Ocular manifestations in renal diseases

Abstract

The eyes and kidneys are the targets for end-organ damage in multiple pathologies. Both these organs develop during the same embryonic stage around the fourth to sixth week of gestation, thus sharing a strong correlation between both eye and kidney diseases. Both the eyes and kidneys can be the target of the systemic disease process; however, the eyes can also be affected as a consequence of renal disease or its treatment. Risk factors such as diabetes, hypertension, and smoking are commonly shared between kidney and eye diseases. Ocular manifestations can be predictive of renal disease, and/or patients with renal disease are at higher risk for developing ocular manifestations. Various congenital anomalies of the eyes and kidneys can also present as an oculorenal syndrome. This article summarizes the ocular pathology, which can be seen in renal diseases.

The ocular and renal systems are the targets of end-organ damage in various pathologies. This can occur simultaneously due to common disease processes, or specific renal conditions leading to secondarily ocular involvement. The kidney and retina develop during the same embryonic stage around the fourth to sixth week of gestation, thus sharing a strong correlation between eye and kidney diseases.[1] Chronic kidney disease (CKD) and major eye diseases such as diabetic retinopathy (DR), glaucoma, age-related macular degeneration (ARMD), and cataract are associated with age, metabolic, and vascular risk factors such as diabetes, hypertension, and smoking. Various studies also support the close link between kidney and eye diseases. Ocular manifestations such as retinal microvascular changes can be predictive of CKD development, and patients with CKD are at higher risk for ARMD, DR, glaucoma, and cataract. CKD may also manifest in the eye as developmental anomalies of oculorenal syndromes.[2] In this article, we have discussed the ophthalmic manifestations of various renal pathologies, their pathogenic mechanisms, and common risk factors for kidney and eye diseases.

Materials and Methodology

We used the following keywords for searching the database: chronic kidney disease, chronic renal disease, kidney, hemodialysis with eye, retinopathy, cataract, cornea, conjunctiva, glaucoma and ARMD, retinal vessels, and oculorenal syndromes. We largely selected publications listed in the last 10 years but did not exclude older publications, which are commonly referenced or highly graded. The database selected were Medline (Ovid), PubMed, Scopus, and Cochrane.

Anatomy

The kidneys and eyes share developmental, structural, physiological, and pathological pathways[2,3,4] because the development of the kidneys and retina occur at the same embryonic stage (about the fourth to sixth week of gestation), hence strong correlation is seen between kidney and eye diseases.[1]

• Both glomerulus and choroid have extensive vascular networks of similar structure.

• Inner retina and glomerular filtration barrier share similar developmental pathways.

• The renin–angiotensin–aldosterone system (RAAS) is found in both the kidneys and various ocular tissues, which regulates blood volume and systemic vascular resistance.[3]

Glomerular basement membrane (GBM) and Bruch’s membrane–both membranes contain a3, a4, and a5 type IV collagen chains.[5,6] Thus, diseases involving type IV collagen can affect both eyes and kidneys, resulting in retinopathy and nephropathy developing simultaneously, as seen in Alport syndrome.[7,8] In anti-GBM disease, IgG autoantibodies develop against a3 chains, which gets deposited on GBM resulting in glomerulonephritis.[9] Similarly, IgG deposition on Bruch’s membrane results in the development of choroidal ischemia and retinal detachment.[10,11] The arrangement of retinal pigment epithelium, Bruch’s membrane, and choroidal capillary endothelium resembles glomerular endothelium, GBM, and podocyte. In membranoproliferative glomerulonephritis type II, electron-dense deposits are deposited on GBM and Bruch’s membrane,[12] leading to drusen formation in age-related macular degeneration, indicating the immune regulation link between the eyes and kidneys.[13,14]

Renal and chorioretinal microcirculation–the retinal circulation develops by angiogenesis to supply the inner two-thirds of the retina, whereas peritubular capillaries and vasa recta in the kidneys populate the medulla and inner cortex in the same manner.[15] The choriocapillaris endothelium has fenestrations of approximately 80 nm, which allows fluid exchange within subretinal space, and the glomerular endothelium has similar-sized fenestrations, which facilitate ultrafiltration into Bowman’s capsule.[16]

