eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Medullary Cystic Disease

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
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Updated: Dec 15, 2008

Introduction

Background

Medullary cystic kidney disease (MCKD) and nephronophthisis (NPH) refer to 2 inherited diseases with similar renal morphology characterized by bilateral small corticomedullary cysts in kidneys of normal or reduced size and tubulointerstitial sclerosis leading to end-stage renal disease (ESRD). These disorders have traditionally been considered as parts of a complex (the nephronophthisis complex) because they share many of the clinical and histopathological features. The major differences are in the modes of inheritance, the age of onset of ESRD, and the extrarenal manifestations. In this article, the 2 diseases are discussed as a single clinicopathologic entity of nephronophthisis–medullary cystic kidney disease to reflect current recommendations for the classification of renal cystic diseases. 

Nephronophthisis 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. Nephronophthisis has an autosomal recessive inheritance pattern. Positional cloning and candidate gene approaches have led to the identification of 9 causative genes, all of which appear to encode for proteins expressed in the primary cilia of renal epithelial cells; hence, these disorders are now referred to as ciliopathies.^1,2 Nephronophthisis presents in childhood or adolescence with progressive renal insufficiency and is frequently associated with extrarenal organ involvement such as retinitis pigmentosa, hepatic fibrosis, skeletal defects, and cerebellar aplasia. Three clinical variants have been described, based on the age of onset of ESRD.

• The juvenile form is the most common, in which ESRD usually occurs in the second decade of life (mean age, 13 y). It is characterized by the presence of small medullary cysts, extensive tubular atrophy, thickened tubular basement membranes, and prominent interstitial fibrosis. Recent advances in molecular genetics have identified mutations in 7 distinct genes (designated as NPHP1, NPHP4, NPHP5, NPHP6, NPHP7, NPHP8, and NPHP9) that are associated with defects in distinct proteins that lead to heterogeneity in clinical manifestations. 
• The adolescent form is characterized by ESRD developing around age 20 years. It is associated with defects in the NPHP3 gene but with histologic features similar to the juvenile form. The genotype-phenotype correlations are not always clear-cut, and some patients with an NPHP3 mutation can progress to ESRD before age 10 years.
• The infantile form is characterized by progression to ESRD before age 2 years. It is associated with defects in the NPHP2 gene. Histopathology reveals cystic dilatations of the collecting ducts, but the typical tubular basement changes seen in juvenile nephronophthisis are usually absent. In contrast with the other 2 forms, these children usually demonstrate severe hypertension and moderately enlarged kidneys on ultrasonography.

Medullary cystic kidney disease is inherited in an autosomal dominant pattern and usually presents with adult-onset renal failure and no extrarenal involvement. The following 2 clinical variants have been described:

• Type 1 has a median onset of ESRD at age 62 years and is caused by defects in the MCKD1 gene. The function of the protein product is unknown.
• Type 2 has an earlier onset of ESRD (mean age, 32 y) and is the result of defects in the MCKD2 gene that encodes the uromodulin/Tamm-Horsfall mucoprotein.

Pathophysiology

Advances in molecular genetics have led to the identification of the gene defects underlying several forms of nephronophthisis–medullary cystic kidney disease. Characterization of the encoded proteins is revealing novel pathogenetic mechanisms. Many have been shown to localize to primary cilia, which are highly conserved structures that sense and process various extracellular signals. An important role of normal cilia in renal tubular cells is mechanosensation, whereby flow-mediated bending of primary cilia elicits signal transduction pathways that regulate the cell cycle, cell proliferation, and cell death. Defects in these cellular functions may contribute to cystogenesis. Because cilia are present in almost all cells and tissues, ciliary dysfunction may also account for the extrarenal manifestations encountered in some forms of nephronophthisis. 

• Nephronophthisis type 1 is characterized by mutations in the NPHP1 gene, which encodes the protein nephrocystin-1. Nephrocystin-1 interacts with the products of other NPHP genes as well as components of cell-cell and cell-matrix signaling. Nephrocystin-1 and its interacting partners are localized to the cell-cell junction (adherens junction) and cell-matrix interface (focal adhesion), suggesting important roles in maintaining the integrity of the tubular epithelium. Thus, cystogenesis in nephronophthisis type 1 may result from defects in tubular cell-cell and cell-substratum contacts. Nephrocystin-1 and other NPHP gene products are also prominently localized to the primary cilia in the apical (luminal) membranes of renal tubular epithelial cells.
• In nephronophthisis type 2, the mutated gene NPHP2/INVS encodes for inversin, which interacts with nephrocystin-1 and b-tubulin and localizes to primary cilia in renal tubular cells. B-tubulin constitutes the microtubule axoneme of primary cilia. Hence, defects in these interactions may impair ciliary function and thereby contribute to cyst development.

The products of the other genes mutated in nephronophthisis are currently under investigation, but emerging unifying features include their localization to primary cilia and their interactions with each other.

Frequency

United States

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

International

The incidence of nephronophthisis 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 is noted.

Sex

Both sexes are equally affected.

Age

Nephronophthisis occurs during childhood and progresses to renal failure before the age 20 years. The median age of onset of ESRD is 13 years in juvenile nephronophthisis, 1-3 years in infantile nephronophthisis, and 19 years in adolescent nephronophthisis. If ESRD has not developed by age 25 years, the diagnosis of recessive nephronophthisis is unlikely, and autosomal dominant medullary cystic kidney disease should be considered. ESRD typically develops when patients with medullary cystic kidney disease are aged 25-50 years. Median onset of ESRD is age 62 years for medullary cystic kidney disease type 1 and age 32 years for medullary cystic kidney disease type 2. 

Clinical

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

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.

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.

Molecular Genetic Features of the Nephronophthisis–Medullary Cystic Kidney Disease Complex

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*Co-localizes with familial juvenile hyperuricemic nephropathy

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