Meta-analysis of the impact of hyperuricemia on contrast agent-related acute kidney injury after percutaneous coronary intervention

YAO Zhi, SHI Yue-xin, SUN Lu-ying

Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing 100700, China

Keywords:

ABSTRACT Objective: To evaluate the impact of hyperuricemia on the occurrence of contrast agentrelated acute kidney injury after percutaneous coronary intervention.Methods: Retrieve PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases,and publish articles on the correlation between hyperuricemia and contrast agent-related acute kidney damage after percutaneous coronary intervention from the establishment of the database to August 16 2023.Two researchers independently conducted literature screening and data extraction to evaluate the bias risk of inclusion in the study, and conducted metaanalysis using Review Manager 5.4 software.Results: A total of 12 articles were included,including 11 676 patients.The meta-analysis results showed that compared with patients without hyperuricemia, patients with hyperuricemia had a higher risk of developing PC-AKI,with an incidence rate of 22.3%.Hyperuricemia was a risk factor for the occurrence of PCAKI (OR=2.03, 95%CI: 1.58-2.61); Patients with hyperuricemia have a higher risk of death after PC-AKI, with a mortality rate of 7.5%.Hyperuricemia is a risk factor for early death in PC-AKI patients (OR=2.33, 95%CI: 1.81-3.00); The probability of CRRT treatment after PCAKI in patients with hyperuricemia is higher, at 3.14%.Hyperuricemia is an influencing factor for CRRT treatment in PC-AKI patients (OR=7, 95%CI: 2.83-17.30).Conclusion: Existing research evidence suggests that the presence of hyperuricemia is an independent risk factor for the occurrence of PC-AKI, and it significantly increases the hospital mortality rate and the risk of renal replacement therapy in PC-AKI patients.

1.Introduction

Contrast agent induced acute kidney injury (PC-AKI) is one of the common complications of percutaneous coronary intervention(PCI)/coronary angiography (CAG).The latest definition of PCAKI by the Contrast Agent Safety Committee of the European Society of Urology and Reproductive Radiology is that within 48-72 h of exposure to contrast agents, serum creatinine increases by 0.3 mg/dL (26.5 μ Mol/L, or 1.5 times the basal serum creatinine value [2].PC-AKI is the third leading cause of hospital acquired AKI, accounting for 12% of all cases.In the general population receiving PCI/CAG, the incidence of PC-AKI is less than 3%, but in the high-risk population, the incidence is as high as 40%[4].The mortality rate of PC-AKI patients during hospitalization is 7.1%,and the mortality rate of PC-AKI patients who require hemodialysis is as high as 35.7%, with a mortality rate of 81.2% within 2 years[5].The incidence rate and mortality of chronic kidney diseases caused by PC-AKI are increasing year by year.

PC-AKI is an important adverse reaction that occurs after various radiological surgeries, and its pathogenesis is not fully understood.The epidemiological status, diagnosis, and treatment are not yet unified.The occurrence of PC-AKI may be significantly related to some known risk factors, such as age, basic renal insufficiency,diabetes and unreasonable use of contrast media[7].Although prevention is the key to PC-AKI treatment, accurate early predictive indicators cannot be found at present, and timely risk assessment can only be relied on to strengthen the prevention of PC-AKI.

In recent years, the relationship between hyperuricemia and PCAKI has attracted the attention of scholars.Multiple studies have shown a correlation between hyperuricemia and PC-AKI, and serum uric acid levels may be a new independent predictor of PC-AKI[8].The relationship between preoperative hyperuricemia and the prognosis of PC-AKI in patients is currently unclear.Therefore, our aim is to conduct a meta-analysis to demonstrate the correlation and prognosis between serum uric acid levels and PC-AKI, and further compare the impact of serum uric acid levels on postoperative AKI in patients with different baseline serum creatinine levels, and provide scientific basis for clinical prevention of PC-AKI in PCI/CAG.

2.Materials and Methods

2.1 Literature retrieval strategy

This study strictly referred to the systematic review and metaanalysis entries in the PRISMA statement[9].Retrieve China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP Database, PubMed, Embase, Cochrane Library, and Web of Science databases.The search method adopts a combination of subject words and free words.Chinese search terms include:serum uric acid, hyperuricemia, uric acid, percutaneous coronary intervention, PCI, coronary intervention, coronary stent placement,coronary angiography, coronary angiography, contrast agent nephropathy, contrast agent nephropathy, acute kidney injury, acute renal failure, acute renal insufficiency, and acute renal dysfunction.The English search terms include: Serum uric acid, hyperuricemia,uric acid, chronic coronary intervention, PCI, coronary intervention,coronary stent placement, coronary angiography, coronary angiography, contrast-enhanced neuropathy, contrast-enhanced neuropathy, acute renal injury, acute renal failure, acute renal insufficiency, and acute renal dysfunction The search deadline is from the establishment of each database until August 16 2023.

