Quantitative analysis of macular and optic disc microvascular parameters in patients with immunoglobulin A nephropathy using optical coherence tomography angiography

Abstract

Background

Immunoglobulin A nephropathy (IgAN) is a common chronic glomerulonephritis. The kidneys and eyes have structural and developmental similarities, but ocular microvascular changes in IgAN, especially in the macular and optic disc, are poorly studied. This study aimed to assess these microvascular parameters in IgAN patients using optical coherence tomography (OCT) and OCT angiography (OCTA) and explore their associations with clinical data.

Methods

This is a case-control study. Fifteen patients with IgAN and 15 healthy controls (HCs) who attended The Affiliated Hospital of Southwest Medical University between July 2022 and December 2023 were selected. OCT and OCTA were used to assess macular thickness, retinal nerve fiber layer (RNFL) thickness, the vascular density (VD) and perfusion density (PD) of macular and optic disc, and foveal avascular zone (FAZ). In addition, we analyzed the association between OCT and OCTA parameters and clinical data in patients with IgAN.

Results

VD and PD were significantly lower in the macular area in the IgAN group than the HCs (VD: 18.270±0.683 vs. 18.943±0.357, P<0.001; PD: 0.447±0.019 vs. 0.464±0.009, P<0.001). VD and PD in the macular area were negatively correlated with urine protein levels (VD: ρ=−0.604, P=0.017; PD: ρ=−0.551, P=0.033) and urine microalbumin levels (VD: ρ=−0.762, P=0.001; PD: ρ=−0.751, P=0.001). The FAZ area was positively correlated with 24-h urine volume (ρ=0.651, P=0.009).

Conclusions

Compared with HCs, the status of macular microcirculation in the IgAN group was significantly decreased, and some microvascular parameters were significantly correlated with the clinical data.

Introduction

Immunoglobulin A nephropathy (IgAN) is the most common form of chronic glomerulonephritis worldwide, accounting for approximately 50% of patients with primary glomerular disease in China (1,2). IgAN is characterized by deposition of immunoglobulin A (IgA) or IgA-based immunoglobulin in the glomerular membrane region and activation of the alternative pathway of complement, resulting in mesangial cells (3). Clinical findings in patients with IgAN typically manifest but not limited to asymptomatic hematuria, proteinuria, edema, hypertension and hyperuricemia (3).

The kidneys and eyes have similar structures, development, and genetic pathways, indicating that kidney and eye diseases may have a close connection (4,5). The microvascular complications of diabetes mellitus mainly include diabetic nephropathy and diabetic retinopathy, which further confirm that renal disease is closely related to eye disease (6,7). The eye manifestations of IgAN patients currently reported mainly include uveitis, surface scleritis, scleritis, retinal vasculopathy, drusen, hypertension retinopathy, and Vogt-Koyanagi-Harada (VKH) syndrome (8-12). In addition, retinal microvascular parameters have been shown to predict chronic kidney disease (CKD) (4).

In recent years, with the continuous development of equipment, various ophthalmological inspection techniques have become increasingly accurate. Optical coherence tomography angiography (OCTA) is a new type of noninvasive, fast, and safe clinical application technology, without the use of contrast agents, and can display the structure of the retina and choroidal microvascular network. OCTA can provide blood flow signal from the superficial and deep retinal plexuses and superficial choroidal capillary network to accurately localize the site and morphology of the lesion. With the continuous development of blood flow analysis software, commercial OCTA machines have built-in algorithms to quantitatively assess a range of retinal parameters, such as the size and morphology of the macular foveal avascular zone (FAZ) and the density of blood flow in the retinal choroidal layers (13,14). In addition, OCTA has good reproducibility and repeatability for measuring density of vascularization parameters in the same machine (14,15), which making it a reliable assay. Consequently, OCTA provides a good assessment of vascular disease. It can show the details of the microvasculature in diabetic retinopathy, age-related macular degeneration, choroidal neovascularization, retinal vein occlusion, and central serous chorioretinopathy (16-18). It has been shown that OCTA can be used to evaluate microvascular changes in other systemic diseases such as multiple sclerosis (19), hypertension (20), Alzheimer’s disease (21), systemic lupus erythematosus (22,23), and CKD (24).

