收稿日期: 2025-04-14
网络出版日期: 2025-11-13
基金资助
国家自然科学基金项目(31571169)
Clinical pathological types and pathogenesis of immune checkpoint inhibitor-related kidney injury
Received date: 2025-04-14
Online published: 2025-11-13
免疫检查点抑制剂（immune checkpoint inhibitors， ICIs）是一类新型抗肿瘤药物，通过阻断免疫系统的内源性抑制信号发挥作用，激活T细胞对肿瘤的免疫应答，显著改善了肿瘤患者的预后，然而，由此引发的免疫相关不良事件（immune-related adverse events， irAEs）已成为不可忽视的问题。irAEs可累及包括肾脏在内的多器官系统，其中免疫检查点抑制剂相关急性肾损伤（ICI?associated acute kidney injury，ICI-AKI）是最常见的肾脏毒性表现。病理类型以急性间质性肾炎（acute interstitial nephritis， AIN）最为常见，此外还包括肾小球疾病及血栓性微血管病等非AIN类型。ICI-AKI的发病机制复杂，涉及免疫耐受失衡、自身反应性T细胞的异常激活、自身抗体产生及炎症因子等。ICI-AKI通常对早期糖皮质激素治疗反应良好，大多数患者可达到部分或完全缓解。因此，对疑似患者的及时评估、精准诊断及规范管理具有重要临床价值。深入理解ICIs相关肾损伤的临床病理特征及其免疫学机制，是优化早期识别、精准诊断和有效管理的关键。本综述旨在系统总结当前ICIs相关肾损伤的关键病理学发现，深入探讨其发生发展的免疫学机制，为临床实践提供理论依据与指导。
肖慧玲 , 何伟春 . 免疫检查点抑制剂相关肾损伤的临床病理类型与发病机制[J]. 实用医学杂志, 2025 , 41(21) : 3315 -3321 . DOI: 10.3969/j.issn.1006-5725.2025.21.003
Immune checkpoint inhibitors （immune checkpoint inhibitors， ICIs）， as new anti-tumour drugs， have significantly improved the prognosis of tumour patients by blocking the endogenous immune inhibitory signals and activating the immune response of T cells against tumours. However， the immune-related adverse events （irAEs） they cause have become a significant concern. irAEs can affect multiple organ systems， including the kidneys.Among these， immune checkpoint inhibitor-associated acute kidney injury （ICI-AKI） represents the most common renal toxicity manifestation. The most common pathological type is acute interstitial nephritis （AIN）. Non-AIN types， such as glomerular diseases and thrombotic microangiopathy， can also occur. The pathogenesis of ICI-AKI is complex， involving immune tolerance imbalance， abnormal activation of autoreactive T cells， autoantibody production， and inflammatory cytokines. ICI-AKI typically responds well to early corticosteroid therapy， with most patients achieving partial or complete renal recovery. Therefore， the timely evaluation， precise diagnosis， and standardized management of suspected cases hold crucial clinical value. A deep understanding of the clinical and pathological features and immunological mechanisms of ICI-related renal injury is the key to optimizing early identification， accurate diagnosis， and effective management. This review aims to systematically summarize the key pathological findings of current ICI-related kidney injury and deeply explore its immunological mechanisms of occurrence and development， providing theoretical basis and guidance for clinical practice.
