Objectives: Hyperuricemia is common in pediatric renal transplant recipients, and it is associated with poor allograft outcomes. Hyperuricemia occurs early after transplant and is associated with use of diuretics, cyclosporine therapy, a history of hyper­uricemia, and decreased glomerular filtration rate. We aimed to investigate causes and effects of hyperuricemia on allograft outcomes in our patients.

Materials and Methods: There were 81 pediatric transplant patients (41 female and 40 male) included in the study. Demographic characteristics and laboratory parameters were recorded. Risk factors for hyperuricemia and the effects of plasma uric acid levels at 3, 6, 12, and 36 months on allograft outcomes were evaluated.

Results: Mean age was 16.9 ± 5.6 years. Mean follow-up after transplant was 3.5 ± 0.47 years. Hyperuricemia was detected in 17.6% patients. A significant negative correlation was observed between 6-month uric acid level and 36-month glomerular filtration rate (r = -0.33, P = .04; r = -0.33, P = .017). A significant positive correlation between 3- and 6-month uric acid levels and 36-month plasma creatinine level was observed (r = -0.44, - = .01; r = -0.51, P = .001). There was no significant correlation between plasma uric acid level and body mass index, plasma lipid levels, use of diuretics, or immunosuppressive treatment (tacrolimus or cyclosporine).

Conclusions: Uric acid levels may have predictive value in the long-term assessment of renal function. Posttransplant hyperuricemia can be used as a long-term prognostic marker of poor renal outcome. Patients with hyperuricemia should be monitored closely for renal function.

Key words : Children, Graft survival, Kidney transplant, Uric acid

Introduction

Hyperuricemia is common in pediatric renal transplant recipients, and it is associated with poor allograft outcomes, as in adult patients.^1,2 In most studies, serum uric acid level was a marker of renal dysfunction.^2-6 However, hyperuricemia occurs early after transplant and is associated with use of diuretics, cyclosporine therapy, a history of hyper­uricemia, and decreased glomerular filtration rate (GFR).^1,3,5,7,8 The effect of hyperuricemia after kidney transplant on graft outcome has not been fully established, but a small number of studies have suggested that an increased serum uric acid level is a prognostic factor for the development of renal allograft impairment.

We aimed to investigate causes and effects of hyperuricemia on allograft outcomes in our pediatric kidney transplant recipients by evaluating patients during 3 years after transplant.

Materials and Methods

Patients
We determined the prevalence of hyperuricemia in pediatric renal transplant recipients for transplants that were performed from December 2000 to December 2012 in our Transplant Center. There were 81 patients included in the study. Both living- and deceased-donor renal transplant recipients were included. We analyzed patient data retrospectively, and 3-year follow-up data of the patients were evaluated. Uric acid concentration was measured for each patient. The demographic characteristics and laboratory parameters were recorded. All laboratory tests were done in the same laboratory. Hemoglobin values, serum creatinine concentration, fasting blood glucose concentration, cyclosporine concentration, and lipid profile (levels of cholesterol, triglycerides, low-density lipoprotein, and high-density lipo­protein) were evaluated. In these 3 years, we examined serum uric acid levels and GFR of patients at 3, 6, 12, and 36 months after transplant and evaluated associations between the data. Hyper­uricemia was defined by level of serum uric acid ≥ 6 mg/dL. Risk factors for hyperuricemia and the effects of serum uric acid levels on allograft outcomes at 3, 6, 12, and 36 months were evaluated.

All patients were given calcineurin inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil, and steroids as the immunosuppressive regimen. If the patient was treated with cyclosporine, the target trough level was 200-300 ng/mL for the first 3 months, 100 to 250 ng/mL for 4 to 12 months, and 100 to 150 ng/mL after 12 months; we used target levels (at 2 hours after the dose) of 800 to 1000 ng/mL in the first 3 months after transplant and 400 to 600 ng/mL after 3 months. For tacrolimus, trough level was 10 to 12 ng/mL for the first 3 months, 6 to 10 ng/mL for 4 to 12 months, and 3 to 6 ng/mL after 12 months.

Statistical analyses
Data analyses were performed with statistical software (IBM SPSS for Windows, Version 21.0, IBM Corp., Armonk, NY, USA). The chi-square test was used to compare patient characteristics, and t test was used to detect differences between groups. The data were expressed as mean ± standard deviation (SD), and differences with P ≤ .05 were considered statistically significant. Numeric variables were reported as number (%).

