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Podocyte dysfunction in atypical haemolytic uraemic syndrome

Nature Reviews Nephrology volume 11, pages 245–252 (2015)Cite this article

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Abstract

Genetic or autoimmune defects that lead to dysregulation of the alternative pathway of complement have been associated with the development of atypical haemolytic uraemic syndrome (aHUS), which is characterized by thrombocytopenia, haemolytic anaemia and acute kidney injury. The relationship between aHUS, podocyte dysfunction and the resultant proteinuria has not been adequately investigated. However, the report of mutations in diacylglycerol kinase ε (DGKE) as a cause of recessive infantile aHUS characterized by proteinuria, highlighted podocyte dysfunction as a potential complication of aHUS. DGKE deficiency was originally thought to trigger aHUS through pathogenetic mechanisms distinct from complement dysregulation; however, emerging findings suggest an interplay between DGKE and complement systems. Podocyte dysfunction with nephrotic-range proteinuria can also occur in forms of aHUS associated with genetic or autoimmune complement dysregulation without evidence of DGKE mutations. Furthermore, proteinuric glomerulonephritides can be complicated by aHUS, possibly as a consequence of podocyte dysfunction inducing endothelial injury and prothrombotic abnormalities.

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Figure 1: The phosphatidylinositol cycle regenerates PI from PA at the plasma membrane.
Figure 2: The effect of AADAG signalling in endothelium, platelets and podocytes.
Figure 3: Mechanisms of complement-mediated injury in the podocyte.

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Article 13 August 2020

Jeffrey B. Kopp, Hans-Joachim Anders, … Paola Romagnani

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Acknowledgements

The authors' work is supported by Fondazione ART per la Ricerca sui Trapianti ART ONLUS (Milano, Italy), the European Union Seventh Framework Programme FP7-EURenOmics project number 305608 and by Telethon (grant #GGP09075).

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  1. IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Via Camozzi 3, Ranica, 24020, Bergamo, Italy

    Marina Noris, Caterina Mele & Giuseppe Remuzzi

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M.N. and C.M researched data for the article. M.N. wrote the article. All authors contributed to discussion of the article's content and reviewed/edited the manuscript before submission.

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Correspondence to Marina Noris.

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M.N. has received honoraria from Alexion Pharmaceuticals for giving lectures and participating on advisory boards. G.R. has consultancy agreements with AbbVie, Alexion Pharmaceuticals, Bayer Healthcare, Reata Pharmaceuticals, Novartis Pharma, AstraZeneca, Otsuka Pharmaceutical Europe and Concert Pharmaceuticals but receives no personal remuneration; compensations are instead paid to his institution for research and educational activities. C.M. declares no conflict of interest.

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Noris, M., Mele, C. & Remuzzi, G. Podocyte dysfunction in atypical haemolytic uraemic syndrome. Nat Rev Nephrol 11, 245–252 (2015). https://doi.org/10.1038/nrneph.2014.250

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