Última actualización:
April 24, 2020
Años publicados: 1986, 1990, 1994, 2004, 2011, 2014, 2017, 2020
NORD gratefully acknowledges Anthony J. Bleyer, MD, Section on Nephrology, Wake Forest University School of Medicine, for assistance in the preparation of this report.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) describes a group of diseases that affect the tubules of the kidney. These conditions have the following characteristics: They are inherited in an autosomal dominant manner; this means that a parent has a 50% chance of passing the disease on to their children. Often many family members are affected. (2) Chronic kidney disease develops. This initially is noticed as an elevated blood creatinine level. There are no symptoms from an elevated creatinine until it is very high, so often the elevated creatinine is found out on blood testing at a doctor’s office or in the hospital. Often, doctors are uncertain why the creatinine is elevated. As chronic kidney disease progresses, and the creatinine rises more, patients develop symptoms of fatigue, anemia, and feel cold all the time. Decreased appetite and fluid retention develop as the patient nears the need for dialysis. (3) Dialysis or kidney transplant is required sometime between the 4th and 7th decade of life. (4) Several types of the disease are associated with elevated uric acid concentrations in blood and gout, which sometimes starts in the teenage years. In ADTKD-UMOD and ADTKD- REN, some – but not all – family members are affected by gout.
ADTKD-UMOD (also known as 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 previously been called familial juvenile hyperuricemic nephropathy type1 or medullary cystic kidney disease type 2. Preferred terms at present include ADTKD-UMOD and uromodulin kidney disease (UKD).
ADTKD-REN is caused by mutations in the gene producing a protein called renin. There are several types of this disorder. Children can present as early as infancy with elevated blood potassium levels, low blood bicarbonate levels, decreased kidney function, and anemia. Some individuals present later in childhood with anemia and decreased kidney function. Often, their blood potassium levels are mildly elevated, and their blood uric acid levels are also elevated. These individuals also suffer from gout. Some families with this disorder may have a less severe mutation and may present in their early twenties with gout and later develop chronic kidney disease. This condition has previously been called familial juvenile hyperuricemic nephropathy type 2.
ADTKD-MUC1 (MUC1 kidney disease) is due to mutations in the gene producing the protein mucin-1. Patients with this type of autosomal dominant tubulointerstitial 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. Mildly decreased kidney function may first be noted in the late teens/early twenties, 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 tubulotubulointerstitial 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. Some of these families have mutations in the MUC1 gene that have not yet been identified and are difficult to find.
All individuals with ADTKD show slow loss of kidney function that may be present as early as childhood. 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. Doctors will check the urine, and will find that it does not contain blood and little or no protein. A kidney ultrasound is usually normal, and even a kidney biopsy may not point to a cause for this condition. Doctors are often confused because the patient has an elevated creatinine but the urine tests and the kidney ultrasound look normal. Thus, ADTKD is frequently not properly diagnosed. The kidney disease progresses slowly, and patients eventually develop symptoms of kidney failure (nausea, fluid retention) and require dialysis or kidney transplant. The age that kidney transplant or dialysis is required is highly variable, with some individuals requiring it as early as age 17, while other family members may not even require it at age 70. The reason for this variation is unclear.
Individuals with ADTKD-MUC1 only have symptoms of chronic kidney disease progression and do not suffer from other distinctive symptoms, making this form of the disease even more difficult to diagnose.
In addition to chronic kidney disease, patients with ADTKD-UMOD have elevated levels of blood uric acid that can lead to gout. 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. While many families with ADTKD-UMOD have gout, it is not present in all families.
In addition to high uric acid levels, gout, and chronic kidney disease, Individuals with ADTKD-REN all suffer from anemia early in life, being present as early as one year of age. Anemia usually resolves during adolescence but returns when kidney failure worsens (usually in the 30’s or 40’s). Often, the cause of the anemia is not known when diagnosed. Patients also tend to have low blood pressures and high blood potassium levels. Some, but not all, affected individuals produce more than normal amounts of urine, which can result in bed-wetting in childhood.
