Relationship Of Fasting Glucose Status With Glomerular Hyperfiltration And The Effect Of Hyperfiltration On The Development Of Renal Diseases Progression In Adults With Hypertension In China

Background:Chronic kidney disease?CKD?,characterized by chronic advancing loss of renal function,substantially elevates the risk of end-stage renal disease?ESRD?,cardiovascular diseases,and mortality.The prevalence of CKD,which has been increasing in recent decades,is exceeding 10%both in China and in the western world.Besides,because of poor awareness,difficulty in treatment and high cost,CKD now has received increased attention as a leading public health problem.Therefore,a better understanding of the modifiable risk factors of early renal dysfunction,for example,glomerular hyperfiltration and hypofiltration,leading to early detection and prevention,might alleviate the future burden of CKD and associated complications.Diabetes mellitus?DM?and hypertension have been recognized as the risk factor of CKD,and one of the main reasons of the end-stage renal disease?ESRD?.Due to the changes in life style and diet along with the economic development,rapid increase in the prevalence of risk factors such as diabetes and hypertension,At the same time,studies showed that the prevalence of coexisting of Diabetes and hypertension is very high.However,no study has system evaluated the association of fasting glucose levels with hyperfiltration and hypofiltration,the early and reversible stages of kidney damage in a hypertensive sample.Furthermore,Many studies have attempted to determine the predictive role of hyperfiltration for subsequent development of renal function damage,however,the study outcomes have been ambivalent.In conclude,in the current study,we aimed to evaluate the relationship of fasting glucose levels with glomerular hyperfiltration through cross-sectional and prospective research,and to examine the effect of glomerular hyperfiltration on the risk of the new onset proteinuria,rapid glomerular filtration decline and renal composite outcomes?the following serum creatinine level as the 1.5 times of the baseline value or the following eGFR value<15 mL/min/1.73 m² or needing maintain dialysis treatment?in a Chinese hypertensive cohort.Objectives:We first?Chapter 1:cross-sectional and Chapter 2:prospective?aimed to examine the relationship of fasting glucose levels with glomerular hyperfiltration and hypofiltration and possible modifiable factors,and then?Chapter 3?examine the effect of glomerular hyperfiltration on the risk of the new onset proteinuria,rapid glomerular filtration decline and renal composite outcomes?the following serum creatinine level as the 1.5 times of the baseline value or the following eGFR value<15 mL/min/1.73 m² or needing maintain dialysis treatment?.Methods:We conducted a community-based screening in 20 townships in Lianyungang of Jiangsu province,East China,from October 2008 to September 2009.This study was approved by the Institutional Review Boards from the Institute of Biomedicine in the Anhui Medical University in Hefei and the Institutional Review Boards from the Nanfang Hospital in Guangzhou.Written informed consent was obtained from each participant before data collection.Baseline data collection was conducted by trained research staff according to the standard operating procedure.Each participant was interviewed using a standardized questionnaire designed specifically for this study,including socio demographic status,occupation,diet,lifestyle,health behavior,disease and medical history,blood pressure,Anthropometric measurements,including height,weight and waist circumference,as well as blood tests were taken by trained research staff according to protocols described previously.After 12-15 hours of fasting,a venous blood and urine samples were obtained from all subjects.Serum and plasma were separated from blood cells in the field within 30 minutes and kept frozen at-20? and then transferred to a-80 ?refrigerator within one week,and kept frozen until be detected.Serum creatinine,lipids and glucose at both the baseline and the exit visit were measured using automatic clinical analyzers?Beckman Coulter,CA,USA?at the core lab of the National Clinical Research Center for Kidney Disease?Nanfang Hospital,Guangzhou,China?.Estimated glomerular filtration rate?eGFR?was calculated using the following equation derived from the Chronic Kidney Disease Epidemiology Collaboration?CKD-EPI?:eGFR = 141 x min?Scr/?,1?? x max?Scr/?,1?