Koda Ryo, Watanabe Hirofumi, Tsuchida Masafumi, Iino Noriaki, Suzuki Kazuo, Hasegawa Go, Imai Naofumi, Narita Ichiei
Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, 4132 Urasa, Minami Uonuma-shi, Niigata, 949-7302, Japan.
Department of Respiratory Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, 4132 Urasa, Minami Uonuma-shi, Niigata, 949-7302, Japan.
BMC Nephrol. 2018 Feb 27;19(1):48. doi: 10.1186/s12882-018-0848-y.
Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management.
We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.
The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.
急性肾小管间质性肾炎（ATIN）日益被认为是与使用免疫检查点抑制剂（抗程序性死亡蛋白1和抗细胞毒性T淋巴细胞相关抗原4）相关的肾损伤的重要表现。虽然确切的病理生理学仍不清楚，但皮质类固醇是主要的治疗方法。
我们描述了一名67岁的IV期非小细胞肺癌男性患者，他在使用抗程序性死亡蛋白1抗体纳武单抗治疗期间发生了肾损伤。肾活检显示为无肉芽肿形成的ATIN。考虑到其作用机制，免疫检查点抑制剂可改变对长期安全使用的伴随药物的免疫耐受性。在开始纳武单抗治疗前的4年多时间里，该患者一直在接受质子泵抑制剂兰索拉唑治疗，已知该药物可引起药物性ATIN，但未出现包括肾损伤在内的明显不良事件。停用兰索拉唑后，他的肾功能在3天内迅速改善（肌酐从2.74降至1.82mg/dl）。然后他接受了3天的500mg静脉注射甲泼尼龙，随后是1mg/kg/天的口服泼尼松龙，他的肌酐水平最终稳定在1.7mg/dl左右。兰索拉唑的药物诱导淋巴细胞刺激试验（DLST）呈阳性。
停药后肾功能迅速改善以及DLST阳性表明兰索拉唑促成了纳武单抗治疗期间ATIN的发生。考虑到时间进程，纳武单抗改变了该患者对兰索拉唑的长期免疫耐受性是合理的。据我们所知，这是免疫检查点抑制剂治疗前已安全使用的药物DLST阳性的首例病例报告。虽然推荐使用皮质类固醇治疗，但识别和停用伴随药物，尤其是已知可诱导ATIN的药物，对于管理与抗程序性死亡蛋白1治疗相关的肾损伤是必要的。
