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NDT Advance Access originally published online on February 16, 2006
Nephrology Dialysis Transplantation 2006 21(6):1575-1581; doi:10.1093/ndt/gfl033
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

Do inflammatory markers add predictive information of death beyond that provided by age and comorbidity in chronic renal failure patients?

Francisco Caravaca, María Victoria Martín, Sergio Barroso, Belén Ruiz and Román Hernández-Gallego

Department of Nephrology, Hospital Infanta Cristina, Badajoz, Spain

Correspondence and offprint requests to: Francisco Caravaca S. Nefrología, Hospital Infanta Cristina, 06080 Badajoz, Spain. Email: fcaravacam{at}senefro.org



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Elevated levels of inflammatory markers have been shown to be associated with increased mortality in chronic kidney disease (CKD) patients. Comorbid indexes are also helpful clinical instruments for predicting mortality. At present, it is unknown whether inflammatory markers add predictive information of death beyond that provided by comorbid indexes.

Methods. This observational single-centre study included 404 patients (mean age 63±16 years) with CKD stage 4 and 5 predialysis who were prospectively followed-up. Data obtained at baseline: demographics, grade of comorbidity by Davies index, serum albumin, creatinine clearance, total white blood cell (WBC), polymorphonuclear leukocyte (PMN) counts, and high-sensitivity C-reactive protein (CRP) were analysed as potential determinants of the subsequent all-cause mortality. Receiver-operating characteristic (ROC) curves were used to determine the values of CRP, WBC and PMN most closely related to mortality. These cut-off values were used to define subgroups with high or low inflammatory markers. Uni- and multivariate Cox regression models were performed.

Results. Median follow-up time was 583 days, with a mortality of 26%, and overall survival rate of 47%. In unadjusted Cox models, inflammatory markers (CRP, WBC and PMN) were all significantly associated with all-cause mortality. Age (HR 1.05; 95% CI 1.03–1.07, P<0.0001) and comorbid index (HR 2.15; 95% CI 1.54–3.00, P<0.0001) were strongly associated with mortality. The introduction of inflammatory markers into the multivariate Cox regression model did not add significant predictive power. In a stepwise Cox model, the age, comorbid index, serum albumin levels and creatinine clearance were the best predictive variables of mortality.

Conclusions. Although elevated inflammatory markers are associated with a worse outcome in CKD patients, they did not add predictive information of all-cause mortality beyond that provided by age and the comorbid index.

Keywords: chronic renal failure; C-reactive protein; inflammatory markers; mortality; white blood cell count



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Elevated levels of inflammatory markers have been shown to be associated with increased mortality in chronic kidney disease (CKD) patients [1–11]. Numerous studies have demonstrated that increased serum levels of C-reactive protein (CRP) [1,2,4–8], IL-6 [3,9], or even elevated total white blood cells (WBCs) or polymorphonuclear leucocyte (PMN) counts [10,11] predict a worse outcome. Despite these findings, many doubts remain about the biological significance of increased inflammatory markers and their utility as outcome predictors.

The aetiology of inflammation in CKD patients seems to be multifactorial [12,13]. Disorders commonly associated with chronic azotaemia such as atherosclerotic ischaemic disease and left ventricular dysfunction are associated with a high prevalence of inflammation among these patients [12,13].

Apart from the potential negative effects of inflammation on endothelial function, coagulation or nutrition [14], increased inflammatory markers reflect tissue damage, and therefore they may also represent the degree of severity of pre-existing cellular or organ damage of diverse nature. Although adjustments for separate comorbid illnesses have been performed in most of the studies addressing the predictive value of inflammatory markers over mortality, very few studies have taken into consideration the aggregate comorbidity by means of comorbid indexes [9,15].

Age and comorbid indexes are helpful clinical data which have been demonstrated to accurately predict mortality in CKD patients [16].

The aim of this study was to determine if inflammatory markers such as CRP, total WBC or PMN counts add predictive information of mortality beyond that provided by age and comorbid index in patients with chronic renal failure stages 4 and 5.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients
This observational prospective study included all incident pre-end stage renal disease patients who were referred to the predialysis outpatient clinic of the Infanta Cristina Hospital, Badajoz, Spain, from January 1999 to December 2004. Twenty-one patients were excluded because of overt inflammatory or infectious diseases. There were no other study exclusion criteria. The study group consisted of 404 patients (206 males) with chronic renal failure stages 4 and 5 (according to the National Kidney Foundation classification) not yet on dialysis.

The mean age was 63±16 years. The aetiologies of renal failure were: unknown origin (114 patients), primary glomerulonephritis (68 patients), diabetic nephropathy (92 patients), chronic interstitial nephropathy (62 patients), polycystic kidney disease (29 patients), ischaemic nephropathy (31 patients), and other aetiologies (8 patients).