Results

There were 81 pediatric transplant patients (41 female and 40 male) included in the study. The mean age of the patients was 16.9 ± 5.6 years, and the mean age at transplant was 12.4 ± 4.7 years. Patients who underwent transplant received 57 (70.4%) grafts from living donors and 24 (29.6%) grafts from deceased donors (Table 1). The primary renal disease was vesicoureteral reflux (32%), and many patients had no known cause of kidney failure (20%). The other etiologies of kidney failure were focal segmental glomerulosclerosis, polycystic kidney disease, neurogenic bladder, nephrolithiasis, nephro­nophthisis, and pyelonephritis (Figure 1).

Hyperuricemia was detected in 14 patients (17.3%) after transplant. The serum uric acid level range was 1.6-10.2 mg/dL. Mean follow-up after transplant was 3.5 ± 0.47 years. The uric acid and serum creatinine levels were measured at 3, 6, 12, and 36 months after kidney transplant, and we estimated GFR simultaneously (Table 2). Hyperuricemia was detected equally in male and female patients.

A significant negative correlation was observed between 6-month uric acid level and 36-month GFR value (r = -0.33, P = .04). A significant positive correlation between 3- and 6- month uric acid levels and 36-month plasma creatinine level was demonstrated (r = 0.44, P = .01; r = 0.51, P = .001). There was no significant correlation between plasma uric acid level and body mass index, plasma lipid levels, use of diuretics, or immunosuppressive treatment (tacrolimus or cyclosporine). Comparison between normouricemic and hyperuricemic groups showed significant differences between the groups in plasma creatinine and GFR at 36 months (Table 3).

Discussion

Hyperuricemia is a frequent metabolic disorder after renal, liver, and heart transplants. High uric acid levels can damage endothelial cells, leading to accumulation of inflammatory cells, which can accelerate atherosclerosis.³ High uric acid levels also may cause tubulointerstitial inflammation and transition of epithelial cells to mesenchymal cells which may cause production of extracellular matrix. These events lead to renal fibrosis, and fibrosis is associated with a decrease in GFR.^3,6,9,10 Elimination of uric acid becomes less efficient with increasing kidney dysfunction.^2,5,11,12 Our study findings demonstrate a significant negative correlation between hyperuricemia and GFR.

The reported prevalence of hyperuricemia in renal transplant recipients has ranged between 15.5% and 84%.^3,5,8,12,13 In our series, the prevalence of hyperuricemia was 22.2%, and this is similar to results of recent studies. We measured serum uric acid levels at 3, 6, 12, and 36 months after transplant. Although there was a significant correlation between hyperuricemia and GFR at 6 and 36 months, there was no relation at 3 and 12 months. We did not encounter graft loss. In a manner similar to our study, Haririan and coworkers assessed the predictive value of serum uric acid levels to determine graft survival and function during the first year after transplant.¹⁴ Akalin and associates investigated the association between hyperuricemia at 6 months after transplant and clinical outcomes, and Choi and Kwon investigated the association between serum uric acid levels at 3 months after transplant and renal allograft outcomes.^3,15 These studies all indicated that hyperuricemia may lead to graft dysfunction and loss.

The findings of many studies demonstrated that hyperuricemia is associated with body mass index, serum lipid levels, serum potassium levels, use of diuretics, reduced glomerular filtration rate, use of calcineurin inhibitors, increased recipient age at transplant, and pre-existing history of hyperuricemia and gout.^8,16-18 In our study, there was no significant correlation between hyperuricemia and these clinical factors. Similar to some studies, there were no significant differences in the pharmacokinetics of cyclosporine and tacrolimus between patients with and without hyper­uricemia.^2,9

In addition, some clinical trials have emphasized that hyperuricemia may increase the risk of graft loss, cardiovascular events, and death.^5,19 In our series, there were no cases of graft loss, cardiovascular events, or death. This may be a result of the small number of patients and short follow-up. These risks should be evaluated with new and larger clinical studies.

In conclusion, posttransplant hyperuricemia can be used as a long-term prognostic marker of poor renal outcome, and patients with hyperuricemia should be monitored closely for renal function.

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