Editorial

The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration☆

Chronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) because of shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium.

Cross-sectional study.

Fifty-one thousand two hundred fifty-three participants from 10 distinct population-based Asian studies.

Age-related macular degeneration was defined using the Wisconsin Age-Related Maculopathy Grading System, the International Age-Related Maculopathy Epidemiological Study Group Classification, or the Beckman Clinical Classification. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 m². A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol, and study groups.

Odds ratio (OR) of early and late AMD.

Among 51 253 participants (mean age, 54.1 ± 14.5 years), 5079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and that of late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% confidence interval [CI], 1.11–1.93; P = 0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05–1.19; P = 0.001). Nevertheless, CKD and eGFR were not associated significantly with early AMD (all P ≥ 0.149).

Pooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are associated significantly with late AMD. This finding further underscores the importance of ocular examinations in patients with CKD.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Age-related macular degeneration (AMD) is the leading cause of visual impairments and blindness worldwide in the elderly and its incidence strongly increases with ages. The etiology of AMD is complex and attributed to the genetic modifiers, environmental factors and gene-environment interactions. Recently, the impacts of air pollution on the development of eye diseases have become the new area of focus, and disordered air exposure combined with inadequate health management has caused problems for the eye health, such as dry eye, glaucoma, and retinopathy, while its specific role in the occurrence of AMD is still not well understood. In order to summarize the progress of this research field, we performed a critical review to summarize the epidemiological and mechanism evidence on the association between air pollutants exposure and AMD. This review documented that exposure to air pollutants will accelerate or worsen the morbidity and prevalence of AMD. Air pollutants exposure may change the homeostasis, interfere with the inflammatory response, and take direct action on the lipid metabolism and oxidative stress in the macula. More attention should be given to understanding the impact of ambient air pollution on AMD worldwide.

This study investigated the pathogenesis of age-related macular degeneration (AMD) using histological methods that are commonly used for atherosclerotic vascular disease (ASVD). 1 normal, 3 early dry AMD, and 1 late dry AMD eyes were obtained from the Lions Eye Bank of Oregon and systematically dissected. They were stained with hematoxylin and eosin, Oil red O, Masson, Elastica van Gieson, Alizarin red, and Prussian blue. Additionally, the normal and late dry AMD eyes were immunostained for a-smooth muscle actin, CD45, and CD68 with Nile red and DAPI. Correlations were found between severity of AMD and lipid accumulation in the deep sclera (+), numbers of drusen between the Bruch's membrane and retinal pigment epithelium (RPE) (+), amount of collagen in the deep sclera (+), and amount of elastin in the deep sclera (-) (P < 0.1). Geographic atrophy, RPE detachment, and abnormal capillary shape and distribution in the choriocapillaris were observed in the fovea of late AMD. There were no stenosis, plaque, hemorrhage, and calcification. Additionally, late AMD tended to have higher smooth muscle thicknesses of the choroidal vascular walls, lower numbers of T lymphocytes in the choroid, and higher numbers of macrophages near the RPE and in the choroid relative to normal (P < 0.1). Macrophages-derived foam cells were detected near the Bruch's membrane in late AMD. Therefore, the present study showed many histological characteristics of ASVD in AMD, which suggests an association between them; however, there were also some histological characteristics of ASVD that were not found in AMD, which indicates that there exist pathogenic differences between them. The results generally support the vascular model of AMD, but some details still need clarification.

