Prevalence, clinical predictors, and prognostic impact of chronic

ORIGINAL ARTICLEPrevalence,clinical predictors,and prognostic impact of chronic renal insufficiency in very old Chinese patients with coronary artery diseaseShihui Fu •Shuangyan Yi •Bing Zhu •Yuan Liu •Liang Wang •Yongyi Bai •Ping Ye •Leiming LuoReceived:12August 2012/Accepted:12February 2013/Published online:13June 2013ÓSpringer International Publishing Switzerland 2013AbstractBackground and aims An aging population leads to the increased prevalence of coronary artery disease (CAD)and chronic renal insufficiency (CRI).Nevertheless,the prev-alence,clinical predictors,and prognostic impact of CRI in very old Chinese patients with CAD are unclear.Methods Baseline characteristics were obtained from 1,050old patients with CAD.The endpoint was all-cause mortality during the mean follow-up period of 417days.Results The median age of the subjects was 86years (range 60–104years).CRI was present in 372patients (35.4%).Age [hazard ratio (HR)1.032,95%confidence interval (95%CI) 1.010–1.054],chronic heart failure (CHF)(HR 2.361,95%CI 1.747–3.191),hypertension (HR 1.878,95%CI 1.291–2.731),hemoglobin (HR 0.973,95%CI 0.965–0.981),serum albumin (HR 0.954,95%CI 0.912–0.995),HDL-C (HR 0.371,95%CI 0.238–0.580),and LDL-C levels (HR 0.795,95%CI 0.656–0.965)were independent predictors of CRI (all P \0.05).In addition,CRI was independently associated with mortality in patients with CAD (HR 1.366,95%CI 1.024–1.822,P =0.034).Age (HR 1.036,95%CI 1.015–1.059),acute myocardial infarction (AMI;HR 1.795,95%CI 1.239–2.602),CHF New York Heart Association class IV (HR 1.691,95%CI 1.187–2.410),heart rate (HR 1.019,95%CI 1.011–1.026),hemoglobin (HR 0.982,95%CI 0.975–0.990),and serum albumin levels (HR 0.905,95%CI 0.874–0.938)were also independently related to mor-tality in CAD patients (all P \0.05).Conclusions A high prevalence of CRI with a high associated mortality rate existed in very old Chinese patients with CAD.CRI was an independent risk factor of adverse prognosis for these patients,and multiple predic-tors could be used to identify CAD patients at increased risk for CRI or poor survival.Keywords Coronary disease ÁChronic renalinsufficiency ÁPrevalence ÁPredictive value of tests ÁPrognosisIntroductionOn a global scale,evolving changes in demographics have led to an aging population along with an increased preva-lence of chronic renal insufficiency (CRI)in patients with coronary artery disease (CAD).A cross-sectional study using data from the China Heart Survey demonstrated that Chinese adults with CAD had a high prevalence of CRI (24.8%)[1];however,a higher prevalence of CRI may exist in very old Chinese with CAD,who were under-rep-resented in that study.Because CRI plays an important role in the progression and adverse outcome of cardiovascular disease [2–4],the co-occurrence of CAD and CRI may result in a higher mortality rate.Because the population becomes much more heterogeneous as age increases and co-morbidities develop (e.g.,CRI),the ability of traditional risk factors to predict mortality accurately in these patients has been a subject of debate,suggesting that a search for other risk factors should be undertaken.However,most related studies have been based on relatively young patients,and very few studies have focused on very oldS.Fu and S.Yi were the co-first authors.S.Fu ÁS.Yi ÁB.Zhu ÁY.Liu ÁL.Wang ÁY.Bai ÁP.Ye ÁL.Luo (&)Department of Geriatric Cardiology,Chinese PLA General Hospital,Haidian District,Beijing 100853,China e-mail:lleim@Aging Clin Exp Res (2013)25:385–391DOI 10.1007/s40520-013-0059-0patients[5].In addition,race and national conditions always have important influences on the prevalence,outcome,and risk factors of CRI in very old patients.Most of the studies that have reported the impact of CRI on mortality in CAD patients only included Caucasians and African-Americans, and such studies are limited in China[6].We conducted a survey which sought to determine the prevalence and mortality of CRI