The relationship between Hyperuricemia and Contrast-induced acute kidney injury undergoing primary percutaneous coronary intervention: the protocol of secondary analysis for ATTEMPT RESCIND-1 study

The relationship between Hyperuricemia and Contrast-induced acute kidney injury undergoing primary percutaneous coronary intervention: the protocol of secondary analysis for ATTEMPT RESCIND-1 study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol The relationship between Hyperuricemia and Contrast-induced acute kidney injury undergoing primary percutaneous coronary intervention: the protocol of secondary analysis for ATTEMPT RESCIND-1 study Wei Guo, Feier Song, Shiqun Chen, Li Zhang, Guoli Sun, Jin Liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.9436/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jun, 2020 Read the published version in Trials → Version 2 posted 8 You are reading this latest preprint version Show more versions Abstract Background: Contrast-induced acute kidney injury (CI-AKI) contributes toward unfavorable clinical outcomes after primary percutaneous coronary intervention (pPCI). We assessed whether hyperuricemia is an independent predictor of CI-AKI and outcomes in patients undergoing pPCI. Methods/design: Our study was a secondary analysis for the database from ATTEMPT study, enrolling 560 ST-segment elevation myocardial infarction (STEMI) patients undergoing pPCI. Eligible patients received peri-procedural either via aggressive (left ventricular end-diastolic pressure guided) or routine (25% or 0.5 mg/dL increase in serum creatinine from baseline during the first 48-72 hours post-procedurally. Patients were divided into 2 groups according to the admission serum uric acid (SUA) level. Hyperuricemia was defined as a SUA level >7 mg/dL (417 mmol/L) in males and >6 mg/dL (357 mmol/L) in females. Multivariate analyses for CI-AKI and long-term mortality were performed using the logistic regression and Cox regression analyses, respectively. Discussion: This study will determine the predictive value of hyperuricemia for the development of CI-AKI and outcomes in patients with STEMI undergoing pPCI. We predict that hyperuricemia will be associated with a risk of CI-AKI in patients with pPCI. Furthermore, after adjusting for other variables, long-term mortality after pPCI was higher in those with hyperuricemia than in those with normouricemia. Results of this study may provide scientific evidence for the effect of hyperuricemia on CI-AKI and long-term outcomes, thereby offering the potential possibility of lowering SUA on the development of CI-AKI and outcomes. Interdisciplinary Medicine Hyperuricemia Contrast-induced acute kidney ST-segment elevation myocardial infarction Primary percutaneous coronary intervention Figures Figure 1 Background ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI) are commonly complicated by contrast-induced acute kidney injury (CI-AKI) [1]. CI-AKI is associated with higher hospitalization rates, long-term morbidity, and mortality [2]. Therefore, patients recognized with high-risk factors of CI-AKI should be carefully monitored and treated with appropriate prophylactic strategies. Based on previous study, chronic kidney disease, diabetes, hypotension, contrast volume, congestive heart failure, advanced age, and anemia have been identified as risk factors of CI-AKI [3]. Uric acid is the final product of purine metabolism, which is metabolized by xanthine oxidase [4]. In previous studies, we reported that hyperuricemia was an independent risk factor for CI-AKI after PCI [5, 6]. However, the conclusion remains controversial [7-14]. In addition, only a limited number of studies reported that hyperuricemia was an independent predictor of CI-AKI in STEMI patients undergoing pPCI. Moreover, it was uncertain about the role of uric acid in the long-term outcome [15-17]. We aimed to investigate the association of hyperuricemia with CI-AKI in patients with high-risk STEMI undergoing pPCI, and to determine the predicting role in prognosis. Methods/design Study design and population This is a secondary analysis of aggressive hydration in patients with STEMI undergoing pPCI to prevent contrast-induced nephropathy, the first study for reduction of contrast-induced nephropathy following cardiac catheterization (ATTEMPT RESCIND-1 study). 560 patients aged 18 years or older, treated with pPCI and provided written informed consent were included from 15 medical research centers in China. Inclusion and exclusion criteria were described elsewhere [18]. Study protocol Baseline Data includes demographics, diagnosis, medical history, laboratory parameters, medications, and physical examination. Hyperuricemia was defined as serum uric acid (SUA) level >7 mg/dL (417 mmol/L) in male and >6 mg/dL (357 mmol/L) in female. The comorbidities include hypertension, diabetes mellitus, hyperlipidemia, heart failure, chronic kidney disease, stroke, peripheral arterial disease, chronic obstructive pulmonary disease. The concomitant therapies were decided by the doctors and were relied on the routine standards of care recommended by the current guidelines. The primary outcome, CI-AKI, was defined as a 25% or 0.5 mg/dL increase in serum creatinine from baseline at 48-72 hours after pPCI [18]. The secondary endpoints were different definitions of CI-AKI, persistent renal impairment, major adverse clinical events