eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Medullary Cystic Disease: Differential Diagnoses & Workup

Author: Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Contributor Information and Disclosures

Updated: Dec 15, 2008

Differential Diagnoses

Medullary Sponge Kidney
Pyelonephritis
Multicystic Renal Dysplasia
Smith-Lemli-Opitz Syndrome
Oculocerebrorenal Dystrophy (Lowe Syndrome)
Polycystic Kidney Disease
Posterior Urethral Valves

Other Problems to Be Considered

Simple renal cysts
Tuberous sclerosis

Workup

Laboratory Studies

  • Urinalysis may be helpful in patients with nephronophthisis (NPH)–medullary cystic kidney disease (MCKD) complex.
    • A low specific gravity in the first morning voiding sample, which should be concentrated, is a characteristic feature of this disease. The concentrating ability rarely exceeds 800 mOsm/kg of water.
    • Hematuria, proteinuria, and bacteriuria are uncommon.
    • Proteinuria, if present, is mild and of tubular origin.
    • Significant proteinuria develops late in the course of the disease, reflecting secondary glomerular sclerosis.
  • Metabolic acidosis, elevated serum BUN and creatinine concentrations, hypocalcemia, and hyperphosphatemia are indicators of renal failure.
  • The CBC count frequently reveals profound normocytic normochromic anemia.
    • Approximately one third of patients develop anemia before renal insufficiency occurs.
    • Low erythropoietin (EPO) levels have been found in patients with nephronophthisis.
  • Liver function tests are used to detect congenital hepatic fibrosis.

Imaging Studies

  • Contrast-enhanced thin-section CT scanning is the modality of choice.3
    • The kidneys are imaged with 1-mm to 2-mm-thick sections.
    • Multiple cysts are typically seen in the medulla and corticomedullary region.
    • The cysts range from smaller than 0.5 mm to 2 cm in diameter.
  • Renal ultrasonography may be helpful in assessing nephronophthisis–medullary cystic kidney disease.
    • The kidneys are of normal or moderately reduced size, with a smooth outline.
    • Typically, corticomedullary differentiation is lost, and echogenicity is increased.
    • Cysts may or may not be present at the corticomedullary border.
    • These findings are distinct from those of autosomal dominant or autosomal recessive polycystic kidney disease (PKD), in which the kidneys are enlarged and the cysts are uniformly distributed throughout the entire kidney.
    • Patients with end-stage renal disease (ESRD) have multiple small and large cysts that can be seen in the corticomedullary area.
    • No cysts are located in organs other than the kidney.
    • The absence of cysts on the sonogram does not exclude the diagnosis of nephronophthisis–medullary cystic kidney disease.
  • Hepatic ultrasonography is used to detect congenital hepatic fibrosis.
  • Skeletal radiography is used to identify dysplastic lesions.

Other Tests

  • Ophthalmoscopy and electroretinography are used to determine the presence or tapetoretinal degeneration.
  • Molecular genetic analysis is the only diagnostic procedure with which the diagnosis of nephronophthisis can be confirmed with certainty. Details are available at Renal Genes.
    • Before genetic counseling is given, a thorough pedigree analysis should be performed to distinguish recessive (early-onset) disease from dominant (late-onset) disease, and extrarenal involvement should be excluded.
    • Blood may be obtained from a patient with clinical and renal ultrasonographic findings suggestive of nephronophthisis–medullary cystic kidney disease complex or from an affected parent. DNA is extracted from this blood and amplified by using the polymerase chain reaction (PCR) to detect the homozygous deletion in the NPH1 gene.
    • Approximately 66% of children with nephronophthisis type 1 have this large homozygous deletion.
    • However, because of the additional loci for nephronophthisis, the disease cannot be excluded if mutations in the NPH1 gene are not detected.
    • If a homozygous deletion is not found, a heterozygous deletion can be detected by performing fluorescence in situ hybridization (FISH) and/or by performing direct sequencing of all 20 nephronophthisis type 1 exons to seek a corresponding heterozygous point mutation.

Histologic Findings

  • On renal biopsy findings, the characteristic histologic triad is identical in the findings in childhood and adult forms of nephronophthisis. First, tubular basement membrane disintegration with irregular thickening is present with membrane attenuation. In later stages, biopsy findings include distal tubular atrophy and cystic formation predominantly at the corticomedullary junction. Second, the interstitium shows round cell infiltration and fibrosis. Third, periglomerular fibrosis is observed. These histologic changes are characteristic but not pathognomonic for the disease complex. Nephronophthisis type 3 should be considered if the histologic features are consistent with nephronophthisis in the absence of molecular defects in nephronophthisis type 1.
  • Early histologic findings reveal peritubular lymphohistiocytic infiltrations. As renal failure progresses, diffuse tubulointerstitial fibrosis occurs, with tubular atrophy and dilatation. Light microscopy and electron microscopy reveal periglomerular and peritubular basement membrane thickening and splitting.
  • The renal architecture is characterized by a uniformly thinned cortex and a segmental distribution of variably sized cysts in the medulla and corticomedullary junction. Cysts can be barely visible to several centimeters in size, and they vary in number from fewer than 5 to more than 50 in a segmental distribution. The cysts do not communicate with nephrons. The presence of cysts is not a diagnostic requirement because it is a late finding, and cysts may not be detected at biopsy.

More on Medullary Cystic Disease

Overview: Medullary Cystic Disease
Differential Diagnoses & Workup: Medullary Cystic Disease
Treatment & Medication: Medullary Cystic Disease
Follow-up: Medullary Cystic Disease
References
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References

  1. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-148. [Medline].

