Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney disease)
- Anthony Bleyer, MD, MS
Anthony Bleyer, MD, MS
- Professor of Internal Medicine/Nephrology
- Wake Forest University School of Medicine
- Section Editors
- Gary C Curhan, MD, ScD
Gary C Curhan, MD, ScD
- Section Editor — Chronic Kidney Disease
- Professor of Medicine
- Harvard Medical School
- Ronald D Perrone, MD
Ronald D Perrone, MD
- Section Editor — Cystic Disease
- Professor of Medicine
- Tufts University School of Medicine
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an uncommon group of genetic disorders characterized by progressive decline in kidney function and autosomal dominant inheritance . There are approximately 400 families in the United States suffering from this condition, and the prevalence in other countries is likely to be similar. Individual families may have a large number of affected individuals due both to autosomal dominant inheritance and to the late onset of chronic kidney disease (CKD). Underreporting due to incorrect diagnosis may contribute to the low estimated prevalence.
The etiology, clinical presentation, diagnosis, and treatment of the major subtypes of ADTKD are discussed in this topic. Discussions of other inherited renal disorders associated with progressive CKD, such as polycystic kidney disease, hereditary nephritis, and nephronophthisis, are presented elsewhere. (See "Diagnosis of and screening for autosomal dominant polycystic kidney disease" and "Autosomal dominant polycystic kidney disease in children" and "Autosomal recessive polycystic kidney disease in children" and "Clinical manifestations, diagnosis and treatment of hereditary nephritis (Alport syndrome)" and "Clinical manifestations, diagnosis, and treatment of nephronophthisis".)
OVERVIEW AND CLASSIFICATION
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by the following features:
●Autosomal dominant inheritance
●Slowly progressive kidney disease, with impaired renal function typically appearing in the teenage years, and end-stage renal disease (ESRD) onset that is highly variable, usually between the ages of 20 and 70 years
- Bleyer AJ, Hart PS, Kmoch S. Hereditary interstitial kidney disease. Semin Nephrol 2010; 30:366.
- Scolari F, Viola BF, Prati E, et al. Medullary cystic kidney disease: past and present. Contrib Nephrol 2001; :68.
- Eckardt KU, Alper SL, Antignac C, et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. Kidney Int 2015; 88:676.
- Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002; 39:882.
- Zivná M, Hůlková H, Matignon M, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet 2009; 85:204.
- Bleyer AJ, Zivná M, Hulková H, et al. Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. Clin Nephrol 2010; 74:411.
- Kirby A, Gnirke A, Jaffe DB, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 2013; 45:299.
- Dahan K, Fuchshuber A, Adamis S, et al. Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2: two facets of the same disease? J Am Soc Nephrol 2001; 12:2348.
- Lens XM, Banet JF, Outeda P, Barrio-Lucía 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; 46:52.
- Bleyer AJ, Hart TC, Willingham MC, et al. Clinico-pathologic findings in medullary cystic kidney disease type 2. Pediatr Nephrol 2005; 20:824.
- Bleyer AJ, Hart TC. Medullary cystic kidney disease type 2. Am J Kidney Dis 2004; 43:1142; author reply 1142.
- Kudo E, Kamatani N, Tezuka O, et al. Familial juvenile hyperuricemic nephropathy: detection of mutations in the uromodulin gene in five Japanese families. Kidney Int 2004; 65:1589.
- Dahan K, Devuyst O, Smaers M, et al. A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 2003; 14:2883.
- Turner JJ, Stacey JM, Harding B, et al. UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003; 88:1398.
- Calado J, Gaspar A, Clemente C, Rueff J. A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy. BMC Med Genet 2005; 6:5.
- Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy associated with hyperuricemia and gout. Arch Intern Med 1993; 153:357.
- Scolari F, Caridi G, Rampoldi L, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 2004; 44:987.
- Gusmano R, Caridi G, Marini M, et al. Glomerulocystic kidney disease in a family. Nephrol Dial Transplant 2002; 17:813.
- Lee DH, Kim JK, Oh SE, et al. A case of familial juvenile hyperuricemic nephropathy with novel uromodulin gene mutation, a novel heterozygous missense mutation in Korea. J Korean Med Sci 2010; 25:1680.
- Williams SE, Reed AA, Galvanovskis J, et al. Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum. Hum Mol Genet 2009; 18:2963.
- Bollée G, Dahan K, Flamant M, et al. Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations. Clin J Am Soc Nephrol 2011; 6:2429.
- Wei X, Xu R, Yang Z, et al. Novel uromodulin mutation in familial juvenile hyperuricemic nephropathy. Am J Nephrol 2012; 36:114.
- Köttgen A, Hwang SJ, Larson MG, et al. Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 2010; 21:337.
- Köttgen A, Pattaro C, Böger CA, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet 2010; 42:376.
- Hoyer JR, Sisson SP, Vernier RL. Tamm-Horsfall glycoprotein: ultrastructural immunoperoxidase localization in rat kidney. Lab Invest 1979; 41:168.
- Serafini-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003; 42:658.
- Mutig K, Kahl T, Saritas T, et al. Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner. J Biol Chem 2011; 286:30200.
- Renigunta A, Renigunta V, Saritas T, et al. Tamm-Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function. J Biol Chem 2011; 286:2224.