2.2 Criteria for inclusion and exclusion of literature

Inclusion criteria: (1) Study design type: cohort study or casecontrol study; (2) Chinese and English literature that has been publicly published both domestically and internationally and can be accessed in databases; (3) Research subjects: Adult patients with PC-AKI who meet the 2012 KDIGO diagnostic criteria for AKI[10];(4) Research content: Clinical research on the relationship between preoperative high uric acid levels and PC-AKI can be obtained; (5)Require complete information, comparable data, and clear outcome indicators.

Exclusion criteria: (1) Relevant literature on serum uric acid level as a continuous variable for research; (2) Repeated indexed literature(including 1 identical literature); (3) Literature with missing data or inability to obtain full text; (4) Literature with a score of＜6 on the Newcastle Ottawa Scale (NOS); (5) Review, conference abstract,systematic review, animal experiments, and other non clinical studies.

2.3 Literature screening and data extraction

Two reviewers independently screen literature and examine data.Differences will be resolved through discussion or consultation with a third party.Extract raw data from relevant studies, including information from researchers, basic clinical characteristics of the study population, NOS scores, diagnostic criteria for hyperuricemia and AKI.Learn and master the Newcastle Ottawa Scale (NOS),which includes three dimensions: sample selection, comparability,and reliability of results, with a total of 8 items and a maximum score of 9.Two researchers independently evaluated the quality of the selected study, and the higher the score, the better the quality of the study.Exclude articles with scores below 6.

2.4 Statistical processing

Perform meta-analysis on the included literature using Review Manager 5.4 software.Using software default Q-test method(α= 0.05), calculate the I2 statistic and test to determine if there is heterogeneity between the studies.When I2＜50% and P 0.1,it indicates that the statistical heterogeneity between the studies is small, and a fixed effects model is chosen; WhenI250% andP＜0.1, it indicates significant statistical heterogeneity between studies.After verifying the input data, subgroup analysis is used to analyze the sources of heterogeneity.When merging the data, a random effects model is used; If P＜0.1 and the source of heterogeneity cannot be determined, descriptive analysis will be used.Draw a funnel plot to test publication bias.The difference is statistically significant withP＜0.05.

3.Results

3.1 Literature search results

After searching the literature database, 322 studies were obtained,and 241 studies were included after deleting 81 duplicate articles.After reading the literature titles and abstracts 194 studies were excluded.After reading the full text of the remaining 47 studies, 35 studies were again excluded.Among them, 15 studies were unable to obtain data, 10 were unrelated to this study, and 10 were low-quality literature.12 studies were ultimately included in the meta-analysis(Figure 1).

3.2 Basic characteristics of included literature

A total of 12 articles were included, including 3 Chinese articles [19 20,22] and 9 English articles[11-18,21], with a total of 11676 research subjects.The basic characteristics of the included research and the results of literature quality evaluation are shown in Table 1.

3.3 Meta analysis results

3.3.1 The incidence of PC-AKI in patients with hyperuricemia

Twelve studies[11-22] reported the occurrence of PC-AKI in patients with hyperuricemia.Due to high heterogeneity between studies(I2=74%,P＜0.01), a random effects model was used.The results showed that compared with patients without hyperuricemia, patients with hyperuricemia had a higher risk of developing PC-AKI, with an incidence rate of 22.3%.Hyperuricemia is a risk factor for the occurrence of PC-AKI (OR=2.03, 95%CI: 1.58-2.61), as shown in Figure 2.

3.3.2 Risk of death in patients with hyperuricemia after PCAKI

Fig 2 Forest map of the impact of hyperuricemia on the incidence of PC-AKI

Seven studies[12,16-18 20-22] investigated the impact of hyperuricemia on early mortality in PC-AKI patients.Due to low heterogeneity between studies (I2=0%, P＜0.01), a fixed effects model was used.The results showed that compared with patients without hyperuricemia, patients with hyperuricemia had a higher risk of death after PC-AKI, with a mortality rate of 7.5%.Hyperuricemia is a risk factor for early mortality in PC-AKI patients (OR=2.33,95%CI: 1.81-3.00), as shown in Figure 3.

3.3.3 Impact of hyperuricemia on CRRT treatment in PCAKI patients

There are 5 studies[12,16,18,19,22] exploring the impact of hyperuricemia on CRRT treatment in PC-AKI patients.Due to low heterogeneity between studies (I2=0%, P＜0.01), a fixed effects model was used.The results showed that compared with patients without hyperuricemia, patients with hyperuricemia had a higher probability of undergoing CRRT treatment after PC-AKI, at 3.14%.Hyperuricemia is an influencing factor for CRRT treatment in PCAKI patients (OR=7, 95% CI: 2.83-17.30), as shown in Figure 4.