Comorbidity among the study patients was highly prevalent. In 122 patients, diabetes mellitus (103 patients with type 2 diabetes, and 19 patients with type 1 diabetes) had been diagnosed, 80 patients had a previous history of left ventricular dysfunction, 57 had a previous history of coronary artery disease, 83 had peripheral vascular disease, 35 had chronic pulmonary obstructive disease, and 39 had other significant comorbidities.

Most patients were on angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers, HMG Co-A reductase inhibitors or antiplatelet drugs, as well as other drugs commonly used in end-stage renal disease, such as phosphate binders, diuretics and vitamin supplementation.

Data collection and laboratory analysis
Data were obtained from these patients during their first visit. The grade of comorbidity was quantified by the method devised by Davies et al. [17]. Briefly, the comorbid score for each patient was the number of the following domains affected: diabetes, malignancy, ischaemic heart disease, peripheral vascular disease, left ventricular dysfunction, systemic collagen vascular disease, and other significant pathology. The grade of comorbidity was derived directly from this score. Grade 0 was a zero score, grade 1 was a score of 1–2 and grade 2 was a cumulative score ≥3.

Medical records were used as a source to obtain information about comorbid illnesses. Ischaemic heart disease was diagnosed if patients had one of the following evidences: previous myocardial infarction, clinical signs of ischaemic heart disease, positive coronary angiography or other diagnostic procedures (exercise test, MIBI scan). Peripheral vascular disease included either symptomatic disease or significant stenoses (>50%) in distal aortic, renovascular, lower limb, or cerebrovascular territories. Patients with aortic aneurysms were also included in this domain. Left ventricular dysfunction was defined as clinical evidence of pulmonary oedema, and/or moderate to severe left ventricular dysfunction on echocardiography.

After an overnight fast, blood samples were taken for the following laboratory measurements: haemoglobin, total WBC and PMN counts, serum albumin (bromocresol green), urea, creatinine and other biochemical parameters not used in this study (Hitachi 747–200, Roche Diagnostics, Germany). High-sensitivity CRP was measured by nephelometry (N High-sensitivity CRP, Behring, Marburg, Germany, detection limit of 0.160 mg/l).

Creatinine clearance (Ccr) was calculated from a 24 h urinary collection, and the results were corrected for a standard body surface area of 1.73 m2.

Study design and statistical analysis
The clinical outcome evaluated in this study was all-cause mortality. Patients were prospectively followed-up after baseline assessment. Censoring was performed for renal transplantation. There was no loss to follow-up.

A single baseline measure of CRP, total WBC and PMN counts were taken as predictive variables of the subsequent mortality.

Associations between comorbidity and inflammatory markers were analysed by comparing mean inflammatory markers according to the grades of comorbid index, and by comparing the prevalence of comorbid conditions across CRP tertiles. Comparisons of continuous variables between groups were performed by analysis of variance (ANOVA and MANOVA) or by Kruskal–Wallis test where applicable. Post-hoc comparisons were performed by Scheffe's tests and Dunn's test where applicable. Differences between the groups were tested using the chi-square test for categorical variables.

By receiver-operating characteristic (ROC) curves, the values of CRP, WBC and PMN counts most closely related to mortality were determined. These values were taken as cut-off points for dividing patients into subgroups with high or low CRP, WBC or PMN counts.

Kaplan–Meier survival plots for differences in survival between patients divided according to high or low CRP, WBC and PMN counts, as well as comorbid index, were compared using log-rank test.

Association between survival and covariates were determined by uni- and multivariate analysis using the Cox proportional hazards method. For the multivariate analysis, a stepwise selection procedure of variables with backward elimination was performed. In order to confirm the proportionality assumption, plots of log (–log survival rate) against log survival time, and plots of partial residuals for each covariate against survival time were performed and examined.

Data are presented as mean±SD or as median and inter-quartile (IQ), ranges with P<0.05 taken to indicate a statistical significance. Statistical analysis was performed and graphics generated using SPSS software version 13.0 (SPSS, Chicago, IL, USA).



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Association between comorbidity and inflammation
Baseline clinical and biochemical characteristics of the study group are shown in Table 1. As expected, CRP values were not normally distributed. CRP in the lower tertile was 0.16–2.21 mg/l, 2.22–6.34 mg/l in the middle tertile, and 6.35–129 in the upper tertile. Total WBC count in the lower tertile was 3100–6600/mm3, 6700–8600/mm3 in the middle tertile, and 8700–22 500/mm3 in the upper tertile. PMN count in the lower tertile was 1700–4200/mm3, 4300–5800/mm3 in the middle tertile, and 5900–19 400/mm3 in the upper tertile.


