Notes and emendations (August 31, 1999) by Webmaster Curtis L. Atkin are [bracketed].
[This article by D.F. Barker, C.J. Pruchno, X. Jiang, C.L. Atkin, E.M. Stone, J. Denison, P.R. Fain, and M.C. Gregory appeared in The American Journal of Human Genetics 58(6):1157-1165, June 1996.] The following is a brief summary of some background information and the new results presented in the article. We have also included a glossary of technical medical terms which may be helpful when reading the summary.
GLOSSARY
Alport Syndrome is an inherited disorder characterized by hematuria often leading to renal failure. It may be accompanied by extrarenal manifestations including sensorineural hearing loss, anterior lenticonus, retinal stippling, esophageal leiomyomatosis, and macrothrombocytopenia. After renal transplantation, some AS patients develop [anti-glomerular basement membrane (anti-GBM)] disease in the transplanted kidney, often resulting in loss of the transplant. Defects in COL4A5, the gene encoding the a 5 [alpha5] chain of Type IV collagen, account for a substantial fraction of AS, with close to 100 different mutational defects now described. These lesions affect basement membrane structure, causing the progressive glomerular deficiency and, presumably, many of the extrarenal abnormalities. Clinical heterogeneity exists between different families with respect to age of onset of renal abnormalities and of renal failure, degree of hearing loss, the presence or absence of lenticonus or retinal stippling and the propensity to develop anti-GBM disease in a renal transplant. Most kindred studies have demonstrated limited intrafamilial variation, and concluded that individual families may be placed in distinct phenotypic classes, suggesting that the molecular nature of a mutation is the essential determinant of disease expression and progression, particularly in affected males. Gene-carrier females usually exhibit hematuria, however the occurrence of ESRD and hearing loss is much rarer and of later onset than for males, with severity of disease expression likely related to the degree of skewing of X-chromosome inactivation in critical cell population(s) during development.
Type IV collagens are heterotrimeric molecules composed of [alpha] chains that form a non-fibrillar supramolecular meshwork integral to all basement membranes. The a 1(IV) and a 2(IV) chains are thought to be the primary type IV chains, present as the major components of all different basement membrane collagens in the form of an (a 1)2(a 2) heterotrimer. The minor chains, a 3(IV), a 4(IV), a 5(IV) and a 6(IV) have tissue specific distribution patterns, possibly conferring distinct functional properties. However, the a 3(IV) and a 4(IV) chains must have some functional commonality with a 5(IV) since mutations in these genes cause an autosomal recessive form of AS syndrome and complete absence of the a 5(IV) chain results in the loss of an a 3(IV)-specific epitope from GBM. The minor type IV chains may form a network that is independent of the a 1a 2(IV) network, however the precise molecular structures and stoichiometries are not well-defined.
We have identified a single base substitution in the COL4A5 gene in nine independently identified families. The T to G transversion affects the NC1 domain of the protein, and is predicted to change a conserved leucine to arginine. Screening of 160 chromosomes from normal controls excluded the possibility that the base substitution represents a polymorphism. Genetic marker haplotype data and existing genealogical records strongly indicate that all nine families are related to a common ancestor born more than 200 years ago. Interviews and clinical histories of 87 affected males in this larger kindred revealed that hearing loss occurred significantly later than in another large, well-characterized kindred with adult type AS. There was, however, a broad range of age of onset of hearing loss and ESRD in both kindreds.
A reader asks about the role of herbal medicine in preventing kidney damage from Alport Syndrome. According to the World Health Organization, at least 80% of the world uses herbal remedies, and a recent US survey found one American in three uses herbal medicines. Obviously, many people place a great deal of reliance on herbs, but despite this wide use, very little is known about the possible benefits or harm from herbs. The National Institutes of Health in Bethesda has set up an Office of Alternative Medicine that is looking into herbal remedies. This office plans to assemble information that will be available to the public about the uses and safety of herbs. Several herbs, such as dandelion and anything containing caffeine, have a diuretic action, that is to say that they increase urine flow, but there is little to suggest that this is of long term benefit to the kidneys.
Some of Dr. Alport's original patients noted that eating black currants, strawberries, or asparagus could provoke bouts of blood in the urine. I suspect that this was purely coincidental and does not for a moment mean that these foods are harmful. We simply don't know which particular foods may be good or bad. There is no doubt that some herbs can be very harmful. Around fifty people in Belgium have chronic renal failure and require lifelong dialysis because of kidney damage from a Chinese herbal mixture that they took as a slimming aid. Whether it was really the herb, or whether it was a contaminant harvested along with it or introduced during packaging is not clear, but the result for these people was tragic. Before taking any herb or medicine, it is worth thinking hard about what benefits you can reasonably expect, how confident you can be about the constancy of the dose and the purity of the product, and what harmful effects there may be.