during hospitalization, total hospitalization costs, and length of hospital stay [18]. Follow-up adverse events were recorded by trained investigators via office visits or telephone interviews at 3, 6, 12, 18, and 24 months after the pPCI. Long-term outcomes are major adverse cardiovascular events (MACEs), including mortality, stent restenosis, non-fatal myocardial infarction, and target vessel revascularization. All data are collected with standardized electronic case report forms. At the time of enrollment, the data management team of Guangdong Provincial People’s Hospital conducts consistency checks and issues data clarification forms to deal with discrepant data. All data were collected after the approval by the ethics committee of all participating centers. An independent data monitoring committee reviewed the ongoing safety events of every paticipant. Statistical Analysis Continuous variables were presented as the mean ± standard deviation if normally distributed and median plus interquartile ranges if nonnormally distributed. They were compared by t-test or Wilcoxon rank sum test according to distribution. The categorical data, expressed as a percentage were analyzed using the Pearson chi-square test or Fisher's exact test. The association between risk predictors and CI-AKI, as well as long-term mortality were performed using multivariate logistic regression and Cox regression analysis. Kaplan-Meier curve and Log-rank test were performed on the survival time of the hyperuricemia group and the normouricemia group. These data were analyzed on the basis of valid cases. A Two-tailed p -value <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 or later (SAS Institute, Cary, NC, USA) and R software (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria). Discussion CI-AKI is closely associated with prolonged hospital stay, long-term morbidity, and mortality in patient undergoing PCI. The incidence of CI-AKI is about 2% in the general population and over 50% in high-risk population [3]. Previous study supported the relationship between CI-AKI and higher incidence of adverse short- and long-term cardiovascular outcomes, including mortality [19]. Patients with STEMI are likely to present with hypotension, or even cardiogenic shock, higher volume of contrast media, and impossibility of renal prophylactic therapy, which are associated with an increased risk of CI-AKI [20]. Advanced age, diabetes, dehydration, hypotension, sepsis, cardiovascular disease, underlying acute kidney injury, chronic kidney disease, and concomitant use of nephrotoxic drugs were identified as well-known risk factors for CI-AKI [3, 21]. In previous studies [5, 6], we reported that hyperuricemia was an independent risk factor for CI-AKI in PCI patients, which was consistent with other studies [7-12]. However, other studies did not show the same conclusion [13, 14]. Several studies explored the effect of serum uric acid (SUA) on CI-AKI among high-risk patients such as STEMI undergoing primary PCI. Elbasan et al. showed that SUA was associated with CI-AKI in STEMI patients undergoing pPCI (mean SUA=6.2±0.9 mg/dL, 95% CI, 1.877- 3.236; p =0.002) [15]. In another study, Mendi MA et al. demonstrated that SUA ≥ 5.4 mg/dL was an independent risk factor for CI-AKI (OR 1.26, 95% CI, 1.10-1.42; p < 0.001) [16]. Saritemur M et al. showed that elevated uric acid was lined with CI-AKI in multivariate analysis after adjusting for potential confounding factors (OR 1.01, 95% CI, 1.00-1.01; p = 0.01) [17]. However, even though they reported that high SUA was an independent predictor of CI-AKI in STEMI patients, there was no uniform standard for the definition of hyperuricemia. In our study, we employed the definition consistent with our previous study. In addition, these studies did not compare the prognosis between CI-AKI group and non-CI-AKI group in STEMI patients undergoing PCI. Some observational studies proved the relationship between hyperuricemia and clinical outcomes in the presence of gout, but not for asymptomatic hyperuricemia [22, 23]. Nevertheless, a recent study by Pagidipati et al, including the PLATO and TRACER study population, demonstrated a significant association between uric acid (UA) and short-term adverse outcomes, independent of the presence of gout [24]. Regarding the relationship between UA and long-term prognosis, the data also supported the relationship between elevated UA and long-term prognosis in patient with acute coronary syndromes and treated with PCI [25]. Therefore, whether hyperuricemia is still a predictor of poor long-term prognosis after adjusting for CI-AKI should be studied in STEMI patients receiving pPCI. Although the pathophysiological mechanisms of adverse reactions to hyperuricemia has not been fully elucidated, it appears to be multifactorial. In experimental models, hyperuricemia was linked to a variety of proatherogenic processes, including increased oxidative stress [26], vascular smooth muscle cell proliferation [27], inflammation [28], and endothelial dysfunction [29]. Limitations Our current secondary analysis is subject to the following restrictions. First, its sensitivity was lower due to the definition of >0.5 mg/dL because it was less selective for patients with higher risk of mortality and morbidity. Second, a single baseline SUA measurements were used to predict CI-AKI and long-term mortality. However, a