An early morphological sign is the presence of microaneurysms. These have been interpreted as abortive attempts to vascularize ischemic areas. Other early signs are intraretinal (flame-shaped or dotted) hemorrhages and lipoprotein deposits (hard exudates). They are indicative of increased capillary permeability, which could be due to modified LDL, free radical damage of endothelial cells, or AGE formation in the endothelial matrix proteins, which attract platelets and macrophages and stimulate the expression of vascular permeability factor (VPF) and other cytokines. Disruption and fenestrations of the endothelial layer and vascular proliferation may occur. Another important clinical sign of vascular permeability is focal or diffuse macular edema.
A later morphological sign is capillary closure. This may be caused by the activated hemostasis with expression of adhesion molecules in platelets and leukocytes as well as by procoagulatory changes of the endothelium and matrix areas exposed to the blood flow because of endothelial disrupture.
Capillary closure is followed by ischemia, which is a potent trigger of new vessel formation. This process is normally suppressed by collagen IV, but it is stimulated by collagen fragments, fibronectin, and local growth factors such as vascular endothelial growth factor (VEGF; secreted in response to hypoxia), fibroblast growth factor(FGF), and TGF-β. Formation of new vessels may not be restricted to the retina. They may grow into the preretinal space and vitreous and eventually cause retinal detachment. New vessel formation may also occur in the iris, where it causes rubeosis iridis and possibly neovascular glaucoma.
Classification
For the purposes of therapy and prognosis, diabetic retinopathy may be classified according to the Early Treatment Diabetic Retinopathy Study Research Group [165] as follows:
1. Background retinopathy, characterized by microaneurysms, hard exudates, generalized venous dilatation, intraretinal hemorrhages, and occasional cotton wool spots (retinal infarcts). Background diabetic retinopathy does not necessarily progress to more advanced stages.
2. Preproliferative retinopathy, characterized by localized irregularities of venous caliber (beading), which are strong predictors of neovascularization; venous looping and reduplication: multiple (≥ 5) cotton wool spots; and intraretinal microvascular abnormalities (IRMAs—abnormally branched vessels within the retina).
3. Proliferative retinopathy, characterized by abnormal new vessels growing into the preretinal space, vitreous, or, occasionally, on the iris. Bleeding from these vessels, retinal detachment due to contraction of fibrotic structures that develop in the hemorrhages, and neovascular glaucoma may cause impairment of vision.
Another cause of impaired vision is maculopathy due to capillary leakage (edematous, wet maculopathy) or to ischemia (dry maculopathy).
Management
The different classes of diabetic retinopathy require different action depending on the risk of loss of vision. In general, the best primary prevention is near-normal metabolic control, normal blood pressure, and giving up smoking [127,130,158,159,166,167]. In secondary prevention, abrupt normalization of poor metabolic control of long duration should be avoided because of the so-called normoglycemic re-entry phenomenon [168,169]. Dyslipoproteinemia increases the risk of hard exudates, maculopathy [170], and vascular proliferations [171] and should be effectively treated. Guidelines for ophthalmological intervention have been developed (for references see [172–174]). The most important technical methods of treating diabetic retinopathy are photocoagulation and vitreous surgery, which may save useful vision in up to 70% of cases of severe proliferative diabetic retinopathy. A difficult problem is dry (ischemic) maculopathy. Treatments based on improving the microcirculation are still experimental [175].
Any diabetic person requires an ophthalmological checkup at diagnosis and annually thereafter. Background retinopathy should be monitored every 6 months. Referral to the ophthalmologist is indicated soon in the case of preproliferative diabetic retinopathy or maculopathy. Referral is urgent if new vessels develop, particularly if they originate from the optic disk. Immediate referral is indicated if retinal detachment, vitreous hemorrhage, or neovascular glaucoma is suspected.
Nephropathy
Diabetic nephropathy is a microvascular disease of the glomerulus (diabetic glomerulosclerosis). It begins with hyperfiltration followed by proteinuria, hypertension, and progressive renal failure. The pathogenesis and clinical course of diabetic nephropathy are better known in type 1 than in type 2 diabetes. They appear to be similar but not identical.
Epidemiology
The prevalence of microalbuminuria or any more advanced stage of nephropathy in IDDM increases during the first 20 years after diagnosis (or, in children, after puberty) to > 50% and levels off thereafter. During this time only about half of the microalbuminuric subjects will develop macroproteinuria and only a minority will develop end-stage renal disease [176]. The cumulative incidence of persistent macroproteinuria is about 35% in both IDDM and NIDDM. However, endstage renal disease after 30 years of diabetes is more often present in IDDM (>20%) than in NIDDM (10%) [177–179]. About 30–50% of all patients on chronic dialysis have diabetes (which does not imply that the reason is always the diabetes). Since type 2 diabetes is much more frequent than type 1 diabetes, it contributes the majority of these subjects.
The incidence and progression of diabetic nephropathy are related to metabolic control [127,130–133] and blood pressure [158,159]. A threshold phenomenon was postulated [180], but was rejected [181,182]. Mortality is high in subjects with diabetic nephropathy. Microalbuminuria has been identified as a strong predictor of cardiovascular disease.
In proteinuric subjects coronary artery disease is about 15 times more frequent than in diabetic subjects without proteinuria [154], and cardiovascular mortality is increased nine-fold [183,184]. Ten-year survival of subjects with persistent proteinuria used to be only 20-50% [179,185].