Anti−PD-1 Immunotherapy May Induce Interstitial Nephritis With Increased Tubular Epithelial Expression of PD-L1

Abstract

Introduction Novel anticancer therapies include anti–programmed cell death protein-1 (PD-1) and anti–programmed death ligand-1 (PD-L1) drugs. These novel medications have side effects in different organs, including the kidney. The most common adverse effect in the kidney is acute interstitial nephritis (AIN). No diagnostic criteria are available to distinguish AIN associated with anti–PD-1 therapy from other AINs. Methods Kidney biopsy specimens from patients on anti–PD-1 therapy were stained with antibodies to PD-1 and PD-L1. Herein we report morphologic and immunohistochemical findings in 15 patients who received anti–PD-1 therapy and developed acute kidney injury requiring a kidney biopsy. Results Among these patients, 9 had AIN and 6 had no AIN but showed acute tubular necrosis (ATN). Immunohistochemistry with antibodies to PD-1 and PD-L1 was performed on all of these biopsy specimens and on 9 randomly selected biopsy specimens with AIN from patients who did not receive anti–PD-1 medications, as well as 9 patients with lupus nephritis and active-appearing interstitial inflammation. There was weak staining for PD-1 in T cells in all patients with AIN and lupus; however, tubular epithelial cell membrane staining for PD-L1 was seen only in patients with anti–PD-1 therapy−associated AIN, and not in patients with anti–PD-1 therapy−associated ATN, and not in those with AIN secondary to other medications, or patients with lupus nephritis. Conclusion We propose that immunohistochemistry with PD-L1 could be a useful tool to differentiate AIN associated with anti–PD-1 therapy from other AINs.

Kidney Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor–Associated Acute Kidney Injury: PRO

“…First described by Izzedine et al (18), but also reported by Mamlouk et al (17) and Cassol et al (19) in their case series, acute tubular injury was observed with only modest inflammation in a substantial proportion of cases. It is not clear that this is an immunemediated entity, as supported by the immunohistochemical findings (19). More experience is needed in the natural course of tubular injury with limited interstitial inflammation during CPIT use.…”

Kidney Biopsy Should Be Performed to Document the Cause of Immune Checkpoint Inhibitor–Associated Acute Kidney Injury: CON

“…In patients that develop ICPi-AKI, the most common pathologic finding identified to date is AIN (10)(11)(12)19 These case series emphasize that it is reasonable to assume that AIN is the cause for ICPi-AKI in the majority of cases. Finally, in a recent multicenter study of AKI in this setting, 60 patients underwent a kidney biopsy and 93% of samples were consistent with AIN (14).…”

“…Acute tubular necrosis (ATN) is another finding reported after biopsy in patients with ICPi-AKI (13,19). Izzedine et al (13) report ATN in five out of 12 cases and highlight that without kidney biopsy patients would have been inappropriately treated with steroids.…”

Nephrotoxicity in patients receiving immune checkpoint inhibitors

“…This assumption, though, differs from what is observed in animal models, where the absence of immune checkpoints suffices to cause ATIN 11 . The latter is also evident in patients with no known exposure to conventional nephrotoxic therapies that have also developed ATIN 27,30 .…”

“…Clinically, patients typically present with AKI that might sometimes be oliguric, pyuria, hematuria, and proteinuria that is usually bland 2,27,31 , such as seen in other cases of classic ATIN 28 . Eosinophilia is a rare finding.…”