Chapter 31
The Eye and Renal Diseases
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Bright, in 1836, was the first to associate renal disease with blindness. Liebreich,1 in 1859, described fundus changes in uremic patients, and subsequently this condition was named Bright's disease, or albuminuric retinitis. At the end of the 19th century and as a result of the study of hypertensive changes, albuminuric retinitis was no longer considered a separate entity but a manifestation of hypertension in uremic patients.

In recent years medical treatment of arterial hypertension and facilities for dialysis and kidney transplantation have become available, and patients are now treated at a much earlier stage of their renal disease. Consequently, we are seeing fewer patients with renal failure and severe hypertensive fundus changes. Nevertheless, arterial hypertension is still a very important problem in kidney diseases and complications of atherosclerosis are extremely common in renal patients as a result of chronic hypertension and hyperlipidemia. Meanwhile, attention has been focused on drug-induced side effects and on complications of dialysis and kidney transplantation.

A new field of interest has been opened with the identification of specific ocular and renal features in patients with multiple congenital anomalies, metabolic disorders, or other multisystemic diseases. The longer survival of renal patients and the opportunity to compose study groups of patients with identical clinical syndromes and similar morphologic changes in renal biopsy specimens have contributed to the identification of a large and still expanding group of oculorenal syndromes.

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Arterial hypertension is a frequent complication of congenital and acquired renal and renovascular disorders. Arteriolar narrowing, tortuosity, and arteriovenous nicking are common retinal vascular abnormalities in patients with arterial hypertension. In subjects with malignant hypertension, ischemic changes may occur in retina, choroid, and optic nerve and produce cotton-wool spots, flame-shaped hemorrhages, hard exudates, Elschnig's spots, exudative detachment, papilledema, and optic atrophy (Fig. 1). In patients with severe and long-standing hypertension a sudden relative fall in arterial pressure may cause infarction of the optic nerve and blindness. Anterior ischemic optic neuropathy and retinal infarction have been described as complications of hemodialysis-associated hypotension. Uremia, anemia, and papilledema of intracranial hypertension are other risk factors for optic neuropathy in patients with chronic renal diseases.2 In addition, patients with chronic hypertension are predisposed to retinal arterial and venous obstructive diseases leading to visual loss.

Fig. 1. Malignant hypertension with retinal and choroidal vascular manifestations: retinal hemorrhages, exudative retinal detachment, numerous edematous Elschnig's spots (A), and fluorescein angiographic abnormalities with areas of hypoperfusion of the choriocapillaris in the early phase (B), and diffuse leak of fluorescein in the late phase of angiography (C).

Thrombotic microangiopathy with fibrinoid necrosis of the vascular wall is a histopathologic lesion that may occur in a number of different clinical contexts as hemolytic-uremic syndrome of childhood with diarrhea or infection; familial forms of hemolytic-uremic syndrome; hemolytic-uremic syndrome associated with drugs; thrombotic thrombocytopenic purpura; malignant hypertension; collagen vascular diseases; and other conditions causing damage of the vascular wall and local or disseminated intravascular coagulation. The clinical features in these patients include acquired hemolytic anemia, thrombocytopenia, central nervous system symptoms, and renal injury that is frequently associated with sudden onset of renal failure and hypertension.3 Ocular fundus changes are common and result from localized thrombotic microangiopathy in the choriocapillaris or from hypertension, anemia, or thrombopenia. Fibrin-platelet occlusion of the choriocapillaris and necrosis of the overlying retinal pigment epithelium cause serous retinal detachments and visual loss, particularly in patients with arterial hypertension. In most patients the serous retinal detachments resolve with normalization of visual acuity at the time of remission of thrombotic microangiopathy, but rarely blindness may occur owing to ischemic ocular changes.

Severe vascular lesions may occur in patients with collagen disorders such as systemic lupus erythematosus, scleroderma, relapsing polychondritis, polyarteritis nodosa, and Wegener's granulomatosis. In these diseases renal failure and blindness may be the major clinical features. Ocular vascular complications may be caused by immune complex vasculitis, thrombotic microangiopathy, occlusion of large vessels, and changes induced by anemia and systemic hypertension. In addition, other signs of inflammatory anterior and posterior segment involvement may be present.

Sudden blindness due to Purtscher's-like retinopathy with or without central nervous symptoms may occur in patients with chronic renal failure without evidence of trauma, pancreatitis, or autoimmune disorder. The precipitating factors of this retinal vaso-occlusive disorder remain unclear. The condition has been described in renal transplant recipients experiencing allograft rejection, in hemodialysis patients, and in a subject with chronic renal failure without renal replacement therapy.4

Acute posterior multifocal placoid pigment epitheliopathy with or without inflammatory changes in the vitreous or anterior chamber may occur in patients with a viral syndrome and a mild passing form of nephritis. The condition appears to be caused by vasculitis in the choriocapillaris and kidneys.


Serous retinal detachment resembling central serous chorioretinopathy may follow organ transplantation or occur in patients receiving hemodialysis.5,6 In severe forms, bilateral bullous retinal detachment, multiple retinal pigment epithelial detachments, and yellow, fibrin-like subretinal exudate beneath the sensory retinal detachment may be observed. Several factors may play a role in precipitating serous detachments in patients with renal failure, including impaired fluid and electrolyte balance; choroidopathy associated with systemic hypertension, thrombotic microangiopathy, or immune complex vasculitis; and dysfunction of the overlying retinal pigment epithelium, which may be influenced by stress and immunosuppressive therapy. In some cases, photocoagulation is successful in causing resolution of the retinal detachment.6


Intraocular pressure may rise during hemodialysis and cause acute glaucoma in predisposed patients with increased resistance of aqueous outflow. Rise in pressure is thought to be part of the cerebral edema that occurs as a consequence of the rapid drop in serum osmolality. Prevention of glaucoma includes control of intraocular pressure of patients who are beginning long-term hemodialysis and medical treatment of any rise in pressure. Nonpupillary block angle-closure glaucoma has been described as a complication of renal hypertension.

