Medullary cystic kidney disease
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Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease. Autosomal dominant interstitial kidney disease (ADIKD) is a rare and heterogeneous genetic disorder .
Medullary cystic kidney disease (MCKD) − MCKD is another term that has been used for ADIKD.
Medullary cystic kidney disease may be classified according to genetic mutation into :
- Mutations in the UMOD gene, which encodes uromodulin are present in the majority of cases of ADIKD . This condition has also called uromodulin-associated kidney disease (UAKD) , medullary cystic kidney disease type 2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN) .
- Mutations in the REN gene, which encodes renin.
- Mutations in the MUC1 gene, which encodes mucin 1 ,called as medullary cystic kidney disease type 1 (MCKD1).
- Uromodulin associated kidney disease ( UAKD ) :
- UAKD is due to mutations in the UMOD gene on chromosome 16p12, which encodes uromodulin (Tamm-Horsfall mucoprotein).
- Missense Mutation in exon 4 or 5 , it very rare mutation in exons 6 or 8
- Uromodulin is produced exclusively in the thick ascending limb of the loop of Henle . It is an insoluble protein whose sticky, adherent properties are probably important in maintaining the watertight integrity of the thick ascending limb.
- Uromodulin also appears to facilitate intracellular transport of both the Na-K-2Cl furosemide-sensitive transporter and the ROMK potassium channel on the apical surface of the thick ascending loop tubular cells .
- intracellular accumulation of abnormal uromodulin proteins can lead to tubular cell atrophy and death.
- The abnormal uromodulin appears to impair the synthesis and secretion of normal uromodulin produced from the unaffected allele, resulting in a marked reduction in urinary uromodulin excretion. 
- There is two major pathophysiologic effects of uromodulin gene mutations (1 ) hyperuricemia , ( 2 ) progressive chronic kidney disease .
- Hyperuricemia :
- Is due to accumulation of abnormal uromodulin in thick ascending limb cells leads sequentially to impaired NaCl reabsorption, mild renal salt wasting, volume contraction, and a secondary increase in proximal urate reabsorption , which restores volume status to normal but leads to hyperuricemia.
- Progressive chronic kidney disease :
- Is due to tubular cell death in the thick ascending limb due to accumulation of mutant uromodulin.Renal biopsy reveals tubulointerstitial disease but no uric acid crystals. 
- Mutations in the REN gene :
- The renin gene is located on chromosome 1.Two REN gene mutations associated with ADIKD which is due to signal sequence of pre-prorenin.
- Mutations in this signal sequence disrupt the translocation of pre-prorenin into the endoplasmic reticulum of renin expressing cells.
- Renin is necessary for nephrogenesis, homozygous deletions of renin result in death during uterine development .
- Renin is present in multiple segments of the renal tubule, also on the juxtaglomerular complex. In these cells, pre-prorenin is translocated into the endoplasmic reticulum, where it is converted to prorenin.
- prorenin is secreted, while the remainder is targeted to lysosomes where it is further cleaved to active renin.
- Mutations which disrupt the signal sequence of prorenin prevent proper translocation to the endoplasmic reticulum,as a result accumulation of pre-prorenin in the cytoplasm of renin producing cells.
- Due to accumulation of pre-prorenin in renal tubular cells leads to ultrastructural damage and apoptosis .
Differentiating [disease name] from other Diseases
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Epidemiology and Demographics
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Natural History, Complications and Prognosis
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Other Diagnostic Studies
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- Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, Büchler M, Cochat P, Cosyns JP, Mougenot B, Rider MH, Antignac C, Verellen-Dumoulin C, Pirson Y (November 2003). "A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin". J. Am. Soc. Nephrol. 14 (11): 2883–93. PMID 14569098.
- Bleyer AJ, Trachtman H, Sandhu J, Gorry MC, Hart TC (August 2003). "Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene". Am. J. Kidney Dis. 42 (2): E20–6. PMID 12900848.
- Williams SE, Reed AA, Galvanovskis J, Antignac C, Goodship T, Karet FE, Kotanko P, Lhotta K, Morinière V, Williams P, Wong W, Rorsman P, Thakker RV (August 2009). "Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum". Hum. Mol. Genet. 18 (16): 2963–74. doi:10.1093/hmg/ddp235. PMC 2714724. PMID 19465746.
- Zivná M, Hůlková H, Matignon M, Hodanová K, Vylet'al P, Kalbácová M, Baresová V, Sikora J, Blazková H, Zivný J, Ivánek R, Stránecký V, Sovová J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gübler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S (August 2009). "Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure". Am. J. Hum. Genet. 85 (2): 204–13. doi:10.1016/j.ajhg.2009.07.010. PMC 2725269. PMID 19664745.