Familial Absorptive Hypercalciuria in a Large Kindred

Abstract

The occurrence of calcareous renal stones in 12 members of a family was consistent with an autosomal dominant mode of inheritance. All 6 members with stones who were evaluated were shown to have absorptive hypercalciuria. The mother of 2 members with stones did not suffer stones but had biochemical evidence of absorptive hypercalciuria (increased intestinal calcium absorption, hypercalciuria and normal parathyroid function). Nephrolithiasis was encountered only in the progeny of members who had stones of biochemical absorptive hypercalciuria. The results suggest that physiological feature(s) of absorptive hypercalciuria may be an expression of the genetic trait.

Molecular Mechanisms of Primary Hypercalciuria

“…Given evidence for a genetic predisposition to hypercalciuria in both humans and rats (14,19,139,140), Bushinsky and coworkers screened adult male and female Sprague-Dawley rats for hypercalciuria and used the animals with the highest urinary calcium excretion to breed the next generation, followed by subsequent selection and inbreeding of their most hypercalciuric offspring, repeating the selection for almost 60 generations (16,20 -30). By the thirtieth generation, the GHS rats (for genetic hypercalciuric stone-forming) were excreting nearly ten times as much calcium as simultaneously studied control female rats (Figure 1) (13,16,17,20 -31).…”

Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption.

“…Abbreviations used in this paper: Gt, tissue conductance; IH, idiopathic hypercalciuria; Isc, short circuit ccurrent; Jms, mucosal to serosal flux; Jsm, serosal to mucosal flux; VDR, vitamin D receptor. mon cause of hypercalciuric calcium oxalate nephrolithiasis (3), is accompanied by intestinal calcium overabsorption in almost all patients (4)(5)(6)(7)(8)(9) and is the major source of urinary calcium excess during adequate calcium intake (10). The pathogenesis of intestinal calcium hyperabsorption and hypercalciuria in IH are unknown, but clinical evidence suggests the disease is heterogenous with at least three possible pathogenetic mechanisms for the calcium hyperabsorption: inappropriate renal 1,25 (OH)2D3 synthesis with increased serum 1,25(OH)2D31evels (11)(12)(13)(14); a primary increase in enterocyte calcium transport with normal serum 1,25(OH)2D3 levels (7,8,10,14); and a primary renal tubule defect in calcium reabsorption with compensatory increases in parathyroid hormone, 1,25(OH)2D3, and intestinal calcium absorption (7,8,15).…”

“…IH affects 5-10% ofthe adult population ( 16,17) and familial patterns of inheritance suggest a genetic disorder with a dominant mode of inheritance (18)(19)(20)(21). Because of the difficulty in separating dietary and genetic factors that may influence calcium metabolism in patients with IH, a colony ofgenetically hypercalciuric rats was established (22) through breeding spontaneously hypercalciuric male and female Sprague-Dawley rats (23,24).…”

Mapping a Gene Defect in Absorptive Hypercalciuria to Chromosome 1q23.3-q241

“…A family history of nephrolithiasis was noted in 45% of AH patients studied (1). The evaluation of large stone-forming kindreds by Coe et al (8) and by our group (9) indicated that AH was inherited in an autosomal dominant manner. However, no molecular genetic basis for the intestinal hyperabsorption of calcium in AH has been identified.…”

“…Moreover, in patients with severe AH presenting with markedly increased intestinal calcium absorption and hypercalciuria, 24-h urinary calcium often exceeded absorbed calcium (6), indicating that these patients were in negative calcium balance. There is strong evidence of genetic inheritance of AH (1,8,9). A family history of nephrolithiasis was noted in 45% of AH patients studied (1).…”