Corticosteroid-induced glaucoma may occur and corticosteroid-induced posterior subcapsular cataract is common in renal transplant patients. Lens stippling has been described as a complication of end-stage renal disease with severe hypocalcemia or secondary hyperparathyroidism.


In patients with renal failure and associated hyperparathyroidism and elevated serum calcium concentrations, soft tissue calcifications may occur, which are often first detected in the peripheral interpalpebral cornea and adjacent conjunctiva. The corneal calcifications eventually spread toward the visual axis in patients on chronic intermittent hemodialysis, producing band keratopathy with decreased visual acuity and epithelial erosions, resulting in severe pain. Patients with renal failure and high serum calcium concentrations may present with inflamed pingueculae or more diffuse inflammatory reactions.7


Both infectious and neoplastic processes are more common in renal transplant recipients and other immunocompromised patients and may affect the ocular and periocular tissues. Necrotizing retinitis is the most frequent severe ocular complication and is usually caused by cytomegalovirus and rarely by herpes simplex or zoster with or without associated keratitis. In addition to viral infections, numerous bacterial and fungal pathogenic organisms have been associated with endophthalmitis in renal transplant patients.

Neoplastic processes reported in renal transplant recipients include lymphoma of the vitreous and keratoacanthoma and squamous cell carcinoma of the eyelids. A brown tumor of the orbit has been observed in several patients with chronic renal failure and secondary hyperparathyroidism.8 Brown tumors are focal bony lesions composed of giant cell masses with extravasation of blood affecting patients with primary or secondary hyperparathyroidism and osteitis fibrosa.

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Combined disorders of eyes and kidneys may result from a metabolic or a developmental defect or from vascular or autoimmune disease, infection, tumoral process, or use of toxic products. The term oculorenal syndromes refers to a large and still expanding group of inherited and noninherited malformations and multisystemic diseases with peculiar ocular and renal features. Table 1 shows a classification of this group of disorders according to the present etiologic knowledge. The classic and a few recently recognized oculorenal syndromes are discussed here in detail.


TABLE 1. An Etiologic Classification of the Oculorenal Syndromes

  Chromosomal Abnormality Syndromes
  Trisomy 13 syndrome
  Trisomy 18 syndrome
  Partial trisomy 10q syndrome
  Cat-eye syndrome
  Cri-du-chat syndrome
  WAGR syndrome (aniridia—Wilms' tumor association)
  Deletion of the long arm of chromosome 13 (13q— syndrome)
  Deletion of the short arm of chromosome 18 (18p— syndrome)
  Turner syndrome
  Syndromes With Mendelian Mode of Inheritance
  Autosomal Dominant Syndromes
  Acrorenal syndrome
  Apert's syndrome
  Alagille's syndrome
  Beckwith-Wiedemann syndrome
  Charcot-Marie-Tooth disease
  Coloboma-brachydactyly association type Sorsby
  Familial amyloidosis type 3
  Nail-patella syndrome
  Papillorenal syndrome
  Tuberous sclerosis
  Von Hippel-Lindau syndrome
  Autosomal Recessive Syndromes
  Alström syndrome
  Bardet-Biedl syndrome
  Carbohydrate-deficient glycoprotein (CDG) syndromes
  Cockayne's syndrome
  Choroidal coloboma—mental retardation association
  Fraser-cryptophthalmos syndrome
  Fryns syndrome
  Hunter's syndrome
  Hypercalciuria—macular coloboma association
  Jeune's syndrome
  Mainzer-Saldino syndrome
  Meckel-Gruber syndrome
  Pierson's syndrome
  Potter's syndrome
  Primary hyperoxaluria
  Senior-Loken syndrome
  Sialidosis and galactosialidosis
  Sickle cell anemia
  Smith-Lemli-Opitz syndrome
  Wilson's disease
  Zellweger syndrome
  X-linked Syndromes
  Alport's syndrome
  Fabry's disease
  Lenz microphthalmos syndrome
  Lowe oculocerebrorenal syndrome
  Other Disorders (Multifactorial, Teratogenic, or Unknown Etiology)
  Congenital rubella
  Cornelia de Lange syndrome
  Diabetes mellitus
  Goldenhar syndrome, CHARGE and VATER associations
  Membranoproliferative glomerulonephritis type II
  Nephronophthisis-mitochondropathy association syndrome
  Wildervanck syndrome



WAGR Syndrome

Deletion of band p13 of chromosome 11 produces the WAGR syndrome consisting of Wilms' tumor, sporadic aniridia, genitourinary malformations, and mental retardation.9,10 Wilms' tumor is an embryonic neuroblastoma and is the most common malignant renal tumor in both children and adolescents.11 About 6% of all primary renal tumors regardless of age are Wilms' tumors. Although most Wilms' tumors occur as an isolated sporadic event, there are several syndromic associations of Wilms' tumor, including WAGR syndrome.10 A Wilms' tumor suppressor gene has been localized to band p13 of chromosome 11 near the gene responsible for sporadic aniridia. Sporadic aniridia is present in 1% of children with Wilms' tumor and results from a 11p13 deletion that includes both genes. The Wilms' tumor suppressor gene appears to play an important role in the normal development and maturation of the kidneys and gonads. Any newborn with nonfamiliar aniridia should be examined by a geneticist and followed by a medical team familiar with detection and management of Wilms' tumor.11,12