in very old Chinese patients with CAD,identify the clinical predictors of CRI, evaluate the impact of CRI on mortality,and screen risk factors for mortality in very old patients with co-existing CAD and CRI.MethodsStudy populationThis study included1,050Chinese patients(C60years of age)diagnosed with CAD.The diagnoses based on history, symptoms of typical angina,cardiac markers and specific cardiac tests,such as electrocardiogram(resting/exercise), echocardiogram,radionuclide imaging,computed tomog-raphy(CT)and coronary arteriography,were made by chief physicians or associate chief physicians according to the American College of Cardiology(ACC)/American Heart Association(AHA)/European Society of Cardiology(ESC) guidelines[7–9].Of the1,050CAD patients,741had stable CAD,238had unstable angina,and71had acute myocar-dial infarction(AMI).The exclusion criteria included severe aortic stenosis,anticipated cardiac transplantation, and use of a left ventricular assist device.Each participant provided written informed consent to be included in the study.Our study protocol was approved by the Ethics Committee of the Chinese People’s Liberation Army(PLA) General Hospital(Beijing,China)and in accordance with the Helsinki Declaration of1975(as revised in1983).The baseline characteristics were collected from all patients after admission to the Chinese PLA General Hospital(from October11th,2007to July2nd,2011);the patients were followed for an average of417days(median 319days;75%range185–557days).The baseline char-acteristics of subjects available for this study included demographics(age and gender),lifestyle(smoking),mea-surements obtained during physical examination[height, weight,heart rate,systolic and diastolic blood pressure (SBP and DBP)],laboratory measurements[hemoglobin, high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),triglyceride,and fasting plasma glucose(FPG)].After asking patients or their family members to describe their symptoms,the New York Heart Association(NYHA)functional classification system was used to assess the stage of chronic heart failure(CHF).In all1,050subjects(100%),glomerularfiltration rate (GFR)was calculated by the modified Modification of Diet in Renal Disease(MDRD)equation based on data from Chinese CRI patients,as follows:1759serum creatinine (mg/dl)-1.2349age(years)-0.17990.79(if female)[10].A standard echocardiogram was performed and several structural parameters were assessed.Left ventricular ejec-tion fraction was measured by Simpson’s method[11].Left ventricular mass was calculated as the formula described by Devereux et al.[12],and left ventricular mass index was obtained by dividing the left ventricular mass by the body surface area.Smoking status was categorized as current, former,and never.Subjects were considered to be current smokers if they smoked[1cigarette/day for the last year. Former smoking was defined as a history of cigarette consumption on a regular basis([1cigarette/day),but no current smoking.Body mass index(BMI)was defined as the weight in kilograms divided by the square of the height in meters.SBP and DBP were the average offive separate measurements.Determination of diseasesThe study defined CRI as a GFR\60ml/min/1.73m2, according to the Kidney Disease Outcome Quality Initiative (KDOQI)working group definition[13].Atrialfibrillation (AF)and CHF were diagnosed by chief physicians or asso-ciate chief physicians on the basis of the ACC/AHA/ESC guidelines for AF[14]and ESC guidelines for CHF[15]. Subjects with a SBP C140mmHg,a DBP C90mmHg,or receiving medication for treatment of hypertension were defined as having hypertension,and those with a FPG C7mmol/L or receiving an oral hypoglycemic agent/insulin were considered to have diabetes mellitus(DM).Data managementAll information was obtained and preserved by trained researchers.To verify the accuracy of the results,other independent researchers performed the logistical check and re-evaluation of the data.OutcomeGiven the priority of all-cause mortality in