Individuals with autosomal dominant tubulointerstitial 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 tubulointerstitial 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. We all have two copies of each gene. Individuals with ADTKD have one normal copy and one abnormal copy. The parent has a 50/50 chance of passing the abnormal gene on to their child. Thus, children of an affected individual have a 50/50 chance of having the disease. The risk is the same for males and females. There are usually a number of family members affected, with at least a parent and child almost always affected.
ADTKD-UMOD 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.
ADTKD-REN 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.
ADTKD-MUC1 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, and every other organ/tissue is completely normal.
Autosomal dominant tubulointerstitial kidney disease of unknown cause is caused by a mutation in a gene, but the gene that causes the disease is not yet known.
All types of autosomal dominant tubulointerstitial kidney disease are very uncommon.
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 in ADTKD-UMOD and ADTKD-REN (though not elevated early on in ADTKD-MUC1). 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 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. The real key to the diagnosis is that a parent and a child are usually both affected with kidney disease. Kidney biopsy may be performed, but the kidney biopsy cannot specifically diagnose ADTKD: genetic testing is required.
Molecular genetic testing is available for ADKTD-MUC1, ADTKD-UMOD, and ADTKD-REN. Genetic testing for ADTKD-UMOD and ADTKD-REN is available in commercial laboratories. ADTKD-MUC1 testing is available at present free of charge from the Broad Institute, Boston, Massachusetts. In order to arrange for this testing, please contact Anthony Bleyer MD at [email protected].
If no mutations are found, individuals have autosomal dominant tubulointerstitial kidney disease of unknown genetic cause. Further genetic testing can be done at academic medical centers to help diagnose this disease. Contact [email protected] for further information.
Treatment
Many affected individuals with ADTKD-UMOD and ADTKD-REN 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 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. Febuxostat is an alternative to allopurinol. Both febuxostsat and allopurinol should be stopped immediately in pregnancy is considered or becoming pregnant is possible. There are other uric acid lowering therapies that can be considered and discussed with the treating physician.
Some doctors believe that allopurinol can slow progression of kidney disease in ADTKD-UMOD, 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.
For ADTKD-MUC, 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 ADTKD-REN who have 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. It is very important that patients with ADTKD-REN are NOT put on a low sodium diet, as this could worsen kidney function.
Anemia occurring in childhood with ADTKD-REN 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. However, the anemia is usually mild and asymptomatic and may not require therapy.
There are no specific treatments for ADTKD-MUC1 or ADTKD 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
Email: [email protected]
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about autosomal dominant tubulointerstitial kidney disease:
Anthony J. Bleyer, M.D.
Section on Nephrology
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157
336-716-4513
[email protected]
TEXTBOOKS
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.
REVIEW ARTICLES
Devuyst O, Olinger E, Weber S, Eckardt KU, Kmoch S, Rampoldi L, Bleyer AJ: Autosomal dominant tubulointerstitial kidney disease. Nature Reviews Disease Primers 2019; 5: 60-69.
Bleyer AJ, Kidd K, Zivna M, Kmoch S. Autosomal Dominant Tubulo-Interstitial Kidney Disease. Adv Chronic Kidney Dis 2017; 24: 86-93.
Eckardt KU, Alper SL, Antignac C, Bleyer AJ, Chauveau D, Dahan K, Deltas C, Hosking A, Kmoch S, Rampoldi L, Wiesener M, Wolf MT, Devuyst O: Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—a KDIGO consensus report. Kidney Int. 2015; 88: 676-683.
JOURNAL ARTICLES.
Bleyer AJ, Kidd K, Robins V, Martin L, Taylor A, Santi A, Tsoumas G, Hunt A, Swain E, Abbas M, Akinbola E, Vidya S, Moossavi S, Bleyer AJ Jr, Živná M, Hartmannová H, Hodaňová K, Vyleťal P, Votruba M, Harden M, Blumenstiel B, Greka A, Kmoch S: Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases. Genet Med 2020; 22:142-149.
