The association between Uric Acid and Diabetic Retinopathy: Review and meta-analysis

doi:10.21203/rs.3.rs-1763321/v1

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The association between Uric Acid and Diabetic Retinopathy: Review and meta-analysis

https://doi.org/10.21203/rs.3.rs-1763321/v1

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Background

Diabetic retinopathy (DR) is a serious neuro-microvascular complication of diabetes mellitus (DM), which is due to the disturbance of metabolism. Uric acid (UA) is one of the most important indicators of the occurrence and development of metabolism disorders. Many studies reported UA in DR patients was higher than that in non-DR patients. however, the results are controversial. The purpose of this meta-analysis study was to reveal the relationship between UA level and DR.

Method

We searched the online electronic database and retrieved all the relevant articles published before March 2022. Demographic data and UA biochemical parameters in different studies were collected. The pooled standard mean deviation (SMD) and its 95% confidence interval (CI) were calculated and meta-analysis was performed.

Results

A total of 32 articles including 20658 patients were involved in this meta-analysis. The UA levels in DR group was significantly higher than that in non-DM group and NDR group (P = 0.0001; P < 0.00001, respectively). Subgroup analysis showed that there were significant differences in UA level between NPDR and PDR groups (P < 0.00001), NPDR and NDR groups (P = 0.02). In addition, UA levels were significantly higher in DR group comparing NDR group in plasma (P < 0.0001), vitreous (P < 0.00001) and aqueous humor (P < 0.0001) samples. It was also showed UA level was significantly ascended in DR patients no matterT1DM(P < 0.00001) and T2DM (P < 0.00001).

Conclusions

The UA level is definitely associated with DR severity. Therefore, increased UA concentration maybe a potential biomarker that distinguishes DR from DM, and elevated UA level implied the gradual progress of DR.

diabetic retinopathy

uric acid

meta-analysis

Diabetic retinopathy (DR) is one of the major neuro-microvascular complications of diabetes mellitus (DM), which is caused by the destruction of blood-retinal barrier, resulting in the increased retina neurodegeneration and vascular permeability [1–3]. Retina is one of the most metabolic and catabolic tissue in human body. Therefore, retina is vulnerable after diabetic metabolic dysfunction and finally result in retina disorders and vision impaired [4, 5]. Hence, it is crucial to reveal the relationship between metabolites and DR to better understand the pathogenesis of DR.

Uric acid (UA), a weak organic acid with a pK_a of 5.75, is the end product of purine degradation in human [6], and high UA level in serum is a risk factor for T2DM as reported in different population-based studies [7, 8]. UA level in serum is associated with the severity of DR in T2DM patients [9]. Meanwhile increased UA level in aqueous is an independent risk factor for diabetic macular edema (DME) [10]. However, some studies drew opposite conclusions that the serum UA level had no significant difference between DR patients and no-DR patients in both T1DM [11] and T2DM [12]. Another study indicated that non-proliferative DR (NPDR) patients in Japan had an even lower serum UA level than that in patients without DR in T2DM [13]. To date, the relationship between UA and DR is still unclear. Therefore, we pooled the UA levels in different group of DR patients and revealed explicit relationship between UA level and DR using meta-analysis.

Literature search

Comprehensive literature search and review were conducted by searching PubMed, Embase and Web of Science databases to determine relevant articles up to March 2022. We searched the literature by the following keywords: “Uric acid” or “UA” combined with “diabetic retinopathy” or “DR”.

Inclusion and exclusion criteria

First of all, the including criteria are as follow: (1) The study must contain the trial and control group. (2) The UA concentrations are recorded as mean and standard deviation (mean ± SD), or median and quartile, and UA concentrations are available in all groups. (3) The study was published in English. Studies were excluded based on the following conditions: (1) review articles, case reports, animal-based experiments and in vitro studies; (3) duplication of a previous published articles.

Data extraction and quality assessment

The following data were extracted from the included studies: first author name, year of publication, UA concentration, country, DR stages, gender, DM type and sample type. UA concentration in median and quartile were converted to mean ± SD according to the previous studies [14, 15], and the concentrations of UA in different groups were combined in accordance with the Cochrane Handbook for Systematic Reviews of Intervention version 6.0 [16]. All concentration were calculated in terms of µmol/L.

