Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis

Abstract

BackgroundNon-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.MethodsA 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 ofIL2RA,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.ResultssIL-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 forIL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.ConclusionElevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Immune checkpoint inhibitors and their interaction with proton pump inhibitors–related interstitial nephritis

“…In addition, our recent study showed that at time of AKI diagnosis, compared to non-ICI-AKI, serum C-reactive protein (CRP) was increased in ICI-AKI patients (median [IQR] 54.0 [33.7, 90.0] vs 3.5 [3.0, 7.9] mg/L, P < 0.001), and urine retinol binding protein to urine creatinine ratio was also significantly elevated (median [IQR] 1927 [1174, 46 522] vs 233 [127, 989] µg/g creatinine, P = 0.013) in patients with ICI-AKI [ 36 ]. Furthermore, systemic soluble interleukin-2 receptor (sIL-2R) has been found to be elevated in patients with ICI-AIN compared to ICI-treated controls and hemodynamic AKI controls (median 2.5-fold upper limit of normal vs 0.8- and 0.9-fold, P < 0.001 and P = 0.008, respectively) [ 83 ]. In this study, a sIL-2R cut-off point of 1.75-fold-upper limit of normal was suggested to be maximal specificity (100%) and optimal sensitivity (81%) in differentiating ICI-AKI from ICI-treated controls and hemodynamic AKI controls [ 83 ].…”

“…Furthermore, systemic soluble interleukin-2 receptor (sIL-2R) has been found to be elevated in patients with ICI-AIN compared to ICI-treated controls and hemodynamic AKI controls (median 2.5-fold upper limit of normal vs 0.8- and 0.9-fold, P < 0.001 and P = 0.008, respectively) [ 83 ]. In this study, a sIL-2R cut-off point of 1.75-fold-upper limit of normal was suggested to be maximal specificity (100%) and optimal sensitivity (81%) in differentiating ICI-AKI from ICI-treated controls and hemodynamic AKI controls [ 83 ]. However, sIL-2R did not differ significantly in ICI-treated patients with extrarenal irAE (such as pneumonitis and colitis), suggesting that another extrarenal inflammatory process may also increase its levels as it does with CRP.…”

Immunological mechanisms underlying clinical phenotypes and noninvasive diagnosis of immune checkpoint inhibitor‐induced kidney disease

“…64 We prospectively identified clinically diagnosed and/or biopsyproven cases of ICI-AIN (n = 24) and measured sIL-2R levels in the peripheral blood of those patients before initiation of corticosteroid therapy. 65 We found that sIL-2R levels were much higher in patients scan can be increased in renal cortex in patients with ICI-associated AIN; however, this has not been rigorously studied. [66][67][68] More advanced imaging techniques that are being developed to diagnose inflammation; however, none have been systematically studied in this setting.…”

“…We prospectively identified clinically diagnosed and/or biopsy‐proven cases of ICI‐AIN ( n = 24) and measured sIL‐2R levels in the peripheral blood of those patients before initiation of corticosteroid therapy 65 . We found that sIL‐2R levels were much higher in patients with ICI‐AIN when compared to two control groups that included patients with hemodynamic AKI (not receiving ICIs) or patients with cancer on ICIs without AKI or other irAEs.…”

Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management

“…However, there are some biomarkers that are under investigation and hold promise as potential indicators. Notably, a retrospective study highlights the potential of elevated soluble interleukin-2 receptor (sIL-2R) levels as a highly indicative biomarker for identifying ICI-AKI [ 24 ]. The application of sIL-2R measurement emerges as a valuable diagnostic aid for ICI-induced renal injury, potentially streamlining the diagnostic process.…”