Metformin reduces urate nephropathy in experimental nephrolithiasis

Keywords: oral hypoglycemic agents, uric acid, urate deposits, free radical oxidation


The objective of the article is to evaluate the effectiveness of metformin in the prevention and treatment of experimental urate nephropathy. About 33% of the populations of developed countries suffers from metabolic syndrome. The relationship between metabolic syndrome, especially insulin resistance, with gout and urate nephrolithiasis, is now proven. The search for a common pathophysiological link in the development of these conditions allows us to identify insulin-dependent excessive urinary acidification due to impaired education and renal ammonium transport. We suggested the use of drugs that can increase the sensitivity of tissues to insulin, and induce a decrease in the manifestations of urate nephropathy. The study was performed on 30 male Wistar rats weighing 250–300 g. For the induction of urate nephropathy in rats, we used the classical model of inhibition of uricase by oxononium acid. Metformin was administered at a dose of 150 mg/kg in the treatment and prophylactic regimens. It was found that the use of metformin both in prophylactic and therapeutic regimen leads to a reliable decrease the level of uric acid in blood plasma and urine in rats with experimental urate nephrolithiasis. We found that the preventive use of metformin brought significant relief after experimental urate nephropathy, as evidenced by a shift in urine pH to the alkaline side, a decreased lactate dehydrogenase activity in urine, as well as a decrease in the processes of free radical oxidation in the blood and in the kidneys of the animals. 


Abate, N., Chandalia, M., Cabo-Chan, A. V., Moe, O. W., & Sakhaee, K. (2004). The metabolic syndrome and uric acid nephrolithiasis: Novel features of renal manifestation of insulin resistance. Kidney International, 65(2), 386–392.

Akman, T., Binbay, M., Erbin, A., Tepeler, A., Sari, E., Kucuktopcu, O., & Muslumanoglu, A. (2012). The impact of metabolic syndrome on long-term outcomes of percutaneous nephrolithotomy (PCNL). British Journal of Urology International, 110(11c).

Bobulescu, I. A., Maalouf, N. M., Capolongo, G., Adams-Huet, B., Rosenthal, T. R., Moe, O. W., & Sakhaee, K. (2013). Renal ammonium excretion after an acute acid load: Blunted response in uric acid stone formers but not in patients with type 2 diabetes. American Journal of Physiology-Renal Physiology, 305(10), F1498–F1503.

Burckhardt, G. (2012). Drug transport by organic anion transporters (OATs). Pharmacology and Therapeutics, 136(1), 106–130.

Cameron, M. A., Maalouf, N. M., Adams-Huet, B., Moe, O. W., & Sakhaee, K. (2006). Urine composition in type 2 diabetes: Predisposition to uric acid nephrolithiasis. Journal of the American Society of Nephrology, 17(5), 1422–1428.

Choo, J., Yoon, S. J., Ryu, H., Park, M. S., Lee, H. S., Park, Y. M., & Lim, D. S. (2016). The seoul metropolitan lifestyle intervention program and metabolic syndrome risk: A retrospective database study. International Journal of Environmental Research and Public Health, 13(7), 667.

Curthoys, N. P. (2013). Renal ammonium ion production and excretion. Seldin and Giebisch’s the kidney (Fifth edition).

Daskalopoulou, S. S., Mikhailidis, D. P., & Elisaf, M. (2004). Prevention and treatment of the metabolic syndrome. Angiology, 55(6), 589–612.

Davidson, M. B., Thakkar, S., Hix, J. K., Bhandarkar, N. D., Wong, A., & Schreiber, M. J. (2004). Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. The American Journal of Medicine, 116(8), 546–554.

Glantzounis, G. K., Tsimoyiannis, E. C., Kappas, A. M., & Galaris, D. A. (2005). Uric acid and oxidative stress. Current Pharmaceutical Design, 11(32), 4145–4151.

Kim, Y. J., Kim, C. H., Sung, E. J., Kim, S. R., Shin, H. C., & Jung, W. J. (2013). Association of nephrolithiasis with metabolic syndrome and its components. Metabolism, 62(6), 808–813.

Kramer, H. J., Choi, H. K., Atkinson, K., Stampfer, M., & Curhan, G. C. (2003). The association between gout and nephrolithiasis in men: The health professionals’ follow-up study. Kidney International, 64(3), 1022–1026.

