背景:免疫检查点抑制剂(ICIs)在2-5%的患者中诱发急性间质性肾炎(AIN),当它们与铂衍生物结合使用时,发病率明显更高。不幸的是,缺乏合适的疾病模型和非侵入性生物标志物。为了填补我们在理解上的空白,我们研究了顺铂和抗PD-L1抗体对小鼠的肾脏作用,评估患有AIN的小鼠的PD-1肾脏表达和细胞因子水平,然后我们将这些发现与AIN诊断的癌症患者进行了比较。
方法:20只C57BL6J小鼠腹膜内接受200µg抗PD-L1抗体和5mg/kg顺铂,并与接受顺铂的小鼠进行比较(n=6),抗PD-L1(n=7),或盐水(n=6)。7天后,对小鼠实施安乐死。血清和尿液中TNFα的浓度,通过Luminex测量CXCL10、IL-6和MCP-1。将肾切片染色以确定PD-1组织表达。纳入了39例AKI癌症患者(AINn=33,急性肾小管坏死(ATN)n=6),测量尿液MCP-1(uMCP-1),和肾切片染色以评估PD-1表达。
结果:顺铂和抗PD-L1治疗导致小鼠发生40%AIN(p=0.03),伴有血清肌酐和uMCP1升高。AIN诊断的癌症患者的uMCP1水平也高于ATN诊断的患者,证实了我们之前的发现.AIN小鼠表现出间质PD-1染色和更强的肾小球PD-1表达,尤其是联合治疗。相反,人类AIN患者仅显示间质性PD-1阳性。
结论:只有接受顺铂和抗PDL1的小鼠同时出现AIN,伴有更严重的肾损伤。这种药物联合诱导的AIN与uMCP1升高有关,与人类AIN一致,这表明uMCP1可能被用作AIN生物标志物。
BACKGROUND: Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients.
METHODS: Twenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression.
RESULTS: Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity.
CONCLUSIONS: Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.