number of previous studies have used this method as well. Third, the measurement of serum creatinine (SCr) was standardized at 72 hours after pPCI rather than at random, which might lead to the ignorance at the increase in delayed SCr (>72 hours). Finally, it is a secondary analysis that is not capable of testify a causal relationship. In conclusion, our study will determine the association between hyperuricemia and contrast-induced acute kidney injury (CI-AKI) after primary percutaneous coronary intervention (pPCI), and will identify if Hyperuricemia is a risk factor for long-term death after adjusting for CI-AKI. Trial status The first patient was included in the RESCIND –1 ATTEMPT Trial (Protocol version 2.0, 11th June 2014) on 1st July 2014 and expected to complete recruitment in December 2018. As of October 24, 2018, recruitment is ongoing with 555 patients randomized at 15 centers in China. Abbreviations CI-AKI: Contrast-induced acute kidney injury; pPCI: primary percutaneous coronary intervention. STEMI: ST-segment elevation myocardial infarction; SUA: serum uric acid; SCr: serum creatinine. Declarations Acknowledgments The authors are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper and its final contents. Special thanks go to the project managers Mr. Yongquan Yang and Ms. Lingfen Chen for their considerable time and effort in the ATTEMPT study. Funding: Guangdong society of interventional cardiology (grant no. GSIC20140526); Science and Technology Planning Project of Guangdong Province (grant No.2014B070706010); The National Science Foundation for Young Scientist of China (grant no. 81500520). Authors’ contributions NT and YL are the principal investigator. WG, FES and SQC is the main coordinator of the project. GLS and JL participated in the development of the protocol. LZ and JYC provided the basic suggestions for the study. WG drafted the manuscript of the present paper. All the authors were involved in the manuscript’s revision and approved the final version. Ethics approval and consent to participate The study protocol has been approved by the Guangdong Provincial People’s Hospital Ethics Committee. All the participants will sign an informed consent form. Summary data will be used only for statistical analysis to ensure that personal information is not leaked. Consent for publication Not applicable. Availability of data and material Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Competing interests The authors declare that they have no competing interests. References Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-5. Goldberg A, Hammerman H, Petcherski S, et al. Inhospital and 1-year mortality of patients who develop worsening renal function following acute ST-elevation myocardial infarction. Am Heart J 2005;150:330-7. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-9. Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013;99:759-66. Guo W, Liu Y, Chen J-Y, et al. Hyperuricemia Is an Independent Predictor of Contrast-Induced Acute Kidney Injury and Mortality in Patients Undergoing Percutaneous Coronary Intervention. Angiology 2015;66:721-6. Liu Y, Tan N, Chen J, et al. The relationship between hyperuricemia and the risk of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with relatively normal serum creatinine. Clinics (Sao Paulo) 2013;68:19-25. Barbieri L, Verdoia M, Schaffer A, et al. Uric acid levels and the risk of Contrast Induced Nephropathy in patients undergoing coronary angiography or PCI. Nutr Metab Cardiovasc Dis 2015;25:181-6. Kanbay M, Solak Y, Afsar B, et al. Serum Uric Acid and Risk for Acute Kidney Injury Following Contrast. Angiology 2017;68:132-44. Park S-H, Shin W-Y, Lee E-Y, et al. The Impact of Hyperuricemia on In-Hospital Mortality and Incidence of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention. Circulation Journal 2011;75:692-7. Toprak O, Cirit M, Esi E, Postaci N, Yesil M, Bayata S. Hyperuricemia as a risk factor for contrast-induced nephropathy in patients with chronic kidney disease. Catheter Cardiovasc Interv 2006;67:227-35. Toprak O, Cirit M, Yesil M, et al. Impact of diabetic and pre-diabetic state on development of contrast-induced nephropathy in patients with chronic kidney disease. Nephrol Dial Transplant 2007;22:819-26. 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. Karabulut A, Sahin I, Ilker Avci I, et al. Impact of serum alkaline phosphatase level on the pathophysiologic mechanism of contrast-induced nephropathy. Kardiol Pol 2014;72:977-82. Kowalczyk J, Francuz P, Swoboda R, et al. Prognostic significance of hyperuricemia in patients with different types of renal dysfunction and acute myocardial infarction treated with percutaneous coronary intervention. Nephron Clin Pract 2010;116:c114-22. Elbasan Z, Sahin DY, Gur M, et al. Contrast-induced nephropathy in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Angiology 2014;65:37-42. Mendi MA, Afsar B, Oksuz F, et al. Uric Acid is a Useful Tool to Predict Contrast-Induced Nephropathy. Angiology 2016;68:627-32. Saritemur M, Turkeli M, Kalkan K, Tanboga IH, Aksakal E. Relation of uric acid and contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention in the ED. Am J Emerg Med 2014;32:119-23. Liu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1 (First study for REduction of contraSt-induCed nephropathy followINg carDiac catheterization) trial. Am Heart J 2016;172:88-95. Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy. Eur Heart J 2014;35:1533-40. Zoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med 2009;151:631-8. Bhatt H, Turkistani A, Sanghani D, Julliard K, Fernaine G. Do Cardiovascular Risk Factors and Coronary SYNTAX Score Predict Contrast Volume Use During Cardiac Catheterization? Angiology 2015;66:933-40. Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH, Group MR. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med 2008;168:1104-10. Kuo CF, See LC, Luo SF, et al. Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford) 2010;49:141-6. Pagidipati NJ, Hess CN, Clare RM, et al. An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome. Am Heart J 2017;187:53-61. Tscharre M, Herman R, Rohla M, et al. Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Atherosclerosis 2018;270:173-9. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584-96. Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269-75. Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005;16:3553-62. Kanbay M, Yilmaz MI, Sonmez A, et al. Serum uric acid level and endothelial dysfunction in patients with nondiabetic chronic kidney disease. Am J Nephrol 2011;33:298-304. 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study","fulltext":[{"header":"Background","content":"\u003cp\u003eST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI) are commonly complicated by contrast-induced acute kidney injury (CI-AKI) [1]. CI-AKI is associated with higher hospitalization rates, long-term morbidity, and mortality [2]. Therefore, patients recognized with high-risk factors of CI-AKI should be carefully monitored and treated with appropriate prophylactic strategies. Based on previous study, chronic kidney disease, diabetes, hypotension, contrast volume, congestive heart failure, advanced age, and anemia have been identified as risk factors of CI-AKI [3].\u003c/p\u003e\n\u003cp\u003eUric acid is the final product of purine metabolism, which is metabolized by xanthine oxidase [4]. In previous studies, we reported that hyperuricemia was an independent risk factor for CI-AKI after PCI [5, 6]. However, the conclusion remains controversial [7-14]. In addition, only a limited number of studies reported that hyperuricemia was an independent predictor of CI-AKI in STEMI patients undergoing pPCI. Moreover, it was uncertain about the role of uric acid in the long-term outcome [15-17].\u003c/p\u003e\n\u003cp\u003eWe aimed to investigate the association of hyperuricemia with CI-AKI in patients with high-risk STEMI undergoing pPCI, and to determine the predicting role in prognosis.\u003c/p\u003e"},{"header":"Methods/design","content":"\u003cp\u003e\u003cstrong\u003eStudy design and population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a secondary analysis of aggressive hydration in patients with STEMI undergoing pPCI to prevent contrast-induced nephropathy, the first study for reduction of contrast-induced nephropathy following cardiac catheterization (ATTEMPT RESCIND-1 study). 560 patients aged 18 years or older, treated with pPCI and provided written informed consent were included from 15 medical research centers in China. Inclusion and exclusion criteria were described elsewhere [18].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline Data includes demographics, diagnosis, medical history, laboratory parameters, medications, and physical examination. Hyperuricemia was defined as serum uric acid (SUA) level \u0026gt;7 mg/dL (417 mmol/L) in male and \u0026gt;6 mg/dL (357 mmol/L) in female. The comorbidities include hypertension, diabetes mellitus, hyperlipidemia, heart failure, chronic kidney disease, stroke, peripheral arterial disease, chronic obstructive pulmonary disease. The concomitant therapies were decided by the doctors and were relied on the routine standards of care recommended by the current guidelines. The primary outcome, CI-AKI, was defined as a 25% or 0.5 mg/dL increase in serum creatinine from baseline at 48-72 hours after pPCI [18]. The secondary endpoints were different definitions of CI-AKI, persistent renal impairment, major adverse clinical events during hospitalization, total hospitalization costs, and length of hospital stay [18].\u003c/p\u003e\n\u003cp\u003eFollow-up adverse events were recorded by trained investigators via office visits or telephone interviews at 3, 6, 12, 18, and 24 months after the pPCI. Long-term outcomes are major adverse cardiovascular events (MACEs), including mortality, stent restenosis, non-fatal myocardial infarction, and target vessel revascularization.\u003c/p\u003e\n\u003cp\u003eAll data are collected with standardized electronic case report forms. At the time of enrollment, the data management team of Guangdong Provincial People\u0026rsquo;s Hospital conducts consistency checks and issues data clarification forms to deal with discrepant data.