Ocular biomarkers in diabetes mellitus with diabetic kidney disease: A minireview

Abstract

Diabetes mellitus ranks among the most prevalent non-communicable diseases worldwide, affecting a vast number of individuals. It can impact almost every organ in the body, leading to serious complications such as diabetic retinopathy (DR), diabetic nephropathy, and diabetic neuropathy. Scientific literature indicates that patients with severely compromised kidney function may develop non-responsive DR. Moreover, anaemia in individuals with diabetic kidney disease (DKD) complicates DR and can contribute to significant health issues. Optical coherence tomography (OCT) is a widely used non-invasive imaging tool for diagnosing, managing, and predicting DR. OCT findings in patients with DR and DKD include cystoid macular oedema, diffuse retinal thickening, disruptions in the ellipsoid layer, hyperreflective dots, and damage to the external limiting membrane. The review examines OCT patterns of diabetic macular oedema in DKD, correlating these patterns with declines in kidney function and visual acuity. Additionally, we review various biomarkers linked to DR in DKD patients and the growing importance of novel imaging biomarkers in predicting and connecting the severity of DR with DKD.

Key Words: Ocular biomarkers; Diabetic retinopathy; Diabetic nephropathy; Chronic kidney disease; Optical coherence tomography; Optical coherence tomography angiography; Fundus photography

Core Tip: The assessment of optical coherence tomography (OCT) biomarkers in diabetic retinopathy (DR) and their correlation with diabetic kidney disease plays an essential role in the prognostication of kidney disease. The OCT biomarkers can help to detect nephropathy before the clinical signs appear and facilitate an early initiation of renoprotective therapy, which may potentially reduce morbidity and mortality due to renal disease in patients with DR.

INTRODUCTION

Diabetes mellitus (DM) is a chronic metabolic disorder characterised by hyperglycaemia resulting from insulin resistance and/or impaired insulin secretion. Recently, there has been an exponential increase in the number of patients with DM. TThe World Health Organisation estimates that by 2050, about 1.3 billion people worldwide will suffer from DM[1]. The disease is associated with significant morbidity and mortality. Poor control of DM can lead to complications in almost all body organ systems. The organs and tissues commonly involved include the eyes, kidneys, and nerves. Complications can arise from vasculopathy (both macro and micro) associated with the disease. The potentially debilitating microvascular complications include diabetic retinopathy (DR), diabetic neuropathy (DN), and diabetic kidney disease (DKD). A large proportion of patients with DM may develop DR (approximately 30%)[2].

Additionally, chronic kidney disorders may develop in 40% of patients[3]. Both DR and DKD are referred to as "diabetic microangiopathies" and represent the leading causes of blindness and end-stage kidney disease (ESKD), respectively. Patients with DR have a high risk of developing DKD, while DKD is also a risk factor for severe grades of DR[4]. A significant number of patients with DM may require kidney transplants due to ESKD[5]. Early diagnosis, monitoring, prompt treatment, and strict glycaemic control are critical to preventing and delaying disease progression. While clinical examination and laboratory tests are essential in managing DM and its complications, ocular biomarkers have garnered attention for their non-invasive, easily accessible, and potentially cost-effective role in monitoring disease progression. Several researchers have demonstrated a significant association between the severity of DR and DKD, and renal vascular abnormalities may coexist with retinal vascular changes[6]. The early detection of retinal abnormalities may lead to the detection of DKD, thus aiding in early treatment[7]. Studies have shown that histological changes in the kidneys may be detected earlier than functional changes using ocular biomarkers, thereby decreasing morbidity and mortality in diabetic patients[8,9]. Fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA) are non-invasive imaging modalities commonly employed for patients with DR. These modalities provide an opportunity to identify various biomarkers specific to DKD in patients with DR. These biomarkers can also be used for the prognostication of kidney disease. Researchers have looked into the possibility of using non-invasive modalities like OCTA to correlate the severity of DR changes with DKD changes[10]. Ahmadzadeh Amiri et al[11] in their study showed that the foveal avascular zone on OCTA was larger in patients with severe DKD. OCT is a non-invasive imaging modality widely used in the management of retinal diseases. OCT has been used in the management of retinal diseases in patients with coexistent kidney disease. Bineshfar et al[12] reviewed the measurements of retinal layers on OCT in patients with CKD. Their analysis showed that the various retinal thickness measurements, like nerve fibre layer thickness, central retinal thickness, choroidal thickness, and ganglion cell layer thickness, were reduced as compared to controls. Kumaresan et al[13] highlighted that more than 40% of patients with Type V nephropathy had Diabetic Macular Edema on OCT scans. This review explores recent advances in ocular biomarkers, especially in OCT related to diabetes, focusing on their potential relevance in coexisting DKD.

