Living with Uromodulin Associated Kidney Disease (UMAK)
By Anthony J. Bleyer, M.D., Professor, Section on Nephrology, WFUBMC
The material in this brochure provides general information about UMAK. Specific treatment recommendations should come from your local doctor or your kidney doctor.
DISCLAIMER: The information in this brochure is provided for general informational purposes only and SHOULD NOT be relied upon as a substitute for sound professional medical advice, evaluation or care from your physician or other qualified healthcare provider. Nothing in this brochure should be used for treating or diagnosing a medical or health condition or for replacing any relationship with your physician or other qualified healthcare provider. The health information furnished in this brochure are not intended to or implied to be professional medical advice. You are encouraged to consult other sources and confirm the information contained in this brochure. Consult your own physician regarding the applicability of any opinions or recommendations with respect to your symptoms or medical condition. For medical concerns, including decisions about medications and other treatments, you should always consult your physician or other, qualified healthcare professional.
This manual is for individuals and their families that are affected with a mutation (mistake) in the uromodulin gene. This disease has been called by other names, including:
Medullary Cystic Kidney Disease Type 2
Familial Juvenile Hyperuricemic Nephropathy
Familial Gouty Nephropathy
Glomerulocystic kidney disease
Familial Gout-Kidney Disease
Mutations of other genes may also result in the above illnesses. It is important to state from the outset that this manual is specifically written for individuals who have had a mutation in the uromodulin gene. These mutations were identified by research studies at various centers or by Athena Diagnostics, Worcester, Massachusetts. This is the only company at present doing this testing commercially.
Finding Out About the Disease
“There is a disease that has run in my family for a long time, but no one knew what it was.”
“A lot of my family members have gout and kidney failure.”
“I have a kidney disease, and I am worried if my children have it.”
“I recently found out I have this disease. What should I do about it?”
“Our kidney doctor said we have an inherited kidney disease, but he is not sure of the exact name for it.”
These statements are very common in families that suffer from this condition. In 2002, the gene that caused this condition for many families was finally discovered.. Perhaps your doctor referred you to be tested because he considered this as a possible cause of your disease. Perhaps you belong to a family that has been under study and already diagnosed with this condition. Perhaps you read about this disease on the internet, thought you had it, and underwent testing. These are the ways that most patients have found out about the disease.
However, once you have found out that you have the condition, the next questions are:
- “What is this disease?”
- “Why do I have it?”
- “Will my children get it?”
- “Are there any treatments available?”
- “What can I do now about it?”
This booklet will try to answer these questions for you. It will start with a brief overview about genes.
What is a gene and a mutation?
The information that directs our body in everything that it does comes from the genes that we inherit from our parents. These genes make up the chromosomes that are given from parent to child at the time the child is conceived. We have two copies of most genes in the body – one from our father and one from our mother. From these genes, the body makes all the proteins and other substances that make our body work. Genes work in our body the way that a blueprint works when a factory is built. If there is a mistake in the blueprint, and ultimately in the construction, the factory will have a problem. If the mistake is minor, no one may ever even know. If the mistake is major, it may affect the factory’s ability to make its products. A mistake in a gene is called a mutation. In UMAK, there is a mistake (mutation) in one of the genes that makes the protein uromodulin.
What is the cause of UMAK?
UMAK is a disease caused by a mutation (mistake) in one of the genes that makes the protein uromodulin. We have two genes that make most proteins. In UMAK, one of the genes makes uromodulin normally, and the other makes uromodulin abnormally.
Uromodulin is a common protein that the kidney makes. This protein is excreted by the kidney into the urine. It is the most common protein found in the normal human urine. Uromodulin used to be called the Tamm Horsfall protein. It has been studied for more than thirty years, but still no one knows the function of normal uromodulin.
In UMAK, one of the uromodulin genes that has been inherited from a father or mother has a mistake in it. This mistake prohibits the secretion of uromodulin from the cell that normally makes it. The abnormal uromodulin remains in the protein processing part of the cell called the endoplasmic reticulum. The abnormal protein “gums up the works.” It makes it so that even the normal uromodulin (produced by the healthy gene) does not get out of the cell. In the person with the mutation, the uromodulin deposits in chunks abnormally. These deposits likely lead to cell death over time, leading to kidney failure.
How is UMAK inherited?
UMAK is inherited in an autosomal dominant manner. What does this mean? We each receive one uromodulin gene from our father and one from our mother. All it takes is for one of these genes to be abnormal to get the disease. In general, if our parent has the disease, he or she has one normal and one abnormal gene. Therefore, if you are the child of an affected parent, you have a 50-50 chance of getting the disease. If you have the disease, your child has a 50-50 chance of getting the disease. This is why so many family members can get the disease: There is always a 50:50 chance that each child will have it.
This disease does not “skip a generation.” There are no ways to predict if the child will have the disease without testing. Whether a child looks like or does not look like his affected parent will have no relationship to whether he has the disease or not.
What are the signs and symptoms of the disease?
The first sign of the disease may be bedwetting as a child. This occurs in some but not all children affected by the disease. It also may occur in some children in the family who do not have the disease, but bed wet for other reasons. About 1/3 of individuals with the disease have bedwetting (compared to 1 in 5 children who have bedwetting and do not have the disease). The bedwetting is related to an inability of the kidney to concentrate the urine as much as in normal individuals. This results in making more urine at night and ultimately in the increased rate of bedwetting.
