The Impact of hyperuricemia on long-term clinical outcomes of renal transplant recipients: a systematic review and meta-analysis.

PURPOSE
To evaluate the effect of hyperuricemia on clinical outcomes of renal transplant recipients (RTRs).


METHODS
A literature search of PubMed, Cochrane, Embase was conducted up to March 20, 2020. The primary outcome was the estimated glomerular filtration rate (eGFR). The second outcomes were the risk of graft loss, death, cardiovascular event and the level of triglyceride. The following search terms were utilized: ((Hyperuricemic group) OR (Hyperuricaemia) OR (Hyperuric) OR (Urea acid) OR (Uric acid) OR (Acid urate) OR (Urate) OR (Gout)) and ((Transplantation) OR (Transplantations) OR (Transplant) OR (Transplants) OR (Graft)).


RESULTS
28 studies with 18224 patients were eligible for inclusion. There was no significant difference in eGFR (<12 months, p=0.07), the risk of graft loss (<60 months, p=0.07) and death (<60months, p=0.19) between the hyperuricemic and normouricemic group in the early post-transplantation period. But increased uric acid levels contributed to the long-term decline of eGFR, the risk of graft loss and death increased after transplantation. Hyperuricemia increased the risk of cardiovascular event with no significant difference in the level of triglyceride between the two groups.


CONCLUSIONS
Increased uric acid levels contributed to the long-term decline of eGFR, increased risk of graft loss and death after transplantation. Although there was no significant effect on triglyceride, hyperuricemia increased the risk of cardiovascular event.


INTRODUCTION
Kidney transplantation is considered the best treatment for patients with end-stage renal disease. However, there are many complications after transplantation, such as hypertension, dyslipidemia, obesity, diabetes, bone metabolism, blood system problems, malignant tumor, electrolyte and acidbase balance disorder and hyperuricemia. It is reported that the incidence of hyperuricemia in renal transplant recipients ranged from 25% to 84% (1). The risk factors of hyperuricemia after transplantation are: a decreased estimated glomerular filtration rate (eGFR), diuretic use, cyclosporine therapy, increasing age of the transplant, obesity, metabolic syndrome, as well as the presence of pre-transplant hyperuricemia (2).
In recent years, many studies have been published dealing with the impact of hyperuricemia on the clinical outcomes of renal transplant recipients (RTRs). However, whether hyperuricemia is an independent risk factor, or a marker of progressive graft dysfunction remains a controversial topic (3)(4). Huang et al conducted a meta-analysis which included 12 cohort studies in 2012 and found that RTRs with hyperuricemia had a lower estimated glomerular filtration rate (eGFR) and higher serum creatine (SCr) than those with a normal uric acid level. Meta-analysis showed that hyperuricemia might be a risk factor of chronic allograft nephropathy and graft loss (5). However, due to the small sample size of meta-analysis, no clear conclusion could be drawn. In addition, they did not take into account the relationship between the duration of hyperuricemia since transplantation and the clinical outcomes. Many new studies with large samples and comprehensive clinical outcomes have been published in recent years (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Therefore, it is important and necessary to systematically investigate the clinical effect of hyperuricemia on the RTRs in order to produce an evidence-based recommendation for clinical practice.

Search Strategy
Relevant studies included in this study were identified using PubMed, Cochrane and Embase (from inception up to March 20, 2020). References of relevant articles were also reviewed. The following search terms were utilized: ((Hyperuricemic group) OR (Hyperuricaemia) OR (Hyperuric) OR (Urea acid) OR (Uric acid) OR (Acid urate) OR (Urate) OR (Gout)) and ((Transplantation) OR (Transplantations) OR (Transplant) OR (Transplants) OR (Graft)). No language restriction was applied to the search. The details of the search strategy were summarized in the Supplementary Table 1s.

Study selection
Studies were included according to the following criteria: (1) population-based studies including cohort, case-control, and randomized controlled trial (RCT) studies, and (2) articles that reported the association between hyperuricemia and clinical outcomes in RTRs.
Studies were excluded if the following items were identified: without control group, without available clinical outcomes, and duplicates.