We reviewed articles from PubMed and MEDLINE using the keywords "ocular biomarkers", "diabetic retinopathy", "diabetic nephropathy", "chronic kidney disease", "optical coherence tomography", "optical coherence tomography angiography", and "fundus photography". Articles published in the English language were considered for review.

OCULAR BIOMARKERS IN DKD

Biomarkers on retinal imaging

Retinal vascular abnormalities have long been studied as biomarkers for systemic diseases. Wong et al[14] in a review of literature relating to eye and kidney disease, highlighted that the damage to both organs shares common risk factors. The authors highlighted that there is a significant narrowing of the retinal arteries and veins in patients with CKD. Microaneurysms and cotton wool spots are the microvascular abnormalities commonly observed in patients with DKD. The authors also showed that the patients with DR changes were at increased risk of DKD. The authors advocated screening for ocular diseases like age-related macular degeneration, cataracts, and glaucoma in patients with CKD. Sng et al[15] employed fractal analysis of retinal vasculature in patients with chronic kidney disease. The study found that the retinal fractal dimension was lower in CKD patients than in controls. The study also concluded that an abnormal vascular network was often associated with the risk of CKD, highlighting microvascular abnormalities in both organs. Another survey by Cankurtaran et al[9] showed diabetic patients had impaired retinal microvascular circulation. Additionally, vessel densities were lower in patients with microalbuminuria compared to controls. Thus, detecting microvascular abnormalities using fractal dimension is an essential biomarker in patients with DKD.

OCT biomarkers in DKD

The OCT biomarkers in patients with DM and DKD include hyperreflective dots, diffuse retinal thickening, subfoveal serous retinal detachment, and hyperreflective foci. A study by Gopalakrishnan et al[16] showed that diffuse retinal thickening was one of the most common OCT biomarkers seen in patients with DKD with anaemia. They also highlighted that external limiting membrane and ellipsoid zone abnormalities (ELM-EZ) were an essential biomarker in patients with DKD with anaemia. Agarwal et al[17] also highlighted that cystoid macular edema and diffuse retinal thickening were common OCT findings in patients with DKD and DR. This study correlated the OCT biomarkers with the stage of kidney disease. DME is one of the most common findings in patients with DKD and DR. The various biomarkers in DME on OCT include hyper-reflective dots (HRD), disorganisation of inner retinal layers, and ELM-EZ abnormalities. The morphological forms of DME included serous, cystoid, and mixed types. The most common DME was the cystoid type. The authors found that the higher grades of CKD were associated with severe vision loss. They also found that the cystoid pattern was typical in patients with DKD on dialysis therapy. ELM-EZ defects were common in patients with end-stage DKD, leading to poor vision. Another biomarker studied by the authors was foveal subfield retinal thickness; they found that the thickness was higher in patients with a higher grade of CKD. However, the presence of HDR and disorganisation of retinal layers did not correlate with the stage of the kidney disease. Knudsen et al[18] found in their study that increased retinal thickness was associated with increased excretion of proteins in patients with DR. Zhang et al[19] also showed that subretinal fluid was common in patients with abnormal renal profiles. Takamura et al[20] also found that serous fluid accumulation on OCT was a standard biomarker in patients with DKD undergoing dialysis. Menchaca et al[21], in their study, showed that OCT biomarkers, like disruption of outer retinal layers, correlated with the severity of albuminuria. Severe kidney disease was associated with disruption of the outer retinal layers. He et al[22] showed that choroidal thickness significantly decreased after a single session of hemodialysis. Changes in subfoveal choroidal volume after hemodialysis were also documented in this study (Figures 1, 2, 3 and 4).