There is good evidence that a diet low in protein can delay loss of kidney function in animals with kidney disease, and there is some evidence that this is true in humans as well. For the meantime, it seems prudent for people who carry the gene for Alport syndrome to eat a good mixed diet with plenty of fresh fruits and vegetables and to avoid an excess of red meat, fat and salt. Of course, should renal failure occur, there will be specific dietary needs that must be addressed by your nephrologist and dietitian.
The following article appeared in The Salt Lake Tribune on Friday, March 29, 1996 and is reprinted with their permission. According to Martin C. Gregory, MD, work like this gives us hope that even if a specific genetic cure for inherited kidney disease is not found, a general means of slowing or preventing kidney failure will become available.
University of Utah scientists Wayne Border and Nancy Noble have a dream: They want to develop a treatment to prevent kidney failure and reduce taxpayers' multibillion-dollar annual bill for kidney dialysis and transplantation.
The husband-and-wife research team took a significant step toward achieving that dream by using gene therapy to halt kidney damage in rats. They injected the rats with genes that made the rodents produce more decorin, a protein that blocked the buildup of kidney-damaging scar tissue.
"Current therapies to treat progressive kidney disease are ineffective," said Border, a physician and head of nephrology at the University's medical school. "This is the first practical treatment that does stop the kidney scarring," but it will take at least five years before it can be used to prevent kidney failure in people.
Border, Noble, Utah cell biologist Douglas Brees and researchers at Japan's Osaka University published their findings in the April issue of Nature Medicine, which was released Thursday.
The treatment won't help people who already require dialysis because their kidneys failed. Instead, it would be used to prevent kidney failure in people whose kidneys have been damaged by diabetes, high blood pressure or other ailments.
"It is the first time we really have something that will work in many kinds of kidney disease," said Gary Striker, director of the kidney-disease division at the National Institutes of Health (NIH) in Bethesda, Md. "It offers hope."
"We don't know if this will work in humans, but it's come through a long trial period in animals and looks good," said Alan R. Hull, president of the National Kidney Foundation and a professor at the University of Texas Southwestern Medical School. "Now it needs to be applied in humans....If it works, it's one of the breakthroughs we've been looking for."
Noble and Border said the study suggests a similar treatment might work against other diseases caused by scarring of organ tissue. Such ailments include cirrhosis of the liver, reclogging of arteries after they are opened by balloon angioplasty, some forms of congestive heart failure and lung-scarring ailments such as black lung disease.
The kidneys are twin bean-shaped, fist-size organs below the ribs on each side of the spine. They filter waste products from blood and excrete them in urine. People need at least one kidney to survive. When both kidneys fail, a person must either have their blood filtered by a kidney dialysis machine or get a transplant.
About 220,000 Americans with kidney failure now receive kidney dialysis; more than 10,000 each year receive kidney transplants, Hull and Striker said. The cost of treating those patients exceeds $9.5 billion per year and continues to increase, according to the National Kidney Foundation. Taxpayers foot most of the bill through Medicare.
Kidney failure results from a buildup of scar tissue that clogs the kidney's filtering units. Many people with kidney failure have diabetes, which can take years to scar the kidneys. Others suffer kidney damage due to high blood pressure.
Still others suffer glomerulonephritis, which is inflammation and scarring of the kidneys' filtering units caused by immune-system ailments such as lupus or immune reactions to infections such as strep throat. Another group suffers kidney failure due to rare genetic disorders.
Border, Noble and colleagues injected rats with antibodies that attack the kidneys and mimic the injury and inflammation that leads to scarring in human glomerulonephritis.
They also injected rats' buttocks with genes that made muscle cells produce more decorin, which in turn entered the blood stream and reached the kidneys. Some rats were treated a day before their kidneys were injured; others were treated a day after. The treatment prevented kidney scarring in all the rats.
Striker said that while kidney scarring is similar in patients with glomerulonephritis and diabetes, it isn't yet proven that decorin will prevent diabetes-related kidney scarring. Border and Noble believe it will.
A recent NIH report said gene therapy has been oversold because it has yet to yield effective treatments for disease. Border said his study raises new hope for gene therapy by demonstrating it can work in an animal - just the kind of research the NIH said was needed.