A previous study has shown that the retinal vascular density (VD) of a patient with CKD decreases significantly, and the decline in estimated glomerular filtration rate (eGFR) is significantly related to the decrease in shallow vascular complex (SVC) VD in the macular area (25). Our team’s previous study has shown that in adult patients with primary nephrotic syndrome (PNS), the decrease in VD and perfusion density (PD) was mainly observed in the macular area. The VD of the macular area was positively correlated with plasma prealbumin levels and negatively correlated with urinary protein level (26). IgAN is one of the most common kidney diseases worldwide, and previous studies have shown that kidney arteriolar microangiopathic lesions are common in IgAN, and their presence is independently associated with the progression of kidney failure (27,28). However, no relevant studies have been conducted in patients with IgAN.

Therefore, this study used optical coherence tomography (OCT) and OCTA to assess macular thickness, retinal nerve fiber layer (RNFL) thickness, VD and PD of the macular and optic discs, and FAZ of the IgAN group and healthy controls (HCs). We also explored the changes in the microvascular parameters of the eyes of patients with IgAN and their correlation with clinical data. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2113/rc).

Methods

Subjects

This is a case-control study. The study was reviewed and approved by the Ethics Committee of The Affiliated Hospital of Southwest Medical University (approval No. KY2021031). All subjects were informed of the study and agreed to participate. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Fifteen patients with IgAN and 15 HCs who were treated in The Affiliated Hospital of Southwest Medical University, between July 2022 and December 2023 were selected. Subjects satisfying the following criteria were included: patients with a diagnosis of IgAN confirmed by needle biopsy of the kidney and were diagnosed with IgAN according to the KDIGO Clinical Practice Guideline (29,30); age >18 years; patients and family members were informed about the study and cooperated. Subjects satisfying the following criteria were excluded: any previous eye disease, including glaucoma, cataract, etc.; any previous eye surgery, including cataract surgery, corneal refractive surgery, etc.; refractive errors exceeding +3.0 or −3.0 D or astigmatism; any systemic diseases, such as hypertension, diabetes, and systemic lupus erythematosus; and not cooperating or unwilling to participate in the research. Healthy adults with matched sex and age were selected as HC subjects.

Baseline examination

Collect and record the results of all the subject’s name, age, sex, best-corrected visual acuity (BCVA), non-contact intraocular pressure, slit lamp examination, retinal imaging examination, and fundus examination.

The following laboratory results were collected from the IgAN group: body mass index (BMI), systolic pressure, diastolic pressure, erythrocyte, hemoglobin, platelet, total protein, albumin, prealbumin, triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, urea nitrogen, uric acid, glomerular filtration rate (GFR), urine protein concentration, urinary creatinine, urine protein/creatinine, urine microalbumin, 24-h urine volume, 24-h urine protein quantification, and urine erythrocytes.

OCT and OCTA imaging

All OCT and OCTA examinations were performed by the same experienced ophthalmic technician using a Cirrus 5000 device with AngioPlex software (version 9.5, CarlZeiss Meditec, Inc., Dublin, CA, USA).

The OCTA system automatically segments the superficial capillary plexus (SCP) of the macular and optic disc. Quantitative parameters including VD, PD, FAZ area, FAZ perimeter, and circularity index were obtained automatically with the built-in software. The macular and optic disc areas were segmented into three concentric circles with diameters of 1, 3, and 6 mm, which were termed the fovea, pericentral ring, and peripheral ring, respectively. According to the Early Treatment Diabetic Retinopathy Study (ETDRS) (31), the pericentral and peripheral rings were equally divided into four regions: superior, nasal, inferior, and temporal. VD and PDs in each area were recorded (Figure 1).

Figure 1.

OCTA images in the SCP obtained in the patient with IgAN. (A-C) Macular 6 mm × 6 mm OCTA scan. (D) OCTA sectors: central, IS, IT, II, IN, OS, OT, OI, ON. (E-G) Optic nerve 6 mm × 6 mm OCTA scan. (A) VD of the macular. (C) PD of the macular. (E) VD of the optic disc. (G) PD of the optic disc. IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; SCP, superficial capillary plexus; VD, vascular density.

Using macular OCT scan, macular OCT images were acquired to record the macular thickness in each region; using optic nerve OCT scan, optic disc OCT images were acquired to obtain RNFL thickness.

