Abdelrahim, Saifudeen

Abudayyeh, Ala

Ahmad, Raisa

Al Shaarani, Majd

Goswami, Sangeeta

Hanif, Imran Humza

Lu, Huifang

English

DigitalCommons@The Texas Medical Center

NEPHROLOGY ROUNDS1534Immune Checkpoint Therapy–InducedLupus NephritisImran Humza Hanif1, Saifudeen Abdelrahim2, Majd Al Shaarani3, Huifang Lu4,Raisa Ahmad5, Sangeeta Goswami5,6,7 and Ala Abudayyeh11Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas,USA; 2Houston Methodist Hospital, Houston, Texas, USA; 3Department of Pathology and Laboratory Medicine, The Universityof Texas Health Science Center McGovern Medical School, Houston, Texas, USA; 4Section of Rheumatology and ClinicalImmunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas,USA; 5Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas,USA; 6Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and 7James P.Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas, USACorrespondence: Ala Abudayyeh, Section of Nephrology, Division of Internal Medicine, The University of Texas MD AndersonCancer Center, 1515 Holcombe Blvd, Unit 1468, Houston, Texas 77030, USA. E-mail: aabudayyeh@mdanderson.orgReceived 21 December 2023; revised 1 February 2024; accepted 12 February 2024; published online 16 February 2024Kidney Int Rep (2024) 9, 1534–1537; https://doi.org/10.1016/j.ekir.2024.02.1396ª 2024 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).INTRODUCTIONImmune checkpoint therapy (ICT), an emergingtransformative cancer treatment, targets inhibitoryproteins in the immune system, such as programmedcell death protein 1 (PD-1) and its ligand (PD-L1), andcytotoxic T-lymphocyte–associated protein 4 (CTLA-4).This strategy has remarkably improved disease out-comes for various cancers.1 However, ICT can lead toimmune-related adverse events (irAEs), which arecharacterized by an uncontrolled and dysregulatedimmune response that affects multiple organs.Although the precise mechanisms underlying ICT-induced autoimmune disease are not fully under-stood, autoantibody development in response to treat-ment has been well established.Renal irAEs are less frequent but potentially severe.Despite the reported incidence of renal irAEs beingrelatively low, any renal impairment can significantlyimpact patient outcomes, leading to reduced overallsurvival and potential ineligibility for future clinicaltrials.1 Close monitoring of kidney function during ICTis critical to preserve and optimize renal health. RenalirAEs have diverse clinical presentations, includingelectrolyte disturbances, acute tubulointerstitialnephritis, acute tubular necrosis, vasculitis, glomeru-lonephritis, and, rarely, sarcoidosis.2,3 Among these,glomerulonephritis, an autoimmune disease affectingthe glomeruli, is a rare, serious complication followingICT exposure. Recent studies have shown thatglomerulonephritis accounts for a significantproportion of ICT-associated glomerular disease, withpauci-immune glomerulonephritis and renal vasculitisbeing the most commonly observed subtypes.2However, the association between preexisting auto-antibodies and irAE risk remains inconclusive, partic-ularly regarding renal irAEs. Further investigation intospecific autoantibodies, such as antineutrophil cyto-plasmic antibodies (ANCAs), before and after ICTexposure may provide valuable insights into predictingirAEs and overall survival in patients with cancer.4,5Management of glomerulonephritis after ICT in-volves kidney biopsies for accurate diagnosis andtailored treatment approaches. Corticosteroids are acommon treatment approach; however, a more targetedapproach is required to prevent immune checkpointinhibitor (ICI) discontinuation and enhance outcomes.Rituximab is an effective treatment for inducingremission in ICT-induced kidney injury and vasculitisand continued cancer remission.6,7Because renal irAEs are clinically significant andpotentially impact patient outcomes, further research isneeded to better understand the pathophysiology ofinduction of autoimmune disease after ICT. Identifyingpredictive factors and refining treatment strategies isessential to optimize ICT use and ensure patient safetyand treatment efficacy.Here, we report on an older patient with solitarymetastatic renal cell cancer with prior ICT exposurewho developed lupus nephritis characterized by theproduction of autoantibodies. The study was con-ducted in accordance with the Declaration of HelsinkiKidney International Reports (2024) 9, 1534–1537Figure 1. Kidney biopsy. (a) Hematoxylin and eosin stain: a glomerulus with segmental sclerosis and mesangial expansion and hypercellularity.