UEDONO H, TSUDA A, ISHIMURA E, NAKATANI S, KURAJOH M, MORI K, UCHIDA J, EMOTO M, NAKATANI T, & INABA M. (2017). U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects. American Journal of Physiology. Renal Physiology. 312, F992-F997. U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects Hideki Uedono, Akihiro Tsuda, Eiji Ishimura, Shinya Nakatani, Masafumi Kurajoh, Katsuhito Mori, Junji Uchida, Masanori Emoto, Tatsuya Nakatani, Masaaki Inaba Citation American Journal of Physiology-Renal Physiology, 312(6); F992-F997 Issue Date 2017-06-01 Type Journal Article Textversion author Right The following article has been accepted by American Journal of Physiology-Renal Physiology. After it is published, it will be found at https://doi.org/10.1152/ajprenal.00645.2016 URI http://dlisv03.media.osaka-cu.ac.jp/il/meta_pub/G0000438repository_15221466-312- 6-F992 DOI 10.1152/ajprenal.00645.2016 SURE: Osaka City University Repository http://dlisv03.media.osaka-cu.ac.jp/il/meta_pub/G0000438repository
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UEDONO H, TSUDA A, ISHIMURA E, NAKATANI S, KURAJOH M, MORI K, UCHIDA J, EMOTO
M, NAKATANI T, & INABA M. (2017). U-shaped relationship between serum uric acid levels and
intrarenal hemodynamic parameters in healthy subjects. American Journal of Physiology. Renal Physiology. 312, F992-F997.
as an antioxidant in vascular endothelial cells (33) and hypouricemia is a risk factor for ALPE 249
induced by non-myoglobinuria. Ishikawa et al. reported exercise-induced acute renal failure 250
12
in three patients with renal hypouricemia (17). The cause of acute kidney injury in ALPE is 251
unclear, but several hypotheses have been proposed (15). A plausible explanation is that the 252
decreased antioxidant potential due to the reduced uric acid level leads to reduction of renal 253
plasma flow by increased ROS (1, 30). Patchy vasoconstriction of renal vessels may then 254
be induced by the oxidative imbalance in ALPE (14). 255
These reports suggest that reduction of renal blood flow is promoted by endothelial 256
dysfunction of the kidney in patients with hypouricemia. In this study, we showed that 257
mild hyper- and hypouricemia are both associated with decreased GFR and RPF and 258
increased Ra although weakly. The increase in Ra in subjects with mildly higher or lower uric 259
acid levels may lead to dysfunction of glomerular perfusion. To the best our knowledge, this 260
is the first description of the relationships between serum uric acid levels and intrarenal 261
hemodynamic parameters in healthy subjects. The mechanisms underlying our results may be 262
associated with vasoconstriction of afferent arterioles in both mild hyper- and hypouricemia. 263
There are some limitations in this study. First, the measurements were performed in a 264
relatively small number of Japanese subjects, and a large-scale study would be needed to 265
confirm whether hyper- or hypouricemia increases Ra. In particular, the generalizability of 266
the findings is not known as this was a study performed in a relatively small number of 267
Japanese adults, which may not be relevant to other ethnicities, who may exhibit different 268
frequencies for URAT1 mutations. Second, we did not measure renal hemodynamics directly, 269
since this is very difficult in humans. Instead, we used Gomez’s formulae to calculate renal 270
hemodynamics. These formulae are based on several assumptions, but many studies have 271
validated their clinical utility (26, 28, 31, 36). Third, there could be differences in renal 272
hemodynamics based on the mechanism underlying the low uric acid, such as diet (although, 273
during the course of admissions including the present study period, all participants took 274
hospital food, including salt 6 g/day and protein 60-70 g/day), or the genetic background on 275
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the fractional excretion of uric acid and endothelial function in response to lower serum uric 276
acid. Future studies will be needed to determine if the mechanism for low uric acid is related 277