outcome stud-ies,as well as the obviously high incidence of multiple organ failure in very old patients,the endpoint chosen for the present analysis was all-cause mortality over the fol-low-up period.Follow-up data was obtained from medical records or telephone interviews.No patient was lost to follow-up.Death was ascertained from the death record,a legal document including time,site,and other information. The Chinese PLA General Hospital was the designatedhospital for these patients,and had their integrated long-term medical andfinal death records.Therefore,follow-up was carried out effectively,and endpoints could be judged accurately.Statistical analysisThe proportions of patients with CRI and other co-mor-bidities in the study population were expressed as a prev-alence rate.Continuous variables were described using the mean with standard deviation(SD)for those with a normal distribution and the median with a75%range for non-normally distributed variables.The bivariate associations between CRI and variables in Table1(excluding MDRD-eGFR)were assessed by Student’s t test for continuous variables(normal distribution),Mann–Whitney U test for continuous variables(abnormal distribution),and v2anal-ysis for categorical variables.To identify independently clinical predictors of CRI,co-variates with a P\0.10were selected from the results of bivariate association analysis and applied to backward stepwise multivariable logistic regression(likelihood ratio test),which was used to avoid the interaction of variables.A multivariate logistic regression model(enter)was then developed with CRI as a dependent variable and variables from backward stepwise regression(P\0.10)as inde-pendent variables,and variables were kept in the last model at a significance level of two-tailed P\0.05[16].To screen risk factors for mortality,co-variates with a P\0.10 were selected by Cox regression univariate analysis and applied to the multivariate Cox regression models with death as the dependent variable,which were divided into two steps(stepwise and enter).The Kaplan–Meier estimate of survival for these patients with and without CRI was calculated.Receiver-operating characteristic(ROC)curves and areas under the curve(c-statistics)were used to assess the ability of the models to discriminate between patients with and without CRI/survival and death.After excluding variables missing from[15%of the study population,missing values of included variables were \2.7%(28patients),except BMI[113patients,(10.8%)]. To minimize bias,missing values were calculated by the multiple imputation method,and then the results were pooled[16].All statistical analyses were performed with SPSS17(SPSS Inc.,Chicago,IL,USA).ResultsPatient characteristicsThe median age of the study population was86years (100%range60–104years)and80.8%(848patients)of the cohort was[80years of age.The majority of the patients(89.2%)were male,and all of the patients were Chinese(100%).Among the1,050old CAD patients, there were327(31.1%)with CHF,839(79.9%)with hypertension,219(20.9%)with AF,and417(39.7%) with DM.The baseline characteristics of all patients or of patients grouped according to whether or not they had CRI are listed in Table1.Prevalence of CRICRI was present in a total of372patients(35.4%),including 168(51.4%)with CHF,323(38.5%)with hypertension,88 (40.2%)with AF,and160(38.4%)with DM.The preva-lence of CRI among patients with stable CAD,unstable angina,and AMI were34.8%(258/741),32.8%(78/238), and50.7%(36/71),respectively.There was no significant distinction in the prevalence of CRI between patients with stable CAD and those with unstable angina(P=0.563).A significant difference in CRI prevalence was observed between patients with stable CAD/unstable angina and patients with AMI[P=0.008,hazard ratio(HR)1.926, 95%confidence interval(CI)1.181–3.141;P=0.006,HR 2.110,95%CI1.232–3.614].Among patients in the60–75, 75–90,and90–105years age groups,there were26(21.1%, 123patients),260(35.8%,726patients),and86patients (42.8%,201patients)with