elucidating sex differences in diabetes is a necessary step toward personalized medicine and improved public health [ 13 ] . there is growing evidence to indicate that diabetic females have a greater relative risk of cardiovascular disease ( cvd ) than diabetic males [ 49 ] . the japan public health centre - based prospective study revealed that diabetes was associated with an increased risk of death by cvd : hazard ratio ( hr ) 1.76 [ 95% confidence interval ( ci ) , 1.532.02 ] for males , and hr 2.49 [ 95% ci , 2.063.01 ] for females . several possible explanations for the increased risk in females with diabetes were suggested , including the greater impact of cvd risk factors and/or diabetes on cvd [ 6 , 912 ] , a heavier burden of cvd risk factors due to disparities in medical treatment [ 4 , 5 , 7 , 9 , 10 , 12 ] and lower achievement rates of target blood pressure values and lipid and glycemic profiles , even when they are treated similarly to males [ 4 , 79 , 13 ] . furthermore , recent studies suggest that the increased diabetes - related risk of cvd in females is strongly associated with the chronic increase of their cvd risk profile , both in impaired glucose tolerance ( igt ) and in impaired fasting glucose ( ifg ) states [ 4 , 8 , 10 , 12 , 14 ] . reported that females who progressed from normoglycemia to a prediabetic state ( fasting glucose : 100125  mg / dl ) showed greater endothelial dysfunction and a greater degree of fibrinolysis / thrombosis than males . these findings may emphasize the importance of early aggressive therapeutic interventions to prevent diabetic vascular complications in females . recently , there has been increasing interest in the sex differences in the development of microvascular as well as macrovascular complications in patients with diabetes . we previously reported that japanese females with type 2 diabetes mellitus ( t2 dm ) exhibit a higher incidence of diabetic retinopathy ( dr ) ( hr , 1.85 ; 95% ci , 1.063.24 ) and are at greater risk for progression to proliferative diabetic retinopathy ( pdr ) [ odds ratio ( or ) , 2.62 ; 95% ci , 1.384.98 ] than males . in that study , the incidence of pdr at baseline was significantly higher in females than in males , and a delay in diagnosis seemed to play a crucial role in the increased risk of dr in females . on the other hand , few studies have focused on the association between sex and the development of nephropathy in t2 dm patients , and it remains to be definitely determined whether a sex difference exists . several clinical reports suggest that , although the risk of development and progression of nondiabetic renal disease is lower in females than in males , such protections against renal dysfunction seem to disappear in hyperglycemic females [ 10 , 16 ] . based on the facts stated above , we hypothesized that in females with t2 dm a delayed diagnosis and a poorly controlled risk profile may have a greater impact on the progression of early stage nephropathy than that which is observed in males . on the basis of this information , the present exploratory study investigated the sex differences in longitudinal renal function among t2 dm patients , with a focus on the differences in the risk factors at early stage of renal dysfunction . in this clinic - based retrospective longitudinal study , the records of 1,515 consecutive t2 dm patients who visited the jinnouchi clinic , diabetes care center in kumamoto , japan , between february 2002 and january 2011 were reviewed . among them , the patients who had been treated at the clinic for less than five years , those who were over 65 years of age at baseline , and/or those with incomplete data were excluded . the study protocol was approved by the institutional ethics committees and written informed consent was obtained from each subject . the patient 's characteristics at their first visit ( baseline ) and during follow - up were obtained from their medical records . t2 dm was diagnosed according to the criteria of the japan diabetes society ( jds )   or based on the patient 's history of t2 dm . the value of hemoglobin a1c ( hba1c ) was originally calculated using the jds method and then converted to the internationally used hba1c , as defined by the national glycohemoglobin standardization program . the body mass index ( bmi ) was calculated by dividing the weight in kilograms by the square of the height in meters . hypertension was defined as a systolic blood pressure ( sbp ) value of 140  mmhg , a diastolic blood pressure ( dbp ) value of 90  mmhg , and/or a history of hypertension . dyslipidemia was defined by the following serum concentrations : total - cholesterol , 5.2  mmol / l ; low - density lipoprotein ( ldl ) cholesterol , 3.4 mmol / l ; high - density lipoprotein ( hdl ) cholesterol , < 1.0  mmol / l ( in males ) or < 1.3  mmol / l ( in females ) ; triglycerides , 1.7  mmol / l ; and/or a history of dyslipidemia . dr was classified , according to the criteria determined at the third national ophthalmology conference held in 1985 , into the following stages : no retinopathy , nonproliferative diabetic retinopathy ( npdr ) , or pdr . the estimated glomerular filtration rate ( egfr ) was calculated using the japanese egfr - estimating equation : egfr ( ml / min/1.73  m ) = 194  scr   age   0.739 ( if female ) . the japanese egfr - estimating equation has a relatively little bias across a wide range of gfr values in the japanese population and is thus recommended for use in japanese individuals by the japanese society of nephrology [ 21 , 22 ] . an egfr decline of > 4% per year was considered to be a rapid decline in egfr [ 21 , 23 ] . the data are presented as the mean  standard deviation ( sd ) or standard error ( se ) and number ( % ) . the continuous variables