NPHP is a clinical diagnosis that is suggested by characteristic fibrocystic renal involvement along with involvement of other organs such as eye (retinitis pigmentosa) and brain (cerebellar atrophy) with a pedigree consistent with autosomal-recessive inheritance. Kidney manifestations There is a large spectrum of severity with regards to renal involvement. Traditionally they have been classified according to the age of presentation but this is only relevant as a clinical tool. Genetic diagnosis is fast superseding this classification. a. Infantile NPHP Infantile NPHP is rare but is noteworthy due to its severe phenotype with ESRD typically occurring during the first year of life (Gagnadoux et al., 1989). There may be antenatal presentation with oligohydramnios and bilateral enlarged cystic kidneys. There may also be severe cardiac anomalies including situs inversus and ventricular septal defects (Wolf and Hildebrandt, 2011). There has been a recent report of an extremely severe phenotype presenting with enlarged cystic kidneys at a prenatal scan at 22 weeks of gestation. b. Juvenile NPHP Juvenile NPHP is the classical form of NPHP and is characterized by symptoms of polyuria, urinary concentration defects in patients within the first decade of life and ESRD at a mean age of 13 years (Hildebrandt et al., 1997b). c. Adolescent NPHP The adolescent form of NPHP presents at a median age of ESRD of 19 years (Olbrich et al., 2003). The term “adolescent NPHP” is thus somewhat arbitrary and merely extends the phenotypic spectrum from juvenile NPHP. d. Late-onset NPHP A number of case reports have highlighted the fact that NPHP may first present to adult nephrologists. Georges et al. report 3 (genetically unsolved) families with retinal dystrophy, NPHP on renal biopsy and slowly progressive renal failure and ESRD between the ages of 42-56 years (Georges et al., 2000). In another family with a homozygous NPHP1 deletion (Hoefele et al., 2011) ESRD was reported between 27 and 43 years of age for 3 of the affected patients. These cases of NPHP extend the age of ESRD from birth to up to the 6th decade of life. NPHP should be distinguished from other inherited causes of end stage kidney disease such as Medullary Cystic Kidney Disease (also known as ADTKD- autosomal dominant tubulointerstitial kidney disease) (Table 1). Where renal biopsies have been performed in NPHP patients, distinct histological features have been reported. The histological changes can be divided into early or late stages of disease. In the early stages of the NPHP there is interstitial fibrosis with sparse inflammation and lack of infiltration with neutrophils or monocytes. The tubules are tortuous and atrophic with segmented tubular basement membrane thickening (Zollinger et al., 1980). The distal tubules have focal diverticulum like protrusions. The glomeruli are usually normal but there may be periglomerular fibrosis that can extend into the glomerular tuft leading to focal or global collapse of the tuft and obsolescence of the glomeruli (Gagnadoux et al., 1989, Waldherr et al., 1982). In later stages of the disease the tubules may demonstrate basement membrane abnormalities with both atrophy and thickening. There often is cystic dilatation of the distal tubules and the glomeruli may show collapse and severe periglomerular fibrosis (Gibson and Arneil, 1972, Waldherr et al., 1982). NPHP is not an immune mediated disease and consequently there is no immune or complement deposition (Waldherr et al., 1982, Zollinger et al., 1980). Electron microscopy may reveal tubular basement membrane duplication, thickening and folding (Waldherr et al., 1982, Zollinger et al., 1980)
Table: 1 Comparison of NPHP with MCKD and other ciliopathies
There is no specific treatment for NPHP. Care for affected patients should be provided in specialised centres with expertise in the disorder. Renal replacement therapy is almost always needed and hence care should be provided by a renal unit.
Figure 1: A flow chart detailing the clinical presentation, symptoms, clinical signs and investigations when NPHP is suspected in a patient (Srivastava and Sayer, 2014)
Srivastava S, Molinari E, Raman S, Sayer JA. Many Genes—One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders. Frontiers in Pediatrics. 2017;5:287. doi:10.3389/fped.2017.00287.
Srivastava S, Sayer JA. Nephronophthisis. Journal of Pediatric Genetics. 2014;3(2):103-114. doi:10.3233/PGE-14086.
Simms RJ, Hynes AM, Eley L, Sayer JA. Nephronophthisis: A Genetically Diverse Ciliopathy. International Journal of Nephrology. 2011;2011:527137. doi:10.4061/2011/527137.