the prevalence of type 2 diabetes mellitus ( t2 dm ) has significantly increased worldwide in the past 25 years [ 1 , 2 ] .
dr is one of the most common microvascular complications of diabetes mellitus ( dm ) and is the leading cause of visual impairment and blindness in working - aged people . in recent years
, the prevalence of dr is rapidly increasing [ 3 , 4 ] , as the number of people with t2 dm increased .
the results of a cross - sectional study in a multiethnic asian population showed that the overall age - standardized prevalence of dr was 25.4% ( 20% , 24.8% , and 28.9% in chinese , malays , and indians , resp .
more than 50% of t2 dm patients likely suffer from dr within twenty years after diagnosis . because the symptoms of dr are not apparent in early stages of this disease
, patients often miss the best opportunity for treatment when diagnosed , leading to a high rate of blindness . according to the world health organization ( who ) , dr accounts for 4.8% of the total cases of blindness ( thirty - seven million worldwide ) in 2006 .
therefore , it is important to investigate the risk factors that promote or predict dr .
diabetic nephropathy ( dn ) , also known as diabetic kidney disease or diabetic glomerulosclerosis , is another major complication of dm and the leading cause of end - stage renal disease ( esrd ) .
previous studies have shown that microalbuminuria not only is an important clinical marker for dn , but also is closely associated with the progression of dr . however , suffering from dr and the appearance of microalbuminuria do not occur at the same time .
gfr describes the flow rate of filtered fluid through the kidney and can be estimated using formulas , thereafter referred to as estimated gfr ( egfr ) . unlike microalbuminuria , gfr increases during the early stages of dm due to high blood sugar and decreases during the later stages of dm , reflecting a decline in renal function .
that is to say , changes in gfr appear earlier than microalbuminuria in diabetic patients .
past studies have reported that gfr is but one variable of many that affects the likelihood of developing dr and the other complications of dm [ 9 , 10 ] .
in addition , due to the limited medical condition , routine funduscopic examination or microalbuminuria can not be performed in primary hospital in rural china , especially poverty - stricken areas .
so we wondered if egfr could be used for the early detection of dr , in order to screen it in the general population .
hence , our researchers are embarking on a series of studies to investigate the relationship between gfr and dr , and this is the baseline study .
the aim of this study was to evaluate the prevalence of dr in hospital - based t2 dm patients and investigate the correlation between gfr and dr , so that gfr could be used for dr screening , especially in primary hospital of poor areas .
dm patients were admitted to the department of endocrinology and ophthalmology of the first affiliated hospital in china medical university from september 2010 to march 2012 .
a total of 1613 patients , 844 ( 52.3% ) males and 769 ( 47.7% ) females , with t2 dm were enrolled in this study after rigorous diagnosis and exclusion criteria .
the project was performed in accordance with the principles of the declaration of helsinki and approved through the ethics committee of china medical university .
the dr severity was classified according to the international clinical diabetic retinopathy disease severity scale .
patients were excluded if they had type 1 diabetes mellitus , acute metabolic disorders ( such as diabetic ketoacidosis and a hyperglycemic hyperosmolar state ) , opaque refractive media of one or both eyes ( affecting fundus observation ) , or other eye diseases or serious illnesses ( such as cancer ) .
because dn is often complicated with dr , these patients were not excluded to avoid selection bias .
information , including the age , gender , duration of diabetes , family history of diabetes , and history of hypertension , was collected for each patient .
the blood pressure was measured during the medical examination and recorded as the means of two measurements after the patients rested for 5 minutes .
fasting blood was drawn from the cubital vein and used for biochemical assays , including fasting blood glucose ( fbg ) , glycosylated hemoglobin ( hba1c ) , triglycerides ( tg ) , total cholesterol ( tc ) , high density lipoprotein cholesterol ( hdl - c ) , low - density lipoprotein cholesterol ( ldl - c ) , serum creatinine ( scr ) , and blood urea nitrogen ( bun ) . for the 2-hour postprandial glucose ( 2hpg ) measurement , blood was drawn at 2 hours after ingestion of 75  g glucose powder or bread ( equivalent amount of carbohydrates ) .
