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Nivolumab-associated glomerular endothelial injury in a patient with gastric cancer.

ABSTRACT: A 68-year-old male with gastric cancer was treated with tegafur/gimeracil/oteracil and oxaliplatin for 6 months. Thereafter, he was treated with paclitaxel and ramucirumab for 3 months. However, neither regimen had much effect. Thus, he was treated with nivolumab for 2 months, but he developed proteinuria, microhematuria, and an acute kidney injury. A kidney biopsy revealed occasional swollen endothelial cells and proliferating mesangial cells. Few abnormal findings were seen in the tubules or interstitial tissue. Immunofluorescent staining showed segmental immunoglobulin A and complement component 3 deposition, in the mesangial area. Electron microscopy showed a small amount of electron-dense deposits in the paramesangial area and swollen endothelial cells. Mesangial interposition, the loss of endothelial cell fenestration, and subendothelial edema were also observed. Furthermore, foot process effacement and villous transformation of epithelial cells were noted. After the discontinuation of nivolumab, the patient's renal function gradually improved, and his proteinuria disappeared. Nivolumab treatment was restarted at that time because of cancer progression; however, it was ineffective. No occult blood was detected from 7 months after the administration of the last dose of nivolumab. This is a unique case, in which a kidney biopsy revealed evidence of nivolumab-associated glomerular endothelial injury.

SUBMITTER: Shim J

PROVIDER: S-EPMC8494862 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS:We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS:Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS:These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

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Nivolumab-associated glomerular endothelial injury in a patient with gastric cancer.

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