Antineutrophil Cytoplasmic Antibody-Associated Rapid Progressive Glomerulonephritis after Pembrolizumab Treatment in Thymic Epithelial Tumor: A Case Report.

Renal immune-related adverse events (irAEs) related to immune checkpoint inhibitors have rarely been reported, with an estimated incidence of 1% to 5%.1Murakami N, Motwani S, Riella LV. Renal complications of immune checkpoint blockade [e-pub ahead of print]. Curr Probl Cancer. http://dx.doi.org/10.1016/j.currproblcancer.2016.12.004, accessed April 6, 2017.Google Scholar, 2Cortazar F.B. Marrone K.A. Troxell M.L. et al.Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.Kidney Int. 2016; 90: 638-647Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar In most cases, renal events have involved acute tubulointerstitial nephritis.2Cortazar F.B. Marrone K.A. Troxell M.L. et al.Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.Kidney Int. 2016; 90: 638-647Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar In 2013, a WHO type B3 thymic epithelial tumor (TET) with metastasis to the lung, spine, and sternum was diagnosed in a 56-year-old man (Fig. 1). He had no history of autoimmune disorders. The patient received third-line chemotherapy including paclitaxel plus cisplatin, paclitaxel plus carboplatin, and cyclophosphamide and doxorubicin plus cisplatin. However, progression in the liver, thymus, and bones was noted. The patient participated in a phase II study of pembrolizumab for patients with advanced TETs (NCT02607631). Beginning in May 2016, the patient received 200 mg of pembrolizumab intravenously every 3 weeks. After two cycles, follow-up imaging revealed partial response of the TET. In August 2016, after the fifth cycle of pembrolizumab, the patient presented with generalized edema and skin rash on both the hands and feet. He had a 1-week history of fever, joint pain, and myalgia. His blood urea nitrogen and serum creatinine levels were 49.7 mg/dL and 2.73 mg/dL, respectively, which were higher than the previous values of 17.2 and 0.78 mg/dL. Blood analysis revealed a white blood cell count of 16,180 per mm3, hemoglobin level of 10.4 g/dL, platelet count of 371,000 per mm3, C-reactive protein level of 13.2 mg/dL, albumin level of 2.5 g/dL, and potassium level of 6.2 mmol/L. Proteinuria and microscopic hematuria were detected on urinalysis. On kidney sonography, signs of urinary obstruction and/or vascular abnormalities were not detected. Renal biopsy was performed, and light microscopy revealed a global sclerosing glomerulonephritis, suggesting immune-associated crescentic glomerulonephritis (Fig. 2A). Both acute tubular damage and mild arteriosclerosis were observed. Electron microscopy revealed diffuse effacement of the glomerular basement membrane as well as mesangium and endocapillary proliferation. Perinuclear antineutrophil cytoplasmic antibody was detected in serum (at a titer of 1:160). Skin biopsy of the foot revealed diffuse neutrophilic and lymphocytic infiltration with necrosis of the dermis (Fig. 2B). Because of rapid progression of oliguria, the patient underwent hemodialysis (three times per week). Because of suspicion of irAEs, including of the skin and kidney, high-dose methylprednisolone (2 mg/kg/d) was started immediately. Although improvement in renal function and skin lesions was observed initially, 2 weeks later, renal function worsened (peak serum creatinine level of 4.49 mg/dL). A single course of combination therapy with oral cyclophosphamide, 150 mg/d, and intravenous methylprednisolone, 500 mg/d, for 3 days was administered. The patient has since shown improvement in renal function and skin rash (Fig. 3) and regular hemodialysis is no longer required. The patient had been taking methylprednisolone, 0.25 mg/kg/d orally, on a tapering schedule. The last follow-up evaluation of TET was in November 2016, and the extent of TET has not progressed despite discontinuation of pembrolizumab. We report the first case of antineutrophil cytoplasmic antibody–associated rapid progressive glomerulonephritis that was diagnosed by renal biopsy in a patient with pembrolizumab treatment for TET. In irAEs related to immune checkpoint inhibitors, T-cell activation is a key event in adaptive immunity that can result in impaired self-tolerance. The etiology of thymoma-associated autoimmune disease remains unclear. The most probable explanation is that the damage induced by tumor growth within the thymus diminishes its ability to maintain self-tolerance through loss of immune regulation.3Shelly S. Agmon-Levin N. Altman A. Shoenfeld Y. Thymoma and autoimmunity.Cell Mol Immunol. 2011; 8: 199-202Crossref PubMed Scopus (135) Google Scholar Similarly, loss of self-tolerance due to T-cell activation by immune checkpoint inhibitors and due to damaged immune regulation related to TET could affect the development of irAEs. Recent trials have reported that TET is associated with a higher frequency of irAEs after immune checkpoint inhibitor administration.4Giaccone G. Thompson J. Crawford J. et al.A phase II study of pembrolizumab in patients with recurrent thymic carcinoma.J Clin Oncol. 2016; 34 ([abstract]): 8517Google Scholar, 5Rajan A. Heery C. Mammen A. et al.OA18. 03 Safety and clinical activity of avelumab (MSB0010718C; anti-PD-L1) in patients with advanced thymic epithelial tumors (TETs).J Thorac Oncol. 2017; 12: S314-S315Abstract Full Text Full Text PDF PubMed Google Scholar The use of immune checkpoint inhibitors should be carefully considered and closely monitored in patients with TET.