Autosomal dominant interstitial kidney disease describes a group of diseases affecting solely the proper function of the kidney and having the following characteristics: They are inherited in an autosomal dominant manner; kidney disease develops, and dialysis or kidney transplant is required sometime between the 4th and 7th decade of life; and several types of the disease are associated with elevated uric acid concentrations in blood and gout, which usually starts in the teenage years. Not all family members are affected by gout, but many are.
There has been a lot of confusion with regards to different names given to these conditions. This has created confusion for patients and doctors alike.
The term medullary cystic kidney disease is sometimes used to describe this condition. However, many, if not most, individuals with this disease do not have medullary cysts, so this name is being used less frequently. Some doctors still use this term.
The term familial juvenile hyperuricemic nephropathy is also used. "Familial" refers to the fact that the disease is inherited. "Juvenile" refers to the fact that it is first noticed frequently in childhood. "Hyperuricemic" refers to the fact that many patients have high blood uric acid levels (this causes gout). "Nephropathy" refers to the fact that this is a kidney disease.
Autosomal dominant interstitial kidney disease currently includes the following disorders. It is likely that additional forms of this disease will be indentified.
Uromodulin kidney disease is the most common form of this condition. It is caused by a mutation in a gene producing a protein called uromodulin. This protein is only made in the kidney. The mutation causes affected individuals to develop gout, frequently in their teenage years, and progressive kidney disease. This particular condition has also been called familial juvenile hyperuricemic nephropathy type1 or medullary cystic kidney disease type 2.
Autosomal dominant interstitial kidney disease due to renin mutations is caused by mutations in the gene producing a protein called renin. Affected individuals usually develop anemia in childhood. Often, their blood potassium levels are mildly elevated, and their blood uric acid levels are also elevated. These individuals also suffer from gout frequently. This condition has also been called familial juvenile hyperuricemic nephropathy type 2.
Autosomal dominant interstitial kidney disease due to MUC1 mutations (also known as medullary cystic kidney disease type1 ) is another cause of this condition. Patients with this type of autosomal dominant interstitial kidney disease have slowly progressive chronic kidney disease. They do not have any symptoms when they are young, but as they get older, their kidney function declines, and affected individuals usually require dialysis or a kidney transplant between the 3rd and seventh decades of life. Unlike the other types of the disease (uromodulin kidney disease or disease due to renin mutations), patients with MUC1 mutations do not have frequent gout, anemia or other symptoms.
Autosomal dominant interstitial kidney disease of unknown genetic cause is the term used to describe families with this disease in whom the cause is not known. These individuals usually have chronic kidney disease but do not have gout. Researchers are now trying to find the cause of this disease.
Individuals affected with uromodulin kidney disease almost always have high blood uric acid levels and often develop gout in their teenage years. Gout is a form of arthritis (joint inflammation) that commonly affects the big toe, knee, elbow, or other joints. Gout is usually a disease of middle-aged men. Therefore, gout may be misdiagnosed in teenagers with this condition. When gout is diagnosed, doctors frequently are unsure why the gout is present.
Slow loss of kidney function develops, and patients may first be diagnosed with this disease when they are found to have an elevated blood creatinine level (measure of kidney function) on a routine blood test at their doctor’s office. For many individuals, there may be no other symptoms. The kidney disease progresses slowly, and patients eventually develop symptoms of kidney failure (nausea, fluid retention) and require dialysis or kidney transplant, usually in their 4th through 7th decade of life.
Individuals with autosomal dominant interstitial kidney disease due to renin mutations frequently develop anemia, which has been detected as early as the first year of life. Anemia may improve but return when kidney failure worsens (usually in the 30’s or 40’s). Often, the cause of the anemia is not known when diagnosed. Some, but not all, affected individuals produce more than normal amounts of urine, which can result in bed-wetting in childhood. Other symptoms that might be present include small kidneys, mildly low or low normal blood pressure, mildly high blood potassium levels, and gout that may begin in the late teenage years.
