Z.Sh. Pavlova – Ph.D. (Med.), Endocrinologist, University Hospital, Medical Scientific 

and Educational Center of M.V. Lomonosov Moscow State University E-mail: zukhra73@gmail.com

I.I. Golodnikov – Student, Faculty of Basic Medicine, M.V. Lomonosov Moscow State University E-mail: golodnikov@fbm.msu.ru

A.A. Kamalov – Academician of RAS, Dr. Sc. (Med.), Urologist, Director of the Medical Scientific and Educa-

tional Center of M.V. Lomonosov Moscow State University; Faculty of Basic Medicine, 

M.V. Lomonosov Moscow State University E-mail: armais.kamalov@rambler.ru

Yu.A. Manuylova – Ph.D. (Med.), Endocrinologist, University Hospital, Medical Scientific 

and Educational Center of M.V. Lomonosov Moscow State University 

E-mail: juliakolish@yahoo.com

Nephrolithiasis is one of the most common diseases of the genitourinary system. At the moment, the composition of calculi has been reliably studied, where the main part is accounted for by calcium stones, but there is still no complete understanding of the causes of stone formation. It is important to realize that the whole thing is a combination of factors. 

The Vitamin D3 has a significant effect on calcium-phosphorus metabolism, which is regulated by many other substances, of which, apart from D3, the most important are Parathyroid hormone and FGF23. The level of parathyroid hormone depends on the concentration of calcium and phosphorus, increasing with hypocalcemia and hyperphosphatemia, and those in turn depend on the level of D3.

The vitamin D receptor gene is localized on the short arm of chromosome 12 (12q13.11). To date, 60 single-nucleotide variants of the vitamin D receptor gene polymorphism are known, however, five are the most studied: ApaI, BsmI, FokI, TaqI, Cdx2. Many studies have shown an association between the polymorphism of this gene and various diseases. A large number of works demonstrated directly opposite results regarding different variants of the vitamin D gene polymorphism, and exactly the same conflicting results were obtained in studies on the relationship between the level of vitamin D and the frequency of nephrolithiasis.

Urat is a natural metabolite of purines. Its level is significantly higher than in most animals, due to the fact that in evolutionary development, humans and higher primates lost the hepatic enzyme uricase, which prolongs the metabolism of uric acid to allantoin. An increase in uric acid often accompanies people with obesity, impaired carbohydrate metabolism – insulin resistance, diabetes mellitus, dyslipidemia, arthropathy, and cardiovascular diseases.

15% of the stones in the general pool of kidney stone disease are based on uric acid and this is a very significant value. Moreover, if you know that hyperuricemia contributes to the formation of stones and another nature, then its contribution to the kidney stone disease becomes even more significant. Initially, GLUT-9 was only perceived as a transporter of glucose and fructose. A little later it was found out that he is a carrier of urate. 

GLUT-9 is expressed not only on the basolateral and apical membranes of the distal nephron, but also in hepatocytes. Its presence in both the basolateral and apical parts of the cells suggests that GLUT-9 can carry out both stages of transepithelial transport of uric acid. However, the development of idiopathic hypouremia was demonstrated during the formation (in experiments) or the presence of inactivating mutations in the genes of these vectors URAT1 and GLUT9a, confirming their purpose. URAT-1 is a carrier protein that returns up to 90% of urate entering the kidneys. And only about 10% of the total volume of uric acid is excreted from the body. Moreover, with hyperuremia, the reabsorption rate decreases, and the amount of uric acid excreted increases accordingly. Due to the fact that the angiotensin II receptor antagonist (potassium losartan) is able to reduce the activity of both GLUT-9 and URAT-1 proteins, it becomes possible to reduce the number of drugs prescribed for patients with hypertension and hyperuricemia.

Pavlova Z.Sh., Golodnikov I.I., Kamalov A.A., Manuylova Yu.A. The role of vitamin D3 and transport proteins URAT-1 and GLUT-9 in the development of nephrolithiasis (review). Technologies of living systems. 2020. V. 17. № 3. P. 24–33. DOI: 10.18127/j20700997-202003-03 (In Russian).