all samples were measured using the architect c8000 biochemical analyzer ( toshiba , tokyo , japan ) .
the unit of scr in the ckd - epi formula should be  mg / dl ,  while the levels of scr through colorimetric method were in 
 1  mg / dl = 17.1  mol / l  and put it into the formula to obtain egfr .
direct ophthalmoscopy and fundus photography were conducted after the participants were administered mydriatic eye drops to dilate the pupils .
the center of the macula and optic disc of both eyes was photographed using a 45-degree digital camera ( cr - dgi , canon , japan ) .
if there were different opinions , they would discuss to make decision or consult the superior .
based on the results of the assessment , the subjects were divided into two groups : a dr group and a non - dr ( dm without dr ) group . there were 550 patients in dr group ( male 269 , female 281 ) and 1063 patients in ndr group ( male 575 , female 488 ) .
all statistical analyses were performed using the statistical package from the social sciences ( spss ) version 19.0 , empowerstats ( http://www.empowerstats.com/ ) , and medcalc software programs . the basic description and logistic regression analyses were performed using spss 19.0 software .
the stratified analysis , the interaction test , covariate screening , and curve fitting were performed using empowerstats statistical software .
medcalc was used to draw the receiver operating characteristic curve ( roc curve ) , a graphical plot illustrating the performance of a binary classifier system with varying discrimination thresholds .
the numerical variables of normal distribution were expressed as the means  standard deviation ( means  sd ) and percentage ( % ) .
the independent samples t - test was used to analyze the continuous variables , whereas the odds ratio ( or ) and chi - square (  ) test was used to analyze the categorical variables .
based on the exclusion criteria , 1613 t2 dm patients aged 54.75  12.19 years were selected into this study . among these subjects ,
no differences in tg , dbp , and bun were detected between the dr and ndr groups .
in contrast , statistically significant differences were detected for age ( p = 0.003 ) , family history of dm ( p = 0.036 ) , duration of dm ( p < 0.001 ) , fbg and 2hpg ( p < 0.001 ) , hba1c ( p = 0.003 ) , tc ( p <
0.001 ) , hdl - c ( p = 0.013 ) , ldl - c ( p = 0.002 ) , sbp ( p < 0.001 ) , dbp ( p = 0.033 ) , egfr ( p < 0.001 ) , and scr ( p < 0.001 ) ( table 1 ) . to determine the risk factors for dr , a logistic regression model was performed .
different risk factors , identified in the univariable analysis , were used as independent variables ( table 2 ) .
there were significant associations between dr and age ( p < 0.001 ) , dm duration ( p < 0.001 ) , hba1c ( p = 0.007 ) , hdl - c ( p = 0.024 ) , sbp ( p < 0.001 ) , dbp ( p = 0.007 ) , and egfr ( p = 0.010 ) . according to the severity of the disease ,
dr patients were divided into 3 groups : nondiabetic retinopathy ( ndr ) , nonproliferative diabetic retinopathy ( npdr ) , and proliferative diabetic retinopathy ( pdr ) groups .
the mean value of egfr was 106.27  23.37 , 100.12  30.85 , and 83.33  33.77 ( ml / min ) for the ndr , npdr , and pdr groups , respectively . in order to accurately study the relationship between egfr and dr
, we need to excluded the influence factors that have an effect on their relationship through stratified analysis , interaction tests , and covariate screening .
first of all , we analyzed the relationship between dr and all risk factors through stratified analysis ( table 3 ) .
each continuous variable was divided into three groups according to its value from low to high .
 sex  group was divided into  male  and  female  groups on the basis of gender .
 fhd  group was divided into  no  ( not having family history of dm ) and  yes  ( having family history of dm ) group .
in addition , the relationships between dr and tg and dr and dbp were not identified using univariate analysis but were observed using stratified analysis .
interaction tests were performed to detect the influence of each stratified factor on the relationship between egfr and dr .