We evaluated the studies quality based on the Newcastle-Ottawa Scale (NOS), which consist of selection, comparability and exposure. A quality score of each study was assigned from 0 to 9. A total score of ≤ 3 was considered poor, 4–6 was considered moderate, and 7–9 was considered high quality.

Statistical analysis

Review Manager 5.3 software and Stata MP13.0 were used for Meta analysis. Standardized mean difference (SMD), mean difference (MD) and 95% confidence interval (CI) were used to determine the heterogeneity among studies. SMD was used to assess in different type of samples or measurements, otherwise MD was used. The threshold for significant heterogeneity was P < 0.1 for Q test or I² > 50%. The random-effect model was used to test the heterogeneity of included trails, and Egger’s test was used to detect the asymmetry of funnel plot. Unless otherwise stated, statistically significance was considered the existence of publication basis.

Literature search

A total of 458 articles were retrieved through systematic search of online databases, and 135 articles were from PubMed; 218 articles were from Embase; 105 articles were from Web of Science. 148 duplicated studies were excluded, 204 articles were excluded by browsing titles and abstracts, and another 74 articles were excluded according to the inclusion and exclusion criteria. Finally, 32 articles were included in this meta-analysis. The flow chart of articles retrieval was shown in Fig. 1.

Characteristics of the selected studies

In total 32 involved studies, 20657 participants were eligible in this study. Twenty-six studies were based on T2DM and three were based on T1DMincluding 863normal control participants without DM (non-DM group), 12088 patients with DM but without any symptoms of DR (including 8 donors) (NDR group) and 7706 patients with DR (including 8 donors) (DR group). In addition, twenty-four studies were carried out in Asia, five studies were conducted in Europe, two studies were in Africa and only one study in South America. Three studies were based on vitreous specimen, one is based on aqueous humor and other thirty studies collected plasma samples. Only three studies reported significant reduction in UA level in the DR group, nineteen studies showed that UA level increased in DR group compared with control group, while other 9 studies showed no difference between DR group and control group. The NOS scoring system was used to rate the quality of included studies. Three studies had a score of 9; nineteen studies had a score of 8; nine studies were scored 7; one studies were scored 6, suggesting that all studies had relatively good quality. The basic characteristics and UA concentration in different groups of 32 studies were summarized in Table 1.

