Background

Nephronophthisis is an autosomal recessive tubulo-interstitianl cystic kidney disease. It was first described in 1951 by Fanconi et al. as “familial juvenile nephronophthisis”. The term “Nephphronophthisis” literally means “degeneration of the kidney” describing the decreasing function and size of the kidneys during disease course. The incidence ranges around 1:50000 and therefore NPH is considered a rare disease. Nevertheless it is one of the most important causes of chronic renal failure in childhood. NPH belongs to the group of hereditary cystic renal diseases put together with the polycystic kidney diseases Autosomal Dominant Polycystic Kidney disease (ADPKD), Autosomal Recessive Polycystic Kidney disease (ARPKD), HNF1ß associated nephropathy and rare syndromes (Bardet-Biedl Syndrome and other). Even though each disease presents with a specific phenotype and prognosis, there is a significant clinical as well as genetic overlap that hampers a definite diagnosis and an individual management.

All diseases mentioned above ground on the same pathophysiological mechanism: the genes causing renal cysts encode for proteins in the primary cilium, a cellular antennae like organelle projecting from the cell surface of most cells. Thus, as cystic kidney diseases are caused by dysfunctional primary cilia, they are nowadays considered as ciliopathies.

Symptoms

NPH patients present typically with polyuria and polydipsia as well as progressive chronic renal failure due to a reduced tubular urinary concentration capacity in early childhood. Additional symptoms such as growth retardation, failure to thrive or persisting enuresis can indicate NPH but are not mandatory findings. There are no characteristic abnormalities in urine analysis. Proteinuria and arterial hypertension are not typically found until onset of end stage renal disease (ESRD). Depending on the onset of ESRD the terms infantile, juvenile and adolescent NPH are used.

• Juvenile NPH: ESRD around the 13.th year of age
• Infantile NPH: ESRD before the 4.th year of age
• Adolescent NPH: ESRD around the 19.th year of age

Ultrasound

Renal ultrasound initially shows normal sized kidneys with increased echogenicity and blurred cortico-medullary differentiation. With progress of disease kidneys often are small with highly increased echogenicity. At this point of time around 50% of the patients present renal cysts located at the cortico-medullary junction. The absence of cysts does not exclude NPH especially as they occur only late in disease course. This feature discerns NPH from other early onset cystic kidney diseases. In contrast infantile NPH often shows already in utero enlarged kidneys with numerous cysts.

Histology

Due to fast and reliable possibilities of genetic testing nowadays a renal biopsy is most often not necessary for diagnosing NPH. If performed, histopathology in juvenile NPH typically shows tubular atrophy with thickening or thinning of the tubular membrane, corticomedullar cysts, diffuse interstitial fibrosis and peritubular lymphocytic infiltration. In contrast hisopathology of infantile NPH combines characteristic aspects of NPH (tubular atrophy, interstitial fibrosis) with polycystic kidney disease (cortical cysts, enlarged kidneys).

Genetics

NPH is genetically very heterogeneous. Since NPHP1 was discovered in 1997 nineteen different NPHP genes could be identified and many more are to be discovered. Despite rapid progress in the past years 40 – 60 % of NPH cases remain genetically unidentified. The most common genetic alteration which is responsible for approximately 20-25% of NPH is a homozygous deletion in NPHP1. All other genes found make only 10 % of all NPH cases. Certain NPHP genes cause extrarenal disease manifestation.

Extrarenal manifestation

NPH appears either as an isolated renal disease or presents as complex syndrome with involvement of multiple organs. Most often anomalies are found in the eyes, liver, skeleton or the central nervous system. Depending on the underlying genetic alteration extrarenal manifestation can be observed in 10 – 40% of NPH patients (see also NPH related ciliopathies – NPH-RC).