\u003c/p\u003e\n\u003cp\u003eAll data were collected after the approval by the ethics committee of all participating centers. An independent data monitoring committee reviewed the ongoing safety events of every paticipant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were presented as the mean \u0026plusmn; standard deviation if normally distributed and median plus interquartile ranges if nonnormally distributed. They were compared by t-test or Wilcoxon rank sum test according to distribution. The categorical data, expressed as a percentage were analyzed using the Pearson chi-square test or Fisher's exact test. The association between risk predictors and CI-AKI, as well as long-term mortality were performed using multivariate logistic regression and Cox regression analysis. Kaplan-Meier curve and Log-rank test were performed on the survival time of the hyperuricemia group and the normouricemia group. These data were analyzed on the basis of valid cases. A Two-tailed \u003cem\u003ep\u003c/em\u003e-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using SAS version 9.4 or later (SAS Institute, Cary, NC, USA) and R software (version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCI-AKI is closely associated with prolonged hospital stay, long-term morbidity, and mortality in patient undergoing PCI. The incidence of CI-AKI is about 2% in the general population and over 50% in high-risk population [3]. Previous study supported the relationship between CI-AKI and higher incidence of adverse short- and long-term cardiovascular outcomes, including mortality [19]. Patients with STEMI are likely to present with hypotension, or even cardiogenic shock, higher volume of contrast media, and impossibility of renal prophylactic therapy, which are associated with an increased risk of CI-AKI [20].\u003c/p\u003e\n\u003cp\u003eAdvanced age, diabetes, dehydration, hypotension, sepsis, cardiovascular disease, underlying acute kidney injury, chronic kidney disease, and concomitant use of nephrotoxic drugs were identified as well-known risk factors for CI-AKI [3, 21]. In previous studies [5, 6], we reported that hyperuricemia was an independent risk factor for CI-AKI in PCI patients, which was consistent with other studies [7-12]. However, other studies did not show the same conclusion [13, 14]. Several studies explored the effect of serum uric acid (SUA) on CI-AKI among high-risk patients such as STEMI undergoing primary PCI. Elbasan et al. showed that SUA was associated with CI-AKI in STEMI patients undergoing pPCI (mean SUA=6.2\u0026plusmn;0.9 mg/dL, 95% CI, 1.877- 3.236; \u003cem\u003ep\u003c/em\u003e=0.002) [15]. In another study, Mendi MA et al. demonstrated that SUA \u0026ge; 5.4 mg/dL was an independent risk factor for CI-AKI (OR 1.26, 95% CI, 1.10-1.42; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) [16]. Saritemur M et al. showed that elevated uric acid was lined with CI-AKI in multivariate analysis after adjusting for potential confounding factors (OR 1.01, 95% CI, 1.00-1.01; \u003cem\u003ep\u003c/em\u003e = 0.01) [17]. However, even though they reported that high SUA was an independent predictor of CI-AKI in STEMI patients, there was no uniform standard for the definition of hyperuricemia. In our study, we employed the definition consistent with our previous study.\u003c/p\u003e\n\u003cp\u003eIn addition, these studies did not compare the prognosis between CI-AKI group and non-CI-AKI group in STEMI patients undergoing PCI. Some observational studies proved the relationship between hyperuricemia and clinical outcomes in the presence of gout, but not for asymptomatic hyperuricemia [22, 23]. Nevertheless, a recent study by Pagidipati et al, including the PLATO and TRACER study population, demonstrated a significant association between uric acid (UA) and short-term adverse outcomes, independent of the presence of gout [24]. Regarding the relationship between UA and long-term prognosis, the data also supported the relationship between elevated UA and long-term prognosis in patient with acute coronary syndromes and treated with PCI [25]. Therefore, whether hyperuricemia is still a predictor of poor long-term prognosis after adjusting for CI-AKI should be studied in STEMI patients receiving pPCI.\u003c/p\u003e\n\u003cp\u003eAlthough the pathophysiological mechanisms of adverse reactions to hyperuricemia has not been fully elucidated, it appears to be multifactorial. In experimental models, hyperuricemia was linked to a variety of proatherogenic processes, including increased oxidative stress [26], vascular smooth muscle cell proliferation [27], inflammation [28], and endothelial dysfunction [29].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur current secondary analysis is subject to the following restrictions. First, its sensitivity was lower due to the definition of \u0026gt;0.5 mg/dL because it was less selective for patients with higher risk of mortality and morbidity. Second, a single baseline SUA measurements were used to predict CI-AKI and long-term mortality. However, a number of previous studies have used this method as well. Third, the measurement of serum creatinine (SCr) was standardized at 72 hours after pPCI rather than at random, which might lead to the ignorance at the increase in delayed SCr (\u0026gt;72 hours). Finally, it is a secondary analysis that is not capable of testify a causal relationship.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study will determine the association between hyperuricemia and contrast-induced acute kidney injury (CI-AKI) after primary percutaneous coronary intervention (pPCI), and will identify if Hyperuricemia is a risk factor for long-term death after adjusting for CI-AKI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first patient was included in the RESCIND \u0026ndash;1 ATTEMPT Trial (Protocol version 2.0, 11th June 2014) on 1st July 2014 and expected to complete recruitment in December 2018. As of October 24, 2018, recruitment is ongoing with 555 patients randomized at 15 centers in China.