datasheet1_Proton Pump Inhibitor and Tacrolimus Uses are Associated With Hypomagnesemia in Connective Tissue Disease: a Potential Link With Renal Dysfunction and Recurrent Infection.docx

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease.
Methods: We retrospectively evaluated patients with connective tissue disease and available serum magnesium data who visited Keio University Hospital in 2019. Patients were divided into two groups: those with (serum magnesium < 1.8 mg/dl) and those without hypomagnesemia; their rates of hospitalization for severe infection and cumulative renal deterioration were compared. Patients’ fractions of lymphocytes and natural killer and dendritic cell subsets, as measured by fluorescence-activated cell sorting (FACS) analysis, were also compared.
Results: Among 284 patients, hypomagnesemia was detected in 63 (22.2%). Multivariate analysis revealed that the use of proton pump inhibitors [odds ratio (OR), 1.48; p = 0.01] and tacrolimus (OR, 6.14; p < 0.01) was independently associated with hypomagnesemia. In addition, the renal deterioration rate was significantly higher in tacrolimus and/or proton pump inhibitor users with hypomagnesemia (p = 0.01). The hospitalization rate for severe infection was also higher in patients with hypomagnesemia (p = 0.04). FACS analysis showed lower CD8+ T cell, CD19+ B cell, natural killer cell, and dendritic cell counts in patients with hypomagnesemia (p = 0.03, p = 0.02, p = 0.02, and p = 0.03, respectively).
Conclusion: The use of tacrolimus and proton pump inhibitors may be associated with hypomagnesemia and lead to poor renal outcomes and severe infection in patients with connective tissue disease.

背景：血清镁水平降低会干扰肾小管细胞功能与淋巴细胞功能，进而引发肾功能恶化及单核细胞失衡。本研究针对结缔组织病患者的低镁血症发生机制与影响展开探究。
方法：本研究回顾性分析2019年于庆应义塾大学医院就诊的、具备血清镁检测数据的结缔组织病患者。将患者分为低镁血症组（血清镁＜1.8 mg/dl）与非低镁血症组，对比两组的重症感染住院率及累积肾功能恶化率；同时通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）检测并对比两组患者的淋巴细胞、自然杀伤细胞及树突状细胞亚群占比。
结果：284例患者中，63例（22.2%）存在低镁血症。多因素分析显示，质子泵抑制剂使用[比值比（odds ratio, OR）=1.48；P=0.01]与他克莫司使用（OR=6.14；P＜0.01）均为低镁血症的独立相关因素。此外，同时/单独使用他克莫司和/或质子泵抑制剂且合并低镁血症的患者，其肾功能恶化率显著升高（P=0.01）；低镁血症患者的重症感染住院率也更高（P=0.04）。流式细胞术检测结果显示，低镁血症患者的CD8+T细胞、CD19+B细胞、自然杀伤细胞及树突状细胞计数均显著降低（分别对应P=0.03、0.02、0.02、0.03）。
结论：在结缔组织病患者中，他克莫司与质子泵抑制剂的使用可能与低镁血症相关，并可导致不良肾功能结局及重症感染发生。