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Medullary Cystic Disease Clinical Presentation

  • Author: Prasad Devarajan, MD, FAAP; Chief Editor: Craig B Langman, MD  more...
 
Updated: Nov 16, 2015
 

History

A family history of consanguinity, early death, or renal disease is present in 67% of patients with nephronophthisis (NPH).

In juvenile nephronophthisis (the most common form), the first symptoms usually develop around age 5 years and consist of polyuria and polydipsia. These symptoms are related to a reduced urinary concentrating capacity and loss of sodium conservation and occur early in the course of the disease, well before a reduction in glomerular filtration rate. Typically, the urine osmolarity is less than 400 mosm/kg in the first morning sample.

Children exhibit decreased growth velocity, initially related to chronic dehydration and subsequently confounded by renal insufficiency.

Features that distinguish nephronophthisis from medullary cystic kidney disease (MCKD) include the following:

  • The inheritance pattern is autosomal recessive.
  • The median age of onset of end-stage renal disease (ESRD) is 13 years in juvenile nephronophthisis, 1-3 years in infantile nephronophthisis, and 19 years in adolescent nephronophthisis.

Extrarenal associations of nephronophthisis include the following:

  • Cogan syndrome - Oculomotor apraxia
  • Senior-Loken syndrome - Retinitis pigmentosa
  • Mainzer-Saldino syndrome - Liver fibrosis, bone dysplasia
  • Joubert syndrome - Coloboma or retinal degeneration, nystagmus, ptosis, aplasia of cerebellar vermis with ataxia and psychomotor retardation, polydactyly, and neonatal tachypnea or dyspnea
  • Sensenbrenner syndrome - Cranioectodermal dysplasia and electroretinal abnormalities

Distinguishing features of medullary cystic kidney disease include the following:

  • The inheritance pattern is autosomal dominant.
  • The median onset of ESRD for medullary cystic disease type 1 is age 62 years and for medullary cystic kidney disease type 2 is age 32 years.
  • Extrarenal associations are restricted to hyperuricemia and gout.

The following conditions have renal histologic features similar to those of nephronophthisis:

  • Jeune syndrome or asphyxiating thoracic dysplasia - Small thorax, short limbs, and hypoplastic Iliac wings
  • Ellis-van Creveld syndrome - Chondroectodermal dysplasia
  • PHYNS syndrome - Retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia
  • Laurence-Moon-Bardet-Biedl syndrome - Retinitis pigmentosa, obesity, polydactyly, and mental retardation

In the case of MCKD, there is usually a family history of hyperuricemia and progressive kidney disease. Patients with MCKD type 2 (the more common form) present as adolescents or young adults with gout and chronic kidney disease, with a relatively bland urinalysis. Patients with MUC1 mutations typically present with slowly progressive chronic kidney disease and usually develop hyperuricemia later in life. Patients with REN mutations present with features similar to those with UMOD mutations, but additionally have manifestations of low renin and angiotensin (anemia out of proportion to the kidney disease, low blood pressure, hyperkalemia, and increased risk of volume depletion).

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Physical

The clinical findings are related to tubular injury that leads to a reduction in urinary concentrating capacity, renal sodium loss, and insidious but inevitable progression to renal failure. The tubular defects precede the decline in renal function and may be present in asymptomatic siblings with the disease.

Nephronophthisis and medullary cystic kidney disease share several clinical features. In most patients, the signs associated with decreased urinary concentration capacity are present by age 5 years. The signs include polyuria, polydipsia, enuresis, and dehydration. Common findings include a failure to thrive and weakness. Anorexia, nausea, pruritus, bone pain, and neurologic symptoms herald ESRD. Because of salt wasting, hypertension is rare, except in the infantile form of nephronophthisis.

Pallor is another characteristic finding. In contrast to other renal diseases in which the degree of anemia depends on the stage of renal insufficiency, in nephronophthisis, the severity of the anemia exceeds the degree of renal insufficiency. Anemia may occur before renal insufficiency develops. This normocytic and normochromic anemia is more severe than that of other chronic renal diseases and does not result from iron deficiency or hemolysis.

Studies have shown that, in patients with nephronophthisis, the serum erythropoietin (EPO) concentration is lower than that of patients with other progressive renal diseases. EPO is a glycoprotein hormone that controls the differentiation of erythroid progenitor cells in the bone marrow and the production of erythrocytes. After birth, EPO is produced mainly in the kidneys, specifically in the peritubular fibroblasts. In patients with nephronophthisis, the synthesis of EPO is decreased.

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Causes

All of the disease variants of the nephronophthisis–medullary cystic kidney disease complex are caused by defects in different genes at distinct chromosomal loci.

Table. Molecular Genetic Features of the Nephronophthisis–Medullary Cystic Kidney Disease Complex (Open Table in a new window)

Disease Inheritance   Chromosome Gene, Protein Genetic Defect
NPH1 Autosomal recessive   2q13 NPHP1, nephrocystin-1 Homozygous deletion, heterozygous deletion
NPH2 Autosomal recessive   9q31 NPHP2/INV, inversin Recessive mutations
NPH3 Autosomal recessive   3q22 NPHP3, nephrocystin-3 Recessive mutations
NPH4 Autosomal recessive   1p36 NPHP4, nephroretinin Point mutations
NPH5 Autosomal recessive   3q21 NPHP5, nephrocystin-5 Truncations
NPH6 Autosomal recessive   12q21 NPHP6, nephrocystin-6 Truncations
NPH7 Autosomal recessive   16p NPHP7, nephrocystin-7 Unknown
NPH8 Autosomal recessive   16p NPHP8, nephrocystin-8 Truncations, missense
NPH9 Autosomal recessive   17q11 NPHP9, nephrocystin-9 Missense
NPH11 Autosomal recessive   8q22.1 NPHP11, nephrocystin-11 Missense
NPH1L Autosomal recessive   22q13 Nephrocystin-1L Deletion
MCKD1 Autosomal dominant   1q21 MUC1,



mucin1



Missense
MCKD2 Autosomal dominant   16p12* UMOD, Uromodulin Missense
*Co-localizes with familial juvenile hyperuricemic nephropathy
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Contributor Information and Disclosures
Author