Liebman, S. E., Taylor, J. G., & Bushinsky, D. A. (2007). Uric acid nephrolithiasis. Current Rheumatology Reports, 9(3), 251–257.

Liu, N., Xu, L., Shi, Y., Fang, L., Gu, H., Wang, H., & Zhuang, S. (2017). Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats. Oncotarget, 8(20), 33807–33826.

Mah, E., Sapper, T. N., Chitchumroonchokchai, C., Failla, M. L., Schill, K. E., Clinton, S. K., & Bruno, R. S. (2015). α-Tocopherol bioavailability is lower in adults with metabolic syndrome regardless of dairy fat co-ingestion: A randomized, double-blind, crossover trial. The American Journal of Clinical Nutrition, 102(5), 1070–1080.

Najeed, S. A., Khan, I. A., Molnar, J., & Somberg, J. C. (2002). Differential effect of glyburide (glibenclamide) and metformin on QT dispersion: A potential adenosine triphosphate sensitive K+ channel effect. The American Journal of Cardiology, 90(10), 1103–1106.

Nissim, I., States, B., Nissim, I., Lin, Z. P., & Yudkoff, M. (1995). Hormonal regulation of glutamine metabolism by OK cells. Kidney International, 47(1), 96–105.

Perfil’ev, V. Y., Zverev, Y. F., Zharikov, A. Y., & Bryukhanov, V. M. (2017). The role of free radical oxidation in the development of experimental urate nephropathy. Bulletin of Experimental Biology and Medicine, 163(1), 28–30.

Rena, G., Pearson, E. R., & Sakamoto, K. (2013). Molecular mechanism of action of metformin: Old or new insights? Diabetologia, 56(9), 1898–1906.

Roberts, C. K., Hevener, A. L., & Barnard, R. J. (2013). Metabolic syndrome and insulin resistance: Underlying causes and modification by exercise training. Comprehensive Physiology, 3(1), 1–58.

Robertson, W. G. (2003). Renal stones in the tropics. Seminars in Nephrology, 23(1), 77–87.

Sakhaee, K., & Maalouf, N. M. (2008). Metabolic syndrome and uric acid nephrolithiasis. Seminars in Nephrology, 28(2), 174–180.

So, A., & Thorens, B. (2010). Uric acid transport and disease. The Journal of Clinical Investigation, 120(6), 1791–1799.

Srikanthan, K., Feyh, A., Visweshwar, H., Shapiro, J. I., & Sodhi, K. (2016). Systematic review of metabolic syndrome biomarkers: A panel for early detection, management, and risk stratification in the West Virginian population. International Journal of Medical Sciences, 13(1), 25–38.

Stavric, B., Johnson, W. J., & Grice, H. C. (1969). Uric acid nephropathy: An experimental model. Proceedings of the Society for Experimental Biology and Medicine, 130(2), 512–516.

Talente, G. M., Coleman, R. A., Alter, C., Baker, L., Brown, B. I., Cannon, R. A., & Herman, G. E. (1994). Glycogen storage disease in adults. Annals of Internal Medicine, 120(3), 218–226.

Won, J. C., Hong, J. W., Noh, J. H., & Kim, D. J. (2016). Association between estimated 24-h urinary sodium excretion and metabolic syndrome in Korean adults: The 2009 to 2011 Korea National Health and Nutrition Examination Survey. Medicine, 95(15), 1–8.

Yarovoi, S. K., Golovanov, S. A., Khaziakhmetova, M. R., & Dzhalilov, O. V. (2017). Nephrolithiasis coexisting with type 2 diabetes: Current concept of the features of stone formation and the effects of hypoglycemic therapy on lithogenesis. Urologiia, 3, 92–97.

Yu, T. F., & Gutman, A. B. (1967). Uric acid nephrolithiasis in gout: Predisposing factors. Annals of Internal Medicine, 67(6), 1133–1148.

How to Cite
Perfil’ev, V. Y., Zverev, Y. F., Perfil’eva, D. Y., Lysenko, I. V., & Miroshnichenko, A. G. (2017). Metformin reduces urate nephropathy in experimental nephrolithiasis. Regulatory Mechanisms in Biosystems, 8(4), 644–648.