p  0.05 means interaction exists between that factor and the relationship . the presence of effect modifiers of egfr and dr was observed .
eligible factors , which as effect modifiers for the relationship between egfr and dr , include scr ( p = 0.003 ) , sbp ( p = 0.043 ) , ldl - c ( p = 0.025 ) , tc ( p = 0.005 ) , and bun ( p = 0.062 ) ( p = 0.062 means there is certain effect modification ) .
the screening criteria included risk factors producing > 10% change in the regression coefficient after introduction into the basic model .
the results showed that the sbp , fbg , 2hpg , hba1c , and the dm duration met the filter criteria ( or change was 13.5 , 13.4 , 16.5 , 18.5 , and 39.0 , resp . ) .
after the adjustment of the variables affecting the relationship between egfr and dr , result of univariate analysis suggested that egfr remained significantly associated with dr ( p < 0.001 ) ( table 4 ) .
in addition , smooth curve fitting was performed after the adjustment of all variables , and the resultant curve exhibited a two - stage change and a breakpoint ( figure 1 ) . when the egfr value was more than the point , the risk of dr was low ; however if the value was less than the point , the risk of dr significantly increased .
the saturation effects were analyzed based on the curve , and the data indicated that the inflection point was 99.4  ml / min ( 34th percentile ) . before and after the adjustment of the covariates ,
the logarithmic likelihood ratio test p value decreased from 0.050 to 0.036 ( table 5 ) .
diabetic retinopathy is one of the most common microvascular complications of dm . with an increase in morbidity of dm ,
the prevalence of dr has increased yearly , becoming the leading cause of visual impairment and blindness in working - aged people .
thus , it is important to characterize the incidence of dr and identify key factors for predicting it .
similar to other hospital - based epidemiologic studies in urban china , the prevalence of dr in the this study was 34.1% , which is much higher than in europe , the united states , south korea , and the other developed countries [ 17 , 18 ] .
this potentially reflects the higher incidence of dm in china   and the poor knowledge or less attention to the complications of dm , particularly dr . to reduce the prevalence of dm and slow down the progression of dr
, further efforts should be exerted on concerning the public health education of dm and the complications of it .
many studies have described the risk factors for dr , which primarily include the extended duration of dm , old age , hyperglycemia , hyperlipidemia , proteinuria , severe obesity , alcohol consumption , genetic factors , and the expression of a variety of hormones , such as growth hormone [ 2023 ] .
similarly , the present study confirmed that age , extended duration of dm , high blood sugar , high blood pressure , and hyperlipidemia were significantly associated with dr .
in addition , we also showed that egfr was negatively correlated with dr , consistent with previous studies [ 13 , 24 ] .
these results suggest that measurements of egfr might help to predict the early stage of dr .
then we successively conducted stratified analysis , interaction test , and covariate screening to get rid of the factors that affect the relationship between dr and egfr .
after the adjustment of these influence factors , the results still suggested that egfr was significantly associated with dr .
the graphical representation of the relationship between them displayed a two - stage pattern and that the value of egfr less than or equal to 99.4  ml / min was significantly correlated with dr .
the auc was 0.591815 , a value between 0.5 and 0.7 , indicating that the diagnostic value was not very useful , likely reflecting a bias in this study based on the fact that absence of the related variables with gfr , like urine protein or microalbumin .
in addition , recent studies have shown that the incidence of kidney disease in some diabetic patients was independent of dn , referred to as nondiabetic renal disease ( ndrd ) [ 25 , 26 ] .
dn and dr normally appear in the same person at the same time , so we can not artificially exclude the patients suffering from dn . however , ndrd patients may consist in the study population and their results could reduce the value of gfr , which affected the results of experimental .
gfr is an important indicator of kidney function and an important factor in the diagnosis of diabetic nephropathy .
although the direct relationship between gfr and other microangiopathy of dm has not been fully established , high levels of gfr have been negatively associated with the onset of macroangiopathy , such as coronary artery disease [ 28 , 29 ] .
a recent study has also confirmed that dr is closely associated with regional arterial stiffness .
