Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na⁺ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg²⁺) and calcium (Ca²⁺) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg²⁺ and Ca²⁺ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg²⁺ preservation but not Ca²⁺, whereas in Gitelman's syndrome, those adaptations favor Ca²⁺ preservation over Mg²⁺. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca²⁺ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg²⁺ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca²⁺ and Mg²⁺ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg²⁺ preservation over Ca²⁺ in Bartter's syndrome and Ca²⁺ preservation over Mg²⁺ in Gitelman's syndrome and are stronger in females than in males.