1. Geng Y., Mosyak L., Kurinov I., Zuo H., Sturchler E., Cheng T. C., Subramanyam P., Brown A.P., Brennan S.C., Mun H.C., Bush M., Chen Y., Nguyen T.X., Cao B., Chang D.D., Quick M., Conigrave A.D., Colecraft H.M., McDonald P., Fan Q.R. Structural mechanism of ligand activation in human calcium-sensing receptor. Elife. 2016. V. 5. P. e13662.
2. De S. K., Liu X., Monga M. Changing trends in the American diet and the rising prevalence of kidney stones. Urology. 2014. V. 84. № 5. P. 1030–3.
3. Turney B.W., Appleby P.N., Reynard J.M., Noble J.G., Key T.J., Allen N.E. Diet and risk of kidney stones in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). Eur. J. Epidemiol. 2014. V. 29. № 5. P. 363–9.
4. Mirnaya S., Pigarova E., Belyaeva A., Mokrysheva N., Tyul'pakov A. Rol' kal'cij-chuvstvitel'nogo receptora v podderzhanii sistemy kal'cievogo gomeostaza. Osteoporoz i osteopatii. 2010. T. 13. № 3. S. 32–36  (In Russian).
5. Ferraro P.M., Bonello M., Frigo A.C. D'Addessi A., Sturniolo A., Gambaro G. Cadmium exposure and kidney stone formation in the general population--an analysis of the National Health and Nutrition Examination Survey III data. J. Endourol. 2011. V. 25. № 5. P. 875–80.
6. Hirvonen T., Pietinen P., Virtanen M., Albanes D., Virtamo J. Nutrient intake and use of beverages and the risk of kidney stones among male smokers. Am J Epidemiol. 1999. V. 150. № 2. P. 187–94.
7. Tang J., McFann K., Chonchol M. Dietary zinc intake and kidney stone formation: evaluation of NHANES III. Am. J. Nephrol. 2012. V. 36. № 6. P. 549–53.
8. Holoch P.A., Tracy C.R. Antioxidants and self-reported history of kidney stones: the National Health and Nutrition Examination Survey. J. Endourol. 2011. V. 25. № 12. P. 1903–8.
9. Stamatelou K.K., Francis M.E., Jones C.A., Nyberg L.M., Curhan G.C. Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int. 2003. V. 63. № 5. P. 1817–23.
10. Curhan G.C., Willett W.C., Rimm E.B., Stampfer M.J. Family history and risk of kidney stones. J. Am. Soc. Nephrol. 1997. V. 8. № 10. P. 1568–73.
11. Kim W.T., Kim Y.J., Yun S.J., Shin K.S., Choi Y.D., Lee S.C., Kim W.J. Role of 1,25-dihydroxy vitamin D3 and parathyroid hormone in urinary calcium excretion in calcium stone formers. Yonsei Med. J. 2014. V. 55. № 5. P. 1326–32.
12. Hu H., Zhang J., Lu Y., Zhang Z., Qin B., Gao H., Wang Y., Zhu J., Wang Q., Zhu Y., Xun Y., Wang S. Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis. Nutrients. 2017. V. 9. № 3. P. 301.
13. Lin Y., Mao Q., Zheng X., Chen H., Yang K., Xie L. Vitamin D receptor genetic polymorphisms and the risk of urolithiasis: a meta-analysis. Urol. Int. 2011. V. 86. № 3. P. 249–55.
14. Cakir O.O., Yilmaz A., Demir E., Incekara K., Kose M.O., Ersoy N. Association of the BsmI, ApaI, TaqI, Tru9I and FokI Polymorphisms of the Vitamin D Receptor Gene with Nephrolithiasis in the Turkish Population. Urol. J. 2016. V. 13. № 1. P. 2509–18.
15. Bid H.K., Kumar A., Kapoor R., Mittal R.D. Association of vitamin D receptor-gene (FokI) polymorphism with calcium oxalate nephrolithiasis.  J. Endourol. 2005. V. 19. № 1. P. 111–5.
16. Liu C.C., Huang C.H., Wu W.J., Huang S.P., Chou Y.H., Li C.C., Chai C.Y., Wu M.T. Association of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int. 2007. V. 99. № 6. P. 1534–8.
17. Aykan S., Tuken M., Gunes S., Akin Y., Ozturk M., Seyhan S., Yuruk E., Temiz M.Z., Yilmaz A.F., Nguyen D.P. ApaL1 urokinase and Taq1 vitamin D receptor gene polymorphisms in first-stone formers, recurrent stone formers, and controls in a Caucasian population. Urolithiasis. 2016. V. 44. № 2. P. 109–15.