many studies have confirmed that both dr and dn are microvascular complications with similar pathological bases , associated with dm [ 3133 ] . a report from the atherosclerosis risk in communities ( aric ) study demonstrated that retinopathy and renal dysfunction have a strong association , independent of age , diabetes , hypertension , and other risk factors .
systemic markers of inflammation and endothelial dysfunction associated with retinal vascular abnormalities could contribute to the development of kidney disease .
animal studies have also shown that pathological changes in the retina are highly associated with renal microcirculation . for dm patients , dr and dn have a common pathological basis and a similar course of evolution .
hyperglycemia causes glomerular hyperperfusion and high filtration , leading to an increase of gfr during the early stages of t2 dm .
the accumulation of advanced glycation end products , due to hyperglycemia , promotes mesangial proliferation and basement membrane thickening in the glomerulus .
in addition , the activation of the polyol pathway , the protein kinase c pathway , the pentose phosphate pathway , oxidative stress , and various cytokines cause a range of variations in kidney , which include capillary obstruction , a reduction of podocyte proliferation , the loss of the urinary proteins , and a decline in renal function . with further thickening of the glomerular basement membrane , the mesangial matrix increases , resulting in the appearance of cracks and an increase in urinary protein leakage .
accordingly , changes in gfr appear earlier than those in urine protein levels , and these changes remain throughout the entire course of dm .
the pathological mechanisms described above are similar to those observed in the retina . as in the kidney ,
the high blood sugar exerts deleterious effects on the retina , which include the apoptosis of muller cells , ganglion cells , and pericytes , the thickening of the capillary basement membrane , and the proliferation of endothelial cells in the retina . these effects lead to pathological changes in dr , including nonperfusive capillaries , the appearance of microaneurysms , and exudation .
hence , gfr not only may be an important clinical marker for dn , but also could be correlated with dr .
taken together , these data highlight the use of egfr as a predictor of dr . however , the results of the present study are important to the primary hospital for dr screening , especially to the ones with limited resources in china .
first , this study was a retrospective case - control study , including hospital - based patients with dm .
second , dr was diagnosed using ophthalmoscopy and fundus photography , but not fundus fluorescein angiography ( ffa ) .
third , the gfr values were estimated by formula , and some of the factors associated with gfr , such as urinary protein excretion or microalbuminuria , were not included in this study .
therefore , a long - term follow - up study should be performed in the future . moreover
, more factors should be included in this study to provide an in - depth examination of the relationship and mechanism of gfr and dr . in summary ,
the results of the present study indicate that gfr may have certain implications for dr , which is important to dr screening in primary hospital of china , especially in poverty - stricken areas .
 diabetic retinopathy ( dr ) is the leading cause of visual impairment and blindness in working - aged people . 
 several studies have suggested that glomerular filtration rate ( gfr ) was correlated with dr . 
 this is a hospital - based study and the aim of it was to examine the relationship between the gfr and dr in patients with type 2 diabetes mellitus ( t2 dm ) . 
 we used ckd - epi equation to estimate gfr and spss 19.0 and empowerstats software to assess their relationship . among the 1613 participants ( aged 54.75  12.19 years ) , 550 ( 34.1% ) patients suffered from dr 
 . 
 the multivariate analysis revealed that the risk factors for dr include age ( p < 0.001 , or = 0.940 ) , duration of diabetes ( p < 0.001 , or = 1.163 ) , hemoglobin a1c ( p = 0.007 , or = 1.224 ) , systolic blood pressure ( p < 0.001 , or = 1.032 ) , diastolic blood pressure ( p = 0.007 , or = 0.953 ) , high density lipoprotein cholesterol ( p = 0.024 , or = 3.884 ) , and egfr ( p = 0.010 , or = 0.973 ) . through stratified analysis and saturation effect analysis , 
 our data suggests that egfr of 99.4  ml / min or lower might imply the early stage of dr in diabetic patients . 
 thus , the evaluation of egfr has clinical significance for the early diagnosis of dr . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion