Notes and emendations (October 31, 1999) by Webmaster Curtis L. Atkin are [bracketed].
The long-standing Alport studies at the University of Utah and more recent studies at the University of Oulu, Finland, have now yielded complete understanding of the genetic causes of most varieties of Alport syndrome. See the accompanying announcement of the DNA Diagnostic Laboratory for the first practical rewards, or payoff for all our work.
Each of most families with Alport syndrome has a unique abnormality (mutation) in the COL4A5 gene on the X chromosome. This gene specifies a part of type IV collagen which is an integral component of the filtration membranes (glomerular capillary epithelial basement membranes or GBM) in kidneys. Methods developed by this research now offer much more precise and certain diagnoses of Alport syndrome, as well as suggests future lines of research that may lead to prevention, better treatment, or even cure of this kidney disease.
The First International Congress on Alport Syndrome was held August 22-25, 1992, by Dr. Karl Tryggvason at the University of Oulu, Finland. The Utah Alport study was represented by Dr. Martin Gregory, Dr. David Barker, and me. We each gave major speeches. At that time about 30 different mutations of the COL4A5 gene had been shown by various labs to cause Alport syndrome in different families. Worked out were plans for systematic determination of genetic abnormalities, as well as for future directions of research. In September, 1991, in Quebec City, I spoke on the new Alport findings at a symposium "Genetic Probes in Nephrology" for the Royal Canadian Society of Physicians and Surgeons.
Our research continues, albeit with severe funding problems. My Alport grant support for the National Institutes of Health expired in February, 1992, but Dr. David Barker's important molecular biological work fortunately receives the support of his new small research grant from the same source.
My failures delayed this Newsletter almost a year, for which I apologize. Increasing health problems impair all my work. Another kidney transplant may free me from some of the problems as well as from hemodialysis.
In about 1977, Gary Perryman introduced me to Loren Burr as another person interested in kidney research and education of kidney patients. Loren had just retired and started dialysis, having suffered ESRD from adult polycystic kidney disease. Loren soon helped found the Hereditary Nephritis Foundation. He remained an officer and board member. He played large roles in the initial set-up of the HNF and in fund-raising projects. He also prepared financial reports and the HNF's annual tax returns. He was noted for many thoughtful and wise contributions to discussions and planning at board meetings. An hour or so before he died, Monday 10/14/91, I had the privilege of chatting with Loren about some of the problems of dialysis patients. We were both on dialysis in the Dumke Building at the University of Utah Medical Center when he died. He was truly a friend of the HNF. Loren also put many years of service into other kidney and charitable organizations. Requiescat in pacem .
People with healthy kidneys can eat any reasonable diet without fear of harming their kidneys. You may actually be able to help your kidneys by making some fairly simple changes in what you eat.
Reducing the amount of protein in the diet definitely slows the development of kidney failure in animals with kidney disease and this benefit is also seen in humans with some kidney conditions, but it hasn't been studied in Hereditary Nephritis. At present it seems wise to take a moderate or slightly reduced protein intake but not to go overboard about it. For most people, there is no need to stick to a strict diet, simply avoiding being greedy for meat is enough. If you want to be more careful about it, your doctor can prescribe a defined protein intake and you can speak to a dietitian who will work out a detailed meal plan for you. Your doctor will likely recommend a 0.6 to 0.8 g/kg/day diet which works out to about 40 to 60 grams of protein a day for a person of average size. If you are really interested in doing every possible thing to slow your kidney disease, there is a National study called the Modification of Diet in Renal Disease Study (MDRD). You can find out more about this study by calling Dr. John Kusek in Maryland (301-496-7133).
Excess in anything is bad, so you should not go on a rigid diet without having a word with your doctor. The most extreme example I know is of a few unfortunate people who severely damaged their kidneys by eating Worcestershire sauce - but they were using a bottle a day!
Salt is bad for many people with hypertension, and this eventually includes almost everyone with Alport syndrome. If you have Alport syndrome, it is a good idea to reduce the amount of salt in your diet because eventually this will be necessary. It is much easier to make any reductions gradually. You will find that you begin to appreciate the flavors of the food more and prefer tastes with less salt. Begin by adding less and then no salt at table and gradually reduce the amount that is added during cooking. Beware of salt substitutes: nearly all contain potassium, which is fine for those with healthy kidneys, but which is poison for people with severe kidney disease. Because kidney disease may worsen without your being aware of it, it is better for anyone with a kidney problem to steer clear of salt substitutes unless specifically advised by a dietitian or physician. The worst enemy when you are taking a reduced-salt diet is fast food: most fast food (except salads) contains far more salt than is needed.
