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Nephronophthisis: a pathological and genetic perspective

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Abstract

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents. Over 20 genes cause NPHP and over 90 genes contribute to renal ciliopathies often involving multiple organs. About 15–20% of NPHP patients have additional extrarenal symptoms affecting other organs than the kidneys. The involvement of additional organ systems in syndromic forms of NPHP is explained by shared expression of most NPHP gene products in centrosomes and primary cilia, a sensory organelle present in most mammalian cells. This finding resulted in the classification of NPHP as a ciliopathy. If extrarenal symptoms are present in addition to NPHP, these disorders are defined as NPHP-related ciliopathies (NPHP-RC) and can involve the retina (e.g., with Senior-Løken syndrome), CNS (central nervous system) (e.g., with Joubert syndrome), liver (e.g., Boichis and Arima syndromes), or bone (e.g., Mainzer-Saldino and Sensenbrenner syndromes). This review focuses on the pathological findings and the recent genetic advances in NPHP and NPHP-RC. Different mechanisms and signaling pathways are involved in NPHP ranging from planar cell polarity, sonic hedgehog signaling (Shh), DNA damage response pathway, Hippo, mTOR, and cAMP signaling. A number of therapeutic interventions appear to be promising, ranging from vasopressin receptor 2 antagonists such as tolvaptan, cyclin-dependent kinase inhibitors such as roscovitine, Hh agonists such as purmorphamine, and mTOR inhibitors such as rapamycin.

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Acknowledgements

We thank Drs. J. Gattineni and M. Attanassio for critical review of the manuscript.

Funding

The first author is supported by NIH funding (R01DK119631, P30DK079328), Department of Defense (W81XWH1910205), and the Children’s Clinical Research Advisory Committee (CCRAC), Children’s Medical Center, Dallas.

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  1. Division of Pediatric Nephrology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Matthias T. F. Wolf

  2. Division of Pediatric Nephrology, C.S. Mott Children’s Hospital, University of Michigan, 1150 W. Medical Center Dr, Ann Arbor, MI, 48109, USA

    Matthias T. F. Wolf

  3. Arkana Laboratories, Little Rock, AR, USA

    Stephen M. Bonsib & Christopher P. Larsen

  4. Division of Nephrology, Boston Children’s Hospital, Boston, USA

    Friedhelm Hildebrandt

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Wolf, M.T.F., Bonsib, S.M., Larsen, C.P. et al. Nephronophthisis: a pathological and genetic perspective. Pediatr Nephrol (2023). https://doi.org/10.1007/s00467-023-06174-8

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