(b) Hematoxylin and eosin stain: interstitial nephritis with lymphocytes, plasma cells and a few eosinophils. (c) Hematoxylin and eosin stain:acute tubular injury. (d) Immunofluorescence: mesangial/paramesangial and capillary walls staining for IgG. Similar findings are seen with IgMand IgA. (e) Immunofluorescence: mesangial/paramesangial and capillary walls staining for C1q. Similar findings are seen with C3. (f) Electronmicroscopy: organized electron-dense deposits with fingerprint pattern.IH Hanif et al.: ICI-Induced Glomerulonephritis NEPHROLOGY ROUNDSand approved by the Institutional Review Board at TheUniversity of Texas MD Anderson Cancer Center(PA16-1016). Informed consent was not required.CASE PRESENTATIONA Caucasian man in his 80s was admitted to the hospitalwith acute kidney injury, volume overload, ascites,and hyponatremia. He had a history of hypertension,coronary artery disease, hypothyroidism, prostatecancer, and metastatic renal cell carcinoma and hadundergone a left radical nephrectomy. Approximately ayear later, his renal cell cancer recurred, and hereceived 3 cycles of pembrolizumab and axitinitib. Heinitially responded to treatment; however, his diseaseprogressed and subsequently cabozantinib was startedlater that year.At the time of hospital admission, the patient’screatinine level was 6.0 mg/dl (baseline: 2.0 mg/dl). Hehad hematuria, eosinophilia, and proteinuria (4.5 g) andan albumin level of 2.1 mg/dl, which were all negativebefore he started pembrolizumab and axitinitib. Anautoimmune workup revealed an antinuclear antibodylevel of 1:320, with positive results for anti–double-stranded DNA and antihistone antibodies, and normalcomplement levels. Notably, the workup findings werealso positive for myeloperoxidase antibodies (>8 ng/l).Of note, the patient had been started on hydralazineafter initiation of axitinitib due to uncontrolled hy-pertension a month before admission for acute kidneyKidney International Reports (2024) 9, 1534–1537injury. Renal ultrasonography indicated an 11.8 cm-long kidney with increased echogenicity. Because ofcontinued elevated creatinine levels, a kidney biopsywas performed. The biopsy showed mild glomerulo-nephritis with segmental endocapillary hyper-cellularity, and immunofluorescence staining revealedpositive for C3, C1q, IgA, IgM, IgG, Kappa, andLambda referred to as a “full-house” immunofluores-cence pattern. It also revealed ultrastructural featuresconsistent with thrombotic microangiopathy–likechanges with focal global glomerulosclerosis (6 of 41glomeruli, approximately 15%), mild and focal acutetubulointerstitial nephritis with diffuse acute tubularinjury, interstitial fibrosis and tubular atrophy(approximately 30%), and moderate to severe arterio-sclerosis and arteriolosclerosis, consistent with the pa-tient’s history of hypertension (Figure 1).Because the findings indicated an autoimmune pro-cess, the patient was given methylprednisolone 250 mgpulse as an i.v. infusion daily for 3 days and then startedon prednisone 60 mg daily. He was also started onhydroxychloroquine 200 mg twice daily. His creatininelevel initially improved to 4.53 mg/dl; however, due toincreasing azotemia and volume overload, hemodialysiswas started. Suspecting autoimmune disease, the patientwas treated with a course of rituximab consisting of two1 g doses given by i.v. infusion 2 weeks apart. Dialysiswas discontinued after 4 months. At the time of writing,the patient has a stable glomerular filtration rate of 15ml/min (Supplementary Figure S1A and B). His1535NEPHROLOGY ROUNDS IH Hanif et al.: ICI-Induced Glomerulonephritisproteinuria and hypervolemia have resolved, and he isreceiving prednisone 7.5 mg daily, hydroxychloroquine200 mg twice daily, and minimal diuretics due to hischronic kidney disease.DISCUSSIONRecently, the increasing use of ICTs in patients withrelapsed and refractory cancer has highlighted the irAEsassociated with these therapies. As the use of ICT hasgrown, renal irAE incidence has risen, providing valu-able insights into the pathogenic mechanisms underly-ing ICI-associated nephrotoxicity.8 Initial reportssuggested that anti-CTLA-4 agents may be more likelyto cause glomerular diseases than PD-1 and PD-L1 in-hibitors, but a recent meta-analysis indicated that PD-1and PD-L1 inhibitors may be more likely than anti-CTLA-4 agents to cause glomerular diseases.2 Here, wereport a patient with solitary kidney who experiencedlupus nephritis after receiving pembrolizumab, a PD-1inhibitor, and was effectively treated with rituximabwith maintenance off dialysis and stable cancer.ICT-induced acute interstitial nephritis has beenassociated with increased urinary tumor necrosis fac-tor-a, which induces human