We showed a significantly increased risk of developing OAG and ACG within the CKD cohort compared to the non-CKD cohort. Notably, this increased glaucoma risk persisted among both the dialytic and non-dialytic CKD cohorts. Our combined multivariate Cox proportional hazard regression and Poisson regression models further demonstrated that all genders, all age groups (< = 40, 50–59, 60–69, 70–79, > 80), and all socioeconomic brackets from the CKD cohort were associated with an increased risk for glaucoma compared to their respective non-CKD comparators. Furthermore, an increased risk of glaucoma was observed irrespective of whether CKD patients had a history of comorbidities such as hypertension, hyperlipidemia, stroke, dementia or diabetes.

Our study significantly contributes to the existing literature by employing rigorous methodology, including long follow-up durations and frequency score matching, to investigate the risk of glaucoma among the CKD cohort. Ours is also one of the largest studies to investigate the association between the risk of developing primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) subtypes within the chronic kidney disease (CKD) cohort in a population-based study. Using a large dataset enables researchers to elucidate better the real-world epidemiology of glaucoma and its predictive factors among CKD patients. When identifying a condition's causes, ideally one can examine relevant data directly from individual medical records. However, such a retrospective chart review is often time-consuming, limiting the number of patients able to be recruited via this method. Therefore, employing multi-institutional electronic records and utilizing electronic diagnostic codes allows researchers to identify cohorts of CKD patients with glaucoma efficiently. This study design can also be modified to recruit subgroups of the disease of interest and conduct subgroup analyses on covariates of interest. This was one of our strengths, as previous studies, such as the one by Ro et al., did not explore the risks of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) subtypes within their CKD group [5]. Furthermore, our study is among the first to analyze glaucoma's associations with dialytic and non-dialytic CKD. Understanding the comorbidities of CKD is important as the effective management of comorbidities among CKD patients has been found to affect their overall clinical outcomes [10].

However, it should be highlighted that there is currently a lack of mention regarding glaucoma-related complications among CKD patients among current guidelines. This gap underscores the need for further research to understand the associations between glaucoma and CKD better. For example, current guidelines for CKD care from the United States (US) and the United Kingdom [11] prioritize the management of complications such as diabetic-related issues [12, 13]. For example, the 2023 US guidelines recommend ophthalmologic screening only for diabetic retinopathy at the time of a type 2 diabetes diagnosis in CKD patients [14]. Therefore, our findings have implications in terms of raising awareness of glaucoma risk for at-risk CKD patients.

It is also worth noting that a higher proportion of patients in the CKD cohort received oral CAI and topical medications containing CAI (seen in both the topical CAI and the β-blocker-CAI hybrid medication) compared to the non-CKD cohort (p < 0.001). This is interesting as the use of such medications among those with impaired renal function is generally done under extreme caution, as it potentially increases the risk of metabolic acidosis and long-term dialysis [15]. Our findings may also highlight the importance of increased awareness regarding the suitability of specific medications, such as CAIs, for CKD patients.

One thousand three hundred eighteen CKD patients were recruited in Ro et al. using diagnostic codes from a Korean electronic health registry [5]. Ro et al. reported an increased risk for open-angle glaucoma (OAG) among CKD patients (HR: 1.546 [CI: 1.363–1.754], p < 0.001). They also found an increased risk of OAG among both their mild cases and advanced cases of CKD, as well as an increased OAG risk among females and those 40 years and older. They also found increased OAG in rural areas (p < 0.001) and lower income (p < 0.001). Their findings complemented our own. One of the similarities between our study design and that of Ro et al. pertained to the primary outcome [5]. Both studies utilized diagnostic codes related to glaucoma and glaucoma-related medications to identify new incident glaucoma among CKD patients. One major difference was that our study utilized internationally recognized ICD diagnostic codes. Unfortunately, diagnostic codes have limitations, such as the inability to determine the eGFR levels. Additionally, we could not assess glaucoma-related ophthalmic parameters such as visual fields. Zhu et al. hinted towards the implications of such limitations. Zhu et al. was a cross-sectional study investigating the risks of major eye diseases, including glaucoma, among CKD patients. Major differences between their study and ours included its cross-sectional nature and the use of actual measurements of eGFR and ophthalmological parameters like cup-to-disc ratio to assess glaucoma risk among CKD patients [16]. Using such a study design, Zhu et al. found no significant association between CKD and glaucoma. This is a factor that future studies should explore further.

We also showed an increased risk of glaucoma among dialytic CKD patients compared to their non-CKD comparators. Interestingly, there is a lack of consensus concerning the association between glaucoma and dialysis. Lim et al. was another retrospective cohort study conducted using a similar electronic health registry. However, the primary difference between their study and ours was that Lim et al. recruited end-stage renal disease patients (ESRD) receiving dialysis and propensity-matched controls without dialysis to investigate their risk for glaucoma. In contrast, our study recruited CKD patients, which encompassed those with End-Stage Renal Disease (ESRD). Such a design by our study allows for a more comprehensive investigation into the effects of CKD on glaucoma risk. Another point to note was that Lim et al. demonstrated an increased risk of closed-angle glaucoma (ACG) among dialytic ESRD patients (HR: 1.550, 95% CI: 1.074–2.239) [17]. However, contrary to our findings, Lim et al. did not observe an increased risk of OAG among their dialysis patients. One possible reason for their results is the variation in study periods. Lim et al. recruited Taiwanese ESRD patients up to the year 2013, while our study included CKD patients up to 2017. This is an important difference as there has been a steady increase in the prevalence of myopia and high myopia over the years, linked in part to the increasing urbanization of Taiwanese society [18]. Furthermore, myopia and high myopia have been associated with an elevated risk of OAG [19].

Regarding gender, our study's aHRs and IRRs for glaucoma were higher in males than females. This contrasts with other studies [5, 17], which identified an increase in glaucoma risk primarily among females. Gender-related factors like ocular axial length may partially explain these findings [20], as axial length has been found to affect the autoregulatory function of the eye in terms of intraocular pressure.

Regarding income and urbanization, ours aligned with Ro et al., who reported an increased risk among those of lower income and in rural areas. Such findings may be due to lower-income individuals being more likely to maintain a less balanced diet, which could contribute to increased glaucoma risk [21, 22]. Additionally, individuals from higher-income brackets residing in urban areas are more likely to attain higher levels of education, potentially leading to increased eye strain in this subgroup. This, in turn, may contribute to their increased glaucoma risk [23]. Our findings emphasize the need to be aware that CKD patients, regardless of their income level, may be at an increased risk of developing glaucoma.

Another finding was the lower magnitude of aHRs and IRRs associated with the glaucoma development among CKD patients with comorbidities compared to those without such a history. This contrasts with findings from Lim et al. [17]. Given that our study is retrospective and relies on diagnostic codes, it is plausible that the clinical severity, duration and history of receiving treatment (e.g. antihypertensives and statins) for the comorbidities studied may have influenced our results obtained [24,25,26,27].

Limitations of our study include the retrospective design and reliance on diagnostic codes that could possibly introduce misclassification bias or the inability to incorporate clinical parameters like proteinuria and eGFR levels [17]. Other unaccounted confounders include ethnicity [28], renal transplant history [29], smoking history as well as medication histories like statins and steroids [27, 29, 30]. Future prospective studies that incorporate laboratory and clinical measurements, such as cup-to-disc ratio, proteinuria, and eGFR, as well as additional subgroup analysis of other covariates like renal transplant history, smoking history, and systemic medication history, can better confirm our findings regarding the association between CKD and glaucoma.