| Background and ObjectiveAccounting for more than 30%of global deaths,cardiovascular disease(CVD)is the leading cause of mortality worldwide.Despite the significant increase in public awareness of CVD hazards in recent years,CVD deaths still top the list of total causes of death among urban and rural residents in China,with 43.81%among urban residents and 46.66%in rural areas.As the largest developing country with a large population base,China faces the colossal burden of CVD.Meanwhile,the 2015 World Alzheimer’s Disease Report states that about 46.8 million people worldwide currently suffer from dementia,and the prevalence of dementia in China is estimated at 6.19%.A population base of over 1.4 billion means that China also has the highest burden of dementia disease.Reduced arterial elasticity and increased arterial stiffness are the most common causes and independent risk factors for common chronic CVD and have also been shown to be associated with white matter destruction and cognitive impairment.In addition to being an independent predictor of cardiovascular disease risk,large arterial stiffness is a high-priority efficacy indicator for improving the global burden of cardiovascular disease.There is an inextricable link between kidney disease and cardio-cerebrovascular disease,and chronic kidney disease(CKD)is recognized as a major risk factor for cardio-cerebrovascular disease.Cardio-cerebrovascular and its risk factors alter renal plasma flow and glomerular filtration through activation of the renin-angiotensin-aldosterone system as well as the sympathetic nervous system,among other pathways.In addition,cardiovascular disease combined with renal disease significantly increases the risk of death,with cardiovascular mortality being approximately two times higher in patients with CKD stage 3(e GFR of 30-59ml/min/173 m2)and three times higher in patients with CKD stage 4(e GFR of 15-29ml/min/173 m2)compared to those with normal renal function,using estimated glomerular filtration rate as a grading criterion for renal insufficiency.At the same time,hypertension,the most prevalent CVD in China,significantly increases the risk of cardio-cerebrovascular disease and CKD.Kim CS et al.showed that the risk of end-stage renal disease in non-CKD hypertensive patients increased 1.35 to 2.28 times with increasing blood pressure load,and the increased risk was more significant in patients with combined CKD.While most of the above studies are based on estimating reduced glomerular filtration rate(e GFR),in recent years,an increasing number of studies have found that high levels of e GFR are also independently associated with adverse outcome events,such as:cardiovascular events,diabetes and prediabetes,depression,cancer,and decreased renal function.However,most of the aforementioned studies are in the general population or diabetic population,and there are no reports on the association of high e GFR levels with all-cause mortality,first stroke,and related efficacy indicators,such as arterial stiffness and cognitive function,in the hypertensive population.Angiotensin-converting enzyme inhibitors(ACEI)are a class of antihypertensive drugs with renoprotective effects and have been shown to improve renal hyperfiltration status,but it is unclear whether the conclusion that high e GFR is associated with adverse outcomes is still supported in the hypertensive population treated with ACEI drugs,and it is proposed to further investigate the effect of ACEI antihypertensive therapy on renal function and adverse outcomes.Based on the above study background,the aim of this study was to investigate the following study objectives:(i)the association between e GFR and arterial stiffness assessed by brachial-ankle pulse wave velocity(ba PWV)in a hypertensive population without CKD;(ii)the association between high e GFR levels and cognitive dysfunction;and(iii)the relationship between renal hyperfiltration and first-ever stroke and all-cause mortality in a population receiving an ACEI class-based antihypertensive regimen.MethodsChapters 1&2:Analyses were performed using real-world hypertensive population data from the China H-type Hypertension Registry Study.Dose-dependent associations of e GFR level with ba PWV and MMSE scores were estimated by generalized additive regression models and smoothing curves(penalized spline method),respectively.Since the formula for calculating e GFR involves serum creatinine,age,BMI,and sex,covariance inflation factors were used to test for covariance in order to avoid incorrect results due to covariance between these variables and e GFR.If nonlinear associations were detected in the regression analysis model,we would further apply a two-segment regression model to test for threshold effects of e GFR with ba PWV and MMSE scores.Turning points were determined using likelihood ratio tests and bootstrap resampling methods.Considering the sample size,when verifying the nonlinear relationship between e GFR and ba PWV,e GFR levels were divided into 12 groups at intervals of 5ml/min/1.73m~2,and the interval containing the turning point was used as the reference group for multivariate regression analysis.In Chapters 2,e GFR levels were divided