Introduction

The identification of associated kidney disease and retinal blindness has a long history that continues to the present day. At the forefront of this association stand two of the major diseases of

L.H. Spielberg, M.D. ( )

Department of Ophthalmology, The Rotterdam Eye

Hospital, Schiedamse Vest 180, Rotterdam 3011 BH,

The Netherlands

e-mail: Leigh.Spielberg@gmail.com

A.M. Leys, M.D., Ph.D.

Department of Ophthalmology, Medical Retina, University Hospital Leuven, Capucijnenvoer 33, Leuven 3000, Belgium

e-mail: anita.leys@uzleuven.be

modern times, namely arterial hypertension and diabetes. Moreover, the retina is one of the most common tissues involved in nonpolycystic kidney disease (PKD) types of cystic kidney disorders.

The kidney and the eye are closely linked in many diseases, both common and rare. Despite their vastly different functions, both the kidney and the retina are frequently vulnerable to the same systemic pathological processes such as vascular stress and complement pathway dysregulation. Several factors play a joint pathophysiological role in impaired kidney function and associated ocular disease, and mutual vulnerability of both retina and kidney underlies several syndromes and disease entities. Disorders involving both the eye and the kidney can result from

developmental problems, metabolic defects, vascular disease, autoimmune conditions, infections, tumors, and pharmacological side effects. The term “oculorenal syndromes” points to a large and heterogeneous group of malformations and systemic diseases with particular and unusual ocular and renal features.

Patients with renal disease may require specific ophthalmic management, and vice versa. Several systemic diseases contribute to both retinal and renal pathology. The most widespread, and thus important, of these are diabetes mellitus and arterial hypertension, in which patients frequently develop both nephropathy and retinopathy. Both conditions can cause significant microvascular pathology that can injure the retinal and renal capillary beds and lead to structural and functional damage.

Diabetes

Diabetic retinopathy is a microangiopathic condition caused by hyperglycemia in its early stages and capillary closure as the condition progresses. Hyperglycemia causes vascular basement membrane thickening and a loss of both vascular endothelial cells and pericytes. Capillary nonperfusion results in retinal ischemia, which then determines the further course of the damage. Hypoxia induces preretinal neovascularization (Fig. 27.1), the development of which is modulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and insulinlike growth factor 1 (IGF-1). These new vessels are very fragile, predisposing them to microaneurysms and vascular leakage. Increased vascular permeability leads to several complications

(Table 27.1), with macular edema representing the most debilitating problem in terms of visual function.

Both diabetic retinopathy and microalbuminuria, the telltale indication of early diabetic renal pathology, are expressions of microvascular damage. They are promoted by hypertension, hyperglycemia, dyslipidemia, and elevated levels of angiotensin II and are prevented and initially treated by adjusting these risk factors to the nearnormal range. Due to structural similarities between the renal and retinal microvasculature, both organs are particularly susceptible. Angiotensin II leads to vascular constriction, increased capillary permeability, and increased blood pressure. This has a similar effect in both renal and retinal microvasculature, namely leakage. In the kidneys, increased filtration pressure in the glomerular capillaries causes leakage of albumin into the urine. In the retina, increased retinal capillary pressure and permeability lead to macular edema [1]. The association between high blood pressure and renal and retinal dysfunction is well recognized [2]. Similarly, microalbuminuria is associated with an increased risk of proliferative retinopathy and blindness [3].

The renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic retinopathy [4]. Indeed, early blockade of the reninangiotensin system in patients with type 1 diabetes has been shown to slow the progression of retinopathy [5]. Angiotensin II has been shown to be synthesized in the eye, particularly in those areas susceptible to diabetic retinopathy [6]. Further, there is a correlation between vitreous angiotensin-converting enzyme (ACE) activity and vitreous levels of VEGF [7], which is increased in the eyes of patients with proliferative

Fig. 27.1 (continued) (asterisk) and relatively mild leakage from the retinal vessels in the macular area, which is responsible for decreased visual acuity. In the left eye, the color fundus photograph (e) shows multifocal, peripheral neovascular tufts as well as neovascularization of the optic nerve head (arrow) and fibrosis (asterisk). In the macula and temporomacular region, vascular leakage has led to lipoid exudates (arrowheads) and edema with marked visual loss. Further temporal, hemorrhages and

capillary nonperfusion are present. Capillary nonperfusion is better recognized on the red-free image (f), which also shows the extent of the neovascular tufts and of the fibrosis. FA (g) shows massive leakage from the neovascular membranes and, on the upper left side of the image, extensive capillary nonperfusion, indicated by a neartotal lack fluorescence (asterisk). The late-stage FA (h) shows massive leakage in the posterior pole and capillary nonperfusion peripherally

Fig. 27.1 Color fundus photograph (a) of the right eye of a diabetic patient with multifocal proliferative retinopathy and a relatively well-preserved macula, despite lipoid exudates temporal of the macula (arrow). The redfree photograph (b) better shows the fan-shaped neovascular membrane in the inferotemporal region (arrow). On the fluorescein angiograph (c), the darker area (asterisk)

indicates peripheral capillary dropout. Fluorescence indicates leakage of fluorescein dye from the neovascular tufts (arrows) and from the veins (arrowhead), especially obvious in the omega-shaped venous dilatation (double arrow), nasal of the optic disk. Fluorescein angiography of the papillomacular region (d) shows pronounced leakage from the inferotemporal neovascular membrane