Although many new immunodepressants have been continuously emerging, and renal transplant technique has been progressed much more than before, the long term outcome of RTRs was still not optimistic. Both immune and no-immune factors influence on the long term outcome of the RTRs[7]. This study showed that there was a high incidence of hyperuricemia in despite of the RTRs with normal graft function. The incidence rate of hyperuricemia in female RTRs was higher than male RTRs. Meanwhile by long term follow-up, the study also shown that SCr level is significantly higher in RTRs with persistent post-transplant hyperuricemia, than those with a normal level of post-transplant SUA. Furthermore it is suggested that post-transplant hyperuricimia, but not pre-transplant hyperuricemia, would be a factor inducing chronic renal allograft dysfunction. Min et al[5] reported that early-onset moderate-to-severe hyperuricaemia was found to be a significant risk factor for chronic allograft nephropathy and a poorer graft survival. Even after control of the baseline graft function, hyperuricaemia was also found to be a marker of long-term graft dysfunction and failure. The impact of moderate-to-severe hyperuricaemia on renal transplant survival was dependent on the duration of exposure.
The fact is well known that post-transplantation hyperuricemia is closely associated with insufficient renal function[8]. The RTRs with abnormal graft function were excluded in our study just as in our study, so their high level of SUA obviously not due to poor graft function. Furthermore analyses of the clinical data of the recipients transplanted in our center shown that the main primary diseases causing their chronic renal failure before the transplantation were glomerulonephritis (60.6%), tubulointerstitial nephropathies (24.2%), hypertension-associated renal disease (6.9%) and diabetic nephropathy (5.6%), but only 2.7% of them with primary hyperuricemia. It demonstrated that the main cause of post-transplant hyperuricemia of RTRs in was not primary hyperuricemia. According to literature, therapies with immunosuppressive agents including cyclosporine[9], mizoribine[10] and glucocorticoids many cause post-transplant hyperuricemia. Additional risk factors include diuretic therapy, male RTRs, elder RTRs, graft dysfunction and obesity [3, 11]. Diet may be one of the important factors inducing post-transplant hyperuricemia. Improvement of internal environment of RTRs improves their appetite after transplantation, and improved appetite and the ignoring of diet restriction often result in the increasing of SUA. The patients in our study were treated mainly on cyclosporine, mizoribine and different dosage of glucocorticoids.
It had been reported that gout in renal allograft recipients was associated to the pretransplant hyperuricemic status[12]. But some of RTRs in our study with normal SUA before transplantation developed hyperuricemia after transplantation. Adequate dialysis before transplantation can keep a lower prevalence of hyperuricemian than after transplantation. 184 of the 216 patients were dialyzed 12 hours a week and only 32 of the 216 patients were dialyzed 8 hours a week. Cohen et al[13] reported that the incidence of gout in patients with ESRD may be similar to that of general medical populations, with a 5% incidence of gout after 1 year on dialysis and 15.4% incidence after 5 years, the incidence of gout in the predialysis patients or RTRs was higher than that in maintenance dialysis patients.
As we have known, the incidence of primary hyperuricemia is more common in males than in females. Research from China reported that hyperuricemia was significantly more prevalent in men than in women (32.1% vs. 21.8%)[14]. But our data showed that the incidence rate of post-transplant hyperuricemia was higher in female RTRs than that in male RTRs, due to the different diagnosis standard. But the average SUA level was lower in female RTRs, compared to male RTRs, which is to say, hyperuricemia in female RTRs was not more serious than male RTRs.
Previously it was considered that soluble uric acid was an inactive substance in physiology and mild or moderate hyperuricemia without gout was not a pathopoiesis factor of chronic kidney disease as well as other important disorders[1]. Now our results showed that the eGFR in RTRs with mildly elevated SUA levels (< 500 μmol/L) was significantly lower than RTRs with normal average SUA levels at the end of 36 months follow-up. It is suggested that continuous elevation of post-transplant SUA levels may damage long-term graft function. Recent clinical and epidemiological studies have found that hyperuricemian could induce pathological restructure of vessels and vascular nephrosclerosis, and was associated with the mortality and development of hypertension[15-16], cardiovascular diseases and chronic renal diseases[2, 17-18]. It has been reported recently that soluble uric acid has important biologic roles such as pro-inflammatory and proliferative effects on vascular smooth muscle cells, induction of the dysfunction of endothelial cells in rats[19], and hyperuricemia may induce systemic inflammatorome and generation of oxidative stress[17]. In the other hand, there are vast evidences proving that hypertension, vascular nephrosclerosis, and systemic inflammatorome are important factors inducing chronic graft dysfunction[20]. Uric acid can elevate the immune response[21], by stimulating dendritic cell maturation and enhancing T-cell responses to foreign antigens[22]. These research results may explain the discovery in the study.
Associations between SUA levels and metabolic syndrome (MS) have been reported, that men with high SUA concentrations had a 1.60-fold increase in risk of MS as compared with those who had low SUA concentrations. Among women, the risk of MetS was at least 2-fold higher for high SUA concentrations[23]. Many authors suggested that hyperuricemia is a composite of MS[24-25]. Our transplant team had found that insulin resistance and MS after renal transplantation also played an important role on long term allograft outcome[26]. Hyperuricemia may be a risk factor of insulin resistance[27].
Several reasons made these patients SUA level elevated for a long time and exactly because the long time high levels of SUA deteriorated their graft function[5]. Due to considerate of the adverse effect of allopurinol or asymptomatic hyperuricemia can be ignored[28]. Allopurinol was not used in these patients except SUA was extremely high. In patients with primary hyperlipidemia, atorvastatin but not simvastatin, has been shown to be able to reduce SUA concentrations[29], while patients with postoperative hyperlipidemia in the study were treated with simvastatin but not atorvastatin. Another measure to abate the affection of hyperuricemia was using an angiotensin II receptor antagonist, Losartan, which has been reported to have a uricosuric effect[30] and it was rarely used in our patients too. This condition may explain why the long term graft function of our patients was affected more by post-transplantation hyperuricemia than in other researches.
The results of the study also suggested that effective prevention and treatment of hyperuricemia in RTRs would be important in protection of graft function, and also reduce all-cause mortality and cardiovascular mortality in patients with CKD[9, 31].