Table 1

Characteristics of the included studies
Study	Publication year	Country	DM type	Sample size	Sample	UA concentration (mean ± SD) (µmol/L)			NOS score
Study	Publication year	Country	DM type	Sample size	Sample	Non-DM	NDR	DR	NOS score
Anan F [17]	2010	Japan	T2DM	102	Plasma	—	359.4 ± 89.85	401.33 ± 65.89	8
Cai X [18]	2014	China	T2DM	2025	Plasma	—	305.9 ± 88.8	321.37 ± 95.11	7
Chen D [9]	2020	China	T2DM	518	Plasma	—	360.7 ± 100.2	408.68 ± 102.1	8
Haj B [19]	2021	Romania	T2DM	209	Plasma	—	263.56 ± 89.85	287.52 ± 83.86	7
Hameed YA [20]	2021	Iraq	T2DM	232	Plasma	269.55 ± 89.85	293.51 ± 77.87	281.53 ± 71.88	6
Hsing SC [21]	2021	China	T2DM	2565	Plasma	—	352.21 ± 106.62	367.46 ± 111.64	9
Hu Y [22]	2021	China	T2DM	2803	Plasma	—	317.39 ± 97.8	313.22 ± 97.44	8
Huang EJ [23]	2006	China	T2DM	461	Plasma	354.61 ± 103.03	342.63 ± 108.42	340.23 ± 93.44	8
Jin H [24]	2019	China	T2DM	34	Plasma	371 ± 44.49	388.1 ± 110.2	390.00 ± 76.2	8
Jin S [25]	2021	China	T2DM	654	Plasma	—	315.58 ± 82.92	314.84 ± 81.66	8
Krizova L [26]	2011	Czech Republic	T1DM, T2DM	129	Plasma	315 ± 88	—	345 ± 73	8
Krizova L [26]	2011	Czech Republic	T1DM, T2DM	129	Vitreous	52 ± 36	—	170 ± 71	8
Krizova L [27]	2015	Czech Republic	T2DM	29	Vitreous	86.97 ± 74.33	—	149.84 ± 99.89	8
Liang CC [28]	2016	China	T2DM	385	Plasma	—	341.43 ± 101.83	387.78 ± 120.75	8
Longo-Mbenza B [29]	2014	DR Congo	T2DM	195	Plasma	281.53 ± 95.84	323.46 ± 119.8	323.46 ± 107.82	8
Melo LGN [30]	2018	Brazil	T1DM	1644	Plasma	—	288.12 ± 97.64	332.24 ± 125.19	7
Nakayama Y [13]	2021	Japan	T2DM	214	Plasma	—	347.72 ± 89.85	335.44 ± 89.85	9
Nishimura M [31]	1998	Japan	NA	202	Plasma	287.52 ± 11.98	269.55 ± 11.98	279.13 ± 22.64	7
Pilemann-Lyberg S [11]	2019	Denmark	T1DM	648	Plasma		253.5 ± 82.4	314.1 ± 113.8	9
Qin YJ [10]	2022	China	T2DM	486	Plasma	376.77 ± 97.04	392.94 ± 115.61	377.97 ± 98.24	8
Qin YJ [10]	2022	China	T2DM	486	Aqueous	118 ± 31.15	129.38 ± 38.34	183.29 ± 55.11	8
S N [32]	2013	India	T2DM	94	Plasma	236.01 ± 13.18	255.77 ± 28.15	289.92 ± 33.54	8
Shawki HA [33]	2020	Egypt	T2DM	150	Plasma	325.26 ± 122.2	203.66 ± 107.82	509.15 ± 125.79	7
Sun S [34]	2021	China	T2DM	1376	Plasma	—	338.95 ± 82.43	339.76 ± 76.52	8
Sun W [35]	2021	China	T1DM	188	Plasma	—	242.23 ± 79.26	303.83 ± 101.25	7
Thounaojam MC [36]	2019	Italy	T1DM, T2DM	16	Vitreous (donor)	—	237.5 ± 63.52	404.5 ± 73.64	7
Thounaojam MC [36]	2019	Italy	T1DM, T2DM	18	Vitreous (subject)	—	239.1 ± 142.8	473.3 ± 235.2	7
Vinuthinee-Naidu MN [37]	2017	Malaysia	T2DM	180	Plasma	—	377.53 ± 95.41	360.09 ± 94.69	8
Weitzman S [38]	1997	Israel	T2DM	491	Plasma	—	333 ± ± 89.2	339 ± 83.2	7
Xia Q [12]	2020	China	T2DM	2961	Plasma	—	331 ± 100	339 ± 83.2	8
Xia J [39]	2014	China	T2DM	115	Plasma	279.31 ± 14.44	322.32 ± 14.14	422.59 ± 23.78	7
Yanko L [40]	1983	Jerusalem, Israel	NA	73	Plasma	—	328.85 ± 71.88	311.48 ± 92.25	8
Zhang D [41]	2018	China	T2DM	742	Plasma	—	280.88 ± 73.57	322.61 ± 90.8	8
Zhao X [42]	2021	China	T2DM	418	Plasma	—	321.68 ± 85.82	339.5 ± 113.93	8
Zhong ZL [43]	2011	China	T2DM	300	Plasma	268 ± 823	—	318 ± 76	8

The association between UA and DR

We pooled all 32 studies and found the UA level in DR group was significantly higher than that in non-DM group and NDR group (SMD: 0.97, 95% confidence interval (CI): 0.48–1.47, P = 0.0001; SMD: 0.38, 95%CI: 0.24–0.52, P < 0.00001, respectively). Significant heterogeneity among studies were displayed (P < 0.00001, I² = 96%; P < 0.00001, I² = 93%, respectively). (Fig. 2A, B).