RAAS is widely expressed in retinal and choroidal vasculature, where angiotensin II acts via type I receptors, leading to chorioretinal vasoconstriction, and excessive activation of RAAS leads to DR and CKD.[17] Endothelin-1 in the eyes mediates vasoconstriction via endothelin-A receptors, localized predominantly in choroidal and retinal vascular smooth muscles, whereas in the kidneys, these receptors are localized to the vascular smooth muscle of glomeruli and vasa recta. Selective blockade of endothelin-A receptor in the eyes increases retinal blood flow and reduces retinal pericyte apoptosis and retinal thinning, whereas, in the kidneys, it causes intraglomerular hypertension, podocytopathy, and fibrosis leading to the progression of CKD.[18,19]

Risk factors

CKD is an emerging health problem worldwide affecting about 10% of the world`s population[20] and is associated with serious cardiovascular and renal problems and decreased quality of life. CKD is a progressive and irreversible problem resulting in end-stage renal disease (ESRD), which increases with increasing age and with chronic diseases such as diabetes, hypertension, and obesity.[21] Common risk factors between CKD and eye include old age,[22,23] smoking,[24] hypertension,[24,25,26] diabetes mellitus,[27,28] obesity, and hyperlipidemia.[29,30]

Common pathophysiological mechanisms between kidney and eye diseases

Major mechanisms contributing to CKD and eye diseases are atherosclerosis, endothelial dysfunction, vascular remodeling, inflammation, and oxidative stress. The renin–angiotensin–aldosterone hormonal cascade is found in both the kidneys and eyes.[3] Table 1 summarises the common pathogenic mechanisms underlying both kidney and eye diseases.

Table 1.

Summary of common pathogenic mechanisms underlying both kidney and eye diseases

Mechanisms of CKD	Associated eye diseases
RAAS dysfunction	DR, glaucoma, retinal vascular damage
Inflammation	AMD, DR, retinal vascular damage
Genetic polymorphisms	AMD
Klotho	AMD, cataract, retinopathy
Endothelial dysfunction	AMD, cataract
Atherosclerosis	Cataract, AMD, DR, glaucoma, retinal vascular damage
Oxidative stress	AMD, DR, cataract, glaucoma, retinal vascular damage

Renin–angiotensin–aldosterone system (RAAS)

Localized RAAS is found in various components of the retina including microvasculature, retinal pigment epithelium, muller cells, and ganglion cells.[31,32] The vasoproliferative vascular disorders such as DR and retinopathy of prematurity (ROP) are associated with elevated levels of prorenin, rennin, and angiotensin II,[33] indicating the benefit of RAAS blockade on retinopathy.[17,34,35] Also, RAAS is implicated in the pathogenesis of glaucoma through its effects on aqueous humor production and drainage.[36] Vasoconstriction of the iris and ciliary body vessels with sodium homeostasis reduces the aqueous humor production, resulting in a lowering of intraocular pressure (IOP).[37]

Advanced glycation end products (AGEs)

These are heterogeneous groups of structures formed during hyperglycemia or under high oxidative stress. Advanced glycation end products (AGEs) cause crosslinking and insolubility of lens proteins, yellowing of the lens, and accumulation of glycation end products in the lens, contributing to its role in the formation of cataracts.[38,39] In DR, the toxic effects of AGEs target the retinal pericytes and thus induce retinopathy.[40]

Genetic polymorphisms

Mutations of complement factor H (CFH) is found in association with membranoproliferative glomerulonephritis and hemolytic uremic syndrome ARMD in the eyes. A genome-wide association study has found an increased risk of ARMD in individuals with genetic pleomorphism in the CFH gene.[41]

Vitamin D deficiency

Vitamin D plays a protective role in AMD due to its anti-inflammatory and anti-angiogenic properties by suppressing the proliferation of immune cells and proinflammatory cytokines.[42] Also, it inhibits angiogenesis by its action on endothelial cells and interruption of the signal pathways, which is a key mechanism in wet ARMD.[43] Thus, the intake of vitamin D in foods and supplements is associated with a lower risk of AMD and it also has a protective role in DR.[44]

Accelerated atherosclerosis

Atherosclerosis is accelerated in CKD by various mechanisms including increased serum lipoprotein and homocysteine,[45,46] decreased transforming growth factor-b1 levels,[47] and increased oxidative stress owing to decreased glomerular filtration of free radical-generating nitrogenous waste products. A few studies have shown that the sclera and Bruch’s membrane of choroid share the same connective tissue (collagen and elastin), as that of medium and large-sized arteries; thus, atherosclerosis has similar effects on both structures.[48] Deposition of lipids in the sclera and Bruch’s membrane results in elevated choriocapillaris pressure, increased levels of vascular endothelial growth factor (VEGF), and calcification of Bruch’s membrane, resulting in exudative AMD.

