* Lin-Kou Medical Center, Taipei Chang Gung Memorial Hospital, Taoyuan Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taiwan, Republic of China
Correspondence: Dr. Ja-Liang Lin, Department of Nephrology and Division of Clinical Toxicology, Chang Gung Memorial Hospital, 199, Tung-Hwa North Road, Taipei, Taiwan, ROC. Phone: +886-3-3281200-8181; Fax: +886-3-3288662; E-mail: jllin99{at}hotmail.com
Received for publication December 28, 2006.
Accepted for publication April 24, 2007.
Chronic inflammation and malnutrition relate to increased risksfor cardiovascular death. This study compared fasting glucoselevels (FGL) and impaired fasting glucose (IFG) with malnutritionand inflammation in nondiabetic maintenance hemodialysis (MHD)patients to investigate the adverse affects and risks for mortality.In total, 693 MHD patients were enrolled in this study and followedup for 1 yr. Geographic, hematologic, biochemical, and dialysis-relateddata were collected. According to 1997 and 2003 definitions,all patients were classified into three groups: Diabetic, nondiabeticwith IFG, and nondiabetic with normal FGL. More diabetic andnondiabetic with IFG group patients were malnourished (2 = 24.55,P < 0.0001) and had inflammatory changes (2 = 9.32, P = 0.0095)than those with normal FGL. The IFG group had higher high-sensitivityC-reactive protein and ferritin and lower serum albumin, creatininelevels, and normalized protein catabolic rate than the normalFGL group. Age and parameters of nutrition and inflammationwere associated with FGL. Stepwise multiple regression analysisdemonstrated that FGL were negatively associated with serumalbumin (P = 0.0026) and positively correlated with Log high-sensitivityC-reactive protein (P = 0.0004) in nondiabetic MHD patients.In addition, after 1 yr of follow-up, Cox multivariate analysisdemonstrated that, after adjustment for other significant relatedfactors, FGL (relative risk 1.049; 95% confidence interval 1.007to 1.093; P = 0.0232) or presence of IFG (relative risk 3.798;95% confidence interval 1.168 to 12.344; P = 0.0265) was a significantrisk factor for 1-yr all-cause mortality of these patients.On the basis of these findings, basal FGL or presence of IFG,a preventive and treatable status, plays an important role ininflammation, malnutrition, and short-term mortality of nondiabeticMHD patients.
Fasting glucose levels (FGL) are important for diagnosis ofdiabetes and impaired fasting glucose (IFG).1 Diabetes is associatedwith increased incidence of cardiovascular disease (CVD) inboth men and women in most racial and ethnic groups.1,2 Individualswith IFG have increased risk for future diabetes and may alsohave increased risk for CVD.3–5 Because IFG is associatedwith increased CVD risk, initiating preventive interventionsis important for these patients. However, the clinical significanceof FGL and IFG in maintenance hemodialysis (MHD) patients remainsunclear.
According to the US Renal Data System, the annual mortalityrate for MHD patients is 25%, with nearly 50% of all reportedMHD patient deaths being attributed to cardiovascular complications.6Although traditional risk factors for CVD are common in patientswith ESRD, these factors alone may not explain the high prevalenceof CVD.7 Clinical evidence has indicated that chronic inflammation,a nontraditional risk factor for CVD, is common in MHD patientsand may cause protein-energy malnutrition and progressive atherosclerosis.8–10Protein-energy malnutrition and inflammation, two relativelycommon and concurrent conditions in MHD patients, have beenidentified as the main cause of poor short-term survival inthis population.11 Correcting malnutrition and/or inflammationhas the potential to reduce rates of CVD in MHD patients. Consequently,it is important to identify correctable factors that are associatedwith malnutrition and/or inflammation in MHD patients. WhetherFGL and IFG12 in patients who do not have diabetes and are onMHD correlates with mortality, inflammation, and/or malnutritionin these patients remains unknown.
This multicenter 1-yr longitudinal study investigated the relationshipamong FGL, IFG, malnutrition, and inflammation by clinicallyexamining nondiabetic MHD patients. Moreover, this study analyzedwhether FGL or IFG contributed to the mortality risk for thesepatients.