Autosomal Dominant Syndromes

ACRO-RENAL-OCULAR SYNDROME. The acro-renal-ocular syndrome is an autosomal dominant dysmorphogenetic syndrome with high penetrance and variable expression. The main components of the syndrome are hand, urinary tract, and ocular anomalies. In addition, there may be perceptive deafness, cardiac anomalies, and anal stenosis.13,14 The radial ray abnormalities of the hand vary in expression from mild thenar hypoplasia or inability to flex the interphalangeal joint of the thumb to hypoplastic thumbs or prominent upper limb abnormalities. The urinary tract anomalies include unilateral renal agenesis, renal ectopia, malrotation, and bilateral renal hypoplasia. Duane's anomaly is the most common ocular abnormality in patients affected by the acro-renal-ocular syndrome. Microcornea and uveal and optic nerve colobomas have been reported on occasion.14,15

NAIL-PATELLA SYNDROME. Nail-patella syndrome (hereditary osteo-onychodysplasia, HOOD) is an autosomal dominant disorder of nails, skeleton, and kidney. The nail-patella locus has been assigned to the distal end of the long arm of chromosome 9 (9q34). The collagen gene COL 5A1, which encodes the pro alpha 1(V) chain, maps in the same region, providing evidence that the nail-patella syndrome could be an inherited connective tissue disorder attributable to mutations of the COL 5A1 gene.

The nails are hypoplastic or absent, particularly affecting the thumb and index finger. Characteristic skeletal abnormalities include small or absent patellae, iliac horns, and hypoplasia of the capitellum and lateral epicondyle of the distal humerus together with deformity of the radial head. Recurrent subluxations of knees and elbows, flexion deformities of the elbows, and Madelung's deformity with volar position of the wrists often occur in patients with nail-patella syndrome but rarely are incapacitating.

Nephropathy is usually mild and manifests as proteinuria or intermittent nephrotic syndrome, but end-stage renal failure may occur and nephropathy may be the most serious complication in some families. Typical renal lesions are focal glomerular basement membrane thickening with subendothelial fibrillar electron-dense deposits and moth-eaten appearance of the glomerular basement membrane.

A cloverleaf dark pigmentation of the central area of the iris with scalloped iris collarette (Lester's sign of the iris16) is a peculiar finding in some patients with the nail-patella syndrome. Keratoconus, microcornea, sclerocornea, microphakia, and cataracts have also been described.17

PAPILLORENAL SYNDROME. The papillorenal syndrome has been defined by Bron18 as a dominantly inherited disorder with a bilateral dysplasia of the optic discs associated with a severe form of glomerulonephritis that may lead to renal failure. The disc anomaly ranges from morning glory anomaly or the Handmann anomaly to coloboma or optic pit (Fig. 2). Optic nerve function may be impaired, and in addition there is a risk of visual loss as a result of serous macular detachment. The pathogenesis of the renal changes and the genetic mechanism linking the renal and ocular abnormalities are unknown.

Fig. 2. Papillorenal syndrome with the Handmann optic disc anomaly and macular changes as a result of chronic macular detachment in a renal transplant patient. An optic pit and severe hypertensive changes were observed in his brother, who also received a renal transplant (see Fig. 1). Poor renal function had been recorded in six other family members in three generations.

VON HIPPEL-LINDAU DISEASE. Von Hippel-Lindau disease is a dominantly inherited familial cancer syndrome affecting eyes, brain, and kidneys. The characteristic manifestations are capillary angiomas of the retina and optic nerve head; cerebellar, medullary, and spinal hemangioblastomas; renal cell carcinoma; pheochromocytoma; and renal, pancreatic, and epididymal cysts. The penetrance of von Hippel-Lindau disease is age and tumor dependent. The cumulative risk of a patient with von Hippel-Lindau disease developing retinal angioma, cerebellar hemangioblastoma, and renal cell carcinoma at age 30 years are 44%, 38%, and 5%, respectively, rising to 84%, 70%, and 69%, respectively, at age 60 years.19 Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma, and there is convincing evidence that the gene for von Hippel-Lindau disease functions as a tumor suppressor gene of the retinoblastoma type.19 Presymptomatic diagnosis of von Hippel-Lindau disease with flanking DNA markers has become available, but the number of families in which presymptomatic diagnosis is possible is still limited, and presymptomatic diagnosis remains impossible for relatives of isolated cases. All affected patients and at-risk relatives require lifelong ocular screening and investigation for extraocular complications.19

The disease is often lethal. Renal cell carcinoma is the most frequent cause of death, followed by cerebellar hemangioblastoma.20 Renal cell carcinoma often presents as hematuria, obstructive nephropathy, or an abdominal mass.21 Delayed diagnosis and surgical removal of the tumor may result in death from metastasis or uremia. Cerebellar hemangioblastoma may present as signs of increased intracranial pressure or cerebellar dysfunction. Symptomatic lesions should be excised. Pheochromocytoma tends to cluster in certain predisposed families. The more common cysts and angiomatous tumors of several visceral organs rarely cause symptoms. Screening of extraocular complications requires annual physical examination, renal ultrasound examination, and urinary estimation of vanillylmandelic acids or catecholamines. In addition, magnetic resonance imaging of the brain and computed tomography of the kidneys should be performed in all symptomatic patients because they appear to be more sensitive diagnostic tests. In the Cambridge screening protocol, abdominal computed tomographic scans and brain magnetic resonance imaging or computed tomographic scans are also planned at regular intervals in asymptomatic individuals.19,20

