The eye, the kidney, and cardiovascular disease: old concepts, better tools, and new horizons
Authors: Tariq E. Farrah, Baljean Dhillon, Pearse A. Keane, David J. Webb, Neeraj Dhaun
Journal: Kidney International (2020)

Chronic kidney disease (CKD) is common, with hypertension and diabetes mellitus acting as major risk factors for its development. Cardiovascular disease is the leading cause of death worldwide and the most frequent end point of CKD. There is an urgent need for more precise methods to identify patients at risk of CKD and cardiovascular disease. Alterations in microvascular structure and function contribute to the development of hypertension, diabetes, CKD, and their associated cardiovascular disease. Homology between the eye and the kidney suggests that noninvasive imaging of the retinal vessels can detect these microvascular alterations to improve targeting of at-risk patients. Retinal vessel–derived metrics predict incident hypertension, diabetes, CKD, and cardiovascular disease and add to the current renal and cardiovascular risk stratification tools. The advent of optical coherence tomography (OCT) has transformed retinal imaging by capturing the chorioretinal microcirculation and its dependent tissue with near-histological resolution. In hypertension, diabetes, and CKD, OCT has revealed vessel remodeling and chorioretinal thinning. Clinical and preclinical OCT has linked retinal microvascular pathology to circulating and histological markers of injury in the kidney. The advent of OCT angiography allows contrast-free visualization of intraretinal capillary networks to potentially detect early incipient microvascular disease. Combining OCT’s deep imaging with the analytical power of deep learning represents the next frontier in defining what the eye can reveal about the kidney and broader cardiovascular health. Chronic kidney disease (CKD) is common, with hypertension and diabetes mellitus acting as major risk factors for its development. Cardiovascular disease is the leading cause of death worldwide and the most frequent end point of CKD. There is an urgent need for more precise methods to identify patients at risk of CKD and cardiovascular disease. Alterations in microvascular structure and function contribute to the development of hypertension, diabetes, CKD, and their associated cardiovascular disease. Homology between the eye and the kidney suggests that noninvasive imaging of the retinal vessels can detect these microvascular alterations to improve targeting of at-risk patients. Retinal vessel–derived metrics predict incident hypertension, diabetes, CKD, and cardiovascular disease and add to the current renal and cardiovascular risk stratification tools. The advent of optical coherence tomography (OCT) has transformed retinal imaging by capturing the chorioretinal microcirculation and its dependent tissue with near-histological resolution. In hypertension, diabetes, and CKD, OCT has revealed vessel remodeling and chorioretinal thinning. Clinical and preclinical OCT has linked retinal microvascular pathology to circulating and histological markers of injury in the kidney. The advent of OCT angiography allows contrast-free visualization of intraretinal capillary networks to potentially detect early incipient microvascular disease. Combining OCT’s deep imaging with the analytical power of deep learning represents the next frontier in defining what the eye can reveal about the kidney and broader cardiovascular health. Chronic kidney disease (CKD) affects ∼10% of the world’s population, and its incidence is increasing.1Gansevoort R.T. Correa-Rotter R. Hemmelgarn B.R. et al.Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.Lancet. 2013; 382: 339-352Abstract Full Text Full Text PDF PubMed Scopus (703) Google Scholar Hypertension and diabetes mellitus are also common worldwide, with an estimated prevalence of ∼30% and ∼10%, respectively; both are important risk factors for the development and progression of CKD.2Kearney P.M. Whelton M. Reynolds K. et al.Global burden of hypertension: analysis of worldwide data.Lancet. 2005; 365: 217-223Abstract Full Text Full Text PDF PubMed Scopus (3983) Google Scholar,3Sarwar N. Gao P. 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Thus, there is an urgent unmet need for simple noninvasive methods to allow earlier identification and risk stratification of patients at increased risk of progressive end-organ injury and subsequent end-stage renal disease and CVD. Microvessels (luminal diameter <300 μm) regulate tissue perfusion and contribute to systemic vascular resistance. This ability is closely linked to endothelial function. Several pathophysiological processes may contribute to and be a consequence of endothelial dysfunction, with downstream effects on microvessels (Figure 1).5Brunner H. Cockcroft J.R. Deanfield J. et al.Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. 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Higano S.T. et al.Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.J Am Coll Cardiol. 