into 8 groups at an interval of 10 ml/min/1.73m~2,and the interval containing the turning point was used as the reference group to verify the nonlinear relationship between e GFR values and MMSE scores and dementia.As a further exploratory analysis,stratified analysis and interaction tests assessed the stability of the association of e GFR levels with ba PWV and MMSE scores in different subgroups of the population.Chapters 3:Data from the Chinese Stroke Primary Prevention Study(CSPPT)renal subgroup study were used.Renal hyperfiltration was defined as e GFR levels greater than the 95th percentile after sex and age quintile.This study defined the normal glomerular filtration as the e GFR value between the 25th and 75th percentile after sex-age stratification.Cumulative event rates for the first stroke and all-cause death in the total population were estimated using Kaplan-Meier for the normal glomerular filtration group and renal hyperfiltration group.Relative risk ratios for the first stroke and all-cause death after full adjustment for covariates were estimated using Cox proportional risk regression models,and consistency of results across subgroups of individuals was assessed by stratified analysis and interaction tests.ResultsChapter 1:A total of 4371 hypertensive participants were included in this study,of whom 2127(48.7%)were male patients with a mean age of 63.9±9.3 years.The mean e GFR level was 91.1±13.4 ml/min/1.73 m~2 and the mean ba PWV level was 1837.2±402.5 cm/s.The smooth fitting curve of the fully adjusted model suggested a“J”curve for the association between e GFR and ba PWV,with a linear positive association between e GFR and ba PWV on the right side inflection point.The threshold analysis for e GFR level was evaluated by developing two-segment multivariate regression models,and the result indicated a best-fit inflection point of 101.82 ml/min/1.73 m~2.Theβvalue of ba PWV was-3.99(95%CI:-14.78,6.80)and 41.09(95%CI:4.30,77.89)on both sides of the inflection point,respectively,indicating that ba PWV increased by 41.09 cm/s for each 1-unit increase in e GFR among population with e GFR≥101.82 ml/min/1.73m~2.Chapter 2:9527 hypertensive patients entered the analysis of the association between e GFR and cognitive function;the mean age of these individuals was at 63.7±9.8 years and 67%(4755 cases)were female.The mean MMSE score was 22.1±6.4 and the mean e GFR level was 86.3±19.6 ml/min/1.73m~2.The association between e GFR values and MMSE scores was nonlinear in the smooth fitting curve,with both high and low e GFR levels associated with lower MMSE scores and worse cognitive performance,whereas participants with moderate levels of e GFR performed better on cognitive assessments.The two-segment regression model yielded a best-fit turning point of 71.52ml/min/1.73 m~2.Among participants with e GFR<71.52 ml ml/min/1.73 m~2,MMSE scores increased significantly with increasing e GFR levels(for each 10 ml/min/1.73m~2 increase in e GFR value:β,0.27;95%CI:0.12,0.41);while participants with e GFR≥71.52 ml/min/1.73 m~2,the trend was reversed(for each 10 ml/min/1.73 m~2 increased in e GFR value:β-0.28;95%CI:-0.39,-0.17).In the subgroup analysis of participants with e GFR≥71.52 ml/min/1.73 m~2,the negative association between e GFR and MMSE was more significant in women and in BMI≥24 kg/m~2.Chapter 3:755 participants in the CSPPT renal sub-study who met the definition of renal hyperfiltration and 7548 in the normal glomerular filtration range were included in the study.Of these,3244(39.1%)were male,with a mean age of 59.5±7.6 years and a mean e GFR value of 97.6±8.4 ml/min/1.73 m~2.During a median follow-up of 4.3years,253 cases of first stroke and 210 all-cause deaths were collected for the endpoint event.Kaplan-Meier curves for cumulative event rates suggested that there was no significant difference in the incidence of first stroke events between the normal glomerular filtration and renal hyperfiltration groups.Still,all-cause mortality was significantly higher in the ultrafiltration group than in the normal glomerular filtration group.The Cox proportional risk model showed HRs of 0.96(95%CI:0.61,1.52)and1.55(95%CI:1.04,2.33)for the first stroke and all-cause mortality,respectively.ConclusionsIn the Chinese hypertensive population,high e GFR levels were independently and positively associated with ba PWV and cognitive impairment.After adjusting for sex and age,higher e GFR levels were accompanied by increased arterial stiffness and decreased cognitive performance.Furthermore,in a Chinese hypertensive population receiving an enalapril-based blood-pressure-lowering regimen,baseline renal hyperfiltration status was an independent risk factor for all-cause mortality but not for the first stroke.During a median follow-up of 4.3 years,the risk of all-cause death was1.55 times higher in the renal hyperfiltration group than in the normal renal glomerular filtration group.This study brings renal hyperfiltration status to the forefront,suggesting that renal hyperfiltration,like renal insufficiency with low e GFR levels,requires urgent attention from clinicians and public health practitioners. |
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