Figure 1  Fundus Image of a patient with laser-treated proliferative diabetic retinopathy with clinically significant macular edema and diabetic nephropathy.

Figure 2  Optical coherence tomography image showing cystoid spaces with hyper-reflective dots and disorganization of outer and inner retinal layers.

Figure 3 Left eye treated for proliferative diabetic retinopathy with dull foveal reflex in a patient with diabetic nephropathy. OS: Outer segment.

Figure 4  Optical coherence tomography photograph of the left eye showing massive cystoid spaces and intraretinal fluid leading to diffuse retinal thickness and disorganization of inner retinal layers.

OCTA biomarkers in DKD and DR

The role of OCTA in patients with DKD has been studied recently. Chilet et al[23], in their study, showed that patients with decreased vessel densities and foveal avascular zone perimeter were at increased risk of having poor GFR and had a poor prognosis. They also highlighted that the patients with reduced vascularity on OCTA have a higher risk of DKD progression. A study by Surawatsatien et al[24] enrolled 186 eyes of 94 subjects categorised into three groups: No diabetic nephropathy, early nephropathy, and late diabetic nephropathy. Regarding vessel densities in these patients, the study noted that the patients with no DR had better vessel densities than those with DR. The patients with increased 24-hour urine albumin excretion had lower vessel densities. The study also noted that the risk of developing diabetic nephropathy correlated with lower vessel densities. The authors concluded that vessel densities can be used as a biomarker to monitor albuminuria and reflect damage to the microvasculature secondary to hyperglycemia. Zhuang et al[25] also showed that a decrease in the microcirculation detected on OCTA was associated with impaired kidney function. They proposed that the metrics in OCTA can be used for monitoring CKD progression. Lin et al[26], in their study, showed that OCTA could be used to differentiate between nephropathy due to diabetes and other diseases. Yao et al[27] also showed that vessel densities on OCTA are reduced in patients with DM. Other authors have also evaluated the use of OCTA in patients with hypertensive kidney disease and other kidney disorders[28]. Tom et al[29] showed that non-perfusion of retinal layers was significantly associated with glomerular filtration rate (eGFR). Cankurtaran et al[9] and Yeung et al[30] showed a significant decrease in the densities of retinal vessels with progression of DKD. Yong et al[31] highlighted the use of OCTA in various forms of CKD and showed that the perfusion density of the retina and vessel densities were decreased in severe forms of the disease. The authors, however, did not recommend the use of OCTA for routine screening of patients with CKD[32].

Peripapillary retinal nerve fibre layer thickness

The retinal nerve fibre layer (RNFL) is a part of the retina that OCT can assess. Studies have shown that reduced RNFL thickness is associated with renal dysfunction and can serve as an early marker of DKD. The thinning of the RNFL may indicate the presence of both retinal and renal microvascular damage in diabetes. Choi et al[32] found that patients with DR with albuminuria had higher chances of developing RNFL changes than patients who did not have albuminuria[33].

Choroidal thinning in CKD

Farrah et al[33] highlighted that in patients with CKD, there was significant thinning of the retina, retinal nerve fibre layer, and choroid. These findings can be extrapolated to patients with DKD and can be evaluated in prospective studies[34].

Various systemic biomarkers

A significant search for systemic biomarkers, OCT, and ocular biomarkers is ongoing. Various biomarkers have already been identified that play a key role in the development of DKD and DR. Tufro et al[34] highlighted the role of vascular endothelial growth factor (VEGF-A) and its interaction with the nitrous oxide signalling pathway, playing an essential role in the pathogenesis of DR and DKD[35]. Klein et al[35] highlighted that oxidative stress and inflammation can lead to endothelial dysfunction. The inflammatory by-products can lead to endothelial dysfunction in retinal and renal vasculature, leading to micro-angiopathies. Li et al[36] correlated and compared the OCT biomarkers and systemic biomarkers in patients with DKD and DR. In addition to systemic markers like the neutrophil-to-lymphocyte ratio and urine albumin-to-creatinine ratio, biomarkers on optical coherence tomography like ganglion cell layer and RNFL have been implicated in risk progression for DKD in patients with DR[37].