Excluded images with significant artifacts and low signal-to-noise ratio.

Statistical analysis

All data analyses were performed using the SPSS (IBM, Chicago, IL, USA) software (version 17.0). Measures obeying normal distribution (normality test using the Shapiro-Wilk method) were expressed as mean ± standard deviation (SD); otherwise, the median [interquartile range (IQR)] was used. Independent samples t-tests were used to compare the between-group differences of variables obeying normal distribution, otherwise, the Mann-Whitney U test and Pearson’s or Spearman’s rank correlation analysis were used to correlate OCT and OCTA parameters with clinical indicators (hemoglobin, urine protein concentration, urine microalbumin, urinary creatinine, 24-h urine volume) in patients with IgAN. Statistical significance was set at P<0.05.

Results

Study participants

Fifteen IgAN patients [42 years (range, 26–60 years); eight men and seven women] and 15 HCs [43 years (range, 28–64 years); seven men and eight women] were included in the study. The clinical and demographic characteristics are shown in Table 1. The two groups were not significantly different in terms of sex, age, BCVA, and intraocular pressure (all P>0.05). The clinical data of the patients with IgAN are shown in Table 2.

Table 1. Clinical and demographic characteristics of study participants.

Parameters	IgAN group	Control group	P
Age (years)	42 [26–60]	43 [28–64]	0.820†
Sex (M/F)	8/7	7/8	0.715‡
BCVA	1.2 [1.0–1.5]	1.2 [1.0–1.5]	>0.99§
IOP (mmHg)	16.0 [10.0–18.0]	17.0 [11.0–20.0]	0.063†

Data are presented as mean [range] or n. ^†, independent samples t-test; ^‡, Chi-squared test; ^§, Mann-Whitney U test. BCVA, best-corrected visual acuity; F, female; IgAN, immunoglobulin A nephropathy; IOP, intraocular pressure; M, male.

Table 2. The clinical data of PNS patients.

Clinical data	IgAN group
BMI (kg/m2)	23.60±3.67
Systolic blood pressure (mmHg)	135.13±9.78
Diastolic blood pressure (mmHg)	91.13±11.87
Erythrocyte count (×1012/L)	4.56±0.64
Hemoglobin (g/L)	139.93±21.98
Platelet count (×109/L)	231.07±55.71
Total protein (g/L)	59.17±10.31
Albumin (g/L)	33.06±8.43
Prealbumin (mg/L)	248.15±55.25
Triglyceride (mmol/L)	1.62 (0.68–6.73)
Total cholesterol (mmol/L)	6.32 (4.72–12.97)
HDL-C (mmol/L)	1.62±0.49
LDL-C (mmol/L)	3.53 (2.53–7.70)
Creatinine (μmol/L)	101.50 (48.90–216.70)
Urea nitrogen (mmol/L)	6.98 (3.47–17.56)
Uric acid (μmol/L)	374.15±83.19
GFR (mL/min)	78.68±37.18
Urine protein concentration (g/L)	2.71 (0.42–11.75)
Urinary creatinine (μmol/L)	9,457.70 (4,333.10–33,172.90)
Urine protein/creatinine (g/gcr)	1.70 (0.36–9.98)
Urine microalbumin (mg/L)	786.48 (170.40–6,809.90)
24-h urine volume (mL/24 h)	1650.67±835.04
24-h urine protein quantification (g/24 h)	2.96 (0.77–9.84)
Urine erythrocyte (number/μL)	272.70 (1.00–1,020.00)

Data are expressed as mean ± SD (normal distribution) or median (min–max) (non-normal distribution). BMI, body mass index; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; IgAN, immunoglobulin A nephropathy; LDL-C, low-density lipoprotein cholesterol; PNS, primary nephrotic syndrome; SD, standard deviation.

The macular thickness and RNFL (Table 3)

Table 3. Macular and optic disc OCT parameters of the study participants.

