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Autosomal dominant tubulointerstitial kidney disease

Nature Reviews Disease Primers volume 5, Article number: 60 (2019) Cite this article

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Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a recently defined entity that includes rare kidney diseases characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions, with inescapable progression to end-stage renal disease. These diseases have long been neglected and under-recognized, in part due to confusing and inconsistent terminology. The introduction of a gene-based, unifying terminology led to the identification of an increasing number of cases, with recent data suggesting that ADTKD is one of the more common monogenic kidney diseases after autosomal dominant polycystic kidney disease, accounting for ~5% of monogenic disorders causing chronic kidney disease. ADTKD is caused by mutations in at least five different genes, including UMOD, MUC1, REN, HNF1B and, more rarely, SEC61A1. These genes encode various proteins with renal and extra-renal functions. The mundane clinical characteristics and lack of appreciation of family history often result in a failure to diagnose ADTKD. This Primer highlights the different types of ADTKD and discusses the distinct genetic and clinical features as well as the underlying mechanisms.

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Fig. 1: Function of uromodulin.
Fig. 2: Mechanisms of ADTKD-UMOD.
Fig. 3: Pathobiology of ADTKD-MUC1.
Fig. 4: The transcription factor HNF1β and ADTKD-HNF1B.
Fig. 5: Pathobiology of ADTKD-REN.
Fig. 6: Pathobiology of ADTKD-SEC61A1.
Fig. 7: ER stress and unfolded protein response in ADTKD.
Fig. 8: Diagnostic algorithm for ADTKD.

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Article 06 February 2020

Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

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Acknowledgements

O.D. is supported by the European Community’s 7th Framework Programme (FP7/2007–2013) under grant agreement numbers 246539 and 608847 (IKPP Marie Curie) and grant number 305608 (EURenOmics), the FNRS and FRSM (Belgium), the NCCR Kidney.ch programme (Swiss National Science Foundation), the Gebert Rüf Stiftung (Project GRS-038/12), and the Swiss National Science Foundation 310030–146490. S.W. is supported by the German Federal Ministry of Research and Education (BMBF, grant number 01GM1515). S.K. is supported by grant NV17–29786A from the Ministry of Health of the Czech Republic, by institutional programmes of Charles University in Prague UNCE/MED/007 and PROGRES-Q26/LF1, and by the project LQ1604 NPU II from the Ministry of Education, Youth and Sports of the Czech Republic. L.R. is supported by Telethon-Italy (GGP14263), the Italian Ministry of Health (grant RF-2010–2319394), and Fondazione Cariplo (2014–0827). The authors thank Dr Martina Živná (Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Czech Republic), Drs Guglielmo Schiano and Jennifer Lake (Department of Physiology, University of Zurich, Switzerland), Dr Maria Pia Cratere (IRCCS San Raffaele Scientific Institute, Italy) and Prof Patrick H. Maxwell (University of Cambridge, UK) for help and discussions. The authors apologize to the authors whose contributions could not be referenced due to space limitations.

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Authors and Affiliations

  1. Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zurich, Zurich, Switzerland

    Olivier Devuyst & Eric Olinger

  2. Division of Nephrology, UCLouvain Medical School, Brussels, Belgium

    Olivier Devuyst

  3. Division of Pediatric Nephrology and Transplantation, University Children’s Hospital Marburg, Marburg, Germany

    Stefanie Weber

  4. Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany

    Kai-Uwe Eckardt

  5. Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Stanislav Kmoch

  6. Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Luca Rampoldi

  7. Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Anthony J. Bleyer

Authors
  1. Olivier Devuyst
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  2. Eric Olinger
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  3. Stefanie Weber
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  4. Kai-Uwe Eckardt
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  5. Stanislav Kmoch
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  6. Luca Rampoldi
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  7. Anthony J. Bleyer
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Contributions

Introduction (O.D., S.K., A.J.B. and K.-U.E.); Epidemiology (O.D., E.O., S.W., A.J.B. and K.-U.E.); Mechanisms/pathophysiology (O.D., L.R. and S.K.); Diagnosis, screening and prevention (O.D, E.O., S.K., S.W. and A.J.B.); Management (O.D., E.O., S.W., A.J.B. and K.-U.E.); Quality of life (O.D., S.W. and A.J.B.); Outlook (O.D., L.R., S.K., A.J.B. and K.-U.E.); Overview of the Primer (O.D. and AJ.B.).

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Correspondence to Olivier Devuyst.

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Devuyst, O., Olinger, E., Weber, S. et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers 5, 60 (2019). https://doi.org/10.1038/s41572-019-0109-9

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