尿可溶性程序性死亡受体1作为检查点抑制剂诱导的急性肾小管间质性肾炎的生物标志物。
Urinary soluble PD-1 as a biomarker of checkpoint inhibitor-induced acute tubulointerstitial nephritis.
作者信息
Gomez-Preciado Francisco, Martinez-Valenzuela Laura, Anton-Pampols Paula, Fulladosa Xavier, Tena Marina Gomez, Gomà Montserrat, Jove María, Nadal Ernest, Merino-Ribas Ana, Martin-Alemany Nadia, Cruzado Josep María, Torras Joan, Draibe Juliana
机构信息
Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
Department of Clinical Sciences, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
出版信息
Clin Kidney J. 2024 Jul 2;17(8):sfae200. doi: 10.1093/ckj/sfae200. eCollection 2024 Aug.
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 ( = 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) ( = 18) and ATN ( = 21). The findings were validated in an independent cohort from another institution ( = 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 ( = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN ( = .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 ( = .02). The proportion of patients having >2.64/mm PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN ( = .034). There was a positive correlation ( = .009, = 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.
背景
与免疫检查点抑制剂相关的急性间质性肾炎（ICI-AIN）的病理生理学尚未完全明确。我们的目标是分析可能用于区分急性肾小管坏死（ATN）和AIN的生物标志物，尤其是在癌症患者中，并研究免疫检查点通路在ICI-AIN中的作用。
方法
我们进行了一项观察性研究。我们招募了初诊为ICI-AIN的患者（n = 19）。在诊断时测量血清和尿液中的可溶性PD-1（sPD-1）、sPD-L1和sPD-L2，并与非ICI相关AIN（非ICI-AIN）患者（n = 18）和ATN患者（n = 21）进行比较。研究结果在来自另一家机构的独立队列（n = 30）中得到验证。此外，我们对ICI-AIN患者的肾活检组织进行了PD-L1和PD-L2免疫染色，并与非ICI-AIN患者进行比较。
结果
与ATN患者相比，AIN患者的尿sPD-1（usPD-1）更高（P = 0.03）。AIN患者的血清sPD-1（ssPD-1）也高于ATN患者（P = 0.021）。在癌症患者中，usPD-1<129.3 pg/ml区分ATN和ICI-AIN的敏感性为71.43%，特异性为94.44%，似然比为12.86。在外部验证队列中，相同的临界值显示敏感性为80%。在肾活检中，ICI-AIN患者的PD-L1阳性肾小管密度高于非ICI-AIN患者（P = 0.02）。与非ICI-AIN患者相比，ICI-AIN患者中PD-L2阳性肾小管>2.64/mm的比例更高（P = 0.034）。usPD-1与PD-L1阳性肾小管数量之间存在正相关（P = 0.009，r = 0.72）。
结论
AIN患者的usPD-1和ssPD-1高于ATN患者。此外，usPD-1与肾小管PD-L1表达之间存在强相关性。我们的研究结果表明，usPD-1作为一种非侵入性生物标志物，可用于区分ICI-AIN和ATN，尤其是在癌症患者中，这在外部验证队列中得到了证实。
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