Renal Retinopathy

Key Points at a Glance

Highlights of This Condition

• The essence of renal retinopathy is hypertensive retinopathy, but characteristic fundus findings appear due to the addition of uremic toxins and metabolic disorders.
• In a broad sense, it refers to retinopathy associated with malignant hypertension and chronic glomerulonephritis; in a narrow sense, it refers to that caused by chronic glomerulonephritis.
• Multiple cotton-wool spots, macular star, and serous retinal detachment are characteristic findings.
• Many cases do not complain of visual impairment, but when macular edema occurs, patients often become aware of decreased vision.
• The basic treatment involves medical management of the underlying kidney disease and blood pressure control; fundus findings improve along with renal function improvement.
• Many findings improve with renal function improvement, but irreversible damage such as white deposits and retinal pigment epithelium atrophy may persist.

1. What is Renal Retinopathy?

Renal retinopathy is a general term for retinopathy that occurs due to hypertension associated with kidney disease. In 1967, Duke-Elder et al. defined retinopathy associated with malignant hypertension and chronic glomerulonephritis as renal retinopathy in a broad sense. In a narrow sense, only retinopathy due to chronic glomerulonephritis is called renal retinopathy. On the other hand, Okisaka et al. take the position that retinopathy seen in patients with renal hypertension is renal retinopathy. A large cohort study (CRIC Study) of patients with chronic kidney disease (CKD) showed that the severity of retinopathy is independently associated with a decrease in estimated glomerular filtration rate (eGFR), and it has been reported that retinal vascular lesions can be a marker of renal function decline¹.

The essence of renal retinopathy is hypertensive retinopathy. However, it is distinct from retinopathy caused by ordinary essential hypertension. As renal disease progresses, accumulation of blood urea nitrogen (BUN) and other metabolic disturbances lead to characteristic fundus findings such as multiple cotton-wool spots, star-shaped exudates, and serous retinal detachment.

The main causes of renal hypertension are malignant hypertension and chronic glomerulonephritis. In patients with chronic kidney disease or those on dialysis, various fundus complications are known to occur. Ophthalmic evaluation is often required during the course of renal disease treatment. While fundus changes are frequently discovered through referrals from internal medicine, renal impairment may also be detected following a decline in visual function.

Q What is the difference between renal retinopathy and hypertensive retinopathy?

A

The essence of renal retinopathy is hypertensive retinopathy, but a major characteristic is the addition of uremic toxin accumulation and metabolic disorders (such as azotemia, hyponatremia, and anemia) caused by kidney disease. This leads to findings rarely seen in essential hypertension, such as multiple cotton-wool spots, macular star, and serous retinal detachment. In severe cases, choroidal circulatory disturbance can disrupt the outer blood-retinal barrier, resulting in serous retinal detachment.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Renal retinopathy is a disease in which many patients do not complain of visual impairment. Even when fundus changes occur, there is a stage with few subjective symptoms, so it is often discovered incidentally during fundus examinations requested by internal medicine departments.

When macular edema occurs, patients often notice decreased vision. If serous retinal detachment extends to the macula, vision may significantly decline. Some patients also report visual field defects or distortion (metamorphopsia).

Clinical Findings

Fundus changes appear progressively as renal hypertension advances. The changes from the early to severe stages are described below.

Early Stage

Narrowing of retinal arterioles: A finding observed from the early stage of renal hypertension.

Uneven caliber: Localized narrowing of arterioles causes irregular vessel diameter.

Advanced stage

Posterior pole hemorrhages: Dot-shaped and flame-shaped hemorrhages scattered in the posterior pole.

Hard exudates: Yellow-white deposits due to leakage of lipoproteins.

Multiple cotton-wool spots: White fluffy lesions caused by infarction of the nerve fiber layer. On fluorescein angiography (FA), they appear as areas of retinal nonperfusion. They show a characteristic multifocal distribution in hypertensive retinopathy.

Macular star: Hard exudates arranged in a star-shaped pattern around the macula. Associated with macular edema.

Optic disc edema and retinal edema: Occur in severe hypertension or renal failure.