CRI,respectively.The differ-ence in prevalence of CRI was evident between patients 60–75and75–90years of age(P=0.001,HR2.082,95% CI1.316–3.293);however,there was only a marginal,but not statistically significant difference in the prevalence of CRI for patients75–90versus90–104years of age(P=0.070, HR1.34,95%CI0.975–1.842).Clinical predictors of CRIOn univariate analysis,CRI was associated with many factors as shown in Table1.The participants with CRI were older,less likely to be male,and more likely to have AMI,hypertension,and CHF.The participants with CRI tended to have a lower left ventricular ejection fraction,a thicker interventricular septum,a larger left ventricular end-diastolic diameter,and a lower left ventricular mass index.Lower levels of hemoglobin,serum albumin,HDL-C,LDL-C,and higher levels of triglyceride were more commonly reported among those with CRI than those without CRI.On multivariate analysis,age,CHF,hyper-tension,hemoglobin,serum albumin,HDL-C,and LDL-C levels were independently associated with CRI(Table2). The area under the ROC curve for the multivariate model, equivalent to the c-statistic,was0.740,suggesting good discrimination between those who did and did not develop CRI.Table1Patients characteristics at baseline,by chronic renal insufficiencyCharacteristics Total CRI absent CRI present P valueDemographicsAge(year)a86.0(81.0–89.0)85.0(80.0–89.0)87.0(83.0–90.0)\0.001 Males(%)937(89.2)617(91.0)320(86.0)0.013 History of smoking0.674 Current(%)61(5.8)42(6.2)19(5.1)Former(%)337(32.1)213(31.4)124(33.3)Never(%)652(62.1)423(62.4)229(61.6)BMI(kg/m2)mean(SD)23.9(3.5)23.9(3.5)23.9(3.5)0.601 ComorbidityAMI(%)71(6.8)35(5.2)36(9.7)0.005 CHF(%)327(31.1)159(23.5)168(45.2)\0.001 NYHA class II(%)98(9.3)63(9.3)35(9.4)NYHA class III(%)147(14.0)68(10.0)79(21.2)NYHA class IV(%)82(7.8)28(4.1)54(14.5)Hypertension(%)839(79.9)516(76.1)323(86.8)\0.001 DM(%)417(39.7)257(37.9)160(43.0)0.106 AF(%)219(20.9)131(19.3)88(23.7)0.098 Clinical presentationHR(bpm)a72.0(64.0–80.0)72.0(64.8–80.0)72.0(64.0–80.0)0.723 MSBP(mmHg)a132.4(123.8–142.0)131.8(123.0–141.6)133.4(125.4–143.0)0.053 MDBP(mmHg)a69.0(63.7–74.3)69.2(64.3–74.3)68.8(63.0–74.3)0.294 LVEF(%)a60.0(56.0–63.0)60.0(57.0–63.0)59.0(53.8–62.0)\0.001 IVS(mm)a11.0(10.0–11.0)11.0(10.0–11.0)11.0(10.0–12.0)0.030 LVPW(mm)a10.0(10.0–11.0)10.0(10.0–11.0)10.0(10.0–11.0)0.211 LVEDD(mm)a49.0(46.0–51.0)48.1(46.0–51.0)49.0(46.2–52.0)0.004 LVMI(g/m2)a32.0(29.1–34.0)32.0(30.0–34.0)31.0(28.1–34.0)\0.001 Laboratory resultsMDRD-eGFR(ml/min/1.73m2)a69.2(53.3–82.3)78.6(70.4–89.0)47.2(35.0–54.4)Hemoglobin(g/L)a124.0(109.0–137.0)128.0(114.8–140.0)113.0(101.0–128.0)\0.001 Serum albumin(g/L)a38.3(35.3–40.8)38.8(35.9–41.2)37.7(34.6–39.9)\0.001 Glucose(mmol/L)a 5.4(4.8–6.2) 5.3(4.8–6.1) 5.4(4.8–6.3)0.357 Triglyceride(mmol/L)a 1.2(0.9–1.8) 1.2(0.9–1.6) 1.4(1.0–2.0)\0.001 HDL-C(mmol/L)a 1.1(0.9–1.3) 1.1(0.9–1.3) 1.0(0.8–1.2)\0.001 LDL-C(mmol/L)a 2.1(1.7–2.6) 2.2(1.8–2.7) 2.0(1.6–2.5)0.001 TherapyAspirin(%)537(51.1)355(52.4)182(48.9)0.287 Clopidogrel(%)622(59.2)409(60.3)213(57.3)0.333 b-Blockers(%)705(67.1)445(65.6)260(69.9)0.160 ACEI/ARB(%)530(50.5)346(51.0)184(49.5)0.626 Statins(%)693(66.0)453(66.8)240(64.5)0.452 PCI(%)134(12.8)93(13.7)41(11.0)0.211CRI chronic renal insufficiency,BMI body mass index,AMI acute myocardial infarction,CHF chronic heart failure,NYHA New York Heart Association,DM diabetes mellitus,AF atrialfibrillation,HR heart rate,MSBP mean systolic blood pressure,MDBP mean diastolic blood pressure,LVEF left ventricular ejection fraction,IVS interventricular septum,LVPW left ventricular posterior wall,LVEDD left ventricular end-diastolic diameter,LVMI left ventricular mass index,MDRD-eGFR estimated glomerularfiltration rate calculated by a modifying Modification of Diet in Renal Disease equation,HDL-C high density lipoprotein cholesterol,LDL-C low density lipoprotein cholesterol,ACEI angiotensin-converting enzyme inhibitors,ARB angiotensin receptor blockers,PCI percutaneous coronary interventiona Median(75%range)Mortality