A substance named transforming growth factor-beta (TGF-beta) normally triggers the production of scar tissue to heal wounds. But in a series of studies during the past eight years, Border, Noble and other researchers found TGF-beta's wound-repair process can run amok, scarring the kidneys, heart, liver, lungs, skin and other organs. Research revealed that in the body, TGF-beta and scarring are held in check by naturally occurring decorin. Border, Noble and others then demonstrated that manufactured decorin could be injected into the bloodstream of rats to prevent excessive kidney scarring. But the protein is expensive to manufacture, would require daily injections and may cause harmful side effects because it differs from natural decorin.
So Border and Nobel used a gene therapy method developed by their Japanese colleagues. Gene therapy usually means a new gene is put into an animal to replace a defective gene. In this case, however, the rats still had normal decorin-producing genes. By injecting genes into the rats, the animals simply produced more decorin. Injections of decorin-producing genes would be required only monthly, Border said.
TGF-beta not only helps heal wounds, but also restrains the kind of uncontrolled cell growth known as cancer. Will decorin gene therapy prevent wound healing or promote cancer? Border said the study found no evidence of harmful side effects. Decorin gene therapy seems to reduce TGF-beta to normal levels, not eliminate it. So there's still enough TGF-beta to help heal wounds and prevent cancer, Border said.
Border and Noble said they have gone as far as university researchers can in developing the new treatment, which the University of Utah is seeking to patent. They now hope to get a drug company interested in investing the years and hundreds of millions of dollars necessary to develop and test the effectiveness of decorin gene therapy in humans.
[In support of affected families and in keeping with educational objectives of the Hereditary Nephritis Foundation, we offer the following news release from the Texas Department of Health.]
The Kidney Health Care Division of the Texas Department of Health, Patient and Provider Conference is to be held in Austin, Texas on June 13-14, 1996, at the Holiday Inn South. The theme of this year's conference is "Quality of Care" and nephrologist Alan Hull, M.D., President of the National Kidney Foundation, will be the keynote speaker.
Social Workers CEU's [continuing education credits] will be offered.
Registration for professionals is $15.00. Kidney patients will not be charged a registration fee.
To receive further information, contact Amy Case at 512-458-7796, FAX 512-458-7267, E-Mail ACASE@KIDNEY.TDH.STATE.TX.US
Have you ever wondered where to go for more information on renal rehabilitation? If you have, look no further - the Life Options Rehabilitation Resource Center (RRC) is here to help.
The RRC provides renal rehabilitation materials free of charge, courtesy of an educational grant from Amgen, Inc. In addition, staff at the Resource Center are prepared to help answer questions you may have about the materials or about rehab in general.
If you are looking for information on how to implement a rehabilitation program, Lila Jorgensen, RN, CNN, is available to provide you with personal consultation on establishing rehabilitation programming in your own facility. For 25 years, Lila has been involved with designing and managing in-center and self-care programs with an emphasis in rehabilitation.
The following materials are currently available from the RRC:
Renal Rehabilitation: Bridging the Barriers. This 144-page report introduces and defines the concept of renal rehabilitation, identifies barriers to rehabilitation, and discusses the role of the 5E's as bridges to rehabilitation. Among the wealth of information contained in the booklet are charts focusing on rehabilitation roles for dialysis team members, a rehabilitation timeline, and detailed recommendations for each rehabilitation core principle.
Renal Rehabilitation: Bridging the Barriers Summary. This 16-page companion piece to Bridging the Barriers summarizes the main themes contained in the full report.
Bridging the Barriers: For Patients and their Families. This 44-page booklet outlines rehabilitation and the 5E's for the audience of patients and families. In a format suited for easy reading, it also contains many engaging patient profiles that highlight keys to individualized rehabilitation.
Renal Rehabilitation Report. A bi-monthly newsletter for patients and professionals, this publication serves as a source of information and education about renal rehabilitation and related topics. It reports on local, regional, and national renal rehabilitation research, program, and policy efforts, and reviews work currently underway in those areas. The newsletter also identifies and offers solutions to the barriers of renal rehabilitation.
[To obtain any of the above mentioned RRC publications, please contact:]
LIFE OPTIONS REHABILITATION RESOURCE CENTER
Medical Media Associates, Inc.
603 Science Drive
Madison, WI 53711-1074
800-468-7777, fax 608-238-5046, lifeoptions@medmed.com