Characteristics of the Study Population
A total of 693 MHD patients (329 men and 364 women) with meanMHD duration of 5.7 ± 0.2 yr were enrolled for analysis.Table 1 lists the baseline clinical characteristics, includingage, gender, body mass index (BMI), and biologic and hematologicdata. Mean patient age was 55.5 ± 0.5 yr (range 14 to92 yr). The numbers of patients with renal diseases were asfollows: Diabetes 189 (27.3%), chronic glomerulonephritis 226(32.6%), and hypertensive-related nephropathy 121 (17.5%). Table 1also lists patient characteristics for the three subgroups.The group with diabetes (n = 189) had lower values of Kt/V andintact parathyroid hormone (iPTH), shorter duration of HD, higherprevalence of CVD, and higher BMI and white blood cell (WBC)counts than the other groups. Meanwhile, the normal FGL group(n = 423) were younger; had higher levels of serum albumin,creatinine, and normalized protein catabolism rate (nPCR); andhad lower values of triglycerides, high-sensitivity C-reactiveprotein (hsCRP), and cardiothoracic ratio (CTR) than the othergroups. Furthermore, the IFG group (n = 81) had higher levelsof triglycerides, hsCRP, and ferritin and lower levels of serumalbumin, creatinine, and nPCR than the normal FGL group. Thegroups did not differ in terms of gender; smoking status; presenceof hypertension or viral hepatitis; values of Ca x P; and useof fistula, biocompatible membrane dialyzers, statins, and/oraspirin (data not shown). The IFG and diabetes group patientshad significantly higher percentages of malnutrition (2 = 24.55,P < 0.0001) and inflammatory status (2 = 9.32, P = 0.0095)than the normal FGL group patients (Table 2).
Table 2. Percentage of malnutrition and inflammation in study group patients on MHD (n = 693)a
Significant Correlations among FGL, Baseline Data, Nutrition, and Inflammation Markers in Patients Who Did Not Have Diabetes and Were on MHD
The Spearman correlation analysis demonstrated that FGL wassignificantly and positively correlated with age and inflammatorymarkers, such as hsCRP and ferritin levels, but negatively correlatedwith nutritional parameters, such as albumin, creatinine, andhemoglobin levels in nondiabetic MHD patients (Table 3).
Table 3. Associations between FGL, nutrition, and inflammation markers in patients who did not have diabetes and were on MHD (n = 504) at the beginning of study (Spearman rank correlation coefficients)a
Significant Relations between Serum Albumin and FGL in Patients Who Did Not Have Diabetes and Were on MHD
The variables that were considered as potential covariates ofserum albumin7,9–11 were age, gender, BMI, HD years, smokingstatus, CVD, viral hepatitis B and C, use of aspirin or statins,use of antihypertension drugs, using fistula for vascular access,biocompatible membrane dialyzers, Ca x P, iPTH, Kt/Vurea (Daugirdas),and log hsCRP. Simple linear regression analysis indicated thatage, gender, smoking, BMI, previous CVD, use of a fistula, loghsCRP, CTR, and FGL were associated with serum albumin in thestudy patients (Table 4). After adjustment for these significantvariables, stepwise multiple linear regression analysis revealeda significant inverse correlation between serum albumin levelsand FGL (Table 4). A 1-mg/dl increase in FGL was associatedwith a 0.003-g/dl decrease in serum albumin level (P = 0.0026).
Table 4. Determinants of nutrition (albumin) in patients who did not have diabetes and were on MHD (n = 504)
Significant Relationship between Log hsCRP and FGL in Patients Who Did Not Have Diabetes and Were on MHD
The variables7,9–11 that were considered as potentialcovariates of inflammation were age, gender, BMI, HD years,smoking status, CVD, viral hepatitis B and C, aspirin or statinsdrugs, antihypertension drugs, using a fistula for vascularaccess, biocompatible membrane dialyzers, Ca x P, iPTH, andKt/Vurea (Daugirdas). Simple linear regression analysis indicatedthat age, smoking, BMI, previous CVD, Kt/Vurea (Daugirdas),CTR, and FGL were associated with log hsCRP in these patients(Table 5). After adjustment for these significant variables,stepwise multiple linear regression analysis identified a significantcorrelation between log hsCRP levels and FGL (P = 0.0004; Table 5).
Table 5. Determinants of inflammation (Log hsCRP) in patients who did not have diabetes and were on MHD (n = 504)
Cox Regression Multivariate Analysis for 1-Yr Mortality in MHD Patients
At the end of the 12-mo observation period, the following datawere obtained: 23 (12.2%) patients in the diabetic group, eight(9.9%) patients in the IFG group, and 10 (2.4%) patients inthe normal FGL group died during the 1-yr follow-up. None ofIFG group with sugar <110 died. A total of 606 patients completedthe 1-yr follow-up. During this period, 34 patients were transferredto other outpatient hemodialysis units, 12 patients receivedkidney transplantation, and 41 patients died. Among these patients,35 (72.9%) died of CVD, five (12.2%) died of infection, andone died of hepatoma. Cox multivariate regression analysis revealedthat—after adjustment for other significant related factors—presenceof abnormal CTR (>50%) and FGL were significant risk factorsfor 1-yr mortality of patients who did not have diabetes andwere on MHD (Table 6). Similarly, instead of FGL, presence ofIFG is a significant risk factor (relative risk 3.798, 95% confidenceinterval 1.168 to 12.344; P = 0.0265) for 1-yr mortality inthese patients after adjustment of related significant factors.The Kaplan-Meier survival analysis for all MHD patients showedthat diabetic and nondiabetic IFG group patients had highermortality than those in the normal FGL group (Log rank test,2 = 11.48, P = 0.0007; Figure 1). At the study end, four (4.9%)of 81 patients with IFG had developed diabetes.