| [1] | CARLINO M S， LARKIN J， LONG G V. Immune checkpoint inhibitors in melanoma［J］. Lancet， 2021， 398（10304）： 1002-1014. doi:10.1016/s0140-6736(21)01206-x |
| [2] | HERRMANN S M， ABUDAYYEH A， GUPTA S， et al. Diagnosis and management of immune checkpoint inhibitor-associated nephrotoxicity： A position statement from the American society of onco-nephrology［J］. Kidney Int， 2025，107（1）：21-32. doi:10.1016/j.kint.2024.09.017 |
| [3] | RAMOS-CASALS M， SISó-ALMIRALL A. Immune-related adverse events of immune checkpoint inhibitors［J］. Ann Intern Med， 2024， 177（2）： ITC17-ITC32. doi:10.7326/aitc202402200 |
| [4] | ZHOU P， GAO Y， KONG Z， et al. Immune checkpoint inhibitors and acute kidney injury［J］. Front Immunol， 2024， 15： 1353339. doi:10.3389/fimmu.2024.1353339 |
| [5] | GUPTA S， SAP S， ME S， et al. Acute kidney injury in patients treated with immune checkpoint inhibitors［J］. J Immunother Cancer， 2021， 9（10）：e003467. |
| [6] | ASBY S C， THOMPSON L E， GOEDKEN M， et al. Pathological findings of immunotherapy-induced nephrotoxicity in a humanized immune system mouse model［J］. Kidney Int， 2025，107（5）：930-934. doi:10.1016/j.kint.2025.01.021 |
| [7] | XU L Y， ZHAO H Y， YU X J， et al. Clinicopathological features of kidney injury related to immune checkpoint inhibitors： A systematic review［J］. J Clin Med， 2023， 12（4）： 1349. doi:10.3390/jcm12041349 |
| [8] | CORTAZAR F B， KIBBELAAR Z A， IG G， et al. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI： A multicenter study［J］. J Am Soc Nephrol， 2020， 31（2）：435-446. doi:10.1681/asn.2019070676 |
| [9] | ESPOSITO P， BOTTINI A， LECINI E， et al. Biopsy-proven acute tubulointerstitial nephritis in patients treated with immune checkpoint inhibitors： A pooled analysis of case reports［J］. Front Oncol， 2023， 13：1221135. doi:10.3389/fonc.2023.1221135 |
| [10] | GIACOMO A M D， GUARNIERI A， TRIPODI S A， et al. Brief communication PD1-related nephrotoxicity： Optimizing its clinical management through histopathologic features［J］. J Immunother， 2022， 45（4）： 217-221. doi:10.1097/cji.0000000000000412 |
| [11] | HULTIN S， NAHAR K， MENZIES A M， et al. Histological diagnosis of immune checkpoint inhibitor induced acute renal injury in patients with metastatic melanoma： A retrospective case series report ［J］. BMC Nephrol， 2020， 21（1）： 391. doi:10.1186/s12882-020-02044-9 |
| [12] | MOSS E M， PERAZELLA M A. The role of kidney biopsy in immune checkpoint inhibitor nephrotoxicity［J］. Front Med （Lausanne）， 2022， 9： 964335. doi:10.3389/fmed.2022.964335 |
| [13] | RASHIDI A， SHAH C， SEKULIC M. The role of kidney biopsy in immune checkpoint inhibitor-associated AKI［J］. Kidney360， 2022， 3（3）：530-533. doi:10.34067/kid.0000232022 |
| [14] | KITCHLU A， JHAVERI K D， WADHWANI S， et al. A systematic review of immune checkpoint inhibitor-associated glomerular disease［J］. Kidney Int Rep， 2021， 6（1）： 66-77. doi:10.1016/j.ekir.2020.10.002 |
| [15] | HE X， LIU F， JIN Y， et al. Glomerular diseases after immune checkpoint inhibitors use： What do we know so far？［J］. Ren Fail， 2022， 44（1）： 2058-2067. doi:10.1080/0886022x.2022.2147439 |
| [16] | MAMLOUK O， SELAMET U， MACHADO S， et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis： Single-center experience［J］. Front Med （Lausanne）， 2019， 7（1）： 2. doi:10.1186/s40425-018-0478-8 |
| [17] | BERMEJO S， BOLUFER M， RIVEIRO-BARCIELA M， et al. Immunotherapy and the spectrum of kidney disease： Should we individualize the treatment？［J］. Front Med （Lausanne）， 2022， 9：906565. doi:10.3389/fmed.2022.906565 |
| [18] | GALLAN A J， ALEXANDER E， REID P， et al. Renal vasculitis and pauci-immune glomerulonephritis associated with immune checkpoint inhibitors［J］. Am J Kidney Dis， 2019， 74（6）： 853-856. doi:10.1053/j.ajkd.2019.04.016 |
| [19] | MAMLOUK O， LIN J S， ABDELRAHIM M， et al. Checkpoint inhibitor-related renal vasculitis and use of rituximab［J］. J Immunother Cancer， 2020， 8（2）： e000750. doi:10.1136/jitc-2020-000750 |