Subgroup analysis

In order to assess the association of UA level and DR specifically, the patients were divided into three type subgroups by the DR stage, sample source and DM type. In proliferative DR (PDR) and NPDR subgroups, the UA level in the PDR group was significantly higher than that in the NPDR group (P < 0.00001), and there was significant heterogeneity among these studies (P = 0.009, I² = 61%) (Fig. 3A). We also compared the UA level between NPDR group and NDR group which showed that the UA level in NPDR group was also significantly higher than that in NDR group(P = 0.02), and the heterogeneity was significant (P < 0.0001, I² = 71%) (Fig. 3B). Moreover, there is no significant difference in UA levels between NDR and non-DM group (SMD: 0.22, 95%CI: -0.26-0.69, P = 0.37) (Fig. 3C).

The UA levels in plasma, vitreous and aqueous humor in DR group were significantly higher than that in NDR group (P < 0.0001). There was no significant heterogeneity among studies with vitreous samples (I² = 44%, P = 0.18), but significant heterogeneity among studies with plasma samples (I² = 96%, P < 0.00001) (Fig. 4). Moreover, the UA level in the DR group were significantly higher than that in the NDR group for both T1DM (P < 0.00001) and T2DM (P < 0.00001) patients, and the heterogeneity were not significant in T1DM subgroup, but persisted in T2DM subgroup (P = 0.12, I² = 52%; P < 0.00001, I² = 93%, respectively) (Fig. 5).

Sensitivity analysis

To assess the reliability of the present study, a sensitivity analysis was carried out by excluding studies individually in order to ensure that each study met the aim of this study. By excluding one study at a time, the SMD ranged from 0.62 to 1.09 in the sensitivity analysis of UA level for comparing the DR with non-DM groups. The lower limit of 95%CI was 0.20–0.58 and the upper limit ranged from 1.04–1.62. The I² values were significant (Table 2). The SMD ranged from 0.30 to 0.39 in the sensitivity analysis for comparing DR with NDR groups. The lower limit of 95% CI was 0.18–0.25 and the upper limit ranged from 0.41–0.54. The I²values were also obvious (Table 3). The sensitivity analysis demonstrated that the overall quality stability was good, indicating that our results were convincing.

Table 2

Sensitivity analysis: DR VS non-DM
Study	SMD (95% CI)	P heterogeneity	I²
Hameed YA 2021	1.05(0.52–1.59)	< 0.00001	97
Huang EJ 2006	1.07(0.54–1.61)	< 0.00001	96
Jin H 2019	1.02(0.51–1.54)	< 0.00001	97
Krizova L 2011 (Plasma)	1.03(0.50–1.57)	< 0.00001	97
Krizova L 2011 (Vitreous)	0.89(0.40–1.38)	< 0.00001	96
Krizova L 2015	1.00(0.48–1.51)	< 0.00001	97
Longo-Mbenza B 2014	1.03(0.50–1.56)	< 0.00001	97
Nishimura M 1998	1.09(0.58–1.60)	< 0.00001	96
Qin YJ 2022 (Plasma)	1.07(0.52–1.62)	< 0.00001	96
Qin YJ 2022 (Aqueous)	0.93(0.43–1.43)	< 0.00001	96
S N 2013	0.89(0.39–1.39)	< 0.00001	96
Shawki HA 2020	0.94(0.42–1.45)	< 0.00001	96
Xia J 2014	0.62(0.20–1.04)	< 0.00001	95
Zhong ZL 2011	1.06(0.51–1.61)	< 0.00001	96

