Autophagy inhibition by chloroquine and hydroxychloroquine could adversely affect acute kidney injury and other organ injury in critically ill patients with COVID-19

To the editor:

We read the letter by Izzedine et al. ¹ with great interest, especially the discussion of renal adverse effects of drug treatment options for coronavirus disease 2019 (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 severe acute respiratory syndrome coronavirus 2 by reducing the entry and replication of the virus. Severe acute respiratory syndrome coronavirus 2 enters cells via endocytosis by binding of its trimeric spike protein to cell surface receptors including angiotensin-converting enzyme 2. Expression of angiotensin-converting enzyme 2 is high in proximal tubular cells in the human kidney (see Supplementary Figure S1 and Supplementary References). 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 acute kidney injury (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 that 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 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 cyclic adenosine monophosphate production and signaling in distal tubular cells.⁷ In other preclinical studies, chloroquine inhibits autophagy and worsens ischemic cardiac injury⁸ and sepsis-induced 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.

Figure 1.

Chloroquine could be a double-edged sword. Chloroquine may slow virus infection and replication early but may later potentiate tissue damage and worsen acute organ injury by inhibiting autophagy. ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.