Association between Dry Age-Related Macular Degeneration, Chronic Kidney Disease and Hypertension: a Retrospective Chart Review Study

Introduction

Chronic kidney disease (CKD) and age-related macular degeneration (AMD) are major public health concerns in the recent years. This is due to the increasing prevalence of CKD and AMD in the aging population worldwide. In the US alone, the prevalence of CKD is projected to increase from 14.4% in 2020 to 16.7% in 2030; while the prevalence of AMD is estimated to double by 2050 [1]. CKD is usually defined as decreased glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m2, or by markers of kidney damage e.g. proteinuria and elevated creatinine for at least 3 months [2]. Unfortunately, many cases of kidney failure go largely undiagnosed due to the lack of recognizable symptoms and in turn lead to premature death [3]. On the other hand, AMD is the leading cause of blindness in the elderly, especially those aged 50 and older [4]. Dry AMD, the more common form of the disease, is characterized by the accumulation of lipoprotein deposits called drusen under the retinal pigment epithelial (RPE) cells. Drusen accumulation further causes photoreceptor/RPE cell death, choroidal vascularization, and scarring leading to subsequent loss of vision [5]. Often, AMD has been noted to coexist with CKD and thus has led many investigators to study the relationship between the two diseases.

Both AMD and CKD share common risk factors such as hypertension [2, 6], smoking [2, 7], and obesity [2, 8]. Besides the traditional risk factors, oxidative stress and endothelial dysfunction are also involved in the pathogenesis of both CKD and AMD [2, 9]. Endothelial dysfunction due to atherosclerosis causes microvasculature damage and can occur both in kidney and the eyes [10, 11, 12, 13]. In addition, an association between low eGFR rate, a marker for CKD and increased risk of late AMD has also been reported [14]. Hypertension, a major risk factor for CKD can cause atherosclerosis which in turn contributes to risk for AMD [15, 16]. Because of this common pathogenesis, it is likely that there may be an association between HTN, CKD and AMD.

Although a relationship has been made between AMD and CKD in selected populations, the associated link with HTN remains elusive. The Beaver Dam Eye Study found an association between CKD and early AMD, but did not find an association with exudative AMD or with Geographic Atrophy [17]. In Taiwanese population, patients that have mild to moderate CKD are at a higher risk of developing AMD than those without CKD [18]. On the other hand, Korean subjects with CKD are twice as likely to have AMD or drusen compared to subjects without CKD. Similar conclusion was drawn from a meta-analysis pooled data from 12 studies, where higher rate of AMD in CKD population was found [19]. Indeed, these studies focused on a homogenous population of the Asia-Pacific region, which makes it challenging to generalize the results across other races. These studies also failed to consider comorbid diseases or diagnostic blood/ urine parameters that may play a considerable role in AMD disease manifestation. In the current study we intend to elucidate the relationship between HTN, dry AMD and CKD using data from a population that comprises of diverse racial cohorts. Because, race may play a role in increased risk for AMD, we further explored if there could be an association between race, CKD and dry AMD. This study will help increase understanding of the prospective link between HTN, CKD and dry AMD triad so that when a diagnosis of CKD is made, ophthalmologic surveillance may be initiated.

Discussion

In this cross-sectional population-based study, we investigated the association between HTN, CKD and dry AMD. Though we did not find a significant association between the dry AMD, CKD and hypertension, significant independant effects due to CKD and HTN were noted. Only few studies have addressed the systemic effects of HTN in manifestation of either AMD or CKD alone, this preliminary study highlights the odds of having dry AMD in the scenario of coexisting HTN and CKD. Previous studies show data correlating HTN with CKD and/or AMD, but with discrepancies between their findings. For example, studies by Deva R, et al. [3, 20]; concluded that age and renal failure but not hypertension were determinants for AMD [20]. Both Framingham Heart and Eye and Beaver Dam Eye studies show an association between AMD and hypertension [21, 22]. Along the same lines, a correlation has been shown between the duration of arterial hypertension and increase in count and size of drusen in monkeys [23]. Also, an isolated study linked increased diastolic blood pressure to exudative AMD, however, in the current study we did not include subjects with exudative AMD [24]. Due to the limited number of studies available, further evidence based clinical trials are needed to validate the negative impact of uncontrolled HTN in a setting of CKD patients. While our aim in this study was to find if HTN increased the risk of dry AMD in CKD patients, we acknowledge a few limitations in the study design that may have led to skewed outcomes. For instance, we did not segregate various grades of dry AMD and CKD, nor did we classify HTN patients with respect to their blood pressure control, medication types and compliance, in the study design. In addition, patients with a diagnosis of HTN may technically not be hypertensive, as many would have been on treatment resulting in hypertension control. Exclusion of such parameters may have altered the outcome of this study and therefore should be addressed in any future study. The authors would like to emphasize that the preliminary findings from this exploratory study should not be considered conclusive by any means, but instead lead researchers to investigate further.

