The eye, the kidney, and cardiovascular disease: old concepts, better tools, and new horizons

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. Seshasai S.R. et al.Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.Lancet. 2010; 375: 2215-2222Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These systemic diseases are strongly associated with incident cardiovascular disease (CVD), and their interrelationship contributes to CVD being the most common end point of CKD.4Thomas B. Matsushita K. Abate K.H. et al.Global cardiovascular and renal outcomes of reduced GFR.J Am Soc Nephrol. 2017; 28: 2167-2179Crossref PubMed Scopus (71) Google Scholar The current clinical tools lack precision to detect, stratify, and track individual patients at increased risk of progressive CKD and CVD, and before end-organ damage. 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. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.J Hypertens. 2005; 23: 233-246Crossref PubMed Scopus (546) Google Scholar Alterations in microvascular structure and function contribute to the development and progression of hypertension, diabetes, CKD, and CVD.5Brunner H. Cockcroft J.R. Deanfield J. et al.Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.J Hypertens. 2005; 23: 233-246Crossref PubMed Scopus (546) Google Scholar, 6Houben A. Martens R.J.H. Stehouwer C.D.A. Assessing microvascular function in humans from a chronic disease perspective.J Am Soc Nephrol. 2017; 28: 3461-3472Crossref PubMed Scopus (21) Google Scholar, 7Stehouwer C.D.A. Microvascular dysfunction and hyperglycemia: a vicious cycle with widespread consequences.Diabetes. 2018; 67: 1729-1741Crossref PubMed Scopus (36) Google Scholar Importantly, such changes precede the development of end-organ damage8Halcox J.P. Schenke W.H. Zalos G. et al.Prognostic value of coronary vascular endothelial dysfunction.Circulation. 2002; 106: 653-658Crossref PubMed Scopus (1133) Google Scholar and appear modifiable.9Remuzzi A. Sangalli F. Macconi D. et al.Regression of renal disease by angiotensin II antagonism is caused by regeneration of kidney vasculature.J Am Soc Nephrol. 2016; 27: 699-705Crossref PubMed Scopus (19) Google Scholar Moreover, microvascular dysfunction in peripheral beds mirrors dysfunction in visceral beds,10Anderson T.J. Uehata A. Gerhard M.D. et al.Close relation of endothelial function in the human coronary and peripheral circulations.J Am Coll Cardiol. 1995; 26: 1235-1241Crossref PubMed Scopus (1648) Google Scholar,11Bonetti P.O. Pumper G.M. 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. Leys A. et al.Ocular features in Alport’s syndrome: pathogenesis and clinical significance.Clin J Am Soc Nephrol. 2015; 10: 703-709Crossref PubMed Scopus (0) Google Scholar,15Colville D. Savige J. Branley P. Wilson D. Ocular abnormalities in thin basement membrane disease.Br J Ophthalmol. 1997; 81: 373-377Crossref PubMed Google Scholar As another example, anti-GBM disease is characterized by the development of IgG autoantibodies directed against the α3 chain, which are deposited on glomerular and alveolar basement membranes triggering a crescentic glomerulonephritis and pulmonary hemorrhage, respectively.16McAdoo S.P. Pusey C.D. Anti-glomerular basement membrane disease.Clin J Am Soc Nephrol. 2017; 12: 1162-1172Crossref PubMed Scopus (57) Google Scholar Similar linear IgG deposition on Bruch’s membrane has been reported in patients with anti-GBM disease who developed concurrent choroidal ischemia and retinal detachment.17Jampol L.M. Lahov M. Albert D.M. Craft J. Ocular clinical findings and basement membrane changes in Goodpasture’s syndrome.Am J Ophthalmol. 1975; 79: 452-463Abstract Full Text PDF PubMed Google Scholar,18Rowe P.A. Mansfield D.C. Dutton G.N. Ophthalmic features of fourteen cases of Goodpasture’s syndrome.Nephron. 