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI-AKI: Contrast-induced acute kidney injury; pPCI: primary percutaneous coronary intervention. STEMI: ST-segment elevation myocardial infarction; SUA: serum uric acid; SCr: serum creatinine.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper and its final contents. Special thanks go to the project managers Mr. Yongquan Yang and Ms. Lingfen Chen for their considerable time and effort in the ATTEMPT study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGuangdong society of interventional cardiology (grant no. GSIC20140526); Science and Technology Planning Project of Guangdong Province (grant No.2014B070706010); The National Science Foundation for Young Scientist of China (grant no. 81500520).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNT and YL are the principal investigator. WG, FES and SQC is the main coordinator of the project. GLS and JL participated in the development of the protocol. LZ and JYC provided the basic suggestions for the study. WG drafted the manuscript of the present paper. All the authors were involved in the manuscript\u0026rsquo;s revision and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol has been approved by the Guangdong Provincial People\u0026rsquo;s Hospital Ethics Committee. All the participants will sign an informed consent form. Summary data will be used only for statistical analysis to ensure that personal information is not leaked.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-5.\u003c/li\u003e\n\u003cli\u003eGoldberg A, Hammerman H, Petcherski S, et al. Inhospital and 1-year mortality of patients who develop worsening renal function following acute ST-elevation myocardial infarction. Am Heart J 2005;150:330-7.\u003c/li\u003e\n\u003cli\u003eMehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-9.\u003c/li\u003e\n\u003cli\u003eKanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 2013;99:759-66.\u003c/li\u003e\n\u003cli\u003eGuo W, Liu Y, Chen J-Y, et al. Hyperuricemia Is an Independent Predictor of Contrast-Induced Acute Kidney Injury and Mortality in Patients Undergoing Percutaneous Coronary Intervention. Angiology 2015;66:721-6.\u003c/li\u003e\n\u003cli\u003eLiu Y, Tan N, Chen J, et al. The relationship between hyperuricemia and the risk of contrast-induced acute kidney injury after percutaneous coronary intervention in patients with relatively normal serum creatinine. Clinics (Sao Paulo) 2013;68:19-25.\u003c/li\u003e\n\u003cli\u003eBarbieri L, Verdoia M, Schaffer A, et al. Uric acid levels and the risk of Contrast Induced Nephropathy in patients undergoing coronary angiography or PCI. Nutr Metab Cardiovasc Dis 2015;25:181-6.\u003c/li\u003e\n\u003cli\u003eKanbay M, Solak Y, Afsar B, et al. Serum Uric Acid and Risk for Acute Kidney Injury Following Contrast. Angiology 2017;68:132-44.\u003c/li\u003e\n\u003cli\u003ePark S-H, Shin W-Y, Lee E-Y, et al. The Impact of Hyperuricemia on In-Hospital Mortality and Incidence of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention. Circulation Journal 2011;75:692-7.\u003c/li\u003e\n\u003cli\u003eToprak O, Cirit M, Esi E, Postaci N, Yesil M, Bayata S. Hyperuricemia as a risk factor for contrast-induced nephropathy in patients with chronic kidney disease. Catheter Cardiovasc Interv 2006;67:227-35.\u003c/li\u003e\n\u003cli\u003eToprak O, Cirit M, Yesil M, et al. Impact of diabetic and pre-diabetic state on development of contrast-induced nephropathy in patients with chronic kidney disease. Nephrol Dial Transplant 2007;22:819-26.\u003c/li\u003e\n\u003cli\u003eZuo 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.\u003c/li\u003e\n\u003cli\u003eKarabulut A, Sahin I, Ilker Avci I, et al. Impact of serum alkaline phosphatase level on the pathophysiologic mechanism of contrast-induced nephropathy. Kardiol Pol 2014;72:977-82.\u003c/li\u003e\n\u003cli\u003eKowalczyk J, Francuz P, Swoboda R, et al. Prognostic significance of hyperuricemia in patients with different types of renal dysfunction and acute myocardial infarction treated with percutaneous coronary intervention. Nephron Clin Pract 2010;116:c114-22.\u003c/li\u003e\n\u003cli\u003eElbasan Z, Sahin DY, Gur M, et al. Contrast-induced nephropathy in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Angiology 2014;65:37-42.\u003c/li\u003e\n\u003cli\u003eMendi MA, Afsar B, Oksuz F, et al. Uric Acid is a Useful Tool to Predict Contrast-Induced Nephropathy. Angiology 2016;68:627-32.\u003c/li\u003e\n\u003cli\u003eSaritemur M, Turkeli M, Kalkan K, Tanboga IH, Aksakal E. Relation of uric acid and contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention in the ED. Am J Emerg Med 2014;32:119-23.\u003c/li\u003e\n\u003cli\u003eLiu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1 (First study for REduction of contraSt-induCed nephropathy followINg carDiac catheterization) trial. Am Heart J 2016;172:88-95.\u003c/li\u003e\n\u003cli\u003eNarula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy. Eur Heart J 2014;35:1533-40.\u003c/li\u003e\n\u003cli\u003eZoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med 2009;151:631-8.\u003c/li\u003e\n\u003cli\u003eBhatt H, Turkistani A, Sanghani D, Julliard K, Fernaine G. Do Cardiovascular Risk Factors and Coronary SYNTAX Score Predict Contrast Volume Use During Cardiac Catheterization? Angiology 2015;66:933-40.