Hereditary tubular transport disorders: implications for renal handling of Ca²⁺ and Mg²⁺

The kidney plays an important role in maintaining the systemic Ca²⁺ and Mg²⁺ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca²⁺ and Mg²⁺ concentrations. The reabsorption of Ca²⁺ and Mg²⁺ is driven by transport of other electrolytes, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent's disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca²⁺-sensing receptor defects, markedly change tubular transport of Ca²⁺ and Mg²⁺. In the distal convolutions, several proteins involved in Mg²⁺ transport have been identified [TRPM6 (transient receptor potential melastatin 6), proEGF (pro-epidermal growth factor) and FXYD2 (Na⁺/K⁺-ATPase γ-subunit)]. In addition, conditions such as Gitelman's syndrome, distal renal tubular acidosis and pseudohypoaldosteronism type II, as well as a mitochondrial defect associated with hypomagnesaemia, all change the renal handling of divalent cations. These hereditary disorders have, in many cases, substantially increased our understanding of the complex transport processes in the kidney and their contribution to the regulation of overall Ca²⁺ and Mg²⁺ balance.