According to the studies, several risk factors could contribute to calcium kidney stones. Among them, hypercalciuria is one of the most common urine metabolic abnormalities (5). The excretion of calcium in the urine might be affected by serum variables, demographics, and other urinary metabolites. Our study revealed that 24-U Ca excretion decreases with increasing age, serum PTH and serum Cr. Conversely, 24-U Ca increases with weight gain, increasing 24-U Na, 24-U Cit, 24-U Urea, and 24-U Cr.
Among demographic factors, we included age and weight in our analysis. Previously, two large-sample studies found no association between age and hypercalciuria (10, 11). However, Taylor et al. reported an inverse association between age and 24-U Ca; every five-year increase in age was associated with a 6 mg (95% CI 4 to 9 mg/d) decrease in 24-U Ca (12). Our analyses showed that age indirectly affected urine calcium through serum 25(OH)D, serum Cr and 24-U Cr.
Previous studies showed that higher weight is associated with higher urinary calcium excretion (15). Our findings showed that body weight indirectly affects 24-U Ca through 24-U Na, 24-U Urea, and 24-U Cr. These results suggest that the effect of weight on urinary calcium excretion may be in part due to higher protein and salt intake in patients with higher weight. More studies regarding this finding are warranted.
Vitamin D causes a positive balance of calcium in the body through stimulation of intestinal calcium absorption. However, since different studies' results are inconsistent (11, 16–21), the relationship between serum vitamin D and 24-U calcium excretion is under debate. A recent meta-analysis, including twenty-two observational studies (3510 kidney stone formers and 19,718 controls), revealed that 25(OH)D was similar in both groups. Conversely, 1,25-dihydroxy vitamin D (1,25(OH)2D) was significantly higher in stone formers than controls. More detailed studies on kidney stone formers indicated that hypercalciuric patients had significantly higher 1,25(OH)2D and 25(OH)D compared with normocalciuric stone patients and non-stone forming controls (22). Two population-based studies, InChianti Study (23) and Swiss Survey on Salt Intake Study (10), showed that the level of serum 25(OH)D was positively associated with urinary calcium excretion in men but not in women. Other studies failed to observe any correlations between 25(OH)D and urinary calcium excretion (19–21). The results of our previous study (24) showed that the 24-U Ca increased in vitamin D supplemented patients, which was not associated with serum 25(OH)D or PTH changes. Other results of that study suggested that the increase in 24-U Ca might be due to other factors such as dietary sodium and protein intake. In line with our previous findings, the current study results showed that serum 25(OH)D did not have a direct effect on 24-U Ca, and the indirect effect was through serum PTH. This effect is negligible; therefore, the treatment of hypovitaminosis D could be safe in kidney stone formers, in case other variables, such as sodium intake, are controlled. Further randomized clinical trials are needed in this regard.
PTH is responsible for minute-by-minute regulation of serum ionized calcium, through stimulation of renal calcium reabsorption and bone resorption. Furthermore, PTH stimulates the conversion of 25(OH)D to its active hormonal form (1,25(OH)2D) in the kidney, thereby promoting absorption of calcium in the small intestine (8, 9). A negative correlation between serum PTH and urinary calcium excretion is shown in previous studies, which is considered as the normal process of serum calcium balance. Similarly, our current results showed that PTH had a significant inverse effect on 24-U Ca directly. However, excessive PTH secretion from a parathyroid adenoma (primary hyperparathyroidism) leads to excessive bone resorption and increased renal synthesis of 1,25(OH)2D, which in turn enhances intestinal absorption of calcium. Therefore, the net effect is elevated serum calcium levels, which leads to higher urine calcium. Conversely, the level of urine calcium is decreased in secondary hyperparathyroidism, due to increased calcium resorption from kidney tubules. One of the common causes of secondary hyperparathyroidism are vitamin D deficiency, therefore the level of serum PTH is decreased after vitamin D supplementation.
The previous observational findings of the association between serum Ca and excretion of Ca in 24-h urine are inconsistent. The study, which was conducted on 1293 participants (624 men and 669 women), found a positive association between serum Ca and 24-U Ca in women but not men (10), while the InChianti study (595 subjects including 302 men and 293 women) observed this association in men but not women (23). In an interventional small-sized study by Peacock et al. (25) on 72 individuals, a positive association was observed between serum and urinary Ca in both men and women. Our results revealed that there is no significant direct or indirect association between serum Ca and 24-U Ca. Normally, serum calcium is tightly controlled in a narrow range during calcium hemostasis. Since we excluded patients with primary hyperparathyroidism or any other diseases affecting serum Ca, total serum Ca was in a narrow range in all patients, and we could not find any association between serum and urine Ca. However, serum P appears to influence 24-U Ca indirectly. It seems that the effect of serum P on urinary Ca levels may be more prominent, and further studies are needed in this field.
In line with previous studies (11, 12), our results indicated that higher excretion of Na was positively correlated with 24-U Ca. The positive effect of Na intake, measured through 24-U Na, on urinary Ca excretion has been demonstrated in previous studies (26, 27). Because sodium and Ca are reabsorbed at common sites in the renal tubules, the direct correlation of sodium and Ca in the urine is expected (28).
The relationship between urinary citrate and Ca may be challenging to discuss. Taylor et al. (12) discussed that since acid load could increase urinary Ca and decrease urinary citrate, it would be reasonable to expect an inverse association between urinary citrate and Ca. Moreover, some studies reported that potassium citrate consumption could reduce urinary Ca (29, 30). However, we observed a marked direct effect of 24-U Cit on urinary Ca excretion, which was reported by other studies too (11, 12). Other factors such as dietary Ca intake may play a part in such association. Further studies are needed to elucidate the topic.
Data about the relationship between 24-U Ca and other factors included in our analysis are limited. Taylor et al. did not find any associations between urinary Cr and Ca after multivariate adjustment. However, we observed a positive effect of both serum and urinary Cr on 24-U Ca. Besides, our study revealed a direct effect of 24-U Urea on 24-U Ca. Since 24-U Urea is a substitute for dietary protein intake, our results suggested an increase in 24-U Ca with high protein intake. This finding is in line with existing studies. However, since we did not evaluate the 24-U sulfate or dietary intake, we could not evaluate the effect of animal and vegetable protein intake on 24-U Ca separately.
This study has some limitations. First, we could not assess the effect of calcium on PTH since we did not test ionized calcium. Second, the dietary intake was not available in our study. Third, additional factors affecting 24-U Ca may not be considered in our model.