Familial Juvenile Nephronophthisis
Familial juvenile nephronophthisis (NPH), also termed nephronophthisis type 1 (NPH1), is an autosomal recessive, progressive tubulointerstitial kidney disease. It is characterized clinically by polyuria, polydipsia, anemia, growth failure, and progressive renal failure. Pathologic characteristic features include chronic tubulointerstitial nephritis and medullary cysts. NPH is the most common genetic cause of end-stage renal disease (ESRD) in children; it accounts for 1% of cases of ESRD in the United States.
The renal pathologic features, clinical findings, and course are similar to those of medullary cystic kidney disease; however, the two are distinct syndromes. NPH is inherited as an autosomal recessive pattern, patients average 10 years of age at disease onset, ESRD develops early, and the disease often is associated with nonrenal anomalies. In contrast, medullary cystic kidney disease is inherited as an autosomal dominant pattern, patients average 28 years of age at onset of disease, ESRD develops late, and nonrenal anomalies are rare findings.
Juvenile NPH is caused by a defect in gene locus, NPHP1, which is mapped to chromosome 2q13. The NPHP1 gene and its product, nephrocystin, a novel protein encoded by this gene, have been identified. The function of nephrocystin is unknown, but one hypothesis is that it may be involved in focal adhesion and/or adherens junction signaling.
Kidney biopsy reveals a characteristic triad of disintegration of the tubular basement membrane (TBM), tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis. Typically, the TBM has pronounced thickening and multilayering that represent the most characteristic histologic features of NPH. Small medullary cysts, located at the corticomedullary border, are found in as many as 75% of patients. Medullary cysts arise from both the distal convoluted and collecting tubules. The nature of the primary pathogenic mechanism leading to the NPH is unclear, although likely a defect in the TBM structure may be primarily responsible for cyst formation.