Table 6. Cox regression analysis of the overall risk for all-cause 1-yr mortality, according to baseline prognostic factors, in patients who did not have diabetes and were on MHDa
Figure 1. The Kaplan-Meier survival analysis demonstrated that diabetic and nondiabetic IFG group patients had a higher 1-yr mortality rate than that of the nondiabetic normal FGL group (Log rank test, 2 = 11.48, P = 0.0007).
The analytical results showed that, similar to MHD patientswith diabetes, MHD patients without diabetes and with IFG hadhigher levels of inflammatory markers, including hsCRP and ferritin,and lower levels of nutritional markers, such as serum albumin,creatinine, and nPCR, than MHD patients without diabetes andwith normal FGL. A significantly larger percentage of the IFGand diabetic group patients had malnutrition and inflammationthan did the normal FGL group patients. In addition, FGL arepositively associated with inflammatory markers but negativelycorrelated with nutritional parameters in the Spearman analysis.After adjustment for significantly related variables, stepwisemultiple linear regression analysis revealed that FGL is negativelycorrelated with serum albumin levels but positively associatedwith log hsCRP in MHD patients without diabetes. A 1-mg/dl increasein FGL was associated with a 0.003-g/dl decrease in serum albuminlevel (P = 0.0026). All of these findings indicate that FGLinfluences nutritional and inflammatory status in MHD patientswithout diabetes and that IFG is associated with malnutritionand inflammation in such patients.
Similar to the findings of this investigation of MHD patientswithout diabetes, some previous studies13,14 reported a strongassociation between hsCRP levels and FGL and that hyperglycemiainfluences plasma TNF-, IL-6, and IL-18 in individuals withoutdiabetes. Cases of IFG may result from insulin resistance.15In a survey of 1008 individuals without diabetes,16 hsCRP, fibrinogen,and WBC counts were found to be associated with insulin resistance.The finding is also supported by the Women's Health Study,17which found hsCRP to be independently associated with fastinghyperinsulinemia in women without diabetes. Because few studiesmention the relationship between hyperglycemia and malnutritionin individuals without diabetes and chronic inflammation isa common cause of malnutrition in MHD patients,8–10 thenegative association between FGL and serum albumin identifiedhere may result from hyperglycemia-induced inflammatory changesor oxidative stresses causing malnutrition in MHD patients withoutdiabetes.
At the end of the 12-mo observation period, the 1-yr mortalityrates for MHD patients with diabetes (12.2%) and MHD patientswithout diabetes and with IFG (9.9%) were similar, but the ratefor the MHD patients without diabetes and with normal FGL wasjust 2.2%. The main cause of death was CVD in these patients.Cox hazard multivariate analysis demonstrated that basal FGLor the presence of IFG was a significant independent risk factorfor predicting 1-yr all-cause mortality in MHD patients withoutdiabetes after adjustment of other related factors. BecauseIFG may induce subclinical inflammation and chronic inflammation,which in turn may cause protein-energy malnutrition and progressiveatherosclerosis, protein-energy malnutrition and inflammationhave been identified as the main cause of poor short-term survivalin MHD patients8–11; therefore, it is not surprising thatbasal FGL or the presence of IFG independently predicts theshort-term mortality of MHD patients without diabetes in thisinvestigation.
