Immune checkpoint inhibitors as potential triggers for ANCA vasculitis

Aqeel, Faten; Monroy‐Trujillo, Jose M.; Geetha, Duvuru

doi:10.1136/rmdopen-2022-002500

Cited by 12 publications

(6 citation statements)

References 7 publications

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“…This is in line with the fact that immune checkpoint molecules are present in injured kidneys independent of ICIs [2]. Regarding renal vasculitis, it was recently reported that specifically PD-1 inhibitors could cause de novo or relapsing ANCA-associated renal vasculitis [3]. These observations implicate the presence of the target molecule and a protective role of PD-1 signaling in renal vasculitis.…”

Section: Introductionsupporting

confidence: 65%

“…On a mechanistic level, PD-L1 depletion in antigen-presenting cells results in a failure to convert naïve CD4 + into regulatory T cells (22) and PD-1 knockout mice are prone to enrich for Th1 and Th17 cells [21,22]. The fact that specifically PD-1 inhibitors can cause ANCA-associated renal vasculitis implicates a comparable mechanistic link between impaired immune checkpoint PD-1 signaling (by either targeted PD-1 therapy or loss of PD-1 itself) and disease activation [3]. Finally, PD-1 was associated with decreased local synthesis of complement factor B.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, Banff score lesions include interstitial inflammation (i), tubulitis (t), interstitial fibrosis (ci), tubular atrophy (ct), total inflammation (ti), inflammation in areas of IFTA (i-IFTA) and tubulitis in areas of IFTA (t-IFTA) [27]. The Banff scoring system had three grades: none (0), mild (1), moderate (2) and severe (3). The cut-off points for i were <10%, 10-25%, 26-50% and >50%, respectively.…”

Section: Renal Histopathologymentioning

confidence: 99%

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Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis

Hakroush

Tampe

2023

IJMS

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Immune checkpoint inhibitors (ICIs) have made an important contribution to the survival of patients with certain cancers. ICIs interrupt co-inhibitory signaling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. However, immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested a dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointerstitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1). We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent with the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between impaired PD-1/PD-L1 signaling, complement factor B and active ANCA-associated renal vasculitis. These findings could be of relevance because experimental data have already described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against a complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Renal Histopathologymentioning

confidence: 99%

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Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis

Hakroush

Tampe

2023

IJMS

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“…Aqeel et al suggested that ICIs, specifically PD-1 inhibitors, could cause de novo or even trigger a relapse of an ANCA associated vasculitis [15]. Further kidney lesions like acute tubular injury, anti-glomerular basement membrane disease and C3 glomerulonephritis are described less frequently.…”

Section: Discussionmentioning

confidence: 99%

"Atezolizumab Associated Rapidly Progressive Pauci- Immune Glomerulonephritis: A Case Report"

Gosztonyi

2023

BJSTR

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Immune Checkpoint Inhibitors (ICI) are increasingly prescribed as therapy for a broad spectrum of cancers and have over the past decade contributed to revolutionizing the oncology field. While these humanized monoclonal antibodies have significantly improved survival rates, they are also associated with a variety of autoimmune adverse events. The number of therapies available on the market is growing, while the literature and knowledge of immune-related toxicities and nephrotoxicity of ICI are still limited. Herein, we present a patient with a metastatic small cell lung cancer treated with atezolizumab, an IgG1 monoclonal antibody aimed at the programmed death ligand 1 (PD-L1) of the tumor cell, who presented after 8 months of therapy with rapidly deteriorating kidney function, new onset of glomerular hematuria and proteinuria. Immunological analysis revealed positive PR3-ANCA and renal biopsy showed acute necrotizing pauci-immune glomerulonephritis with necrosis and crescents. High-dose intravenous methylprednisolone were prescribed followed by oral prednisolone with slow tapering and progressive improving of renal function. Atezolizumab was permanently discontinued.

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“… 38 Specific PDCD1 inhibitors promote ANCA-associated renal vasculitis, suggesting a similar mechanistic link between impaired PDCD1 signaling pathways and disease activation. 39 Furthermore, PDCD1 and CD274 deficiencies are associated with lupus-like syndrome phenotypes in mice. The expression levels of EGF, PDGF , transferrin, and folate receptors are upregulated in the kidneys of patients with lupus nephritis and lupus nephritis mouse model.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes as Biomarkers for Uremia

Lyu,

He,

Zhou

et al. 2023

IJGM

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Purpose Uremia, which is characterized by immunodeficiency, is associated with the deterioration of kidney function. Immune-related genes (IRGs) are crucial for uremia progression. Methods The co-expression network was constructed to identify key modular genes associated with uremia. IRGs were intersected with differentially expressed genes (DEGs) between uremia and control groups and key modular genes to obtain differentially expressed IRGs (DEIRGs). DEIRGs were subjected to functional enrichment analysis. The protein-protein interaction (PPI) network was constructed. The candidate genes were identified using the cytoHubba tool. The biomarkers were identified using various machine learning algorithms. The diagnostic value of the biomarkers was evaluated using receiver operating characteristic (ROC) analysis. The immune infiltration analysis was implemented. The biological pathways of biomarkers were identified using gene set enrichment analysis and ingenuity pathway analysis. The mRNA expression of biomarkers was validated using blood samples of patients with uremia and healthy subjects with quantitative real-time polymerase chain reaction (qRT-PCR). Results In total, four biomarkers ( PDCD1, NGF, PDGFRB , and ZAP70 ) were identified by machine learning methods. ROC analysis demonstrated that the area under the curve values of individual biomarkers were > 0.9, indicating good diagnostic power. The nomogram model of biomarkers exhibited good predictive power. The proportions of six immune cells significantly varied between the uremia and control groups. ZAP70 expression was positively correlated with the proportions of resting natural killer (NK) cells, naïve B cells, and regulatory T cells. Functional enrichment analysis revealed that the biomarkers were mainly associated with translational function and neuroactive ligand-receptor interaction. ZAP70 regulated NK cell signaling. The PDCD1 and NGF expression levels determined using qRT-PCR were consistent with those determined using bioinformatics analysis. Conclusion PDCD1, NGF, PDGFRB , and ZAP70 were identified as biomarkers for uremia, providing a theoretical foundation for uremia diagnosis.

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Immune checkpoint inhibitors as potential triggers for ANCA vasculitis

Cited by 12 publications

References 7 publications

Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis

Association between Loss of Immune Checkpoint Programmed Cell Death Protein 1 and Active ANCA-Associated Renal Vasculitis

"Atezolizumab Associated Rapidly Progressive Pauci- Immune Glomerulonephritis: A Case Report"

Identification of Immune-Related Genes as Biomarkers for Uremia

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