- •Diabetic Retinopathy
- •Preface
- •Contents
- •Contributors
- •Nonproliferative Diabetic Retinopathy
- •Nonproliferative Diabetic Retinopathy
- •Inflammatory Mechanisms
- •Microaneurysms
- •Vascular Permeability
- •Capillary Closure
- •Classification Of Nonproliferative Retinopathy
- •Macular Edema
- •Risk Factors For Progression Of Retinopathy
- •Severity of Retinopathy
- •Glycemic Control
- •The Diabetes Control and Complications Trial
- •Epidemiology of Diabetes Interventions and Complications Trial
- •The United Kingdom Prospective Diabetes Study
- •Hypertension
- •The United Kingdom Prospective Diabetes Study
- •Appropriate Blood Pressure Control in Diabetes Trials
- •Elevated Serum Lipid Levels
- •Pregnancy and Diabetic Retinopathy
- •Other Systemic Risk Factors
- •Management Of Nonproliferative Diabetic Retinopathy
- •Photocoagulation
- •Scatter Photocoagulation for Nonproliferative Diabetic Retinopathy
- •Scatter Photocoagulation for Proliferative Retinopathy
- •Focal Photocoagulation for Diabetic Macular Edema
- •Other Treatment of Diabetic Macular Edema
- •Medical Therapy
- •Aspirin And Antiplatelet Treatments
- •Aldose Reductase Inhibitors
- •Other Medical Treatments
- •Summary
- •Acknowledgment
- •References
- •Proliferative Diabetic Retinopathy
- •Development and Natural History
- •Histopathology and Early Development
- •Proliferation and Regression of New Vessels
- •Contraction of the Vitreous and Fibrovascular Proliferations
- •Retinal Distortion and Detachment
- •Burned-Out Proliferative Diabetic Retinopathy
- •Systemic Associations
- •Proliferative Diabetic Retinopathy and Glycemic Control
- •Other Risk Factors for Proliferative Diabetic Retinopathy
- •Rubeosis Iridis
- •Anterior Hyaloidal Fibrovascular Proliferation
- •Management of Proliferative Diabetic Retinopathy
- •Pituitary Ablation
- •Photocoagulation
- •Randomized Clinical Trials of Laser Photocoagulation
- •The Diabetic Retinopathy Study
- •Risks and Benefits Photocoagulation In The Drs
- •The Early Treatment Diabetic Retinopathy Study
- •Indications For Photocoagulation of Pdr
- •PRP and Macular Edema
- •PRP Treatment Techniques
- •Vitrectomy for PDR
- •Pharmacologic Treatment of PDR
- •Acknowledgment
- •References
- •Brief Historical Background
- •The Wesdr
- •Prevalence of Diabetic Retinopathy
- •Incidence of Diabetic Retinopathy
- •Diabetic Retinopathy in African American and Hispanic Whites
- •Native Americans and Asian Americans
- •Age and Puberty
- •Genetic and Familial Factors
- •Modifiable Risk Factors
- •Hyperglycemia
- •Clinical Trials of Intensive Treatment of Glycemia
- •Diabetes Control and Complications Trial
- •The United Kingdom Diabetes Prospective Study (UKPDS)
- •Hypertension
- •Lipids
- •Subclinical and Clinical Diabetic Nephropathy
- •Microalbuminuria and Diabetic Retinopathy
- •Gross Proteinuria and Retinopathy
- •Diabetic Retinopathy as a Risk Indicator of Subclinical Nephropathy
- •Other Risk Factors For Retinopathy
- •Smoking and Drinking
- •Body Mass Index and Physical Activity
- •Hormone and Reproductive Exposures in Women
- •Prevalence and Incidence of Visual Impairment
- •Conclusions
- •Acknowledgments
- •References
- •Introduction
- •Fluorescein Angiography
- •Properties
- •Side Effects
- •Normal Fluorescein Angiography
- •Terminology
- •Fluorescein Angiography in the Evaluation of Diabetic Retinopathy
- •Fluorescein Angiography in the Evaluation of Diabetic Macular Edema
- •Optical Coherence Tomography
- •Low-Coherence Interferometry
- •OCT Image Interpretation
- •OCT Technology Development
- •The Role of OCT in Diabetic Macular Edema
- •Morphologic Patterns of Diabetic Macular Edema
- •Clinical Applications of OCT in Diabetic Macular Edema
- •Conclusions
- •References
- •Diabetic primates
