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.

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.

Experiments with the knockout mice and in vitro 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, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA.

Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

慢性低镁血症通常由腹泻、酗酒和药物引起。更罕见的是，它是由肾镁重吸收效应器的遗传缺陷引起的。

在一名患有获得性严重低镁血症、低钙血症、肾小管间质性肾病和快速进展性肾损伤的成年患者中，患者的表现与肾镁转运遗传性疾病特征之间的相似性促使我们调查该患者是否患有导致肾镁消耗的获得性自身免疫原因。为了确定患者的病情是否可以通过针对claudin-16或claudin-19（参与肾镁吸收的跨膜旁细胞蛋白）的自身抗体来解释，我们用claudin敲除小鼠和表达人claudin-16或claudin的转染小鼠肾细胞进行了实验。 19. 我们还研究了静脉注射从患者或对照血清中纯化的 IgG 对大鼠肾镁处理的影响。

对基因敲除小鼠和体外转染细胞进行的实验表明，患者的低镁血症与针对claudin-16的自身抗体有因果关系，claudin-16控制着亨利氏袢粗升肢的细胞旁镁重吸收。静脉注射从患者血清中纯化的 IgG 会导致大鼠出现明显的镁尿废物。血浆置换和利妥昔单抗相结合的免疫抑制治疗与患者 GFR 的改善相关，但低镁血症持续存在。该患者随后被诊断患有表达高水平 Claudin-16 mRNA 的肾癌。

致病性claudin-16自身抗体代表了特定肾小管转运障碍和肾小管间质性肾病的新自身免疫原因。对于患有不明原因低镁血症的患者，可能需要筛查针对claudin-16以及肾脏中其他潜在镁转运蛋白或通道的自身抗体。