were compared by student 's t - test or a one - way anova ; the categorical variables were compared by fisher 's exact test . for each patient , a univariate linear regression model of time versus egfr ( least - squares method ) was created , and the slope of the regression line was used to estimate the patient 's changes in egfr over the observational period , in accordance with the methods of a previous study . the egfr slope was expressed as percentage per year by dividing the slope by the baseline egfr value ( i.e. , the annual egfr change ) . sex differences in annual egfr decline were assessed using multivariate linear regression analysis with calculation of unstandardized partial regression coefficient ( b ) adjusted for age , dr , proteinuria , diabetes duration , hba1c , sbp , ldl - cholesterol , overweight , and ever - smoking . additionally , in order to identify the possible predictors for annual egfr decline , we performed linear regression analyses in which the standardized partial regression coefficient (  ) was calculated separately in males and females . the baseline characteristics including dr , proteinuria , diabetes duration , hba1c , sbp , ldl - cholesterol , overweight , and ever - smoking were considered as the possible predictors of renal function decline . a p value of < 0.05 in the univariate model was adopted as the entry criterion for variables to be included in the multivariable models . all  were adjusted for the patient 's age . furthermore , the interaction between sex and each of the factors with the annual egfr decline was assessed using a multivariable linear model . in this model , the effects of the combination of sex and metabolic status abnormalities such as hba1c ( 7.0% , i.e. , 53.0  mmol / mol ) , ldl - cholesterol ( 3.4  mmol / l ) , and sbp ( 140  mmhg ) on the annual egfr decline were also assessed . the longitudinal associations between sex and these clinical parameters were analyzed using the generalized estimating equations approach . autoregressive models were applied for the analyses with the calculations of the b and the or and 95% ci . all of these calculations were performed using the data obtained over the entire observational period in each patient . to verify the results of the above - mentioned analyses , a supplementary analysis was performed using propensity score ( ps ) matching in order to reduce selection bias and confounding bias . the variables included in the ps matching model are age , diabetes duration , dr , hba1c , proteinuria , sbp , and ldl - cholesterol at baseline . female patients were matched in a 1  :  1 ratio with male patients , using the nearest neighbor matching algorithm without replacement on the logit of the ps using a caliper of width equal to 0.001 sd of the logit of the ps . in addition , bootstrap analyses were performed to validate the findings for sex differences in renal function decline . one thousand replicated datasets were generated by random sampling with replacement and stratified according to the study population , including total study patients ( i.e. , unmatched ) and ps - matched patients , to ensure a representative study population distribution using the individual as the sampling unit . a two - tailed p value of < 0.05 was considered to be statistically significant . multiple comparisons were corrected using bonferroni 's method , and p values of < 0.05/n were considered to be statistically significant after correcting for the number of comparisons . ps matching was performed with a contributed r package (  matching  ) using the r software program ( version 3.0.0 , r foundation for statistical computing , vienna , austria ) . other statistical analyses were performed using the spss software package for windows ( version 23.0 , ibm japan ltd . , tokyo , japan ) . among 1,515 patients with t2 dm , the results of the subjects who had been followed for less than five years ( n = 946 ) were considered to be inadequate for the assessment of longitudinal changes of renal function . we further excluded patients who were older than 65 years of age at baseline ( n = 174 ) and/or those with incomplete data ( n = 51 ) ; consequently 344 subjects ( 247 males and 97 females ) were included in the analysis . the mean observation period of the 344 subjects in the present study was 8.1  1.4 years ( 2,800 person - years of follow - up ) . the prevalence of dr , sbp , and ldl - cholesterol values was significantly higher in females than in males . the mean annual change in egfr was 3.5  2.7%/year in females and 2.0  2.2%/year in males ( p < 0.001 ) , and female sex was significantly associated with a larger decline of egfr ( b , 1.025 ; 95% ci , 1.6450.405 ) . a greater number of females were  rapid decliners  compared to males ( 34.0% versus 17.4% , p = 0.001 ) . the egfr values at the endpoint were 60  ml / min/1.73  m in 285 subjects ( 209 males and 76 females ) , 3059.9  ml / min/1.73  m in 46 subjects ( 32 males and 14 females ) , and < 30  ml / min/1.73  m in 13 subjects ( 6 males and 7 females ) . all of patients with endpoint egfr values of < 30  ml / min/1.73  m were rapid decliners . table 2 presents the results of the univariate and multivariable linear regression analyses , separated by sex . in both sexes , the baseline dr and proteinuria were significantly associated with a larger decline of egfr after multivariable adjustment . hba1c and ldl - cholesterol were significantly associated with an annual egfr decline in females only . furthermore , interactive effects were observed between sex and the dr , proteinuria , hba1c , or ldl - cholesterol levels on the annual egfr decline ( p < 0.05 ) , indicating that females with these risk factors were at a greater risk of egfr decline . the statistical significance of