Retinal angiomatosis is the most frequent complication and often the initial manifestation of von Hippel-Lindau disease. The screening protocol for von Hippel-Lindau disease in affected patients and at-risk relatives should include at least annual direct and indirect ophthalmoscopy and, preferably, fluorescein angiography or angioscopy to permit early detection and treatment of retinal angiomas. Tumors to 3 mm respond well to laser photocoagulation.22 Larger peripheral angiomas and those with exudative detachment or arising close to the ora serrata require cryocoagulation or other surgical treatment modalities.19 Vitreoretinal surgery may be indicated in cases with extensive epiretinal fibrosis and traction retinal detachment. In addition, radiation therapy may be used for optic disc hemangiomas and for tumors not responding to cryotherapy.19,22

Autosomal Recessive Syndromes

BARDET-BIEDL SYNDROME AND RELATED DISORDERS. The cardinal features of Bardet-Biedl syndrome are retinal dystrophy, polydactyly, obesity, mental retardation, and hypogenitalism. Renal and urinary tract abnormalities are common. Incomplete manifestation of the cardinal signs is frequent, but retinal dystrophy is a essential feature for the Bardet-Biedl syndrome.23

The electroretinogram is a sensitive detector of retinopathy in patients with Bardet-Biedl syndrome and may allow identification of the photoreceptor cell degeneration (cone-rod dystrophy) in young children with normal fundus appearance.24,25 Fundus changes appear at the end of the first decade, or in the second or third decade of life, and usually present as atypical central and peripheral pigmentary abnormalities, attenuated retinal vasculature, and pale discs. Loss of visual acuity is usually mild in the first decade of life and marked in the second and third decades.

In addition to classic Bardet-Biedl syndrome, several variants and related disorders with or without ocular abnormalities have been described.23 Those with ocular abnormalities include Laurence-Moon syndrome, Biemond II syndrome, and Alström syndrome. Patients with Laurence-Moon syndrome share most features of Bardet-Biedl patients but are spastic and do not have polydactyly. Patients with Biemond II syndrome have an iris coloboma and lack pigmentary retinopathy. Alström syndrome can be distinguished from Bardet-Biedl syndrome by severe visual loss in the first decade of life, nerve deafness, and diabetes mellitus. Slowly progressive nephropathy and renal failure are very common as well in Alström syndrome as in Bardet-Biedl syndrome, and renal failure is probably the most frequent cause of death.26

CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROMES. The carbohydrate-deficient glycoprotein syndromes are a group of genetic multisystemic diseases with characteristic deficiency of several carbohydrates in a number of glycoproteins. The severity of symptoms is variable, and several subtypes have been identified.27,28 These syndromes are mainly nervous system disorders, but ocular and renal involvement are part of the syndromes.

The disease may present in infancy or early childhood with combinations of failure to thrive, developmental delay and strokelike episodes, esotropia, lipoatrophic changes, liver dysfunction, or pericardial effusions.27,28 In older children and in adults the combination of mental retardation, olivopontocerebellar atrophy, peripheral neuropathy, and photoreceptor cell degeneration29–31 is strongly suggestive of carbohydrate-deficient glycoprotein syndrome. Renal cysts are common.31,32

CYSTINOSIS. Cystinosis is an autosomal recessive lysosomal storage disorder. In affected patients a primary defective transport of cystine out of lysosomes causes intracellular cystine accumulation and deposition of cystine crystals in many body tissues, including the kidneys and the eyes. The infantile form of nephropathic cystinosis is the most common and severe variant. In late-onset or adolescent cystinosis the symptoms are similar but usually milder. Benign or adult cystinosis is a rare nonnephropathic variant. Corneal crystal deposition invariably occurs in all types of cystinosis, which allows easy clinical diagnosis of the disorder based on the biomicroscopic observation of refractile crystals. The diagnosis may be confirmed by measuring the white blood cell cystine content. Cystinosis has an autosomal recessive pattern of inheritance, and the various forms of cystinosis appear to result from different defects in the same gene.33 Heterozygotes can be detected by measuring the cystine content of polymorphonuclear leukocytes, and prenatal diagnosis of nephropathic cystinosis can be made using cultured amniocytes or chorionic villi.

The systemic features of nephropathic cystinosis usually present in the first year of life with failure to thrive and dehydration due to proximal renal tubular dysfunction. Rickets and corneal crystals often appear by 1 to 2 years of age. The typical phenotype of patients with nephropathic cystinosis includes short stature and light complexion. As a result of progressive renal failure, end-stage renal disease generally occurs by the end of the first decade of life, necessitating dialysis or renal transplantation. In young children, growth can be improved and renal deterioration delayed by cysteamine, a cystine-depleting agent.34

Since the advent of renal transplantation many cystinotic patients live to adulthood and become susceptible to new complications caused by long-standing cystine accumulation in nonrenal organs. Cerebral atrophy is a common finding on computed tomographic scans of older cystinotic patients, but severe involvement of the central nervous system is rare. A large spectrum of neurologic features has been described, including nonabsorptive hydrocephalus and a peculiar form of encephalopathy, leading to a “pseudo-bulbar state.”33,35 Hypohidrosis, hypothyroidism, late sexual maturation, insulin-dependent diabetes, liver enlargement with portal hypertension, and severe epistaxis have been observed in several patients who survived into their second and third decades.34,35

