Aashish Aggarwal

Abstract

Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are, with diabetic neuropathy, the classic microvascular complications of long-standing diabetes. The two conditions share several pathophysiological mechanisms, including endothelial dysfunction, oxidative stress, capillary injury and changes to the basement membrane. However, they do not necessarily progress together, and either can occur without the other. Renal status is assessed using the estimated glomerular filtration rate (eGFR), the urine albumin-to-creatinine ratio (UACR) and related clinical findings, while retinal status is assessed through diabetic eye screening and ophthalmological examination.

In this article we propose that DR, particularly in its advanced forms, gives prognostic information about systemic microvascular risk and the likelihood of kidney disease progression. This information adds to standard renal assessment and does not replace it. This paper suggests that a combined cardio-renal-retinal approach may help identify high-risk patients, improve communication between services and make intensive diabetes treatment safer.

Introduction

Diabetes is a systemic metabolic and vascular disorder, but its complications are often managed by separate teams. A patient with DKD may be reviewed in nephrology or diabetes clinics for blood pressure, albuminuria, medication and fluid balance. Their retinal surveillance takes place separately, through the screening programme or the hospital eye service. In England, people at lowest risk may be offered diabetic eye screening every two years after two consecutive screens without retinopathy (1). Those with retinopathy or other risk factors are generally reviewed more often, either in surveillance clinics or by an ophthalmologist.

These services often use separate clinical systems, so results are not always visible from one to the other. A nephrologist monitoring declining kidney function may not know that the patient has proliferative diabetic retinopathy (PDR). Similarly, an ophthalmologist treating diabetic macular oedema may have limited access to the UACR, the eGFR trend or the patient’s cardiovascular risk profile. In this situation, the relationship between retinal and renal microvascular disease is easily overlooked. Better integration of the two may improve risk assessment. Even so, retinal findings cannot be used to diagnose DKD, and chronic kidney disease (CKD) in a person with diabetes is not always diabetic in origin.

Shared Pathophysiology

The retina and the kidney have similar vulnerabilities and are exposed to many of the same metabolic and haemodynamic stresses. The retinal capillary network and the glomerulus are both highly specialised microvascular beds. Both can be injured by chronic hyperglycaemia, hypertension, inflammation and oxidative stress.

In broad terms, hyperglycaemia and raised blood pressure promote the build-up of advanced glycation end-products, oxidative stress, inflammation and abnormal intracellular signalling. Together, these lead to endothelial dysfunction and basement-membrane abnormalities. In the retina, the results are pericyte loss, capillary leakage, non-perfusion and ischaemia. In the kidney, there is podocyte and glomerular endothelial injury, albuminuria and reduced filtration. The pathways in the two organs overlap considerably, but they are not identical.

Endothelial dysfunction and advanced glycation end-products

Persistent hyperglycaemia promotes the formation of advanced glycation end-products and activates signalling pathways such as protein kinase C. This leads to oxidative stress, inflammation, endothelial dysfunction and reduced bioavailability of nitric oxide.

Basement-membrane and vascular change

Basement-membrane thickening occurs in both retinal and glomerular disease. It affects vascular permeability and the local regulation of blood flow, and it contributes to progressive tissue injury.

Loss and dysfunction of supporting cells

In early DR, pericyte loss and endothelial injury cause microaneurysms, capillary leakage and areas of non-perfusion. The corresponding changes in DKD are podocyte injury or loss, glomerular endothelial dysfunction and disruption of the filtration barrier. These may lead to albuminuria and declining kidney function.

Given this overlap, advanced DR can reasonably be seen as a marker of a high-risk systemic microvascular phenotype. This interpretation should still be applied with caution. Retinal neovascularisation is not direct evidence of glomerular injury, and the absence of retinopathy does not rule out DKD or other causes of CKD.

Retinopathy as a Marker of Renal Prognosis

Longitudinal cohort data, including from the Atherosclerosis Risk in Communities study (2), and systematic reviews (3) have linked DR to a higher risk of incident CKD, progression of kidney disease and kidney failure. The risk rises with the severity of retinopathy. Non-proliferative DR carries a modest excess renal risk, whereas severe non-proliferative DR and PDR identify patients in whom adverse kidney outcomes are particularly common (3).

These findings do not show that retinopathy causes renal decline. Nor do they show that retinal deterioration reliably comes before a rapid loss of kidney function. Both may instead result from shared exposure to long diabetes duration, hyperglycaemia, hypertension, dyslipidaemia, smoking and other vascular risk factors. The association often remains after adjustment for conventional risk factors. Even so, retinal examination cannot substitute for measuring eGFR, UACR and blood pressure, or for investigating possible non-diabetic kidney disease.

Instead, a finding of advanced DR should prompt closer review of several things: the current eGFR and how fast it is changing, whether albuminuria is present and persistent, blood pressure and overall cardiovascular risk, glycaemic history and current medication. It should also prompt a check for features that suggest another renal diagnosis. A rapid decline in kidney function, an active urinary sediment, haematuria, nephrotic syndrome of abrupt onset or other atypical features should raise the possibility of non-diabetic CKD.