Table 3

Sensitivity analysis: DR VS NDR
Study	SMD (95% CI)	P heterogeneity	I²
Anan F 2010	0.38(0.23–0.50)	< 0.00001	93
Cai X 2014	0.39(0.24–0.53)	< 0.00001	93
Chen D 2020	0.37(0.23–0.51)	< 0.00001	93
Haj B 2021	0.38(0.24–0.51)	< 0.00001	93
Hameed YA 2021	0.39(0.25–0.53)	< 0.00001	93
Hsing SC 2021	0.39(0.25–0.54)	< 0.00001	93
Hu Y 2021	0.39(0.25–0.53)	< 0.00001	93
Huang EJ 2006	0.39(0.25–0.52)	< 0.00001	93
Jin H 2019	0.38(0.24–0.51)	< 0.00001	93
Jin S 2021	0.39(0.25–0.53)	< 0.00001	93
Liang CC 2016	0.37(0.23–0.51)	< 0.00001	93
Longo-Mbenza B 2014	0.38(0.25–0.52)	< 0.00001	93
Melo LGN 2018	0.37(0.23–0.51)	< 0.00001	93
Nakayama Y 2021	0.39(0.25–0.53)	< 0.00001	93
Nishimura M 1998	0.37(0.23–0.50)	< 0.00001	93
Pilemann-Lyberg S	0.38(0.24–0.52)	< 0.00001	93
Qin YJ 2022 (Plasma)	0.39(0.25–0.53)	< 0.00001	93
Qin YJ 2022 (Aqueous)	0.33(0.20–0.46)	< 0.00001	92
S N 2013	0.35(0.22–0.49)	< 0.00001	93
Shawki HA 2020	0.30(0.18–0.42)	< 0.00001	91
Sun S 2021	0.39(0.25–0.53)	< 0.00001	93
Sun W 2021	0.36(0.22–0.49)	< 0.00001	93
Thounaojam MC 2019 (Vitreous from donors)	0.35(0.22–0.49)	< 0.00001	93
Thounaojam MC 2019 (Vitreous from subjects)	0.36(0.23–0.50)	< 0.00001	93
Vinuthinee-Naidu MN 2017	0.39(0.25–0.53)	< 0.00001	93
Weitzman S 1997	0.39(0.25–0.52)	< 0.00001	93
Xia J 2014	0.39(0.25–0.54)	< 0.00001	93
Xia Q 2020	0.30(0.18–0.41)	< 0.00001	90
Yanko L 1983	0.39(0.25–0.52)	< 0.00001	93
Zhang D 2018	0.37(0.23–0.51)	< 0.00001	93
Zhao X 2021	0.38(0.24–0.52)	< 0.00001	93

Assessment of publication bias

A funnel plot analysis was performed to investigate the potential publication bias among 32 included articles. The results showed that the distribution of studies was symmetrical and therefore no significant publication bias existed for comparison between DR and non-DM groups (Fig. 7, Egger test: P = 0.051). However, the distribution of studies for comparing the DR and NDR groups was not symmetrical which means the publication bias existed (Fig. 8, Egger test: P = 0.018).

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 [13]. Another reason is the exclusion of NPDR patients with moderate or severe DME [37]. 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 [44]. 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 [45]. 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 [46]. In vivo, anti-UA drugs could inhibit the inflammatory factors, such as NLRP3, TLR4 and IL-1b, in STZ-induced rat model [36]. Moreover, when UA concentration arose above threshold 6mg/dL, it would form urate crystal which would also induce inflammation [47]. In addition, UA was found to inhibit production of nitric oxide, a vasodilation factor, in retinal endothelial cells [48]. 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 [49]. 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.

To summarize, this study displays the level of UA is significantly different between the PDR, NPDR and NDR group. In addition, the elevated UA concentrations are also associated with DR in plasma, aqueous and vitreous samples and in T1DM and T2DM patients, respectively. These results indicate that UA may be used as a biomarker for DR occurrence and progress, and as a potential therapeutic target of DR.

Ethics approve and consent to participate

Not applicable

Consent for publication

All the authors have seen and approved the submitted manuscript.

Availability of data and materials

The data used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that there is no conflict of interest regarding the publication of this paper.

Funding

Not applicable

Authors contributions

Zhang LY and Li XR conceived the ideas. Zhang LY analyzed the data and wrote the manuscript. Li XR supervised the study. All the authors have read and approved the final version for publication.

Acknowledgements

Not applicable

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No competing interests reported.

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The association between Uric Acid and Diabetic Retinopathy: Review and meta-analysis

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Abstract

Background

Method

Results

Conclusions

Figures

Introduction

Materials And Methods

Inclusion and exclusion criteria

Data extraction and quality assessment

Statistical analysis

Results

Characteristics of the selected studies

The association between UA and DR

Subgroup analysis

Sensitivity analysis

Assessment of publication bias

Discussion

Conclusions

Declarations

References

Additional Declarations

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