Future directions and discussion

Ocular biomarkers can potentially revolutionise the early detection and management of both DR and DKD. Key future directions for research include integration of retinal imaging with renal biomarkers: Combining retinal imaging technologies, such as OCT and fundus photography, with renal biomarkers like albuminuria and estimated eGFR could provide a more holistic view of diabetic microvascular health. This could lead to more precise monitoring of patients at risk for DR and DKD.

Molecular biomarkers: Advances in molecular biology and proteomics may enable the identification of novel biomarkers in the retina and serum that can predict the onset or progression of DR and DKD. Biomarkers such as inflammatory cytokines, advanced glycation end products, and matrix metalloproteinases are currently under investigation[38]. Identifying reliable ocular biomarkers for DN can facilitate non-invasive monitoring of diabetic complications. Future research should focus on longitudinal studies to establish causative links and integrate multimodal imaging techniques with biomarker profiling. Additionally, targeted therapies addressing common molecular pathways may improve outcomes in both DR and DN. The correlation between DR and DN ocular biomarkers highlights the interconnected nature of diabetic microvascular complications. Advancing our understanding of these biomarkers may enhance early detection, risk stratification, and personalised treatment strategies for diabetic patients. Various ocular findings in DKD have been listed in Table 1[39-41].

Table 1 Various ocular involvements in early and late diabetic kidney disease.

Ophthalmic findings in early and late diabetic kidney disease
Lid edema due to fluid overload
Dry eye disease
Conjunctival pallor (association with anaemia)
Cataract, glaucoma, age-related macular degeneration
Retinal vascular abnormalities (associated hypertensive retinopathy)
Foveal avascular zone abnormalities, abnormalities in retinal capillaries

CONCLUSION

DKD is classified into stages based on the eGFR and the presence of albuminuria. The eGFR can be calculated based on the Chronic Kidney Disease Epidemiology (CKD-EPI) equation or the Modification of Diet in Renal Disease (MDRD) equation. However, the CKD-EPI method is considered a more accurate method for GFR than the MDRD. Also, DR is graded according to the severity of retinal changes observed during fundoscopic examination. However, these clinical measures often fail to detect early changes in the renal and retinal vasculature, underscoring the need for more sensitive and reliable biomarkers to aid in early detection and prognosis. DR and DKD share standard pathophysiological mechanisms, including endothelial dysfunction, inflammation, hyperglycaemia-induced oxidative stress, and altered renal and retinal vascular permeability. The presence of DKD significantly increases the risk of developing DR, and conversely, the severity of DR is associated with worsened renal function.

Early detection and intervention are crucial to mitigate the associated risks and improve patient outcomes. Ocular biomarkers have the potential to play a critical role in the early diagnosis, monitoring, and management of diabetic retinopathy and DKD. Retinal imaging technologies and molecular biomarkers offer promising avenues for non-invasive, cost-effective screening tools that can improve patient outcomes by facilitating early detection of both DR and DKD. Further research is needed to better understand the complex interplay between the retina and kidneys and to develop integrated diagnostic strategies that can improve the clinical management of diabetic patients. There is limited literature on the association of DKD and various ocular biomarkers. Further studies should be done to assess the OCT biomarkers and incorporate these in managing patients with DKD. Also, artificial intelligence (AI) can be harnessed to identify patients at increased risk of developing DKD based on ocular biomarkers. AI has been used in assessing the perfusion densities in ultra-wide OCTA scans of patients with DR and DN. So, in the future, AI-based screening models will be of help in screening patients with DM with an increased risk of nephropathy and vice versa.