Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Microalbuminuria Is Associated With Early Retinal Neurodegeneration in Patients With Type 2 Diabetes

Lucas Brandolt Farias, MD; Daniel Lavinsky, MD, PhD; Camila Zanella Benfica, MD; Jacó Lavisnky, MD, PhD; Luis Henrique Canani, MD, PhD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate retinal layer changes in patients with type 2 diabetes, microalbuminuria, and no diabetic retinopathy, and to investigate its possible relationship with age, gender, diabetes duration, urinary albumin excretion (UAE), glycosylated hemoglobin, and hypertension.

PATIENTS AND METHODS:

A prospective, cross-sectional study was performed in 60 patients divided into three groups: diabetic patients with normal UAE, diabetic patients with microalbuminuria, and controls. Retinal thickness was evaluated by Early Treatment Diabetic Retinopathy Study grid using spectral-domain optical coherence tomography.

RESULTS:

The average and sectoral macular thicknesses of the ganglion cell layer (GCL) were significantly thinner in the microalbuminuria group compared to normal UAE group and controls (P < .005). UAE was the only factor related to this reduction in a multiple linear regression analysis.

CONCLUSIONS:

The GCL thickness was reduced in eyes in patients with type 2 diabetes and microalbuminuria before clinical signs of diabetic retinopathy. Inner retinal neurodegeneration was independently associated with albuminuria.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e36–e43.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate retinal layer changes in patients with type 2 diabetes, microalbuminuria, and no diabetic retinopathy, and to investigate its possible relationship with age, gender, diabetes duration, urinary albumin excretion (UAE), glycosylated hemoglobin, and hypertension.

PATIENTS AND METHODS:

A prospective, cross-sectional study was performed in 60 patients divided into three groups: diabetic patients with normal UAE, diabetic patients with microalbuminuria, and controls. Retinal thickness was evaluated by Early Treatment Diabetic Retinopathy Study grid using spectral-domain optical coherence tomography.

RESULTS:

The average and sectoral macular thicknesses of the ganglion cell layer (GCL) were significantly thinner in the microalbuminuria group compared to normal UAE group and controls (P < .005). UAE was the only factor related to this reduction in a multiple linear regression analysis.

CONCLUSIONS:

The GCL thickness was reduced in eyes in patients with type 2 diabetes and microalbuminuria before clinical signs of diabetic retinopathy. Inner retinal neurodegeneration was independently associated with albuminuria.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:e36–e43.]

Introduction

Clinical findings have suggested that microalbuminuria may be a precursor to diabetic retinopathy (DR).1–3 Microalbuminuria is a marker of vascular endothelial dysfunction and has been related to an increased risk of retinopathy in patients with type 2 diabetes.4–5 A reduction in retinal blood flow also has been demonstrated in early diabetic kidney disease.6 Although previous studies have focused on the relationship between renal function and vascular signs of DR, the retinal neurodegenerative component has not been evaluated.

There is increasing evidence that retinal neurodegeneration is associated with DR, especially in early stages.7–11 Various retinal abnormalities, including loss of neural tissue, apoptosis, Müller cell activation, and selective decrease of inner retinal layer thickness, have been previously reported in eyes with diabetes.12–16 Electrophysiological studies also indicated that neuroretinal alterations might be present even before the first clinical signs of DR.17–19

The development of optical coherence tomography (OCT) has allowed measurement of total and individual retinal layer thicknesses with high accuracy.20,21 Different authors have reported a decrease in intraretinal thickness in diabetic eyes with or without clinical signs of DR compared to normal subjects.22–25 With the advent of spectral-domain OCT (SD-OCT), the faster scanning time, reduced motion artifacts, and increased depth resolution enable significant improvement of retinal thickness mapping segmentation.26 Proper identification of the retinal layers that are affected by diabetes could offer new perspectives for the early detection of diabetic retinal damage and help to understand its mechanisms.