Erythropoietin (EPO): EPO is a cytokine with anti-inflammatory, anti-apoptotic, and neuroprotective properties. Hypoxia induces the production of EPO, which up-regulates hemoglobin and acts as a neuroprotector by facilitating the cellular oxygenation of retinal ganglion cells.[49,50,51] CKD patients with decreased EPO lack this neuroprotective mechanism and thus have a high risk of glaucoma.

Cystatin C: Cystatin C is found in virtually all human tissues and body fluids including retinal pigment epithelium and is a sensitive biomarker of CKD.[52,53] Cystatin C is found to be associated with both AMD and DR by its inhibitory action on cathepsins involved in photoreceptor outer segment phagocytosis and suppression of vascular endothelial growth factors.[54,55]

Clinical manifestations

Richard Bright, a pioneer in morbid anatomy and clinical signs and symptoms of kidney diseases, first reported the association between blindness and renal disease in 1836.[56] Any disturbance in embryogenesis between the fourth to sixth weeks of gestation can cause anatomical and functional abnormalities in these two organs. Many ocular findings can be seen in both the anterior and posterior segments.

Anterior segment manifestations

Ocular manifestations can be seen in patients with CKD.[57] Secondary hyperparathyroidism due to renal condition leads to hypercalcemia, which causes the deposition of calcium within various ocular structures. Metastatic calcification can occur on the lid margins, conjunctiva, and cornea in patients with advanced CKD and end-stage renal disease.[58]

Conjunctiva and Cornea

Calcium deposition within the conjunctiva causes chronic inflammation, which can lead to further reactive changes such as pinguecula and superior limbic keratitis. As CKD progresses, increasing concentrations of serum calcium and phosphorus precipitate in the interpalpebral conjunctiva and Bowman’s layer of cornea forming band-shaped keratopathy, causing impaired visual acuity and ocular discomfort.[59] CKD also causes morphological changes in corneal endothelium such as pleomorphism and polymegathism, making them more vulnerable to endothelial decompensation.[60] Patients undergoing hemodialysis develop chronic irritation due to decreased tear production[61] and alterations in the blink reflex.[62] Treatment consists of tear film supplementation with artificial tears.

Cataract development

A few studies have reported the rise of cataracts with increasing levels of markers of kidney disease. Serum cystatin C was associated with a 15-year incidence of cortical and PSC, whereas blood urea nitrogen and creatinine were associated with posterior subcapsular cataracts.[63] The cataract formation results due to metabolic disturbances in the natural history of CKD. Angra and Goyal (1987) reported the rapid development of bilateral osmotic cataracts following hemodialysis in a case of chronic renal failure.[64]

Intraocular pressure

It is hypothesized that the osmotic pressure exerted by increased urea concentration in aqueous humor results in fluid overload in the anterior chamber.[65] Also, toxic metabolites accumulate in the trabecular meshwork and block the aqueous outflow, resulting in a rise in IOP in patients undergoing hemodialysis.[66]

In dialysis disequilibrium syndrome, hemodialysis rapidly removes the uremic toxins and other solutes from the vascular compartment, thus lowering the serum osmolality more rapidly than ocular osmolality. Thus, a urea gradient is generated between the aqueous humor and blood owing to the blood–aqueous barrier,[67] causing water to move into the anterior chamber and increasing IOP.[68]

Posterior segment manifestations

Retinopathy

Arterial hypertension is a significant cause of visual morbidity in patients with chronic renal failure. The eyes can be involved in CKD patients due to microvascular changes in the retina. The high volume and velocity of blood flow within the arteries result in damage to the small caliber vessels of the eye. A few studies have shown that retinal arteriolar narrowing was associated with CKD with an estimated glomerular filtration rate <45 mL/min per 1.73 m².[68,69,70] Arterial narrowing leads to ischemic retinal changes, which result in the formation of cotton wool spots, flame-shaped hemorrhages, hard exudates, and retinal edema. Optic disc edema may develop in severe cases and thus can be confused with neuro retinitis such as the image on fundus examination [Fig. 1]. Damage to choroidal vessels may produce Elschnig’s spots, which are areas of focal chorioretinal infarcts. These patients are also at high risk for developing both retinal arterial and venous obstructive disease.

Figure 1.