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  		Table 1. Baseline clinical and biochemical characteristics

 
There were significant differences in the mean values of inflammatory markers according to the grade of comorbidity (Table 2). In the whole group, patients without comorbidity had significantly lower CRP levels, total WBC and PMN counts than patients with grade 1 or 2. These differences were more marked in older than in younger patients, though MANOVA analysis ruled out a statistically significant effect of comorbidity by age on inflammatory markers.


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  		Table 2. Mean values of inflammatory markers according to the grade of comorbidity in the total group and in patients older or younger than 65 years

 
Comorbidity was not evenly distributed across CRP tertiles (Table 3). Patients in the upper tertile were older, with significantly lower mean serum albumin levels, and a higher incidence of coronary and peripheral vascular diseases, left ventricular dysfunction, as well as higher aggregation of comorbid illnesses, as denoted by worse comorbid indexes, than patients in the other two tertiles. However, there were not significant differences in gender, percentage of diabetic patients, or level of renal function across CRP tertiles (Table 3).


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  		Table 3. Clinical characteristics and comorbidity according to CRP tertiles

 
Serum albumin levels correlated significantly with CRP levels (log-transformed) (r = 0.21), total WBC count (r = 0.26) and PMN count (r = 0.26). A less strong correlation was observed between Ccr and CRP levels (r = 0.12, P = 0.017). Ccr did not correlate with total WBC or PMN counts.

Mortality
Median follow-up time was 583 days (IQ range: 346–1007 days). Of the 404 patients, 106 (26%) had died at the end of the study period.

Dialysis was initiated in 205 patients (159 haemodialysis and 49 peritoneal dialysis), and 27 patients received a kidney allograft (none of them before dialysis initiation) during the study period. Mean Ccr at the time of dialysis initiation was 10.4±2.5 ml/min/1.73 m2. Of the 106 deaths, 50 occurred before dialysis initiation, 54 in haemodialysis, and 2 in peritoneal dialysis. The cause of death was: sudden death (11 patients), cardiovascular events (51 patients), infectious disease (15 patients), malignancy (11 patients), terminal uraemia for rejection of dialysis treatment (2 patients), or other causes (digestive haemorrhage, acute pancreatitis, mesenteric thrombosis, etc.) (16 patients).

Survival analysis
By ROC curve analysis, CRP, WBC and PMN counts were shown to be related to mortality. The area under the curve (AUC) for CRP was 0.66, P<0.0001, and the best predictive value was 3.90 mg/l (sensitivity 63% and specificity 57%). The AUC for total WBC and PMN counts was 0.58 and 0.62, respectively. Their best predictive values were 8950/mm3 (sensitivity 37% and specificity 74%), and 6500/mm3 (sensitivity 38% and specificity 78%), respectively.

The overall survival rate was 47%. Figures 1–3GoGo depict survival curves of subgroups according to CRP and total WBC count above or below cut-off values and grades of comorbidity. There were significant differences in survival when patients with inflammatory markers above or below cut-off values were compared. Patients with CRP levels or WBC count above cut-off values showed a significant increase in the risk of all-cause mortality. Differences were strongly evident when survival curves were compared according to the grades of comorbidity (Figure 3). Survival according to cut-off values of PMN count is not shown, though differences were also significant in a similar manner to that observed with total WBC count (log-rank = 1.88, P = 0.003).


Figure 1
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  		Fig. 1. Kaplan–Meier analysis of survival according to C-reactive protein above or below 3.90 mg/l. Log-rank test = 13.65, P<0.0001.

 

Figure 2
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  		Fig. 2. Kaplan–Meier analysis of survival according to total white blood cells count above or below 8950/mm3. Log-rank test = 8.32, P = 0.004.

 

Figure 3
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  		Fig. 3. Kaplan–Meier analysis of survival according to the grade of comorbidity. Log-rank = 76.17, P<0.0001.

 
In unadjusted Cox models (Table 4), CRP, WBC and PMN counts were all associated with a greater risk of all-cause mortality. Age and comorbid index were strongly associated with mortality.


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  		Table 4. Uni- and multivariate Cox regression models

 
In the multivaritate Cox proportional model (Table 4), age, comorbid index, serum albumin and Ccr retained statistical significance, while CPR, WBC and PMN were eliminated from the model. By stepwise selection, age (HR 1.04, 95% CI 1.02–1.06), comorbid index (HR 2.43, 95% CI 1.77–3.31), serum albumin (HR 0.64, 95% CI 0.44–0.93) and Ccr (HR 0.96, 95% CI 0.92–0.98) were the covariates which entered the best predictive equation for mortality. Neither CRP (P = 0.66) nor total WBC (P = 0.12) or PMN (P = 0.10) entered this selection.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Numerous studies have demonstrated that increased inflammatory markers strongly predict all-cause and cardiovascular mortality among the CKD patient population [1–11,15]. This finding has favoured the idea that these non-specific parameters can be used as outcome predictors. Moreover, the concept that inflammation should be considered not only as a risk marker but also as a risk factor has been substantiated by the demonstration that some inflammatory markers are actively involved in the mechanisms of atherothrombogenesis [14]. Despite all the evidence, many questions concerning the utility of inflammatory markers as outcome predictors remain unanswered.