All cystinotic patients have ocular involvement, and older patients with nephropathic cystinosis are at risk of severe ocular complications. In nephropathic cystinosis, crystal deposits usually appear in the cornea within the first year of life. Initially, crystals can be identified in the anterior peripheral part of the cornea by slit lamp biomicroscopy. With time, progressive accumulation of crystals occurs throughout the corneal stroma, inducing photophobia even in young children and provoking a hazy, ground-glass appearance of the cornea in older patients.36 Crystal deposits are also formed in conjunctiva, iris, and retinal pigment epithelium.37 Focal degeneration of the retinal pigment epithelium with patchy depigmentation of the fundus may appear early in life and is generally present by age 7.37 The fundus lesions are bilateral and symmetric and involve mainly the periphery, although some patients also develop atrophic macular changes (Fig. 3). Abnormal retinal function with reduced or extinguished responses on electroretinograms and decreased visual acuity are frequent complications in older cystinotic patients.37,38 Several other complications have been described in patients with nephropathic cystinosis, including superficial punctate keratopathy, recurrent erosions, corneal vascularization, band keratopathy, tight miosis, posterior synechiae, and pupillary-block glaucoma.35,37–39

Fig. 3. Cystinotic fundus changes in a 19-year-old patient, demonstrating a pale optic disc and numerous peripheral and macular small white spots at the level of the retinal pigment epithelium. Fluorescein angiography confirmed marked degenerative changes of the retinal pigment epithelium with macular, peripapillary, and peripheral window defects.

Oral administration of cysteamine does not appear to improve the corneal deposits, and the effectiveness in improving other nonrenal complications is uncertain. However, frequent instillation of topical cysteamine (0.1% to 0.5%) has been shown to clear the cornea in young patients, to reduce the amounts of intracorneal cystine crystals in older patients, to diminish photophobia and blepharospasm, and to improve visual function.40,41 Corneal complications may require symptomatic therapy including artificial tears or bandage contact lenses, and, rarely, penetrating keratopathy may be indicated.36

Nephronophthisis (nephronophthisis-medullary cystic disease complex) includes a group of hereditary disorders characterized by urinary concentrating defects and progressive renal failure. The renal disease can be the only abnormality or be a part of multiorgan involvement with mainly skeletal and ocular abnormalities. The fundamental defect in nephronophthisis appears to be production of abnormal tubular basement membranes.42

Patients with nephronophthisis have multiple cysts at the corticomedullary junction and in the medulla that can be visualized on ultrasonography and computed tomography of the kidneys. The clinical course is variable, but tubulointerstitial nephropathy frequently leads to progressive renal insufficiency, requiring dialysis or renal transplantation.

A number of extrarenal abnormalities have been described in patients with nephronophthisis, singly or in various combinations.43 The term renal-retinal dysplasiarefers to the syndromes with associated retinal abnormalities. The ocular manifestations frequently resemble Leber's amaurosis or present as retinitis pigmentosa or congenital stationary nightblindness. Senior-Loken syndrome is characterized by nephronophthisis and retinal degeneration-type Leber's amaurosis with flat or severely reduced electroretinograms from early age. The fundus appearance varies from near normal to manifest retinal degeneration with changes typical of retinitis pigmentosa or atypical features or marbleized fundus.44 Abnormal electroretinograms have been recorded in patients with nephronophthisis without clinical evidence of ocular involvement45 and in some carriers.43

Mainzer-Saldino syndrome is the association of nephronophthisis, tapetoretinal degeneration resembling Leber's amaurosis, cone-shaped epiphyses, and cerebellar ataxia. Boichis syndrome is the association of nephronophthisis with liver fibrosis and may occur in combination with deafness, cerebellar ataxia, and tapetoretinal degeneration. Nephronophthisis and retinal degeneration have been reported in association with asphyxiating thoracic dystrophy (Jeune's syndrome) and with mitochondrial cytopathy and features of Kearns-Sayre syndrome.

Primary hyperoxaluria type I is an autosomal recessively inherited metabolic disorder caused by a deficiency of the peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) in liver. The defective transamination of glyoxylate causes overproduction and urinary excretion of oxalate and glycolate and leads to recurrent calcium oxalate urolithiasis and nephrocalcinosis, end-stage renal failure, and systemic oxalosis with precipitation of calcium oxalate crystals throughout the body. A similar but frequently milder pattern of disease may occur in the rare types II and III of primary hyperoxaluria and in secondary hyperoxaluria resulting from increased intake or absorption of dietary oxalate or precursors of oxalate.

Three clinically distinguishable variants of primary hyperoxaluria type I have been recognized.46 Infantile oxalosis, the most severe form, generally presents before the age of 4 months with manifestations of progressive renal insufficiency, including failure to thrive, vomiting, pallor, anemia, metabolic acidosis, and convulsions. The diagnosis of infantile oxalosis can be established by the finding of increased urinary and plasma values of oxalate and glycolate and by renal ultrasound examination demonstrating increased echogenicity due to nephrocalcinosis. Death occurs within the first year of life. The juvenile form of primary hyperoxaluria is the most common variant, presenting between 2 years and 18 years with repeated urolithiasis and a variable degree of renal failure. The clinical course is similar to the adult form. The adult variant is characterized by repeated attacks of renal colic with hematuria and spontaneous passing of stones and progressive renal damage as a result of obstruction and urinary tract infections. As renal insufficiency occurs, the effect of oxalate retention is superimposed on overproduction, leading to systemic oxalosis with deposition of calcium oxalate crystals in many tissues, including the eyes. The most severe extrarenal complications are oxalotic osteodystrophy, peripheral vascular insufficiency, and heart block. Nearly one third of older patients with type I hyperoxaluria respond to pyridoxine treatment. Renal transplantation is life saving in oxalotic patients with end-stage renal disease, but it leaves the patient exposed to the risk of recurrent stone formation and nephrocalcinosis. Liver transplantation replaces the enzyme-deficient organ and may offer definitive treatment if combined with renal transplantation or performed before irreversible renal damage has occurred.47