for the entire cohort and association with CRI During the follow-up period,the mortality was 20.8%(218patients)for the CAD patients.The MDRD-eGFR differed markedly between the survivors and those who had died [71.3(56.5–82.3)versus 58.7(38.4–82.3)ml/min/1.73m 2,P \0.001].There was a significant difference (P \0.001)in survival time between patients with CRI (median 206days;75%range 100–355days)and without CRI (median 245days;75%range 136–420days).The Kaplan–Meier estimate of survival for these patients with and without CRI is shown in Fig.1.Patients with CRI experienced a significantly higher mortality rate (30.1%,112patients)than those without CRI (15.6%,106patients)(P \0.001,HR 2.325,95%CI 1.716–3.148).Moreover,CRI was an independent predictor for mortality after adjusting for other factors in Table 1(P =0.034,HR 1.366,95%CI 1.024–1.822).In addition,the associations between age,AMI,CHF NYHA class IV,heart rate,hemoglobin,serum albumin level,and mortality in CAD patients remained significant after the same adjustment (Table 3).Mortality of patients with co-existing CAD and CRI and relative risk factorsIn 372patients with co-existing CRI and CAD,there were 112deaths (30.1%)during the follow-up period.In this population,risk factors,such as AMI,CHF NYHA class IV,AF,MDRD-eGFR,heart rate,and serum albumin level showed independent associations with mortality after adjusting for the factors in Table 1(Table 3).DiscussionAn important cross-sectional study using data from the China Heart Survey (CHS)showed that the prevalence of CRI among the participants with CAD and a mean age of 69years (100%range 56–67years)was 24.8%[1].In comparison with that trial,our study showed a higher prevalence of CRI (35.4%)in patients with CAD due to inclusion of many very old patients C 80years of age (80.8%).This study also demonstrated that CAD patients with or without CRI had important differences in many aspects,and several factors were independent clinical predictors for the occurrence of CRI.Not only was the prevalence of CRI increased in proportion to age,but the patients with CKD were also likely to have CHF,hyper-tension,and low levels of hemoglobin,serum albumin,and lipoproteins.Therefore,it may be necessary to pay more attention to the role of these factors in the generation and progression of CRI.Several previous studies have shown that the risk of mortality is significantly increased in CAD subjects with CRI when compared to those without CRI [2–4];however,this risk has not been clearly defined in old patients with CAD,especially in the Chinese population.In the current study,CRI was shown to be an independent risk factor for death in CAD patients,as well as age,AMI,CHF NYHA class IV,heart rate,hemoglobin,and serum albumin.A combination of functional glomerulopenia and structural glomerulosclerosis leads to progressive reduction in GFR with age.However,this study demonstrated that the age-related changes in the kidneys may be further complicated by co-morbidities (e.g.,CRI)common in older patients.Excluding the influence of age and other risk factors,CRI itself was independently associated with the death of old patients with CAD.Although the exact mechanisms by which CRI leads to higher mortality for patients with CAD remain unclear,the activation of the renin–angiotensin–aldosterone system,sympathetic nervous system,Table 2Correlates of chronic renal insufficiency on multivariable analysis Characteristics a Adjusted HR 95%CI P value Age 1.032[1.010–1.054]0.004CHF 2.361[1.747–3.191]\0.001Hypertension 1.878[1.291–2.731]0.001Hemoglobin (g/L)0.973[0.965–0.981]\0.001Serum albumin (g/L)0.954[0.912–0.995]0.027HDL-C (mmol/L)0.371[0.238–0.580]\0.001LDL-C (mmol/L)0.795[0.656–0.965]0.021HR hazard ratio,CI confidence interval,CHF chronic heart failure,HDL-C high density lipoprotein cholesterol,LDL-C low density lipoprotein cholesterolac-statistic for this model was0.740Fig.1Kaplan–Meier estimate of survival for CAD patients.Very old CAD patients with CRI experienced a significantly