key: cord-0703633-1dhj7ixu
authors: Edelstein, Charles L.; Venkatachalam, Manjeri A.; Dong, Zheng
title: Autophagy inhibition by chloroquine and hydroxychloroquine could adversely affect AKI and other organ injury in critically ill patients with COVID-19
date: 2020-05-08
journal: Kidney Int
DOI: 10.1016/j.kint.2020.05.001
sha: 78dcc35fc52f9f7b9f4d78fe1caf17d8a2831623
doc_id: 703633
cord_uid: 1dhj7ixu

nan

We read the letter by Izzedine et al (1) with great interest especially the discussion of renal adverse effects of drug treatment options for COVID-19. We would like to draw particular attention to the potential adverse effect of chloroquine and hydroxychloroquine, the lysosomotropic antimalarial drugs that may inhibit the infection of SARS-CoV-2 by reducing the entry and replication of the virus. SARS-CoV-2 enters cells via endocytosis by binding of its trimeric spike protein to cell surface receptors including angiotensin-converting enzyme 2 (ACE2). Expression of the ACE2 is high in proximal tubular cells in the human kidney (Supplemental Figure S1 ). Based on the in vitro observation of inhibitory effects of chloroquine and hydroxychloroquine, clinical studies of their treatment in COVID-19 patients are under way. However, we believe that these lysosomotropic agents have the potential to make AKI and other organ failures worse due to their known effect to increase lysosomal pH and inhibit autophagy (2), a fundamental mechanism for the survival of injured cells. Chloroquine mainly inhibits autophagy by impairing autophagosome-lysosome fusion and the degradative activity of the lysosome (2). Also, chloroquine can induce an autophagy-independent severe disorganization of the Golgi and endosomal-lysosomal systems which may contribute to its effect on autophagosome-lysosome fusion (2) . Inhibition of autophagy by chloroquine results in the accumulation of damaged mitochondria due to the lack of clearance via mitophagy, which, together with attendant oxidative stress, leads to renal tubular dysfunction (3). In patients, chloroquine increases cancer cell killing by inhibiting autophagy, an idea being tested in clinical trials (4) . In mouse models of septic AKI, autophagy protects against renal tubule injury and pharmacological inhibition of autophagy with chloroquine worsens kidney damage (5). Chloroquine also blocks 3 autophagic flux and worsens both ischemic and cisplatin-induced nephrotoxic AKI in mice (6) . Chloroquine has also been shown to be nephrotoxic by autophagy-dependent as well as autophagy-independent pathways, including interference with the cAMP production and signaling in distal tubular cells (7) . In other preclinical studies, chloroquine inhibits autophagy and worsens ischemic cardiac injury (8) and sepsisinduced liver or lung injury (9) (10). Thus, chloroquine could be a double edged sword: it may slow virus infection and replication early, but may later potentiate tissue damage and worsen acute organ injury by inhibiting autophagy (Figure 1 ). We write to strike a cautionary note on using chloroquine or hydroxychloroquine in COVID-19 patients with acute organ injury including AKI. 

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Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney

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Autophagy is activated to protect against endotoxic acute kidney injury

Autophagy in proximal tubules protects against acute kidney injury

The chronic adverse effect of chloroquine on kidney in rats through an autophagy dependent and independent pathways

Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury

Complete activation of the autophagic process attenuates liver injury and improves survival in septic mice

Autophagy activation improves lung injury and inflammation