Inflammatory markers have been questioned as outcome predictors because of their poor specificity and significant variability over time [18,19]. Likewise, inflammatory markers may merely reflect the aggregate comorbidity, and, it is unknown, so far, whether or not they add or not predictive information of death beyond that provided by other predictive instruments such as the comorbid indexes.

In most of the studies addressing this issue, HRs for predicting mortality of inflammatory markers have been calculated with adjustment for common comorbid illnesses, such as coronary artery disease, peripheral vascular disease, diabetes and left ventricular dysfunction [1–8,10,11]. However, these independent variables have always been entered separately into the multivariate models. This statistical procedure may confer to the inflammatory marker an advantageous predictive power, through leaving it as the best variable for reflecting aggregate comorbidity.

In agreement with other previous studies [1–11,15], CRP, total WBC and PMN cell counts predicted all-cause mortality in the CKD patient population included in the present study. However, these inflammatory markers did not add predictive information on mortality after adjustment for age and comorbidity in the multivariate analysis. When comorbid index was substituted by comorbid illnesses, entered separately into the multivariate model of the present study, CRP remained statistically significant as an independent variable in the best predictive equation for mortality (data not shown).

The risk of death for CKD patients is much higher than for the general population. Notwithstanding, differences can be expected in the outcome of these patients according to their age and comorbidity. Several comorbid indexes have been shown to be accurate instruments for predicting mortality in CKD patients [16]. As long as age is taken into account, there appear to be no differences among them in predicting mortality [16]. Although the comorbid index devised by Davies et al. [17] was originally developed for peritoneal dialysis patients, it does not utilize any exclusive characteristic for patients on peritoneal dialysis, and therefore, we believe that it can be used as a predictor of death in CKD patients independent of their treatment, as is demonstrated in the present study.

Unlike inflammatory markers, serum albumin levels added predictive information of death to that provided by age and comorbid index. Inflammation can inhibit albumin synthesis [20], and serum albumin is considered a ‘negative’ acute-phase reactant. Since albumin is a long-lived protein in plasma, its levels may be more sensitive than the highly variable levels of commonly used inflammatory markers to indicate the severity of comorbid illnesses or the inflammatory process associated with them or both.

This study has limitations. Relying on a single baseline determination of an inflammatory marker is an important shortcoming for outcome prediction. However, we aimed specifically at this point in a similar manner to that applied in the majority of studies addressing this issue. Serial measurements of the levels of inflammatory markers could improve their sensitivity for outcome prediction [9]. Furthermore, persistent elevations of inflammatory markers in asymptomatic CKD patients may be helpful for the diagnosis of unsuspected severe comorbidities [21]. Hence, although the predictive value of a single baseline determination of inflammatory markers is questioned in this study, we do not negate their clinical utility.

Statins, and ACE inhibitors have been shown to possess anti-inflammatory effects [12,13]. A large percentage of the patients included in this study were receiving these drugs. Thus, we cannot rule out interferences from the action of these drugs on the relationship between the inflammatory state and comorbidities.

The number of diabetic patients included in the present study was high. The utility of CRP levels as predictor of arteriosclerosis risk in these patients has recently been questioned [22]. Thus, we cannot rule out a potential influence of the characteristics of the study patients on the present results.

The patients included in this study were not on dialysis at the time of baseline determination of inflammatory markers. Exposure of blood to bioincompatible dialysis membranes, plasticizers or lipopolysaccharide-containing dialysates have been shown to be sources of inflammation in CKD patients on dialysis [12,13]. It is unclear to what extent inflammation related to dialysis procedures may specifically influence mortality [23]. Therefore, we cannot rule out a different predictive value of elevated inflammatory markers in either pre-dialysis or dialysis CKD patients.

In conclusion, although elevated inflammatory markers are associated with a worse outcome in CKD patients, they did not add predictive information of all-cause mortality beyond that provided by age and a comorbid index. These data should be taken into consideration in the design of future clinical trials or other studies addressing the mortality of CKD patients.

Conflict of interest statement. We have had no involvements that might raise the question of bias in the work reported or in the conclusions, implications or opinions stated.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 29. 9.05
Accepted in revised form: 23. 1.06


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