Parameters	IgAN group	Control group	P
Thickness of macular (μm)
CMT	247.60±18.728	240.67±21.643	0.190†
IS	328.33±13.855	320.73±11.730	0.025†*
IT	312.17±13.879	307.73±11.326	0.181†
II	323.73±12.401	313.53±11.319	0.002†*
IN	327.83±14.765	318.20±12.305	0.008†*
OS	288.20±12.178	283.73±12.768	0.234‡
OT	265.47±9.748	264.67±11.192	0.501‡
OI	271.60±5.263	267.40±13.698	0.122†
ON	308.07±10.379	299.20±15.668	0.012†*
Thickness of optic disc (μm)
RNFL thickness	104.90±8.868	101.33±12.704	0.158‡

Data are expressed as mean ± SD. ^†, independent samples t-test; ^‡, Mann-Whitney U test; *, P<0.05 (statistically significant). CMT, central macular thickness; IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OCT, optical coherence tomography; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; RNFL, retinal nerve fiber layer; SD, standard deviation.

The macular thickness

Compared with the HCs, the thickness of the macula in the IgAN group tended to increase, and the thicknesses of the superior inner (IS), inferior inner (32), nasal inner (IN), and nasal outer (ON) regions were significantly higher (IS: 328.33±13.855 vs. 320.73±11.730 µm, P=0.025; II: 323.73±12.401 vs. 313.53±11.319 µm, P=0.002).

The thickness of the RNFL

Compared with the HCs, the IgAN group showed no statistically significant difference in RNFL thickness (RNFL: 104.90±8.868 vs. 101.33±12.704 µm, P=0.158).

The SCP of the macular and optic disc

The PD, VD, and FAZ of the macular (Table 4)

Table 4. Macular OCTA parameters of the superficial vascular plexus in both groups.

Parameters	IgAN group	Control group	P
FAZ area (mm2)	0.296±0.116	0.229±0.070	0.010†*
FAZ perimeter (mm)	2.211±0.474	1.973±0.335	0.029†*
FAZ circularity	0.738±0.077	0.732±0.091	0.853‡
VD of macular
Central	8.960±2.512	10.683±2.220	0.007†*
IS	18.500±0.675	19.183±0.550	<0.001‡*
IT	18.137±0.726	18.893±0.564	<0.001†*
II	18.187±0.850	19.003±0.571	<0.001†*
IN	18.123±1.298	18.970±0.845	0.001‡*
OS	18.873±0.585	19.330±0.573	0.003†*
OT	17.037±1.342	18.140±0.776	<0.001‡
OI	18.563±0.989	19.163±0.482	0.005‡*
ON	20.040±0.789	20.423±0.329	0.034‡*
Inner circle	18.240±0.680	19.017±0.471	<0.001†*
Outer circle	18.643±0.742	19.263±0.324	<0.001‡*
Whole	18.270±0.683	18.943±0.357	<0.001‡*
PD of macular
Central	0.202±0.060	0.238±0.050	0.014†*
IS	0.444±0.021	0.462±0.011	<0.001‡*
IT	0.432±0.019	0.449±0.017	0.001†*
II	0.439±0.023	0.452±0.016	0.012†*
IN	0.430±0.034	0.447±0.022	0.019‡*
OS	0.471±0.014	0.483±0.012	0.001†*
OT	0.417±0.037	0.445±0.019	<0.001‡*
OI	0.463±0.027	0.481±0.011	0.001‡*
ON	0.488±0.022	0.500±0.009	0.010‡*
Inner circle	0.436±0.020	0.453±0.013	<0.001†*
Outer circle	0.460±0.021	0.477±0.008	<0.001‡*
Whole	0.447±0.019	0.464±0.009	<0.001‡*

Data are expressed as mean ± SD. ^†, independent samples t-test; ^‡, Mann-Whitney U test; *, P<0.05 (statistically significant). FAZ, foveal avascular zone; IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OCTA, optical coherence tomography angiography; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; PD, perfusion density; SD, standard deviation; VD, vascular density.

Compared with the HCs, VD and PD in the whole macular area in the IgAN group has significantly lower [VD (whole): 18.270±0.683 vs. 18.943±0.357, P<0.001; PD (whole): 0.447±0.019 vs. 0.464±0.009, P<0.001; VD (IS): 18.500±0.675 vs. 19.183±0.550, P<0.001; PD (IS): 0.444±0.021 vs. 0.462±0.011, P<0.001; VD (IT): 18.137±0.726 vs. 18.893±0.564, P<0.001; PD (IT): 0.432±0.019 vs. 0.449±0.017, P=0.001; Figures 2,3].

Figure 2.

