Urinary soluble PD-1 as a biomarker of checkpoint inhibitor-induced acute tubulointerstitial nephritis

Francisco Gomez-Preciado; Laura Martinez-Valenzuela; Paula Anton-Pampols; Xavier Fulladosa; Marina Gomez Tena; Montserrat Gomà; María Jove; Ernest Nadal; Ana Merino-Ribas; Nadia Martin-Alemany; Josep María Cruzado; Joan Torras; Juliana Draibe

doi:10.1093/ckj/sfae200

Urinary soluble PD-1 as a biomarker of checkpoint inhibitor-induced acute tubulointerstitial nephritis

Clin Kidney J. 2024 Jul 2;17(8):sfae200. doi: 10.1093/ckj/sfae200. eCollection 2024 Aug.

Authors

Affiliations

¹ Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
² Department of Clinical Sciences, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
³ Department of Pathology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain.
⁴ Department of Medical Oncology, Catalan Institute of Oncology, and Clinical Research in Solid Tumors Group, Oncobell, l'Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet, Barcelona, Spain.
⁵ Department of Nephrology, Dr Josep Trueta University Hospital, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.

Abstract

Background: Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN.

Methods: We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n = 18) and ATN (n = 21). The findings were validated in an independent cohort from another institution (n = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN.

Results: Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P = .021). In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%. In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P = .02). The proportion of patients having >2.64/mm² PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P = .034). There was a positive correlation (P = .009, r = 0.72) between usPD-1 and the number of PD-L1 positive tubules.

Conclusions: UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort.

Keywords: PD-1; PD-L1; PD-L2; checkpoint; nephritis.