1Department: UMR S 1155, Sorbonne Université-UPMC Paris 06, F-75020 Paris, France; [email protected]
2Institut Nationwide de la Santé et de la Recherche Médicale (INSERM), UMR S 1155, F-75020 Paris, France
3Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, F-75020 Paris, France
1Department: UMR S 1155, Sorbonne Université-UPMC Paris 06, F-75020 Paris, France; [email protected]
2Institut Nationwide de la Santé et de la Recherche Médicale (INSERM), UMR S 1155, F-75020 Paris, France
3Explorations Fonctionnelles Multidisciplinaires, AP-HP, Hôpital Tenon, F-75020 Paris, France
Summary
1. Introduction
Urolithiasis is a rising public well being drawback worldwide, with an estimated lifetime threat of round 10% of the inhabitants in some international locations [1,2]. This enhance has been attributed, not less than partly, to dietary environmental elements, equivalent to elevated salt and protein intakes, that are accountable for hypercalciuria, one of many important determinants of calcium-dependent kidney stone formation [3]. Kidney stones fabricated from calcium oxalate and, to a lesser extent, calcium phosphate signify greater than 80% of whole stones in Western international locations [4,5]. Furthermore, we have now noticed an elevated proportion of stones developed on Randall’s plaques over the last a long time [6]. These plaques are calcium phosphate deposits showing in kidney interstitial tissue whose formation is related to hypercalciuria, and continuously constitutes step one in stone formation [7,8,9,10,11]. Whether or not vitamin D dietary supplements or excessive 25-hydroxyvitamin D serum ranges might enhance urinary calcium excretion and promote kidney stone formation has been debated. Current research have highlighted that some subgroups of sufferers could also be prone to creating kidney stones when receiving vitamin D dietary supplements, primarily cholecalciferol [12,13,14]. As well as, current meta-analyses have highlighted that 25-hydroxyvitamin D serum ranges are greater in kidney stone sufferers affected by hypercalciuria and kidney stones [15,16]. These observations ought to sound a warning, particularly in medical settings the place a vitamin D complement profit has not been established. We assessment hereafter the seminal research that established a hyperlink between vitamin D metabolites (particularly calcitriol) and hypercalciuria or kidney stone formation in people, the information ensuing from animal experimental research and the epidemiological and interventional research devoted to vitamin D and kidney stones, and focus on the potential hyperlink between vitamin D and Randall’s plaque formation.
2. Strategies
Literature Search and Research Choice:
NIH-PubMed/Medline, ISI-Net of Science and Cochrane Library had been searched to establish related research reporting the connection between vitamin D, hypercalciuria and kidney stones. The search was carried out a number of instances between September 2017 and November 2017. The preliminary search course of was designed to search out all related printed authentic articles with out limitation by 12 months or language. Detailed search phrases had been (“stone” OR “kidney stone” OR “urolithiasis” OR “nephrolithiasis” OR “calculus” OR “Randall’s plaque” OR “hypercalciuria” or “urine calcium”) AND (“vitamin D” OR “calcitriol” OR “cholecalciferol” OR “25-hydroxyvitamin D” OR “25-hydroxycholecalciferol” OR “1,25-dihydroxyvitamin D” OR “Vitamin D receptor” OR “(Vitamin D receptor) VDR”). Two authors (E.L. and M.D.) screened citations returned from the search technique to establish eligible research.
Convention abstracts weren’t included, however all peer-reviewed research had been thought of and mentioned within the assessment. As well as, some important research devoted to Randall’s plaque and to the organic position of vitamin D are additionally cited and mentioned on this assessment.
3. Vitamin D and Kidney Stones: An Outdated Story
4. Vitamin D and Kidney Stones: Classes from Animal Fashions – “vitamin d kidney stones”
Among the many few animal fashions of kidney stone formation, probably the most attention-grabbing is definitely the genetic hypercalciuric stone-forming rat (GHS). This mannequin has been obtained by inbreeding probably the most hypercalciuric progeny of successive generations of Sprague–Dawley rats [46,47]. When consumed a regular food plan, these rats have a dramatically greater urinary calcium excretion than controls and develop kidney stones fabricated from calcium phosphate, or calcium oxalate with the addition of hydroxyproline to the food plan [48]. As in people, hypercalciuria is a polygenic trait [49]. This rat mannequin is crucial for addressing the pathophysiology of hypercalciuria. There’s dramatically elevated intestinal calcium absorption in GHS rats but additionally elevated bone resorption and lowered renal tubular calcium reabsorption [50,51,52]. These rats have elevated organic exercise of VDR within the bones and intestines and an elevated VDR expression within the intestines, bones and kidneys. Calcitriol administration to GHS rats exacerbates calciuria by rising intestinal calcium absorption but additionally bone resorption [49,50,51]. These observations help the position of VDR in human hypercalciuria, but additionally the potential roles of calcitriol and VDR in bone demineralization which continuously impacts kidney stone formers [52,53].