18. Abate N., Chandalia M., Cabo-Chan A.V., Jr., Moe O.W., Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004. V. 65. № 2. P. 386–92.
19. Atan L., Andreoni C., Ortiz V., Silva E. K., Pitta R., Atan F., Srougi M. High kidney stone risk in men working in steel industry at hot temperatures. Urology. 2005. V. 65. № 5. P. 858–61.
20. Borghi L., Meschi T., Amato F., Novarini A., Romanelli A., Cigala F. Hot occupation and nephrolithiasis. J. Urol. 1993. V. 150. № 6. P. 1757–60.
21. Kwan B., Champion B., Boyages S., Munns C. F., Clifton-Bligh R., Luxford C., Crawford B. A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1. Endocrinol Diabetes Metab Case Rep. 2018. V. 2018. P. 18–0107.
22. Pal'shina A.M., Pal'shina S.G., Safonova S.L., Pal'shin V.G. Na zametku klinicistu: sovremennyj vzglyad na metabolizm vitamina d i polimorfizm gena receptora vitamina D. Vestnik Severo-Vostochnogo federal'nogo universiteta imeni M.K. Ammosova. Ser. Medicinskie nauki. 2018. T. 3.  № 12. C. 34–42 (In Russian).
23. Volkov M.M., Kayukov I.G., Smirnov A.V. Fosforno-kal'cievyj obmen i ego regulyaciya. Nefrologiya. 2010. T. 14. № 1. S. 91–103 (In Russian).
24. Amar A., Afzal A., Hussain S.A., Hameed A., Khan A.R., Shakoor M., Abid A., Khaliq S. Association of vitamin D receptor gene polymorphisms and risk of urolithiasis: results of a genetic epidemiology study and comprehensive meta-analysis. Urolithiasis. ‒ 2019.10.1007/s00240-019-01157-7.
25. Chen W.C., Chen H.Y., Lu H.F., Hsu C.D., Tsai F.J. Association of the vitamin D receptor gene start codon Fok I polymorphism with calcium oxalate stone disease. BJU Int. 2001. V. 87. № 3. P. 168–71.
26. Dion M., Ankawi G., Chew B., Paterson R., Sultan N., Hoddinott P., Razvi H. CUA guideline on the evaluation and medical management of the kidney stone patient – 2016 update. Can Urol. Assoc. J. 2016. V. 10. № 11–12. P. E347–e358.
27. Eisner B.H., Thavaseelan S., Sheth S., Haleblian G., Pareek G. Relationship between serum vitamin D and 24-hour urine calcium in patients with nephrolithiasis. Urology. 2012. V. 80. № 5. P. 1007–10.
28. Gunes S., Bilen C.Y., Kara N., Asci R., Bagci H., Yilmaz A.F. Vitamin D receptor gene polymorphisms in patients with urolithiasis. Urol Res. 2006. V. 34. № 1. P. 47–52.
29. Malihi Z., Wu Z., Stewart A.W., Lawes C.M., Scragg R. Hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin D supplementation: a systematic review and meta-analysis. Am J. Clin. Nutr. 2016. V. 104. № 4. P. 1039–1051.
30. Mossetti G., Vuotto P., Rendina D., Numis F. G., Viceconti R., Giordano F., Cioffi M., Scopacasa F., Nunziata V. Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J. Intern. Med. 2003. V. 253. № 2. P. 194–200.
31. Seo I.Y., Kang I.H., Chae S. C., Park S. C., Lee Y.J., Yang Y.S., Ryu S.B., Rim J.S. Vitamin D receptor gene Alw I, Fok I, Apa I, and Taq I polymorphisms in patients with urinary stone. Urology. 2010. V. 75. № 4. P. 923–7.
32. Vitale C., Tricerri A., Bermond F., Fabbrini L., Guiotto C., Marangella M. [Metabolic effects of Cholecalciferol supplementation in kidney stone formers with vitamin D deficiency]. G. Ital. Nefrol. 2018. V. 35. № 5.
33. Zhou T.B., Jiang Z.P., Li A.H., Ju L. Association of vitamin D receptor BsmI (rs1544410), Fok1 (rs2228570), TaqI (rs731236) and ApaI (rs7975232) gene polymorphism with the nephrolithiasis susceptibility. J. Recept Signal Transduct Res. 2015. V. 35. № 2. P. 107–14.
34. Zhu C., Ye Z., Chen Z., Xia D., Hu J. Association between vitamin D receptor gene polymorphisms and idiopathic hypocitraturia in the Chinese population. Urol Int. 2010. V. 85. № 1. P. 100–5.
