Soluble and cell-based markers of immune checkpoint inhibitor associated nephritis
Authors: Sise Meghan E. , Wang Qiyu , Seethapathy Harish , Moreno Daiana , Harden Destiny , Smith R. Neal , Rosales Ivy A. , Colvin Robert B. , Chute Sarah , Cornell Lynn D. , Herrmann Sandra , Fadden Riley , Sullivan Ryan J. , Yang Nancy , Barmettler Sara , Villani Alexandra Chloe , Reynolds Kerry , Farmer Jocelyn 
Published: October 2022

Background

Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulation previously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aide the diagnosis of ICI-nephritis.

Methods

A retrospective cohort of patients diagnosed with ICI-nephritis was compared to three prospectively enrolled control cohorts: ICI-treated controls without immune related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression ofIL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared to other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.

Results

sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal [ULN], IQR 1.9-3.3), compared to ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9,P<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7-1.1,P=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (AUC >96%) when compared to either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+ T cells, CD45RA+CD8+ T cells, memory CD27+ B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared to ICI-treated controls. Gene expression forIL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared to controls.

Conclusion

Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Key Messages

What is already known on this topic

There are no non-invasive biomarkers of immune checkpoint inhibitor-associated nephritis (ICI-nephritis); kidney biopsy, the gold standard for diagnosing ICI-nephritis, can be challenging or even contraindicated given its periprocedural risk. There are mechanistic and clinicopathologic similarities between immune-related adverse events and congenital CTLA4 deficiency.

What this study adds

Established biomarkers of congenital CTLA4 deficiency, including elevated serum sIL-2R level and flow cytometric markers of both B and T cell dysregulation, are promising biomarkers for diagnosis of ICI-nephritis. These markers are not altered in patients treated with immune checkpoint inhibitors who are not experiencing immune-related adverse events.

How this study might affect research, practice or policy

Prospective study with longitudinal sIL-2R and peripheral flow cytometry measurements are needed to validate the result and may limit the need for invasive diagnosis of ICI-nephritis.