- •Type of Diabetes
- •Histopathology and Rate of Development of the Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic dogs
- •Type of Diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic cats
- •Type of Diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Therapies Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic rats
- •Type of Diabetes
- •Type 1 diabetes
- •Type 2 diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Vascular disease
- •Neuronal disease
- •Therapies or Gene Modifications Studied in this Model
- •Advantages and Disadvantages of the Model
- •Diabetic mice
- •Type of Diabetes
- •Type 1 diabetes
- •Type 2 diabetes
- •Histopathology and Rate of Development of Retinopathy
- •Vascular disease
- •Neural disease
- •Therapies or Gene Modifications Studied in this Model
- •Advantages and Disadvantages of the Model
- •Other Rodents
- •Galactose Feeding
- •Nondiabetic Models in Which Growth Factors are Altered
- •VEGF overexpression
- •IGF overexpression
- •PDGF-B-deficient mice
- •Oxygen-Induced Retinopathy
- •Sympathectomy
- •Retinal Ischemia–Reperfusion
- •Summary
- •References
- •Introduction
- •Biochemistry and Genetics of The Polyol Pathway
- •Aldose Reductase
- •The Aldose Reductase Enzyme
- •The Aldose Reductase Gene
- •Polymorphisms of the AR Gene
- •Sorbitol Dehydrogenase
- •The Sorbitol Dehydrogenase Enzyme
- •The Sorbitol Dehydrogenase Gene
- •Ar Polymorphisms and Risk of Diabetic Retinopathy
- •Sdh Polymorphisms and Diabetic Retinopathy
- •Ar Overexpression
- •Sdh Overexpression
- •Ar “Knockout” Mice
- •Sdh-Deficient Mice
- •Osmotic Stress
- •Oxidative Stress
- •Activation of Protein Kinase C
- •Generation of AGE Precursors
- •Proinflammatory Events and Apoptosis
- •Ari Structures and Properties
- •Effects of Aris in Experimental Diabetic Retinopathy
- •The Polyol Pathway in Human Diabetic Retinopathy
- •The Sorbinil Trial
- •Perspective and Needs
- •Rationale for Defining the Pathogenic Role of the Polyol Pathway
- •Needs to be Met to Arrive at Anti-Polyol Pathway Therapy
- •References
- •Introduction to Diabetic Retinopathy
- •Biochemistry of Age Formation
- •Pathogenic Role of Ages In Diabetic Retinopathy
- •AGEs and Clinical Correlation of Diabetic Retinopathy
- •AGE Accumulation in the Eye
- •Effect of AGEs on Retinal Cells
- •RAGE in Diabetic Retinopathy
- •Other AGE Receptors in Diabetic Retinopathy
- •Anti-Age Strategies For Diabetic Retinopathy
- •Conclusion
- •References
- •Introduction
- •Dag-Pkc Pathway
- •Diabetes and Retinal Blood Flow
- •Basement Membrane and Ecm Changes
- •Vascular Permeability and Angiogenesis
- •Conclusions
- •References
- •Sources of Oxidative Stress in The Diabetic Retina
- •Overview
- •Mitochondrial Electron Transport Chain (ETC)
- •Advanced Glycation End (AGE) Product Formation
- •Cyclo-oxygenase (COX)
- •Flux Through Aldose Reductase (AR) Pathway
- •Activation of Protein Kinase C (PKC)
- •Endothelial NO Synthase (eNOS)
- •Inducible NOS (iNOS)
- •NADPH Oxidase
- •Antioxidants in Diabetic Retinopathy
- •Overview
- •Glutathione (GSH)
- •Superoxide Dismutase (SOD)
- •Catalase
- •Effects of Oxidative Stress in The Diabetic Retina
- •Overview
- •Growth Factors and Cytokines
- •Cytoxicity
- •Therapeutic Strategies For Reducing Oxidative Stress
- •Overview
- •Antioxidants
- •PKC Inhibitors
- •Inhibitors of the Renin-Angiotensin System
- •Inhibitors of the Polyol Pathway
- •HMG-CoA Reductase Inhibitors (Statins)
- •PEDF
- •Cannabinoids
- •Cyclo-oxygenase-2 (COX-2) Inhibitors
- •References
- •Pericyte Loss in the Diabetic Retina
- •Introduction
- •Origin and Differentiation
- •Morphology and Distribution
- •Identification
- •Function
- •Contractility
- •Role in Vessel Formation and Stabilization
- •Loss In Diabetic Retinopathy
