PAD4 Inhibition Repairs, Reverses Cancer Tumor-Induced Kidney Damage

More than 50% of all cancer patients have renal insufficiency at the time of diagnosis.
More than 50% of all cancer patients have renal insufficiency at the time of diagnosis.

A potential treatment targeting neutrophils holds promise for limiting kidney damage and improving renal function in cancer, according to results from research in mice.

Kidney failure is a frequent issue facing patients with cancer. In fact, more than half of all cancer patients have renal insufficiency at the time of diagnosis. Kidney failure is correlated with worse survival rates in cancer patients.

Often, clinicians reduce cancer therapy dosages in patients with renal insufficiency to limit the toxic effects on the kidneys, but this approach also reduces efficacy of anticancer therapy.

In this study, researchers revealed that the formation of neutrophil extracellular traps (NETs) caused kidney damage in mice with tumors. These mice experienced impaired creatinine clearance and increased total urine protein levels, both of which indicate impaired kidney function.

Electron microscopy imaging revealed reversible damage in the kidneys, including mesangial hypercellularity. Irreversible damage, such as necrosis, was not observed.

Next, the researchers pharmacologically inhibited an enzyme called peptidylarginine deiminase 4 (PAD4), which removed the NETs on the kidneys. The treatment restored kidney function in the mice. PAD4 inhibition also reduced systemic inflammation induced by tumors and repaired impaired perfusion of peripheral blood vessels.

Reference

1. Cedervall J, Dragomir A, Saupe F, et al. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice [published online April 20, 2017]. OncoImmunol. doi: 10.1080/2162402X.2017.1320009

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