Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studiesBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2376 (Published 07 June 2017) Cite this as: BMJ 2017;357:j2376
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Very recently Xi and co-workers published a huge review on any possible relationship between serum uric acid and several clinical conditions involving also the cardio-renal and metabolic systems. They conclude that an indisputable causative role for uric acid can be established only for gout while all the other evidence should be considered with caution. I basically agree with this conclusion since there is no doubt that hyper-uricemia and gout are strictly related, but I am not so convinced that the interpretation of the possible effects of uric acid beyond gout can be explained by using the plasma levels as discriminatory tool.
In particular the same serum level of uric acid can be found in patients bearing to a completely different pathophysiological pathway since serum uric acid is the final result of the balance between production and excretion.
Second, those who are affected by a condition of overproduction of uric acid usually have some functional over expression of xanthine-oxidase and associated oxidative strass that can selectively contribute to the cardio-renal and metabolic settings. The identification of these subjects will be a mandatory goal for the near future since they will probably be the target of cardiovascular prevention by xanthine-oxidase inhibitors.
Third, the studies of Mendelian randomisation included in the manuscript are focused exclusively on the importance of SNP involved in renal transport of uric acid, a mechanism that is significantly altered in patients with gout but is probably only minimally involved in cardiovascular, renal and metabolic diseases. The same procedure of spontaneous randomisation applied to genetic polymorphisms involving xanthine-oxidase have given completely different results leading to a possibility that serum uric levels per se are only partially representative of the negative effects of uric acid in some important populations of patients.
Fourth, the many adjustments that have been applied to the observational data should be re-considerd after the demonstration that elevated levels of uric acid can precede some of the adjusting factors (e.g hypertension) leading to an unfair conclusion in therms of causative role.
Finally, the threshold level for the different conditions related to uric acid seems to be largely different ranging from 4-5 mg/dl for cardio-metabolic diseases to 6-5 for gout. Most of the cross-sectional data have been analysed by considering as a threshold for elevated serum uric acid levels those qualifying for the diagnosis of gout (usually > 7 mg/dl) so attributing to the normal range a remarkable proportion of patients with an increased risk of cardio-metabolic disease with a consequent reduction in the discriminatory power of the analysis.
For all these reasons we do not believe the the puzzling interpretation of the role of serum uric acid beyond gout can be inspired by any huge analysis and review of all the available literature; more attention should be paid to the possibility of going beyond the plasma phenotype. Any comprehensive paper that does not consider the heterogeneity of the phenotype will have only the effect of increasing the uncertainty and reducing the probability to find a solution (if any) to a very interesting and unresolved problem.
Competing interests: No competing interests
We read with great interest the umbrella review by Li et al.1 As an anaesthetist with scientific interest for perioperative medicine and postoperative complications, I would like to discuss the association between preoperative high serum uric acid level and postoperative acute kidney injury. Perioperative high serum uric acid levels were frequently found in the surgical patients who develop acute kidney injury (AKI).2-6 There has been debate whether preoperative hyperuricemia is an independent risk factor or one of the causal factor of postoperative AKI. The renal elimination of serum uric acid means that serum uric acid level will increase as glomerular filtration rate (GFR) declines, with the possibility that increasing preoperative uric acid level may simply reflect decreased GFR, a well-established risk factor for AKI after cardiac surgery. Also, there is a gender-difference regarding the normal range of serum uric acid (7.0 mg/dL for male and 6.0 mg/dL for female). Despite this difference, many previous studies did not consider this difference in their data analysis. Most importantly of all, most of the previous studies were observational or retrospective study, which means the results could only show an association, not causation.
As we know, to prove a causal relationship between a potential predictor and an outcome variable, Hill’s criteria should be met such as strength, consistency, specificity, temporality, biological gradient (does-response relationship), biological plausibility, coherence, experiment, and analogy.7 8 As an effort to find a causal relationship between hyperuricemia and postoperative AKI, a previous small single-center randomized trial evaluated the effect of rasburicase, a uric acid lowering agent, on the incidence of AKI after cardiovascular surgery. However, there was no benefit on postoperative serum creatinine, although the authors found that a biomarker of AKI, NGAL, tended to be lower in rasburicase-treated subjects.9 Actually, there has been only limited success to date in the translation of the potentially modifiable risk factors into a reduced burden of cardiac surgery associated AKI, which was the same for hyperuricemia. However, to our knowledge, there are few randomized trials with sufficient power to demonstrate the effect of the uric-acid lowering agent on the incidence of postoperative AKI. Also, this seems to be similar for the association between hyperuricemia and contrast-induced AKI.10 Therefore, at least for the AKI after cardiac surgery or contrast-induced AKI, further research is required to determine whether uric acid lowering agent has beneficial effects for reducing AKI to conclude the association between serum uric acid levels and AKI after cardiac surgery.
Won Ho Kim M.D.,Ph.D.
Jae-Hyon Bahk, M.D.,Ph.D.
Department of Anesthesiology and Pain Medicine
Seoul National University Hospital, Seoul, Republic of Korea
1 Li X, Meng X, Timofeeva M, et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ 2017;357:j2376. doi:10.1136/bmj.j2376.
2 Ejaz AA, Kambhampati G, Ejaz NI, et al. Post-operative serum uric acid and acute kidney injury. J Nephrol 2012;25:497-505. doi:10.5301/jn.5000173.
3 Joung KW, Jo JY, Kim WJ, et al. Association of preoperative uric acid and acute kidney injury following cardiovascular surgery. J Cardiothorac Vasc Anesth 2014;28:1440-7. doi:10.1053/j.jvca.2014.04.020.
4 Lapsia V, Johnson RJ, Dass B, et al. Elevated uric acid increases the risk for acute kidney injury. Am J Med 2012;125:302 e9-17. doi:10.1016/j.amjmed.2011.06.021.
5 Ejaz AA, Beaver TM, Shimada M, et al. Uric acid: a novel risk factor for acute kidney injury in high-risk cardiac surgery patients? Am J Nephrol 2009;30:425-9. doi:10.1159/000238824.
6 Xu X, Hu J, Song N, Chen R, Zhang T, Ding X. Hyperuricemia increases the risk of acute kidney injury: a systematic review and meta-analysis. BMC Nephrol 2017;18:27. doi:10.1186/s12882-016-0433-1.
7 Hill AB. THE ENVIRONMENT AND DISEASE: ASSOCIATION OR CAUSATION? Proc R Soc Med 1965;58:295-300.
8 Karkouti K. Transfusion and risk of acute kidney injury in cardiac surgery. Br J Anaesth 2012;109 Suppl 1:i29-i38. doi:10.1093/bja/aes422.
9 Ejaz AA, Dass B, Lingegowda V, et al. Effect of uric acid lowering therapy on the prevention of acute kidney injury in cardiovascular surgery. Int Urol Nephrol 2013;45:449-58. doi:10.1007/s11255-012-0192-2.
10 Zuo T, Jiang L, Mao S, Liu X, Yin X, Guo L. Hyperuricemia and contrast-induced acute kidney injury: A systematic review and meta-analysis. Int J Cardiol 2016;224:286-94. doi:10.1016/j.ijcard.2016.09.033.
Competing interests: No competing interests