Dilation and tortuosity of retinal arterioles: Morphological abnormalities due to changes in the vessel wall.

Severe stage (end-stage renal failure)

Choroidal circulation disorder: Visualized as filling defects on indocyanine green angiography (ICGA).

Serous (bullous) retinal detachment: Breakdown of the outer blood-retinal barrier leads to exudation from the choroid into the subretinal space. A characteristic finding in end-stage chronic renal failure.

Additional lesions after dialysis: After initiation of hemodialysis, hemodynamic changes may occur, leading to vascular stenosis, occlusion, and retinal degeneration.

Significance of characteristic fundus findings

Among the fundus findings that characterize renal retinopathy, cotton-wool spots reflect infarction of the nerve fiber layer due to occlusion of retinal arterioles caused by renal hypertension. A key feature of this disease is that these spots appear “multiple” rather than solitary, and they are confirmed as retinal non-perfusion areas on FA.

Star-shaped hard exudates are hard exudates arranged in a star-like pattern along the Henle fiber layer of the macula, and are an important finding indicating the presence of retinal edema. Serous retinal detachment occurs in cases with severe choroidal circulatory disturbance and coincides with areas depicted as filling defects on ICGA. These findings are not typically seen in hypertensive retinopathy due to essential hypertension and serve as important clues suggesting renal involvement. In cases of severe hypertension associated with renal transplant failure, concurrent appearance of cotton-wool spots, serous retinal detachment, and optic disc edema as hypertensive retinochoroidopathy and optic neuropathy has been reported ².

Q Can renal retinopathy be asymptomatic?

A

Many patients do not complain of visual impairment. Even when fundus findings such as arteriolar narrowing, hemorrhages, and exudates are present, there is a stage with few subjective symptoms. It is often discovered through fundus examinations requested by internal medicine departments. When macular edema occurs, patients often notice decreased vision, and if serous retinal detachment extends to the macula, vision drops significantly.

3. Causes and Risk Factors

The direct cause of renal retinopathy is renal hypertension. Representative diseases that cause renal hypertension include the following.

• Malignant hypertension: A rapidly progressive state of severe hypertension. It tends to cause acute vascular changes, hemorrhages, and papilledema in the retina.
• Chronic glomerulonephritis: Chronic inflammation and damage of the glomeruli lead to renal hypertension. Metabolic disorders accumulate as kidney function declines.

Renal retinopathy differs from hypertensive retinopathy due to essential hypertension in that it involves metabolic abnormalities associated with kidney disease. Specifically, the following factors exacerbate retinal damage.

• Azotemia (uremic toxin accumulation): Accumulation of metabolic products such as BUN (blood urea nitrogen) acts as direct vascular toxicity and contributes to the formation of multiple cotton-wool spots.
• Hyponatremia: Electrolyte imbalance affects the distribution of extracellular fluid and promotes tissue edema.
• Anemia: Anemia associated with chronic kidney failure further worsens circulatory disorders.
• Progression of kidney failure: In end-stage kidney failure with severely reduced renal function, choroidal circulatory disorders are added, increasing the risk of serous retinal detachment due to disruption of the outer blood-retinal barrier.

In patients who have started hemodialysis, changes in circulatory dynamics associated with dialysis can trigger new retinal vascular disorders. The rapid fluctuations in circulatory dynamics that occur after dialysis may induce vascular stenosis/occlusion and retinal degeneration. In fact, ophthalmological studies in hemodialysis patients have found a high frequency of various ocular complications such as retinal hemorrhage, macular leakage, retinal detachment, and optic neuropathy, highlighting the importance of regular ophthalmological examinations³.

For patients with systemic diseases

• Continuing treatment for kidney disease and hypertension directly prevents fundus complications.
• It is important to have regular eye exams even if you have no symptoms.
• If you are on hemodialysis, pay attention to changes in your vision along with changes in your physical condition before and after dialysis.
• Please make sure to have regular checkups in both internal medicine and ophthalmology.

4. Diagnosis and Examination Methods

Opportunity for Diagnosis and Confirmation

Renal retinopathy, like hypertensive retinopathy, is often discovered through a fundus examination requested by an internist. On the other hand, renal impairment may also be discovered when a patient presents with decreased visual function. If this disease is suspected at the initial visit, the diagnosis is confirmed by measuring blood pressure and performing blood tests in the outpatient setting.