In this study, we used a SD-OCT to detect retinal layer changes, and particularly neuroretinal alterations, in patients with type 2 diabetes with microalbuminuria and no clinically diagnosed retinopathy. We also assessed the potential relationship between clinical parameters and individual loss of retinal layer thickness.

Patients and Methods

Study Participants

A prospective, cross-sectional study was performed in 60 nonglaucomatous patients with type 2 diabetes, no clinically diagnosed retinopathy, and without renal impairment (estimated glomerular filtration rate ≥ 60 mL/minute per 1.73 m2) and normal controls. Patients were recruited consecutively from the outpatient clinic at the Hospital de Clinicas de Porto Alegre, Brazil, and divided into three groups: 19 patients with diabetes with normal urinary albumin excretion (UAE), 24 patients with diabetes with microalbuminuria, and 17 controls. Microalbuminuria was defined as a urinary albumin excretion rate between 17 mg/L and 176 mg/L in a random urinary sample. The study was conducted in accordance to the tenets of the Declaration of Helsinki. Informed written consent was obtained from all patients, and the local ethics committee approved the study protocol.

Patients underwent complete ophthalmic examination after pupil dilatation: indirect ophthalmoscopy, digital retinography, and OCT. Only one eye of each patient was selected for inclusion. Age, gender, diabetes duration, UAE, glycosylated hemoglobin (HbA1c), and arterial hypertension were recorded. Eyes with spherical equivalent greater than 3 diopters or with other ocular diseases were excluded.

Optical Coherence Tomography Scanning Procedure

Eyes were imaged with a Spectralis high-definition SD-OCT (Heidelberg Engineering, Heidelberg, Germany). Eight intraretinal layers were automatically segmented on a horizontal macular volume scan. The scan acquisition protocol had previously shown excellent repeatability and reproducibility for each of eight individual retinal layer thickness measurements27. The layers were identified, from inside to outside, as follows: retinal nerve fiber layer (RNFL); ganglion cell layer (GCL); inner plexiform layer (IPL); inner nuclear layer (INL); outer plexiform layer (OPL); outer nuclear layer (ONL); inner segment/outer segment photoreceptor junction (IS/OS); and retinal pigment epithelium (RPE). Retinal thickness was mapped using the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, which comprised inner and outer rings (diameters: 1 mm to 3 mm and 3 mm to 6 mm, respectively) divided into four quadrants: superior, inferior, temporal, and nasal. To reduce the effects of diurnal variations, all examinations were carried out within 3 hours on the same day.

Statistical Analysis

Statistical analysis was performed with SPSS version 18.0 (SPSS, Chicago, IL). The results of continuous variables are shown as mean values and standard deviation (SD) or the number and percentage of patients. Comparisons between groups were performed using the analysis of variance, followed by Tukey post hoc analysis to correct for multiple comparisons. A multiple linear regression analysis was used to determine the relationship between retinal layer measurements (dependent variables) and diabetes duration, UAE, glycosylated hemoglobin, arterial hypertension, age, and gender (independent variables). A P value less than .05 was considered significant.

Results

Clinical characteristics of subjects enrolled in this study are shown in Table 1. There was a significant difference in age between patients with normal UAE and controls (P = .008); however, the mean age of the microalbuminuric group was not different from the others. No significant differences were observed between the three groups for the other variables, such as sex, gender, arterial hypertension, glycosylated hemoglobin, or diabetes duration.

Characteristics of the Study Population

Table 1:

Characteristics of the Study Population

The mean values and differences in individual retinal layer thickness between type 2 diabetes patients with normal UAE and with microalbuminuria compared to controls in the inner and in the outer ring areas of the macula are given, respectively, in Tables 2 and 3. The average GCL thickness in the microalbuminuria group was thinner in the inner ring area compared to the normal UAE group (41.7 μm ± 5.2 μm vs. 47.8 μm ± 5.6 μm; P = .003). GCL was also reduced when compared to controls (41.7 μm ± 5.2 μm vs. 51.7 μm ± 6.6 μm; P = .001). In the outer ring area of the macula, RNFL thickness was 33.6 μm ± 4.1 μm in patients with microalbuminuria and 38.0 μm ± 4.4 μm in the control group (P = .003). There was no significant difference at the central subfield area in any retinal layer thickness between groups.