leukocyte antigen andactivates antigen-presenting cells and increased den-dritic cells in the kidney tissue of patients treated withICTs. These findings support a loss of toleranceinduced by ICT exposure that leads to autoreactive T-cell infiltration.S1 Another study validated these find-ings, demonstrating that patients exposed to protonpump inhibitors and nonsteroidal antiinflammatorydrugs had an increased risk of acute interstitialnephritis after ICT exposure where tolerance to thesemedications would be lost.S2,S3Previous work demonstrated that increased T-cellinfiltration and expansion can lead to an inflammatoryresponse in ANCA-associated glomerulonephritis andvasculitis. The exhaustion of T cells in vasculitis andother autoimmune diseases prevents disease progres-sion. The expressions of coinhibitory molecules such asPD-1 and CTLA-4 prevent the differentiation of non-exhausted T cells. In the pathogenesis of ANCA-associated vasculitis, CD8þ T cells, which express theCTLA-4 receptor, may activate polymorphonuclearcells, leading to the exposure of proteinase-3 andmyeloperoxidase antigens on their surface. These an-tigens may then react with ANCAs, leading to ANCA-induced disease.S4 Regarding further induction of anautoimmune disease, PD-1 is expressed on B cells,including immunosuppressive B regulatory cells, andhas a well-established role in B-cell tolerance.S5 ICTinduction of B cells has been shown to specificallycorrelate with irAEs.S6 In addition, in patients with1536B-cell depletion who were treated with ICIs for theirunderlying cancer, B-cell depletion was shown not toimpede the ICIs’ antitumor effects.S7Our case had “full-house” immunofluorescence stain-ing results, with positive results for antinuclear anti-bodies, double-stranded DNA, and histones; thesefindings are typical features of lupus nephritis. Therehave been few case reports of lupus nephritis–like syn-drome after ICI exposure; however, in mouse models,disruption of PD-1 has been shown to lead to systemiclupus and glomerulonephritis.S8 Although Pippin et al.indicated that treatment with anti–PD-1 antibodies led toantiaging effects on podocytes in mouse models,continued exposure to anti–PD-1 antibodies may lead tothe induction of an autoimmune disease.S9 Furthermore,in mouse models, treatment with a PD-L1–agonist anti-body reduced proteinuria and decreased serum levels ofanti–double-stranded DNA antibodies and IgG glomer-ular deposition, with an associated increased survivalrate.S10 In the few published case reports of ICT-inducedlupus nephritis, stopping ICTs and starting steroidswhen patients’ proteinuria responded also led to excel-lent tumor response (Supplementary Table S1).S11–S13 Toour knowledge, we are the first to report on a lupusnephritis case with positive histone antibodies, which ishighly associated with drug-induced lupus and couldhave been exacerbated by the patients’ exposure tohydralazine.Initial guidelines for managing renal irAEs recom-mended initiating corticosteroid-based therapy withoutperforming a kidney biopsy.S12 Since then, however,increasing evidence has shown that the induction of anautoimmune kidney disease can be present and lead toboth poor renal outcomes and poor overall survival.2 Arecent case series showed that a kidney biopsy can beused to diagnose vasculitis following ICT exposure,thereby challenging the conventional approach.9Several case reports have demonstrated that ritux-imab, a monoclonal anti-CD20 antibody, can potentiallyinduce renal recovery and disease remission, allowingpatients to continue ICI therapy despite developingglomerulonephritis.2,9 Rituximab disrupts pathogenicB-lymphocyte interaction with cytotoxic T lympho-cytes, reduces chemokine production, and limitsendothelial injury without inhibiting the antineoplasticeffects of ICIs.S7,S14,S15 One study reported partial tocomplete renal recovery and remission following rit-uximab treatment in ICI-induced renal vasculitis.6However, maintenance rituximab should be avoidedafter achieving renal remission because suppression ofthe B cells can reduce the overall antitumor effects ofthe T cells due to the lack of the B-cell antigen pre-sentation. A recent evaluation of the role of intra-tumoral B cells confirmed their importance in tumorKidney International Reports (2024) 9, 1534–1537Table 1. Teaching points1. Kidney biopsy in patients with suspected ICI kidney toxicity should be first line indiagnosis2. Autoimmune induction in the kidney although rare would need to be in thedifferential of ICI-induced kidney injury to allow a more guided and effectivetreatment3. Rituximab can provide an effective steroid sparing