In diagnosis, differentiation from simple hypertensive retinopathy is important. Confirmation of abnormal renal function indicators (BUN, creatinine) reveals the involvement of renal factors.

Major Examinations

The following examinations are used for the diagnosis and evaluation of renal retinopathy.

Examination	Purpose/Findings
Fundus examination (ophthalmoscopy)	Arteriolar changes (narrowing, caliber irregularity), hemorrhages, hard exudates, cotton-wool spots, papilledema
FA (fluorescein angiography)	Retinal non-perfusion areas in cotton-wool spots
ICGA (Indocyanine Green Angiography)	Depicts filling defects in areas of choroidal circulatory disturbance
OCT (Optical Coherence Tomography)	Quantitative assessment of macular edema and serous retinal detachment
Blood pressure measurement	Confirmation and severity assessment of hypertension
Blood test (BUN, creatinine)	Confirmation and severity assessment of renal dysfunction

Fundus examination is the most basic test and should ideally be performed under mydriasis. FA is useful when cotton-wool spots are numerous, allowing detailed assessment of the extent and distribution of retinal nonperfusion areas. ICGA is essential for evaluating the degree of choroidal circulatory disturbance and helps in assessing the etiology of serous retinal detachment. OCT can noninvasively evaluate the presence of macular edema and subretinal fluid, and is also useful for follow-up.

Differential Diagnosis

In the differential diagnosis of renal retinopathy, the following diseases should be considered.

• Hypertensive retinopathy (essential hypertension): Differentiated by the absence of renal dysfunction and azotemia. Multiple cotton-wool spots and serous retinal detachment are rare in essential hypertension.
• Diabetic retinopathy: Characterized by microaneurysms; in patients with nephropathy, both conditions may coexist. Assess glycemic control and the severity of nephropathy together.
• Secondary hypertension due to renal artery stenosis: Important for differential diagnosis of the underlying cause; renal artery imaging may be necessary.

Epidemiological studies have shown that retinal arteriolar narrowing in hypertensive patients significantly increases the risk of CKD complications, and fundus findings may contribute to screening for kidney damage⁴.

Q How is renal retinopathy discovered?

A

It is often discovered through fundus examination requests from internal medicine. Fundus examinations are performed during management of hypertension and kidney disease, and retinal changes are found. On the other hand, when a patient visits an ophthalmologist complaining of visual dysfunction (decreased visual acuity, visual field defects, etc.), renal impairment may be suspected based on fundus findings. If renal retinopathy is suspected at the initial visit, blood pressure measurement and blood tests (BUN, creatinine) are performed in the outpatient clinic to confirm the diagnosis.

5. Standard Treatment

Basic Treatment Policy

Since renal retinopathy is essentially a change caused by hypertension, the basic treatment is to investigate and treat the underlying kidney disease and to manage hypertension medically. Invasive ophthalmic treatments (such as vitrectomy or intraocular injection) are generally not required, and improvement in fundus findings is expected through systemic management.

The pillars of treatment are the following three points.

• Treatment of the underlying disease: Medical treatment for renal diseases such as chronic glomerulonephritis is performed. Suppressing the activity of the underlying disease is expected to improve renal hypertension.
• Blood pressure management: Blood pressure targets considering renal protection are set in collaboration with internal medicine. Since excessive rapid blood pressure reduction may cause ischemic damage to the kidneys and retina, gradual blood pressure reduction is the principle.
• Ophthalmologic follow-up: The course of fundus findings is observed while checking blood pressure and renal function control. Serous retinal detachment often improves with blood pressure management.

Management of Each Condition

Cotton-wool spots and hemorrhages are expected to resolve over time with systemic management (antihypertensive and renoprotective treatment).

Macular edema, when present, should also first be managed by controlling systemic blood pressure and renal function. Macular edema often improves with treatment of the underlying disease.

