Autosomal dominant tubulointerstitial kidney disease-UMOD

Autosomal dominant tubulointerstitial kidney disease-UMOD (ADTKD-UMOD) is part of a group of disorders (collectively called autosomal dominant tubulointerstitial kidney disease or ADTKD) that cause a slow loss of kidney function. In people with ADTKD-UMOD, the signs and symptoms of kidney disease often begin in adolescence or early adulthood. Over time, the kidneys become less able to filter fluids and waste products from the body. People with ADTKD-UMOD eventually develop kidney failure, which requires either dialysis to remove waste from the blood or a kidney transplant. The age at which people with ADTKD-UMOD develop kidney failure can vary, though the average age is approximately 45 years. 

People with ADTKD-UMOD typically develop high levels of a waste product called uric acid in their blood. Normally, the kidneys transfer uric acid from the blood into urine, which then removes it from the body. People with ADTKD-UMOD are unable to remove uric acid from the blood effectively. In about 50 percent of people with ADTKD-UMOD, uric acid builds up in the joints and causes a form of arthritis called gout, typically in late adolescence or early adulthood. Gout is characterized by a sudden onset of severe joint pain and redness, often starting in the big toe. Untreated episodes of gout typically worsen over time.

ADTKD-UMOD is believed to account for fewer than 1 percent of all cases of kidney failure. Researchers aren't sure how common ADTKD-UMOD actually is, but it is considered to be one of the most common forms of kidney disease that is caused by changes in a single gene. 

Variants (also called mutations) in the UMOD gene cause ADTKD-UMOD. This gene provides instructions for making the uromodulin protein. This protein is produced by the kidneys and then released from the body in urine. Uromodulin is the most common protein found in the urine of healthy individuals. It is thought to play a role in the transport of minerals such as sodium and potassium. 

Most variants in the UMOD gene change single protein building blocks (amino acids) in the uromodulin protein. These variants typically alter the structure of the protein, though some variants have more severe effects on protein function than others. People with UMOD variants that have a greater effect on protein function generally have severe kidney disease, and these individuals experience signs and symptoms of kidney disease at a younger age. Typically, UMOD gene variants prevent kidney cells from releasing the uromodulin protein. The buildup of uromodulin may trigger the self-destruction (apoptosis) of cells in the kidneys, leading to kidney disease and eventual kidney failure.

Genetic Testing Information

• Genetic Testing Registry: Familial juvenile hyperuricemic nephropathy type 1

Genetic and Rare Diseases Information Center

• UMOD-related autosomal dominant tubulointerstitial kidney disease

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT, 1; ADTKD1

Scientific Articles on PubMed

• PubMed

• Bleyer AJ, Hart TC. Genetic factors associated with gout and hyperuricemia. Adv Chronic Kidney Dis. 2006 Apr;13(2):124-30. doi: 10.1053/j.ackd.2006.01.008. Citation on PubMed
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• Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, Fasel DA, Weng C, Radhakrishnan J, Canetta P, Appel GB, Bomback AS, Ahn W, Uy NS, Alam S, Cohen DJ, Crew RJ, Dube GK, Rao MK, Kamalakaran S, Copeland B, Ren Z, Bridgers J, Malone CD, Mebane CM, Dagaonkar N, Fellstrom BC, Haefliger C, Mohan S, Sanna-Cherchi S, Kiryluk K, Fleckner J, March R, Platt A, Goldstein DB, Gharavi AG. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019 Jan 10;380(2):142-151. doi: 10.1056/NEJMoa1806891. Epub 2018 Dec 26. Citation on PubMed
• 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 Genet. 2002 Dec;39(12):882-92. doi: 10.1136/jmg.39.12.882. Citation on PubMed or Free article on PubMed Central
• Lens XM, Banet JF, Outeda P, Barrio-Lucia V. A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease. Am J Kidney Dis. 2005 Jul;46(1):52-7. doi: 10.1053/j.ajkd.2005.04.003. Citation on PubMed
• Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, Tardanico R, Dagnino M, Colussi G, Scolari F, Ghiggeri GM, Amoroso A, Casari G. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet. 2003 Dec 15;12(24):3369-84. doi: 10.1093/hmg/ddg353. Epub 2003 Oct 21. Citation on PubMed
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• Vylet'al P, Kublova M, Kalbacova M, Hodanova K, Baresova V, Stiburkova B, Sikora J, Hulkova H, Zivny J, Majewski J, Simmonds A, Fryns JP, Venkat-Raman G, Elleder M, Kmoch S. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int. 2006 Sep;70(6):1155-69. doi: 10.1038/sj.ki.5001728. Epub 2006 Aug 2. Citation on PubMed
• Zivna M, Kidd KO, Baresova V, Hulkova H, Kmoch S, Bleyer AJ Sr. Autosomal dominant tubulointerstitial kidney disease: A review. Am J Med Genet C Semin Med Genet. 2022 Sep;190(3):309-324. doi: 10.1002/ajmg.c.32008. Epub 2022 Oct 17. Citation on PubMed