NDT Advance Access originally published online on January 31, 2006
Nephrology Dialysis Transplantation 2006 21(6):1588-1595; doi:10.1093/ndt/gfk092
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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
The effect of single and repeatedly high concentrations of C-reactive protein on cardiovascular and non-cardiovascular mortality in patients starting with dialysis
1 Department of Clinical Epidemiology, Leiden University Medical Centre, 2 Hans Mak Institute, Naarden and 3 Department of Nephrology, Academic Medical Centre, University of Amsterdam, The Netherlands
Correspondence and offprint requests to: F. W. Dekker, Leiden University Medical Centre, Department of Clinical Epidemiology, C9-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Email: f.w.dekker{at}lumc.nl
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Abstract |
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Background. Single measurements of C-reactive protein (CRP) predict cardiovascular mortality in dialysis patients. However, CRP can be temporarily elevated due to infections. Therefore, we investigated the effect of single and repeatedly high concentrations of CRP on cardiovascular and non-cardiovascular mortality in incident dialysis patients.
Methods. In the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), patients starting with dialysis were enrolled between 1997 and 2002. From 635 patients, plasma CRP concentrations were determined at 3 and 6 months of follow-up. Concentrations >10 mg/l were regarded as ‘high’. Patients were followed until time of death, or censored at the end of follow-up (1 May 2004). Cox regression models were performed to compare mortality between patients with repeatedly low CRP, with varying CRP and with repeatedly high CRP.
Results. At the end of follow-up, 247 patients had died, of which 107 patients died of cardiovascular disease (47.8%). Patients with low CRP3 months and high CRP6 months were at increased cardiovascular [adjusted hazard ratio (HR): 2.59, 95% CI: 1.25–5.37] and non-cardiovascular (adjusted HR: 2.18, 95% CI: 1.11–4.28) mortality risk compared with patients with low CRP on both occasions. Moreover, patients with high CRP on both occasions had a higher cardiovascular (adjusted HR: 1.51, 95% CI: 0.72–3.18) and non-cardiovascular (adjusted HR: 2.25, 95% CI: 0.96–5.28) mortality risk than patients with high CRP3 months and low CRP6 months.
Conclusions. Single and repeatedly high concentrations of CRP (>10 mg/l) are related to both cardiovascular and non-cardiovascular mortality in dialysis patients. A high CRP concentration, therefore, has implications for the treatment of cardiovascular as well as non-cardiovascular disease.
Keywords: cardiovascular mortality; C-reactive protein; dialysis patients; inflammation
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Introduction |
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Dialysis patients have a much higher mortality rate than the general population. A large part of this increased mortality risk can be attributed to an increased cardiovascular mortality rate [1]. From cross-sectional studies, it is known that inflammation, which is present in 35–65% of the dialysis patients, is associated with the presence of atherosclerosis [2–4]. Single measurements of CRP are highly predictive of cardiovascular mortality in patients on both haemodialysis and peritoneal dialysis treatment [5–8]. However, besides atherosclerosis, other conditions can also lead to an elevation of CRP, such as acute or chronic infections and the presence of systemic diseases other than atherosclerosis [2,9]. Therefore, it can be hypothesized that a high serum CRP in dialysis patients will not only be predictive of cardiovascular mortality, but also of non-cardiovascular mortality. If so, an increased CRP not only has implications for treating cardiovascular disease, but other treatment strategies should also be considered.
The aim of this study was to examine the effect of single and repeatedly high concentrations of CRP on cardiovascular and non-cardiovascular mortality in patients starting with dialysis. For this purpose, plasma CRP was measured on two occasions after the start of dialysis. We compared cardiovascular and non-cardiovascular mortality between dialysis patients with repeatedly low CRP concentrations (
10 mg/l), patients with varying CRP concentrations (10 and >10 mg/l) and patients with repeatedly high CRP concentrations (>10 mg/l).
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Subjects and methods |
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Subjects
The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) is a prospective follow-up study, in which all new end stage renal disease (ESRD) patients from 38 Dutch dialysis centres were enrolled. Only patients above 18 years of age starting with their first renal replacement therapy were included in the study. The inclusion period was between 1997 and 2002. Patients were followed until time of death, or censored at the date of leaving the study due to kidney transplantation, transfer to a non-participating centre, recovery of renal function or at the end of follow-up (1 May 2004). All patients gave informed consent. The Medical Ethical Committees of all the participating dialysis centres approved the study.