1994; 68: 52-56Crossref PubMed Google Scholar The arrangement of the choroidal capillary (choriocapillaris) endothelium, Bruch’s membrane, and retinal pigment epithelium mirrors that of the glomerular endothelium, GBM, and podocyte (Figure 2). The pathological relevance of this homology is readily appreciated in membranoproliferative glomerulonephritis type II, in which electron dense deposits are found on the GBM and on Bruch’s membrane.19McAvoy C.E. Silvestri G. Retinal changes associated with type 2 glomerulonephritis.Eye. 2005; 19: 985-989Crossref PubMed Scopus (31) Google Scholar Evidence of complement system dysregulation as a key driver of renal and retinal deposit formation in membranoproliferative glomerulonephritis20Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis—a new look at an old entity.N Engl J Med. 2012; 366: 1119-1131Crossref PubMed Scopus (288) Google Scholar and drusen deposition on Bruch’s membrane in age-related macular degeneration has extended the link between the eye and the kidney to include immune regulation.21Whitmore S.S. Sohn E.H. Chirco K.R. et al.Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.Prog Retin Eye Res. 2015; 45: 1-29Crossref PubMed Scopus (83) Google Scholar,22Dalvin L.A. Fervenza F.C. Sethi S. Pulido J.S. Manifestations of complement-mediated and immune complex-mediated membranoproliferative glomerulonephritis: a comparative consecutive series.Ophthalmology. 2016; 123: 1588-1594Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The human retinal circulation develops predominantly by angiogenesis, where new vessels bud from preexisting ones, to supply the inner two-thirds of the retina.23Hughes S. Yang H. Chan-Ling T. Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis.Invest Ophthalmol Vis Sci. 2000; 41: 1217-1228PubMed Google Scholar In the kidney, the peritubular capillaries and vasa recta populate the medulla and inner cortex in a similar manner.24Sequeira Lopez M.L. Gomez R.A. Development of the renal arterioles.J Am Soc Nephrol. 2011; 22: 2156-2165Crossref PubMed Scopus (86) Google Scholar In contrast, the choroidal and glomerular endothelium is reported to develop by vasculogenesis, where clusters of progenitor cells form islands of de novo vessels, giving rise to the choriocapillaris and renal corpuscle, respectively24Sequeira Lopez M.L. Gomez R.A. Development of the renal arterioles.J Am Soc Nephrol. 2011; 22: 2156-2165Crossref PubMed Scopus (86) Google Scholar,25Nickla D.L. Wallman J. The multifunctional choroid.Prog Retin Eye Res. 2010; 29: 144-168Crossref PubMed Scopus (683) Google Scholar; although for the glomerulus, this is debated.26Munro D.A.D. Davies J.A. Vascularizing the kidney in the embryo and organoid: questioning assumptions about renal vasculogenesis.J Am Soc Nephrol. 2018; 29: 1593-1595Crossref PubMed Scopus (3) Google Scholar The choriocapillaris endothelium has ∼80 nm fenestrations allowing fluid exchange within the subretinal space.27Anand-Apte B. Hollyfield J.G. Developmental anatomy of the retinal and choroidal vasculature.in: Dratt D. Besharse J. Dana R. Encyclopedia of the Eye. Elsevier, Amsterdam2010: 9-15Crossref Google Scholar The glomerular endothelium has similarly sized fenestrations that facilitate ultrafiltration into the Bowman’s capsule.28Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (498) Google Scholar The retinal and medullary circulations each receive <20% of the total ocular and renal blood flow, respectively, despite the high metabolic activity of the retinal photoreceptors and the medullary countercurrent exchange system. Thus, both regions have a lower oxygen tension than do their choroidal and cortical counterparts, creating matched chorioretinal and corticomedullary oxygen gradients (Figure 2). The choroidal circulation receives ∼80% of ocular blood flow and passively oxygenates key visual apparatus including the pigment epithelium and photoreceptors, particularly within the avascular fovea.25Nickla D.L. Wallman J. The multifunctional choroid.Prog Retin Eye Res. 2010; 29: 144-168Crossref PubMed Scopus (683) Google Scholar This role demands blood flow that is 4-fold higher per unit mass than the kidney and 10-fold higher than the brain,25Nickla D.L. Wallman J. The multifunctional choroid.Prog Retin Eye Res. 2010; 29: 144-168Crossref PubMed Scopus (683) Google Scholar indicating the importance of the choroid to global retinal health. Choroidal vascular change may therefore predate the onset of overt retinopathy and, if detectable, might allow earlier identification of incipient disease. All components of the renin-angiotensin-aldosterone system are widely expressed throughout the retinal and choroidal vascular networks (Figure 2).29Wilkinson-Berka J.L. Agrotis A. Deliyanti D. The retinal renin-angiotensin system: roles of angiotensin II and aldosterone.Peptides. 