Kidney and eye diseases: common risk factors, etiological mechanisms, and pathways

Chronic kidney disease is an emerging health problem worldwide. The eye shares striking structural, developmental, and genetic pathways with the kidney, suggesting that kidney disease and ocular disease may be closely linked. A growing number of studies have found associations of chronic kidney disease with age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract. In addition, retinal microvascular parameters have been shown to be predictive of chronic kidney disease. Chronic kidney disease shares common vascular risk factors including diabetes, hypertension, smoking, and obesity, and pathogenetic mechanisms including inflammation, oxidative stress, endothelial dysfunction, and microvascular dysfunction, with ocular diseases supporting the ‘Common Soil Hypothesis.’ In this review, we present major epidemiological evidence for these associations and explore underlying pathogenic mechanisms and common risk factors for kidney and ocular disease. Understanding the link between kidney and ocular disease can lead to the development of new treatment and screening strategies for both diseases. Chronic kidney disease is an emerging health problem worldwide. The eye shares striking structural, developmental, and genetic pathways with the kidney, suggesting that kidney disease and ocular disease may be closely linked. A growing number of studies have found associations of chronic kidney disease with age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract. In addition, retinal microvascular parameters have been shown to be predictive of chronic kidney disease. Chronic kidney disease shares common vascular risk factors including diabetes, hypertension, smoking, and obesity, and pathogenetic mechanisms including inflammation, oxidative stress, endothelial dysfunction, and microvascular dysfunction, with ocular diseases supporting the ‘Common Soil Hypothesis.’ In this review, we present major epidemiological evidence for these associations and explore underlying pathogenic mechanisms and common risk factors for kidney and ocular disease. Understanding the link between kidney and ocular disease can lead to the development of new treatment and screening strategies for both diseases. The kidney and eye share striking structural, developmental, physiological, and pathogenic pathways.1.Wilkinson-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 (14) Google Scholar, 2.Izzedine H. Bodaghi B. 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The retinal renin-angiotensin system: roles of angiotensin II and aldosterone.Peptides. 2012; 36: 142-150Crossref PubMed Scopus (14) Google Scholar Chronic kidney disease (CKD) and the major eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, and cataract are strongly associated with age and metabolic and vascular risk factors, such as hypertension, diabetes, and smoking. Accordingly, it has long been suggested that kidney and eye diseases may be closely linked, supported by a growing number of studies. Ocular manifestations such as retinal microvascular parameters have been shown to be predictive of CKD development, and patients with CKD may be at higher risk for AMD, DR, glaucoma, and cataract. CKD may also manifest in the eye as associated developmental abnormalities of oculorenal syndromes.2.Izzedine H. Bodaghi B. Launay-Vacher V. et al.Eye and kidney: from clinical findings to genetic explanations.J Am Soc Nephrol. 2003; 14: 516-529Crossref PubMed Scopus (13) Google Scholar In this paper, we reviewed the evidence for the associations between CKD and major eye diseases and explored the underlying pathogenic mechanisms and common risk factors for kidney and ocular diseases. We searched MEDLINE using PubMed with the search terms ‘chronic kidney disease’ or ‘chronic renal disease’ in combination with ‘eye,’ ‘retinopathy,’ ‘retinal vessels,’ ‘retinal fractals,’ ‘cataract,’ ‘cornea,’ ‘conjunctiva,’ ‘glaucoma,’ and ‘age-related macular degeneration.’ We largely selected publications listed in the past 5 years, but did not exclude older publications that are commonly referenced or highly regarded. We also searched the reference lists of articles identified by this search strategy and selected those that we judged relevant. 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Agron E. et al.Risk factors associated with incident cataracts and cataract surgery in the Age-related Eye Disease Study (AREDS): AREDS report number 32.Ophthalmology. 2011; 118: 2113-2119Abstract Full Text Full Text PDF PubMed Scopus (8) Google ScholarTable 1Common risk factors shared between CKD and eye diseasesRisk factors of CKDAssociated eye diseasesAgeCataract, AMD, DR, glaucoma, retinal vascular damageSmokingAMD, cataractDiabetes mellitusCataract, DR, AMD, glaucoma, retinal vascular damageHypertensionAMD, DR, retinal vascular damage, glaucomaObesityAMD, DR, cataractHyperlipidemiaAMD, DRAbbreviations: AMD, age-related macular degeneration; CKD, chronic kidney disease; DR, diabetic retinopathy. Open table in a new tab Abbreviations: AMD, age-related macular degeneration; CKD, chronic kidney disease; DR, diabetic retinopathy. The major mechanisms that contribute to CKD are atherosclerosis, vascular remodeling, endothelial dysfunction, inflammation, and oxidative stress—mechanisms that are also implicated in many eye diseases (Table 2 and Figure 1). These will be discussed in further detail, with focus on more recent developments in our understanding of pathophysiological mechanisms in both eye and kidney diseases.Table 2Common pathogenic mechanisms underlying both CKD and eye diseasesMechanisms of CKDAssociated eye diseasesAtherosclerosisCataract, AMD, DR, glaucoma, retinal vascular damageEndothelial dysfunctionAMD, cataractOxidative stressCataract, DR, AMD, glaucoma, retinal vascular damageInflammationAMD, DR, retinal vascular damageRenin–angiotensin system dysfunctionDR, retinal vascular damage, glaucomaGenetic polymorphismsAMD, retinal venular diameterKlothoAMD, cataract, retinopathyAbbreviations: AMD, age-related macular degeneration; CKD, chronic kidney disease; DR, diabetic retinopathy. Open table in a new tab Abbreviations: AMD, age-related macular degeneration; CKD, chronic kidney disease; DR, diabetic retinopathy. Angiotensin II (Ang II) induces inflammatory responses and endothelial dysfunction through the production of reactive oxygen species. In addition, it is involved in extracellular matrix remodeling, regulation of gene expression, and activation of multiple intracellular signaling pathways that lead to tissue injury.39.Benigni A. Cassis P. Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging.EMBO Mol Med. 2010; 2: 247-257Crossref PubMed Scopus (108) Google Scholar These effects of Ang II contribute not only to renal disease and associated CVD but also to neurodegenerative diseases and possibly autoimmune diseases as well.39.Benigni A. Cassis P. Remuzzi G. 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They act on the receptor for AGEs, leading to cell cycle arrest, apoptosis, altered migration, and generation of proinflammatory cytokines. In the kidney, podocytes and endothelial cells bear these receptors that, when activated, result in cellular hypertrophy, cell cycle arrest, apoptosis, and upregulation of proinflammatory markers.51.Busch M. Franke S. Ruster C. et al.Advanced glycation end-products and the kidney.Eur J Clin Invest. 2010; 40: 742-755Crossref PubMed Scopus (85) Google Scholar In the eye, the role of AGEs in cataract formation is the clearest.52.Nagaraj R.H. Linetsky M. Stitt A.W. The pathogenic role of Maillard reaction in the aging eye.Amino Acids. 2012; 42: 1205-1220Crossref PubMed Scopus (26) Google Scholar To date, more than 15 AGEs have been localized in the human lens with higher levels in the eye with cataract.53.Franke S. Dawczynski J. 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