Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies

作者：Lucile Figueres, Sarah Bruneau, Caroline Prot‐Bertoye, Gaëlle Brideau, Mélanie Néel, Camille Griveau, Lydie Cheval, Yohan Bignon, Jordan D. Dimitrov, Thomas Dejoie, Simon Ville, Christine Kandel-Aznar, Anne Moreau, Pascal Houillier, Fádi Fakhouri · 发表于：Journal of the American Society of Nephrology · 年份：2022 · DOI：10.1681/asn.2022010060 · 被引用次数：13 · 研究领域：Barrier Structure and Function Studies、Magnesium in Health and Disease、Parathyroid Disorders and Treatments

BACKGROUND: Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. METHODS: In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. RESULTS: transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, ...