Pathophysiology of hypercalciuria in children

Abstract

Urinary excretion of calcium is the result of a complex interplay between three organs-namely, the gastrointestinal tract, bone, and kidney-which is finely orchestrated by multiple hormones. Hypercalciuria is believed to be a polygenic trait and is influenced significantly by diet. This paper briefly reviews calcium handling by the renal tubule in normal and in hereditary disorders as it relates to the pathophysiology of hypercalciuria. The effects of dietary sodium, potassium, protein, calcium, and phosphate on calcium excretion, and the association of hypercalciuria with bone homeostasis is discussed, leading to recommendations on means to address excessive urinary calcium excretion.

Fig. 1

Schematic representation of molecular (or transport) mechanisms in the proximal tubule related to Dent’s disease and hereditary hypophosphatemic rickets with hypercalciuria. • low molecular weight proteins; NHE-3 Na⁺-H⁺ exchanger; I, IIa, IIc, and III Na/Pi type I, type IIa, type IIc and type III cotransporters; NBC-1 Na⁺-HCO⁻ ₃ cotransporter; CLC-5 chloride channel-5; AA amino acids; X ⁻ anion; Pi phosphate; CA II cytoplasmic carbonic anhydrase; CA IV membrane-bound carbonic anhydrase

Fig. 2

Schematic representation of molecular (or transport) mechanisms in the thick ascending loop of Henle related to Bartter syndrome and familial hypomagnesemia with hypercalciuria and nephrocalcinosis. NKCC2 Na⁺ - K⁺-2C1⁻ cotransporter, ROMK renal outer-medullary potassium channel, CLC-Kb chloride channel Kb, CaSR calcium-sensing receptor

Fig. 3

Schematic representation of molecular (or transport) mechanisms in the distal tubule related to pseudohypoaldosteronism (PHA) type II and distal renal tubular acidosis. NCCT Na⁺-Cl⁻ cotransporter, TRPV5 calcium channel, AE1 Cl⁻-HCO⁻ ₃ exchanger, CA II cytoplasmic carbonic anhydrase, NCX Na⁺-Ca²⁺ exchanger, WNK1 with-no-lysine kinase 1, WNK4 with-no-lysine kinase 4

Fig. 4

Urine calcium excretion in genetic hypercalciuric stone-forming (GHS) and control (Ctl) rats. Alendronate led to a significant decrease in urine calcium in the GHS, but not in the Ctl rats. GHS rats (open symbols), Ctl rats (closed symbols), NCD normal-calcium diet (1.2% calcium, triangles), LCD low-calcium diet (0.02% calcium, squares), LCD + Aln alendronate (Aln, 50 g/kg per 24 h, circles). Used with permission [106]