Comparison of VD between the IgAN group and the HCs group in the SCP. (A) VD in the central area of macular. (B) VD in the IS area of macular. (C) VD in the IT area of macular. (D) VD in the II area of macular. (E) VD in the IN area of macular. (F) VD in the OS area of macular. (G) VD in the OT area of macular. (H) VD in the OI area of macular. (I) VD in the ON area of macular. (J) VD in the inner circle area of macular. (K) VD in the outer circle area of macular. (L) VD in the whole area of macular. VD in the macular area of the IgAN group were significantly lower than those in the HC group. HC, healthy control; IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; SCP, superficial capillary plexus; VD, vascular density.

Figure 3.

Comparison of PD between the IgAN group and the HCs group in the SCP. (A) PD in the central area of macular. (B) PD in the IS area of macular. (C) PD in the IT area of macular. (D) PD in the II area of macular. (E) PD in the IN area of macular. (F) PD in the OS area of macular. (G) PD in the OT area of macular. (H) PD in the OI area of macular. (I) PD in the ON area of macular. (J) PD in the inner circle area of macular. (K) PD in the outer circle area of macular. (L) PD in the whole area of macular. PD in the macular area of the IgAN group were significantly lower than those in the HC group. HC, healthy control; IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; PD, perfusion density; SCP, superficial capillary plexus.

Compared with HCs, the FAZ area in the IgAN group was significantly higher (FAZ area: 0.296±0.116 vs. 0.229±0.070 mm², P=0.010, Figure 4). Compared with HCs, the IgAN group showed no statistically significant difference in FAZ circularity (FAZ circularity: 0.738±0.077 vs. 0.732±0.091, P=0.853, Figure 4).

Figure 4.

Comparison of VD, PD, and FAZ area between the IgAN group and the HCs group in the SCP. (A) FAZ area in the SCP. (B) FAZ perimeter in the SCP. (C) FAZ circularity in the SCP. (D) VD in the optic disc. (E) PD in the optic disc. (A) The FAZ area in the IgAN group were significantly higher than those in the HCs group. (B) The FAZ perimeter in the IgAN group were significantly higher than those in the HCs group. (C) The FAZ circularity in the IgAN group were not significant than those in the HCs group. (D,E) VD and PD of the optic disc area in the IgAN group showed a tendency to decrease as compared to that in the HCs group, but the differences were not significant. FAZ, foveal avascular zone; HC, healthy control; IgAN, immunoglobulin A nephropathy; PD, perfusion density; SCP, superficial capillary plexus; VD, vascular density.

The PD and VD of the optic disc (Table 5)

Table 5. The optic disc OCTA parameters of the subjects.

Parameters	IgAN group	Control group	P
VD of optic disc
Central	11.793±5.098	11.913±3.574	0.916†
IS	18.610±1.809	18.917±0.805	0.947‡
IT	17.023±3.434	17.447±3.617	0.355‡
II	17.177±2.598	17.750±2.487	0.284‡
IN	19.123±1.313	19.163±0.755	0.496‡
OS	19.377±0.638	19.443±0.653	0.691†
OT	19.637±1.462	19.663±1.033	0.468‡
OI	19.370±0.847	19.400±0.621	0.790‡
ON	17.990±1.779	18.230±0.872	0.836‡
Inner circle	17.993±1.350	18.317±1.302	0.318‡
Outer circle	19.100±0.563	19.177±0.569	0.602†
Whole	18.617±0.591	18.683±0.488	0.636†
PD of optic disc
Central	0.329±0.137	0.336±0.109	0.802†
IS	0.493±0.048	0.507±0.027	0.329‡
IT	0.420±0.085	0.425±0.086	0.813‡
II	0.452±0.075	0.484±0.064	0.053‡
IN	0.503±0.037	0.508±0.016	0.877‡
OS	0.495±0.017	0.502±0.015	0.152†
OT	0.480±0.037	0.480±0.027	0.712‡
OI	0.496±0.020	0.500±0.024	0.348‡
ON	0.456±0.049	0.459±0.025	0.615‡
Inner circle	0.467±0.039	0.481±0.036	0.101‡
Outer circle	0.482±0.015	0.485±0.014	0.473‡
Whole	0.474±0.015	0.477±0.012	0.408†

Data are expressed as mean ± SD. ^†, independent samples t-test; ^‡, Mann-Whitney U test. IgAN, immunoglobulin A nephropathy; II, inferior inner; IN, nasal inner; IS, superior inner; IT, temporal inner; OCTA, optical coherence tomography angiography; OI, inferior outer; ON, nasal outer; OS, superior outer; OT, temporal outer; PD, perfusion density; SD, standard deviation; VD, vascular density.