treatment for autoimmune diseaseinduced by checkpoint inhibitors and allow continued tumor responseICI, immune checkpoint inhibitor.IH Hanif et al.: ICI-Induced Glomerulonephritis NEPHROLOGY ROUNDSresponses in patients treated with anti–PD-1 or anti–PD-L1 immunotherapy.S16 For patients with profoundautoimmune symptoms, plasmapheresis has shownpotential benefits in removing autoantibodies, espe-cially in ANCA-associated vasculitis.S17 A summary oflearning points can be found in Table 1.In conclusion, ICTs have revolutionized cancermanagement, providing durable antitumor responsesand improved survival. However, clinicians mustremain vigilant for ICT-induced irAEs, including ICI-induced vasculitis and glomerulonephritis, that canlead to significant morbidity. Timely monitoring ofserum creatinine levels and prompt initiation ofappropriate therapies, such as corticosteroids, plasma-pheresis, or rituximab, can lead to renal recovery anddisease remission, allowing patients to continue ICTtherapy. Further research should focus on the mecha-nisms and risk factors of ICT-induced autoimmunedisease, which can lead to improved managementstrategies and patient outcomes.DISCLOSUREAll the authors declared no competing interests.PATIENT CONSENTThe authors declare that they have obtained consent fromthe patients discussed in the report.ACKNOWLEDGMENTSEditorial support was provided by Madison Semro, Asso-ciate Scientific Editor, and Stephanie Deming, Senior Sci-entific Editor, in the Research Medical Library at TheUniversity of Texas MD Anderson Cancer Center. Thisstudy was supported by the National Institutes of Health/National Cancer Institute under award numberP30CA016672 (used the Clinical Trials Office and Biosta-tistics Resource Group).AUTHOR CONTRIBUTIONSData acquisition was performed by IHH and AA.Figures were drawn by SA. MAS performed the histologicKidney International Reports (2024) 9, 1534–1537examination of the kidney biopsies and contributed towriting the pathology section of the manuscript. Themanuscript was prepared by IHH, SA, MAS, HL, RA, andSG. All the authors contributed to the quality control data,analysis, interpretation of data and writing and final proofof paper. All authors read and approved the finalmanuscript.SUPPLEMENTARY MATERIALSupplementary File (PDF)Supplementary References.Figure S1. (A) Trend of creatinine mg/dl and (B) Trend ofalbumin and proteinuria over time.Table S1. Summary of all cases published with lupus likeglomerulonephritis after ICI treatment.REFERENCES1. Toi Y, Sugawara S, Sugisaka J, et al. Profiling preexisting an-tibodies in patients treated with anti-PD-1 therapy foradvanced non-small cell lung cancer. JAMA Oncol. 2019;5:376–383. https://doi.org/10.1001/jamaoncol.2018.58602. Kitchlu A, Jhaveri KD, Wadhwani S, et al. A systematic reviewof immune checkpoint inhibitor-associated glomerular dis-ease. Kidney Int Rep. 2021;6:66–77. https://doi.org/10.1016/j.ekir.2020.10.0023. Charkviani M, Herrmann SM. Immune checkpoint inhibitor-associated sarcoidosis reaction in the kidney: case report.Kidney Med. 2023;5:100626. https://doi.org/10.1016/j.xkme.2023.1006264. Sakakida T, Ishikawa T, Chihara Y, et al. Safety and efficacy ofPD-1/PD-L1 blockade in patients with preexisting antinuclearantibodies. Clin Transl Oncol. 2020;22:919–927. https://doi.org/10.1007/s12094-019-02214-85. Barth DA, Stanzer S, Spiegelberg J, et al. Evaluation of auto-antibodies as predictors of treatment response and immune-related adverse events during the treatment with immunecheckpoint inhibitors: a prospective longitudinal pan-cancerstudy. Cancer Med. 2022;11:3074–3083. https://doi.org/10.1002/cam4.46756. Mamlouk O, Lin JS, Abdelrahim M, et al. Checkpoint inhibitor-related renal vasculitis and use of rituximab. J ImmunotherCancer. 2020;8:e000750. https://doi.org/10.1136/jitc-2020-0007507. Abudayyeh A. Evaluation and Management of Suspected Im-mune-Mediated Nephritis. Accessed February 1, 2024. https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-nephritis-web-algorithm.pdf8. Herrmann SM, Perazella MA. Immune checkpoint inhibitorsand immune-related adverse renal events. Kidney Int Rep.2020;5:1139–1148. https://doi.org/10.1016/j.ekir.2020.04.0189. Lin JS, Wang DY, Mamlouk O, et al. Immune checkpoint in-hibitor associated reactivation of primary membranous ne-phropathy responsive to rituximab. J Immunother Cancer.2020;8:e001287. https://doi.org/10.1136/jitc-2020-0012871537

Immune Checkpoint Therapy-Induced Lupus Nephritis

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Immune Checkpoint Therapy-Induced Lupus Nephritis

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