Oxidized lowdensity lipoprotein (OxLDL) can impact the formation of choroidal neovascularization (CNV) via regulating endothelial cell proliferation and secretion of inflammatory and angiogenic factors, but the specific molecular mechanism is not clear. In this study, we evaluated the role of molecular pathways that affect angiogenesis at different stages. In vivo, we found that intravitreal injection of OxLDL following the laser photocoagulation significantly enhanced the CNV size. In vitro experiment confirmed that OxLDL impacts the formation of CNV via regulating endothelial cell proliferation in Rhesus monkey choroid-retinal vascular endothelial cells (RF/6A) and secretion of inflammatory and angiogenic factors. OxLDL promotes angiogenesis through increasing VEGF and some other pro-angiogenic factors expression. Treatment with LY294002, a specific inhibitor of the PI3K pathway, could abrogate VEGF-increased angiogenesis. OxLDL induced the TGF-β2/Smad signaling axis to participate in the maintenance of neovascular formation. Treatment with PD98059, a specific inhibitor of the MEK pathway, could abrogate it. We also found that OxLDL increased the level of pro-angiogenic factors and promoted the endothelium-mesenchymal transition (EndMT) process, which is important for early tube formation and late maintaining of angiogenesis respectively. In summary, our results indicate that OxLDL affects CNV formation by increasing VEGF expression in the early stage, with activation of the MEK/ERK pathway. And OxLDL induces the TGF-β2/Smad signaling axis, which leads to EndMT, to affects the later stage of CNV formation by activating the PI3K/AKT pathway.

To investigate the prevalence and associations of visual impairment (VI) and major eye diseases with chronic kidney disease (CKD) in the United States.

Cross-sectional study.

We investigated the prevalence and associations of VI and major eye diseases with CKD among 5,518 participants aged 40 years or older in the 2005-2008 National Health and Nutrition Examination Survey. An estimated glomerular filtration rate of lower than 60 mL/min/1.73 m² was defined as CKD. Corrected visual acuity of worse than 20/40 in the better-seeing eye was defined as VI. Major eye diseases, including any ocular disease, any objectively determined ocular disease, cataract surgery, any retinopathy, diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma were evaluated from questionnaire or retinal photographs using standardized grading protocols.

The prevalence of VI and major eye diseases were approximately 2- to 7-fold higher in participants with CKD than in those without (all P < .05). After controlling for multiple confounders, the presence of CKD was associated with VI (odds ratio [OR]: 2.01, 95% confidence interval [CI]: 1.14-3.54), any ocular disease (OR: 1.65, 95% CI: 1.22-2.22), any objectively determined ocular disease (OR: 1.52, 95% CI: 1.06-2.19), any retinopathy (OR: 1.70, 95% CI: 1.18-2.45), and DR (OR: 2.34, 95% CI: 1.23-4.42). There was no association of CKD with cataract surgery, AMD, or glaucoma. A significant association between CKD and any ocular disease was observed among nondiabetic participants. The presence of CKD was closely related to VI and any retinopathy among diabetic participants.

This nationally representative sample of the US population demonstrated high prevalence and strong associations of VI and major eye diseases with CKD, highlighting the importance of ocular screening among CKD patients and potential common pathogenesis underlying these conditions.

To compare choriocapillaris (CC) flow deficits in eyes with geographic atrophy (GA) or choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) and age-matched healthy control subjects.

Cross-sectional study.

Patients with GA due to AMD, CNV due to AMD, and age-matched healthy subjects presenting to the Doheny-UCLA Eye Centers were enrolled in this cross-sectional institutional review board–approved study. Swept-source optical coherence tomography angiography was performed using a Zeiss PLEX Elite instrument with a 6 × 6-mm scan pattern centered on the fovea. Two repeated volume scans were acquired to allow for image averaging. The instrument predefined en face slab of the CC was used to isolate and display the CC. Both the structural and optical coherence tomography angiography slabs from this location were exported for averaging and signal compensation using Image J. The resultant image was then binarized. The CC flow deficit percentage (FD%) was computed in 4 peripheral 1 × 1-mm squares located at the corners of the images to allow comparison between equidistant regions unaffected by atrophy or CNV.

Twenty eyes of 20 subjects were enrolled in each of the 3 groups (CNV, GA, normal) for this study. The average CC FD% of the 4 peripheral squares was 17.24% ± 2.86% in GA eyes, 15.55% ± 1.03% in CNV eyes, and 15.31% ± 0.93% in healthy controls of a similar age. The FD% in GA eyes was significantly greater than in both normal eyes and eyes with CNV (p= 0.012 and 0.038 respectively). The difference in FD% was not significantly different between CNV eyes and normal eyes for the tested peripheral macular regions (P = .678).

The CC in peripheral macular regions in eyes with GA shows greater impairment than in eyes with CNV.