- •Rats
- •Mice
- •Chinese Hamster
- •Animal Models Mimicking Retinal Pericyte Loss
- •Pdgf-B-Pdgf-Ssr
- •Angiopoietin-Tie
- •Vegf-Vegfr2
- •Mechanisms of Loss
- •Biochemical Pathways
- •Aldose Reductase
- •Age Formation
- •Modification of Ldl
- •Loss Through Active Elimination
- •Capillary Dropout in Diabetic Retinopathy
- •Diabetic Retinopathy
- •Methods to Measure and Detect Capillary Dropout
- •Models to Study Retinal Capillary Dropout in Diabetes
- •Potential Mechanisms For Capillary Dropout
- •Capillary Cell Apoptosis
- •Proinflammatory Changes/Leukostasis
- •Microthrombosis/Platelet Aggregation
- •Consequences of Capillary Dropout
- •Macular Ischemia
- •Neovascularization
- •Macular Edema
- •Acknowledgments
- •References
- •Neuroglial Dysfunction in Diabetic Retinopathy
- •The Neurons of The Retina
- •The Glial Cells of The Retina
- •Diabetes Reduces Retinal Function
- •Diabetes Induces Neurodegeneration in The Retina
- •Neuroinflammation in Diabetic Retinopathy
- •Historical Perspective on Diabetic Retinopathy
- •Neuroglial Dysfunction in Diabetic Retinopathy.
- •References
- •Introduction
- •Inflammatory Cells Promote and Regulate The Development of Ischemic Ocular Neovascularization
- •VEGF as a Proinflammatory Factor in Diabetic Retinopathy
- •VEGF164/165 as a Proinflammatory Cytokine
- •Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
- •Corticosteroids
- •Anti-VEGF Agents
- •Pegaptanib
- •Ranibizumab and Bevacizumab
- •Conclusions
- •Acknowledgment
- •References
- •Glia-Endothelial Interaction
- •Specialized Retinal Vessels Control Flux into Neural Tissue
- •Overview of Tight Junction Proteins
- •Claudins Confer Tight Junction Barrier Properties
- •Occludin Regulates Barrier Properties
- •Alterations in Occludin in Diabetic Retinopathy
- •Ve-Cadherin and Diabetic Retinopathy
- •Permeability in Diabetic Retinopathy
- •Summary and Conclusions
- •References
- •Introduction
- •Stages of Angiogenesis
- •Vascular Endothelial Growth Factor
- •Regulation of Vegf Expression in The Retina
- •Regulation of VEGF in Proliferative Diabetic Retinopathy
- •Regulation of VEGF in Nonproliferative Diabetic Retinopathy
- •Basic Vegf Biology
- •Receptors
- •Vegf’S Multiple Actions on Retinal Endothelial Cells
- •Main Signaling Pathways
- •Other Actions of Vegf
- •Proinflammatory Effects of VEGF
- •VEGF and Retinal Neuronal Development
- •VEGF and Neuroprotection
- •Modulation of Vegf Action By Other Growth Factors
- •Conclusion
- •References
- •Insulin-Like Growth Factor
- •Basic Fibroblast Growth Factor
- •Angiopoietin
- •Erythropoietin
- •Hepatocyte Growth Factor
- •Tumor Necrosis Factor
- •Extracellular Proteinases
- •The Urokinase Plasminogen Activator System (uPA/uPAR System)
- •Proteinases in Retinal Neovascularization
- •Integrins
- •Endogenous Inhibitors of Neovascularization
- •Pigment Epithelium Derived Growth Factor
- •Angiostatin and Endostatin
- •Thrombospondin-1
- •Tissue Inhibitor of Matrix Metalloproteinases
- •Clinical Implications
- •Acknowledgments
- •References
- •Introduction
- •Pathogenesis
- •Vascular Endothelial Growth Factor (Vegf)
- •Vegf in Physiological and Pathological Angiogenesis
- •Vegf in Ocular Neovascularization
- •Vegf and Diabetic Retinopathy
- •Clinical Application of Anti-VEGF Drugs
- •Pegaptanib
- •Bevacizumab
- •Ranibizumab
- •Use of Anti-VEGF Therapies in Diabetic Retinopathy
- •Safety
- •Clinical Experience with Bevacizumab in Diabetic Retinopathy
- •Ranibizumab in Diabetic Macular Edema
- •Effect on Foveal Thickness and Macular Volume
- •Effect on Visual Acuity
- •Summary
- •References
- •Introduction
- •Pkc Inhibition With Ruboxistaurin
- •Early Clinical Trials With Rbx
- •Rbx and Progression of Diabetic Retinopathy
- •Ongoing Trials With Rbx