Ocular manifestations are variable and include changes of retinal pigment epithelium, retinal vascular obstruction, and optic nerve atrophy. Calcium oxalate crystals are deposited predominantly in the retinal pigment epithelium of the posterior pole and may induce pronounced reactive lesions but generally do not cause severe visual loss.48 The abnormalities reported in patients with infantile oxalosis include scattered crystalline flecks, subretinal small black ringlets, large geographic macular lesions, and optic atrophy, which is rare but invariably associated with severe visual impairment.49 Bilateral symmetric retinopathy has been reported in 30% of patients with primary hyperoxaluria, and the presence of oxalate retinopathy was positively correlated with infantile onset and a severe systemic course of the disease.49

In patients with the juvenile or adult variants the most common abnormalities are crystalline spots or yellowish flecks in the posterior pole, and rare manifestations include macular black lesions, retinal periarterial crystal deposition, retinal vascular occlusions, and neovascularization.50,51

Zellweger (cerebrohepatorenal) syndrome is a childhood multisystemic disorder caused by peroxisomal malfunction. The primary defect is impaired biogenesis of peroxisomes, with resultant peroxisomal enzyme defects and several biochemical abnormalities, including deficiency of ether glycolipids and accumulation of very long chain fatty acids, pipecolic acid, phytanic acid, and bile precursors.52,53 Organs that have an abundance of peroxisomes are principally affected, and death generally occurs within the first year as a result of gross defects of early brain development and major complications. Zellweger syndrome is an autosomal recessive disease. Heterozygotes have lenticular opacities with curvilinear cortical condensations, which can be observed after maximal pupillary dilatation, and these characteristics may be used for detection of the carrier status.54 Prenatal diagnosis of Zellweger syndrome can be made using cultured amniocytes or chorionic villi.

Infants with Zellweger syndrome are severely hypotonic at birth, have a characteristic face with a tall forehead, hypoplastic supraorbital ridges, and epicanthal folds and have a combination of neurologic, hepatic, renal, cardiac, skeletal, and ocular abnormalities.52 The renal abnormalities include multiple cortical cysts, proteinuria, and aminoaciduria.

The ocular abnormalities of Zellweger syndrome are prominent and have dysgenetic and degenerative components.52 Retinal dystrophy and extinguished electroretinograms are consistent features of Zellweger syndrome. Lens opacities at the corticonuclear interface appear to be characteristic abnormalities.54 Opticus hypoplasia, microphthalmos, malformation of the anterior chamber, glaucoma, and corneal clouding can occur in Zellweger syndrome.

X-linked Syndromes

Classic Alport's syndrome is characterized by progressive hematuric nephritis, specific ultrastructural changes in the glomerular basement membrane, progressive perceptive high-tone hearing loss, and ocular signs. The abnormal structure and function of the glomerular basement membrane have been attributed to inadequate production of the alpha 5 chain of collagen IV. The gene COL 4A5, which encodes the alpha 5 chain of type IV collagen, has been localized to the long arm of the X chromosome in the Xq21-q22 region, and a variety of mutations in the gene have been identified in families with Alport's syndrome.

The cardinal clinical manifestation of Alport's nephritis is chronic hematuria; proteinuria is a frequent finding. Renal biopsy shows diagnostic ultrastuctural changes with thinning and splitting of the glomerular basement membrane. Affected males are more likely to develop end-stage renal disease and deafness than are females. Ocular signs are significantly linked to poor renal function.55,56 Variants of Alport's syndrome include Alport's syndrome without hearing loss or ocular lesions56,57 and the variants with associated leiomyomatosis or macrothrombocytopenia.

Alport's syndrome may affect the cornea, lens, and retina, the most characteristic ocular signs being posterior polymorphous dystrophy, anterior lenticonus, and superficial perimacular flecks (Fig. 4). There is growing evidence that the ocular abnormalities, like the glomerular lesions, result from a common defect in basement membrane formation.56,58,59 Changes are uncommon and subtle in young patients with Alport's syndrome and seem to increase in frequency and severity with age.60 The corneal changes associated with Alport's syndrome include endothelial vesicles compatible with posterior polymorphous dystrophy, subepithelial opacities,58 corneal arcus, and recurrent corneal epithelial erosions.

Fig. 4. Superficial perimacular flecks in a 15-year-old boy with normal vision. Alport's nephritis was diagnosed at the age of 3 years and progressed to end-stage renal disease at the age of 14 years. Perceptive high-tone hearing loss was detected at the age of 11 years. The proband's mother has had persistent microscopic hematuria since the age of 20 years but had no other manifestations of the disease.

Anterior lenticonus is a common finding in patients with Alport's syndrome. The “oil droplet” retinoscopy reflex is an early sign of anterior lenticonus. Advanced stages are characterized by increasing myopia, visual loss, and abnormal slit lamp examination showing protrusion of the lens and thinning of the capsule over the conus, with or without anterior subcapsular cataract or capsular rupture. Less specific or rare lenticular abnormalities reported in patients with Alport's syndrome include several other types of cataracts, spherophakia, and posterior lenticonus.

