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Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis
Meghan E Sise1, Qiyu Wang2, Harish Seethapathy2
1Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA msise@partners.org.
Insights
Non-invasive biomarkers, including soluble interleukin-2 receptor alpha (sIL-2R) and cell-based immune markers, show promise for diagnosing immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis). These findings could lead to earlier detection and management of this kidney condition.
Area of Science:
- Nephrology
- Immunology
- Oncology
Background:
- Immune checkpoint inhibitors (ICIs) can cause acute tubulointerstitial nephritis (ICI-nephritis), a condition lacking non-invasive diagnostic markers.
- Dysregulation of immune pathways, particularly involving CTLA4, is implicated in ICI-nephritis.
- Biomarkers identified in congenital CTLA4 deficiency may be relevant for diagnosing ICI-nephritis.
Purpose of the Study:
- To investigate the diagnostic utility of soluble interleukin-2 receptor alpha (sIL-2R) and peripheral blood immune cell markers for ICI-nephritis.
- To compare these biomarkers in patients with ICI-nephritis against various control groups.
Main Methods:
- Retrospective analysis of ICI-nephritis patients compared to ICI-treated controls, hemodynamic AKI controls, and non-ICI-nephritis controls.
- Measurement of sIL-2R levels and flow cytometric analysis of peripheral blood immune cells.
- Gene expression analysis of kidney biopsy samples for IL2RA, IL-2, and T cell receptor signaling.
Main Results:
- Significantly elevated sIL-2R levels were observed in ICI-nephritis patients compared to controls (p<0.001).
- A sIL-2R cut-off of 1.75-fold ULN demonstrated high diagnostic accuracy (>96% AUC) for ICI-nephritis.
- Peripheral blood flow cytometry revealed lower CD8+ T cells, CD45RA+ CD8+ T cells, memory CD27+ B cells, and expanded plasmablasts in ICI-nephritis.
Conclusions:
- Elevated sIL-2R levels in peripheral blood are a strong indicator of ICI-nephritis.
- Specific B and T cell dysregulation patterns identified via flow cytometry may aid ICI-nephritis diagnosis.
- These non-invasive biomarkers offer potential for improved diagnosis of ICI-associated kidney injury.
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 dysregulationpreviously 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 aid the diagnosis of ICI-nephritis.
Methods:
A retrospective cohort of patients diagnosed with ICI-nephritis was compared with 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 of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with 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 with 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 (area under the curve >96%) when compared with 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 with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.
Conclusion:
Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.