^-1.209 x 0.993Age ×1.018[if female]where Scr is serum creatinine[mg/dL],?is 0.7 for females and 0.9 for males,a is-0.329 for females and-0.411 for males,min indicates the minimum of Scr/?or 1,and max indicates the maximum of Scr/?ror 1.Chapter 1:Relationship of fasting glucose levels with glomerular hyperfiltration and hypofiltration in adults with hypertension in China.Diabetes status was defined using the following guideline derived from the the World Health Organization?1999?:?1?.IFG was defined as FPG 6.1-7.0mmol/L.?2?.Diabetes was defined as self-reported use of hypoglycemic agents or physician diagnosed diabetes or FPG of 7.0mmol/L or more.Renal hyperfiltration was defined as an absolute eGFR>90th percentile after adjusting for sex,age.This was done by selecting subjects without diabetes>90th percentile in the distribution of residuals from a multiple linear regression analysis where we used the eGFR as a dependent variable and age,sex as independent variables;while hypofiltration was defined as an eGFR<10th percentile and>60 mL/min/1.73m².The adjusted odds ratios?ORs?and 95%confidence interval?CI?of glomerular hyperfiltration and hypofiltration at different glucose status?IFG and Diabetes?were determined from multivariable logistic-regression models which included age,sex,BMI,systolic BP,diastolic BP,TC,uric acid levels,cigarette smoking status,use of anti-hypertensive drugs and glucose lowering drugs.We also perform the subgroup analyses stratified by the potential confounding factors,which were significantly associated with kidney dysfunction?hyperfiltration,hypofiltration?,including age?45-55,55-65,65-75years?,sex,BMI?<28,?28kg/m²,for 28 is the threshold value of obesity in China?,BP?grade 1:SBP<160 and DBP<100mmHg,grade 2:SBP 160-180 and/or DBP 100-110 mmHg,grade 3:SBP>180 and/or DBP>110 mmHg?and TC?<5.2,?5.2mmol/L?.Two-tailed P<0.05 was considered to be statistically significant in all analyses.Chapter 2:Association of fasting glucose levels with new onset glomerular hyperfiltration in adults with hypertension in China.The participants selected in this study were those with normal glomerular filtration on baseline.IFG and DM were defined as what we defined in chapter 1.The new onset hyperfiltration was defined as:the following eGFR residuals?from a multiple linear regression analysis where we used the following eGFR as a dependent variable and the following age,sex as independent variables?>90th percentile in the distribution of baseline residuals?from a multiple linear regression analysis where we used the eGFR as a dependent variable and age,sex as independent variables?.The new onset hypofiltration was defined as an following eGFR residuals<90th percentile and an eGFR value>60 mL/min/1.73m².The association of fasting glucose status?IFQ DM?with the new onset hyperfiltration and hypofiltration were estimated using logistic regression models with adjustment for baseline covariates including age,sex,eGFR,BMI,systolic BP,diastolic BP,TC,uric acid levels,cigarette smoking status,use of anti-hypertensive drugs and glucose lowering drugs,the following mean SBP,the following mean DBP.Chapter 3:The effect of hyperfiltration on the development of renal function declineThe primary outcome of interest was new onset proteinuria?dipstick proteinuria+ or more?;The secondary outcomes of interest were rapid eGFR decline,defined as a decline of eGFR of greater than 3 mL/min/1.73m²/year;and renal composite outcome,defined as the following serum creatinine level as the 1.5 times of the baseline value or the following eGFR value<15 mL/min/1.73m² or need dialysis treatment.The effects of glomerular hyperfiltration and hypofiltration on the risks of RFD,renal composite outcome,and new incident CKD were estimated using logistic regression models with adjustment for baseline covariates including age,sex,BMI,systolic BP,diastolic BP,TC,uric acid levels,cigarette smoking status,use of anti-hypertensive drugs and glucose lowering drugs,and the following mean SBP and DBP.Two-tailed P<0.05 was considered statistically significant in all analyses.R software,version 2.15.1?http://www.R-project.org/?was used to perform all statistical analyses.Results:Chapter 1:Overall,19,884 subjects aged 45-75 years with hypertension were screened.387 participants had their eGFR<60 mL/min/1.73m²,1,243 participants had one or more missing baseline values in age,BP,height,smoking status,fasting glucose,serum creatinine,TC,We excluded above subjects in our analyses,resulting in a final sample size of 18,254?6,652 males and 11,602 females?.Both the cut-points for hyperfiltration and hypofiltration decreased with age increased,ranging from 115 to 91 mL/min/1.73m² and 91 to 67 mL/min/1.73m²,respectively.In the multiple logistic models,IFG was positively associated with glomerular hypofiltration?OR:1.17,95%CI:1.04-1.30?,while diabetes was positively associated with glomerular hyperfiltration?OR:2.19,95%CI:1.93-2.47?and hypofiltration?1.24,1.05-1.46?.Furthermore,the stronger association between diabetes and hyperfiltration was found in those with younger age?45-55 years old:3.14,2.49-3.96,55-65 years old:2.18,1.82-2.61 versus 65-75 years old group:1.47,1.16-1.87,P for interaction<0.001?,or higher total cholesterol?TC?levels?2.33,2.02-2.68 in TC ? 