  2. Fliegauf M, Benzing T, Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol. Nov 2007;8(11):880-893. [Medline].

  3. Elzouki AY, al-Suhaibani H, Mirza K. Thin-section computed tomography scans detect medullary cysts in patients believed to have juvenile nephronophthisis. Am J Kidney Dis. Feb 1996;27(2):216-9. [Medline].

  4. Dixon-Salazar T, Silhavy JL, Marsh SE, et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet. Dec 2004;75(6):979-87. [Medline]. [Full Text].

  5. Eley L, Gabrielides C, Adams M, et al. Jouberin localizes to collecting ducts and interacts with nephrocystin-1. Kidney Int. Nov 2008;74(9):1139-1149. [Medline].

  6. Heninger E, Otto E, Imm A. Improved strategy for molecular genetic diagnostics in juvenile nephronophthisis. American Journal of Kidney Disease. 2001;37:1131-9. [Medline].

  7. Hildebrandt F, Omram H. New insights: nephronophthisis-medullary cystic kidney disease. Pediatric Nephrology. 2001;16:168-76. [Medline].

  8. Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol. Sep 2000;11(9):1753-61. [Medline].

  9. Hildebrandt F, Rensing C, Betz R. Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis. Kidney International. 2001;59:434-45. [Medline].

  10. Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol. Jun 2007;18(6):1855-71. [Medline].

  11. Hoefele J, Sudbrak R, Reinhardt R, et al. Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. Hum Mutat. Apr 2005;25(4):411. [Medline].

  12. Komatsuda A, Wakui H. Nephronophthisis: diagnostic difficulties and recent advances in molecular genetic diagnostics. Clin Exp Nephrol. Dec 2005;9(4):340-2. [Medline].

  13. Marshall WF, Nonaka S. Cilia: tuning in to the cell's antenna. Curr Biol. Aug 2006;16(15):R604-R614. [Medline].

  14. Marshall WF. The cell biological basis of ciliary disease. J Cell Biol. Jan 2008;180(1):17-21. [Medline].

  15. Mollet G, Salomon R, Gribouval O, et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet. Oct 2002;32(2):300-5. [Medline].

  16. Nurnberger J, Kribben A, Opazo Saez A, et al. The Invs gene encodes a microtubule-associated protein. J Am Soc Nephrol. Jul 2004;15(7):1700-10. [Medline]. [Full Text].

  17. O'Toole JF, Otto EA, Hoefele J, Helou J, Hildebrandt F. Mutational analysis in 119 families with nephronophthisis. Pediatr Nephrol. March 2007;22(3):366-370. [Medline].

  18. Olbrich H, Fliegauf M, Hoefele J, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet. Aug 2003;34(4):455-9. [Medline].

  19. Omran H, Sasmaz G, Haffner K, et al. Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J Am Soc Nephrol. Jan 2002;13(1):75-9. [Medline]. [Full Text].

  20. Otto EA, Helou J, Allen SJ, et al. Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing. Hum Mutat. Mar 2008;29(3):418-426. [Medline].

  21. Otto EA, Loeys B, Khanna H, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. Mar 2005;37(3):282-8. [Medline].

  22. Otto EA, Schermer B, Obara T, et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet. Aug 2003;34(4):413-20. [Medline].

  23. Parisi MA, Doherty D, Eckert ML, et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet. Apr 2006;43(4):334-9. [Medline].

  24. Pazour GJ. Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease. J Am Soc Nephrol. Oct 2004;15(10):2528-36. [Medline]. [Full Text].

  25. Salomon R, Saunier S, Niaudet P. Nephronophthisis. Pediatr Nephrol. July 8, 2008;[Medline].

  26. Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev. Jun 2005;15(3):324-31. [Medline].

  27. Schafer T, Putz M, Lienkamp S, et al. Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Hum Mol Genet. Dec 2008;17(23):3655-62. [Medline].

  28. Simons M, Gloy J, Ganner A, et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet. May 2005;37(5):537-43. [Medline].

  29. Utsch B, Sayer JA, Attanasio M, et al. Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediatr Nephrol. Jan 2006;21(1):32-5. [Medline].

  30. von Schnakenburg C, Fliegauf M, Omran H. Nephrocystin and ciliary defects not only in the kidney?. Pediatr Nephrol. June 2007;22(6):765-769. [Medline].

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Further Reading

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Keywords

medullary cystic disease, nephronophthisis, NPH, juvenile nephronophthisis, NPH1, infantile nephronophthisis, NPH2, adolescent nephronophthisis, NPH3, medullary cystic kidney disease, MCKD, MCKD1, MCKD2, juvenile nephronophthisis–medullary cystic kidney disease complex, juvenile nephronophthisis–medullary cystic kidney disease, nephronophthisis–medullary cystic kidney disease complex, nephronophthisis–medullary cystic kidney disease, nephronophthisis–medullary cystic disease, NPH-MCKD, ciliopathies, end-stage renal disease, ESRD, renal insufficiency, polyuria, polydipsia, Cogan syndrome, Senior-Loken syndrome, Mainzer-Saldino syndrome, Joubert syndrome, Sensenbrenner syndrome, hyperuricemia, gout, Jeune syndrome, asphyxiating thoracic dysplasia, obesity, Ellis-van Creveld syndrome, PHYNS syndrome, Laurence-Moon-Bardet-Biedl syndrome, renal failure

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Contributor Information and Disclosures

Author

Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Prasad Devarajan, MD is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Deogracias Pena, MD, Medical Director of Dialysis, Department of Pediatrics, Cook Children's Medical Center; Clinical Associate Professor, Texas Tech University School of Medicine
Deogracias Pena, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and American Society of Pediatric Nephrology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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 Academy of Pediatrics, American Association for the Advancement of Science, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Eastern Society for Pediatric Research, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Renal Physicians Association, Sigma Xi, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Abbott Honoraria Speaking and teaching; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

 
 
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