Uromodulin Associated Kidney Disease (UMAK)
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Also sometimes known as:
Medullary Cystic Kidney Disease Type 2
Familial Juvenile Hyperuricemic Nephropathy
Familial Gouty Nephropathy
Glomerulocystic kidney disease
Familial Gout-Kidney Disease
UMAK
What are the signs of this disease?
There are three common features of this disease: |
“Our goal at Wake Forest University School of Medicine is to increase understanding about UMAK. We are committed to finding a cure for this condition. Finding a treatment will require studying the urine of as many affected individuals as possible. If you or someone you know has this condition, we hope that you will consider getting in touch with us to be part of our study. Working together, we believe that we will be able to find an effective treatment.”-- Anthony J. Bleyer, M.D., Professor, Section of Nephrology, Department of Internal Medicine |
(1) Patients develop chronic kidney failure with loss of kidney function beginning in the teenage years and progressing to the need for dialysis or kidney transplantation at an age between 30 and 70 years. Patients have few or no symptoms of kidney disease when they are diagnosed.
Usually, affected individuals are found to have some loss of kidney function when they undergo blood testing by their doctor as part of a general health screening. A blood test called the serum creatinine level is performed. If the blood creatinine level is above 1, this is usually abnormal and means the kidney is not removing the creatinine from the blood well enough. In patients with this condition, the serum creatinine is measured by their doctor and is elevated. Frequently the doctor does not know why the serum creatinine level is high. Even if a kidney biopsy (the removal of a small piece of kidney tissue) is performed, a correct diagnosis is frequently not made.
(2) The patient has gout or some member of the family has a history of gout. Gout is a type of arthritis (joint inflammation) caused by high blood uric acid levels. Affected individuals have high blood uric acid levels, and this leads to gout. Every affected individual in the family may not have gout, but there are usually at least one or two people in the family who have gout. Gout frequently involves the big toe, the foot, or the knee. The big toe will become extremely tender, and even placing a sheet on the toe will cause pain. In this condition, gout occurs in the late teenage years in both men and women. (In contrast, gout developing in the normal adult population tends to occur in overweight men in their 30’s to 50’s.) Family members may develop bumps on their joints called tophi that are deposits of uric acid.
(3) The disease is likely to be inherited. If a person has the disease, their children have a 1 out of 2 (50%) chance of having the disease. The disease does not skip a generation, though a parent may be less severely affected than their child, and may not have gout or other signs of kidney disease for some time. Therefore, there is usually a strong family history of the condition.
The following is an example of a typical patient case:
The patient is a healthy woman in overall good health. At the age of seventeen, she developed a bout of severe pain in her right big toe. This pain lasted for a week. The patient knew this was gout because her father, two uncles, and her grandmother had had gout. Her grandmother had died of kidney failure many years ago, and her father had had a kidney transplant and was doing well. She went to see her doctor who told her that she had gout. He was confused as to why she had gout—she was young and was a woman. He also did not know why so many family members had kidney disease. He ordered a blood uric acid level and a blood creatinine level. The blood uric acid level came back high, and the blood creatinine level was 1.8 (greater than 1 which is abnormal). He did a kidney biopsy which showed “interstitial nephritis (inflammation of the inside of the kidney)”. Later, another doctor suggested that she have a blood test to see if she had the gene for a disease called uromodulin associated kidney disease. She had the test done and found that she suffered from the disease.
What causes UMAK?
There is a protein that is normally made by kidney cells called uromodulin (also known as Tamm Horsfall Protein). This is the most common protein found in the urine of healthy people. It was discovered by Drs. Tamm and Horsfall about thirty years ago, and has been studied for many years, but no one knows what it does. The protein is normally made by kidney cells and then enters the urine.
In UMAK, there is a small change in the gene that makes the protein. This change in the gene causes a change in the amino acids that make up the protein. This results in the protein not being built normally. When the protein cannot be built normally, it precipitates abnormally in the cell and forms deposits. It is thought that these deposits slowly result in kidney cell death. Eventually, these changes lead to kidney failure.