2012; 36: 142-150Crossref PubMed Scopus (43) Google Scholar Similar to effects in the kidney, angiotensin II acting via type I receptors leads to chorioretinal vasoconstriction30Rockwood E.J. Fantes F. Davis E.B. Anderson D.R. The response of retinal vasculature to angiotensin.Invest Ophthalmol Vis Sci. 1987; 28: 676-682PubMed Google Scholar but may also modulate glial-pericyte-vasomotor signaling that maintains retinal neurovascular integrity.31Fletcher E.L. Phipps J.A. Ward M.M. et al.The renin-angiotensin system in retinal health and disease: its influence on neurons, glia and the vasculature.Prog Retin Eye Res. 2010; 29: 284-311Crossref PubMed Scopus (85) Google Scholar Excessive renin-angiotensin-aldosterone system activation contributes to the pathogenesis of diabetic retinopathy and both diabetic and nondiabetic CKD.32Mauer M. Zinman B. Gardiner R. et al.Renal and retinal effects of enalapril and losartan in type 1 diabetes.N Engl J Med. 2009; 361: 40-51Crossref PubMed Scopus (530) Google Scholar Moreover, renin-angiotensin-aldosterone system inhibition in clinical trials prevents the development and progression of diabetic retinopathy and nephropathy, probably independently of effects on blood pressure (BP).32Mauer M. Zinman B. Gardiner R. et al.Renal and retinal effects of enalapril and losartan in type 1 diabetes.N Engl J Med. 2009; 361: 40-51Crossref PubMed Scopus (530) Google Scholar In the eye, endothelin-1 mediates vasoconstriction via endothelin-A receptors, which are predominantly localized to choroidal and retinal vascular smooth muscle cells. In contrast, endothelin-B receptors appear confined to neuronal and glial structures.33MacCumber M.W. D’Anna S.A. Endothelin receptor-binding subtypes in the human retina and choroid.Arch Ophthalmol. 1994; 112: 1231-1235Crossref PubMed Google Scholar Similarly in the kidney, endothelin-A receptors are localized to the vascular smooth muscle of glomeruli and vasa recta whereas endothelin-B receptors are mainly localized to the collecting system (Figure 2). Selective endothelin-A receptor blockade in the eye increases retinal blood flow and reduces both retinal pericyte apoptosis and retinal thinning in a mouse model of type 2 diabetes.34Chou J.C. Rollins S.D. Ye M. et al.Endothelin receptor-A antagonist attenuates retinal vascular and neuroretinal pathology in diabetic mice.Invest Ophthalmol Vis Sci. 2014; 55: 2516-2525Crossref PubMed Scopus (22) Google Scholar These effects are mirrored in the kidney where selective endothelin-A blockade ameliorates intraglomerular hypertension, podocytopathy, and fibrosis to slow CKD progression.35Dhaun N. Goddard J. Webb D.J. The endothelin system and its antagonism in chronic kidney disease.J Am Soc Nephrol. 2006; 17: 943-955Crossref PubMed Scopus (159) Google Scholar,36Heerspink H.J.L. Parving H.-H. Andress D.L. et al.Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.Lancet. 2019; 393: 1937-1947Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Autonomic innervation in the eye is limited to the choroidal circulation where sympathetic activation mediates choroidal vasoconstriction25Nickla D.L. Wallman J. The multifunctional choroid.Prog Retin Eye Res. 2010; 29: 144-168Crossref PubMed Scopus (683) Google Scholar in a similar manner to effects on intrarenal vessels. Thus, the choroidal microvasculature, rather than retinal vessels, may more accurately reflect the renal microvasculature, particularly in diseases characterized by excessive sympathetic activation, such as CKD.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 Qualitative retinopathy grading (e.g., microaneurysms, hemorrhages, or focal arteriolar narrowing) and computer-assisted quantitative retinal vessel caliber analysis of digital fundus photographs have been the mainstay of retinal imaging for the last 20 years (Supplementary Figure S2). As retinopathy reflects established end-organ damage, detecting changes in retinal vessel caliber that precede this overt damage may allow earlier identification of at-risk patients.37Wong T.Y. Mitchell P. The eye in hypertension.Lancet. 