2004; 44: 2137-2141Crossref PubMed Scopus (635) Google Scholar providing a rationale for imaging accessible microvessels, such as those of the eye. Transparency of the ocular media allows direct visualization of the microvasculature that may be affected by systemic diseases such as hypertension, diabetes, and CKD. Here, we discuss the basis for the eye to act as a window to the kidney and evidence for the microcirculation of the eye to report risk of adverse renal and CVD outcomes. The eye and kidney have several structural, developmental, and organizational similarities that support the concept that ocular tissues might reflect renal disease (Figure 2). Bruch’s membrane divides the posterior pole of the eye into the retina (a laminated neurovascular structure) and choroid (an almost entirely vascular structure), collectively termed chorioretinal. Bruch’s membrane and the glomerular basement membrane (GBM) both contain a network of α3, α4, and α5 type IV collagen chains.12Booij J.C. Baas D.C. Beisekeeva J. et al.The dynamic nature of Bruch’s membrane.Prog Retin Eye Res. 2010; 29: 1-18Crossref PubMed Scopus (252) Google Scholar,13Boutaud A. Borza D.-B. Bondar O. et al.Type IV collagen of the glomerular basement membrane.J Biol Chem. 2000; 275: 30716-30724Crossref PubMed Google Scholar Thus, inherited or acquired diseases involving type IV collagen can affect both organs; the presence of coexistent nephropathy and retinopathy in Alport syndrome is a well-described example of this (Supplementary Figure S1).14Savige J. Sheth S. 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Novel indices of retinal vascular network geometry, such as fractal dimension (Dfs), can be derived from skeletonized vessel maps from retinal photographs (Figure 3). These indices identify suboptimal vascular branching patterns that may reflect and promote microvascular damage in systemic disease.38Murray C.D. The physiological principle of minimum work: I. The vascular system and the cost of blood volume.Proc Natl Acad Sci U S A. 1926; 12: 207-214Crossref PubMed Google Scholar,39Patton N. Aslam T.M. MacGillivray T. et al.Retinal image analysis: concepts, applications and potential.Prog Retin Eye Res. 2006; 25: 99-127Crossref PubMed Scopus (438) Google Scholar The presence and severity of retinopathy, vessel caliber change, and fractal deviations have been strongly linked to hypertension, diabetes mellitus, and CKD as well as CVD end points.Table 1Retinal vascular metrics from retinal photographyMetricDerivationInterpretationStrengthsWeaknessesCRAEWidths of the reflective erythrocyte column within the vessel lumen from 6 largest arterioles located in a zone 0.5–1 disc diameters away from the optic disc marginSummarized surrogate measure of internal arteriolar widths that reflect narrowing or wideningProvides insight into disease affecting arteriolesRelatively easy to obtain and automateSummarized rather than absolute valuesPotential for magnification and positioning errorsValues are not true vessel widths nor cross-sectional area that may be more relevant to diseaseCRVEWidths of the reflective erythrocyte column within the vessel lumen from 6 largest venules located in a zone 0.5–1 disc diameters away from the optic disc marginSummarized surrogate measure of internal venular widths that reflect narrowing or wideningProvides insight into disease affecting venulesRelatively easy to obtain and automateSummarized rather than absolute valuesPotential for magnification and positioning errorsValues are not true vessel widths nor cross-sectional area that may be more relevant to diseaseAVRRatio of CRAE to CRVEChanges usually indicative of generalized arteriolar narrowingAvoids magnification errorsDimensionlessProvides little insight into the underlying pathophysiologyIf used alone, it can lead to incorrect inferences: both CRVE and CRAE narrow with increasing blood pressure, producing a normal AVR masking any associationDfImages are binarized and vessel maps are broken into short segments (skeletonization)Entire image divided into boxes, and those containing a vessel segment are counted. The process is repeated with different box sizes. The number of boxes with vessel segments is plotted against the total number of boxes in the imageIndex of vessel network spatial occupancy (complexity)Reduced (sparse) or increased (dense) complexity relative to health or within a cohort reflects suboptimal vascular network geometryBased on robust models of the optimality of vascular branchingMay be more sensitive than calibers in reflecting microvascular disease in other organ bedsLess widely studied than calibersSimplifies 3-dimensional vascular networks into 2-dimensional skeletonized mapsAVR, arteriole-to-venule ratio; CRAE; central retinal arteriolar equivalent; CRVE, central retinal venular equivalent; Df, fractal dimension. Open table in a new tab AVR, arteriole-to-venule ratio; CRAE; central retinal arteriolar equivalent; CRVE, central retinal venular equivalent; Df, fractal dimension. Retinal arteriolar narrowing is thought to reflect increased systemic vascular tone. 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