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We developed a mathematical model of calcium (Ca2+) transport along the rat nephron to investigate the factors that promote hypercalciuria. The model is an extension of the flat medullary model of Hervy and Thomas (Am J Physiol Renal Physiol 284: F65-F81, 2003). It explicitly represents all the nephron segments beyond the proximal tubules and distinguishes between superficial and deep nephrons. It solves dynamic conservation equations to determine NaCl, urea, and Ca2+ concentration profiles in tubules, vasa recta, and the interstitium. Calcium is known to be reabsorbed passively in the thick ascending limbs and actively in the distal convoluted (DCT) and connecting (CNT) tubules. Our model predicts that the passive diffusion of Ca2+ from the vasa recta and loops of Henle generates a significant axial Ca2+ concentration gradient in the medullary interstitium. In the base case, the urinary Ca2+ concentration and fractional excretion are predicted as 2.7 mM and 0.32%, respectively. Urinary Ca2+ excretion is found to be strongly modulated by water and NaCl reabsorption along the nephron. Our simulations also suggest that Ca2+ molar flow and concentration profiles differ significantly between superficial and deep nephrons, such that the latter deliver less Ca2+ to the collecting duct. Finally, our results suggest that the DCT and CNT can act to counteract upstream variations in Ca2+ transport but not always sufficiently to prevent hypercalciuria. [ABSTRACT FROM AUTHOR]