Although hyperglycemia can cause oxidative stress and inflammatorychanges and is an established risk factor for CVD in patientswith diabetes,1,2 the prognostic significance of IFG for macrovascularcomplications remains unclear.18,19 Because this study definesIFG as an FGL between 105 and 125 mg/dl and none of the IFGgroup with sugar <110 died, the findings of this investigationare supported by other studies.20–22 A clinical study20in 1998 surveyed 20-yr mortality in 17,285 working men who didnot have diabetes and were aged 44 to 55 yr. Regarding deathfrom CVD and coronary heart disease (CHD), men with abnormalfasting glucose distributions had higher risk for death fromCHD, with age-adjusted hazard ratios for CHD of 2.7. During2001, a total of 11,853 patients with established CHD, comprising1258 patients without diabetes and with IFG, were followed upover 7.7 yr. IFG was identified as a consistent predictor ofincreased all-cause mortality with a hazard ratio of 1.39.21Furthermore, among 2763 postmenopausal women who had establishedCHD and were followed up for 6.8 yr, 218 women with IFG accordingto the 1997 definition (FGL 110 to 125 mg/dl) had significantlyincreased risk for any CHD events, whereas the 698 women withIFG according to 2003 definition (FGL 100 to 125 mg/dl) hadno such increased risk.22 These findings are similar to theanalytical results of this investigation and suggest that IFGis also a risk factor for macrovascular complications. Becauseexcess mortality risk of the presence of IFG was demonstratedwithin 1 yr in this study, there seems to be an urgent needfor preventive actions such as smoking cessation, obesity reduction,and so forth for MHD patients who do not have diabetes and haveIFG and seem to face a significant survival risk compared withpatients without diabetes and with CHD.
The finding that basal FGL or the presence of IFG can predictshort-term mortality in MHD patients without diabetes is importantbecause hyperglycemia is treatable. Good glycemic control hasbeen demonstrated to reduce the risk for microvascular complications,but equivalent evidence is lacking for CVD risk reduction.23However, the Study to Prevent Non-Insulin Dependent DiabetesMellitus (STOP-NIDDM) found that acarbose can reduce the riskfor any cardiovascular event by 49% compared with the placebo.23Whether good glycemic control is beneficial for MHD patientswithout diabetes and with IFG requires further assessment.
At the end of 1-yr of follow-up, Four (4.9%) of 81 patientswith IFG had developed diabetes. The results are similar toa previous study24 that analyzed six prospective studies anddemonstrated the incidence rates of type 2 diabetes among patientswith impaired glucose tolerance ranging from 3.6 to 8.7 per100 person-years. Further studies are needed to clarify therisk factors that influence the progression from IFG to overtdiabetes in MHD patients without diabetes and with IFG.
This study has some limitations. Two-hour postchallenge glucoselevels were not checked; therefore, we could not compare thestrength of the association of IFG with impaired glucose tolerancefor mortality. In addition, the baseline prevalence of diabeteswas probably underestimated, and some patients with diabeteswere misclassified as having IFG. Although this may have biasedthe study results and increased mortality risk in the IFG group,strict selection criteria were used and three FGL checks wereperformed at 1-mo intervals to determine whether the study patientshad IFG or diabetes, thereby minimizing the bias that resultedfrom this problem.
This study showed that FGL influences nutritional and inflammatorystatus in MHD patients without diabetes and that IFG is associatedwith malnutrition and inflammation in these patients. Furthermore,basal FGL or the presence of IFG independently predicts 1-yrmortality of MHD patients without diabetes. The analytical resultsof this investigation are important for MHD patients withoutdiabetes because IFG is a preventive and treatable conditionand correcting hyperglycemia has the potential to reduce short-termmortality in these patients. Further study is required to confirmthis observation and hypothesis.
Patients
All study patients came from three HD centers: Chang Gung MemorialHospitals (CGMH) in Taipei, Lin-Kou, and Toayuan. All MHD patientswere enrolled, after exclusion of those with malignancies andobvious infectious diseases, as well as those who were hospitalizedor underwent surgery or renal transplantation during the 3 mobefore the study. Patients who were currently using FG-elevatingdrugs, such as postmenopausal replacement hormones, steroids,thyroid hormone; who could not tolerate fasting time; or whohad been receiving regular HD for <6 mo were also excluded.This longitudinal observational study enrolled a total of 693patients. Most HD patients had been undergoing 4 h of HD threetimes per week. HD for these patients used single-use hollow-fiberdialyzers equipped with modified cellulose-based polyamide orpolysulfone membranes. The dialysate used was a standard ioniccomposition, and a bicarbonate-based buffer was used in allcases. Presence of diabetes and CVD, including cerebrovasculardisease, coronary arterial disease, congestive heart failure,and peripheral vascular disease, were recorded. Smoking behaviorand use of drugs that effect inflammatory properties, such asstatins and aspirin, were also recorded. This clinical studyfollowed the Declaration of Helsinki and was approved by theMedical Ethics Committee of CGMH, Taipei.