Serous retinal detachment is a finding seen in severe stages with marked choroidal circulatory disturbance. Although it often improves with blood pressure control, careful follow-up is necessary because involvement of the macula affects visual prognosis. In severe hypertensive retinopathy and choroidopathy, massive bilateral serous retinal detachment can occur, but cases have been reported where subretinal fluid is absorbed in a short period after antihypertensive therapy⁵.

Dialysis patients may develop vascular stenosis, occlusion, and retinal degeneration due to changes in circulatory dynamics after initiating hemodialysis. Close collaboration with internal medicine is necessary to monitor the patient’s general condition and perform frequent ophthalmological examinations.

Precautions in Treatment

• Rapid blood pressure reduction can lead to ischemic complications in the kidneys, retina, and brain, so gradual blood pressure reduction is the principle.
• If serous retinal detachment involves the macula, it affects visual prognosis, so prompt blood pressure management should be performed in collaboration with internal medicine.
• After initiating hemodialysis, circulatory dynamics change and new retinal vascular disorders may occur, so regular fundus examinations should be continued even after starting dialysis.
• If you notice a decrease in visual function, promptly consult an ophthalmologist.

Q Is ophthalmic surgery or injection necessary for renal retinopathy?

A

Basically, treatment of the underlying kidney disease and blood pressure control are the mainstays, and fundus findings often improve with these measures. Serous retinal detachment also often improves with blood pressure management. Invasive ophthalmic treatments (such as vitrectomy or intravitreal injection) are rarely required in principle. However, collaboration with internal medicine is important for systemic management, and regular fundus examinations should be continued.

6. Pathophysiology and Detailed Pathogenesis

Basic Pathophysiology: Renal Hypertension and Retinal Vascular Damage

The basic pathophysiology of renal retinopathy is retinal vascular damage triggered by renal hypertension due to kidney disease (e.g., chronic glomerulonephritis). Elevated blood pressure causes spasm and thickening of retinal arterioles, leading to narrowing and caliber irregularity. This is similar to changes seen in essential hypertension.

Exacerbating Factors Specific to Kidney Disease

The reason renal retinopathy is distinguished from essential hypertensive retinopathy lies in the complex metabolic disorders accompanying the progression of renal failure. In addition to elevated blood pressure, the following exacerbating factors act on the retina.

• Hyperazotemia (elevated BUN) : Uremic toxins act as direct vascular toxins, promoting arteriolar damage. This is involved in the mechanism of multiple infarcts (cotton-wool spots) in the nerve fiber layer.
• Hyponatremia : Electrolyte abnormalities cause redistribution of extracellular fluid, promoting retinal edema.
• Anemia : Reduced oxygen supply to tissues increases the susceptibility of the retina to ischemia.

From Severe Choroidal Circulation Disorder to Serous Retinal Detachment

In the terminal stage of chronic renal failure, the aforementioned metabolic disorders become more severe, leading to choroidal circulation disorder. This process progresses as follows.

1. Progression of renal failure → accumulation of metabolic products, electrolyte abnormalities, severe anemia
2. Damage to choroidal arterioles → choroidal circulation disorder (depicted as filling defects on ICGA)
3. Disruption of the outer blood-retinal barrier (the barrier between the retinal pigment epithelium and the choriocapillaris)
4. Leakage of fluid from the choroid into the subretinal space
5. Formation of serous (bullous) retinal detachment

This pathway is rarely seen in essential hypertension and is a specific pathogenesis of severe cases of renal retinopathy.

Pathophysiological Basis of Each Characteristic Finding

• Multiple cotton-wool spots: Reflect multiple infarctions of the nerve fiber layer caused by direct vascular damage from uremic toxins. Observed as retinal non-perfusion areas on FA.
• Macular star: Hard exudates arranged in a star shape along the Henle fiber layer due to macular retinal edema and metabolic disturbance. Indicates the degree of exudative leakage.
• Papilledema and retinal edema: Result from severe systemic edema and metabolic abnormalities spreading to the ocular region.
• Serous retinal detachment: A condition in which choroidal circulatory insufficiency disrupts the outer blood-retinal barrier, leading to fluid exudation from the choroid into the subretinal space.