higher mortality rate than those without CRI (P \0.001).CAD coronary artery disease,CRI chronic renal insufficiencyinflammatory processes,and oxidative stress caused by kidney function impairment may play important roles[17].In addition,this study identified several risk factors for mortality in a specific group of old patients with co-exist-ing CAD and CRI.In subjects with CRI,mortality was significantly higher than those without CRI as mentioned above,was markedly affected by CHF NYHA class IV and AMI,and tended to increase as the MDRD-eGFR declined. Because age is a variable in the MDRD-eGFR formula,its prognostic value for mortality in patients with co-existing CAD and CRI was not independent after adjusting for the MDRD-eGFR.The MDRD-eGFR of old CAD patients with CRI still had an independent effect on mortality, which emphasizes the need for caution not only for the occurrence of CRI,but also the level of the MDRD-eGFR itself.In some studies involving patients with CAD,AF and elevated heart rate have been demonstrated to have important prognostic implications for mortality[18,19]. Moreover,patients with CRI may experience increased mortality in association with AF and elevated heart rate [20].A relationship was observed in the current study between elevated heart rate and higher mortality for old patients with CAD,with or without CRI,but AF was an independent risk factor only in old patients with co-existing CAD and CRI.Several epidemiologic studies in different populations have revealed an association between low serum albumin level and mortality in patients with CAD [21,22].Low serum albumin level is also an indicator of poor prognosis,not only for patients with end-stage renal disease,but also patients with pre-dialysis CRI[23,24].Ourfinding was consistent with prior studies reporting that low serum albumin level has a deleterious impact on mortality for old patients with CAD,with or without CRI, which given its numerous associated factors,may reflect the combined influence of malnutrition,increased catabolic activity,inflammation,vascular injury,proteinuria,and fluid retention.The current study had several limitations.A limitation was a few important prognostic factors in old patients with CAD,such as mental status,were not tested in our analysis. In addition,our follow-up period was relatively short. Finally,the exact mechanisms by which the risk factors led to higher mortality were not involved in our study and were in need of further study.ConclusionsA high prevalence(35.4%)of CRI with a high associated mortality rate(30.1%)existed in very old Chinese patients with CAD,and patients with co-existing CAD and CRI should be considered a high-risk group for adverse out-comes.In addition,several clinical predictors available were shown to identify CAD patients at increased risk for CRI or poor survival,thus providing information to facil-itate more dynamic monitoring,improved care,and aggressive therapy for these high-risk patients. Acknowledgments The study was supported by the Central Health Special Foundation(Beijing,China).Table3Risk factors for mortality on multivariable analysisPatients Risk factors Adjusted HR95%CI P valueCAD a(1,050patients/model A)Age 1.036[1.015–1.059]0.001 AMI 1.795[1.239–2.602]0.002 CHF NYHA class IV 1.691[1.187–2.410]0.004 CRI 1.366[1.024–1.822]0.034 Heart rate(bpm) 1.019[1.011–1.026]\0.001 Hemoglobin(g/L)0.982[0.975–0.990]\0.001 Serum albumin(g/L)0.905[0.874–0.938]\0.001Coexistent CAD and CRI b (372patients/model B)AMI 1.986[1.260–3.130]0.003 CHF NYHA class IV 1.940[1.269–2.965]0.002 AF 1.822[1.217–2.729]0.004 MDRD-eGFR(ml/min/1.73m2)0.982[0.970–0.993]0.003 Heart rate(bpm) 1.017[1.005–1.028]0.004 Serum albumin(g/L)0.869[0.830–0.909]\0.001HR hazard ratio,CI confidence interval,CAD coronary artery disease,AMI acute myocardial infarction,CHF chronic heart failure,NYHA New York Heart Association,CRI chronic renal insufficiency,AF atrialfibrillation,MDRD-eGFR estimated 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