Data extraction
Two reviewers (QC and HY) independently extracted relevant information for the meta-analysis. The extracted data included the characteristics of each study (author, study design, publication year, country), patient population (numbers of patients, age), length of follow up, definition of hyperuricemic group, time of evaluating eGFR since transplant, adjusted factors and clinical outcomes (glomerular filtration rate, graft loss, overall graft failure, hazard of death, overall survival, cardiovascular event, triglyceride) in each study.

Outcomes
The primary outcome was eGFR, and the secondary outcomes were the risk of graft loss, death, cardiovascular event, and the level of triglyceride.

Quality assessment
The methodological quality of the RCTs was evaluated using the criteria developed by the Cochrane risk of bias tool (26): random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The Newcastle-Ottawa Scales (NOS) was used to assess the quality of observational studies (27). Two authors (QC and HY) independently assessed the quality of the studies selected. Discrepancies were resolved by involvement of the third author (XJY).

Statistical analysis
All statistical analyses were performed using Review Manager for Windows (version 5.3). Mean and standard deviation (SD) were calculated for primary outcomes. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for secondary outcomes.
Heterogeneity was assessed using the Q statistic and the I 2 method. Mantel-Haenszel fixed effects model was used when there was no significant heterogeneity between studies; otherwise, a random effects model was chosen. Publication bias was evaluated using the funnel plot method, of which funnel plot asymmetry was assessed by Egger's linear regression test (28). Sensitivity analysis was performed by exclusion of each study one by one.

Study description
There was no RCT studies reporting the effects of hyperuricemia on clinical outcomes of renal transplant recipients, therefore this meta-analysis was based on the comparison of observational studies. Characteristics of the eligible studies were presented in Table 1. The clinical outcomes of included studies were presented in Table 2.

Quality of included studies
Risk of bias was assessed using the NOS for all studies. Nine factors were used to assess study quality according to NOS. 5 studies (6-8), (12), (19)

The risk of death
A total of 13 studies evaluated the risk of death in RTRs (8-10), (11)(12), (14), (16), (19), (20)(21)(22), (30), (31). The results showed that uric acid concentration was associated with the risk of death (12325 patients, HR=1.42, 95% CI 1.17-1.72, p=0.0004; Figure 4), but the association was only observed after 60 months post-transplantation in subgroup analysis, and the risk increased with time (<60months, HR=1. 15 Figure 4). No obvious asymmetry was found in the funnel plot. The results of the sensitivity analysis showed that the result was reliable after the exclusion of individual study one by one.

The risk of cardiovascular event
A total of 7 studies evaluated cardiovascular event data for RTRs (10), (12), (16), (22), (30), (34), (36). Statistical difference was found in the risk of cardiovascular event between the hyperuricemic group and normouricemic group in RTRs (7591 patients, HR=1.70, 95% CI 1.11-2.60, p=0.01; Figure 5). No obvious asymmetry was found in the funnel plot, and sensitivity analysis showed that the result was reliable after the exclusion of individual study one by one.

The level of triglyceride
Five studies evaluated triglyceride level for RTRs (13), (15), (17), (18), (24). The meta-analysis showed that there was no significant difference in the level of triglyceride between the hyperuricemic group and normouricemic group. (1027 patients, MD =0.08, 95% CI -0.05-0.21, p=0.23; Figure 6). No obvious asymmetry was found in the funnel plot, which indicated that there is no publication bias in the analysis. The results of sensitivity analysis showed that the result was reliable.

