Diabetic retinopathy (DR) is a frequent consequence of diabetes and a primary cause of visual loss in many populations (1). According to a recent nationwide survey in China (2), the morbidity of DR and sight-threatening DR (95% confidence intervals) was 16.3% (15.3%-17.2%) and 3.2% (2.9%-3.5%), respectively. The prevalence of DR varies according to geography, economic level, ethnicity, and so on (3), as well as the duration of diabetes (4), dietary habit (5), lifestyle (6), and blood pressure control (7). Although the prevalence is under control, the global population is, creating considerable public health challenges and economic burdens.

Blood urea nitrogen (BUN) measurement is an ancillary test that checks for glomerular filtration function and is frequently used to assess renal function. Numerous studies have demonstrated that the ratio of BUN to creatinine can be used to assess cardiac function (8) and that a higher BUN/creatinine ratio is correlated with a poor prognosis in individuals with chronic heart failure (9–12). The potential application of blood urea nitrogen has been continually investigated through further research. Higher BUN levels have been contacted with an increased risk of diabetes (13). Furthermore, BUN during pregnancy predicts the risk of DR (14), and BUN can be used independently to predict adverse cardiovascular events (15) and renal impairment following diabetes onset (16). While recent research have shown that BUN is associated with DR (16, 17). A strong association between BUN and DR has been concluded in several clinical studies in recent years on the risk of developing DR and risk factors for fibrovascular proliferation in DR. In the study by Shi Rong et al. (16), a DR risk line was designed and BUN was included to predict the risk of DR. The study by Wu et al. (17) identified BUN as an independent risk factor for fibrovascular proliferation in patients with proliferative diabetic retinopathy by univariate and multivariate analyses. Another study (18) showed that BUN is more closely associated to the risk of DR in persons with type 2 diabetes for shorter time. These studies have focused on the possible inextricable relationship between BUN and DR, but there is no literature focusing on the correlation between BUN and DR separately, and in-depth questions such as how BUN levels affect patients with different characteristics of DR have not been addressed. Our study designed to comprehensively evaluate the correlation between BUN level and DR, as well as whether a combination of BUN and other factors influences the likelihood of DR.

This research used population-based cross-sectional information from the NHANES database from 2005 to 2018. The results showed that after adjusting for all covariates, blood urea nitrogen was positively associated with the likelihood of DR. The relationship was affected by gender, type of diabetes (immaturity or maturity onset), ethnicity and duration of diabetes.

Several earlier studies have shown a correlation between BUN levels and DR. Mingzhi Zhang et al (19) did a multivariate logistic regression analysis of risk factor screening for diabetic retinopathy in China and discovered an association between BUN (OR, 1.012), serum creatinine (OR, 1.003) and DR. A study by Yingzi Li et al (20) found that diabetic patients with BUN greater than 8.2 mmol/L had reduced superficial retinal capillary density compared to those with BUN less than 8.2 mmol/L (P < 0.05). The clinical prediction model for diabetic nephropathy and diabetic retinopathy in diabetic patients developed by Fanhu et al (21) also included blood urea nitrogen as one of the risk factors. These findings are congruent with ours. Furthermore, a recent study used multivariate logistic analysis to confirm that BUN was highly correlated positively with the risk of DR and that the correlation was affected by the duration of diabetes (18). These studies included relatively insufficient sample size or a single source, whereas our examined cross-sectional data from multiple cycles of NHANES and adjusted the weights to make the conclusions more trustworthy. We conducted various subgroup analyses to further explore the relationship, which revealed that the association was related to gender, race, and age at diagnosis of diabetes, as well as being affected by diabetes duration. Subgroup analyses reveal a disparity in diabetic retinopathy (DR) risk between genders, with women exhibiting a heightened susceptibility compared to men, even when baseline blood urea nitrogen (BUN) levels are equated. Numerous investigations corroborate this gender discrepancy, delineating a greater prevalence and accelerated progression of DR in females (22, 23), particularly among those aged over 60 with longstanding diabetes (23). Experimental evidence further intimates that progesterone may instigate vascular endothelial growth factor upregulation (24), thereby fostering neoangiogenesis, a pivotal process in DR advancement. Conversely, supplemental estrogen administration to menopausal women appears to mitigate retinal neurovascular disease risk (25, 26), albeit the precise mechanistic underpinnings remain elusive (27). Notably, conflicting reports also cite male predisposition to DR, engendering ambiguity in gender-based conclusions (28). Concerning racial disparities, Hispanics manifest the highest DR susceptibility, trailed by blacks, findings congruent with extant literature (29, 30). Moreover, subgroup analyses underscore a pronounced DR risk escalation in individuals with an early diabetes onset (<=40 years). Multiple studies corroborate a correlation between younger diabetes onset and augmented diabetic complications (31, 32), positing elevated glycated hemoglobin levels and hastened pancreatic β-cell failure (33) as putative mechanisms, engendering formidable glycemic control challenges in this demographic.

Blood urea nitrogen is extensively utilized in the assessment and prognosis of renal insufficiency and heart failure, therefore many previous studies have concentrated on the connection between BUN and diabetic nephropathy (34) or diabetic adverse cardiovascular events (35). In recent years, studies on the correlation between BUN and DR have shown a positive correlation, implying that DR, diabetic nephropathy, and severe cardiovascular events may all have a shared etiology linked to elevated blood urea nitrogen levels. Previous studies have demonstrated the interdependence of DR with glycol-renal and cardiovascular disease and the existence,indicating a similar pathophysiology (36, 37). Oxidative stress is considered to be one of the primary pathogenic processes of vascular complications in diabetes (38), and DR, diabetic nephropathy (DN) and CVD are all prevalent microvascular and macrovascular complications of diabetes. Metabolic irregularities induced by hyperglycemia promote oxidative stress, which can stimulate stronger inflammation (39). Endothelial dysfunction is considered to be a shared pathogenic mechanism of DR and DN (40), and the glomerular endothelial barrier or blood-retinal endothelial barrier plays a key part in the pathogenic mechanism of DN and DR, which may also be the primary cause of elevated BUN levels in DR patients. In recent years, the study of gut flora has increasingly deepened, bring the association between DR, DN and diabetic cardiovascular disease even closer (41), and the gut flora has an impact on metabolism, intestinal barriers, and immune function (42), which may also contribute to the elevated BUN levels.

The novelty of our work is the inclusion of large-scale cross-sectional data from multiple time-period populations, as well as an in-depth exploration of the combined effects of gender, race, diabetes subtype, and diabetes duration on the BUN-DR relationship. At the same time, our study does have certain limitations. First, the diagnosis of diabetes and DR was on account of the results of a questionnaire survey, which led to some uncertainty in the final inclusion of individuals who may have been eligible. Second, because our study cohort was entirely from the United States, the findings should be interpreted with caution in other regions with significant disparities in living conditions or ethnicity.

In conclusion, our investigation revealed a favorable correlation between BUN and DR. As a result, BUN can be used to evaluate the risk of DR in diabetic patients, with the evaluating effect being particularly strong in women, patients with immaturity-onset diabetes mellitus, and patients with a lengthy history of the condition.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

KD: Conceptualization, Data curation, Investigation, Software, Visualization, Writing – original draft, Writing – review & editing. WL: Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – review & editing, Formal analysis, Methodology.