The expression of vitamin D receptor (VDR) and 1,25-dihydroxyvitamin D3 [1,25(OH)D] levels exceed the values of controls in some but not all hypercalciuric stone formers (HSF). We aimed to evaluate serum 1,25(OH)D levels, the expression of VDR, CYP27B1, and CYP24A1 hydroxylases in HSF in comparison with normocalciuric stone formers (NSF) and healthy subjects (HS). Blood samples, 24-h urine collections and a 3-day dietary record were obtained from 30 participants from each of the groups. The expression of VDR, CYP27B1, and CYP24A1 was measured by flow cytometry. HSF presented significantly higher urinary volume, sodium, magnesium, oxalate, uric acid, and phosphorus than NSF and HS. Calcium intake was lower in HSF versus NSF and HS (442 ± 41 vs 594 ± 42 and 559 ± 41 mg/day, respectively, p = 0.027). Ionized calcium was significantly lower in HSF than NSF (1.29 ± 0.0 vs 1.31 ± 0.0 mmol/L, p < 0.01). Serum 1,25(OH)D was significantly higher in HSF and NSF than HS (22.5 ± 1.2; 22.2 ± 1.2 vs 17.4 ± 1.2 pg/ml, p = 0.007) but serum 25(OH)D, PTH, klotho and plasma FGF-23 did not differ between groups. VDR expression was higher in HSF and NSF than HS (80.8 ± 3.2; 78.7 ± 3.3 vs 68.6 ± 3.2%, p = 0.023). Although CYP27B1 and CYP24A1 expressions were similar among all groups, the ratio of 1,25(OH)D/CYP24A1 was higher in HSF and NSF than in HS (1.43 ± 0.25 and 0.56 ± 0.10 vs 0.34 ± 0.06, p = 0.00). Stone formers, regardless of urinary calcium excretion, had higher VDR expression and 1,25(OH)D levels than HS, even in ranges considered normal. Higher 1,25(OH)D/CYP24A1 ratio suggested a lower degradation of 1,25(OH)D by CYP24A1 in HSF and NSF.
Hypercalciuria Vitamin D receptor Nephrolithiasis CYP27B1 CYP24A1
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The authors thank Altay Alves Lino de Souza for his expert statistical assistance and advice. We also thank Maria Aparecida Dalboni, Caren Cristina Grabulosa and Silvia Regina Moreira for technical assistance. This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—2016/25359-0), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—Scholarship) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ—Grant 309045/2018-5, IPH).
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest. The authors declare that the results presented in this paper have not been published previously in whole.
All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study. Brazil Ethic Committee no 1.156.469 (Plataforma Brasil).
Zerwekh JE, Yu XP, Breslau NA, Manolagas S, Pak CY (1993) Vitamin D receptor quantitation in human blood mononuclear cells in health and disease. Mol Cell Endocrinol 96(1–2):1–6CrossRefGoogle Scholar
Zerwekh JE, Reed BY, Heller HJ, González GB, Haussler MR, Pak CY (1998) Normal vitamin D receptor concentration and responsiveness to 1, 25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria. Miner Electrolyte Metab 24(5):307–313CrossRefGoogle Scholar
Kaplan RA, Haussler MR, Deftos LJ, Bone H, Pak CY (1977) The role of 1 alpha, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Investig 59(5):756–760. https://doi.org/10.1172/JCI108696CrossRefPubMedGoogle Scholar
Shen FH, Baylink DJ, Nielsen RL, Sherrard DJ, Ivey JL, Haussler MR (1977) Increased serum 1,25-dihydroxyvitamin D in idiopathic hypercalciuria. J Lab Clin Med 90(6):955–962PubMedGoogle Scholar
Insogna KL, Broadus AE, Dreyer BE, Ellison AF, Gertner JM (1985) Elevated production rate of 1,25-dihydroxyvitamin D in patients with absorptive hypercalciuria. J Clin Endocrinol Metab 61(3):490–495CrossRefGoogle Scholar
Bataille P, Bouillon R, Fournier A, Renaud H, Gueris J, Idrissi A (1987) Increased plasma concentrations of total and free 1,25-(OH)2D3 in calcium stone formers with idiopathic hypercalciuria. Contrib Nephrol 58:137–142CrossRefGoogle Scholar