35. Apolihin O.I., Sivkov A.V., Konstantinova O.V., Slominskij P.A., Tupicina T.V., Kalinichenko D.N. Poisk polimorfnyh variantov kandidatnyh genov mochekamennoj bolezni v rossijskoj populyacii. Eksperimental'naya i klinicheskaya urologiya. 2013. № 3. S. 56–60 (In Russian).
36. Nizov A.N. Optimizaciya profilaktiki recidiva mochekamennoj bolezni u bol'nyh s recidiviruyushchim urolitiazom: Diss. … kand. med. nauk. M. 2018 (In Russian).
37. Li S., Sanna S., Maschio A., Busonero F., Usala G., Mulas A., Lai S., Dei M., Orru M., Albai G., Bandinelli S., Schlessinger D., Lakatta E., Scuteri A., Najjar S. S., Guralnik J., Naitza S., Crisponi L., Cao A., Abecasis G., Ferrucci L., Uda M., Chen W. M., Nagaraja R. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 2007. V. 3. № 11. P. e194.
38. Hayden M.R., Tyagi S.C. Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle. Nutr Metab (Lond). 2004. T. 1. № 1. P. 10.
39. Puig J.G., Ruilope L.M. Uric acid as a cardiovascular risk factor in arterial hypertension. J. Hypertens. 1999. V. 17. № 7. P. 869–72.
40. Cannon P.J., Stason W.B., Demartini F.E., Sommers S.C., Laragh J.H. Hyperuricemia in primary and renal hypertension. N. Engl. J. Med. 1966.  V. 275. № 9. P. 457–64.
41. Pavlova Z.S., Golodnikov II., Kamalov A.A., Nizov A.N. [A role of fructose in urinary stone formation]. Urologiia. 2019. № 1. P. 114–118.
42. Feig D.I., Soletsky B., Johnson R.J. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. Jama. 2008. V. 300. № 8. P. 924–32.
43. Diamond H.S., Paolino J.S. Evidence for a postsecretory reabsorptive site for uric acid in man. J. Clin. Invest. 1973. V. 52. № 6. P. 1491–9.
44. Gutman A.B., Yu T.F., Berger L. Tubular secretion of urate in man. J. Clin. Invest. 1959. V. 38. P. 1778–81.
45. Pineda C., Soto-Fajardo C., Mendoza J., Gutierrez J., Sandoval H. Hypouricemia: what the practicing rheumatologist should know about this condition. Clin Rheumatol. 2020. V. 39. № 1. P. 135–147.
46. Bobulescu I.A., Moe O.W. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012. V. 19. № 6. P. 358–71.
47. Sutton Burke E.M., Kelly T.C., Shoales L.A., Nagel A.K. Angiotensin Receptor Blockers Effect on Serum Uric Acid-A Class Effect?  J. Pharm. Pract. 2019. P. 897190019866315.
48. Milanesi S., Verzola D., Cappadona F., Bonino B., Murugavel A., Pontremoli R., Garibotto G., Viazzi F. Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4. J. Cell. Physiol. 2019. V. 234. № 7.  P. 10868–10876.
49. Katsiki N., Tsioufis K., Ural D., Volpe M. Fifteen years of LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)-Lessons learned for losartan: An “old dog playing good tricks”. J. Clin. Hypertens (Greenwich). 2018.10.1111/jch.13325.
50. Tan P.K., Farrar J.E., Gaucher E.A., Miner J.N. Coevolution of URAT1 and Uricase during Primate Evolution: Implications for Serum Urate Homeostasis and Gout. Mol. Biol. Evol. 2016. V. 33. № 9. P. 2193–200.
51. Enomoto A., Kimura H., Chairoungdua A., Shigeta Y., Jutabha P., Cha S.H., Hosoyamada M., Takeda M., Sekine T., Igarashi T., Matsuo H., Kikuchi Y., Oda T., Ichida K., Hosoya T., Shimokata K., Niwa T., Kanai Y., Endou H. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002. V. 417. № 6887. P. 447–52.
52. Flotynska J., Uruska A., Araszkiewicz A., Zozulinska-Ziolkiewicz D. Klotho protein function among patients with type 1 diabetes. Endokrynol. Pol. 2018. V. 69. № 6. P. 696–704.
53. Keenan R., Nowatzky J., Pillinger M. Kelley's Textbook of Rheumatology (Ninth Edition) / Eds.: W.B. Saunders. 2013. P. 1533–1553.e5.
54. Shikhman A.R., Brinson D.C., Valbracht J., Lotz M.K. Cytokine regulation of facilitated glucose transport in human articular chondrocytes. J. Immunol. 2001. V. 167. № 12. P. 7001–8.