Pathologic Predictors of Response to Treatment of Immune Checkpoint Inhibitor-Induced Kidney Injury.
Pathologic Predictors of Response to Treatment of Immune Checkpoint Inhibitor-Induced Kidney Injury.
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免疫相关不良事件（irAE）是一项管理挑战，伴随着发病率和死亡率的增加。最常见的肾毒性是急性间质性肾炎（AIN），其可能类似于肾移植排斥反应。在35例活检证实AIN的回顾性队列中，使用移植排斥BANFF标准进行详细的病理学评价。该研究得出结论，与纤维化程度较轻的患者相比，肾活检时间质纤维化程度增加的患者发生肾反应的可能性较低（p = 0.027）。间质性炎症、肾小管炎、嗜酸性粒细胞、中性粒细胞数量和细胞免疫亚型对肾脏反应无影响。此外，与未同时接受ICI且未达到肾脏缓解的患者相比，接受同时ICI且在3个月内达到肾脏缓解的患者具有最佳OS。背景：免疫相关不良事件是接受免疫检查点抑制剂（ICI）的患者的管理挑战。最常见的肾脏免疫相关不良事件急性间质性肾炎（AIN）与患者发病率和死亡率相关。AIN的特征是免疫细胞浸润肾组织，可能类似于肾移植排斥反应。我们评估了临床变量和病理结果，以确定ICI诱导的AIN患者的肾反应和总生存期（OS）的预测因子。设计、设置、参与者和测量：我们回顾了2007年8月至2020年8月期间在我们机构接受ICI诱导AIN治疗的所有35例患者的记录和活检标本，这些患者有可用的活检标本。两名委员会认证的肾脏病理学家使用移植排斥Banff标准对炎症的严重程度和慢性程度进行分级，并进行免疫组织化学分析。如果肌酐在开始AIN治疗后3个月内有任何改善或恢复至基线水平，则将患者归类为肾应答者。比较应答者和非应答者的临床和病理特征以及OS。结果：高水平间质纤维化的患者比纤维化程度较低的患者更不可能成为应答者（p = 0.02）。炎症、肾小管炎、嗜酸性粒细胞和中性粒细胞数量以及CD 8+、CD 4+、CD 20+或CD 68+细胞的聚集或存在与肾脏缓解无关。应答者的OS优于非应答者（12个月OS率为77%，而非27%，p = 0.025）。同时接受ICI的应答者的OS最好，未同时接受ICI的无应答者的OS最差（肾脏应答和同时接受ICI的12个月OS率为100%，肾脏应答且无同时接受ICI的12个月OS率为72%，无肾脏应答且无同时接受ICI的12个月OS率为27%; p = 0.041）。结论：这是首次对ICI诱导的肾炎进行分析，其中进行了详细的病理学和临床评价以预测肾脏反应。肾组织中低水平的间质纤维化与ICI诱导的AIN治疗的肾应答相关，肾应答和同时使用ICI与这些患者的OS更好相关。我们的研究结果强调了早期诊断和治疗ICI-AIN的重要性，同时继续进行ICI治疗。
Immune related adverse events (irAEs) are a management challenge with an associated increased morbidity and mortality. The most common renal toxicity is acute interstitial nephritis (AIN), which may be analogous to kidney transplant rejection. In a retrospective cohort of 35 patients with biopsy confirmed AIN, a detailed pathological evaluation was performed using transplant rejection BANFF criteria. The study concluded that patients with increased interstitial fibrosis on kidney biopsies were less likely to have renal response compared to patients with less fibrosis, (p = 0.027). Interstitial inflammation, tubulitis, number of eosinophils, neutrophils, and immune subtype of cells had no impact on renal response. In addition, patients who received concurrent ICI and achieved renal response within 3 months had the best OS in comparison to patients who did not receive concurrent ICI nor achieved renal response. Background: Immune-related adverse events are a management challenge in patients receiving immune checkpoint inhibitors (ICIs). The most common renal immune-related adverse event, acute interstitial nephritis (AIN), is associated with patient morbidity and mortality. AIN, characterized by infiltration of renal tissue with immune cells, may be analogous to kidney transplant rejection. We evaluated clinical variables and pathologic findings to identify predictors of renal response and overall survival (OS) in patients with ICI-induced AIN. Design, setting, participants, and measurements: We reviewed the records and biopsy specimens of all 35 patients treated for ICI-induced AIN at our institution, between August 2007 and August 2020, who had biopsy specimens available. Two board-certified renal pathologists graded the severity of inflammation and chronicity using transplant rejection Banff criteria and performed immunohistochemistry analysis. Patients were categorized as renal responders if creatinine had any improvement or returned to baseline within 3 months of initiating treatment for AIN. Clinical and pathologic characteristics and OS were compared between responders and non-responders. Results: Patients with high levels of interstitial fibrosis were less likely to be responders than those with less fibrosis (p = 0.02). Inflammation, tubulitis, the number of eosinophils and neutrophils, and the clustering or presence of CD8+, CD4+, CD20+, or CD68+ cells were not associated with renal response. Responders had better OS than non-responders (12-month OS rate 77% compared with 27%, p = 0.025). Responders who received concurrent ICIs had the best OS, and non-responders who did not receive concurrent ICIs had the worst OS (12-month OS rate 100% for renal response and concurrent ICIs, 72% for renal response and no concurrent ICIs, and 27% for no renal response and no concurrent ICIs; p = 0.041). Conclusions: This is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Low levels of interstitial fibrosis in kidney tissue are associated with renal response to treatment for ICI-induced AIN, and the renal response and use of concurrent ICIs are associated with better OS in these patients. Our findings highlight the importance of the early diagnosis and treatment of ICI-AIN, while continuing concurrent ICI therapy.
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影响因子：
19.6
作者：
Cortazar FB;Marrone KA;Troxell ML;Ralto KM;Hoenig MP;Brahmer JR;Le DT;Lipson EJ;Glezerman IG;Wolchok J;Cornell LD;Feldman P;Stokes MB;Zapata SA;Hodi FS;Ott PA;Yamashita M;Leaf DE
通讯作者：
Leaf DE
影响因子：
4.6
作者：
Hagiwara S;Watanabe T;Kudo M;Minaga K;Komeda Y;Kamata K;Kimura M;Hayashi H;Nakagawa K;Ueshima K;Minami Y;Aoki T;Takita M;Morita M;Cishina H;Ida H;Park AM;Nishida N
通讯作者：
Nishida N
影响因子：
10.9
作者：
Mamlouk, Omar;Selamet, Umut;Abudayyeh, Ala
通讯作者：
Abudayyeh, Ala
影响因子：
13.6
作者：
Cortazar, Frank B.;Kibbelaar, Zoe A.;Leaf, David E.
通讯作者：
Leaf, David E.
DOI：
10.2215/cjn.00920121
发表时间：
2021-09-01
影响因子：
9.8
作者：
Adam, Benjamin A.;Murakami, Naoka;Mengel, Michael
通讯作者：
Mengel, Michael