to the hemodynamic findings. Fourth, since we did not measure nitric oxide levels, plasma 278
renin activity, angiotensin II levels or URAT1 gene expression/mutation, we could not 279
determine the mechanism underlying how and to what extent the lower and higher serum uric 280
acid levels affect renal hemodynamic abnormalities. Fifth, since, in the present study, as in 281
the previous studies by ourselves and others (11, 20, 34-37), the bladder was not confirmed as 282
being empty after the subjects had been instructed to completely void their bladder at the 283
specified times, it is possible that a very small amount of residual urine might have affected 284
the data of the clearance study. However, none of the previous studies by others or ourselves 285
utilized methods to confirm voiding of the bladder in human subjects, i.e., by indwelling 286
bladder catheter or ultrasonography. As such, we cannot confirm that the emptiness of the 287
bladder was thoroughly examined at the instructed times in the present study, or in the 288
previous studies (11, 20, 34-37). Sixth, we could not follow-up the data on the same subjects 289
at some interval to determine the predictive value of these measurements. It is a future study 290
needed to explore the significance of these parameters on renal dysfunction. Lastly, we did 291
not examine the mechanisms through which Ra is affected by mildly abnormal serum uric 292
acid levels. Approaches such as comparison of renal hemodynamics in the presence of 293
various vasoactive substances in urine and blood are needed to reveal these mechanisms. 294
In conclusion, the findings in this study show for the first time that mildly lower and 295
mildly higher serum uric acid levels in healthy subjects are both significantly associated with 296
decreased GFR and RPF, and with increased Ra. The increase in Ra in subjects with lower or 297
higher uric acid levels may be related to abnormalities in renal hemodynamics, and may lead 298
to dysfunction of glomerular perfusion. 299
300
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Declaration of interest 301
The authors declare that there is no conflict of interest that could be perceived as 302
prejudicing the impartiality of the reported research. This study was not funded by a grant 303
from a funding agency in the public, commercial or not-for-profit sector. 304
305
Author contributions 306
H.U., A.T. and E.I. generated and analyzed the data and wrote the manuscript. H. U., A.T., 307
E.I., S.U., S.N., J.U.,K.M., M.E., T.N., and M.I. contributed to the discussion and reviewed 308
the manuscript. H.U.., A.T. and E.I. had full access to all of the study data and take 309
responsibility for the integrity of the data and the accuracy of the data analysis. 310
311
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References 312
1. Ames BN, Cathcart R, Schwiers E, and Hochstein P. Uric acid provides an antioxidant defense in 313 humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proceedings of the National 314 Academy of Sciences of the United States of America 78: 6858-6862, 1981. 315 2. Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, and Timio M. Association of uric acid 316 with change in kidney function in healthy normotensive individuals. Am J Kidney Dis 56: 264-272, 2010. 317 3. Chonchol M, Shlipak MG, Katz R, Sarnak MJ, Newman AB, Siscovick DS, Kestenbaum B, 318 Carney JK, and Fried LF. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis 50: 319 239-247, 2007. 320 4. Fathallah-Shaykh SA and Cramer MT. Uric acid and the kidney. Pediatric nephrology 29: 321 999-1008, 2014. 322 5. Fliser D, Dikow R, Demukaj S, and Ritz E. Opposing effects of angiotensin II on muscle and renal 323 blood flow under euglycemic conditions. J Am Soc Nephrol 11: 2001-2006, 2000. 324 6. Fliser D, Zeier M, Nowack R, and Ritz E. Renal functional reserve in healthy elderly subjects. J Am 325 Soc Nephrol 3: 1371-1377, 1993. 326 7. Gomez DM. Evaluation of renal resistances, with special reference to changes in essential 327 hypertension. J Clin Invest 30: 1143-1155, 1951. 