Fundus image of the left eye of a patient with retinopathy due to renal hypertension, showing retinal arteriolar narrowing, venous tortuosity, arteriovenous nicking, optic disc swelling, a few flame-shaped retinal hemorrhages, cotton wool spots, and retinal exudation with macular star

Diabetes mellitus also affects both ocular and renal vascular beds. DR is characterized by the presence of retinal microangiopathy and ischemia.[71] Vascular abnormalities present as microaneurysms, dot and blot hemorrhage, venous beading, and hard exudates [Fig. 2], whereas ischemic changes manifest as cotton wool spots and neovascularization of the disc, retina, iris, or anterior chamber angle.[72] Various studies have shown the bidirectional relationship between diabetic retinopathy and CKD,[70] indicating a common pathogenic pathway or manifestations of common underlying microvascular disease. Patients with coexisting disease often develop an increase in retinal exudate when renal failure develops. A few studies have also reported that retinopathy is associated with an increased risk for CKD.[73]

Figure 2.

Fundus image of the right eye of a patient with diabetes and CKD, showing retinal arteriolar narrowing, arteriovenous nicking, and retinal hemorrhages, with extensive retinal exudation

Retinal detachment

Exudative retinal detachment can rarely manifest in patients with end-stage renal disease on hemodialysis due to changes in choriocapillaris permeability, leading to subretinal fluid accumulation.[74]

Optic neuropathy

Hypotensive and anemic episodes in hemodialysis patients make them more prone to the development of anterior ischemic optic neuropathy.[75] These patients present with an altitudinal visual field defect affecting the superior or inferior hemifield of vision. Uremic optic neuropathy is a reversible cause of optic nerve dysfunction, which can subside if timely management is performed before the optic nerve is compromised.[76]

Congenital Anomalies Affecting Eyes and Kidneys

Ocular and renal organogenesis spans the fourth to sixth weeks of gestation[1] and shares several genes including BMP7, Pax 2, and WT-1. Therefore, the mutation in these genes results in various oculorenal syndromes. Various ocular abnormalities such as aniridia, cataract, coloboma, lenticonus, and microphthalmia can be seen in oculorenal syndromes including Alport syndrome, Fabry’s disease, WAGR syndrome, and Senior–Loken syndrome.[2] In young patients presenting with renal impairment, these ocular findings should be thoroughly searched.

Oculorenal syndromes

1. WAGR is named for its main features; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation. Aniridia is typically the first noticeable sign. Other ocular signs include cataracts, glaucoma, nystagmus, and less frequent optic nerve hypoplasia.[77]

2. Von–Hippel–Lindau (VHL) syndrome is an autosomal dominant trait, which clinically manifests as cerebellar and retinal hemangioblastomas, pancreatic cysts, renal cell carcinoma, and pheochromocytoma. Retinal hemangioblastoma is a benign tumor with feeding vessels of increased diameter and tortuosity.[78]

3. Sturge–Weber syndrome is an ocular–dermal–neural syndrome involving the cutaneous facial nevus in the area of the first and second divisions of the trigeminal nerve with ipsilateral glaucoma, ipsilateral diffuse cavernous hemangioma of the choroid, and leptomeninges. Ocular findings may also present as vascular malformation of the conjunctiva, episclera, choroid, or retina.[79]

4. Tuberous sclerosis complex is an autosomal dominant disease characterized by the presence of angiomyolipomas affecting the brain, adenoma sebaceum, kidneys, eyes, and heart. The most characteristic ocular finding seen in 50 to 85% of patients is retinal astrocytic hamartoma.[80]

5. Alport syndrome Sensorineural hearing loss and nephritis are the classical phenotypes described in Alport syndrome, which often progresses to renal failure. Bilateral anterior lenticonus is the most specific ocular abnormality seen.[81]

6. Bardet–Biedl syndrome is an autosomal recessive disorder associated with obesity, polydactyly, pigmentary retinopathy, renal malformations, and hypogenitalism. The ocular findings include rod–cone dystrophy, cataract, and strabismus.[82]

Conclusion

There is substantial evidence of a close association between eye and kidney diseases. The involvement of the eye in renal disease can be either because both organs are the targets of the same disease process or because the ocular disease is a result of renal involvement. Also, a few oculorenal syndromes involve both organs, and thus eyes should be thoroughly examined in these subjects. Recognition of overlapping pathophysiology between renal and ocular diseases helps in prompt diagnosis and treatment of patients with potential ocular and systemic morbidity.

Future direction

Early recognition and treatment of both the ocular manifestations and the systemic condition can lead to improved visual prognosis and reduction in severe complications and morbidity. Recognizing and understanding the links may lead to the development of new diagnostic and management strategies for both types of diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.