Moyano MJ, Tejada MJGD, Lozano RG, Moruno R, Ortega R, Marti V, Sanchez Palencia R, Palma A, Perez Cano R (2007) Changes in bone mineral metabolism in patients with recurrent urolithiasis and vitamin D receptor gene polymorphisms. Preliminary results. Nefrologia 27(6):694–703PubMedGoogle Scholar
Giannini S, Nobile M, Castrignano R, Pati T, Tasca A, Villi G, Pellegrini F, D’Angelo A (1993) Possible link between vitamin D and hyperoxaluria in patients with renal stone disease. Clin Sci (London, England: 1979) 84(1):51–54CrossRefGoogle Scholar
Heilberg IP, Martini LA, Szejnfeld VL, Carvalho AB, Draibe SA, Ajzen H, Ramos OL, Schor N (1994) Bone disease in calcium stone forming patients. Clin Nephrol 42(3):175–182PubMedGoogle Scholar
Hess B, Casez J-P, Takkinen R, Ackermann D, Jaeger P (1993) Relative hypoparathyroidism and calcitriol up-regulation in hypercalciuric calcium renal stone formers—impact of nutrition. Am J Nephrol 13:18–26CrossRefGoogle Scholar
Vezzoli G, Caumo A, Baragetti I, Zerbi S, Bellinzoni P, Centemero A, Rubinacci A, Moro GL, Adamo D, Bianchi G, Soldati L (1999) Study of calcium metabolism in idiopathic hypercalciuria by strontium oral load test. Clin Chem 45(2):257–261PubMedGoogle Scholar
Misael da Silva AM, dos Reis LM, Pereira RC, Futata E, Branco-Martins CT, Noronha IL, Wajchemberg BL, Jorgetti V (2002) Bone involvement in idiopathic hypercalciuria. Clin Nephrol 57(3):183–191CrossRefGoogle Scholar
Gray RW, Wilz DR, Caldas AE, Lemann J (1977) The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 45(2):299–306. https://doi.org/10.1210/jcem-45-2-299CrossRefPubMedGoogle Scholar
Caldas AE, Gray RW, Lemann J (1978) The simultaneous measurement of vitamin D metabolites in plasma: studies in healthy adults and in patients with calcium nephrolithiasis. J Lab Clin Med 91(5):840–849PubMedGoogle Scholar
Shakhssalim N, Gilani KR, Parvin M, Torbati PM, Kashi AH, Azadvari M, Golestan B, Basiri A (2011) An assessment of parathyroid hormone, calcitonin, 1,25 (OH)2 vitamin D3, estradiol and testosterone in men with active calcium stone disease and evaluation of its biochemical risk factors. Urol Res 39(1):1–7. https://doi.org/10.1007/s00240-010-0276-3CrossRefPubMedGoogle Scholar
Rendina D, Esposito T, Mossetti G, De Filippo G, Gianfrancesco F, Perfetti A, Magliocca S, Formisano P, Prie D, Strazzullo P (2012) A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis. J Clin Endocrinol Metab 97(5):E840–E844. https://doi.org/10.1210/jc.2011-1528CrossRefPubMedGoogle Scholar
Vezzoli G, Dogliotti E, Terranegra A, Arcidiacono T, Macrina L, Tavecchia M, Pivari F, Mingione A, Brasacchio C, Nouvenne A, Meschi T, Cusi D, Spotti D, Montanari E, Soldati L (2015) Dietary style and acid load in an Italian population of calcium kidney stone formers. Nutr Metab Cardiovasc Dis 25(6):588–593. https://doi.org/10.1016/j.numecd.2015.03.005CrossRefPubMedGoogle Scholar
Martini LA, Cuppari L, Cunha MA, Schor N, Heilberg IP (1998) Potassium and sodium intake and excretion in calcium stone forming patients. J Ren Nutr 8(3):127–131CrossRefGoogle Scholar
Moe OW, Preisig PA (2005) Hypothesizing on the evolutionary origins of salt-induced hypercalciuria. Curr Opin Nephrol Hypertens 14(4):368–372CrossRefGoogle Scholar
Martini LA, Cuppari L, Colugnati FA, Sigulem DM, Szejnfeld VL, Schor N, Heilberg IP (2000) High sodium chloride intake is associated with low bone density in calcium stone-forming patients. Clin Nephrol 54(2):85–93PubMedGoogle Scholar
Vezzoli G, Baragetti I, Zerbi S, Caumo A, Soldati L, Bellinzoni P, Centemero A, Rubinacci A, Moro GL, Bianchi G (1998) Strontium absorption and excretion in normocalciuric subjects: relation to calcium metabolism. Clin Chem 44(3):586–590PubMedGoogle Scholar