flat. Autofluorescence showed numerous large, very dark atrophic areas and diffuse RPE abnormalities.

It has been proposed that the progressive LC deposition in choroid and Bruch’s membrane leads to dysfunction of the RPE pump function, causing a flow disturbance between choroid and retina and subsequent RPE detachments and tears and progressive retinal malfunction [156]. Visual function slowly deteriorates in cases with long follow-up, combining reduction of the visual field and loss of visual acuity. We assume that the longterm visual prognosis of all patients with LCDD is guarded, taking into account that renal function replacement and pharmacological treatment have considerably prolonged life in these patients.

Controversies and Perspectives

In 1836, Bright described amaurosis in end-stage renal disease. After the introduction of the ophthalmoscope by von Helmholtz in 1951, Liebreich reported in 1859 albuminuric retinitis or Bright’s disease. In 1860, von Graefe and Schweigger suggested that ocular lesions could be caused by generalized disorders of the vascular system and that in these conditions the kidneys could be affected as well. In 1914, Volhard and Fahr attributed the retinopathy in patients with nephritis to arterial hypertension. Later reports stressed that renal failure can induce arterial hypertension. Today, arterial hypertension is still a very common and important cause of morbidity and mortality. Severe hypertensive retinopathy is at present rare, but hypertension-induced sclerosis is a major cause of retinal vascular accidents and macular edema with visual loss. The other major cause of ocular and kidney disease of modern times is diabetic microangiopathy, with retinopathy and nephropathy requiring optimal lifelong treatment to avoid high morbidity and mortality. In other systemic diseases, such as thrombotic thrombocytopenic purpura, dense deposit disease, and light chain deposition disease, the high vulnerability of the retina and kidney is evident.

Developmental anomalies of kidneys and eyes were previously described as papillorenal

syndrome, and familiar occurrence was recognized, with an autosomal dominant pattern of inheritance. At present, genetic testing is available to screen for an underlying PAX 2 mutation.

Intense genetic and biochemical research has resulted in the identification of a wide spectrum of multisystem diseases with a specific metabolic or structural defect. Some of these diseases predominantly affect kidneys and eyes. For example, Alport syndrome is a hereditary disorder caused by mutations in the biosynthesis of type IV collagen. This collagen subtype is a crucial structural component of the basement membrane in the glomerulus, retina, lens capsule, and cochlea. A second example is the cancer predisposition syndrome von Hippel-Lindau disease, which confers a strong predisposition for renal cancer and for neurological and ocular problems caused by angiomas. In suspected persons and family members of patients with von HippelLindau disease, genetic testing is highly recommended, as carriers of the disease have to be examined on a regular basis and treatment must be considered.

In conclusion, oculorenal syndromes represent a heterogeneous group of malformations and systemic diseases with particular and unusual ocular and renal features. Historically, these syndromes were classified according to their Mendelian pattern of inheritance or according to related diseases without Mendelian inheritance. In this chapter, we classified the diseases based on the actual understanding of the disorders.

Focal Points

•The kidney and eye are closely linked in many diseases, both common and rare. Developmental problems of kidney and eyes can share a common genetic underground. An example is the PAX2 mutation, inherited as an autosomal dominant disease with extremely variable expression. Patients can present with a blind, microphthalmic eye and end-stage renal disease requiring renal function replacement, while family members with the same

genetic defect may have minor changes such as an optic pit or a small kidney without functional abnormalities.

•Patients with the cancer predisposition syndrome von Hippel-Lindau are at risk for renal cancer and for development of angiomas with neurological and ocular complications. Genetic screening is recommended for suspected persons and for direct family members of patients with von Hippel-Lindau.

•Metabolic defects can induce renal and ocular changes and malfunction, and in some of these diseases, an underlying genetic defect has been identified. An example is cystinosis, a rare autosomal recessive disorder caused by the mutation of the CTNS gene, leading to defective transport of cystine out of the cellular lysosome. The kidney and the cornea are particularly vulnerable to the ensuing crystal formation. Renal insufficiency, photophobia, and poor vision are frequent complications.

•The most common metabolic disease affecting eye and kidney is diabetes mellitus, in which patients develop microvascular changes in the retinal and capillary beds leading to microalbuminuria and renal failure and to macular edema and proliferative diabetic retinopathy.

•Alport syndrome is an example of a structural defect responsible for combined renal and ocular disease. The disorder is caused by mutations in the biosynthesis genes of type IV collagen, a crucial component of the basement membrane in the glomerulus, retina, lens capsule, and cochlea. Affected patients suffer from renal failure, deafness, and ocular changes with maculopathy, lenticonus, and fragile cornea.

•The ciliopathies are a group of recently identified disease entities with cilial malfunction. Cilia are common organelles present on nearly every cell in the human body and important in embryogenesis (nodal cilia), fluid and cell movement (motile cilia), and visual and renal function (primary cilia). In the retina, the primary, or sensory, cilium of photoreceptors mediates polarizing trafficking of proteins for efficient phototransduction. Genetic defects in these cilia lead to retinal

dysfunction. Retinal and renal dysfunction is observed across a range of ciliopathies. An example is Senior-Loken syndrome. In the kidney, the primary apical cilia are affected, and in the retina, the outer segments of photoreceptor cells are affected, which are specialized sensory cilia. Manifestations of disease are nephronophthisis with renal dysfunction and retinal dystrophy.

•Arterial hypertension can occur in acute renal conditions and is a frequent complication in long-term renal conditions. The repercussions in the ocular fundus are well known. Due to improved treatment of arterial hypertension and kidney disease, severe hypertensive retinopathy is now less frequently observed than in the past. However, long-standing arterial hypertension, together with aging, leads to sclerotic vasculature and to ocular and nonocular vascular accidents, which are very common problems today.

•Systemic diseases associated with microangiopathy, vasculitis, or diffuse intravascular coagulation can cause both renal and ocular vascular lesions. In lupus erythematosus, sarcoidosis, periarteritis nodosa, Wegener’s disease, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome, the clinical picture is often dominated by renal insufficiency and a marked decrease in visual acuity.

•Dysregulation of the alternative complement pathway is present in dense deposit disease, combining membranoproliferative glomerulonephritis type 2, partial lipodystrophy, and AMD-like fundus changes.

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