| [20] | ANDEEN N K， TROXELL M L， RIAZY M， et al. Fibrillary glomerulonephritis： Clinicopathologic features and atypical cases from a multi-institutional cohort［J］. Clin J Am Soc Nephrol， 2019， 14（12）： 1741-1750. doi:10.2215/cjn.03870319 |
| [21] | KHAN S， GEORGE J N， NUSRAT S. Drug-induced thrombotic microangiopathy and thrombotic thrombocytopenic purpura： A systematic review， 2018-2023［J］. Am J Hematol， 2023， 98（12）：E373-E375. doi:10.1002/ajh.27104 |
| [22] | BADRA S， RUCHI R， ZENG X， et al. Immune checkpoint inhibitor associated renally limited thrombotic microangiopathy-A clinical dilemma［J］. Eur J Cancer， 2022， 169： 126-130. doi:10.1016/j.ejca.2022.03.031 |
| [23] | LI L， HUANG Y， XUE R， et al. T cell-mediated mechanisms of immune-related adverse events induced by immune checkpoint inhibitors［J］. Crit Rev Oncol Hematol， 2025， 213： 104808. doi:10.1016/j.critrevonc.2025.104808 |
| [24] | SCHOOP R， WAHL P， LE HIR M， et al. Suppressed T-cell activation by IFN-gamma-induced expression of PD-L1 on renal tubular epithelial cells［J］. Nephrol Dial Transplant， 2004， 19（11）： 2713-2720. doi:10.1093/ndt/gfh423 |
| [25] | YOUSSEF N， ABUDAYYEH A. Immune checkpoint inhibitor-related acute kidney injury-management and challenges［J］. Am J Nephrol， 2025，7： 1-20. doi:10.1159/000543323 |
| [26] | RAMOS-CASALS M， BRAHMER J R， CALLAHAN M K， et al. Immune-related adverse events of checkpoint inhibitors［J］. Nat Rev Dis Primers， 2020， 6（1）： 38. doi:10.1038/s41572-020-0160-6 |
| [27] | TOMINAGA K， TODA E， TAKEUCHI K， et al. Predominant CD8 cell infiltration and low accumulation of regulatory T cells in immune checkpoint inhibitor‐induced tubulointerstitial nephritis［J］. Pathol Int， 2024， 74（6）： 317-326. doi:10.1111/pin.13428 |
| [28] | GRIGORIOU M， BANOS A， HATZIOANNOU A， et al. Regulatory T-cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors［J］. Cancer Immunol Res， 2021， 9（7）： 726-734. doi:10.1158/2326-6066.cir-20-0969 |
| [29] | MARTINEZ VALENZUELA L， BORDIGNON DRAIBE J， FULLADOSA OLIVERAS X，et al. T-lymphocyte in ANCA-associated vasculitis： What do we know？ A pathophysiological and therapeutic approach［J］. Clin Kidney J， 2019， 12（4）： 503-511. doi:10.1093/ckj/sfz029 |
| [30] | BARBIR E B， KITCHLU A， HERRMANN S M. Immune checkpoint inhibitor-associated nephritis-treatment standard［J］. Nephrol Dial Transplantn， 2024， 39（11）： 1785-1798. doi:10.1093/ndt/gfae184 |
| [31] | MIAO J， HERRMANN S M. Immune checkpoint inhibitors and their interaction with proton pump inhibitors-related interstitial nephritis［J］. Clin Kidney J， 2023， 16（11）：1834-1844. doi:10.1093/ckj/sfad109 |
| [32] | CORTAZAR F B， KIBBELAAR Z A， GLEZERMAN I G， et al. Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI： A Multicenter Study［J］. J Am Soc Nephrol， 2020， 31（2）： 435-446. doi:10.1681/asn.2019070676 |
| [33] | KODA R， WATANABE H， TSUCHIDA M， et al. Immune checkpoint inhibitor （nivolumab）-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis： A case report［J］. BMC Nephrol， 2018， 19（1）： 48. doi:10.1186/s12882-018-0848-y |
| [34] | FAROOQUI N， ZAIDI M， VAUGHAN L， et al. Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors［J］. Kidney Int Rep， 2023， 8（3）： 628-641. doi:10.1016/j.ekir.2022.11.020 |
| [35] | PERAZELLA M A， SHIRALI A C. Nephrotoxicity of cancer immunotherapies： Past， present and future［J］. J Am Soc Nephrol， 2018， 29（8）：2039-2052. doi:10.1681/asn.2018050488 |
| [36] | SISE M E， WANG Q， SEETHAPATHY H， et al. Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis［J］. J Immunother Cancer， 2023， 11（1）： e006222. doi:10.1136/jitc-2022-006222 |
| [37] | VERHEIJDEN R J， EIJS MJM V， MAY A M， et al. Immunosuppression for immune-related adverse events during checkpoint inhibition： An intricate balance［J］. NPJ Precis Oncol， 2023， 7（1）：41. doi:10.1038/s41698-023-00380-1 |
| [38] | RAMOS-CASALS M， BRAHMER J R， CALLAHAN M K， et al. Immune-related adverse events of checkpoint inhibitors［J］. Nat Rev Dis Primers， 2020， 6（1）：38. doi:10.1038/s41572-020-0160-6 |
