference updates, see www.health.gov/partnerships.

See also a related article in the summer 1999 Research Updates, online at http://kidney.niddk.nih.gov/about/Research_Updates/sum99/1.htm.

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