- •Rbx and Other, Nonocular Complications of Diabetes
- •Safety Profile of Rbx
- •Clinical Status of Rbx
- •Conclusions
- •References
- •The Role of Intravitreal Steroids in the Management of Diabetic Retinopathy
- •Clinical Efficacy
- •Safety
- •Pharmacology
- •Pharmacokinetics
- •Combination With Laser Treatment
- •Clinical Guidelines
- •Macular Edema Caused by Focal Parafoveal Leak
- •Widespread Heavy Diffuse Leak
- •Macular Edema and High-Risk Proliferative Retinopathy
- •Macular Edema Prior to Cataract Surgery
- •Juxtafoveal Hard Exudate With Heavy Leak
- •Control of Systemic Risk Factors
- •The Future of Intravitreal Steroid Therapy
- •References
- •Overview
- •Introduction and Historical Perspective
- •Growth Hormone and Diabetic Retinopathy
- •The IGF-1 System and Retinopathy
- •The Role of SST in Diabetic Retinopathy
- •Rationale for the Clinical use of Octreotide
- •Clinical evidence for sst as a therapeutic for pdr
- •Potential Reasons for Mixed Success in Clinical Trials
- •Future Direction: Sst Analogs in Combination Therapy
- •Conclusion
- •Acknowledgements
- •Introduction
- •Diabetic Retinopathy and Mortality
- •Diabetic Retinopathy and Cerebrovascular Disease
- •Diabetic Retinopathy and Heart Disease
- •Diabetic Retinopathy, Nephropathy, and Neuropathy
- •Conclusion
- •References
- •Name Index
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showing the efficacy of lipid lowering agents in reducing the progression of retinopathy, the incidence of macular edema or the loss of vision. In persons with type 2 diabetes, the ACCORD study will permit examination of whether raising the serum HDL cholesterol and lowering triglyceride levels in the context of good glycemic control reduces the incidence of macular edema and progression of retinopathy compared to a strategy that only achieves desirable levels of LDL cholesterol and glycemic control.
SUBCLINICAL AND CLINICAL DIABETIC NEPHROPATHY
Both retinopathy and nephropathy have been linked together as sharing a common “microvascular” origin and similar risk factors. This notion has been supported by data from most studies showing associations between diabetic nephropathy, as manifest by microalbuminuria or gross proteinuria, and retinopathy (13, 14, 39, 87, 89, 91, 94, 120–122). Independent of levels of blood sugar and blood pressure, it has been hypothesized that inflammatory, lipid, rheological, and platelet abnormalities associated with nephropathy may be involved in the pathogenesis of retinopathy.
Microalbuminuria and Diabetic Retinopathy
In the WESDR, in cross-sectional analyses while controlling for duration of diabetes, glycosylated hemoglobin, and diastolic blood pressure, persons with microalbuminuria were more likely to have retinopathy present (for those with type 1 diabetes, OR 1.90, 95% CI, 0.95–3.78 and for those with type 2 diabetes, OR 1.80, 95% CI, 1.22–2.65) than those with normoalbuminuria (123). In multivariable analyses, microalbuminuria remained statistically significantly associated with PDR in those with type 1 (OR 2.14, 95% CI, 1.27–3.61) but not type 2 diabetes (OR 1.05, 95% CI, 0.56–1.96). While controlling for other risk factors, the relationship of microalbuminuria to CSME was not statistically significant in either persons with type 1 diabetes (OR 2.05, 95% CI, 0.81, 5.17, P = 0.13) or those with type 2 diabetes (OR 1.26, 95% CI, 0.52–3.06, P = 0.62). In a cross-sectional analysis of 982 Danish patients with type 1 diabetes, the prevalence of proliferative retinopathy and vision loss increased with increasing levels of albuminuria, being 12% and 1%, respectively, in persons with normoalbuminuria, 28% and 6% in those with microalbuminuria, and 58% and 11% in those with gross proteinuria (124).