Study Groups
Patients who met the inclusion criteria were classified intothree groups according to their FGL, which were checked at leastthree times at 1-mo intervals. All values had to be within theclassification of the IFG and normal FGL ranges, based on the1997 and 2003 definitions.12 The three patient classificationgroups were as follows: The nondiabetic with normal FGL group(fasting glucose <105 mg/dl; n = 423), the nondiabetic withIFG group (fasting glucose <126 and 105 mg/dl; n = 81), andthe diabetic group (twice subsequent fasting glucose 126 mg/dlor diabetes was diagnosed by a physician in the history; n =189). All patients were followed up for 1 yr, and mortalityduring this period was the primary end point.
Laboratory, Nutritional, and Inflammatory Parameters
Laboratory data for each patient were obtained within a fewdays of the clinical examination during stable outpatient HDsessions to minimize any effects of acute events. Blood sampleswere drawn from the arterial end of the vascular access immediatelybefore initiation of a 2-d interval HD, centrifuged, and storedat –70°C until they were used in assays.
Serum albumin, creatinine levels, transferrin saturation, nPCR,triglycerides, and total cholesterol were assayed and recordedas nutritional markers. Moreover, WBC and hemoglobin were measuredas the hematologic indicators. This study used both serum ferritinand hsCRP as inflammation markers. Serum hsCRP concentrationswere measured using immunonephelometry (Nanopia CRP; Daiichi,Tokyo. Japan). The lowest detection limit was <0.15 mg/L.All other markers were measured using standard laboratory approacheswith an automatic analyzer. nPCR in HD patients was calculatedvia validated equations and normalized to actual body weight.25Dialysis clearance of urea was expressed as Kt/Vurea, usingthe method described by Daugirdas26 in HD patients. Serum calcium,phosphate, and iPTH were also detected. Corrected calcium =serum calcium (mg/dl) + [0.8(4.0 – serum albumin [g/dl])].
Definition of Malnutrition and Inflammation
To determine whether FGL reflects the inflammation and/or malnutritionstatus of MHD patients, this work investigated serum albuminand hsCRP levels in different population subgroups on the basisof the absence or presence of malnutrition and inflammation.The presence of inflammation in MHD patients was defined asan hsCRP level >3 mg/dl, a level that is correlated withraised cardiovascular risk in the general population.27 Thiswork defined albumin levels <3.6 g/dl (<36 g/L) as a stateof malnutrition, levels that represent the 10th percentile ofthe Third National Health and Nutrition Examination Survey.28,29
Statistical Analyses
Unless otherwise stated, continuous variables are expressedas means ± SEM, and categorical variables are expressedas numbers or percentages for each item. Comparisons among thethree study groups of patients were analyzed via one-way ANOVAusing Bonferroni test for post hoc analysis. The Kruskal-Wallistest and Mann-Whitney U test were used to detect significantdifferences among non-normally distributed variables, and logarithmicconversion was conducted for hsCRP levels. The 2 test was usedfor categorical variables, including gender, smoking status,CVD, and the presence of malnutrition and inflammation. Moreover,Spearman correlation analysis was conducted to assess the relationsbetween variables. To identify factors that were associatedwith inflammation and nutrition, this investigation used multiplelinear regression models with backward stepwise procedures forbiochemical and demographic variables,7,9–11 such as age,gender, BMI, HD years, smoking status, CVD, viral hepatitisB and C, use of aspirin or statins, use of antihypertensiondrugs, using fistula for vascular access, biocompatible membranedialyzers, Ca x P, iPTH, and Kt/Vurea (Daugirdas). The Cox proportionalhazards model was applied to determine the significance of variablesfor predicting 1-yr mortality (the primary end point). Thismodel included all of the variables that were identified inthe literature7,9–11 as related to HD mortality. The levelof significance was set at P < 0.05. All statistical calculationswere performed using StatView 2.0 for Windows (SAS Institute,Cary, NC).
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Abstract
Introduction
2 = 24.55, P < 0.0001) and had inflammatory changes (
, IL-6, and IL-18 in individuals without diabetes. Cases of IFG may result from insulin resistance.15 In a survey of 1008 individuals without diabetes,16 hsCRP, fibrinogen, and WBC counts were found to be associated with insulin resistance. The finding is also supported by the Women's Health Study,17 which found hsCRP to be independently associated with fasting hyperinsulinemia in women without diabetes. Because few studies mention the relationship between hyperglycemia and malnutrition in individuals without diabetes and chronic inflammation is a common cause of malnutrition in MHD patients,8–10 the negative association between FGL and serum albumin identified here may result from hyperglycemia-induced inflammatory changes or oxidative stresses causing malnutrition in MHD patients without diabetes. 
105 mg/dl; n = 81), and the diabetic group (twice subsequent fasting glucose 