Fig 4 Forest map of the impact of hyperuricemia on CRRT treatment in PC-AKI patients

3.3.4 Subgroup analysis of the incidence of PC-AKI in patients with hyperuricemia

The meta-analysis of the effect of hyperuricemia on the incidence of PC-AKI showed high heterogeneity among the 12 studies included.In order to identify the sources of heterogeneity, a sensitivity analysis was performed by deleting each study once.The results showed that there was no significant change in the combined statistics after excluding each study, indicating that the research results were robust and reliable.Based on the inclusion of similar characteristics in the study, we conducted subgroup analysis and found that the relationship between elevated uric acid levels and the occurrence of PC-AKI was not influenced by the study design and experimental population (see Figures 5 and 7).According to the grouping results based on basic renal function, the incidence rates of PC-AKI in patients with hyperuricemia in the normal renal function group, basic renal insufficiency group, and mixed group were 20.1%,28%, and 6.4%, respectively, with statistical significance (P＜0.05).Patients with basic renal insufficiency who have hyperuricemia have a higher risk after PC-AKI (see Figure 6).According to the study area and racial grouping, the incidence of PC-AKI in patients with hyperuricemia in the European and Asian groups was 31.2% and 15.5%, respectively.The meta-analysis results showed a statistically significant difference (P＜0.05).

3.3.5 Publication bias analysis

Fig 5 Subgroup analysis of the impact of hyperuricemia on the incidence of PC-AKI by study design type

Fig 6 Subgroup analysis of the incidence of PC-AKI in hyperuricemia by basic renal function level

This study used the OR value as the x-axis and the logarithmic standard error SE (log OR) of the OR value as the y-axis to detect publication bias using a funnel plot.We conducted a bias analysis on the incidence and risk of death of PC-AKI in patients with hyperuricemia, and the funnel plots showed relatively symmetrical trends (see Figures 8 and 10).We used Begg rank correlation tests(Figures 9A and 11A), and the results showed P＞0.05.The Egger linear regression method (Figures 9B and 11B) obtainedP＞0.05,and both qualitative and quantitative tests indicated that there was no significant publication bias in this study.

Fig 7 Subgroup analysis of the impact of hyperuricemia on the incidence of PC-AKI by population ethnicity

Fig 8 Publication bias funnel plot of the incidence of PC-AKI in patients with hyperuricemia

Fig 9 Publication bias funnel plot of PC-AKI mortality risk in patients with hyperuricemia

Fig 9 Evaluation of publication bias in the incidence of PC-AKI in patients with hyperuricemia

4.Discussion

A meta-analysis of 12 related studies involving 11676 participants currently indicates that hyperuricemia is a risk factor for the occurrence of PC-AKI (OR=2.03, 95%CI: 1.58-2.61).Compared with patients without hyperuricemia, patients with hyperuricemia have a higher risk of developing PC-AKI, with an incidence rate of 22.3%, which is consistent with most previously reported results[22-24].In addition, our study also suggests that patients with hyperuricemia have a higher hospitalization mortality rate and risk of receiving renal replacement therapy after PC-AKI.Compared with the traditional grouping method based on the occurrence of PCAKI events (PC-AKI group and non PC-AKI group), the studies included in this meta-analysis are grouped according to the serum uric acid level (non hyperuricemic group and hyperuricemic group).This grouping method can better reflect the independent correlation between the serum uric acid level and the incidence rate of PCAKI.So far, few studies focus on the relationship between serum uric acid level and PC-AKI incidence rate based on this grouping method.This is the first meta-analysis that fully considers the impact of basic renal function when exploring the relationship between hyperuricemia and PC-AKI incidence rate.