\u003c/li\u003e\n\u003cli\u003eKrishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH, Group MR. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med 2008;168:1104-10.\u003c/li\u003e\n\u003cli\u003eKuo CF, See LC, Luo SF, et al. Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford) 2010;49:141-6.\u003c/li\u003e\n\u003cli\u003ePagidipati NJ, Hess CN, Clare RM, et al. An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome. Am Heart J 2017;187:53-61.\u003c/li\u003e\n\u003cli\u003eTscharre M, Herman R, Rohla M, et al. Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Atherosclerosis 2018;270:173-9.\u003c/li\u003e\n\u003cli\u003eSautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584-96.\u003c/li\u003e\n\u003cli\u003eCorry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269-75.\u003c/li\u003e\n\u003cli\u003eKang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 2005;16:3553-62.\u003c/li\u003e\n\u003cli\u003eKanbay M, Yilmaz MI, Sonmez A, et al. Serum uric acid level and endothelial dysfunction in patients with nondiabetic chronic kidney disease. Am J Nephrol 2011;33:298-304.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hyperuricemia, Contrast-induced acute kidney, ST-segment elevation myocardial infarction; Primary percutaneous coronary intervention","lastPublishedDoi":"10.21203/rs.2.9436/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.9436/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Contrast-induced acute kidney injury (CI-AKI) contributes toward unfavorable clinical outcomes after primary percutaneous coronary intervention (pPCI). We assessed whether hyperuricemia is an independent predictor of CI-AKI and outcomes in patients undergoing pPCI. Methods/design: Our study was a secondary analysis for the database from ATTEMPT study, enrolling 560 ST-segment elevation myocardial infarction (STEMI) patients undergoing pPCI. Eligible patients received peri-procedural either via aggressive (left ventricular end-diastolic pressure guided) or routine (\u003c=500ml) intravenous hydration with the isotonic solution (0.9% NaCl) with randomization. The primary endpoint was CI-AKI, defined as \u003e25% or 0.5 mg/dL increase in serum creatinine from baseline during the first 48-72 hours post-procedurally. Patients were divided into 2 groups according to the admission serum uric acid (SUA) level. Hyperuricemia was defined as a SUA level \u003e7 mg/dL (417 mmol/L) in males and \u003e6 mg/dL (357 mmol/L) in females. Multivariate analyses for CI-AKI and long-term mortality were performed using the logistic regression and Cox regression analyses, respectively. Discussion: This study will determine the predictive value of hyperuricemia for the development of CI-AKI and outcomes in patients with STEMI undergoing pPCI. We predict that hyperuricemia will be associated with a risk of CI-AKI in patients with pPCI. Furthermore, after adjusting for other variables, long-term mortality after pPCI was higher in those with hyperuricemia than in those with normouricemia. Results of this study may provide scientific evidence for the effect of hyperuricemia on CI-AKI and long-term outcomes, thereby offering the potential possibility of lowering SUA on the development of CI-AKI and outcomes.","manuscriptTitle":"The relationship between Hyperuricemia and Contrast-induced acute kidney injury undergoing primary percutaneous coronary intervention: the protocol of secondary analysis for ATTEMPT RESCIND-1 study","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-12-26 19:38:43","doi":"10.21203/rs.2.9436/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-03-21T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-03-20T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-03-20T12:00:00+00:00","index":1,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\n* This protocol describes a secondary analysis of a trial to elucidate the potential relationship between hyperuricemia and contrast-induced acute kidney injury. There are many points which I believe require clarification.\n* English language editing required.\n* Suggested title revision: \"… coronary intervention: secondary analysis protocol for the ATTEMPT RESCIND-1 study\"\n* Suggestion: the abstract focuses a lot on the design of the trial, which is never really addressed in the body of the protocol as the full trial methods are just cited as being found elsewhere. Consequently, the abstract could potentially be focused more on the methods which you used in your secondary analysis.\n* The tenses in the abstract change a lot from past tense (suggesting the analysis is complete), to future tense (which is what a protocol should be written in as a protocol indicates what is yet to be done). Examples: \"We assessed whether hyperuricemia is an independent predictor of CI-AKI and outcomes in patients undergoing pPCI.\" \"Our study was a secondary analysis for the database from ATTEMPT study\"; and \"This study will determine the predictive value of hyperuricemia for the development of CI-AKI and outcomes in patients with STEMI undergoing pPCI.\" Similarly, the discussion of the abstract appears to be a mix of expected and actual results (e.g., \"We predict that hyperuricemia will be associated with a risk of CI-AKI in patients with pPCI. Furthermore, after adjusting for other variables, long-term mortality after pPCI was higher in those with hyperuricemia than in those with normouricemia.