| [39] | FADEL F， KHALIL E K， BERTRAND K. Anti-CTLA4 antibody-induced lupus nephritis［J］. N Engl J Med， 2009， 361（2）：211-212. doi:10.1056/nejmc0904283 |
| [40] | CHEN M， ZHANG L， ZHONG W， et al. Case report： THSD7A-positive membranous nephropathy caused by tislelizumab in a lung cancer patient［J］. Front Immunol， 2021， 12：619147. doi:10.3389/fimmu.2021.619147 |
| [41] | DAS R， BAR N， FERREIRA M， et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade［J］. J Clin Invest， 2018， 128（2）： 715-720. doi:10.1172/jci96798 |
| [42] | FRIDMAN W H， MEYLAN M， PETITPREZ F， et al. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome［J］. Nat Rev Clin Oncol， 2022， 19（7）： 441-457. doi:10.1038/s41571-022-00619-z |
| [43] | LI Z， LIU S， LIU D， et al. Multiple mechanisms and applications of tertiary lymphoid structures and immune checkpoint blockade［J］. Clin Cancer Res， 2025， 44（1）： 84. doi:10.1186/s13046-025-03318-6 |
| [44] | SINGH S， LONG JP， TCHAKAROV A， et al. Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis［J］. JCI Insight， 2022，1：e165108. doi:10.1172/jci.insight.165108 |
| [45] | GUPTA S， MISTRY K， ALIKHAN F M， et al. Urinary C-X-C-motif ligand 9 （CXCL9） in immune checkpoint inhibitor-associated acute interstitial nephritis［J］. Kidney Int， 2025，108（3）：491-496. doi:10.1016/j.kint.2025.05.029 |
| [46] | GAO Y Q， TAN Y J， FANG J Y. Roles of the gut microbiota in immune-related adverse events： Mechanisms and therapeutic intervention［J］. Nat Rev Clin Oncol， 2025， 22（7）：499-516. doi:10.1038/s41571-025-01026-w |
| [47] | FIDELLE M， RAUBER C， ALVES COSTA SILVA C， et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers［J］. Science， 2023， 380（6649）： eabo2296. doi:10.1126/science.abo2296 |
| [48] | 邓俊， 王均， 高嫦娥， 等. 免疫检查点抑制剂毒性预测生物标志物的研究进展［J］. 实用医学杂志， 2023， 39（20）： 2561-2565. doi:10.3969/j.issn.1006-5725.2023.20.001 |
| [49] | LAURA M V， FRANCISCO G P， JORDI G， et al. Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression［J］. J Transl Med， 2024， 22（1）：421. doi:10.1186/s12967-024-05177-9 |
| [50] | ISIK B， ALEXANDER M P， MANOHAR S， et al. Biomarkers， clinical features， and rechallenge for immune checkpoint inhibitor renal immune-related adverse events［J］. Kidney Int Rep， 2021， 6（4）： 1022-1031. doi:10.1016/j.ekir.2021.01.013 |
| [51] | SCHNEIDER B J， NAIDOO J， SANTOMASSO B D， et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy： ASCO guideline update［J］. J Clin Oncol， 2021， 39（36）：4073-4126. doi:10.1200/jco.21.01440 |
| [52] | THOMPSON J A， SCHNEIDER B J， BRAHMER J， et al. NCCN guidelines insights： Management of immunotherapy-related toxicities， version 1.2020［J］. J Natl Compr Canc Netw， 2020， 18（3）： 230-241. |
| [53] | HAANEN J B A G， CARBONNEL F， ROBERT C， et al. Management of toxicities from immunotherapy： ESMO clinical practice guidelines for diagnosis， treatment and follow-up［J］. Ann Oncol， 2017， 28（）：iv119-iv142. doi:10.1093/annonc/mdx225 |
| [54] | ABUDAYYEH A， SUO L， LIN H， et al. Pathologic predictors of response to treatment of immune checkpoint inhibitor-induced kidney injury［J］. Cancers， 2022， 14（21）： 5267. doi:10.3390/cancers14215267 |
| [55] | YARED H， JOHNSON D H， NOHA A W， et al. Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity［J］. Cancer Cell， 2022， 40（5）：509-523.e6. doi:10.1016/j.ccell.2022.04.004 |
| [56] | SANDBORN W J， SU C， SANDS B E， et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis［J］. N Engl J Med， 2017， 376（18）： 1723-1736. doi:10.1056/nejmoa1606910 |
| [57] | ZHU H， CAO C， WU Z， et al. The probiotic L. casei zhang slows the progression of acute and chronic kidney disease［J］. Cell Metab， 2021， 33（10）： 1926-1942.e8. doi:10.1016/j.cmet.2021.06.014 |
| [58] | ELKRIEF A， WATERS N R， SMITH N， et al. Immune-related colitis is associated with fecal microbial dysbiosis and can be mitigated by fecal microbiota transplantation［J］. Cancer Immunol Res， 2024， 12（3）： 308-321. doi:10.1158/2326-6066.cir-23-0498 |
/
| 〈 |
|
〉 |