In subgroup analysis, it was found that the relationship between hyperuricemia and the occurrence of PC-AKI was not influenced by study design and racial population, but rather by basal renal function.The incidence of PC-AKI in patients with basic renal insufficiency accompanied by hyperuricemia is 28%, which is much higher than that in the population with normal basic renal function.Research has shown that CKD plays a central role in the pathophysiology of PC-AKI[25].As serum creatinine levels increased from 1.5 mg/dL to 6.8 mg/dL, the incidence of PC-AKI increased from 8% to 92% [26].The root cause analysis is as follows: Firstly, 70% of the uric acid in the body is excreted through the kidneys, and about 90% to 95% of the uric acid filtered by the glomeruli is absorbed,mainly by the proximal tubules.The uric acid secreted by the renal tubules themselves is very low[27].Therefore, uric acid concentration depends on glomerular filtration and subsequent tubular reabsorption function[28].Serum uric acid is a clear biomarker of chronic kidney disease and an independent risk factor for the development of chronic kidney disease[29].Preexisting chronic kidney disease increases the risk of AKI.Ishani et al.[30] reported that the AKI incidence rate of patients with chronic kidney disease was 8.8%,while the incidence rate of patients with non chronic kidney disease was 2.3%.Pannu N et al.[31] found that patients with eGFR less than 30 mL/min/1.73 m2had an 18 times higher risk of developing AKI compared to patients with eGFR greater than 60 mL/min/1.75 m2.Therefore, patients with hyperuricemia who already have subclinical chronic renal dysfunction are at an increased risk of developing AKI.Many studies support that hyperuricemia is an independent risk factor for cardiovascular disease, and the incidence rate of cardiovascular disease in hyperuricemia patients is higher than that in normal people[32].PC-AKI is a complex multifactorial disease, which is related to CKD, diabetes, old age, congestive heart failure, anemia and high-dose contrast media[33].Although the risk factors of PC-AKI are known, its clear mechanism is still not fully understood.The general mechanism of PC-AKI occurrence may include two aspects: the cytotoxic effect of contrast agents on renal tissue and changes in renal hemodynamics[34].Some studies suggest that inflammation, oxidative stress, cell apoptosis, and endothelial dysfunction may also have some impact on the development process of PC-AKI[35].Serum uric acid is a degradation product of human purine metabolism, and its potential pathogenic role in renal dysfunction may help understand the relationship between hyperuricemia and the development of PC-AKI.Firstly, contrast agents can increase the excretion of serum uric acid.Elevated uric acid in urine may lead to crystallization, especially when exposed to contrast agents.These urate crystals, combined with the direct toxic effects of contrast agents, may damage renal tubules and cause kidney damage[36].Secondly, an increase in uric acid levels can also activate the renin angiotensin aldosterone system (RAAS), which leads to strong vasoconstriction and further reduces renal blood flow,increasing renal vascular resistance[37].In a previous study, uric acid was found to be associated with an increase in the production of many inflammatory factors, such as interleukin-6 (IL-6), C-reactive protein, etc.These factors can stimulate the inflammatory response and further induce renal tubular injury[38].In addition, hyperuricemia can reduce the bioavailability of nitric oxide (NO), enhance oxidative stress, and these pathological and physiological mechanisms can lead to damage to glomerular endothelial cells, thereby inducing endothelial dysfunction and ultimately affecting renal perfusion[39].All these factors can interact with each other and lead to the development of PC-AKI.

Limitations of this meta-analysis.(1) Most of the included studies were adjusted for multiple variables, but there may be confounding effects of other unadjusted risk factors on the final results.(2)The relevant studies only provided rough OR values for inpatient mortality and renal replacement therapy, which may affect the accuracy of the final results.(3) This meta-analysis is mainly aimed at patients who receive iodine contrast agents administered within the coronary artery.Therefore, the results of the meta-analysis may not be applicable to AKI outcomes caused by enhanced computed tomography (CT), CT angiography, and non coronary angiography.(4) The included studies come from observational studies conducted at centers in different countries and regions, so differences in method evaluation, patient selection, serum uric acid definition, contrast agent use, and PC-AKI definition may have an impact on their final results.There are differences in the definition of hyperuricemia in meta-analyses, which may to some extent affect the quality evaluation and reliability of the results, leading to heterogeneity among studies included in the meta-analysis and confusion in the understanding of the final conclusion.(5) The study only involved Asians and Europeans, making it difficult to accurately assess the association between serum uric acid and PC-AKI among different ethnic groups worldwide.

In summary, through meta-analysis of the large sample data collected from 12 literature, it was found that the presence of hyperuricemia is independently associated with the occurrence of PC-AKI, and it significantly increases the in-hospital mortality rate and the risk of renal replacement therapy in PC-AKI patients.Due to the fact that serum uric acid is a preventable and treatable clinical symptom, measuring its level before coronary angiography may be an effective method for assessing the risk of PC-AKI occurrence and improving clinical prognostic outcomes.Future research, especially high-quality randomized controlled trials, needs to repeatedly verify whether uric acid lowering therapy is beneficial for the prevention and treatment of CI-AKI.

Authors’ contribution

Yao Zhi: Responsible for the research topic selection, literature search and screening, data extraction, statistical analysis, and article writing; Shi Yuexin: Responsible for literature screening and data extraction; Sun Luying: Responsible for feasibility evaluation of topic selection and article revision.

All authors declare that there is no conflict of interest.