Compared with the HCs, the VD and PD in the optic disc in the IgAN group showed a tendency to decrease, but the differences were not significant (VD: 18.617±0.591 vs. 18.683±0.488, P=0.636; PD: 0.474±0.015 vs. 0.477±0.012, P=0.408, Figure 5).

Figure 5.

The correlation between clinical data and VD and PD. (A-D) VD and PD in the macular area were negatively correlated with urine protein level and urine microalbumin level. (E) The FAZ aera were positively correlated with 24-h urine volume. (F,G) The CMT was positively correlated with hemoglobin level and urinary creatinine level. (H) The CMT were negatively correlated with 24-h urine volume. CMT, central macular thickness; FAZ, foveal avascular zone; PD, perfusion density; SCP, superficial capillary plexus; VD, vascular density.

The correlation analysis in all IgAN participants between OCTA parameters and the clinical data (Table 6, Figure 3)

Table 6. The correlation between OCTA parameters and the clinical data in all IgAN participants.

Parameters	Hemoglobin	Urine protein concentration	Urine microalbumin	Urinary creatinine	24-h urine volume
VD of macula (central)
ρ	0.242	0.132	−0.128	0.361	−0.453
P	0.385	0.638	0.650	0.186	0.090
VD of macula (inner circle)
ρ	−0.075	−0.337	−0.492	−0.197	0.142
P	0.792	0.220	0.063	0.481	0.615
VD of macula (outer circle)
ρ	−0.050	−0.635†*	−0.776‡*	−0.436	0.459
P	0.859	0.011	0.001	0.104	0.085
VD of macula (whole)
ρ	−0.016	−0.604†*	−0.762‡*	−0.364	0.378
P	0.954	0.017	0.001	0.183	0.165
PD of macula (central)
ρ	0.223	0.074	−0.154	0.341	−0.419
P	0.424	0.792	0.583	0.213	0.120
PD of macula (inner circle)
ρ	−0.138	−0.253	−0.513	−0.134	0.180
P	0.623	0.363	0.050	0.635	0.521
PD of macula (outer circle)
ρ	−0.016	−0.590†*	−0.756‡*	−0.396	0.494
P	0.955	0.021	0.001	0.144	0.061
PD of macula (whole)
ρ	−0.021	−0.551†*	−0.751‡*	−0.348	0.435
P	0.941	0.033	0.001	0.204	0.106
FAZ
ρ	−0.125	−0.368	−0.222	−0.427	0.651‡*
P	0.658	0.177	0.427	0.113	0.009
CMT
ρ	0.660‡*	0.422	0.399	0.771‡*	−0.609†*
P	0.007	0.117	0.140	0.001	0.016

^†, correlation is significant at the 0.05 level (two-tailed); ^‡, correlation is significant at the 0.01 level (two-tailed); *, P<0.05 (statistically significant). CMT, central macular thickness; FAZ, foveal avascular zone; IgAN, immunoglobulin A nephropathy; OCTA, optical coherence tomography angiography; PD, perfusion density; VD, vascular density.

VD and PD in the macular area were negatively correlated with urine protein levels (VD: ρ=−0.604, P=0.017; PD: ρ=−0.551, P=0.033) and urine microalbumin levels (VD: ρ=−0.762, P=0.001; PD: ρ=−0.751, P=0.001). The FAZ area was positively correlated with 24-h urine volume (ρ=0.651, P=0.009). Central macular thickness (CMT) was positively correlated with hemoglobin level (ρ=0.660, P=0.007) and urinary creatinine level (ρ=0.771, P=0.001). The CMT were negatively correlated with 24-h urine volume (ρ=−0.609, P=0.016). No significant correlation was found between other clinical data and OCTA parameters in the IgAN groups.