328 8. Guidi E, Cozzi MG, Minetti EE, Civati G, Busnach G, and Brando B. Effect of familial 329 hypertension on glomerular hemodynamics and tubulo-glomerular feedback after uninephrectomy. Am J 330 Hypertens 14: 121-128, 2001. 331 9. Hisatome I, Ogino K, Kotake H, Ishiko R, Saito M, Hasegawa J, Mashiba H, and Nakamoto S. 332 Cause of persistent hypouricemia in outpatients. Nephron 51: 13-16, 1989. 333 10. Hong Q, Qi K, Feng Z, Huang Z, Cui S, Wang L, Fu B, Ding R, Yang J, Chen X, and Wu D. 334 Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial 335 calcium overload. Cell calcium 51: 402-410, 2012. 336 11. Horio M, Imai E, Yasuda Y, Hishida A, and Matsuo S. Simple sampling strategy for measuring 337 inulin renal clearance. Clin Exp Nephrol 13: 50-54, 2009. 338 12. Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, and Takishita S. Significance of hyperuricemia as a 339 risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 44: 642-650, 2004. 340 13. Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, and Takishita S. Significance of hyperuricemia 341 on the early detection of renal failure in a cohort of screened subjects. Hypertens Res 24: 691-697, 2001. 342 14. Ishikawa I. Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic 343 exercise in patients with or without renal hypouricemia. Nephron 91: 559-570, 2002. 344 15. Ishikawa I. Comments on 'a young man with acute kidney injury after exercise'. Kidney Int 78: 345 1047-1048; author reply 1048, 2010. 346 16. Ishikawa I, Nakagawa M, Hayama S, Yoshida S, and Date T. Acute renal failure with severe loin 347 pain and patchy renal ischaemia after anaerobic exercise (ALPE) (exercise-induced acute renal failure) in a 348 father and child with URAT1 mutations beyond the W258X mutation. Nephrol Dial Transpl 20: 1015-1015, 349 2005. 350 17. Ishikawa I, Sakurai Y, Masuzaki S, Sugishita N, Shinoda A, and Shikura N. Exercise-induced 351 acute renal failure in 3 patients with renal hypouricemia. Nihon Jinzo Gakkai Shi 32: 923-928, 1990. 352 18. Isshiki T, Amodeo C, Messerli FH, Pegram BL, and Frohlich ED. Diltiazem maintains renal 353 vasodilation without hyperfiltration in hypertension: studies in essential hypertension man and the 354 spontaneously hypertensive rat. Cardiovasc Drugs Ther 1: 359-366, 1987. 355 19. Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, 356 Rodriguez-Iturbe B, Herrera-Acosta J, and Mazzali M. Is there a pathogenetic role for uric acid in 357 hypertension and cardiovascular and renal disease? Hypertension 41: 1183-1190, 2003. 358 20. Kakuta Y, Okumi M, Ichimaru N, Abe T, Nonomura N, Okuyama A, Kojima Y, Isaka Y, 359 Takahara S, Imai E, and Horio M. Utility of the Japanese GFR estimation equation for evaluating potential 360 donor kidney function. Clinical and experimental nephrology 14: 63-67, 2010. 361 21. Kanda E, Muneyuki T, Kanno Y, Suwa K, and Nakajima K. Uric acid level has a U-shaped 362 association with loss of kidney function in healthy people: a prospective cohort study. PloS one 10: e0118031, 363 2015. 364 22. Kaneko K, Taniguchi N, Tanabe Y, Nakano T, Hasui M, and Nozu K. Oxidative imbalance in 365 idiopathic renal hypouricemia. Pediatric nephrology 24: 869-871, 2009. 366 23. Kang DH and Chen W. Uric acid and chronic kidney disease: new understanding of an old problem. 367 Seminars in nephrology 31: 447-452, 2011. 368 24. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, 369 Prabhakar S, and Johnson RJ. Hyperuricemia induces endothelial dysfunction. Kidney Int 67: 1739-1742, 370