Data collection
Data on clinical and demographic characteristics, such as gender, age, smoking, primary kidney disease and co-morbidity, were collected at baseline. The number of co-morbidities was defined according to the Davies’ co-morbidity scale, as having no, intermediate or severe co-morbidity [10]. Nutritional status, blood pressure, dialysis characteristics (modality, Kt/Vrenal), body mass index (BMI), residual renal function and haemoglobin were gathered at 3 months after the start of dialysis. Nutritional status was determined with the 7-point scale of the subjective global assessment (SGA) [11]. Residual renal function, expressed as the glomerular filtration rate (GFR), was determined from the mean of renal creatinine and urea clearance, corrected for body surface area (ml/min/1.73 m2). Primary kidney diseases as well as causes of death were classified according to the European Renal Association–European Dialysis and Transplantation Association (ERA–EDTA) coding system [12].
ERA–EDTA codes 0 (cause of death uncertain/not determined), 11 (myocardial ischaemia and infarction), 12 (hyperkalaemia), 14 (other causes of cardiac failure), 15 (cardiac arrest, cause unknown), 16 (hypertensive cardiac failure), 17 (hypokalaemia), 18 (fluid overload), 22 (cerebrovascular accident), 26 (haemorrhage from ruptured vascular aneurysm) and 29 (mesenteric infarction) were classified as death due to cardiovascular disease. All other codes were regarded as deaths of non-cardiovascular origin, of which codes 31–39 were classified as deaths due to infection.
Blood and urine samples were obtained at 3 and 6 months of follow-up. CRP concentrations were determined in these samples with an immunoturbidimetric assay with a detection limit of 3 mg/l. A CRP concentration >10 mg/l was regarded as ‘high’. Albumin was determined with an immunonephelometric method at 3 months after the start of dialysis.
Analyses
The study population was divided into four groups. Group 1 contained patients with CRP concentrations 10 mg/l at both 3 and 6 months after start of dialysis (low–low group). Group 2 consisted of patients with CRP 10 mg/l at 3 months and >10 mg/l at 6 months (low–high group). Patients with CRP concentrations >10 mg/l at 3 months and 10 mg/l at 6 months were classified in group 3 (high–low group). Group 4 consisted of patients with CRP concentrations >10 mg/l at both 3 and 6 months after start of dialysis (high–high group). Since, groups 1 and 2 did not differ substantially regarding their CRP concentrations at 3 months, these groups were compared to study the effect of a single high CRP concentration vs low CRP on two occasions. For the same reason, groups 3 and 4 were compared to investigate the effect of repeatedly high CRP vs a single high CRP concentration. For all comparisons, the time point of the second CRP measurement (at 6 months after the start of dialysis) was regarded as the starting point of follow-up.
The baseline characteristics of all patient groups were compared with one-way ANOVA for continuous variables and with the 
2-test for categorical variables. Crude differences in all-cause, cardiovascular and non-cardiovascular mortality and mortality due to infection between the patient groups were examined with Kaplan–Meier survival curves and log rank tests. With Cox proportional hazard models, crude HRs for all cause, cardiovascular and non-cardiovascular mortality and mortality due to infection were obtained. In addition, all models were repeated while adjusting for possible confounders, that is CRP at 3 months, age, gender, primary kidney disease, co-morbidity, cardiovascular disease, diabetes mellitus, systolic blood pressure, nutritional status, smoking, haemoglobin, residual renal function, BMI and dialysis modality. Subsequently, we performed Cox proportional hazard models to investigate all cause mortality during each year of follow-up, conditional on having survived the first and subsequent year. Again, all models were adjusted for possible confounders.
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Results |
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CRP was determined in 843 patients at 3 months after the start of dialysis. For 208 of these patients, CRP levels had not yet been determined at 6 months, mostly because of logistic reasons. These patients did not differ with respect to demographic and clinical characteristics (except dialysis centre and modality) compared with the 635 patients for whom CRP levels were available at 3 and 6 months and who were thus included in the present study. There were 335 patients had repeatedly low concentrations of CRP (
10 mg/l). Both groups with patients with varying CRP concentrations contained 84 patients. There were 132 patients with repeatedly high CRP concentrations (>10 mg/l). Table 1 shows the baseline characteristics of the four patient groups. Patients with repeatedly high CRP concentrations had with more cardiovascular disease, more severe co-morbidity, were more often malnourished, were older and had higher BMI levels, had less residual renal function, had lower haemoglobin concentrations and lower albumin concentrations compared with patients with repeatedly low CRP concentrations. Both patient groups with varying CRP showed intermediate characteristics at baseline.
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Until 1st May 2004, 247 patients had died. For 23 patients, the causes of death were unknown, 107 patients died of cardiovascular disease (47.8%) and 117 patients died of non-cardiovascular disease (52.2%). Of those patients dying of non-cardiovascular disease, 19 patients died of infection. Median follow-up was 2.27 years (range 0–6.54 years) after the 6-month assessment. Table 2 show the number of deaths and incidence rates per patient group. Figures 1 and 2 show the crude survival curves for the patient groups all-cause, cardiovascular, non-cardiovascular mortality and mortality due to infection. Low–high patients had a higher crude risk of all mortality outcomes compared with patients with repeatedly low CRP concentrations (Figure 1). Patients with repeatedly high CRP concentrations had a worse crude all-cause, cardiovascular as well as non-cardiovascular survival compared with high–low patients (Figure 2). Between the latter two groups, no differences in mortality due to infection were observed.
