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Subjects and Methods
Study Design and Participants
We performed a retrospective cohort study in patients with DR and CKD to investigate whether DR is associated with the progression of CKD over a 2-year period. The medical records used in this study were collected from patients initially diagnosed with DR and CKD who visited the outpatient clinics of both the Departments of Ophthalmology and Nephrology of Hanyang University Guri Hospital between July 2007 and January 2009. This study was performed in September 2012. We only enrolled the patients who were undergoing FA for clinical purposes at their initial visit to the ophthalmology clinic. The patients were initially diagnosed with CKD by a nephrologist according to the National Kidney Foundation KDOQI (Kidney Disease Outcomes Quality Initiative) classification. All enrolled patients adopted prophylactic strategies such as blood pressure (BP) control, glycemic control, and dietary protein restriction in the Department of Nephrology. Exclusion criteria were history of vitrectomy, panretinal photocoagulation, intravitreal anti-vascular endothelial growth factor injection, and renal replacement therapy including dialysis and renal transplant. In addition, patients who were not regularly followed-up by nephrologists at our hospitals over the 2-year period were excluded. We also excluded patients with concomitant glomerular disease, vascular disease, tubulo-interstitial disease, or cystic disease, which are all other causes of CKD (Figure 1).
(Enlarge Image)
Figure 1.
Flow diagram of the study subjects. CKD, chronic kidney disease; DR, diabetic retinopathy; FA, fluorecein angiography.
The primary outcome measure of this study was the time to the first event of serum creatinine level doubling or development of ESRD defined as dialysis or renal transplant. The primary outcome represented the progression of CKD.
The institutional review board and ethics committee of the Hanyang University Guri Hospital approved the study, which adhered to the tenets of the Declaration of Helsinki. Patient consent was not required.
Measurement of Capillary Nonperfusion Area in Fluorescein Angiographic Images
FA was recorded using a high-resolution digital fundus camera (TRC-50DX; Topcon Corporation, Tokyo, Japan) when DR was initially diagnosed. A series of digital images was taken after the rapid intravenous injection of 5 ml 10% fluorescein solution. FA images of adjacent, overlapping fields were cut and pasted together to form a retinal FA montage using computer-based image reconstruction software (IMAGEnet system; Topcon Corporation). With the FA montage image, we set the center as the point between the disc and the fovea. Then, an imaginary circle was drawn, the radius of which was twice the distance from the disc to the fovea. The capillary nonperfusion area was outlined manually and then the area was measured using an area measurement program (ImageJ; National Institutes of Health, Bethesda, MD, USA) within the imaginary circle. Capillary nonperfusion was defined as a dropout of the retinal capillary bed as detected in the FA image, and enhancing the contrast mode in ImageJ software emphasized the area. The disc area (DA) was measured in the same way and the nonperfusion area was expressed as compared with the DA. Two retinal specialists who were masked to any clinical information performed the measurements.
We classified the perfusion status of DR as ischemic and nonischemic based on FA characteristics. Ischemic DR demonstrated 10 or more DAs of retinal capillary nonperfusion on FA. Nonischemic DR demonstrated <10 DAs in the area of retinal capillary nonperfusion on FA.
Estimation of Glomerular Filtration Rate (GFR) and Determination of CKD
GFR was estimated using the Modification of Diet in Renal Disease Study equation. CKD was defined according to the National Kidney Foundation KDOQI classification. CKD was defined as either kidney damage or eGFR<60 ml/min/1.73 m for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. We classified eGFR in the following ranges: stage 1, ≥90 ml/min/1.73 m; stage 2, 60–89 ml/min/1.73 m; stage 3, 30–59 ml/min/1.73 m; stage 4, 15–29 ml/min/1.73 m; and stage 5, <15 ml/min/1.73 m.
Definitions of Other Risk Factor Variables
At the baseline examination, we checked each patient for a history of hypertension. Hypertension was diagnosed when BP was >140/90 mm Hg or the patient was receiving antihypertensive treatment. We also checked for the duration of hypertension, which was defined as the time from diagnosis of hypertension or the first time the patient was hospitalized. Mean data were used for analyses.
All laboratory measurements were obtained for clinical management purposes, and were not obtained at a specific time. Laboratory measurements were performed in the same laboratory and included: serum creatinine, hemoglobin, albumin, calcium, phosphate, hemoglobin A1c (HbA1c), serum lipid profile including triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentration. Serum creatinine was measured by the Jaffe kinetic method. We defined 'creatinine doubling' as any increase reaching at least twice the baseline.
The presence of albuminuria was defined using urine albumin creatinine ration (UAC). UAC of 30–300 mg/g was defined as microalbuminuria and UAC over 300 mg/g was defined as overt albuminuria.
DR was graded according to the Early Treatment for Diabetic Retinopathy Study (ETDRS) scale as nonproliferative DR (NPDR) and proliferative DR (PDR) by assessment of presence of retinal NV or abnormal growth of new retinal blood vessels in to the vitreous. High-risk PDR (HR-PDR) was defined by ETDRS guidelines. Patients who had the following risk factors were assigned to the HR-PDR group: (1) presence of neovascularization of disc (NVD) >ETDRS standard photograph 10A; (2) less extensive NVD, if vitreous or pre-retinal hemorrhage was present; (3) NV of elsewhere (NVE)≥1/2 disc area, if vitreous or pre-retinal hemorrhage was present. For the analysis in this study, the PDR group only included those with PDR but without high-risk factors.
Statistical Methods
All data are expressed as the mean±SD. For the analysis, we randomly selected one eye from each patient. We categorized the patients as two groups, ischemic and nonischemic DR. Comparisons of baseline χ-tests were used for categorical data and independent-sample t-tests were used for continuous data. Kaplan–Meier curves were used to explore differences in time to primary outcomes from the initiation of follow-up between two groups. A two-step approach was used to identify the prognostic factors associated with CKD progression. First, to identify factors associated with CKD progression, a univariate Cox regression model was used to estimate the hazard ratio and its 95% confidence interval (CI). Second, multivariate analysis using a Cox regression model was used. All the factors that were identified as affecting CKD progression by univariate analysis were included in the multivariate analysis to determine which factors were most associated with CKD progression. A forward selection method was used. P<0.05 was considered statistically significant in all analyses. All statistical tests were performed using the PASW Statistics 18.0 (SPSS Inc., Chicago, IL, USA).
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