the associations of diabetes duration and sbp with renal function decline disappeared after the multivariable adjustment . table 3 shows the effects of the combination of sex and metabolic status abnormalities on annual egfr decline . females with poor hba1c and/or ldl - cholesterol control showed a significantly greater annual egfr decline than males with good control ; however , this difference was not observed in females with good control . the combination of sex and sbp control did not have a statistically significant effect on the annual egfr decline . table 4 shows the mean values for metabolic profiles during the observation period and the longitudinal influence of female sex on the mean values and the risks for abnormal metabolic profiles . the mean ldl - cholesterol level in females remained higher during the initial four years of the observation period . although the mean hba1c level in females did not differ markedly from that in males , the longitudinal association analyses showed that females had poorer control of their hba1c and ldl - cholesterol levels compared to males during the observation period . table 5 shows the clinical characteristics of 41 females and 41 ps - matched males . the basal characteristics were not different between the males and the females , and their hba1c , ldl - cholesterol , and sbp level were not well controlled . the females exhibited a greater annual egfr decline than the males ( 3.3  2.5%/year versus 1.7  1.6%/year , p = 0.001 ) . the results using 1,000 replicated datasets by the bootstrap approach further confirmed that females exhibited a larger annual egfr decline than males in both unmatched ( median b value , 1.025 ; 95% ci , 1.5970.457 ) and ps - matched populations ( 3.3  2.5%/year versus 1.7  1.6%/year , p = 0.004 ) . in the present study , females exhibited a significantly greater decline in renal function than males , and the results from the ps matching model supported this association . hba1c and ldl - cholesterol were significantly associated with annual egfr decline in females only . these preliminary findings suggest that the association between poor metabolic control and annual egfr decline is more common in females . moreover , this study is , to our knowledge , the first report to show that the association between retinopathy and rapid renal function decline is more pronounced in females than in males . it has been proposed that different mechanisms underlie the development of diabetic vascular complications in females and males [ 10 , 25 ] . previous studies have revealed stronger relationships between retinopathy and cvd   and between renal dysfunction and cvd   in females . taken together , the diabetic vascular complications in females were considered to be highly related to each other and there may be female - specific risks and/or a vulnerability to vascular dysfunction underlying these relationships . in this study , female sex was significantly associated with a larger decline of egfr ( b , 1.025 ; 95% ci , 1.6450.405 ) , and rapid decliners were found more often in females ( 34.0% ) than in males ( 17.4% ) . a recent meta - analysis , which included more than 200,000 individuals with type 1 diabetes , revealed that the pooled female - to - male ratio of the standardized mortality ratio for fatal renal disease was 1.44 ( 95% ci 1.022.05 ) . females with t2 dm have also been reported to be at a higher risk of diabetic nephropathy and renal dysfunction in previous studies [ 16 , 25 , 28 , 29 ] , while other studies have indicated a higher risk in males [ 16 , 30 ] . although the reason for the inconsistent results regarding sex differences in the risk of renal dysfunction in t2 dm patients is unclear , it may be due to disparities in the participants ' background characteristics and/or the various definitions of renal dysfunction . de hauteclocque et al . assessed rapid egfr decline using longitudinal serum creatinine data ( as we did in our present study ) and showed that male gender was independently associated with a rapid decline of renal function . in our study population , however , the baseline metabolic profile was obviously worse than in the population of this previous study   and was comparable to or slightly worse than those in the other studies that indicated a higher risk of renal dysfunction in females with diabetes [ 25 , 28 ] . it should also be noted that we examined a relatively early stage of renal dysfunction in this study . this is shown by the fact that only 17.2% of subjects exhibited an egfr of < 60  ml / min/1.73  m at the endpoint . thus far , it has been reported that females with t2 dm have a higher risk of severe renal dysfunction ( renal impairment defined as a decrease in cockcroft - gault estimated creatinine < 60  ml / min or a doubling of plasma creatinine )   and advanced diabetic kidney disease ( an egfr < 30  ml / min/1.73  m ) . the present study provided new information suggesting that among the japanese t2 dm patients , in whom baseline metabolic profiles of most subjects could not be controlled , females were at a higher risk of early - stage renal dysfunction . the females of the present study exhibited poorer metabolic statuses during the observation period , and baseline hba1c and ldl - cholesterol levels were associated with annual egfr decline in females only . in order to diminish the sex disparities in the baseline characteristics and to confirm whether the decline in renal function in females is greater than in males with similar baseline characteristics , we conducted a supplementary analysis using a ps matching model . in this supplementary analysis , where the baseline metabolic statuses of the males and females were equally poor , we confirmed that there was a greater annual egfr decline in