Prasad Devarajan, MD, FAAP Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of the Nephrology Fellowship Program, Medical Director of the Kidney Stone Center, Co-Director of the Institutional Office of Pediatric Clinical Fellowships, Director of Clinical Nephrology Laboratory, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

Prasad Devarajan, MD, FAAP is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, Society for Pediatric Research

Disclosure: Received none from Coinventor on patents submitted for the use of NGAL as a biomarker of kidney injury for none.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna<br/>Received grant/research funds from NIH for none; Received grant/research funds from Raptor Pharmaceuticals, Inc for none; Received grant/research funds from Alexion Pharmaceuticals, Inc. for none; Received consulting fee from DiCerna Pharmaceutical Inc. for none.

Additional Contributors

Deogracias Pena, MD Medical Director of Dialysis, Medical Director of Pediatric Nephrology and Transplantation, Cook Children's Medical Center; Clinical Associate Professor, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Medical Director of Pediatric Nephrology, Florida Hospital for Children

Deogracias Pena, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

References
  1. Kim S, Dynlacht BD. Assembling a primary cilium. Curr Opin Cell Biol. 2013 Aug. 25(4):506-11. [Medline]. [Full Text].

  2. Caliskan Y, Gharavi AG. Working out nephronophthisis genetics one family at a time. J Am Soc Nephrol. 2013 May. 24(6):865-8. [Medline].

  3. Arts HH, Knoers NV. Current insights into renal ciliopathies: what can genetics teach us?. Pediatr Nephrol. 2013 Jun. 28(6):863-74. [Medline]. [Full Text].

  4. Wolf MT, Hildebrandt F. Nephronophthisis. Pediatr Nephrol. 2011 Feb. 26(2):181-94. [Medline].

  5. Benzing T, Schermer B. Clinical spectrum and pathogenesis of nephronophthisis. Curr Opin Nephrol Hypertens. 2012 May. 21(3):272-8. [Medline].

  6. Gascue C, Katsanis N, Badano JL. Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms. Pediatr Nephrol. 2011 Aug. 26(8):1181-95. [Medline]. [Full Text].

  7. 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 Mar. 45(3):299-303. [Medline].

  8. 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 May. 65(5):1589-97. [Medline].

  9. 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 Nov. 14(11):2883-93. [Medline].

  10. Tinschert S, Ruf N, Bernascone I, et al. Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy. Nephrol Dial Transplant. 2004 Dec. 19(12):3150-4. [Medline].

  11. Zivna M, Hulkova H, Matignon M, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug. 85(2):204-13. [Medline].

  12. Halbritter J, Porath JD, Diaz KA, et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013 Aug. 132(8):865-84. [Medline].

  13. Bollee G, Dahan K, Flamant M, et al. Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations. Clin J Am Soc Nephrol. 2011 Oct. 6(10):2429-38. [Medline].

  14. Iorember FM, Vehaskari VM. Uromodulin: old friend with new roles in health and disease. Pediatr Nephrol. 2013 Jul 24. [Medline].

  15. Bleyer AJ, Kmoch S, Antignac C, et al. Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1. Clin J Am Soc Nephrol. 2014 Mar. 9 (3):527-35. [Medline].

  16. Suzuki T, Iyoda M, Yamaguchi Y, Shibata T. A case of sporadic medullary cystic kidney disease type 1 (MCKD1) with kidney enlargement complicated by IgA nephropathy. Pathol Int. 2015 Jul. 65 (7):379-82. [Medline].

 
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Table. Molecular Genetic Features of the Nephronophthisis–Medullary Cystic Kidney Disease Complex
Disease Inheritance   Chromosome Gene, Protein Genetic Defect
NPH1 Autosomal recessive   2q13 NPHP1, nephrocystin-1 Homozygous deletion, heterozygous deletion
NPH2 Autosomal recessive   9q31 NPHP2/INV, inversin Recessive mutations
NPH3 Autosomal recessive   3q22 NPHP3, nephrocystin-3 Recessive mutations
NPH4 Autosomal recessive   1p36 NPHP4, nephroretinin Point mutations
NPH5 Autosomal recessive   3q21 NPHP5, nephrocystin-5 Truncations
NPH6 Autosomal recessive   12q21 NPHP6, nephrocystin-6 Truncations
NPH7 Autosomal recessive   16p NPHP7, nephrocystin-7 Unknown
NPH8 Autosomal recessive   16p NPHP8, nephrocystin-8 Truncations, missense
NPH9 Autosomal recessive   17q11 NPHP9, nephrocystin-9 Missense
NPH11 Autosomal recessive   8q22.1 NPHP11, nephrocystin-11 Missense
NPH1L Autosomal recessive   22q13 Nephrocystin-1L Deletion
MCKD1 Autosomal dominant   1q21 MUC1,



mucin1



Missense
MCKD2 Autosomal dominant   16p12* UMOD, Uromodulin Missense
*Co-localizes with familial juvenile hyperuricemic nephropathy
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