When wild-type Sprague–Dawley rats had been uncovered to injections of cholecalciferol each 3 weeks, they developed hypercalciuria and tiny calcium phosphate kidney stones [54]. The administration of calcium at excessive focus in consuming water didn’t promote the formation of great stones. In distinction, the synergistic administration of calcium and cholecalciferol promoted the event of huge stones, addressing the danger of calcium and cholecalciferol co-administration, not less than on this mannequin. Calcium oral consumption, not less than in regular ranges, isn’t a threat issue for kidney stones and will even be protecting by means of the limitation of digestive oxalate absorption [55]. Whether or not the mixed administration of calcium and cholecalciferol to people might promote kidney stone formation is supported by interventional research described hereafter.
5. Vitamin D Serum Ranges and Vitamin D Prescription: A Hyperlink with Kidney Stones?
Since calcitriol will increase digestive calcium absorption and, not less than quickly, serum calcium ranges, it ought to essentially enhance urine calcium excretion to take care of calcium homeostasis (by rising the calcium filtration load and stimulating the renal calcium sensing receptor). The prescription of cholecalciferol or analogous remedies will increase circulating ranges of 25-hydroxyvitamin D, which can act with low affinity on VDR or be reworked into calcitriol, with a better affinity to VDR [19]. The manufacturing of calcitriol is luckily restricted by parathyroid hormone synthesis suppression, by means of calcium sensing receptors and calcitriol signalling in parathyroid cells. Since parathyroid hormone promotes renal calcium dealing with within the distal tubules, its suppression may additionally enhance urinary calcium excretion.
Though there’s a giant consensus that top calcitriol ranges enhance urine calcium and kidney stone formation, whether or not serum 25-hydroxyvitamin D circulating ranges or widespread vitamin D prescription may affect kidney stone formation remains to be debated.
6. Observational Research
Some research have proven a optimistic affiliation between urinary calcium excretion and 25-hydroxyvitamin D serum ranges in grownup stone formers [56,57]. Different authors didn’t discover a relationship between 25-hydroxyvitamin D and urine calcium excretion or prevalent kidney stone illness. Within the Nationwide Well being Vitamin Examination Survey (NHANES) III cross sectional examine, excessive serum 25-hydroxyvitamin D concentrations weren’t related to prevalent kidney stones (reported historical past or nephrolithiasis) [58]. A retrospective examine carried out in 169 sufferers with nephrolithiasis didn’t present a relationship between serum 25-hydroxyvitamin D degree and 24-h urine calcium excretion [59].
In a potential evaluation of 193,551 contributors within the Well being Professionals Observe-up Research (HPFS) and Nurses’ Well being Research (NHS) I and II, carried out by Ferraro et al. there was no statistically important affiliation between vitamin D consumption and threat of stones within the HPFS and the NHS I teams however doubtlessly a better threat within the NHS II group (Hazard Ratio 1.18, 95% Confidence Interval 0.94, 1.48, p for development = 0.02) [60]. Of word, the NHS II examine has been carried out extra not too long ago and girls included within the NHS II examine had a every day consumption of vitamin D (primarily resulting from supplementation) that was rather more important than within the earlier research. It might be hypothesized that this enhance in vitamin D consumption might have enhanced stone threat on this particular cohort.
Though the position of 25-hydroxyvitamin D serum ranges in kidney stone formation has been mentioned, the position of calcitriol isn’t a matter of debate. As an example, Taylor et al. in contrast calcium and phosphorus regulatory hormones and the danger of incident symptomatic kidney stones in a case-control examine together with 356 incident stone formers and 712 controls [61]. Baseline plasma ranges of 25-hydroxyvitamin D had been related in each teams however greater plasma calcitriol ranges had been independently related to a better threat of symptomatic stones. Curiously, a number of research didn’t discover an affiliation between urinary calcium excretion and 25-hydroxyvitamin D serum ranges when taking into account all stone formers, however recognized a powerful correlation when contemplating hypercalciuric stone formers solely [29,62]. This level is crucial and highlights that affected person phenotype and kidney stone evaluation must be assessed cautiously. Really, vitamin D metabolism influences urinary calcium excretion, however all kidney stones usually are not calcium-dependent. Though calcium oxalate is the principle element of 60 to 80% of all urinary calculi, there’s robust proof that calcium oxalate stones might end result from hypercalciuria but additionally from hyperoxaluria and/or low diuresis, generally within the absence of metabolic dysfunction [4,63,64,65].
A current meta-analysis primarily based upon six case-control research and one randomized managed trial reported within the literature investigated the connection between circulating 25-hydroxyvitamin D and the danger of stone formation [15]. Knowledge had been accessible for 451 kidney stone formers and 482 controls. The outcomes offered proof that kidney stone formers had considerably greater ranges of 25-hydroxyvitamin D than controls, each in European and Asian populations. Lastly, in one other meta-analysis, Hu et al. investigated the affiliation between circulating vitamin D ranges and urolithiasis; twenty-two observational research involving 23,228 contributors had been included [16]. Amongst them, 19,718 had been controls and 3510 had been stone formers. Throughout the latter group, extra exact distinction was made concerning calcium excretion. The principle conclusion of the meta-analysis was that calcitriol was considerably elevated in stone formers in comparison with controls whereas 25-hydroxyvitamin D was related in each teams. Nonetheless, hypercalciuric stone formers had considerably greater calcitriol ranges but additionally greater 25-hydroxyvitamin D serum ranges than normocalciuric sufferers and controls.