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

Lucile Figueres, Sarah Bruneau, Caroline Prot-Bertoye, Gaëlle Brideau, Mélanie Néel, Camille Griveau, Lydie Cheval, Yohan Bignon, Jordan Dimitrov, Thomas Dejoie, Simon Ville, Christine Kandel-Aznar, Anne Moreau, Pascal Houillier and Fadi Fakhouri
JASN June 2022, ASN.2022010060; DOI: https://doi.org/10.1681/ASN.2022010060
Lucile Figueres
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
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  • ORCID record for Lucile Figueres
Sarah Bruneau
2Centre de Recherche en Transplantation et Immunologie, Nantes, France
3Institut de Transplantation Urologie Néphrologie, Nantes, France
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Caroline Prot-Bertoye
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
4Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France
5Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France
6CNRS, Paris, France
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Gaëlle Brideau
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
6CNRS, Paris, France
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Mélanie Néel
2Centre de Recherche en Transplantation et Immunologie, Nantes, France
3Institut de Transplantation Urologie Néphrologie, Nantes, France
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Camille Griveau
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
6CNRS, Paris, France
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Lydie Cheval
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
6CNRS, Paris, France
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Yohan Bignon
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
6CNRS, Paris, France
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Jordan Dimitrov
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
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Thomas Dejoie
7Laboratory of Biochemistry, CHU de Nantes, Nantes, France
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Simon Ville
2Centre de Recherche en Transplantation et Immunologie, Nantes, France
3Institut de Transplantation Urologie Néphrologie, Nantes, France
8Department of Nephrology, CHU de Nantes, Nantes, France
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Christine Kandel-Aznar
9Department of Pathology, CHU de Nantes, Nantes, France
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Anne Moreau
9Department of Pathology, CHU de Nantes, Nantes, France
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Pascal Houillier
1Centre de recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
4Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France
5Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France
6CNRS, Paris, France
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Fadi Fakhouri
10Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
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Significant Statement

Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs; more rarely, genetic defects in the effectors of renal magnesium reabsorption are responsible. The authors report on an adult patient with acquired severe hypomagnesemia, hypocalcemia, and tubulointerstitial nephropathy, with rapidly progressing kidney injury. In in vivo and in vitro studies, they found evidence of a causal link between the patient’s condition and autoantibodies against claudin-16, a transmembrane paracellular protein involved in renal magnesium absorption. 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 renal magnesium transporters or channels may be warranted in patients with acquired unexplained hypomagnesemia.

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.

  • hypomagnesemia
  • claudin-16
  • hypocalcemia
  • autoantibodies
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (6)
Journal of the American Society of Nephrology
Vol. 33, Issue 6
June 2022
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Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies
Lucile Figueres, Sarah Bruneau, Caroline Prot-Bertoye, Gaëlle Brideau, Mélanie Néel, Camille Griveau, Lydie Cheval, Yohan Bignon, Jordan Dimitrov, Thomas Dejoie, Simon Ville, Christine Kandel-Aznar, Anne Moreau, Pascal Houillier, Fadi Fakhouri
JASN Jun 2022, ASN.2022010060; DOI: 10.1681/ASN.2022010060

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Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies
Lucile Figueres, Sarah Bruneau, Caroline Prot-Bertoye, Gaëlle Brideau, Mélanie Néel, Camille Griveau, Lydie Cheval, Yohan Bignon, Jordan Dimitrov, Thomas Dejoie, Simon Ville, Christine Kandel-Aznar, Anne Moreau, Pascal Houillier, Fadi Fakhouri
JASN Jun 2022, ASN.2022010060; DOI: 10.1681/ASN.2022010060
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