Superficial perimacular flecks do not interfere with vision but are a reliable indicator of Alport's syndrome and are often associated with renal deterioration.55,56,60 Midperipheral retinal flecks and pigment epithelial lesions are also specific for Alport's syndrome. Macular pigmentation and weakened foveal reflex have been observed occasionally, and there have been individual reports of macular hole, retinal detachment, and optic disc drusen in patients with Alport's syndrome. Electrophysiologic abnormalities are unusual in classic Alport's syndrome. Retinitis pigmentosa and cone dystrophy, however, have been described in a few families with hereditary nephritis.

No significant eye changes have been reported in patients with Alport's syndrome variant affected by familial nephritis without deafness.56,57 Cataracts have been observed in the leiomyomatosis- and macrothrombocytopenia-associated variants.

Fabry's disease is an X-linked glycosphingolipid storage disease characterized by specific skin and eye lesions and a high risk of developing renal disease and cardiovascular complications. The basic abnormality is α-galactosidase A deficiency as a result of mutation in the encoding X-linked gene. The enzymatic deficiency leads to intracellular glycosphingolipid accumulation in many tissues and primarily affects the vascular endothelium. In the hemizygous males the manifestations of the disease are severe, while the heterozygous females often are healthy carriers or have only mild involvement. Confirmation of Fabry's disease can be obtained by enzyme analysis and study of ultrastructural changes in bioptic specimens (cellular vacuolation and characteristic inclusion bodies). Prenatal diagnosis of α-galactosidase deficiency is available.

Signs of the disease often appear in late childhood and become more profuse during the third and fourth decade. Episodes of burning pain in the limbs are usually the initial symptoms and are often associated with fever and increased sedimentation rate. At the same time clusters of angiectases appear on the lower trunk and mucous membranes. Renal disease and renovascular hypertension often develop. Death usually occurs in mid life as a result of renal failure, stroke, or complications of hypertrophic cardiomyopathy, atrioventricular block, or coronary artery disease.

Whirl-like opacification of the cornea (cornea verticillata) is a subtle but diagnostic sign in Fabry's disease.61,62 The corneal epithelial deposits are present in nearly all hemizygotes and heterozygotes and can be detected from the age of 6 years. Other characteristic abnormalities are anterior and posterior capsular lens opacities, aneurysmal dilatations of the conjunctival vessels, and tortuosity of the retinal vessels.61 Ischemic optic neuropathy and retinal artery occlusion have been reported as ocular complications of Fabry's disease.

The Lowe oculocerebrorenal syndrome is characterized by congenital cataracts, mental retardation, muscular hypotonia, and renal tubular dysfunction. The disorder is X-linked, and the locus has been mapped to Xq25–q26. Although the biochemical defect in Lowe oculocerebrorenal syndrome is not known, there is evidence suggesting that a defect of mitochondrial metabolism could be involved in the pathogenesis.

Affected males have a characteristic hypotonic facial appearance and generalized hypotonia leading to joint dislocations and scoliosis.63 Areflexia, mental retardation, and seizures are common findings in Lowe syndrome. Patchy or diffuse white matter abnormalities have been characterized using magnetic resonance imaging. Renal tubular dysfunction presents within the first year of life and leads to rickets and renal failure.

Cataracts with a small discoid lens and peculiar capsular and epithelial changes are diagnostic for Lowe syndrome and are present at birth in nearly all affected males.63 Changes include a lack of demarcation between the nucleus and cortex, posterior lenticonus adherent to condensed anterior vitreous, chamber angle abnormalities associated with congenital glaucoma, miotic pupils with adhesions to the anterior lens surface, and corneal keloids.63 Heterozygote females develop progressive lens changes, a sign that can be used for carrier detection. Carriers can be diagnosed in the second decade of life, on the basis of presence of several punctate cortical opacities. These cortical dots increase in number with the age of the carriers, and in older carriers subcapsular plaques may be observed as well.64


Diabetes Mellitus

The microangiopathy of diabetes mellitus mainly affects retina and kidney. With time, nearly all diabetics have clinically evident diabetic retinopathy, while manifestations of diabetic nephropathy occur in a subset of patients. Diabetes mellitus causes renal hyperperfusion, glomerular hyperfiltration, microalbuminuria, and structural changes with glomerular membrane thickening and mesangial expansion. The early phase of diabetic nephropathy is characterized by persistent microalbuminuria. Overt diabetic nephropathy with frank proteinuria occurs in nearly 40% of insulin-dependent diabetics approximately 17 years after the onset of diabetes. Poor glycemic control and hypertension appear to be risk factors for diabetic nephropathy. Once proteinuria appears, renal function inexorably declines, with 50% of patients reaching end-stage renal disease within 7 years of the onset of proteinuria.65 In addition to increased risk of progressing to overt diabetic nephropathy, insulin-dependent diabetics with microalbuminuria suffer a high cardiovascular mortality rate. In patients with non-insulin-dependent diabetes mellitus, persistent microalbuminuria also predicts progressive nephropathy and cardiovascular mortality. Strict diabetic control and treatment of hypertension have been shown to protect renal function. Once diabetic nephropathy is established, blood pressure control and low-protein diets may retard the progression of renal failure. Angiotensin-converting enzyme inhibitors decrease albuminuria in patients with diabetic nephropathy and, in addition, have a protective effect on the blood-retina barrier.66 Renal transplantation is the preferred treatment for end-stage renal failure in diabetic patients and provides a better quality of life than dialysis.67,68 Simultaneous pancreas transplantation can further enhance the quality of life but may potentially cause additional complications.