Everyone has two genes that each make a uromodulin molecule. One gene is inherited from the father, and one is inherited by the mother. It only takes one abnormal gene to get the disease. This is because the abnormal protein that is made interferes with the machinery that the cell uses to make the uromodulin protein.
What about research?
This section describes the research that has occurred in this disease over time. The first paper ever written on this was by Duncan and Dixon who described a family with gout and kidney failure. Drs. Simmons and Cameron described a number of families suffering from this condition, and showed that a high blood uric acid level and low urine uric acid were the first signs of the disease and occurred in early childhood. Thereafter, several groups were able to link the disease to a certain area of the chromosome. Drs. Dahan and Hildebrandt then postulated that, based on genetic analysis, medullary cystic kidney disease type 2 and familial juvenile hyperuricemia were two different names given to the same disease. In 2003, Drs. Hart and Bleyer identified a mutation in the uromodulin gene. In 2004, a test became available by Athena Diagnostics so that individuals could be tested for the disease.
How can I find out if I have the disease?
Testing is currently available through Athena Diagnostics. It is available at the following website:
http://www.renaldx.com/content/tests/interstitial-kidney.asp
We would also be most interested to hear from you or your doctor if you think that you have the disease to help you find out more about your condition. Please email us at ableyer@wfubmc.edu .
What can I do if I find out I have the disease?
It is important to see your family doctor or a kidney doctor to help follow your kidney function. Taking a medicine called allopurinol may slow the progression of kidney failure and will prevent gout from becoming severe.
Our goal at Wake Forest University School of Medicine is to increase understanding about UMAK. We are committed to finding a cure for this condition. Finding a treatment will require studying the urine of as many affected individuals as possible. If you or someone you know has this condition, we hope that you will consider getting in touch with us. Working together, we believe that we will be able to find an effective treatment.
Research Update:
What is the latest news?
We are currently still examining urine samples to determine the concentration of the uromodulin protein in the urine. Learning about this protein in the urine will help us to better understand the disease.
We have currently identified the condition in eight families in the United States.
We are trying to obtain as many measurements of blood uric acid and serum creatinine as possible from patients who have had the disease for a long time. This will help us to determine how fast the disease progresses.
If you have any questions concerning this condition, please contact us at (336)-716-4513.
Please click on education booklet to download a patient information guide
Nephrology Section Conducts Research on Uromodulin Associated Kidney Disease (UMAK)
Wake Forest University Baptist Medical Center physician and researcher, Anthony Bleyer, M.D., M.S., a professor in the Section on Nephrology, together with a research team is working to identify individuals and families with potential genetic mutations that lead to Uromodulin Associated Kidney Disease (UMAK). UMAK is a disease caused by a mutation (mistake) in one of the genes that makes the protein uromodulin. Each individual has 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 is produced in the kidneys. 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 over thirty years, but still no one knows the function of normal uromodulin.
In UMAK, one of the uromodulin genes that inherited from the patients’ father or mother is mutated—or carries a mistake. This mistake inhibits the secretion of uromodulin from the cell that normally produces 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 inhibits the normal uromodulin (produced by the healthy gene) from being secreted normally from the cell. The uromodulin deposits in chunks that likely lead to cell death over time, leading to kidney failure.
Other members of the research team are: Tom Hart, D.D.S., Ph.D., who oversees the basic research on UMAK that is performed at the National Institutes of Health;
Vicki Robins, R.N., research coordinator for the UMAK study at Wake Forest, who provides information on the studies being performed and helps to collect samples and data for the study.
UMAK Study Has Two Major Goals:
The UMAK study has two major goals: to improve the understanding of UMAK and to find a treatment for this condition.
The study’s current research activities include:
· Further characterizing uromodulin associated kidney disease by evaluating kidney function in affected individuals
· Evaluating the effects of allopurinol on progression of disease
· Basic laboratory research studying the mutation after it is introduced into cultured cells
· Developing a mouse that has a mutation in uromodulin