While data from cross-sectional studies suggest early nephropathy, as manifest by microalbuminuria, is associated with more severe retinopathy, data regarding the longitudinal relationship of microalbuminuria to incident and progressed retinopathy are less consistent. In a clinic-based study, persons with type 1 diabetes and microalbuminuria had a higher annual incidence of PDR (10–15%) compared to only 1% in patients without signs of nephropathy (125). In another study of 82 patients with type 1 diabetes, of the 13 who developed a progressive increase in their albumin excretion rate and persistent microalbuminuria during the study period, 62% (8/13) developed macular edema or PDR compared with 7% (5/69) who remained normoalbuminuric (126). In the populationbased Epidemiology of Diabetes Complications (EDC) Study, persons with type 1 diabetes and higher albumin excretion rates were more likely to develop incident PDR (127, 128). In the WESDR, while controlling for other factors at baseline, microalbuminuria
The Epidemiology of Diabetic Retinopathy |
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status was not associated with the incidence of retinopathy, its progression to CSME, or the incidence of proliferative disease (123).
Gross Proteinuria and Retinopathy
In cross-sectional analyses in the WESDR, those with gross proteinuria were more likely to have signs of any retinopathy, PDR, or CSME at baseline than those without gross proteinuria (123). While controlling for other factors, the odds of having PDR present when gross proteinuria was present varied from 4.58 (95% CI, 3.10–6.77) in those with type 1 diabetes to 2.27 (95% CI, 1.65–3.11) in those with type 2 diabetes compared to those without gross proteinuria; for CSME, the odds were 2.42 (95% CI, 1.20–4.88) and 1.47 (95% CI, 0.83–2.61) in type 1 and type 2 diabetes, respectively. These findings are also consistent with other epidemiological and clinical studies. In Hispanics, gross proteinuria was cross-sectionally related to diabetic retinopathy (OR 11.14, 95% CI, 1.2–103), but there was no relationship in whites (129).
In a clinical study in Denmark, the cumulative 5-year incidence of nonproliferative retinopathy and PDR in persons with type 1 diabetes with gross proteinuria was 93% and 74%, respectively, and it was 37% and 14%, respectively, in those without (130). In Oklahoma Indians with type 2 diabetes, gross proteinuria was associated with retinopathy at baseline but was not found to be a risk factor for the development of retinopathy (95, 96). In Pima Indians with type 2 diabetes, while controlling for other risk factors, the presence of proteinuria or renal insufficiency at baseline predicted the development of PDR (131). The incidence–rate ratio was 4.8. However, in people with type 2 diabetes in Rochester, Minnesota, persistent proteinuria was not an independent predictor of subsequent incidence of retinopathy (88). In the WESDR, the presence of gross proteinuria was associated with the 10-year incidence of PDR in type 1 diabetes; otherwise, gross proteinuria was not associated with the progression of retinopathy or incidence of CSME (123). The lack of an association in the WESDR may have been due, in part, to the high risk of persons with gross proteinuria who develop severe retinopathy dying and not being seen at follow-up.
There are no clinical trial data to show that interventions that prevent or slow diabetic nephropathy reduce the incidence and progression of retinopathy.
In summary, while both retinopathy and nephropathy are linked together as “microvascular” in origin and share similar risk factors, the fact that after long duration of disease most individuals develop retinopathy but only about two-thirds develop clinical signs of nephropathy suggests possible genetic differences making susceptibility to damage of each system different for a given level of exposure of blood pressure, glycemia, and other risk factors. Epidemiological data support nephropathy as a risk indicator and risk factor for retinopathy and suggest that nephrotic patients might benefit from having regular ophthalmologic evaluation.
Diabetic Retinopathy as a Risk Indicator of Subclinical Nephropathy
Diabetic retinopathy severity has been shown to be related to preclinical glomerulopathy lesions in the baseline biopsies in normotensive normoalbuminuric persons with type 1 diabetes and normal or increased glomerular filtration rate (132). The severity of