Discussion

This study is the first to investigate retinal microvascular parameters in patients with IgAN by using OCTA. Previous studies have demonstrated that the kidney and eye have significant structural, developmental, physiological, and pathogenic functions. Both the glomeruli and choroids have extensive vascular networks with similar structures. The inner retina and glomerular filtration barrier have similar developmental pathways, and the renin-angiotensin-aldosterone hormone cascade has been found in both the eye and kidney (4,5,33,34).

IgAN is considered as a systemic disease, and the most widely recognized theory of the pathogenesis of IgAN is a multihit hypothesis: Patients with IgAN have elevated levels of circulating IgA1 characterized by the presence of galactose-deficient O-glycans in the hinge region of IgA1 (Gd-IgA1). Antiglycan immunoglobulin G (35) autoantibodies are formed and secreted into systemic circulation. Gd-IgA1-antiglycan IgG immune complexes deposit in the mesangium and activate inflammatory and cellular proliferative signaling cascades, contributing to local inflammation, mesangial matrix production, and mesangial cell proliferation. The end products of unchecked inflammation [facilitated by mediators such as interleukin-6 (IL-6) and transforming growth factor-β (TGF-β)] are glomerular and interstitial fibrosis (36). There are so many similarities between the kidney and the eye, and IgAN is a systemic disease, in the course of its development, will autoantibodies as well as IgA1 also go to the eye, causing a series of changes in the eye? Through macular OCT examination, we found that the macular thickness in the IgAN group showed a tendency to increase as compared to that in the HC group, and the thicknesses of the IS, II, IN, and ON regions were significantly higher than that in the HC group. According to previous studies, there may be the following reasons for the existence of the above phenomenon: patients with IgAN suffer from proteinuria and a chronic loss of protein from the kidneys, leading to the development of hypoproteinemia (3), which in turn leads to a decrease in plasma colloid osmotic pressure and the movement of fluid from the blood into the tissue fluid, ultimately producing tissue oedema (37). A previous animal study has demonstrated that albumin is present in the retinal and choroidal vasculature (38), so when albumin is lost, plasma colloid osmolality decreases, and fluid in the choroidal and retinal vasculature passes into the tissue fluid, leading to retinal thickening (39). RPE-Bruch membrane complex is physiologically similar to the glomerular basement membrane (40). When RPE cells are exposed to human serum, IgA1 complexes that deposit on the basal surface of the RPE cell cause activation of the RPE cell, as in the renal mesangium (8). It causes thickening of the retina. This explains why the macular thickness regions of the IgAN group were greater than that of the HC group. Although the thickness of each macular area was not significantly greater than that of the HC group, there was still a thickening trend. This suggests that the thickening of each macular area in patients with IgAN is not a one-time event, but a slow process. This also suggests that we can detect retinal thickness using OCT as a predictive indicator of visual impairment.

At present, conventional fundus fluorescence angiography (FFA) and indocyanine green angiography (ICGA) are still the gold standards for the diagnosis of most fundus vascular lesions (22,41). FFA is mainly used to examine the central retinal arteriovenous system and its branching vascular network at all levels, while ICGA detects the choroidal circulation and vascular status. The presence of fluorescein leakage, staining, and dye accumulation in the fundus suggests that the retinal vascular system and the outer barrier function are abnormal. OCTA is the fastest growing and most widely used noninvasive fundus angiography technique in recent years. It quantitatively evaluates the blood flow status of the retina and the choroid by analyzing the blood flow and the movement and de-correlation signals of the blood cells and visually displays the structure and morphology of the blood vessels of all layers of the retina and the superficial choroidal capillaries (14,22,42). Compared with traditional imaging modalities, OCTA has higher resolution, faster scanning speed, does not require injection of contrast medium and therefore does not have the problem of dye leakage and occlusion, and allows for clear observation of the depth and extent of the lesion, clearer and more accurate display of the non-perfused area, and quantitative analysis of the blood flow density at different levels of the blood vessels (13,22,41,42).

Through OCTA examination, we found that the VD and PD in the macular area of the IgAN group were significantly lower than those in the HC group. In patients with IgAN, macular microvascular structure and VD are already altered before visual impairment occurs.