5.2mmol/L versus 1.77,1.39-2.25 in TC<5.2mmol/L,P for interaction=0.008?.Consistently,significant association between diabetes and hypofiltration was only observed in participants with younger age?45-55 years old:1.63,1.21-2.19 versus 55-65 years old:1.25,0.98-1.59 and 65-75 years old:0.91,0.65-1.26,P for interaction= 0.043?.And detrimentally interaction between diabetes and higher TC levels was also found?TC>5.2mmol/L:3.93,2.93-5.26 versus TC<5.2mmol/L:1.54,0.81-2.91,P for interaction<0.001?on the risk of reduced eGFR.Chapter 2:Participants selected in this study were those with normal glomerular filtration?2,066 with hyperfiltration,1,579 with hypofiltration were excluded?on baseline.2,526 participants had the following serum creatinine missing.We excluded above subjects in our analyses,resulting in a final sample size of 12,083?4,302 males and 7,781 females?.Of the 12,083 participants,the incidence of glomerular hyperfiltration and hypofiltration during the 4.5-year follow-up?Inter-quartile Range:4.2-4.6?was 9.2%and 7.3%,respectively.Participants with IFG or DM both had significantly higher risk of the new onset hyperfiltration.In the multiple logistic models,the ORs?95%CI?of hyperfiltration are 1.33?1.11,1.60?,1.56?1.26,1.93?for IFG and DM,respectively in cohort 1,and 1.94?1.33,2.84?,1.58?0.99,2.50?for IFG and DM,respectively in cohort 2.Furthermore,we did not find any difference of the their association between any subgroups,for example,different baseline age,sex,BMI,BP levels,the following mean SBP and DBP levels?P for interaction>0.05?.However,IFG,DM were not associated with the new onset hypofiltration.Chapter 3:Overall,16,162 subjects?2479 participants in cohort 2 were excluded?aged 45-75 years with hypertension were screened.3,606 participants had one or more missing baseline values in the fasting glucose,serum creatinine,dipstick proteinuria,total cholesterol,387 participants had an eGFR<60 mL/min/1.73m²,957 participants had hypofiltration.We excluded above subjects in our analyses,resulting in a final sample size of 10,890?4,205 males and 6,685 females?.Of the 10,890 participants,the incidence of new onset proteinuria,rapid glomerular filtration decline and renal composite outcome during the 4.4-year follow-up?Inter-quartile Range:4.2-4.6?was 4.0%,16.9%and 2.8%,respectively.In the multiple logistic models,the risk for new onset proteinuria,rapid glomerular filtration decline and renal composite outcome significantly increased in participants with hyperfiltration compared to those with normalfiltration,the OR?95%CI?was 1.34?1.03,1.74?,1.81?1.58,2.08?and 7.15?5.62,9.09?.Exclusion of the subjects with diabetes at baseline did not change the association of hyperfiltration with new onset proteinuria?n=9,520;OR:1.33,0.97-1.82?,rapid glomerular filtration decline?1.67,1.47-1.96?,renal composite outcome?7.44,5.66-9.77?.Furthermore,the stronger association of hyperfiltration with new onset proteinuria was found in those with higher level baseline blood pressure?ORs are 1.46,0.95-2.25 in those with SBP>180 and/or DBP>110 mmHg,and 1.26,0.90-1.76 in those with SBP<180 and DBP<110 mmHg,P for interaction<0.001?.However,we did not find any difference of their association in the other subgroups,for example,age,gender,different baseline BMI,the following mean SBP and DBP levels,baseline fasting glucose,total cholesterol,uric acid?P for interaction>0.05?.Conclusions:1)Diabetes was significantly associated with glomerular hyperfiltration and hypofiltration,particularly in those with younger age or with higher TC levels;2)The risk for new onset glomerular hyperfiltration significantly increased in participants with IFG or DM compared to those with normal glycemia;3)The risk for new onset proteinuria,rapid glomerular filtration decline and renal composite outcome significantly increased in participants with hyperfiltration compared to those with normalfiltration,and their associations were much stronger among the higher baseline BP level participants.