Pierre Bataille

PATHOPHYSIOLOGY AND TREATMENT OF IDIOPATHIC HYPERCALCIURIA

Nearly 50 years after its initial description by Dr. F. Albright, the term idiopathic hypercalciuria (IH) is still in use. The exact mechanism of hypercalciuria is still unknown despite extensive pathophysiologic investigations; recent advances represent the focus of this review. A precise definition of true IH is proposed, taking into account the various nutritional conditions influencing calcium excretion. The potential pathogenic mechanisms are discussed, and the limits of the classical Paks pathophysiological classification are recalled. The evidence supporting the role of an increased intestinal calcium absorption, a defect in renal tubular calcium reabsorption, or an increased bone loss as a primary mechanism in IH are successively examined. Since overall available human data indicates that all three mechanisms may be found in IH, the hypothesis that a broader disorder encompassing all these various abnormalities may be involved in IH is discussed. Three global hypotheses to account for IH physiopathology are examined: a diffuse defect in fatty acid content of cell membranes, an increased expression of the vitamin D receptor of the 25(OH) vitamin D 1 alpha-hydroxylase, or of the calcium sensor receptor and a monocyte disease. Finally, the available clinical data justifying the therapeutic approaches are reviewed, and guidelines for dietary recommendations regarding calcium and also animal protein, sodium chloride, alcohol, carbohydrate, phosphate, and potassium intakes are proposed, and drug therapy indications are discussed.

Renal and Hypertensive Complications of Extracorporeal Shock Wave Lithotripsy: Who Is at Risk?

Extracorporeal shock wave lithotripsy (ESWL) is now used in the treatment of about 90% of renal and ureteral stones. Because of the non-punctual delivery of energy to the stone, a small volume of renal parenchyma is injured giving place to a fibrous scar which can be shown by highly resolutive imaging techniques like magnetic nuclear resonance. Isotopic clearances point to a reduction of 15% in the renal plasma flow on the side of the lithotripsy, but this alteration appears to be transient in nature. In a few cases an abrupt onset of transient hypertension has been reported in clear relation to a compressive perirenal hematoma. The responsibility of ESWL in the late occurrence of permanent hypertension is, however, still uncertain, probably because of the difficulty in showing that this occurrence is not only related to the older age of the patient. The American Food and Drug Administration-sponsored multicentric study begun in 1992 should solve this issue in the future. Recent articles suggest that altered renal function prior to ESWL would predict the late occurrence of hypertension and worsening of renal failure. Furthermore, age and the resistance index of arcuate or interlobar renal arteries (measured by Doppler) could help to screen patients at risk of developing hypertension. In practice in patients over 60 years of age and/or with a plasma creatinine of >to 300 micromol/l, ESWL should be performed with caution, and renal function and blood pressure should be carefully monitored.

Critical Role of Oxalate Restriction in Association with Calcium Restriction to Decrease the Probability of Being a Stone Former: Insufficient Effect in Idiopathic Hypercalciuria

The probability of being a stone former (PSF) was calculated in 3 groups of idiopathic calcium stone formers [with normocalciuria (NC), dietary hypercalciuria (DH) and idiopathic hypercalciuria (IH)] in 4 conditions: while on a free diet; on a calcium- and oxalate-restricted diet during 4 days; after an oxalate load, while on a 1.5-gram calcium diet, and after an oxalate load while on a calcium-restricted diet. Combined calcium and oxalate restriction significantly decreased PSF only in NC and DH whereas the decrease was not significant in IH because of a concomitant significant increase in oxalate excretion. Increase of PSF with the oxalate load was significantly greater during a calcium-restricted diet than during the 1.5-gram calcium diet in all groups of patients (4, 6 and 12 times greater in NC, DH and IH, respectively). These data show the critical role of oxalate restriction when calcium is restricted in order to decrease the PSF. This combined restriction is however not sufficient in idiopathic hypercalciuric patients to decrease their PSF.

Evidence for Magnesium Depletion in Idiopathic Hypercalciuria

Magnesium accounts for about 20% of the total inhibitory activity of urine with respect to calcium stone formation1. Magnesium depletion has been shown to cause calcification in the proximal tubule cells and in the tubular lumen in rats2 and to be responsible for nephrocalcinosis in children. Based on these data, magnesium deficiency has been suspected as a factor in the pathogenesis of calcium stone formation although it has been observed only rarely3. Moreover, the data on magnesium excretion in stone formers are conflicting, and may even be normal4 or increased5. These discrepancies may be explained by the fact that dietary calcium and calcium excretion were not taken into account, despite the fact that in normal individuals magnesium excretion is directly correlated with calcium excretion6. For these reasons it seemed interesting to us to study magnesium metabolism in various groups of idiopathic calcium stone-formers classified according to calcium excretion during a controlled calcium diet.

Idiopathic Hypercalciuria: Proposal for a New Cascade

Idiopathic hypercalciuria (IH) is defined by a 24 hour urinary excretion of calcium greater than 4 mg or 0.1 mmol/kg of body weight on a calcium diet of 1 g and greater than 3 mg or 0.07 mmol/kg on a Ca diet of 400 mg, while there is no excess of sodium (120–180 mmol) nor of protein (1–1.3 g/kg per day). IH with fasting hypercalciuria but without secondary hyperparathyroidism represents in our experiece the most prevalent subtype of IH. Since bone mineral density has been shown to be decreased in this undetermined subtype (Pak’s classification), as in patients with absorptive hypercalciuria type I or with renal hypercalciuria, the clinical relevance of this classification is questioned. A primary bone hyperresorption seems to be the main explanation of IH, since in this group as a whole, fasting hypercalciuria is correlated positively with fasting hydroxyprolinuria which is higher than in controls. This bone resorption may be favored by protein intake of non-dairy origin due to a higher meat intake and hypersensitivity of bone resorption to meat intake, as evidenced by a higher daily urinary excretion of urea on a diet without dairy products and a steeper slope of the regression of fasting calciuria versus 24 hour urea excretion. Furthermore, calcitriol synthesis is increased, probably because of a hypersensitivity of 25 OH vitamin D 1α hydroxylase to phosphate, as evidenced by the fact that plasma calcitriol correlates negatively with plasma phosphate which, however, remains in the normal range. High plasma calcitriol is not responsible for the bone hyperresorption, since it correlates negatively with fasting hypercalciuria and positively with bone density and postprandial calciuria (an index of calcium absorption).