the female subjects . it is well known that females ( especially younger females ) are more insulin sensitive and are at lower risk of vascular disease than males [ 8 , 14 ] . estrogen has various vasoprotective effects ( e.g. , vasodilation , lipid profile improvement , antioxidation , anti - inflammation , and antifibronic effects ) and plays an important role in this advantage of females [ 7 , 31 ] . in the kidney , estrogen activates metalloproteinase enzymes and nitric oxide synthesis , inhibits the renin - angiotensin system and mesangial cell proliferation , and reduces inflammation . in hyperglycemic states such as diabetes and prediabetes , however , these advantages of estrogen appear to be diminished or abolished [ 6 , 8 , 14 , 32 ] . females with t2 dm have been reported to exhibit a reduced productivity of estrogen in comparison to healthy counterparts , even in their twenties [ 7 , 33 ] . furthermore , patients with diabetes appear to exhibit an impaired balance of the estrogen receptors ( er and er ) . the increased expression or activation of er over er could induce a higher level of oxidative stress , a proinflammatory profile , and the increased formation of atherosclerotic plaque . it is considered that biologically , females in hyperglycemic states tend to exhibit a greater arteriosclerotic risk profile and greater endothelial dysfunction [ 6 , 8 , 14 , 32 ] , which suggests that both may have contributed to the increased vulnerability to vascular dysfunction ( such as diabetic nephropathy ) that was observed in the females of this study . to reduce the selection bias , we conducted a supplementary analysis using the ps matching model , a technique that has been used in other recent retrospective studies . although inexact or incomplete matching might have affected the results of this study , we matched male patients with 42.3% of the female patients , with a median standardized difference after matching of 0.08 , which indicates a satisfactory matching . in addition , we verified our findings using the bootstrap approach to address the small sample size . these validation results also indicated a greater decline in renal function in females than in males . second , in the present study , we used the japanese egfr - estimating equation , not the ckd epidemiology collaboration ( ckd - epi ) equation . however , even when analyzing our data using the ckd - epi equation for japanese population , females still exhibited a significantly greater decline in renal function than males ( 2.4  2.8%/year versus 1.6  1.7%/year , p = 0.009 ) . the findings obtained using the ckd - epi equation were generally comparable to those using the japanese egfr - estimating equation ( supplemental tables  13 ; see supplementary material available online at http://dx.doi.org/10.1155/2016/4626382 ) . third , the patients of our study population , which were from a diabetes care center , basically had poor metabolic control at their first visit . the higher risk of rapid renal function decline in females appears to manifest in such situations due to their biological vulnerability . thus , it should be taken into account that it remains unknown whether female sex is a risk factor for renal dysfunction in other populations , especially diabetic patients whose metabolic profiles are well controlled . fourth , information regarding the menopause status of the patients was not available in the present study . however , if we are to assume that menopause occurs between the ages of 45 and 55 , then the pre- and postmenopause age groups were not independently associated with rapid egfr decline . lastly , we could not assess the relationship between albuminuria and a rapid egfr decline due to a lack of data . therefore , further investigations in larger populations , which include longitudinal and quantitative data on albuminuria and serum creatinine levels and other laboratory / descriptive information , are needed to verify our findings . in summary , this exploratory longitudinal study showed that females exhibited a greater decline in renal function than males . an increased susceptibility to poor metabolic control might contribute to a higher risk of renal dysfunction in females with t2 dm . although further investigations are needed to verify these preliminary findings , we provided useful information on sex differences in renal dysfunction in patients with t2 dm . our study highlights the importance of the aggressive therapeutic interventions to improve metabolic profiles at an early stage , especially in females .
aims . we aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus ( t2 dm ) , focusing on the differences in the risk factors at early stage of renal dysfunction 
 . methods . a clinic - based retrospective longitudinal study ( follow - up duration : 8.1  1.4 years ) 
 was conducted to assess the sex differences in the annual estimated glomerular filtration rate ( egfr ) change in 344 ( 247 male and 97 female ) japanese t2 dm patients . 
 the sex differences in the risk factors of annual egfr decline were subjected to linear regression analyses . 
 results . 
 the mean annual egfr change was 3.5  2.7%/year in females and 2.0  2.2%/year in males ( p < 0.001 ) . 
 baseline retinopathy and proteinuria were significantly associated with a larger egfr decline , irrespective of sex , while hba1c and ldl - cholesterol levels were significantly associated with an egfr decline in females only . 
 interactive effects were observed between sex and the hba1c , ldl - cholesterol , retinopathy , or proteinuria levels on the annual egfr decline . 
 conclusions . 
 the increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with t2 dm . 
 our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage , especially in females .