In this cohort study of kidney transplant recipients over a 10-year period, NODAT was found in 21.2% of the patients and the 10-year cumulative incidence was 26.9%. In the tertile stratification, a high SUA level (> 511 μmol/L [8.6 mg/dL] for men and > 457 μmol/L [7.7 mg/dL] for women) was an independent and strong predictor of NODAT in our study. We constructed three Cox hazard regression models that indicated a significant association between SUA and NODAT after adjusting for known risk factors for T2DM onset, NODAT, and factors that directly affect the SUA level. We demonstrated for the first time that a high SUA level is a strong and independent predictor of NODAT.
A previous report did not reveal an association between SUA and NODAT; however, pre-transplant anti-hyperuricaemic medication was associated with NODAT . Conversely, allopurinol therapy did not predict NODAT in our study, but SUA did. SUA level is reportedly affected by the variables in model 1, related to uric acid excretion . We confirm SUA is independent of factors from renal function, and correlation of SUA levels between before and after transplantation with renal function stabilized. Therefore, SUA is suggested to reflect elevated production, predisposed by xanthine oxidoreductase (XOR) activity, in a manner independent of renal function. Uric acid has thought to have diabetogenic action since 1950 , by exacerbating insulin resistance . Moreover, uric acid production via XOR promotion, associated with oxidative stress and inflammation such as macrophage activation , is suggested to induce a vulnerability to NODAT development. The role of uric acid metabolism-related inflammation in pathogenesis of diabetes, non-alcoholic steatohepatitis, and arteriosclerosis has been reported in several studies in many countries [19,20,21,22]. To the best of our knowledge, our study is the first to clarify the association between increased SUA production and development of NODAT.
Many risk factors have been proposed for the development of NODAT: age, race, family history of diabetes, BMI, glucose intolerance, metabolic syndrome, acute rejection, cadaveric kidney transplantation, chronic infection with HCV, and the type of immunosuppression used [1, 3, 5]. Furthermore, SUA is correlated with metabolic syndrome and T2DM [8, 9, 23,24,25]. Another T2DM risk might also be a NODAT risk; therefore, we included known T2DM risks in model 2 for multivariate analysis. HOMA-IR and I-I tended to be higher in patients in the highest tertile for SUA values than for those in the lower 2 tertiles. However, after adjusting for both factors, they were not associated with NODAT. Known risk factors for NODAT relating to transplantation are included in model 3. Older age has consistently been an important contributing factor to the development of T2DM and NODAT [1, 2, 26] and is an important determinant of β-cell dysfunction after renal transplantation . Our recipients represent a relatively young population for T2DM onset, with median ages of 39 and 47 years in non-NODAT and NODAT patients, respectively.
Evidence suggests that immunosuppressive drugs account for the risk for NODAT development . The association between corticosteroids and NODAT is clearly established and is related to cumulative dosages and therapy duration . The avoidance of steroids is associated with a significant reduction in the likelihood of developing NODAT . However, to date, there has been no steroid-free maintenance regimen in Japan, and our protocol is based on pre-transplant induction therapy and does not include post-transplant therapy.
This study has several limitations. First, all donors and recipients were Japanese, and it was not revealed whether the risk of high SUA for NODAT is applicable to other ethnicities. Second, this is a single-institution study; therefore, the magnitude of SUA significance might vary according to unknown factors resulting from intra-institutional differences. Third, it is unknown whether uric acid reduction therapy prevents NODAT because of the observational nature of this study. Fourth, although the results of kidney transplantation in Japan are as good as those observed in European countries and the USA, the number of transplantations performed in Japan is extremely small compared with these countries. An interventional study with a large number of patients is needed to verify the usefulness of pre-transplant uric acid-lowering therapy. Despite these limitations, this is the first long-term follow-up study to report a novel predictor and potential target for NODAT. Certain care for recipients with preoperative hyperuricemia of living-donor kidney transplantation is probably important in clinical situation. From now on, frequent check of the glycemic control and uric acid level are recommended for both clinical practice and future research field.