\"). Please ensure that the correct tense is used throughout the abstract (and the rest of the protocol) and that if any analyses have already been completed these are clearly stated.\n* Needed in the background: Why is this trial chosen for this analysis? i.e., what is the rationale for conducting a secondary analysis of this specific trial and not a different trial?\n* What is meant by \"The secondary endpoints were different definitions of CI-AKI\"? If you are testing the effect of hyperuricemia on a range of potential definitions, please provide the rationale for this and also specify which ones are under consideration and how they will be presented.\n* You note how data are collected: how are data stored and managed/maintained? (e.g., where is data kept, how is data kept secure, who has access, how long will it kept, is it accessible to the public).\n* Please also include a description of the process by which you obtained access to the data from the trial.\n* It is noted that continuous variables \"…were compared by t-test or Wilcozon rank sum test…\". Please elaborate on what is meant by this. Is this that they were compared at baseline in the trial? Or that you performed a comparison of these characteristics between strata of some characteristic? Same issues for the next sentence with the statement about how categorical data were analyzed.\n* In the analysis you describe \"The association between risk predictors and CI-AKI…\" but you have not yet specified what risk predictors are besides the primary objective of hyperuricemia. Are these risk factors the baseline characteristics, the comorbidities, occurrence of other secondary endpoints, or some combination thereof? I see some risk factors are noted in the discussion: are these the same that you used or different? If they are the same then they should be clearly stated earlier, and if they are different it underscores the importance of specifying what you consider to be risk factors for your analysis.\n* What is your model for the logistic and the cox regression analysis (i.e., what covariates are you including in the model)?\n* \"Kaplan-Meier curve and Log-rank test were performed on the survival time of the hyperuricemia group and the normouricemia group.\" For what outcome? Time until CI-AKI?\n* In your testing a range of different definitions for CI-AKI, will you test definitions used by other studies to compare your results to what others have found with different thresholds?\n* How are you accounting for missing data in all of your analyses (i.e., what method are you using)?\n* What kind of power do you have for your analysis, given your available sample size and expected effect size?\n* What are the statistical populations that you are considering in these analysis (e.g., intention to treat analysis, per protocol, etc.) and how are they defined (i.e., who is counted in these populations)?\n* Are there any subgroup analyses that you will be doing for your estimate and might these be important to consider?* Level of interest: **An article of limited interest**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: ** I agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2020-03-13T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-02-01T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-01-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-25T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-24T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-05-02 15:21:17","doi":"10.21203/rs.2.9436/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2019-12-15T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-10-30T12:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **Yes, and I have assessed the statistics in my report**\n* Declaration of competing interests: **I declare I have no competing interest**\n\nComments to Author:\n---\nDear Authors,\n\nI have carefully read your manuscript and I think that it's a good report of Hyperuricemia related - CI - AKI. I think there are minor issues to be fixed:\n\n1) Which AKI criteria you have adopted (AKIN ? RIFLE ?): please, specify\n\n2) About patients' cohort with hyperuricemia: comorbidities ? concomitant therapies ?\n\n"},{"type":"reviewerAgreed","content":"","date":"2019-10-23T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-07-12T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-06-17T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-04-30T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-04-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5e9818bb-57a4-4b15-8d38-82de0e4955db","owner":[],"postedDate":"December 26th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":11852,"name":"Interdisciplinary Medicine"}],"tags":[],"updatedAt":"2020-06-28T15:01:29+00:00","versionOfRecord":{"articleIdentity":"rs-754","link":"https://doi.org/10.1186/s13063-020-04505-w","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2020-06-24 12:00:00","publishedOnDateReadable":"June 24th, 2020"},"versionCreatedAt":"2019-12-26 19:38:43","video":"","vorDoi":"10.1186/s13063-020-04505-w","vorDoiUrl":"https://doi.org/10.1186/s13063-020-04505-w","workflowStages":[]},"version":"v2","identity":"rs-754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-754","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}