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The pathophysiology of distal renal tubular acidosis

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From Nature Reviews Nephrology

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Abstract

The kidneys have a central role in the control of acid–base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5. This defect originates from reduced function of acid-secretory type A intercalated cells. Inherited forms of dRTA are caused by variants in SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, WDR72 and probably in other genes that are yet to be discovered. Inheritance of dRTA follows autosomal-dominant and -recessive patterns. Acquired forms of dRTA are caused by various types of autoimmune diseases or adverse effects of some drugs. Incomplete dRTA is frequently found in patients with and without kidney stone disease. These patients fail to appropriately acidify their urine when challenged, suggesting that incomplete dRTA may represent an intermediate state in the spectrum of the ability to excrete acids. Unrecognized or insufficiently treated dRTA can cause rickets and failure to thrive in children, osteomalacia in adults, nephrolithiasis and nephrocalcinosis. Electrolyte disorders are also often present and poorly controlled dRTA can increase the risk of developing chronic kidney disease.

Key points

  • Primary distal renal tubular acidosis (dRTA) is caused by pathogenic variants in at least five different genes: SLC4A1, ATP6V0A4, ATP6V1B1, FOXI1 and WDR72; additional unidentified genes might also contribute.

  • Acquired forms of dRTA are often found in patients who have autoimmune disorders or who take drugs that reduce the ability of the kidney to excrete acids.

  • Although kidney pathological conditions in dRTA are mostly restricted to intercalated cells, systemic acidosis also affects other renal cell types and extrarenal organs.

  • Pathogenic variants in all known dRTA genes also cause extrarenal pathological conditions owing to their expression in the inner ear, red blood cells or teeth.

  • Primary and secondary forms of dRTA should be diagnosed and treated to prevent the sequelae of systemic acidosis on growth and bone stability; primary dRTA might also be a risk factor for the development of chronic kidney disease.

  • Incomplete dRTA is often associated with kidney stone disease and may represent an intermediate pre-acidotic form of the complete syndrome.

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Fig. 1: Repertoire of cells in the collecting duct system.
Fig. 2: Role of the transcription factor FOXI1 in intercalated cell differentiation.
Fig. 3: Cellular pathophysiology of dRTA-causing mutations in SLC4A1, ATP6V1B1, ATP6V0A4 and WDR72.
Fig. 4: Spectrum of clinical features associated with primary dRTA.

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Acknowledgements

Studies in the laboratory of C.A.W. have been supported by the Swiss National Science Foundation.

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Authors and Affiliations

  1. Institute of Physiology, University of Zurich, Zurich, Switzerland

    Carsten A. Wagner

  2. Department of Renal Medicine, Royal Free Hospital, University College London, London, UK

    Carsten A. Wagner, Robert Unwin, Sergio C. Lopez-Garcia, Robert Kleta, Detlef Bockenhauer & Stephen Walsh

  3. Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

    Sergio C. Lopez-Garcia & Detlef Bockenhauer

Authors
  1. Carsten A. Wagner
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  3. Sergio C. Lopez-Garcia
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  6. Stephen Walsh
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Contributions

C.A.W., S.C.L.-G., D.B. and S.W. researched data for the article. C.A.W., S.C.L.-G. and S.W. wrote the article. All authors contributed substantially to discussion of the content and reviewed or edited the manuscript before submission.

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Correspondence to Carsten A. Wagner.

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Competing interests

C.A.W. reports honoraria from Advicenne, Kyowa Kirin, Chugai and Medice/Salmon Pharma. D.B. has received honoraria from Advicenne. R.U. is currently employed by AstraZeneca BioPharmaceuticals R&D, Early CVRM (CardioVascular Renal and Metabolism), Cambridge, UK. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks George Schwartz, Francesco Trepiccione and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wagner, C.A., Unwin, R., Lopez-Garcia, S.C. et al. The pathophysiology of distal renal tubular acidosis. Nat Rev Nephrol 19, 384–400 (2023). https://doi.org/10.1038/s41581-023-00699-9

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