The link between diabetic retinal and renal microvasculopathy is associated with dyslipidemia and upregulated circulating level of cytokines

Abstract

Purpose: To investigate the mechanisms underlying the correlations between diabetic retinopathy (DR) and diabetic nephropathy (DKD) and examine whether circulating cytokines and dyslipidemia contribute to both DR and DKD in patients with 2 diabetes mellitus (T2DM).

Methods: A total of 122 patients with T2DM were enrolled and categorized into the DM group (without no DR and DKD), DR group [non-proliferative DR (NPDR), and proliferative DR (PDR)] with no DKD), DR complicated with DKD groups (DR+DKD group). The biochemical profile, including fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and lipid profile were estimated, and plasma inflammatory and angiogenic cytokines [monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF)-A, C, D, and placental growth factor (PlGF)] were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein-cholesterol (HDL-C); atherogenic index (AI) was calculated as [(total cholesterol (TC) -HDL-C)/HDL-C], and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C).

Results: By multivariable disordered regression analysis, after controlling for duration of DM and hypertension, LDL-C (p = 0.019) and VEGF-D (p = 0.029) resulted as independent risk factors for DR. Albumin-to-creatinine ratio (uACR) (p = 0.003) was an independent risk factor for DR with DKD. In DR, NPDR, and PDR groups, grades of A1, A2, and A3 of albuminuria increased with the severity of DR. In A1, A2, and A3 grade groups, the severity of DR (DM, NPDR, and PDR) increased with higher albuminuria grades. Kendall's tau-b correlation coefficient analysis revealed that FBG (p = 0.019), circulating level of PlGF (p = 0.002), and VEGF-D (p = 0.008) were significantly positively correlated with the grades of uACR (p < 0.001), and uACR grades were significantly correlated with DR severity (p < 0.001).

Conclusions: The occurrence and severity of DR are closely correlated with kidney dysfunction. Among the three kidney functional parameters, uACR resulted as the better indicator of DR severity and progression than glomerular filtration (eGFR) and serum creatinine (Scr). Impaired FBG was associated with microalbuminuria, emphasizing that well-controlled FBG is important for both DR and DKD. The link between diabetic retinal and renal microvasculopathy was associated with dyslipidemia and upregulated circulating level of angiogenic cytokines.

Keywords: Albumin-to-creatinine ratio; cytokines; diabetes mellitus; diabetic kidney disease; diabetic retinopathy; dyslipidemia; fasting blood glucose.

Figure 1

Univariate logistic regression analysis between DM, DR, and DR+DKD groups. DM, diabetes mellitus; DR, diabetic retinopathy; DKD, diabetic kidney disease; HBP, high blood pressure; TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AI, atherosclerosis index [(TC-HDL-C)/HDL-C]; AIP, atherogenic index of plasma [log (TG/HDL-C)]; API, atherogenic plasma index (LDL-C/HDL-C); HbA1c, hemoglobin; FBG, fasting blood glucose; Scr, serum creatinine; eGFR, estimated glomerular filtration rate; uACR, urinary albumin/creatinine ratio; MCP-1, monocyte chemoattractant protein-1; IL-6, interleukin-6; IL-8, interleukin-8; PlGF, placental growth factor; VEGF, vascular endothelial growth.

Figure 2

Kendall's Tau-b rank correlation coefficient analysis showing angiogenic cytokines were associated with DR and DKD grades, renal function profiles were related with DR grades. DM, diabetes mellitus; DR, diabetic retinopathy; DKD, diabetic kidney disease; TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AI, atherosclerosis index [(TC-HDL-C)/HDL-C]; AIP, atherogenic index of plasma [log (TG/HDL-C)]; API, atherogenic plasma index (LDL-C/HDL-C); HbA1c, hemoglobin; FBG, fasting blood glucose; Scr, serum creatinine; eGFR, estimated glomerular filtration rate; uACR, urinary albumin/creatinine ratio; MCP-1, monocyte chemoattractant protein-1; IL-6, interleukin-6; IL-8, interleukin-8; PlGF, placental growth factor; VEGF, vascular endothelial growth.

Figure 3

Multivariate logistic regression analysis showing uACR, LDL-C, and VEGF-D were risk factors for DR and DKD. DM, diabetes mellitus; DR, diabetic retinopathy; DKD, diabetic kidney disease; HBP, high blood pressure; LDL-C, low-density lipoprotein cholesterol; uACR, urinary albumin/creatinine ratio; VEGF, vascular endothelial growth.

Figure 4

Correlation and proportion between DR and DKD grades. DM, diabetes mellitus; DR, diabetic retinopathy; DKD, diabetic kidney disease; A1, A2, A3, albuminuria categories DKD to three classes (A1–A3); A1, normal to mildly (<30 mg/g); A2, moderately (30–299 mg/g); A3, severely increased (≥300 mg/g).