Mean Layer Thickness of the Individual Intraretinal Layers in the Inner Ring Areaof the Macula

Table 2:

Mean Layer Thickness of the Individual Intraretinal Layers in the Inner Ring Areaof the Macula

Mean Layer Thickness of the Individual Intraretinal Layers in the Outer Ring Areaof the Macula

Table 3:

Mean Layer Thickness of the Individual Intraretinal Layers in the Outer Ring Areaof the Macula

Sectored analysis of GCL showed significant thinning in the inner inferior and inner temporal regions of macula between patients with microalbuminuria and normal UAE (respective difference inferior: −15.6 μm, 95% CI −20.2 μm to −11.1 μm; temporal: −11.3 μm, 95% CI −15.7 μm to −6.9 μm) and compared to controls (respective difference inferior: −18.5 μm, 95% CI −23.4 μm to −13.6 μm; temporal: −16.7 μm, 95% CI −21.5 μm to −12.0 μm) (Figure 1A). In addition, significant differences in values of RNFL thickness were also observed in the outer inferior and outer temporal regions of the microalbuminuria group compared to controls (respective difference inferior: −10.8 μm, 95% CI −15.5 μm to −6.3 μm; temporal: −7.0 μm, 95% CI −11.5 μm to −2.6 μm) (Figure 1B). No other layers showed significant differences. Patients with diabetes and normal UAE showed no significant difference in any retinal layer thickness compared to controls.

Sectorized analysis of ganglion cell layer (GCL) thickness (A) and retinal nerve fiber layer (RNFL) thickness (B) using the ETDRS macular grid. Subfields: CS = central subfield; SI = superior inner; NI = nasal inner; II = inferior inner; TI = temporal inner; SO = superior outer; NO = nasal outer; IO = inferior outer; TO = temporal outer; *indicates statistically significant values.

Figure 1.

Sectorized analysis of ganglion cell layer (GCL) thickness (A) and retinal nerve fiber layer (RNFL) thickness (B) using the ETDRS macular grid. Subfields: CS = central subfield; SI = superior inner; NI = nasal inner; II = inferior inner; TI = temporal inner; SO = superior outer; NO = nasal outer; IO = inferior outer; TO = temporal outer; *indicates statistically significant values.

Multiple linear regression analysis is presented in Table 4. Albuminuria level was significantly associated with the decrease of the GCL values in the inner ring of the ETDRS grid and with RNFL measures in the outer ring (P < .001) after controlling other factors, such as age, gender, diabetes duration, hypertension and HbA1c.

Multiple Linear Regression Analysis of Retinal Layer Thickness and Clinical Parameters

Table 4:

Multiple Linear Regression Analysis of Retinal Layer Thickness and Clinical Parameters

There was also a significant negative correlation between UAE to average inner ring GCL (r = −0.65, P < .001) and outer ring RNFL thickness (r = −0.66, P < .001) (Figures 2 and 3, respectively).

Correlation between ganglion cell layer thickness in inner ring area and urinary albumin excretion; Pearson's r= −0.65, P < .001.

Figure 2.

Correlation between ganglion cell layer thickness in inner ring area and urinary albumin excretion; Pearson's r= −0.65, P < .001.

Correlation between retinal nerve fiber layer thickness in outer ring area and urinary albumin excretion; Pearson's r = −0.66, P < .001.

Figure 3.

Correlation between retinal nerve fiber layer thickness in outer ring area and urinary albumin excretion; Pearson's r = −0.66, P < .001.