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2005. 371 25. Kimata S, Mizuguchi K, Hattori S, Teshima S, and Orita Y. Evaluation of a new automated, 372 enzymatic inulin assay using D-fructose dehydrogenase. Clin Exp Nephrol 13: 341-349, 2009. 373 26. Kimura G, London GM, Safar ME, Kuramochi M, and Omae T. Glomerular hypertension in 374 renovascular hypertensive patients. Kidney Int 39: 966-972, 1991. 375 27. Kohagura K, Kochi M, Miyagi T, Kinjyo T, Maehara Y, Nagahama K, Sakima A, Iseki K, and 376 Ohya Y. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a 377 biopsy-based study. Hypertension research : official journal of the Japanese Society of Hypertension 36: 43-49, 378 2013. 379 28. Kojima S, Fujii T, Ohe T, Yoshitomi Y, Kuramochi M, Shimomura K, and Omae T. Glomerular 380 hemodynamics during supraventricular tachycardia. Jpn Heart J 36: 429-437, 1995. 381 29. Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, Collins AJ, Levey AS, and 382 Menon V. Uric acid and long-term outcomes in CKD. Am J Kidney Dis 53: 796-803, 2009. 383 30. Murakami T, Kawakami H, Fukuda M, and Furukawa S. Patients with renal hypouricemia are 384 prone to develop acute renal failure--why? Clinical nephrology 43: 207-208, 1995. 385 31. Nagai T, Kimura G, Matsuoka H, Sanai T, Imanishi M, Kawano Y, Kojima S, Yoshida K, Abe H, 386 Ashida T, and et al. [Estimation of the intrarenal hemodynamics in patients with primary aldosteronism]. Nihon 387 Jinzo Gakkai Shi 31: 235-241, 1989. 388 32. Nashar K and Fried LF. Hyperuricemia and the progression of chronic kidney disease: is uric acid a 389 marker or an independent risk factor? Advances in chronic kidney disease 19: 386-391, 2012. 390 33. Sugihara S, Hisatome I, Kuwabara M, Niwa K, Maharani N, Kato M, Ogino K, Hamada T, 391 Ninomiya H, Higashi Y, Ichida K, and Yamamoto K. Depletion of Uric Acid Due to SLC22A12 (URAT1) 392 Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia. Circ J 79: 1125-1132, 2015. 393 34. Tsuda A, Inaba M, Ichii M, Ochi A, Ohno Y, Nakatani S, Yamada S, Mori K, Tahara H, and 394 Ishimura E. Relationship between serum TSH levels and intrarenal hemodynamic parameters in euthyroid 395 subjects. Eur J Endocrinol 169: 45-50, 2013. 396 35. Tsuda A, Ishimura E, Ohno Y, Ichii M, Nakatani S, Machida Y, Mori K, Uchida J, Fukumoto S, 397 Emoto M, Nakatani T, and Inaba M. Poor glycemic control is a major factor in the overestimation of 398 glomerular filtration rate in diabetic patients. Diabetes care 37: 596-603, 2014. 399 36. Tsuda A, Ishimura E, Ohno Y, Ichii M, Nakatani S, Mori K, Fukumoto S, Emoto M, and Inaba 400 M. Significant association of poor glycemic control with increased resistance in efferent arterioles--study of 401 inulin and para-aminohippuric acid clearance in humans. Diabetes Res Clin Pract 104: 234-240, 2014. 402 37. Uedono H, Tsuda A, Ishimura E, Yasumoto M, Ichii M, Ochi A, Ohno Y, Nakatani S, Mori K, 403 Uchida J, Nakatani T, and Inaba M. Relationship Between Serum Uric Acid Levels and Intrarenal 404 Hemodynamic Parameters. Kidney & blood pressure research 40: 315-322, 2015. 405 38. Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, and Brunetti P. Relation 406 between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. 407 Hypertension 36: 1072-1078, 2000. 408 39. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, and Levey AS. Uric acid and 409 incident kidney disease in the community. J Am Soc Nephrol 19: 1204-1211, 2008. 410 40. Zhou X, Matavelli L, and Frohlich ED. Uric acid: its relationship to renal hemodynamics and the 411 renal renin-angiotensin system. Current hypertension reports 8: 120-124, 2006. 412 413
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Figure Legends 414
Figure 1. Relationships of serum uric acid levels with glomerular filtration rate (GFR) 415
measured by inulin clearance, renal plasma flow (RPF) measured by para-aminohippurate 416
clearance, and filtration fraction (FF) in all subjects using quadratic regression analysis (n = 417
48). Serum uric acid had significant and inverse U-shaped relationships with GFR and RPF, 418
but not with FF. 419
420
Figure 2. Relationships of serum uric acid levels with resistance of the afferent (Ra) and 421
efferent (Re) arterioles and glomerular hydrostatic pressure (Pglo) in quadratic regression 422
analysis (n = 48). Serum uric acid had a significant and U-shaped relationship with Ra, no 423
significant relationship with Re, and an inverse U-shaped relationship with Pglo that had 424
borderline significance. 425
426
427
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Table 1. Clinical characteristics of the subjects 428