2007; 369: 425-435Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar The most established metrics are derived from arteriolar and venular widths from vessels close to the optic disc (Table 1; Supplementary Figure S2). 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. Large cross-sectional studies demonstrate strong independent associations between BP and generalized and focal arteriolar narrowing.40Cheung C.Y. Ikram M.K. Sabanayagam C. Wong T.Y. Retinal microvasculature as a model to study the manifestations of hypertension.Hypertension. 2012; 60: 1094-1103Crossref PubMed Scopus (115) Google Scholar Longitudinal studies have shown that retinal arteriolar narrowing is associated with a ∼2-fold increased risk of incident hypertension independent of age, sex, baseline BP, and other CVD risk factors (Supplementary Table S1), supporting the concept that retinal microvascular changes precede overt disease and are able to identify at-risk individuals. This paradigm has been challenged more recently by data suggesting a high prevalence of masked hypertension at the time of retinal imaging as detected by ambulatory BP monitoring.41Wei F.F. Zhang Z.Y. Thijs L. et al.Conventional and ambulatory blood pressure as predictors of retinal arteriolar narrowing.Hypertension. 2016; 68: 511-520Crossref PubMed Scopus (0) Google Scholar Additionally, systolic BP and mean arterial pressure show an inverse linear relationship with Df in keeping with rarefaction.42Liew G. Wang J.J. Cheung N. et al.The retinal vasculature as a fractal: methodology, reliability, and relationship to blood pressure.Ophthalmology. 2008; 115: 1951-1956Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 43Cheung C.Y. Tay W.T. Mitchell P. et al.Quantitative and qualitative retinal microvascular characteristics and blood pressure.J Hypertens. 2011; 29: 1380-1391Crossref PubMed Scopus (121) Google Scholar, 44Cheung C.Y. Thomas G.N. 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Microvascular dysfunction and hyperglycemia: a vicious cycle with widespread consequences.Diabetes. 2018; 67: 1729-1741Crossref PubMed Scopus (36) Google Scholar More so than in hypertension, retinal venular widening is prevalent in diabetes, correlates with the severity of retinopathy, and predicts progression to overt retinopathy, suggesting a different pathophysiological basis for the change in vessel caliber.46Nguyen T.T. Wang J.J. Sharrett A.R. et al.Relationship of retinal vascular caliber with diabetes and retinopathy: the Multi-Ethnic Study of Atherosclerosis (MESA).Diabetes Care. 2008; 31: 544-549Crossref PubMed Scopus (126) Google Scholar Wider venules are seen in response to chronic hypoxia47Saldívar E. Cabrales P. Tsai A.G. Intaglietta M. Microcirculatory changes during chronic adaptation to hypoxia.Am J Physiol Heart Circ Physiol. 2003; 285: H2064-H2071Crossref PubMed Google Scholar and associate with endothelial dysfunction,48Nguyen T.T. Islam F.M. 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Klein R. et al.Retinal microvascular calibre and risk of diabetes mellitus: a systematic review and participant-level meta-analysis.Diabetologia. 2015; 58: 2476-2485Crossref PubMed Scopus (0) Google Scholar Finally, reduced Df in those with diabetes can predict incident neuropathy, nephropathy, and progressive retinopathy, independent of other risk factors for microvascular complications although the strength of these associations is modest.54Grauslund J. Green A. Kawasaki R. et al.Retinal vascular fractals and microvascular and macrovascular complications in type 1 diabetes.Ophthalmology. 2010; 117: 1400-1405Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar,55Cheung C.Y. Sabanayagam C. Law A.K. et al.Retinal vascular geometry and 6 year incidence and progression of diabetic retinopathy.Diabetologia. 2017; 60: 1770-1781Crossref PubMed Scopus (0) Google Scholar Retinopathy (diabetic, hypertensive, or otherwise) is more prevalent in patients with CKD, independent of standard CVD risk factors including diabetes and proteinuria.56Grunwald J.E. Alexander J. Maguire M. et al.Prevalence of ocular fundus pathology in patie