AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) refer to 2 inherited diseases with similar renal morphology characterized by bilateral cysts and tubulointerstitial sclerosis leading to end-stage renal disease (ESRD).

NPH was first described by Smith et al in 1945 and then by Fanconi et al in 1951 as a familial disorder leading to progressive renal damage and death in late childhood. NPH has an autosomal recessive inheritance pattern; it appears in childhood or adolescence with progressive renal insufficiency, and it is frequently associated with extrarenal organ involvement such as retinitis pigmentosa, hepatic fibrosis, skeletal defects, and cerebellar aplasia.

Within the recessive variant of NPH, the following 3 forms have purely renal involvement:

• Juvenile nephronophthisis (NPH1)
• Infantile nephronophthisis (NPH2)
• Adolescent nephronophthisis (NPH3)

In the following forms, extrarenal organ involvement also exists:

• Juvenile nephronophthisis (NPH1)
• Juvenile nephronophthisis type 4 (NPH4)

MCKD is inherited in an autosomal dominant pattern and usually appears with adult-onset renal failure and no extrarenal involvement. In this article, the 2 diseases are discussed as a single clinicopathologic entity of juvenile NPH-MCKD to reflect current recommendations for the classification of renal cystic diseases.

Pathophysiology

The pathogenesis of NPH-MCKD is unclear. The histologic and biochemical characteristics of NPH indicate a defect of tubular basement membrane composition. Abnormal expression of the a5 integrin fibronectin receptor has been demonstrated in the tubular basement membrane. This finding has previously led to the hypothesis that renal tubular cells in NPH express a5 receptor as a compensatory mechanism for the defective function of a6 integrin. This process, in turn, may lead to the destruction of the tubular basement membrane, which is a typical and early histologic finding in NPH-MCKD.

Recent advances in molecular genetics have led to the identification of the gene defects underlying several forms of NPH-MCKD. Characterization of the encoded proteins is revealing novel pathogenetic mechanisms. In NPH1, which is characterized by mutations in the NPHP1 gene, the product of NPHP1, nephrocystin, is a docking protein that interacts with proteins of adherens junctions and focal adhesions. Thus, cystogenesis in NPH1 may result from a defect in tubular cell-cell and cell-substratum contacts. In the case of NPH2, the mutated gene INV encodes for inversin, which is normally closely associated with the microtubule cytoskeleton and its spatial distribution is dependent on tubulin polymerization. Hence, altered inversin-tubulin interaction may impair ciliary function and thereby contribute to cyst development.

Frequency

United States

The incidence of NPH is 9 cases per 8.3 million population. NPH is the most common genetic cause of ESRD in the first 2 decades of life, accounting for 5-15% of cases of ESRD. MCKD is rare and has been reported primarily in the United States.

International

The incidence of NPH is higher in Europe, where it accounts for 15-25% of cases of childhood ESRD.

Mortality/Morbidity

ESRD develops in all patients, although the rate of progression is faster in the recessive form of the disease than in the dominant form. Mortality is related to the complications of renal failure.

Race

No racial predilection exists.

Sex

Both sexes are equally affected.

Age

• NPH occurs during childhood and progresses to renal failure before the age of 20 years.
• The mean age at which ESRD develops is approximately 13 years. The median ages of onset of ESRD is 13 years in NPH1, 1-3 years for NPH2, and 19 years for NPH3.
• ESRD typically develops when patients with MCKD are aged 25-50 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

• Distinguishing features of NPH include the following:
• • The inheritance pattern is autosomal recessive.
  • The median ages of onset of ESRD is 13 years in NPH1, 1-3 years for NPH2, and 19 years for NPH3.
  • Extrarenal associations occur only in NPH1.
• Extrarenal associations of NPH1 include the following:
• • Ocular motor apraxia, Cogan type
  • Senior-Loken syndrome - Retinitis pigmentosa
  • Mainzer-Saldino syndrome - Liver fibrosis, bone dysplasia
  • Joubert syndrome - Coloboma or retinal degeneration 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 MCKD include the following:
• • The inheritance pattern is autosomal dominant.
  • The median onset of ESRD for MCKD type 1 (MCKD1) is 62 years and for MCKD type 2 (MCKD2) is 32 years.
  • Extrarenal associations include hyperuricemia and gout

• The following conditions have renal histologic features similar to those of NPH:
• • Jeune syndrome, or asphyxiating thoracic dysplasia - Small thorax, short limbs, and hypoplastic Iliac wings
  • Ellis-van Creveld syndrome or chondroectodermal dysplasia
  • Retinitis pigmentosa, hypopituitarism, NPH, and skeletal dysplasia (RHYNS) syndrome
  • Laurence-Moon-Bardet-Biedl syndrome - Retinitis pigmentosa, obesity, polydactyly, and mental retardation

Physical

The clinical manifestations 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. The earliest presenting symptoms in juvenile nephronophthisis (NPH) appear at approximately 4-6 years of age.

Physical findings and distinguishing features are discussed below and in the History section above.

• NPH and MCKD share 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, even in patients with severe renal insufficiency.
• Pallor is another characteristic finding.
• • In contrast to other renal diseases in which the degree of anemia is dependent on the stage of renal insufficiency, in NPH, 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 it does not result from iron deficiency or hemolysis.
• Studies have shown that, in patients with NPH, 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 NPH, the synthesis of EPO is decreased.

Causes

All of the disease variants of the NPH-MCKD complex are caused by defects in different genes at distinct chromosomal loci (see Table).