- Choi SW, Ryu OH, Choi SJ, et al. Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. J Am Soc Nephrol 2005; 16:3006.
- Rampoldi L, Caridi G, Santon D, et al. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 2003; 12:3369.
- Bleyer AJ, Hart TC, Shihabi Z, et al. Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein. Kidney Int 2004; 66:974.
- Bleyer AJ, Woodard AS, Shihabi Z, et al. Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int 2003; 64:36.
- Moro F, Ogg CS, Simmonds HA, et al. Familial juvenile gouty nephropathy with renal urate hypoexcretion preceding renal disease. Clin Nephrol 1991; 35:263.
- Trudu M, Janas S, Lanzani C, et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med 2013; 19:1655.
- Vyletal P, Bleyer AJ, Kmoch S. Uromodulin biology and pathophysiology--an update. Kidney Blood Press Res 2010; 33:456.
- Bates JM, Raffi HM, Prasadan K, et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 2004; 65:791.
- Cameron JS, Moro F, Simmonds HA. Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 1993; 7:105.
- McBride MB, Rigden S, Haycock GB, et al. Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children. Pediatr Nephrol 1998; 12:357.
- Stiburkova B, Bleyer AJ. Changes in serum urate and urate excretion with age. Adv Chronic Kidney Dis 2012; 19:372.
- Danovitch GM. Uric acid transport in renal failure. A review. Nephron 1972; 9:291.
- Fairbanks LD, Cameron JS, Venkat-Raman G, et al. Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. QJM 2002; 95:597.
- McBride MB, Simmonds HA, Ogg CS, et al. Efficacy of allopurinol in ameliorating the progressive renal disease in familial juvenile hyperuricaemic nephropathy (FJHN). A six-year update. Adv Exp Med Biol 1998; 431:7.
- Lhotta K. Stopping progression in familial juvenile hyperuricemic nephropathy with benzbromarone? Kidney Int 2003; 64:1920.
- Beck BB, Trachtman H, Gitman M, et al. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD. Am J Kidney Dis 2011; 58:821.
- Dzau VJ, Pratt RE, Paul M, Nakamura N. Molecular studies of human renin synthesis and gene expression. Cardiovasc Drugs Ther 1988; 2:459.
- Kiser RL, Wolf MT, Martin JL, et al. Medullary cystic kidney disease type 1 in a large Native-American kindred. Am J Kidney Dis 2004; 44:611.
- Auranen M, Ala-Mello S, Turunen JA, Järvelä I. Further evidence for linkage of autosomal-dominant medullary cystic kidney disease on chromosome 1q21. Kidney Int 2001; 60:1225.
- Wolf MT, Mucha BE, Hennies HC, et al. Medullary cystic kidney disease type 1: mutational analysis in 37 genes based on haplotype sharing. Hum Genet 2006; 119:649.
- Stavrou C, Koptides M, Tombazos C, et al. Autosomal-dominant medullary cystic kidney disease type 1: clinical and molecular findings in six large Cypriot families. Kidney Int 2002; 62:1385.
- Christodoulou K, Tsingis M, Stavrou C, et al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 1998; 7:905.
- Wolf MT, Karle SM, Schwarz S, et al. Refinement of the critical region for MCKD1 by detection of transcontinental haplotype sharing. Kidney Int 2003; 64:788.
- Pastor-Soler NM, Sutton TA, Mang HE, et al. Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 2015; 308:F1452.
- Katabathina VS, Kota G, Dasyam AK, et al. Adult renal cystic disease: a genetic, biological, and developmental primer. Radiographics 2010; 30:1509.
- Meier P, Farres MT, Mougenot B, et al. Imaging medullary cystic kidney disease with magnetic resonance. Am J Kidney Dis 2003; 42:E5.
- Ekici AB, Hackenbeck T, Morinière V, et al. Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin. Kidney Int 2014; 86:589.
- OVERVIEW AND CLASSIFICATION
- UROMODULIN KIDNEY DISEASE (UKD)
- Genetics of UKD
- Pathogenesis of UKD
- Clinical presentation of UKD
- - Gout
- - Chronic kidney disease
- Diagnosis of UKD
- - Presumptive clinical diagnosis
- - Confirm with genetic testing of the UMOD gene
- Differential diagnosis of UKD
- Treatment of UKD
- - Treatment of gout
- - Treatment of CKD
- Prevention of CKD progression
- Management of CKD manifestations
- ADTKD DUE TO MUTATIONS IN THE REN GENE (ADTKD-REN)
- Genetics of ADTKD-REN
- Pathogenesis of ADTKD-REN
- Clinical presentation of ADTKD-REN
- Diagnosis of ADTKD-REN
- - Confirm with genetic testing of the REN gene
- Differential diagnosis of ADTKD-REN
- Treatment of ADTKD-REN
- MUCIN-1 KIDNEY DISEASE (MKD)
- Genetics of MKD
- Pathogenesis of MKD
- Clinical presentation of MKD
- - Autosomal dominant CKD
- - Medullary cysts
- Diagnosis of MKD
- - Confirm with genetic testing of the MUC1 gene
- Differential diagnosis of MKD
- Treatment of MKD
- SUMMARY AND RECOMMENDATIONS
- ADDITIONAL INFORMATION AND CORRESPONDENCE