The Eye, The Kidney, And Cardiovascular Disease: Old Concepts, Better Tools, And New Horizons

Contact: emily.li@wecistanche.com

Tariq E. Farrah1,2 , Baljean Dhillon3,4 , Pearse A. Keane5 , David J. Webb1 and Neeraj Dhaun1,2 

1 University/BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK; 2 Department of Renal Medicine, Royal Infifirmary of Edinburgh, Edinburgh, UK; 3 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK; 4 Princess Alexandra Eye Pavilion, Edinburgh, UK; and 5 NIHR Biomedical Research Centre for Ophthalmology, Moorfifields Eye Hospital, London, UK

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KEYWORDS: chronic kidney disease; hypertension; imaging; microcirculation; ocular; proteinuria

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 defifining what the eye can reveal about the kidney and broader cardiovascular health. 

Chronic kidney disease (CKD) affects w10% of the world’s population, and its incidence is increasing.1 Hypertension and diabetes mellitus are also common worldwide, with an estimated prevalence of w30% and w10%, respectively; both are important risk factors for the development and progression of CKD.2,3 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.4 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 identifification and risk stratifification of patients at increased risk of progressive end-organ injury and subsequent end stage renal disease and CVD.

Microvessels (luminal diameter <300 mm) 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).5 Alterations in microvascular structure and function contribute to the development and progression of hypertension, diabetes, CKD, and CVD.5–7 Importantly, such changes precede the development of end-organ damage8 and appear modififiable.9 Moreover, microvascular dysfunction in peripheral beds mirrors dysfunction in visceral beds,10,11 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.

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THE EYE AS A WINDOW TO THE KIDNEY 

The eye and kidney have several structural, developmental, and organizational similarities that support the concept that ocular tissues might reflflect renal disease (Figure 2).

Bruch’s membrane and glomerular basement membrane 

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 a3, a4, and a5 type IV collagen chains.12,13 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).14,15 As another example, the anti-GBM disease is characterized by the development of IgG autoantibodies directed against the a3 chain, which are deposited on glomerular and alveolar basement membranes triggering a crescentic glomerulonephritis and pulmonary hemorrhage, respectively.16 Similar linear IgG deposition on Bruch’s membrane has been reported in patients with antiGBM disease who developed concurrent choroidal ischemia and retinal detachment.17,18

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.19 Evidence of complement system dysregulation as a key driver of renal and retinal deposit formation in membranoproliferative glomerulonephritis20 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.21,22 

Chorioretinal and renal microcirculations Development and ultrastructure. The human retinal circulation develops predominantly by angiogenesis, where new vessels bud from preexisting ones, to supply the inner two-thirds of the retina.23 In the kidney, the peritubular capillaries and vasa recta populate the medulla and inner cortex in a similar manner.24 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, respectively24,25; although for the glomerulus, this is debated.26 The choriocapillaris endothelium has w80 nm fenestrations allowing fluid exchange within the subretinal space.27 The glomerular endothelium has similarly sized fenestrations that facilitate ultrafifiltration into the Bowman’s capsule.28