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Hum Pathol. 2018 Mar;73:89-101. doi: 10.1016/j.humpath.2017.12.018. Epub 2018 Jan 5.

Decreased expression of megalin and cubilin and altered mitochondrial activity in tenofovir nephrotoxicity.

Author information

1
Department of Nephrology and Dialysis, Tenon Hospital, APHP, F-75020 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR-S 1155, Tenon Hospital, F-75020 Paris, France; INSERM, UMR_S 1155, F-75020 Paris, France.
2
INSERM, UMR_S 1155, F-75020 Paris, France; Department of Pathology, Pitié Salpétrière Hospital, APHP, F-75020 Paris, France.
3
Department of Infectious Diseases, Bichat Hospital, APHP, F-75018 Paris, France; Univ Paris Diderot, IAME, UMR1137, Sorbonne Paris Cité, F-75018 Paris, France; Department of Infectious Diseases, Tenon Hospital, APHP, F-75020 Paris, France.
4
Department of Pathology, Bicêtre Hospital, APHP, F-94275 Le Kremlin Bicêtre, France.
5
Sorbonne Universités, UPMC Univ Paris 06, UMR-S 1155, Tenon Hospital, F-75020 Paris, France; Department of Infectious Diseases, Saint Antoine Hospital, APHP, F-75012 Paris, France.
6
Sorbonne Universités, UPMC Univ Paris 06, UMR-S 1155, Tenon Hospital, F-75020 Paris, France; Department of Infectious Diseases, Tenon Hospital, APHP, F-75020 Paris, France.
7
Institute of Molecular Medicine, University of Southern Denmark, DK-5000, Denmark.
8
Department of Biochemistry, Tenon Hospital, APHP, F-75020 Paris, France.
9
Department of Nephrology and Dialysis, Tenon Hospital, APHP, F-75020 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR-S 1155, Tenon Hospital, F-75020 Paris, France; INSERM, UMR_S 1155, F-75020 Paris, France. Electronic address: emmanuelle.plaisier@aphp.fr.

Abstract

Tenofovir disoproxil fumarate (TDF) is a commonly used antiretroviral drug for HIV, rarely causing Fanconi syndrome and acute kidney injury. We retrospectively analyzed the clinico pathological presentation of 20 cases of tenofovir-induced tubulopathy, and investigated the renal expression of the megalin and cubilin proteins, as well as the mitochondrial respiratory chain activity. Estimated glomerular filtration rate (eGFR) before TDF exposure was 92 ml/min/1.73m2, decreasing to 27.5 ml/min/1.73m2 at the time of biopsy, with 30% of patients requiring renal replacement therapy. Proximal tubular expression of megalin and cubilin was altered in 19 and 18 cases, respectively, whereas it was preserved in patients exposed to TDF without proximal tubular dysfunction and in HIV-negative patients with acute tubular necrosis. Loss of megalin/cubilin was correlated with low eGFR and high urine retinol binding protein at the time of biopsy, low eGFR at last follow-up, and was more severe in patients with multifactorial toxicity. Patients with additional nephrotoxic conditions promoting tenofovir accumulation showed a lower eGFR at presentation and at last follow-up, and more severe lesions of acute tubular necrosis, than those with isolated tenofovir toxicity. Altered mitochondrial COX activity in proximal tubules was observed and may be an early cellular alteration in tenofovir nephrotoxicity. In conclusion, altered megalin/cubilin expression represents a distinctive feature in tenofovir-induced tubulopathy, and its severity is correlated with urine retinol binding protein loss and is associated with a poor renal prognosis. Concomitant exposure to other nephrotoxic conditions severely impacts the renal presentation and outcome.

KEYWORDS:

Cubilin; Fanconi syndrome; Megalin; Nephrotoxicity; Tenofovir; Tubulopathy

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