Slow loss of kidney function is the only symptom of autosomal dominant interstitial kidney disease due to MUC1 mutations. Patients are diagnosed with this disease when they are found to have an elevated serum creatinine level (measure of kidney function) on a routine blood test at their doctor’s office. The kidney disease progresses slowly, and patients eventually develop symptoms of kidney failure (nausea, fluid retention) and require dialysis or kidney transplant, usually in their 4th through 7th decade of life.
Individuals with autosomal dominant interstitial kidney disease of unknown genetic cause are similar to those with disease due to MUC1 mutations, in that the only symptom is slowly progressive kidney disease.
All types of autosomal dominant interstitial kidney disease follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Uromodulin kidney disease is caused by a mistake (mutation) in a gene that encodes the protein called uromodulin. The abnormal protein builds up in kidney cells and causes slow progression of kidney disease. The reason why affected individuals develop gout is unclear, but likely related to improper function of kidney cells and/or abnormally low amounts of the uromodulin in sites where it is needed.
Autosomal dominant interstitial kidney disease due to renin mutations is caused by a mutation in a gene that encodes the protein called renin. The abnormal protein either builds up in kidney cells or is not produced in substantial amounts when needed, and this causes slow progression of kidney disease. Because affected individuals have low amounts of normal renin, patients may have mildly low blood pressure and mildly high potassium levels.
Autosomal dominant interstitial kidney disease due to MUC1 mutations is caused by a mutation in the gene that encodes mucoprotein-1. Mucoprotein-1 is a protein that is made in many of the cells of the body and provides a protective lining to the stomach, lungs, kidney tubules, and many other areas of the body. For some reason, the mutation only leads to problems in the kidney.
Autosomal dominant interstitial kidney disease of unknown cause is caused by a mutation in a gene, but the gene that causes the disease is not yet known.
Several lab tests are very helpful in pointing to this diagnosis. First, a blood test is done to measure the blood creatinine. In this condition, the blood creatinine is usually elevated, beginning in the second decade of life. A blood uric acid level is also tested and is almost always elevated. A urine test (urinalysis) is done. The absence of blood or protein in the urine rules out other possible causes of kidney damage. Thus, most individuals with this condition have high blood uric acid levels, high blood creatinine levels, and a normal urinalysis. A kidney ultrasound is also frequently done and usually shows normal kidneys, though some individuals may be found to have cysts in the middle of the kidney.
Molecular genetic testing is available for the uromodulin, renin, and MUC1 gene mutations associated with these conditions. Parents who have child with a specific mutation may want to screen younger children to see if they have the disease. In young children, the serum uric acid level and serum creatinine may be normal. To be certain, genetic testing must be done to determine if the disease is present.
If no mutations are found, individuals have autosomal dominant interstitial kidney disease of unknown genetic cause. Further genetic testing can be done at academic medical centers to help diagnose this disease
Many affected individuals suffer from gout beginning in the teenage years. The gout is easily treated with a medication called allopurinol. Allopurinol is a medicine that is commonly used in the treatment of gout. It has been used for many years and by thousands of patients with gout. Patients occasionally have allergies to the medication, which only rarely are severe. This medication easily controls gout in affected individuals. In uromodulin kidney disease, gout, if untreated, will continue and worsen over time. Therefore, early treatment is advisable.
Some doctors believe that allopurinol can slow progression of kidney disease in uromodulin kidney disease, even in patients who do not have gout. It is not clear if allopurinol slows progression of disease. It does not appear to stop progression of the kidney disease entirely.
If individuals cannot tolerate allopurinol, similar medicines (febuxostat or probenecid) should be considered.
There are a group of medications called angiotensin converting enzyme (ACE) inhibitors that have been shown to slow progression of kidney failure in many kidney diseases. It is unclear if they slow progression of disease in uromodulin kidney disease, but it is possible.
For patients with mildly high blood potassium and mildly low blood pressures, the medication fludrocortisone may be an effective treatment. This treatment was found to improve kidney function in one child with this disease, but did not have an effect on an older patient with advanced kidney disease.
