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.


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 year of age
  • Infantile NPH: ESRD before the year of age
  • Adolescent NPH: ESRD around the year of age


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.


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).


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).


Nephronophthisis summary
short description Nephronophthisis is a autosomal recessive tubulo interstitial cystic kidney disease and one of the most common genetic cause for end stage renal disease in childhood. Depending on the onset of ESRD the terms infantile, juvenile and adolescent NPH are used.
main symptoms
  • Polyuria, Polydipsia
  • chronic renal failure
  • small to normal sized, hyperechogenic kidneys with cysts in the cortico-medullary junction in 50% of cases
additional findings
  • short stature, enuresis, anemia
  • arterial hypertension typically only in infantile NPH
  • Juvenile NPH: ESRD around the year of Age
  • Infantile NPH: ESRD before the 4. th year of Age
  • Adolescent NPH: ESRD around the 19. th year of age
inheritance autosomal – rezessive
Pathogenesis 19 know NPHP genes that encode for proteins in the primary cilium. Therefore NPH counts among the group of ciliopathies
progress and prognosis Depending on the form of NPH progress of chronic renal failure. Dependig on underlying genetic alteration also extrarenal mainfestation.
treatment No causal therapy available to date. A symptomatic treatment of chronic renal failure with renal replacement therapy and renal transplantation is necessary.

Known NPH genes to date
Disease OMIM Phenotype Nr Gene OMIM – Gene Nr alternative Phenotype + OMIM Phenotype Nr
1 NPHP1 256100 NPHP1 607100 JBTS4 609583
SLSN1 266900
2 NPHP2 602088 INVS 243305
3 NPHP3 604387 NPHP3 608002 MKS7 267010
4 NPHP4 606966 NPHP4 607215 SLSN4 606996
5 NPHP5 609254 IQCB1 609237 SLSN5 609254
6 NPHP6 610189 CEP290 610142 BBS14 615991
JBTS5 610188
LCA10 611755
MKS4 611134
SLSN6 610189
7 NPHP7 611498 GLIS2 608539
8 NPHP8 RPGRIP1L 610937 COACH syndrome 216360
JBTS7 611560
MKS5 611561
9 NPHP9 613824 NEK8 609799
10 NPHP10 SDCCAG8 613524 BBS16 615993
SLSN7 613615
11 NPHP11 613550 TMEM67 609884 COACH syndrome 216360
JBTS6 610688
MKS3 607361
12 NPHP12 613820 TTCB21B 612014 SRTD4 613819
13 NPHP13 614377 WDR19 608151 SRTD5 614376
SLSN8 616307
14 NPHP14 614844 ZNF423 604557
15 NPHP15 614845 CEP164 614848
16 NPHP16 615382 ANKS6 615370
17 NPHP17 615630 IFT172 607386 SRTD10 615630
18 NPHP18 615862 CEP83 615847
19 NPHP19 616217 DCDC2 605755
20 NPHP20 617271 MAPKBP1 616786


  • 1. Fanconi G, Hanhart E, von AA, et al. Familial, juvenile nephronophthisis (idiopathic parenchymal contracted kidney) Helv Paediatr Acta. 1951;6:1–49.
  •  2. Antignac C, Kleinknecht C, Habib R. Nephronophthisis. 1998 in: Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E (Hrsg) Oxford Textbook of Clinical Nephrology. Oxford University Press, Oxford, S2417-2426.
  • 3. Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. N Engl J Med. 2011;364:1533–1543.
  • 4. Bergmann C. Educational paper: ciliopathies. Eur J Pediatr. 2012 Sep;171(9):1285-300.
  • 5. Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol. 2009;20:23–35.
  • 6. Hildebrandt F, Strahm B, Nothwang HG, et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Kidney Int. 1997;51:261–269.
  • 7. Gagnadoux MF, Bacri JL, Broyer M, Habib R. Infantile chronic tubulo-interstitial nephritis with cortical microcysts: variant of nephronophthisis or new disease entity? Pediatr Nephrol. 1989;3:50–55.
  • 8. Omran H, Fernandez C, Jung M, et al. Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet. 2000;66:118–127.
  • 9. Salomon R, Saunier S, Niaudet P. Nephronophthisis. Pediatr Nephrol. 2009;24:2333–2344.
  • 10. Waldherr R, Lennert T, Weber HP, et al. The nephronophthisis complex. A clinicopathologic study in children. Virchows Arch A Pathol Anat Histol. 1982;394:235–254.
  • 11. Wolf M. Nephronophthisis and related syndromes. Curr Opin Pediatr. 2015 Apr; 27(2): 201–211.