CD163 detection in immune check-point inhibitors-related acute interstitial nephritis

Abstract

Background: Acute interstitial nephritis (AIN) is the most common renal immune-related adverse event after immune check-point inhibitors (ICI). We hypothesized that alternatively activated macrophages (CD163-M) could be involved in ICI-AIN and wished to evaluate the use of their soluble urinary form (us)CD163 as a non-invasive diagnostic marker.

Methods: CD163-M infiltrates were evaluated by both immune-histochemistry and multiplex immunofluorescence and imaging. usCD163 was detected with ELLA technology and evaluated together with urinary creatinine to be expressed as a ratio to creatinuria in ng/mmol. Clinical data were collected to perform correlations with renal function assessed by estimated glomerular filtration rate (eGFR).

Results: A retrospective cohort of 63 ICI-exposed patients with tubular acute kidney injury profile requiring a biopsy were selected. AIN patients (n = 44) were compared to acute tubular necrosis (ATN) patients (n = 19). CD163-M staining was detectable in all ICI-AIN patients, which was significantly higher than in ATN patients (18.4% vs 3.6% of area, P = .005). CD163-M staining was restricted to the interstitial compartment. CD163-M infiltrate inversely correlated with initial eGFR (r = -0.6, P = .003), and was positively correlated with delta eGFR, reflecting a renal improvement outcome (r = 0.48; P = .02). usCD163 was well detected in urines of patients, but did not allow us to distinguish ATN from AIN patients at diagnosis. No correlation was observed, neither between usCD163 and CD163-M staining nor with renal response after 3 months of glucocorticoid tapering.

Conclusion: CD163-M are detected in ICI-AIN and correlate both with severity at diagnosis and better prognosis at 3 months. CD163-M may help us to distinguish AIN from ATN but, it does not allow us to assess ICI imputability. Although detected in urine, usCD163 is clearly not a surrogate biomarker for AIN diagnosis.

Keywords: CD163; alternatively activated macrophage; immune check-point inhibitors acute interstitial nephritis ICI-AIN; urinary soluble usCD163.

Figure 1:

Flowchart of the study.

Figure 2:

CD163-(M) macrophages in ICI-AIN kidney biopsies. CD163 immunohistochemistry detection in kidney biopsies. (a) A representative example is depicted for both ATN and AIN patients, in the left and right panels, respectively. (b) CD163 staining, expressed in percentage of area in each group (n = 8 for ATN and n = 26 for ICI-AIN) P = .0005. (c) CD163 infiltration was associated with severity of ICI-AIN at diagnosis (a high CD163-M staining was found to be associated with a low eGFR, n = 25, **P = .003). (d) CD163-M infiltration at ICI-AIN diagnosis was associated with a favourable delta eGFR at 3 months (delta = eGFR at 3 months; eGFR at AIN diagnosis), n = 22, *P = .02.

Figure 3:

usCD163 detection in patients with ICI-AIN. (a) Albuminuria/urinary creatinine (A/C) ratio, expressed in mg/g. Threshold at 300 mg/g is indicated with horizontal line. (b) Proteinuria/urinary creatinine (P/C) ratio, expressed in mg/g. (c) usCD163 correlation with CD163 staining. (d, e, f) usCD163 correlation with degree or fibrosis and severity of AKI (initial eGFR).

Figure 4:

UsCD163 kinetic across AIN evolution in patients with available samples and renal response after 3 months (M3) of glucocorticoids (n = 19). (a) Individual values are plotted at diagnosis and M3. The proportion of patients with stable, increase, or decrease values is represented in a pie chart. (b) An illustrative example is depicted for a patient with longitudinal usCD163 monitoring and complete renal response. (c) UsCD163 values are depicted at diagnosis, in patients with PR compared to CR. (d) Patients in PR only (n = 8). Individual values are plotted at diagnosis and M3. Proportion of patients with stable, increase, or decrease values is represented in pie chart. (e) Patients in CR only (n = 11). Individual values are plotted at diagnosis and M3. The proportion of patients with stable, increase, or decrease values is represented in a pie chart.