Although you cannot usually stop nephritis in its tracks, there are definitely things that you can do to slow it up and to keep you in good health for as long as possible. The single most important thing is to keep your blood pressure as low as possible. Visit your doctor regularly or buy a blood pressure machine and keep track of your own blood pressure. (Get a regular one such as you've seen nurses use, the fancy electronic ones are more expensive and can give misleading results). For people with nephritis it is particularly important for your blood pressure to be really good, not just "good enough". As soon as your blood pressure begins to go up, this rise should be confirmed by further blood pressure measurements and steps taken to bring it down. Ways to bring blood pressure down include weight loss, controlling salt intake, regular exercise, and medications. There are now a number of very effective medications available for treating high blood pressure. These medications have few side effects if chosen carefully, and some of them are particularly good for slowing up the damage from nephritis. Diet is also important (see the answer to the previous question).
**If you have questions about inherited kidney diseases, please send them to the Hereditary Nephritis Foundation and we shall answer them in the next issue of the Newsletter.
What an upsetting thought, that you or a member of your family will someday develop kidney failure, and require either dialysis or a transplant! Yet, the truth is that most patients with chronic kidney disease, whatever the cause, will experience a slow loss of kidney function so that sooner or later these unpleasant things will occur. And most of our readers know that once a person develops end-stage renal failure, life changes dramatically. The upheaval is social, emotional and financial as well as medical. The subject may change from an independent and contributing member of his family and his community to someone largely dependent on the services of others.
The unpleasantness of this scenario can be minimized if the patient and his physician make realistic decisions beforehand. Let's go through them step by step.
First, there must be an accurate diagnosis. Over the years I've met many people who assumed that they would develop kidney failure because their father, mother or brother did so. For instance, the earliest studies of hereditary nephritis in Utah often were based on incomplete information. Some people believed that they had the disease when they did not. Years later it was difficult to convince them that they were healthy! Anyone at risk should have appropriate tests--urinalysis, blood chemistries, kidney x-rays or ultrasound, kidney biopsy--whatever is necessary to establish the presence and the type of renal disease.
Second, knowing the type of kidney problem establishes a prognosis, that is, tells the patient whether he will develop kidney failure and when. Chronic kidney disease tends to progress slowly; blood tests warn of kidney failure long before it occurs and give plenty of time to prepare.
Third, there are treatments which can slow the progression of kidney disease and delay the onset of renal failure. Examples are surgical correction of urinary tract deformities, prompt treatment of urinary infections, precise control of high blood pressure, better control of diabetes if present, prevention of kidney stones, adjustment of diet, avoidance of harmful medications, and the selected use of cortisone-like drugs and of blood platelet inhibitors in those diseases where antibodies are attacking the kidneys. In almost all cases of chronic kidney disease, one or more of these measures should be used sometime during the course, not only to slow the disease but to help the patient feel better.
Fourth, a definite plan for transplant or dialysis should be made before either of these treatments becomes necessary. Most patients develop symptoms of uremia when the serum creatinine reaches 8 or 9, which indicates that only 10 percent of kidney function remains. At that point a transplant or dialysis becomes necessary. In my opinion, a kidney transplant is always preferable to dialysis when circumstances permit. Now that we transplant older patients, some with serious diseases such as diabetes, heart disease and lupus erythematosus, many more patients can be given a transplant. In my practice, approximately two-thirds of new end-stage renal failure patients are transplanted, and most of these have never even had a dialysis!
This approach takes preparation. By the time the serum creatinine reaches 4 (25 percent kidney function), the options have been discussed and a decision made to move toward transplant or dialysis. If transplant, potential family donors are tested. If an appropriate donor is available, the transplant is performed when the serum creatinine is 7 or 8, and symptoms are still mild. If there is no family donor, the patient is placed on the cadaveric organ list when his creatinine is still in the range of 4 to 5. On the average, the wait for a cadaveric kidney transplant is one year. Hopefully, the patient will receive his transplant before he requires dialysis. If he develops uremic symptoms first, he can be maintained on dialysis for a few months until an organ comes along.