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The effect of single and repeatedly high concentrations of CRP was further studied by means of Cox proportional hazard models (Table 3). Adjusted HRs for low–high patients compared with low–low patients were 2.22 (95% CI: 1.38–3.55) for all-cause mortality, 2.59 (95% CI: 1.25–5.37) for cardiovascular mortality, HR 2.18 (95% CI 1.11–4.28) for non-cardiovascular mortality and 5.43 (95% CI 1.20–24.49) for mortality due to infection (Table 3).
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High–high patients had an increased all-cause mortality (HR: 1.74, 95% CI: 1.02–2.97), cardiovascular (HR: 1.51, 95% CI: 0.72–3.18) as well as non-cardiovascular mortality risk (HR: 2.25, 95% CI: 0.96–5.28) compared with high–low patients (Table 3). Due to the low number of events, the adjusted HR for mortality due to infection could not be calculated.
Table 4 shows the results from the second analysis, in which we performed Cox proportional hazard models during each year of follow-up, conditional on having survived the first and subsequent year. During the first and second year of follow-up, low–high patients were at increased all-cause mortality risk compared with low–low patients. In the third year, no differences in mortality risk were observed between the patient groups.
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In the first year of follow-up, patients in the high–high group had a slightly increased mortality risk compared with the high–low group. For the other two years of follow-up, no differences in mortality risk were observed between high–high patients and high–low patients.
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Discussion |
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The present prospective follow-up study of incident dialysis patients has shown that a single or repeatedly high concentration of CRP (>10 mg/l) is associated with a higher cardiovascular as well as with a higher non-cardiovascular mortality risk compared with repeatedly low CRP concentrations (
10 mg/l). The mortality risk was highest in the patients with repeatedly high CRP particularly in the first year. This effect was present despite extensive adjustment for possible confounders such as age, co-morbidity, cardiovascular disease, diabetes mellitus, nutritional status, smoking, haemoglobin, residual renal function and dialysis modality. A limitation of our study might be that the CRP concentrations were not measured with a high-sensitivity (HS) method. In the general population, CRP concentrations between 1 and 3 mg/l were associated with increased cardiovascular mortality risks [13]. Any association between CRP below 3 mg/l and mortality in our study population could have been missed, since the detection limit of our assay was 3 mg/l. However, in our study population, mean CRP at 3 months was 14.2 mg/l, which was much higher than in the general population [9]. In the general population, high CRP levels are often regarded as a sign of an acute infection, while in the dialysis population it may merely reflect a chronic inflammatory process since the high CRP levels often persist. If every patient with a CRP concentration below the detection limit of 3 mg/l had actually had a CRP concentration of 0 mg/l, the mean CRP would have been 13.0 mg/l, which still is much higher than the mean CRP concentration in the general population. Furthermore, an association between CRP levels higher than 3 mg/l was observed and it seems unlikely that this association would not have been present in the CRP range of 0–3 mg/l. In addition, even with the use of a high-sensitivity CRP, patients would have been classified into the same groups in the present study. Above 3 mg/l, a high-sensitivity assay would not yield systematically different CRP levels than the CRP assay we used in the present study. Moreover, Stenvinkel et al. [6] found that a cut off point for CRP concentrations of 10 mg/l was one of the best cut off points with regard to the prediction of survival in ESRD patients. The use of high-sensitivity CRP might, therefore, be of minor importance for the purposes of this study.
An association between a single time point elevated CRP and mortality has been reported previously [5–8]. This is remarkable because of the short half-life of CRP and its immediate elevation during intercurrent infections leading to marked fluctuations over time [9,14]. To allow some discrimination between an occasionally high CRP concentration and a persistently high CRP concentration, we measured CRP at 3 months after start of dialysis and 3 months later. Still, the measurements of CRP might not have reflected the true inflammatory state of the patient during the entire period. Although the patients with repeatedly high concentrations of CRP had the greatest mortality risk, the results must be interpreted cautiously. A patient with a CRP concentration of 11 mg/l at 3 months and 9 mg/l at 6 months was classified as having varying CRP concentrations, although their CRP concentrations were actually rather similar. Additionally, a patient with 14 mg/l at one occasion and 35 mg/l at the other occasion was classified as having high CRP on two occasions; the differences between these two measurements are actually quite large. For this reason, we also excluded those patients in the repeatedly low CRP group with differences between two measurements above 5 mg/l, as well as patients with differences below 5 mg/l in the varying CRP groups, and we also set the concentration of inflammation at 15 mg/l for the group with repeatedly high CRP. The results were not substantially different from the original analyses (data not shown). Interestingly, subjects with CRP concentrations between 4 and 10 mg/l (which might indicate a kind of micro-inflammation in ESRD patients) did not have an increased mortality risk compared with patients with CRP concentrations of 3 mg/l or lower. Moreover, only those patients within the highest quartile of the mean of the two CRP concentrations at 3 and 6 months (>15 mg/l) carried an increased mortality risk (data not shown). Thus, these results might indicate that macro-inflammation—rather than micro-inflammation—is most predictive of mortality.