• Molecular Genetic Features of the NPH-MCKD Complex

  Disease	Inherit*	Locus	Chromosome	Gene	Genetic defect
  NPH1	AR	NPH1	2q12-q13	NPHP1, nephrocystin-1	Homozygous deletion, heterozygous deletion
  NPH2	AR	NPH2	9q22-q31	INV, inversin	Recessive mutations
  NPH3	AR	NPH3	3q21-q22	NPHP3, nephrocystin-3	Unknown
  NPH4	AR	NPH4	1p36	NPHP4, nephroretinin	Unknown
  Senior-Loken syndrome, early onset	AR	NPH3	3q21-q22	NPHP3, nephrocystin-3	Unknown
  Senior-Loken syndrome, late onset	AR	NPH5	2q12-q13	NPHP5, nephrocystin-5	Point mutations
  Joubert syndrome	AR	AH1	6q23.2-q23.3	AH1	Homozygous mutations
  MCKD1	AD	MCKD1	1q21	Unknown	Unknown
  MCKD2	AD	MCKD2	16p12†	UMOD, uromodulin	Unknown

  *AD indicates autosomal dominant; AR, autosomal recessive.
  †Co-localizes with familial juvenile hyperuricemic nephropathy.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Simple renal cysts
Tuberous sclerosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinalysis may be helpful.
• • 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 blood urea nitrogen (BUN) and creatinine concentrations, hypocalcemia, and hyperphosphatemia are indicators of renal failure.
• The complete blood count frequently reveals profound normocytic normochromic anemia.
• • Approximately one third of patients develop anemia before renal insufficiency occurs.
  • Low EPO levels have been found in patients with NPH.
• Liver function tests are used to detect congenital hepatic fibrosis.

Imaging Studies

• Contrast-enhanced thin-section CT is the modality of choice.
• • The kidneys are imaged with 1- 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 NPH-MCKD.
• • 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 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 NPH-MCKD.
• 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 NPH1 can be confirmed with certainty.
• • 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 NPH-MCKD 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 NPH1 have this large homozygous deletion.
  • However, because of the additional loci for NPH, 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 NPH1 exons to seek a corresponding heterozygous point mutation.

Histologic Findings

At renal biopsy, the characteristic histologic triad is identical in the findings in childhood and adult forms of NPH. 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. NPH3 should be considered if the histologic features are consistent with NPH in the absence of molecular defects in NPH1.

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.

Other histologic findings are discussed in Pathophysiology and History.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• In all variants of NPH-MCKD, ESRD insidiously ensues within characteristic age ranges, and no specific therapy exists. Management is symptomatic and directed at preventing and treating complications of progressive renal insufficiency, such as the correction of electrolyte, acid-base, and water-balance disturbances.
• Anemia may be treated with erythropoietin.
• Growth retardation is responsive to recombinant growth hormone.
• All patients eventually require renal replacement therapy including peritoneal dialysis or hemodialysis, or preemptive kidney transplantation. Transplantation is required before dialysis.

Surgical Care

• Access for hemodialysis or peritoneal dialysis should be secured before ESRD develops.
• Kidney transplantation is the treatment of choice for patients who have NPH-MCKD and ESRD.
• • ESRD does not recur in the transplanted kidney.
  • Living, related donors should be thoroughly screened for the disease prior to the transplantation procedures.

Consultations

• All children with polyuria, polydipsia, or a failure to thrive must be evaluated by a pediatric nephrologist. Children found to have NPH-MCKD should be referred for an ophthalmologic examination and closely followed up by the nephrologist.
• Offer genetic counseling to the family.
• • A carefully constructed pedigree may help in distinguishing between the recessive and dominant forms of the disease.
  • Because of the genetic locus heterogeneity among diseases in the NPH-MCKD complex, prenatal diagnosis can be performed only by means of direct genetic testing. This testing requires a setting in which a specific deletion or mutation of the NPH1 gene has already been characterized in an affected sibling. The urinary concentrating ability of asymptomatic siblings should be tested at yearly intervals.

Diet

• In children with NPH, their nutrition should be appropriate for their age.
• Adequate hydration is important to replace urinary water losses and sodium loss in patients with salt-wasting.
• As renal insufficiency progresses, foods high in phosphorus and potassium should be limited.

Activity

• Activities may be pursued as tolerated.
• Strenuous exercise and prolonged heat exposure should be avoided because children with NPH-MCKD are prone to dehydration.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Pharmacotherapy is symptomatic and directed at preventing and treating complications of progressive renal insufficiency.

Drug Category: Erythropoietin

This is a glycoprotein normally produced in the kidneys that is responsible for the stimulation of red blood cell production. Anemia occurs because of deficient erythropoietin production during renal failure.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Transfer

• Transfer to a pediatric dialysis unit is required when the child develops ESRD.

Complications

• Complications are those of progressive renal failure.

Prognosis

• ESRD develops in all patients.
• The disease does not recur in transplanted kidneys.

Patient Education

• As ESRD develops, appropriate nutritional and medical education should be made available.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize NPH-MCKD in a child with polyuria, anemia, growth retardation, and normal kidney function

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• 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].
• 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].
• 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].
• Hildebrandt F, Omram H. New insights: nephronophthisis-medullary cystic kidney disease. Pediatric Nephrology. 2001;16:168-76. [Medline].
• 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].
• Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol. Sep 2000;11(9):1753-61. [Medline].
• 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].
• Komatsuda A, Wakui H. Nephronophthisis: diagnostic difficulties and recent advances in molecular genetic diagnostics. Clin Exp Nephrol. Dec 2005;9(4):340-2. [Medline].
• 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].
• 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].
• 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].
• 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].
• 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].
• 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].
• 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].
• 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].
• Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev. Jun 2005;15(3):324-31.
• 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].
• 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].

Article Last Updated: Jul 28, 2006