Diabetic retinopathy is characterized by increased vascular permeability leading to retinal edema and capillary closure leading to retinal ischemia and new vessel growth. With time, diabetic retinopathy occurs in nearly all diabetics; many will develop proliferative retinopathy. In patients with diabetic nephropathy, retinopathy is always present and proliferative retinopathy is common. However, 35% of patients with proliferative retinopathy have no signs of diabetic nephropathy, and these patients will probably never develop nephropathy.69,70 Retinopathy tends to deteriorate as renal failure develops, particularly in patients with poorly controlled blood pressure and in patients in whom no retinal treatment has been given before development of renal failure. Hypertension changes the funduscopic aspect and the course of background retinopathy by producing diffuse macular edema, cotton-wool spots, and numerous flame-shaped hemorrhages, particularly in the peripapillary area and along the main retinal veins (Fig. 5). In addition, hypertension accelerates the evolution of background to proliferative retinopathy. Treatment of hypertension and of end-stage renal failure will improve the retinopathy, particularly macular edema, and stabilize vision.68 It is currently accepted that preservation of vision correlates well with blood pressure control and that patients with end-stage renal disease suffering from diabetic retinopathy now enjoy an equivalent visual prognosis whether treated by dialysis or given a kidney transplant.71 Since the progression of diabetic retinopathy is independent of diabetic nephropathy and not reversed by treatment of nephropathy, further follow-up and treatment of diabetic retinopathy is imperative. Patients with persistent macular edema may benefit from macular photocoagulation. In diabetics with active proliferative retinopathy, panretinal photocoagulation and vitrectomy may improve the visual prognosis by inducing involutional retinopathy and by removing vitreous hemorrhages and vitreoretinal traction. Moreover, diabetic patients with end-stage renal disease are predisposed to cataract, which may require surgical intervention. The progress made in improving the visual prognosis in diabetic end-stage renal disease reflects the synergistic efforts made by internists and ophthalmologists and emphasizes the importance of team approach in preventing blindness.71

Fig. 5. Combined diabetic and hypertensive retinopathy in a 52-year-old patient with long-standing diabetes and end-stage renal disease. Note optic disc and retinal new vessels, diffuse retinal edema, numerous hemorrhages, and several cotton-wool spots along the main veins.

Membranoproliferative Glomerulonephritis Type II

A systemic disease of unknown origin, membranoproliferative glomerulonephritis (MPGN) type II, affects mainly the glomerular basement membrane and the complex of choriocapillaris, Bruch's membrane, and retinal pigment epithelium. Electron-dense deposits are characteristically observed within the lamina densa of the glomerular basement membrane and have been described in Bruch's membrane and choriocapillaris by Duvall-Young and co-workers, who also made the first clinical reports of fundus changes with drusen-like deposits and mottled pigmentation.72,73

MPGN represents a group of disorders characterized by proliferation of mesangial cells, increased mesangial matrix, and irregular thickening of the glomerular capillary wall. Several immunofluorescence and electron microscopic patterns have been identified. In MPGN type II (dense deposit disease), the lamina densa of the glomerular basement membrane is largely replaced by electron-dense material, which does not include immunoglobulin or complement. Similar dense deposits are also found in the basement membranes of Bowman's capsule, of the tubules, and of the spleen and in Bruch's membrane and choriocapillaris. The renal disease frequently shows a progressive course, with onset usually occurring in childhood. Type II MPGN almost invariably recurs morphologically in renal allografts. Other clinical features of MPGN type II include chronic hypocomplementemia with increased susceptibility for infections, partial lipodystrophy, and a higher incidence of diabetes mellitus.

Drusen-like lesions and retinal pigment epithelium damage have also been recognized as a feature of MPGN type II.72–79 In a fluorescein angiographic study of 26 patients who had biopsy-proven MPGN type II, specific fundus lesions were identified in 24 patients (92%).79 Two adolescents with a history of renal disease of 13 months and 2 months had normal fundi. Small-sized lesions similar to small hard drusen were observed in all 24 patients with a history of renal disease lasting for 16 months or more (Fig. 6). In all 15 subjects with a history of renal disease of at least 12 years, larger drusen-like lesions were also noticed. In all 11 patients with renal disease persisting for 18 years or more, drusen occupied most of the fundus and areas of geographic atrophy were seen as well. Foci of new vessels and disciform scarring were observed in eight eyes of five patients with a renal history of 15 years or more (Fig. 7). Most eyes that did not show subretinal neovascularization had normal or nearly normal vision and visual fields. Three patients, however, exhibited ocular symptoms, which were related to pronounced macular atrophic changes, hypertensive retinopathy, and cataracts. The type of fundus lesions was statistically correlated (p<0.0001) with the duration of the renal disease, but not with age, sex, or renal insufficiency. Fundus changes between first and last visit as well as cross-sectional studies suggest a slow progression of retinal disease, which is probably independent of treatment and age of the patient.77–79

Fig. 6. Specific fundus lesions of membranoproliferative glomerulonephritis type II in a 12-year-old child with renal disease since the age of 3 years. The fluorescein angiogram shows numerous small lesions similar to hard drusen. (Leys A, Vanrenterghem Y, Van Damme B et al: Fundus changes in membranoproliferative glomerulonephritis type II: A fluorescein angiographic study of 23 patients. Graefes Arch Clin Exp Ophthalmol 229:406, 1991)

Fig. 7. Fluorescein angiographic changes in a 32-year-old patient with renal signs of membranoproliferative glomerulonephritis type II since the age of 9 years. Numerous small and larger drusen-like lesions, atrophic changes, and a small infrafoveolar subretinal neovascular membrane that was successfully treated with argon laser coagulation can be seen. (Leys A, Michielsen B, Leys M et al: Subretinal neovascular membranes associated with chronic membranoproliferative glomerulonephritis type II. Graefes Arch Clin Exp Ophthalmol 228:499, 1990)

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