Additional lesions after initiation of hemodialysis

When hemodialysis is initiated, rapid fluid and electrolyte shifts during dialysis cause changes in circulatory dynamics. These changes may induce retinal vascular stenosis, occlusion, or retinal degeneration. In dialysis patients, dialysis-related changes are superimposed on retinal changes associated with renal failure, making continuous fundus monitoring important.

7. Prognosis and course

Reversible Changes

If blood pressure control and renal function improve with treatment of the underlying disease, fundus findings often improve. In particular, the following changes may resolve with systemic management.

• Retinal hemorrhage: Resolves within weeks to months with blood pressure reduction.
• Cotton-wool spots: Often resolve with blood pressure control.
• Serous retinal detachment: Subretinal fluid is absorbed and improves with blood pressure control. It often resolves as renal function improves.

Irreversible changes

On the other hand, the following changes may not be reversible once they occur.

• Residual hard exudates: Even after resolution, hard exudate deposits may remain as traces.
• Atrophy of the retinal pigment epithelium (RPE): When serous retinal detachment persists for a long time, irreversible atrophic changes may remain in the RPE.
• Optic atrophy: This can occur when severe papilledema persists.

Visual Prognosis

Visual prognosis is often determined by the extent of macular involvement. If macular edema, star-shaped exudates, or serous retinal detachment extends to the macula, visual recovery may be incomplete even with good systemic management. Early systemic management intervention is important for improving visual prognosis.

Key Points of Long-Term Management

Close follow-up with concurrent internal medicine consultation is necessary to monitor systemic status. In dialysis patients, there is a risk of additional lesions due to hemodynamic changes even after dialysis initiation, so regular fundus examinations should be continued. In cases of progressive chronic renal failure where renal function does not improve, fundus findings may progress, making it important to optimize medical treatment and establish an ophthalmologic follow-up system. Long-term follow-up of the CRIC cohort has shown that progression of retinopathy is independently associated with cardiovascular events, and evaluation of fundus changes is useful as an indicator of systemic prognosis ⁶.

Q Can renal retinopathy be cured?

A

Fundus findings often improve with improvement in renal function; hemorrhages, cotton-wool spots, and serous retinal detachment often improve with systemic management. However, irreversible changes such as hard exudates and retinal pigment epithelium atrophy may remain. Visual prognosis depends on the degree of macular involvement, so early systemic management intervention and regular fundus examinations are important.

References

Footnotes

1. Grunwald JE, Alexander J, Maguire M, et al; CRIC Study Group. Retinopathy and chronic kidney disease in the Chronic Renal Insufficiency Cohort (CRIC) study. Arch Ophthalmol. 2012;130(9):1136-1144. PMID: 22965589 ↩

2. Sánchez-Vicente JL, López-Herrero F, Martínez-Borrego AC, Lechón-Caballero B, Moruno-Rodríguez A, Molina-Socola FE. Hypertensive choroidopathy, retinopathy and optic neuropathy in renal transplantation failure. Arch Soc Esp Oftalmol (Engl Ed). 2019;94(11):558-562. PMID: 31409516 ↩

3. Kianersi F, Taheri S, Fesharaki S, et al. Ocular Manifestations in Hemodialysis Patients: Importance of Ophthalmic Examination in Prevention of Ocular Sequels. Int J Prev Med. 2019;10:20. PMID: 30820307 ↩

4. Sabanayagam C, Tai ES, Shankar A, Lee J, Sun C, Wong TY. Retinal arteriolar narrowing increases the likelihood of chronic kidney disease in hypertension. J Hypertens. 2009;27(11):2209-2217. PMID: 19620884 ↩

5. Villalba-Pinto L, Hernández-Ortega MÁ, Lavid de los Mozos FJ, et al. Massive Bilateral Serous Retinal Detachment in a Case of Hypertensive Chorioretinopathy. Case Rep Ophthalmol. 2014;5(2):190-194. PMID: 25120474 ↩

6. Grunwald JE, Pistilli M, Ying GS, et al. Progression of retinopathy and incidence of cardiovascular disease: findings from the Chronic Renal Insufficiency Cohort Study. Br J Ophthalmol. 2021;105(2):246-252. PMID: 32503932 ↩