Rapid Glycaemic Improvement and Early Worsening of Retinopathy

Existing retinopathy may worsen temporarily after a rapid and marked improvement in glycaemic control. This was first described with intensive glucose management and later contributed to concern about retinopathy outcomes in some trials of GLP-1 receptor agonists (4,5). The patients at greatest risk are those with a high baseline HbA1c, a large or rapid fall in HbA1c, long-standing diabetes, existing moderate, severe or proliferative retinopathy, or diabetic macular oedema.

The evidence on GLP-1 receptor agonists is inconsistent. Any excess risk may be due to how fast and how far glucose falls rather than to a direct effect of the drugs on the retina. A separate concern is non-arteritic anterior ischaemic optic neuropathy (NAION), an optic nerve disorder that is distinct from diabetic retinopathy. The European Medicines Agency has concluded that NAION is a very rare adverse effect of semaglutide (6). Early worsening has not been specifically linked to SGLT2 inhibitors. These drugs usually lower HbA1c only modestly, especially in advanced CKD.

The mechanism of early worsening remains unclear. Changes in retinal blood flow, vascular permeability and growth-factor signalling have all been proposed, but none has been confirmed. When a treatment is expected to lower HbA1c quickly and substantially, the patient’s retinal status should be established beforehand. Ophthalmology should be involved if significant retinopathy is present. The National Institute for Health and Care Excellence recommends informing the ophthalmologist when a treatment likely to lower HbA1c is started in a person with diabetic retinopathy (7). This allows the eyes to be assessed before treatment and monitored afterwards. However, treatment of severe or symptomatic hyperglycaemia should not be delayed while waiting for an eye examination. The two should be arranged in parallel, with the timing of follow-up based on the severity of existing eye disease.

A Practical Model for Integrated Care

Health services could take a more integrated approach to retinal, renal and cardiovascular risk. The proposals below are suggestions for service development and are not part of current clinical guidance.

Linking electronic records

Clinical systems could display the most recent retinal grade alongside eGFR and UACR results. Advanced or rapidly progressing retinopathy could then prompt a review of kidney function. Likewise, a significant deterioration in kidney function could prompt a check that retinal assessment is up to date.

Risk assessment in primary and diabetes care

DR severity could be used as an additional marker of renal and cardiovascular risk. Advanced retinopathy together with albuminuria or a falling eGFR should be treated as a reason for greater concern. Specialist referral should still follow established criteria, which are based on the severity and course of kidney disease and on diagnostic uncertainty.

Coordinated multidisciplinary care

Patients with advanced retinal disease, progressive CKD or high cardiovascular risk may benefit from coordinated input from diabetes, primary care, nephrology, cardiology and ophthalmology services. This does not have to mean a single combined clinic. Shared records, agreed referral pathways and multidisciplinary case review may achieve similar results.

Feature	Diabetic retinopathy	Diabetic kidney disease
Primary assessment	Two-field digital retinal photography in the English screening programme (8), with OCT surveillance for suspected maculopathy and ophthalmological examination when indicated	Serum creatinine with eGFR, and spot UACR
Key cellular injury	Dysfunction or loss of retinal pericytes and endothelial cells	Podocyte and glomerular endothelial injury
High-risk finding	Severe non-proliferative DR, PDR or diabetic macular oedema	Severely increased albuminuria (A3), sustained rapid decline in eGFR, or advanced CKD
Terminology	PDR is graded R3 in the English diabetic eye-screening system, subdivided into R3A (active) and R3S (stable after treatment) (8)	CKD is classified by both GFR and albuminuria category, e.g. G3a A3 (9)
Main clinical implications	Risk of visual loss, vitreous haemorrhage and wider vascular disease	Risk of kidney failure, cardiovascular events, electrolyte disturbance and fluid overload

“Macroalbuminuria” is now considered an outdated term. “Severely increased albuminuria” or “A3 albuminuria” is preferred, ideally with the measured UACR reported (9). An eGFR of 45 mL/min/1.73 m² falls within CKD G3a and does not by itself indicate kidney failure.

Similarly, “kidney failure” has replaced the terms “end-stage kidney disease” and “end-stage renal failure”. It generally corresponds to CKD G5, meaning an eGFR below 15 mL/min/1.73 m², or to the need for kidney-replacement therapy (9,10).

Conclusion

The separation between nephrology and ophthalmology reflects how health services are organised more than how diabetic complications develop. The retina does not measure renal injury directly, but it gives useful insight into systemic microvascular risk. Advanced DR should be treated as a prognostic warning sign. It should lead to a review of kidney function, albuminuria, blood pressure, cardiovascular risk and glycaemic management. In the same way, progressive DKD should prompt clinicians to make sure that retinal screening and ophthalmological follow-up are adequate. When interpreted alongside eGFR, UACR and conventional risk factors, retinal findings may help identify high-risk patients and allow intensive treatment to be coordinated more safely. A cardio-renal-retinal framework of this kind would add to existing evidence-based care pathways and work within them.

References

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