The kidney plays an important role in maintaining the systemic Ca 2+ and Mg 2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca 2+ and Mg 2+ concentrations. The reabsorption of Ca 2+ and Mg 2+ 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 Ca 2+ -sensing receptor defects, markedly change tubular transport of Ca 2+ and Mg 2+ . In the distal convolutions, several proteins involved in Mg 2+ 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 Ca 2+ and Mg 2+ balance.

Nephrocalcinosis may be defined as a generalized increase in the calcium content of the kidneys. This renal calcification may occur at a molecular, microscopic or macroscopic level leading to progressive amounts of renal damage. The major causes include those associated with an increase in urinary levels of calcium, oxalate and phosphate. Under these conditions, urine concentration and supersaturation leads to calcium crystal precipitation, which may be an intratubular event or initiate within the renal interstitium. The focus of discussion concerning renal calcification is often limited to factors that lead to renal stones (calculi and nephrolithiasis); however, nephrocalcinosis is a more sinister event, and often implies a serious metabolic defect. This review will discuss the hypotheses concerning initiating lesions of nephrocalcinosis using available laboratory and clinical studies and will examine whether new understanding of the molecular basis of tubulopathies, that lead to nephrocalcinosis, has given further insights.

1. Chronic reduction of salt intake can reduce the natriuretic effect of exogenously administered atrial natriuretic factor. The purpose of this study was to elucidate the intrarenal site(s) of such atrial natriuretic factor resistance. Renal clearance and collecting duct microcatheterization experiments were made before and during infusion of atrial natriuretic factor in three groups of rats: group 1 consisted of rats fed a high salt diet (8% NaCl) for 1 week before the experiment; group II were fed a low salt diet (< 0.008%); group III received the same low salt diet, but were acutely replenished with salt at the time of experiment. 2. Baseline sodium chloride excretion was 6480 ± 810 nmol min −1 g −1 kidney weight in group 1 compared to 99 ± 16 in group 1. Fractional re-absorptions in the medullary collecting duct were 37 ± 6% and 95 ± 2% of delivered load, respectively ( P < 0.05). The fractions of filtered sodium remaining at the beginning of the medullary duct were 6.6 ± 1.0% of filtered load in group 1 and 2.7 ± 0.7% in group II ( P < 0.05), indicating increased tubular reabsorption in group II, not only in the medullary duct, but also in upstream nephron segments. 3. During infusion of atrial natriuretic factor, marked saluresis (13240 ± 750 nmol min −1 g −1 kidney weight), together with decreased fractional reabsorption at both sites (duct, −13 ± 9%; upstream remainder, 7.9 ± 0.7%; P < 0.05 each, compared to corresponding control values) was found in group 1, whereas the excretory (150 ± 28 nmol min −1 g −1 kidney weight), and the tubular transport (duct = 84 ± 3%; upstream remainder =2.2 ± 0.4%) changes were quantitatively insignificant in group II. Glomerular filtration rate was increased in group 1 from 1.07 ± 0.03 to 1.26 ± 0.04 ml min −1 g −1 kidney weight ( P < 0.05), but not in group II (0.93 ± 0.07 to 0.96 ± 0.09, not significant). 4. In group III, acute salt replenishment was associated with increased excretion (1940 ± 440 nmol mm −1 g −1 kidney weight, P < 0.05 compared to group II) and with reduction of tubular reabsorption in the collecting duct only (69 ± 8%, P < 0.05). Infusion of atrial natriuretic factor in this group further increased natriuresis (7810 ± 780 nmol min −1 g −1 kidney weight) and decreased tubular reabsorption in the duct (−32 ± 22%, P < 0.05 compared to the corresponding control value). 5. We conclude that chronic salt deprivation can effectively prevent, via a rapidly reversible counter-regulatory mechanism, the expected actions of atrial natriuretic factor on sodium reabsorption in the medullary collecting duct. Operation of such a mechanism may explain salt retention despite elevated endogenous levels of atrial natriuretic factor in pathological states such as congestive heart failure and liver cirrhosis.