Although many previous studies have indicated an association between UA and diabetic retinopathy, these results are controversial. Our meta-analysis pooled 32 studies involving a total of 20657 diabetic patients from fourteen countries and regions in four continents. We were convinced the result that elevated UA level was associated with DR progress. Specifically, UA level of PDR group was significantly higher than that of NPDR group. Meanwhile, the UA level also obviously ascended in NPDR group compared with NDR group. However, subgroup analysis indicated no significant difference between NDR group and non-DM group in UA level. This result suggested that increased UA level was a biomarker that only distinguishes DR from DM. This result was consistent with majority studies [9, 11, 28]. However, several articles showed opposite result that NPDR group had lower UA level in plasma compared with NDR group [13, 37]. One reason may be the coverage error caused by the NPDR patients who lost follow-up due to slow DR progression and normal vision . Another reason is the exclusion of NPDR patients with moderate or severe DME . Therefore, UA concentration is associated with high risk of DR severity.
Some evidence has been presented that how UA impact the DR progression. UA can not only be produced by retinal purine metabolism, but also can cross over the blood-retinal barrier into the eye from peripheral blood through the organic anion quasi-transport protein (OAT3) expressed by retina vascular endothelial cell . Highly increased UA concentration in retina has a variety of disadvantages. UA is a potent anti-oxidant under normal concentration, but may become a pro-oxidant along with its concentration elevated, which could induce endothelial cell proliferation, angiotensin Ⅱrelease and oxidative stress by activating renin-angiotensin (RAS) system . Moreover, highly increased UA concentration also play a pro-inflammatory role in DR progression. High UA level could promote expression of inflammatory mediators and adhesion molecules, such as ICAM-1, MCP-1, TNF-αand IL-6 in human retinal endothelial cells by activating Notch pathway under high glucose environment in vitro . In vivo, anti-UA drugs could inhibit the inflammatory factors, such as NLRP3, TLR4 and IL-1b, in STZ-induced rat model . Moreover, when UA concentration arose above threshold 6mg/dL, it would form urate crystal which would also induce inflammation . In addition, UA was found to inhibit production of nitric oxide, a vasodilation factor, in retinal endothelial cells . Therefore, UA may lead to the retinal dysfunction during DR progress by inducing oxidative stress, vascular dysfunction and inflammation-related activities.
We also carried out subgroup analysis based on different samples. Our study revealed that the UA concentrations derived from plasma, vitreous and aqueous humor samples were significant higher in DR group than that in the NDR group. However, some studies indicated UA concentration in plasma were not increased in DR group comparing the NDR group. this may due to the other factor which influence the UA concentration in systemic circulation, such as fasting blood glucose (FBG). It has been reported that UA level in serum may decrease along with the ascending FBG . In addition, our meta-analysis also showed that the change of UA concentration in plasma was liable to fluctuate than that in intraocular fluid [10, 50], suggesting that the change of UA concentration in aqueous and vitreous could imply the occurrence and development of DR more accurately than that in plasma. Moreover, we also found that elevated UA concentration is better associated with the progress of DR in T1DM than T2DM.
The overall quality of the articles in this meta-analysis is good, but some limitations still exist. First, the publication bias exists among the involved articles, and the reason may be the huge difference of sample sizes among the studies. Second, lack of studies based on vitreous and aqueous samples may affect the accuracy of the result in these two subgroups. Finally, due to language restricted in English, some high-quality studies published in other language shave been missed.