Discussion

The results of the present study revealed average and sectoral macular thinning of the GCL in patients with type 2 diabetes, microalbuminuria, and no retinopathy. Mean macular RNFL thickness was also significantly reduced in the microalbuminuria group compared to controls. These findings support the evidence of previous studies that there is a retinal neurodegeneration in eyes with diabetes before the development of clinically detectable microvascular damage.

Type 2 diabetes affects initially the inner retinal layers, usually clinically detected by presence of microaneurysms and microhemorrhages. The inner retina seems to be more vulnerable to metabolic stress and direct effects of hyperglycemia induced by diabetes, since it has a high metabolic demand, it is relatively hypoxic compared to outer retina, and its blood supply is controlled mainly by vascular autoregulation, rather than by autonomic control.28

In our study, GCL was reduced in the inner ring area of the macula, and RNFL thickness was thinner peripherally. These regions may have been the first to present significant differences because their thicknesses are greater and thus the thinning may be more pronounced. These results confirm previous studies, indicating that the retinal neuropathy is characterized by secondary axonal loss resulting from the central ganglion cell death induced by diabetes.11,29 Similar findings were demonstrated by Rodrigues et al.22 The authors found a significant reduction of RNFL and CGL+IPL in patients with type 2 diabetes with no DR when compared to healthy individuals. Another study also evaluated the thinning of individual retinal layers in type 2 diabetic patients. Van Dijk et al. showed that RNFL, GCL, and IPL were reduced in patients with minimal DR compared to controls;30 however, both authors did not analyze the impact of albuminuria.

In this study, albuminuria was independently associated with the loss of GCL and RNFL at the macula after controlling for other confounding factors. There was a significant negative correlation between the UAE and the selective loss of neuroretinal tissue in patients without DR, indicating that the higher the albuminuria, the smaller retinal thickness.

Microalbuminuria is an indicator of generalized endothelial damage and seems to be related to decreased retinal microcirculation in early stage type 2 diabetes.6 In addition, microalbuminuria has been considered a marker for the risk of retinopathy development.1 Our results suggested that early kidney disease in diabetes might be related to structural neuroretinal abnormalities in eyes, regardless of DR. Choi et al. evaluated the presence of a RNFL defect in a red-free fundus photograph in patients with type 2 diabetes and determined potential risk factors related.31 Consistent with our study, they found that RNFL loss was associated with albuminuria, although there was no significant difference on average peripapillary RNFL thickness between groups with and without RNFL defects. The authors did not evaluate RNFL at the posterior pole as we did. Since macular nerve fiber layer thickness detects earlier morphological changes compared to peripapillary RNFL and it could be related to the macular increased susceptibility to hypoxia damage compared to peripapillary region,32 we focused our analysis on posterior pole rather than the optic disc.

It is unclear whether RNFL/GCL changes in diabetic eyes are a result of the effect of vascular DR or they are primarily caused by direct neurological damage from chronic hyperglycemia.33 Our results indicate that vascular insufficiency might be related with the common pathogenesis of diabetic complications, suggesting that impaired renal dysfunction and retinal neurodegeneration might be associated with decreased microcirculation.

Our study has potential limitations that should be mentioned. The series presented here is relatively small. However, the population studied had a strict inclusion criteria for both groups, as well as the similarity of groups with respect to meaningful baseline characteristics such as diabetes duration and HbA1c levels. Mean age of type 2 diabetes patients with normal UAE was significantly higher as compared to the normal subjects, however we did not identify differences between these groups in any retinal layer. Although HbA1c levels of normal subjects were unknown, controls with a history of normal glycemic and arterial hypertension were chosen to limit the chances of inclusion of undiagnosed diabetes.

In conclusion, this study demonstrated that there is a selective loss of inner retinal layer thickness in type 2 diabetic patients with microalbuminuria and no clinically detected retinopathy. Albuminuria was independently associated with a neurovascular retinal damage, regardless of DR. Patients with type 2 diabetes and microalbuminuria might benefit from careful macular examination. Larger prospective populational studies are warranted to confirm these findings.