CRP is a non-specific acute-phase protein that can be temporarily elevated as a result of acute infections or can be chronically elevated, as is seen in many chronic systemic diseases [9]. It is not exactly known to what extent temporary elevations of CRP add to the high prevalence of the high CRP concentrations seen in dialysis patients. Although this was not the primary aim of our study, we found that 80% of the patients with CRP concentrations 10 mg/l at 3 months of follow-up also had a CRP concentration of 10 mg/l at 6 months of follow-up. More than 60% of the patients with a CRP concentration >10 mg/l at 3 months also had CRP concentrations of >10 mg/l at 6 months, suggesting that these high levels of CRP determined on one occasion, reflect a chronic inflammatory state in many patients. Twenty percent of our study population persistently had CRP levels >10 mg/l, which corresponds with another study investigating the effect of persistently and occasionally high CRP [15].
Inflammation has been shown to be associated with atherosclerosis and cardiovascular disease in dialysis patients [3–8,16]. Recently, Nascimento et al. [15] reported that prevalent haemodialysis patients with persistently high CRP on four occasions had a higher all cause mortality risk compared with patients with an occasionally high CRP. Although CRP was measured on two occasions in our study, we also found that a repeatedly high CRP concentration is related to an increased cardiovascular mortality risk. This is in line with studies suggesting that CRP may actively participate in the development of the atherosclerotic plaque, since CRP can induce the formation of adhesion molecules, stimulate low density lipoproteins (LDL) uptake by macrophages, enhance complement activation and smooth muscle cell migration and proliferation, and inhibit endothelial progenitor cell differentiation and survival [17–19].
Although other authors mention that CRP is involved in non-cardiovascular disease as well, previous studies did not analyse non-cardiovascular disease as an outcome. In our study, we also found an association of elevated CRP with non-cardiovascular mortality. The increased mortality risk remained apparent during 2 years of follow-up. It is therefore unlikely that the increased non-cardiovascular mortality risk could only be attributed to the risk of acute infections. We also performed an additional analysis for non-cardiovascular mortality in which we excluded the deaths due to infection. The adjusted HRs were not substantially different from the HRs mentioned in Table 3. Therefore, our results suggest that CRP is not only involved in cardiovascular disease and infectious disease, but is also involved in other systemic diseases in dialysis patients.
The present study shows that high concentrations of CRP (>10 mg/l) measured on one occasion, may reflect a chronic inflammatory process in many patients. Patients with single or repeated CRP concentrations of >10 mg/l on two occasions were both at increased cardiovascular and non-cardiovascular mortality risk compared with patients with CRP concentrations 10 mg/l on these two occasions. Therefore, our results do not indicate a specific association between CRP and cardiovascular disease, but might show that CRP is a sign of general malaise in dialysis patients. Further studies, e.g. with more repeated measurements, with more patients or with longer follow-up are needed to get more insight into the mechanism behind the relation of CRP and mortality in dialysis patients. The present study indicates that patients with single or repeatedly high concentrations of CRP have a worse prognosis than patients without these high CRP concentrations. This implicates that patients with an increased CRP not only have to be treated for cardiovascular disease, but that treatment for other conditions should also be considered.
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Acknowledgments |
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This work was supported by a grant from The Dutch Kidney Foundation (E.018).
NECOSAD-study group members: Apperloo AJ, Bijlsma JA, Boekhout M, Boer WH, van der Boog PJM, Büller HR, van Buren M, de Charro FTh, Doorenbos CJ, van den Dorpel MA, van Es A, Fagel WJ, Feith GW, de Fijter CWH, Frenken LAM, Grave W, van Geelen JACA, Gerlag PGG, Gorgels JPMC, Huisman RM, Jager KJ, Jie K, Koning-Mulder WAH, Koolen MI, Kremer Hovinga TK, Lavrijssen ATJ, Luik AJ, van der Meulen J, Parlevliet KJ, Raasveld MHM, van der Sande FM, Schonck MJM, Schuurmans MMJ, Siegert CEH, Stegeman CA, Stevens P, Thijssen JGP, Valentijn RM, Vastenburg GH, Verburgh CA, Vincent HH, Vos PF.
Conflict of interest statement. None declared.
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[Abstract/Free Full Text]
Accepted in revised form: 4. 1.06
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