Gout frequently occurs in this condition. In UMAK, the kidney is unable to excrete uric acid in the urine as efficiently as in the health kidney. Why a mutation in the uromodulin gene causes this is unknown, but it is a common characteristic of the disease. The increased blood uric acid levels lead to deposits of uric acid in the joints, causing the condition known as gout. Gout typically develops in the big toe, but affects many other joints including the knees and elbows. Patients develop attacks of gout.
Gout occurs in many individuals who do not have UMAK. In people who do NOT have UMAK, gout usually develops in overweight males. They frequently develop gout in their 40’s and 50’s. They often have diabetes. In contrast, in UMAK patients gout frequently develops in the teenage years and is found in male and female individuals. Not all persons with UMAK have gout, but in almost every family affected with UMAK, someone has a history of gout.
Kidney failure also develops in individuals with UMAK and is the major cause of sickness. Kidney failure is usually determined by a blood test called the blood creatinine level. This test may have been obtained as part of “routine blood testing”- for example, for preoperative testing or during an annual physical. The results of the test may have been a surprise. Doctors then usually perform a urine test – “a urinalysis.” In patients with UMAK this test usually shows no blood or protein. Doctors may then consider performing a kidney biopsy. A kidney biopsy almost always reveals the cause of a patient’s kidney failure. However, in UMAK, the kidney biopsy is usually not helpful. The patient will be told that the cause of kidney disease is “high blood pressure” or “focal sclerosis” or “interstitial nephritis.”
Kidney failure progresses slowly. Men with this condition end up requiring dialysis or a kidney transplant in their 30’s to 50’s. Women require dialysis or kidney transplant between 40 and 70.
What can I do if I have UMAK?
There is one medication that has been found to be effective specifically for UMAK: allopurinol. Allopurinol is a drug that prevents the production of uric acid. A
(1) It keeps the blood uric acid level down and prevents gout from developing. It prevents the development of tophi – bumps that develop on elbows, ankles, and fingers that are caused by uric acid deposits. Affected individuals who start allopurinol at a young age will never develop gout. They will never have tophi.
(2) Allopurinol also appears to slow the progression of kidney disease. The English doctors who study this condition believe that allopurinol STOPS progression of disease in affected individuals if started at an early age.
What are the side effects of allopurinol?
When allopurinol is started, it can actually cause a gout attack. However, if one continues allopurinol, it will prevent future gout attacks. Allopurinol is not a treatment when there is an active gout attack occurring. Allopurinol PREVENTS gout attacks. For this reason, allopurinol must be taken on a daily basis and should not be stopped.
When beginning therapy with allopurinol, some patients can develop an allergic reaction to allopurinol. This allergic reaction is very rare. If it does occur, results in a skin rash and a rash inside the mouth. The liver can be affected, and severe liver damage can occur. This reaction can be life-threatening and the allopurinol should be stopped immediately and a physician contacted if this occurs.
Another drug called benzbromarone has been found to potentially slow the rate of kidney disease in some patients. Benzbromarone is not available in the United States. Currently, there is not enough evidence to show that benbromarone truly prevents progression of disease.
Colchicine and prednisone are two other medications that can be used to treat gout. However, allopurinol is the key medication that is used in the treatment of UMAK.
Other ways to treat the kidney failure associated with UMAK:
At this point, it appears that many patients will slowly progress to kidney failure. Therefore, the treatment of chronic kidney failure is very important. The primary cornerstones of treatment of kidney failure include:
(1) Treatment of high blood pressure. The blood pressure should be maintained at less than 140/90.
The use of ACE inhibitors (a specific type of blood pressure medication) may slow the progression of kidney disease and should be considered even if the blood pressure is normal. Each patient should discuss this with his or her kidney doctor.
In general, it is important to maintain good health and a healthy lifestyle. Avoiding smoking, eating a sensible diet, and gettingexercise will help the patient stay in otherwise good shape. This will help him or her to be a good candidate for kidney transplant in the future.
Should my children be tested?
The decisions regarding the testing of children and at what age they should be test are difficult decisions for parents. Since boys develop both gout and kidney failure at an earlier age, we believe that all boys should be tested by their mid teens. Allopurinol may prevent progression of disease, especially when started early. For this reason, it may be advisable to test children at a young age. The testing of children before ages 5 or 6 hasn’t proven to result in any benefit.
What else can I do if I have UMAK?
Participating in research trials on UMAK is likely to be helpful. Please contact Dr. Bleyer at ableyer@wfubmc.edu if you are interested.
What does my doctor know about UMAK?
UMAK is a very rare disease. Your doctor did not learn about it in medical school! Most nephrologists do not know about this condition. For this reason, it may be useful to provide your physician with a copy of this brochure. The listed references may help him or her understand the disease better.
References:
Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ: Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genetics 2002; 39: 882-892.
Bleyer AJ, Trachtman H, Sandhu J, Gorry MC, Hart TC: Renal manifestations of a mutation in the uromodulin (Tamm Horsfall Protein) gene. Am J Kidney Dis 2003 Aug 42(2): E20-26.
Bleyer AJ, Woodard AS, Shihabi Z, Sandhu J, Zhu H, Gorry MC, Barmada MM, Hart TC: Clinical and genetic characterization of a family with familial juvenile hyperuricemic nephropathy. Kidney International; 64: 36-42.
Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SP, Rees L, Van'T Hoff W, Mansell M, Pattison J, Goldsmith DJ, Simmonds HA: Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM 2002; 9: 597-607.