References

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Characteristics of the Study Population

ControlsDiabetesP Value
Normal UAE*Microalbuminuria
(n = 17)(n = 19)(n = 24)
Women (%)10 (58.8)12 (63.1)15 (62.5).959
Age (Years)49.2 ± 10.359.5 ± 8.853.8 ± 9.5.008
Arterial Hypertension (%)47.347.350.0.418
Duration of DM (Years)NA9.0 ± 2.88.8 ± 3.4.865
Urinary Albumin Excretion (mg/L)NA7.4 ± 2.671.1 ± 33.9< .001
HbA1c (%)NA7.7 ± 1.17.8 ± 1.3.877

Mean Layer Thickness of the Individual Intraretinal Layers in the Inner Ring Areaof the Macula

ParametersControlsDiabetesP Value
Normal UAEMicroalbuminuria
(n = 17)(n = 19)(n = 24)
RNFL22.7 ± 2.121.8 ± 2.521.7 ± 1.6.291*/.976/.293
GCL51.7 ± 6.647.8 ± 5.641.7 ± 5.2< .001*/.003/.001
IPL41.6 ± 3.739.3 ± 3.940.3 ± 4.2.240*/.713/.557
INL41.5 ± 3.140.5 ± 4.541.4 ± 4.4.689*/.739/.996
OPL33.2 ± 4.234.0 ± 4.034.9 ± 4.7.479*/.776/.453
ONL71.6 ± 9.469.5 ± 8.668.5 ± 7.3.498*/.916/.468
ISOS81.1 ± 2.680.3 ± 2.981.1 ± 2.6.529*/.562/.618
RPE15.0 ± 1.514.8 ± 1.215.1 ± 1.2.792*/.773/.954

Mean Layer Thickness of the Individual Intraretinal Layers in the Outer Ring Areaof the Macula

ParametersControlsDiabetesP Value
Normal UAEMicroalbuminuria
(n = 17)(n = 19)(n = 24)
RNFL38.0 ± 4.435.5 ± 3.333.6 ± 4.1.005*/.299/.003
GCL36.0 ± 4.335.1 ± 3.335.9 ± 3.9.762*/.80/.997
IPL30.0 ± 2.529.3 ± 2.429.5 ± 3.1.740*/.985/.813
INL33.5 ± 2.033.7 ± 3.333.8 ± 2.5.926*/.998/.924
OPL27.5 ± 2.828.0 ± 1.528.4 ± 2.2.307*/.765/.275
ONL58.3 ± 8.255.3 ± 6.855.6 ± 7.2.392*/.989/.470
ISOS78.5 ± 2.577.4 ± 2.878.3 ± 2.2.390*/.476/.984
RPE13.1 ± 1.313.0 ± 1.113.2 ± 1.0.951*/.946/.990

Multiple Linear Regression Analysis of Retinal Layer Thickness and Clinical Parameters

VariablesB95% CIP Value

LowerUpper

GCL*
  UAE−0.100−0.139−0.060< .001
  Duration of DM−0.412−1.1180.294.244
  HbA1c0.246−1.0401.531.701
  Arterial hypertension0.172−3.6093.953.927

RNFL*
  UAE−0.062−0.087−0.037< .001
  Duration of DM0.012−0.4290.454.955
  HbA1c0.590−0.2151.394.146
  Arterial hypertension0.871−1.4943.237.460
Authors

From the Department of Ophthalmology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (LBF, DL, CZB, JL); the Department of Endocrinology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (LHC); and Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (LBF, DL, CZB, JL, LHC).

This study received funds from the Coordination for the Improvement of Higher Education Personnel (CAPES).

The authors report no relevant financial disclosures.

Address correspondence to Lucas Brandolt Farias, MD, Alvorada Street, 152/92. 04550-000. São Paulo, SP, Brazil; email: lucas.bfarias@yahoo.com.br.

Received: August 29, 2017
Accepted: February 13, 2018

10.3928/23258160-20180907-05

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