Using this plan, there is minimal social and emotional displacement, and costs are less. I know of many patients who worked full time until transplanted, and returned to work a few weeks afterward. Some patients achieve an impressive degree of rehabilitation on long-term dialysis. Yet the numbers are fewer, and those who do well are less vigorous than the usual transplant patient. And there is another facet of this decision that is seldom discussed between physician and patient, the growing belief that transplant patients live significantly longer than dialysis patients, whatever their ages when treatment starts.
Of course, any plan can be altered when circumstances change. If an early transplant fails, the patient can switch to dialysis, and vice versa. However, the fact that the patient and his physician have discussed a plan indicates that they both are prepared for the event of kidney failure, and that all will go smoother when the time comes.
I had the opportunity to review pediatric transplantation results in the context of summarizing our experience at the University of Utah. Transplantation started in 1954 with the first twin to twin transplant and really was launched for the pediatric age group in the 1970's. It was not until 1984 that pediatric transplantation mushroomed at the University of Utah. I think this was due to the use of cyclosporin as well as a critical mass of physicians at the University who were interested in pediatric transplantation.
There are three categories of factors which influence transplant outcome: donor factors, recipient factors and center factors. Donor factors include such items as whether the transplant is from a living donor versus a cadaveric donor (someone who has died and donated an organ), the age of the donor, the time the kidney has been stored while awaiting transplant plus numerous other factors. Living related kidneys do in general work better and last longer. For instance, a national pediatric survey started in 1987 which looks at the outcome of pediatric transplantation, has documented a 2 year survival for living related transplant kidney function of 83% versus 67% for cadaveric kidneys. This means that 83% of the people who received living related kidneys still have a kidney working well enough to be off dialysis after 2 years. We know from other studies that this number should remain in the 65-70% range after 5 years have elapsed. We presume that living related kidneys do better because the surgery is planned and the recipient can be in the best possible medical shape, the kidney is as normal as we can assure ourselves through pre-donation testing and there is no cold storage. Additionally though, the genes of the donor are closer to the genes of the recipient in the living related transplant and that means that the body will be less likely to reject the kidney. The living related survival at the University of Utah since 1984 for all those who received their first graft is 84% at 2 years whereas the cadaveric rate is 59%. The cadaveric rate has been very much improved since 1989 when we instituted a new immunosuppression protocol (the drugs which keep your body from rejecting a foreign graft). Our rate in first grafts since 1989 is now 84%, although numbers of patients are small at this time.
Recipient factors are also important and influence graft survival. These factors include the age of recipient, the drugs used for immunosuppression, the number of transplants received plus many others. Recent studies have shown that if kidneys from donors under 5 years of age are used, it is best to put them into small recipients for example, those under 10 years of age. Small kidneys put into adults and small kidneys put into those under 1 year of age do not do as well as bigger kidneys. We think this is related to difficulty diagnosing rejection and technical difficulties for the surgeon during implantation. This fact is recognized in the national donation policies which mandate that donor kidneys under the age of 15 be implanted into children under the age of 10. One of the newer recipient variables that is currently being investigated now that kidneys survive longer is the factor of patient compliance. In other words, how many kidneys are lost because the recipient has stopped taking the immunosuppressive medications which are needed to prevent rejection? The rate seems to vary from 10-40% of kidneys lost in most studies, although one study showed that all their kidneys lost after 36 months were due to patient non-compliance. As scarce as donor kidneys are becoming, the recipient can ill afford to stop taking those medications. Center effect has not been formally studied although it makes sense that those centers which do more will have more experience and therefore do a better job. This concept encompasses the kidney specialist that will see the patient in follow-up, the adequacy of immunosuppressive protocol and enough help to ensure that visits with the doctor are kept. Federal legislation has established a minimum number of 15 transplants per year for adult programs to be able to perform transplantation. There are very few programs that do that number of pediatric transplants per year so that a pediatric program linked to an adult program is very common. Our team at the University of Utah is 2 surgeons that do adult and pediatric transplants, about 40-50 adults and 12-14 children per year, as well as 3 pediatric nephrologists who participate in the care of the children during and after transplantation.
Transplantation is growing out of its infancy. It seems that about every 5 years a new technique or drug is available to help us keep people off dialysis and live the best quality of life possible. We have a formidable enemy in the form of graft rejection although the second enemy seems to be the patient who forgets how important daily medication is for the life of the graft. When we know how to create the situation in which the transplant graft is not recognized by the recipient's body (a state called tolerance) we might make a significant dent in the problem of immunosuppression and the need for life-long medication taking. I hope it happens in my lifetime and yours!