Lucile Figueres1, Sarah Bruneau2,3, Caroline Prot-Bertoye1,4,5,6, Gaëlle Brideau1,6, Mélanie Néel2,3, Camille Griveau1,6, Lydie Cheval1,6, Yohan Bignon1,6, Jordan Dimitrov1, Thomas Dejoie7, Simon Ville2,3,8, Christine Kandel-Aznar9, Anne Moreau9, Pascal Houillier10,4,5,6, Fadi Fakhouri11. 1. Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France. 2. Centre de Recherche en Transplantation et Immunologie, Nantes, France. 3. Institut de Transplantation Urologie Néphrologie, Nantes, France. 4. Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France. 5. Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France. 6. CNRS, Paris, France. 7. Laboratory of Biochemistry, CHU de Nantes, Nantes, France. 8. Department of Nephrology, CHU de Nantes, Nantes, France. 9. Department of Pathology, CHU de Nantes, Nantes, France. 10. Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France fadi.fakhouri@unil.ch pascal.houillier@inserm.fr. 11. Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland fadi.fakhouri@unil.ch pascal.houillier@inserm.fr.
Abstract
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: 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. CONCLUSIONS: 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.
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: 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. CONCLUSIONS: 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.
Authors: Nils Landegren; Mina Pourmousa Lindberg; Jakob Skov; Åsa Hallgren; Daniel Eriksson; Trine Lisberg Toft-Bertelsen; Nanna MacAulay; Eva Hagforsen; Anne Räisänen-Sokolowski; Heikki Saha; Thomas Nilsson; Gunnel Nordmark; Sophie Ohlsson; Jan Gustafsson; Eystein S Husebye; Erik Larsson; Mark S Anderson; Jaakko Perheentupa; Fredrik Rorsman; Robert A Fenton; Olle Kämpe Journal: J Am Soc Nephrol Date: 2016-03-16 Impact factor: 10.121