Genetics of primary hypercalciuria

Introduction

Primary hypercalciuria (PH) is a multifactorial disorder whose onset depends both on environmental and genetic factors. As for other complex diseases, such as diabetes, hypertension, osteoporosis, molecular technologies will be helpful to identify either the responsible genetic factors or subjects susceptible to develop such disorders, providing the opportunity for ade­quate clinical management and therapy. PH is a complex highly heterogeneous defect of calcium metabolism character­ized by an elevated urinary excretion of calcium, in the ab­sence of other alterations. According to Frick and Bushinsky, it can be caused by a “dysregulation of calcium transport at sites where large fluxes of calcium must be precisely con­trolled: these sites are the intestine, kidney and bone”. Generally, it is defined by the occurrence of a urinary calcium excretion exceeding the threshold values, established in 1957 by Hodgkinson and Pyrah, at 7.5 mmol/24 hours for men and 6.25 mmol/24 hours for women. Alternatively, urinary calci­um may be normalized to body weight and hypercalciuria is considered as the calcium excretion above 100 mmol/24 hours per kg of body weight in both sexes. Hypercalciuric sub­jects represent the 5-10% of general population. Online Pharmacy 

Their presence causes a skewness to high values in the urinary cal­cium distribution curve, which is more evident in the stone forming (Figure 1) or osteoporotic populations. The frequency of hypercalciuria among these patients is higher than usually found in general population and may involve 20-50% of them. Analysis of the calcium excretion distribution curve in 471 stone formers indicates that it better fits a bimodal model (Figure 1). According to this model, stone formers appear to be composed by two different subsets of subjects. The first one is composed by 23% of patients, mostly hypercalciurics, whose calcium excretion can be estimated of 153±48 mmol/kg body weight in 24 hours. The other group, mainly composed by normocalciuric subjects, has an estimated calcium excre­tion of 85±33 mmol/kg body weight in 24 hours. Overlapping of calcium excretion curves, representing these subpopulations, reveals that PH may include subjects with different character­istics.

Distribution of the values of calcium excretion in a population of 471 patients with calcium kidney stone disease fits a bimodal model. Analysis for mixture of distribution was performed with specific software. The analysis considered the patients followed at outpatient's clinic for kidney stones at San Raffaele Hospital in Milan.

Figure 1 – Distribution of the values of calcium excretion in a population of 471 patients with calcium kidney stone disease fits a bimodal model. Analysis for mixture of distribution was performed with specific software. The analysis considered the patients followed at outpatient’s clinic for kidney stones at San Raffaele Hospital in Milan.