Cormican S, Kennedy C, Connaughton DM, O’Kelly P, Murray S, Živná M, Kmoch S, Fennelly NK, Benson KA, Conlon ET, Cavalleri GL, Foley C, Doyle B, Dorman A, Little MA, Lavin P, Kidd K, Bleyer AJ, Conlon PJ. Renal transplant outcomes in patients with autosomal dominant tubulointerstitial kidney disease. Clin Transplant 2020; e13783
Bleyer AJ, Kidd K, Johnson E, Robins V, Martin L, Taylor A, Pinder AJ, Bowline I, Frankova V, Živná M, Taylor KB, Kim N, Baek JJ, Hartmannová H, Hodaňová K, Vyleťal P, Votruba M, Kmoch S. Quality of life in patients with autosomal dominant tubulointerstitial kidney disease. Clin Nephrol 2019; 92: 302-311.
Cormican S, Connaughton DM, Kennedy C, Murray S, Živná M, Kmoch S, Fennelly NK, O’Kelly P, Benson KA, Conlon ET, Cavalleri G, Foley C, Doyle B, Dorman A, Little MA, Lavin P, Kidd K, Bleyer AJ, Conlon PJ. Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland. Renal Failure 2019; 41: 832-841.
Dvela-Levitt M, Kost-Alimova M, Emani M, Kohnert E, Thompson R, Sidhom EH, Rivadeneira A, Sahakian N1, Roignot J, Papagregoriou G, Montesinos MS, Clark AR, McKinney D, Gutierrez J, Roth M, Ronco L, Elonga E, Carter TA, Gnirke A, Melanson M, Hartland K, Wieder N, Hsu JC, Deltas C, Hughey R, Bleyer AJ, Kmoch S, Živná M, Barešova V, Kota S, Schlondorff J, Heiman M, Alper SL, Wagner F, Weins A, Golub TR, Lander ES, Greka A: Small molecule targets TMED9 and promotoes lysosomal degradation to reverse proteinopathy. Cell 2019; 178: 521-535.
Martina Živná, Kendrah Kidd, Anna Přistoupilová, Veronika Barešová, Mathew DeFelice, Brendan Blumenstiel, Maegan Harden,Peter Conlon, MD, MHS, FRCPI, FRCP, FACP, Peter Lavin, MB, PhD, Dervla M. Connaughton, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Alena Vrbacká, Petr Vyleťal, Jan Živný, Miroslav Votruba, Jana Sovová, Helena Hůlková, Victoria Robins, Rebecca Perry, Andrea Wenzel, Bodo B. Beck, Tomáš Seeman, Sylvie Rajnochová-Bloudíčková, Ondřej Viklický, Gregory Papagregoriou, Constantinos Deltas, Seth L. Alper, Anna Greka, Anthony J. Bleyer, Stanislav Kmoch: Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulo-Interstitial Kidney Disease. J Am Soc Nephrol 2018. 29:2418-2431.
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.
INTERNET
Uromodulin Kidney Disease https://www.wakehealth.edu/Condition/u/Uromodulin-Kidney-Disease Accessed April 8, 2020.
Mucin-1 Kidney disease https://www.wakehealth.edu/Condition/m/Mucin-1-Kidney-Disease Accessed April 8, 2020.
Bleyer AJ, Kmoch S. Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related. 2013 Aug 15 [Updated 2016 Jun 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK153723/ Accessed April 8, 2020.
Bleyer AJ, Hart PS, Kmoch S. Autosomal Dominant Tubulointerstitial Kidney Disease, UMOD-Related. 2007 Jan 12 [Updated 2016 Jun 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1356/ Accessed April 8, 2020.
Kmoch S, Živná M, Bleyer AJ. Autosomal Dominant Tubulointerstitial Kidney Disease, REN-Related. 2011 Apr 5 [Updated 2015 Dec 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53700/ Accessed April 8, 2020.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report