The role of hyperuricemia in the pathogenesis and development of CKD is attracting more attention because of its pathogenic effect on the renal glomeruli and tubules, especially in IgAN. This study analyzed the role of hyperuricemia in the progression and prognosis of IgAN. Consequently, the present study conducted a regular follow up of 463 IgAN patients enrolled from the General Hospital of Tianjin Medical University. In addition, the level of uric acid in patients during treatment was evaluated using TA-UA.
Analysis using the Cox model showed that TA-UA was significantly correlated with the prognosis of IgAN. Notably, TA-UA was still significantly correlated with the prognosis of IgAN after gradually adding age, gender, pathological and time average clinical indicators. It was previously recommended that the level of serum uric acid should be controlled within the normal range based on the age and gender of patients with CKD complicated with hyperuricemia, so as to avoid the possible adverse effects of crystal deposition and extremely low levels of serum uric acid(Roddy et al. 2018). In the present study, survival analysis showed that individuals with hyperuricemia had higher levels of TA-UA than that the normal patients. Additionally, patients with hyperuricemia had worse prognoses than those in which TA-UA was within the normal range. Interestingly, the results differed from those previously reported in that for every 1 mg / dL increase in TA-UA, the increased risk of IgAN progression was higher than that reported before(Matsukuma et al. 2017; Oh et al. 2020). This may be due to the fact that TA-UA was more comprehensive and sensitive to changes in the patient's condition during the follow-up period than the baseline value of serum uric acid (used by previous studies). Although TA-UA may not fully reflect the actual situation of serum uric acid, it provides a basis of studying the effect of serum uric acid on the progression of IgAN.
Previous studies showed that there are significant gender differences in the impact of serum uric acid on different diseases, especially in cardiovascular and cerebrovascular diseases, chronic kidney disease, diabetes and other ailments(Barbieri et al. 2015; Kohagura et al. 2013; Lou et al. 2020; Sun et al. 2019). However, gender differences in the progression of IgAN are yet to be established since different studies report contradictory results(Ruan et al. 2018; Zhu et al. 2018). For instance, Goto et al.(Goto et al. 2009) showed that men were more likely to progress to ESRD than women. Additionally, Riispere Ž et al.(Riispere et al. 2016) analyzed the factors influencing IgAN and concluded that the disease progressed more rapidly in men than in women. However, a study by Cattran DC et al.(Cattran et al. 2008) showed that there was no significant difference in long-term survival from IgAN, between men and women. Moreover, Matsukuma et al.(Matsukuma et al. 2017) found a correlation between the levels of serum uric acid and IgAN progression in both men and women although the association was more significant in women. According to Yang et al.(Deng et al. 2018), uric acid is an important predictor of IgAN prognosis in both males and females. Furthermore, a study of 935 IgAN patients showed that elevated levels of serum uric acid was an independent risk factor for the progression the disease in women but not in men(Nagasawa et al. 2016). The same results were obtained even after age and serum creatinine matching as well as propensity score matching. The present study similarly found that TA-UA was an independent risk factor for renal outcomes in women with IgAN but not in men.
Additionally, the restricted three sample map revealed that TA-UA and IgAN progression did not show a "U" shape in women and men, which was different from previous reports(Mori et al. 2021). This may be related to the small number of low-level TA-UA in the population analyzed by the present study. Notably, it was easier to increase the level of blood uric acid than to decrease it during the entire follow-up period. In addition, progression to kidney failure and improvement of diet may increase the level of blood uric acid.
However, the reason for the difference in the effect of serum uric acid between women and men is still unclear. The secretion and excretion of uric acid are regulated by a variety of uric acid transporters, such as the uric acid transporter 1, ABCG2 and the Glucose Transporter 9 (GLUT9)(Li et al. 2020). Notably, the reabsorption function of the uric acid transporter 1 can be inhibited by estrogen, promoting the excretion of uric acid in urine(Hak & Choi 2008). Additionally, Kao et al.(Kolz et al. 2009; Zhang et al. 2013) reported that mutations in ABCG2 had a stronger effect in increasing the levels of serum uric acid in men than in women. Moreover, the SLC2A9 gene regulates GLUT9 and the rs734553 allele was shown to have a greater effect on the levels of uric acid in women than in men(Dehghan et al. 2008). Another possible explanation is that male IgAN patients are associated with more risk factors for ESRD, including smoking, obesity, hypertension and hyperlipidemia, which were not included in the present study.
Despite the insightful findings, this study had a number of limitations. First, this was a single center retrospective study and the median follow-up time was 36 months (6 months, 126 months). Compared to the development of the disease, the follow-up time used in the present study was not long enough. Therefore, we will continue to follow up these patients. Second, IgAN treatment may have been a confounding factor affecting the prognosis of the disease. However, treatment was not included in the study because of the individualization, flexibility and variability of clinical treatment. Third, given that patient information was obtained from the follow-up records in our hospital, some patients were lost during follow-up. Additionally, there were deviations in the classification and analysis of data. Therefore, further studies that are well-designed, multicenter and with a larger cohort as well as a longer regular follow-up time, are needed to confirm these findings.