DISCUSSION
Hyperuricemia is a common comorbid condition experienced in RTRs (37). It is unclear, however, whether hyperuricemia plays a casual role in the development of graft dysfunction. To the best of our knowledge, this was the most comprehensive systematic review and meta-analysis to evaluate the association between hyperuricemic status and RTRs' long-term outcomes. Besides, we took into account the relationship between the duration of hyperuricemia since transplantation and the clinical outcomes. Our study found that there was no significant difference in eGFR, the risk of graft loss and death at the early time post-transplantation between the hyperuricemic and normouricemic group. However, increased uric acid levels contributed to the long-term decline of eGFR, the risk of graft loss and death increase after transplantation. Hyperuricemia increased the risk of cardiovascular event with no significant difference in the level of triglyceride between the two groups. Our study showed that hyperuricemia was associated with lower eGFR compared with normal serum UA levels. Previous studies reported that uric acid induced graft dysfunction and chronic allograft nephropathy and accelerated the progress of chronic kidney disease (38)(39). The proposed mechanisms included that uric acid was a mediator of endothelial dysfunction, inflammation, and vascular disease (35), (40)(41). Our results were similar with previous study, and our study found that this impact was only observed at 12-months following transplantion. Gerhardt et al found that patients with hyperuricemia demonstrated a 5-year graft survival rate of 68.8%, compared with 83.3% in patients with normouricemia (42). Our studies also found that hyperuricemia post-kidney transplantation reduced graft survival. Several mechanisms for the effect of       (45) and arterial stiffness (46)(47). These factors resulted in chronic allograft nephropathy, which were the major causes of late graft loss (48)(49). And our study found that the association was only observed at 60 months after operation.
National Health and Nutrition Examination Survey (NHANES) has demonstrated an association between hyperuricemia/gout and cardiovascular disease (50). The uric acid (UA) levels are associated with coronary artery calcium (51). Viazzi et al demonstrated that each standard deviation increase in serum uric acid entailed a 75% higher risk of having cardiac hypertrophy and a 2-times greater risk of having carotid abnormalities (52). There are many proposed mechanisms for the influence of hyperuricemia on the cardiovascular risks. Uric acid causes cardiovascular disorders by stimulating the vascular renin-angiotensin systems, serving as a bridging mechanism mediating (enabling) or potentiating the deleterious effects of cardiovascular risk factors on vascular tissue and myocardium (53)(54). The impact of uric acid concentrations on cardiovascular event is limited. This was the first meta-analysis to demonstrate this association.
Our study suggested that hyperuricemia increased the risk of poor outcomes of RTRs. Therefore, the treatment of hyperuricemia is essential. But consensus on whether to treat asymptomatic hyperuricemia in CKD has not been established, treatment of asymptomatic hyperuricemia has not been generally recommended in the general population or KTRs, and it is only advocated in those with recurrent symptomatic episodes of gout, tophi, or radiographic changes of gout (55). But our analysis demonstrated that hyperuricemia was associated with lower eGFR, higher risk of graft loss, death and cardiovascular events. In addition, studies stated that using medication, like xanthine oxidase inhibition, was shown to reverse endothelial dysfunction (56), improve coronary and peripheral endothelial function (57), slow the GFR decline (58), defer the deterioration of renal dysfunction in CKD (59). Therefore, strengthening the management of asymptomatic hyperuricemia is needed. It is worth noting that low levels of serum UA appear also to contribute to poor clinical outcomes (21). The treatment of hyperuricemia should perhaps give priority to maintaining an appropriate serum UA level, rather than to simply lowering serum UA. We believe that it will be the next developments in the management for KTRs. Our review has the following limitations: first, all included studies were retrospective cohort studies, which might bring estimation bias. Second, some studies have shown that dietary factors are associated with the hyperuricemic group, however these dietary factors have not been evaluated in most of the included studies. Third, since the study population was from different transplant centers and uric acid measurements were from different laboratories, there may be variability in uric acid values. Fourth, although the included studies have been adjusted for confounding factors, the specific adjustment factors are different which may lead to a biased estimation of the results.

CONCLUSION
Our analysis found that increased uric acid levels contributed to the long-term decline of eGFR, the risk of graft loss and death increase after transplantation. Hyperuricemia increased the risk of cardiovascular event with no significant difference in the level of triglyceride between the two groups. Future research is needed to verify whether lowering uric acid level could improve the kidney function and prognosis of RTRs with hyperuricemia. ETHICAL APPROVAL. This study was a systematic review and meta-analysis and based on the published articles, so ethical approval was not required.

CONFLICT OF INTEREST.
No conflict of interest to report. FUNDING DISCLOSURE. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CONTRIBUTORS. HY, and LHL designed the experiments, and QC, AWH, XJY, GC, XPH, WW, HL and XDZ collected and analyzed the data. This article was written by HY and QC. All authors reviewed the article. Hui Yang and Qing Chen are coprincipal authors and have contributed equally.