Increased macular thickness in IgAN patients can lead to thinning of the macular vascular layer, thus affecting retinal blood supply; however, the significant VD and PD reductions caused by increased retinal thickness alone are not fully explained. In the pathogenesis of IgAN, we found that this manifestation may also be related to the renin-angiotensin system (RAS), which has been shown to be involved in blood pressure regulation and vasoconstriction, leading to inflammatory responses, oxidative stress, and endothelial dysfunction (43). The RAS is found in localized tissues and organs, in addition to the circulatory system (43). Laboratory and clinical studies have demonstrated the presence of localized RAS in the retina, with components most abundantly expressed in retinal microvessels, glial cells, and neurons (ganglion cells), contributing to the development of retinal vascular disease (33). The Gd-IgA1-antiglycan IgG immune complexes of IgAN patients deposit in the mesangium, contributing to local inflammation, mesangial cell proliferation, cellular proliferative signaling cascades, and secretion of components of the extracellular matrix, angiotensin II (Ang II), and aldosterone (3). Therefore, the reduction in retinal VD and PD in IgAN patients may also be associated with activation of the RAS system. To know if autoantibodies are also present in ocular tissues, studies with histologic samples are needed.

In addition, IgA immune complexes in retinal vessels and capillaries are similar to those observed at the glomerular level, causing local vascular changes with local inflammation, leading to platelet adhesion, aggregation, and thrombus formation, which in turn leads to retinal ischemia (9). This may also explain why IgA patients show a decrease in retinal VD.

The FAZ is the most visually acute retinal zone. It is surrounded by interconnected capillary plexuses in the macular region of the retina and has no capillary structure of its own (44). The morphology of the FAZ can reflect changes in macular microcirculation, and capillary loss in the macular central plexus is a prominent feature of ischemic retinal and retinal vascular occlusive diseases (45). Clinically, the size of the FAZ is evaluated through parameters such as area, perimeter, and Feret diameter, and the shape of the FAZ is evaluated through parameters such as circularity index, acircularity index, and axial ratio (46).

The FAZ is now widely used in clinical practice. In diabetic retinopathy, increased FAZ area and circumference and reduced retinal blood flow density in the macular region suggest pre- or early retinal ischemic (47); FAZ is enlarged in highly myopic eyes compared to non-highly myopic eyes and is accompanied by reduced blood flow density in the macular region (48); in retinopathy of prematurity, the FAZ is smaller in area and volume and has significant abnormalities of retinal microvascular structure in the macular (49); in adult PNS patients, the FAZ is enlarged and is accompanied by reduced blood flow density in the macular area (26). Compared with the HCs, the patients with IgAN showed not only a significant decrease in VD and PD in the macular area, but also a significant enlargement of the FAZ area and FAZ perimeter, however, the difference in circularity index was not statistically significant. Several previous studies have shown that the FAZ circularity index is more sensitive than FAZ area and perimeter in reflecting the degree of disease progression (46,50). Compared to HCs, the circularity index of patients with IgAN was not significant. This also confirms that visual acuity was not impaired in the early stages of IgAN despite changes in macular microvascular structure, perfusion, and density, suggesting that the FAZ circularity index measured by OCTA can be used as an important indicator to closely monitor the ocular conditions of IgAN patients. In addition, we found a good correlation between VD and IgAN-related clinical data. Blood and urine creatinine levels and urine protein concentration respond well to human’s kidney function. Elevated creatinine and urinary protein concentrations can indicate impaired kidney function, and urinary protein levels can reflect not only impaired glomerular barrier function but also systemic endothelial dysfunction (51,52). Therefore, we believe that any reduction in VD caused by retinal vascular endothelial dysfunction may reflect the severity of IgAN.

For the time being, our study is still insufficient. Our sample size, age and gender grouping are not perfect. Next, we will further deepen our study to expand the study sample size; further break down the patients’ age stage, disease duration, gender, etc., to explore the changes of the fundus microvascular structure and blood flow in the eyes of patients with IgAN.

Conclusions

In summary, we found that in IgAN patients without ocular symptoms, alterations in macular retinal structure and retinal capillary VD and PD occurred and correlated with some of the indicators of kidney disease. However, the study is purely exploratory and may serve as a guide for further prospective studies with larger sample sizes.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was reviewed and approved by the Ethics Committee of The Affiliated Hospital of Southwest Medical University (approval No. KY2021031). All subjects were informed of the study and agreed to participate. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data Sharing Statement

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DOI: 10.21037/qims-24-2113