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Heterogeneity is a common ground in familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN19 gene mutations

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Abstract

Background

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy caused by mutations in the CLDN16 or CLDN19 genes. Patients usually develop hypomagnesemia, hypercalciuria, nephrocalcinosis and renal failure early in life. Patients with CLDN19 mutations may also have ocular abnormalities. Despite clinical variability, factors associated with kidney function impairment, especially in patients with CLDN19 mutations, have not been addressed.

Methods

Retrospective multicenter study of 30 genetically confirmed FHHNC Spanish patients. We analyzed kidney function impairment considering as outcomes chronic kidney disease (CKD) stage 3 and annual estimated glomerular filtration rate (eGFR) decline, to identify factors associated with the different phenotypes.

Results

Of thirty patients, 27 had mutations in the CLDN19 gene (20 homozygous for the p.G20D mutation) and 3 in the CLDN16. Age at diagnosis was 1.71 (0.67–6.04) years and follow-up time was 8.34 ± 4.30 years. No differences in CKD stage 3-free survival based on CLDN19 mutation (p.G20D homozygous vs. other mutations) or gender were found, although females seemed to progress faster than males. Patients with more pronounced eGFR decline had higher PTH levels at diagnosis than those with stable kidney function, despite similar initial eGFR. Approximately 60% of CLDN19 patients presented ocular abnormalities. Furthermore, we confirmed high phenotypic intrafamilial variability.

Conclusions

In a contemporary cohort of FHHNC patients with CLDN19 mutations, females seemed to progress to CKD-stage 3 faster than males. Increased PTH levels at baseline may indicate a more severe renal course. There was high phenotype variability among patients with CLDN19 mutations and kidney function impairment  differed even between siblings.

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Acknowledgements

This study could not have been done without the collaboration of patients and families, the FHHNC patient advocacy group HIPOFAM (http://hipofam.org) and the Renaltube group (http://renaltube.com). We are also grateful to the physicians for their cooperation: Marisa Justa and Belen Campos (Pediatric Nephrology, and Nephrology. Hospital Infantil Miguel Servet. Zaragoza), Mireia Aguirre, María Herrero and Leire Madariaga (Pediatric Nephrology. Hospital Universitario Cruces. Bizkaia), Carmen de Lucas and Cristina Aparicio (Pediatric Nephrology. Hospital Infantil Universitario Niño Jesús. Madrid), Javier Lumbreras (Pediatric Nephrology. Hospital Universitari Son Espases. Palma de Mallorca), Ainhoa Iceta (Pediatric Nephrology. Hospital Virgen del Camino. Pamplona), Inés Vergara (Pediatric Nephrology. Complexo Hospitalario Universitario A Coruña), Ana Sánchez (Pediatric Nephrology. Hospital Universitario Virgen del Rocío. Sevilla), Marta Melgosa (Pediatric Nephrology. Hospital Infantil La Paz. Madrid), Santiago Rodríguez (Pediatric Nephrology. Hospital de Terrassa), Ana Ruiz (Pediatric Nephrology. Hospital Universitario Torrecárdenas), Juan David González (Pediatric Nephrology. Hospital General Universitario Santa Lucía. Cartagena), Montse Antón (Pediatric Nephrology. Hospital Universitario Reina Sofía de Córdoba), Jonay Pantoja (Nephrology. Hospital Universitari Doctor Peset de Valencia), Manel Perelló (Pediatric Nephrology. Hospital Universitari Vall d’Hebron. Barcelona), Ramón Saracho (Pediatric Nephrology. Hospital Universitario de Álava. Vitoria-Gazteiz), Rebeca Garrote (Pediatric Nephrology. Hospital Clínico Universitario de Valladolid) and Francisco Aguilar (Pediatric Nephrology. Hospital General de Valencia).

Funding

Research grants from Fondo de Investigación Sanitaria (PI14/01107 and PI18/01107) and HIPOFAM contribution supported this work. FCM was supported by grant PI17/00153 co-financed by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación and the European Regional Development Fund “Another way to build Europe”.

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Author notes

  1. Mònica Vall-Palomar and Carla Burballa contributed equally to this manuscript.

Authors and Affiliations

  1. Fisiopatologia Renal, Centre D’Investigacions en Bioquímica I Biologia Molecular (CIBBIM), Institut de Recerca Vall D’Hebron (VHIR), Barcelona, Spain

    Mònica Vall-Palomar, Carla Burballa, Anna Meseguer & Gema Ariceta

  2. Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

    Félix Claverie-Martín

  3. Departament de Bioquímica I Biologia Molecular. Unitat de Bioquímica de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    Anna Meseguer

  4. Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Madrid, Spain

    Anna Meseguer

  5. Servicio de Nefrología Pediátrica, Hospital Universitari Vall D’Hebron, 08035, Barcelona, Spain

    Gema Ariceta

  6. Departamento de Pediatría, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain

    Gema Ariceta

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  1. Mònica Vall-Palomar
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Contributions

MV-P and CB contributed equally in research design, research performance, data analysis and writing of the manuscript. FC-M participated in the diagnosis of patients and writing of the manuscript. AM participated in research design, data analysis and writing of the manuscript. GA participated in research design, research performance, data analysis and writing of the manuscript.

Corresponding author

Correspondence to Gema Ariceta.

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The authors declare that they have no conflict of interest.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Vall d’Hebron Hospital [Date 01.04.201/No. (PR(AMI)280/2015)].

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All patients, or their caregivers, provided written informed consent before participation in the study.

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Vall-Palomar, M., Burballa, C., Claverie-Martín, F. et al. Heterogeneity is a common ground in familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN19 gene mutations. J Nephrol 34, 2053–2062 (2021). https://doi.org/10.1007/s40620-021-01054-6

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  • DOI: https://doi.org/10.1007/s40620-021-01054-6

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