Deep Capillary Plexus Microaneurysms A Sign of CKD in Diabetic Retinopathy

New research has identified an association between chronic kidney disease (CKD) and reduced vessel length density in the deep capillary plexus (DCP) ischemia with increased instances of macular microaneurysms (MA), introducing MA count as a possible marker for systemic microvascular disease in patients with referable diabetic retinopathy (refDR).1

“A heavier MA burden would signal deep capillary plexus (DCP) ischemia and track with extraocular vascular comorbidity in high-risk patients with refDR,” wrote study investigator Amani Fawzi, MD, a professor of ophthalmology at Northwestern University’s Feinberg School of Medicine, and colleagues.1 “Demonstrating such relationships could elevate MA counting from a purely ophthalmic marker of DR activity to a readily accessible proxy for an individual's broader microvascular health, enabling earlier interventions and closer collaboration between ophthalmologists and primary care providers.”

A noninvasive, depth-resolved approach to microvessel imaging, optical coherence tomography angiography (OCTA) provides particular quantitative perfusion metrics within the deep capillary plexus (DCP), the network tied to visual decline and DR complications. There has been limited exploration of these OCTA-derived macular perfusion metrics with MA counts, ultra-widefield fluorescein angiography ischemia, and CKD.2

To evaluate the utility of MA count as a screening tool for systemic vascular comorbidities, Fawzi and colleagues conducted a cross-sectional study of patients who underwent multiple fovea-centered 3 × 3-mm OCTA scans (304 × 304 pixels). They calculated vessel density, vessel length density, and geometric perfusion deficits on the averaged images for the superficial capillary plexus (SCP) and DCP slabs. In the DCP, large superficial vessels were subtracted before GPD calculation to avoid projection artifacts.1

OCTA imaging was captured in 83 eyes for 65 patients with refDR without diabetic macular edema (DME), and with CKD, defined as an eGFR persistently below 60 mL/min/1.73 m² for at least 3 months. While DME commonly occurs in refDR, this study excluded eyes with this condition.1

Univariate linear mixed models were fitted for macular MA count with fixed effects for DR severity (moderate nonproliferative DR [NPDR], severe NPDR, or proliferative DR [PDR]), axial length, lens status (phakia or pseudophakia), diabetes type and duration, HbA1c, as well as the presence of hypertension, ischemic heart disease, CKD, cerebrovascular disease, or dyslipidemia.1

Additionally, among the DCP and SCP slabs, investigators analyzed vessel density (VD-DCP/VD-SCP), vessel length density (VLD-DCP/ VLD), geometric perfusion deficits (GPD-SCP/ GPD-DCP), and nonperfusion index (NPI).1 In univariate analyses, with MA count as the dependent variable and each parameter entered as a single fixed effect, increased MA count was significantly associated with CKD, NPI, VLD-DCP, GPD-SCP, and GPD-DCP.1

To further understand these associations as independent of potential confounders, Fawzi and colleagues fitted 3 multivariable large multimodal models, including VLD-DCP, GPD-SCP, or GPD-DCP.1 Upon multivariable analysis, CKD remained a significant independent predictor of higher macular MA count across all models (β ≈ 9.6–10.6; P ≤ 0.013). Among the OCTA metrics, only VLD-DCP remained significant (β = −2.46; P = 0.003), whereas GPD-SCP (P = 0.201) and GPD-DCP (P = 0.089) were not. Age showed a modest inverse association with MA count in the VLD-DCP model (P = 0.049).1 In a sensitivity analysis including BMI as an additional covariate, CKD and VLD-DCP remained independently associated with MA count, whereas BMI was not significant.1

In a receiver operating characteristic analysis, investigators used MA count as the predictor and CKD status as the binary outcome, demonstrating that macular MA burden had a fair discriminative ability for identifying CKD, with an area under the curve (AUC) of 0.755. The Youden index was maximized by a threshold of 14 macular MAs, yielding a sensitivity of 58.8% and a specificity of 86.4% for detecting CKD.1

“Taken together, our findings highlight macular MA burden as a cross-disciplinary biomarker that encapsulates both localized deep capillary plexus ischemia and systemic microvascular injury reflected by CKD,” investigators concluded. “By combining high-resolution OCTA with UWF-FA, we demonstrate that macular MAs can stratify systemic risk within a relatively high-risk cohort."1

References

1. Busza A, Fawzi AA. Macular Microaneurysms Are Associated With Chronic Kidney Disease and Deep Capillary Plexus Ischemia in Referable Diabetic Retinopathy. Investigative Ophthalmology & Visual Science. 2025;66(15):3-3. doi:https://doi.org/10.1167/iovs.66.15.3

2. Ong JX, Konopek N, Fukuyama H, Fawzi AA. Deep Capillary Nonperfusion on OCT Angiography Predicts Complications in Eyes with Referable Nonproliferative Diabetic Retinopathy. Ophthalmology Retina. Published online July 2022. doi:https://doi.org/10.1016/j.oret.2022.06.018