Molecular mechanisms of primary hypercalciuria.

Nephrolithiasis, with a lifetime incidence of up to 13% (1–9), results in significant morbidity as well as substantial economic costs, not only directly from medical treatment but also indirectly through time lost from work. Approximately 70% of kidney stones are composed of calcium, generally combined with oxalate and/or phosphate (1,7). Hypercalciuria is the most consistent metabolic abnormality found in patients with calcium nephrolithiasis (1–10). Indeed, idiopathic hypercalciuria (IH), excess calcium excretion with no identifiable metabolic cause, is found in up to 40% of stone-formers (11) but has an incidence of less than 10% in the overall population (12). The elevation in urinary calcium leads to increased supersaturation with respect to a solid phase, generally calcium oxalate or calcium phosphate, which increases the propensity to kidney stone formation (13). Idiopathic hypercalciuria is an inherited metabolic abnormality (14–17). In pediatric patients with nephrolithiasis, 73% had a family history of kidney stones in at least one first-order or second-order relative, as opposed to a prevalence of 22% in a control population of pediatric renal and urologic patients (18). Of the patients with hypercalciuria, the prevalence of nephrolithiasis in the family history was 69% (18). Coe et al. (19) found a strong inheritance pattern in patients with nephrolithiasis that they conjectured was autosomal dominant. In support of a genetic basis for hypercalciuria, we have selectively bred a strain of rats for this disorder. After almost 60 generations of inbreeding, all of the rats are hypercalciuric: they excrete approximately 8 to 10 times as much calcium as control animals and almost uniformly form kidney stones (13,16,17,20–31) (Figure 1). The ability to select for this trait, hypercalciuria, solidifies the genetic nature of this disorder. In a normal, nonpregnant, adult, intestinal calcium absorption is precisely balanced by urine calcium excretion so that the total amount of body calcium remains constant. Consuming a typical diet of 20 mmol of calcium per day, approximately 16 mmol are lost to fecal excretion, indicating that 4 mmol are absorbed through the intestine (Figure 2) (9,32,33). The primary reservoir of body calcium, the skeleton, contains about 20 mol of calcium, of which about 14 mmol per day are exchanged through balanced bone formation and resorption. Extracellular fluid includes another 25 mmol of calcium. The kidney filters approximately 270 mmol of calcium per day, of which all but 4 mmol are reabsorbed (3,4). It is logical to assume that idiopathic hypercalciuria is caused by dysregulation of calcium transport at sites where large fluxes of calcium must be precisely controlled: these sites are the intestine, kidney, and bone. If one could understand the molecular mechanism(s) by which primary hypercalciuria occurs, clinical investigators could then screen families of stone formers before the onset of overt disease and possibly direct treatment at the specific underlying molecular defect(s) in calcium transport. Complicating the search for genes responsible for hypercalciuria are the following caveats: mutations in several pathways can be responsible for hypercalciuria; expression of more than one gene may need to be altered to cause a discernible phenotype; and penetrance of the mutation(s) may be incomplete. A single genetic abnormality responsible for idiopathic hypercalciuria is unlikely, as there appears to be a continuum in the rates of calcium excretion between normal and hypercalciuric humans (7,34) and control and inbred hypercalciuric rats (16,17). This focus of this review will be the delineation of potential mechanisms responsible for idiopathic hypercalciuria by studying selected known genetic disorders resulting in excess urine calcium excretion. We will exclude hypercalciuria resulting from metabolic abnormalities for which there is no known genetic defect for calcium transport, such as primary hyperparathyroidism, malignancy with production of PTHrP, renal tubular acidosis, vitamin D toxicity, immobilization, hyperthyroidism, and Paget disease (9). We will partition our discussion into disorders affecting the intestine, the kidney, and the bone, as these sites are responsible for regulation of calcium homeostasis and molecular defects in these sites of calcium transport can contribute to hypercalciuria and subsequent stone formation. Although this is an organ-based separation, we must recognize that calcium transport pathways are often generalized and not limited to one anatomic site. In addition, as studies of the genetic hypercalciuric rats have shown (see below), hypercalciuria may involve a dysregulation of multiple calcium transport systems.