Medullary cystic kidney disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: nabeel ahmed

Overview

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.

Classification

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).[1]

Pathophysiology

  • 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. [2]
  • 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. [3]
  • 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 .[4]

Clinical Features

Differentiating [disease name] from other Diseases

  • [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:
  • [Differential dx1]
  • [Differential dx2]
  • [Differential dx3]

Epidemiology and Demographics

  • The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
  • In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].

Age

  • Patients of all age groups may develop [disease name].
  • [Disease name] is more commonly observed among patients aged [age range] years old.
  • [Disease name] is more commonly observed among [elderly patients/young patients/children].

Gender

  • [Disease name] affects men and women equally.
  • [Gender 1] are more commonly affected with [disease name] than [gender 2].
  • The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

Race

  • There is no racial predilection for [disease name].
  • [Disease name] usually affects individuals of the [race 1] race.
  • [Race 2] individuals are less likely to develop [disease name].

Risk Factors

  • Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

Natural History, Complications and Prognosis

  • The majority of patients with [disease name] remain asymptomatic for [duration/years].
  • Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
  • If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
  • Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
  • Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Diagnosis

Symptoms

  • [Disease name] is usually asymptomatic.
  • Symptoms of [disease name] may include the following:
  • [symptom 1]
  • [symptom 2]
  • [symptom 3]
  • [symptom 4]
  • [symptom 5]
  • [symptom 6]

Physical Examination

  • Patients with [disease name] usually appear [general appearance].
  • Physical examination may be remarkable for:
  • [finding 1]
  • [finding 2]
  • [finding 3]
  • [finding 4]
  • [finding 5]
  • [finding 6]

Laboratory Findings

  • There are no specific laboratory findings associated with [disease name].
  • A [positive/negative] [test name] is diagnostic of [disease name].
  • An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
  • Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

  • There are no [imaging study] findings associated with [disease name].
  • [Imaging study 1] is the imaging modality of choice for [disease name].
  • On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
  • [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

  • [Disease name] may also be diagnosed using [diagnostic study name].
  • Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

  • There is no treatment for [disease name]; the mainstay of therapy is supportive care.
  • The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
  • [Medical therapy 1] acts by [mechanism of action 1].
  • Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

  • Surgery is the mainstay of therapy for [disease name].
  • [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
  • [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

  • There are no primary preventive measures available for [disease name].
  • Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
  • Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.



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