Another exciting finding of our study was noted when we stratified subjects by race due to the diverse ethical presence in the study population. We report a positive association between dry AMD and CKD in the Hispanic population after adjusting for confounders. Specifically, we found that Hispanics are 2.35 times more likely to present with dry AMD in the presence of CKD when compared to those without. To our knowledge, this is the only study to report such an association with racial preference in manifesting of comorbid diseases like dry AMD and CKD. While an association between CKD and AMD has been reported previously, many of those studies have solely focused on homogenous population largely involving the Asia-Pacific geographic region. Therefore, extrapolating their findings universally may not be appropriate. In addition, variability between population-based studies also exists in design, methodology and statistical analysis. Specifically, there are significant differences between inclusion criteria, study populations, biomarkers for CKD, CKD severity, and AMD grading. Furthermore, studies utilized different effect estimates to document the relationship between CKD and AMD (Incidence, prevalence, crude odds ratio, multivariate odds ratio, etc). Lastly, depending on the study, different confounding factors were included for their multivariate adjustment [19]. While the findings of this racial disparity on dry AMD and CKD is a novel finding, studies are warranted to further define this relationship.

It is not new to the readers that racial disparity may influence AMD and CKD disease differently. In review, Caucasians have a higher risk of developing AMD, and African Americans and Hispanics are at a higher risk for developing CKD [25, 26, 27]. However, sadly, since 2000, the number of Hispanics with kidney failure have increased by more than 70 percent compared to non-Hispanics. Hispanics are almost 1.3 times more likely to be diagnosed with kidney failure [28]. The reason behind this disparity is not well understood, but is suggestive of an association with lower socio-economic status and lack of health insurance or access to preventive care [29]. Other factor that may add negative impact on the health of Hispanic Americans is their reduced physical activity and overall sedentary lifestyle. Another study found that 44% of Hispanic Americans were not taking their blood pressure medication despite a diagnosis of HTN [30]. The fact that CKD is a major public health concern with marked variability in disease progression with respect to age, gender and race; information from this study advocates nephrology health care providers to act as sentinels for early detection of other concomitant diseases like dry AMD.

In summary, we present a positive correlation between dry AMD, CKD, and HTN without adjusting for age, gender and race. Like any population-based study, this study is not free of limitations:

• Due to possible selection bias as we used the ICD-10 codes for data retrieval.
• We did not account for the grade/severity of either CKD or dry AMD, which may have limited our ability to correlate HTN with the severity of either disease.

Nonetheless, the observation presented here does not undermine the risk of HTN in dry AMD and CKD disease manifestations. Both CKD and AMD are multifactorial disease and HTN is a common modifiable risk factor and therefore needs to be managed stringently at the primary health care level. While, we also report an incidental but novel finding of Hispanic race correlating to higher prevalence for dry AMD in CKD patients, this needs further definition with studies solely focused on racial disparity. The meaningful findings from this study not only initiates an area of research for future exploration, in addition it may guide clinicians to increased awareness of such relationships so that they may educate patients on routine health exams, lifestyle changes and potential vitamin supplementation when appropriate. Additionally, dry AMD may progress to the exudative form, which may result in irreversible loss of vision and blindness, particularly in patients with other vascular risk factors, and increased surveillance would improve visual outcomes in these patients.

Funding Sources

Robertson-Poth Distinguished Chair in Ophthalmology Endowment Fund, UTMB.