Anemia occurring in childhood may be treated with a medication called erythropoietin. This medication is given as a shot once every week or every other week and will correct the anemia.
There are no specific treatments for autosomal dominant interstitial kidney disease due to MUC1 mutations or of unknown genetic cause.
Individuals with renin mutations should avoid non-steroidal anti-inflammatory agents such as ibuprofen (Advil, Aleve) or naprosyn.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about autosomal dominant interstitial kidney disease:
Anthony J. Bleyer, M.D.
Section on Nephrology
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157
Simkes AM. Medullary Cystic Kidney Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:693-94.
Bleyer AJ. Familial Juvenile Hyperuricemic Nephropathy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:696.
Bleyer AJ, Zivná M, Kmoch S. Uromodulin-associated kidney disease. Nephron Clin Pract. 2011;118(1):c31-6.
Bleyer AJ, Hart PS, Kmoch S: Hereditary Interstitial Kidney Disease. Bleyer AJ, Hart PS, Kmoch S. Seminars in Nephrology. 2010; 30: 366-373.
Kirby A, Gnirke A, Jaffe DB, Barešová V, Pochet N, Blumenstiel B, Ye C, Aird D, Stevens C, Robinson JT, Cabili MN, Gat-Viks I, Kelliher E, Daza R, Defelice M, Hulková H, Sovová J, Vylet’al P, Antignac C, Guttman M, Handsaker RE, Perrin D, Steelman S, Sigurdsson S, Scheinman SJ, Sougnez C, Cibulskis K, Parkin M, Green T, Rossin E, Zody MC, Xavier RJ, Pollak MR, Alper SL, Lindblad-Toh K, Gabriel S, Hart PS, Regev A, Nusbaum C, Kmoch S, Bleyer AJ, Lander ES, Daly MJ. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet. 2013;45(3):299-303. doi: 10.1038/ng.2543. PMID: 23396133.
Bleyer AJ, Zivná M, Hulková H, Hodanová K, Vyletal P, Sikora J, Zivný J, Sovová J, Hart TC, Adams JN, Elleder M, Kapp K, Haws R, Cornell LD, Kmoch S, Hart PS. Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. Clin Nephrol 2010;74:411-422.
Schaffer P, Gombos E, Meichelbeck K, Kiss A, Hart PS, Bleyer AJ: Childhood course of renal insufficiency in a family with a uromodulin gene mutation. Pediatr Nephrol 2010;25(7):1355-1360.
Zivna M, Hulkova H, Matignon M, Hodanova K, Bylet’al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S: Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009; 85: 204-213.
Bleyer AJ, Hart TC, Willingham MC, Iskandar SS, Gorry MC, Trachtman H: Clinico-pathologic findings in medullary cystic kidney disease type 2. Pediatr Nephrol. 2005;20:824-827.
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. 2003;64:36-42.
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;42:E20-E26.
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 hyperuricemic nephropathy. J Med Genet. 2002;39:882-892.
Bleyer AJ, Hart PS. UMOD-Associated Kidney Disease. 2007 Jan 12 [Updated 2013 Sep 12]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1356/ Accessed Jan 2, 2014.
Kmoch S, Živná M, Bleyer AJ. Familial Juvenile Hyperuricemic Nephropathy Type 2. 2011 Apr 5. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK53700/ Accessed Jan 2, 2014.
Cohen D. Medullary cystic disease. Medical Encyclopedia, MEDLINEplus. www.nlm.nih.gov/medlineplus/ency/article/000465.htm
Last Updated: 9/19/2011. Accessed Jan 2, 2014.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Medullary Cystic Kidney Disease 1; MCKD1. Entry No: 174000; Last Edited 07/03/2013. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed Jan 2, 2014.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Medullary Cystic Kidney Disease 2; MCKD2. Entry No: 603860; Last Updated 07/03/2013. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed Jan 2, 2014.
Devarajan P. Medullary Cystic Disease.Medscape www.emedicine.com/ped/topic1393.htm. Updated Aug 21, 2013. Accessed Jan 2, 2014.