Hemodialysis International 2014; 18:674–679
The level of C-reactive protein in chronic hemodialysis patients: A comparative study between patients with noninfected catheters and arteriovenous fistula in two large Gulf hemodialysis centers Alaa A. SABRY,1 Eid M. ELSHAFEY,2 Khalid ALSARAN,3 Medhat SHALABY,3 Sherrine ALSHERBEINY,3 Mohamed ABDELKADER3 1 Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt; 2Nephrology Division, Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt; 3Prince Salman Center for Kidney Diseases, Riyadh, Kingdom of Saudi Arabia
Abstract Hemodialysis (HD) patients have greater morbidity and mortality when they have a central venous catheter (CVC) rather than an arteriovenous fistula (AVF) access. Inflammation associated with dialysis catheter use and resultant higher C-reactive protein (CRP) levels could have an independent adverse effect on patient outcomes. In this prospective study, we investigated whether HD catheters induce inflammation independent of infection. We compared the mean levels of the inflammatory marker (CRP) in 67 patients on maintenance HD using noninfected catheters with 86 HD patients using AVFs at Prince Salman Center for Kidney Diseases, Saudi Arabia (KSA), and Jahra Hospital, Kuwait, who met our inclusion criteria. C-reactive protein levels were measured every 2 months over a period of 6 months using immunoturbidimetric assay. One hundred fifty-three patients on maintenance HD for more than 6 months were included in the study, with mean age of 52.19 ± 16.06 years; 66% were males and 34% were females. Serial levels of mean CRP were statistically and significantly higher in group with noninfected catheters (1.33, 1.24, and 1.10 mg/ dL) compared to those with AVFs (0.65, 0.59, and 0.68 mg/dL) with P value of 0.000. In our study, we found no relation between CRP level and age, sex, hemoglobin, albumin, calcium, phosphorus, and iPTH level in both groups. Hemodialysis patients with a catheter have a heightened state of inflammation independent of infection, and thus our study supports the avoidance of catheters and a timely conversion to AVFs with catheter removal. Key words: CRP, access, inflammation, hemodialysis
INTRODUCTION Correspondence to: E. M. Elshafey, MD, Nephrology Division, Internal Medicine Department, Tanta University Hospitals, Tanta, Egypt. E-mail: [email protected]
The mortality rate for end-stage renal disease (ESRD) patients, especially for those on maintenance hemodialysis (HD), is 6 times higher than in the general population.1
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12145
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CRP in HD
Factors associated with poor clinical outcomes in HD patients include the presence of increased inflammation.2 Chronic inflammation is an important component in the development and progression of atherosclerosis.3 C-reactive protein (CRP) has been shown to be both a marker and a mediator of atherosclerosis.4 In subjects undergoing HD, CRP is a potent, independent predictor of cardiovascular mortality as well as malnutrition.5–9 Central venous catheters are associated with infection and resultant higher CRP levels, suggesting that catheters may be an important determinant of the increased inflammatory response.10–14 Catheter utilization in HD patients has increased by an alternating rate of 50% between 1998 and 2004, and data from the United States Renal Data System indicate that 81% of the patients initiate HD through a catheter.1 Recent data showed that change from an arteriovenous access to catheter is associated with increased mortality in adult HD patients.11 Therefore, avoidance or removal of catheters may represent an effective strategy to limit the inflammatory response in HD patients. In fact, a recent review suggested that “nephrologists are ethically obliged to explain to patients the harms of tunneled catheters.”10 Although catheters might predispose to infection and result in inflammation,12 no much data exist to assess catheter-induced inflammation independent of infection. In this prospective, controlled study, HD patients were evaluated to determine the influence of persistent use of noninfected catheter vs. use of a matured arteriovenous fistula (AVF) on inflammation, using CRP as a marker. We hypothesized that the presence of persistent catheter use would be associated with higher CRP when compared with fistula use.
PATIENTS AND METHODS This prospective multicenter study was conducted at Prince Salman Center for Kidney Diseases (PSCKD), Saudi Arabia (KSA), and Jahrah Hospital, Kuwait, over a period of 6 months. One hundred fifty-three patients (101 males and 52 females) receiving maintenance HD for at least 6 months were enrolled in this study, after signing the informed written consent; their mean age was 52.19 ± 16.02 years. No patient died during the study period. In addition, all patients in the groups studied longitudinally completed 6 months of follow-up. C-reactive protein levels in all patients were followed prospectively with longitudinal analysis of laboratory values every 2 months for 6 months using turbidimetric immunoassay technique (fully automated chemistry analyzer). The following were exclusion criteria: (1) a clotted nonfunctional arteriovenous graft (AVG) in place; (2) a failed
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renal allograft in place; (3) patients who were hospitalized for infection during the month of scheduled blood draw; and (4) patients with fever in the week before scheduled blood draw (fever defined as equal to or greater than 37.5°C) throughout the study period. The study protocol was approved by the Institutional Review Board/Ethics Committee and adhered to the principles of Declaration of Helsinki.
Description of study groups Catheter group This group consisted of 67 patients (44 males and 23 females) on maintenance HD via only a tunneled internal jugular catheter for 6 months. Fistula-only group This group consisted of 86 patients (57 males and 29 females) on maintenance HD through only AVF for 6 months.
Dialysis prescription and patient care The dialysis machines applied in the trial were 4008 and 5008 monitors (both Fresenius Medical Care, Bad Homburg, Germany) equipped with OCM, and enabling both HD and online HDF treatment modes. Patients were dialyzed according to their individual prescription with high-flux membranes (Nephral ST 500, HOSPAL Industrie, Meyzieu, France and FX 80 & FX 100, Fresenius Medical Care) with UFcoeff of 65 and 59 and 73 mL/h × mmHg, and effective surface areas of 2.15 m2 and 1.8 m2 and 2.2 m2, respectively. The dialysate flow (Qd) was 500 mL/min and effective blood flow (Qbeff) was 280– 300 mL/min. Dialysis adequacy was assessed by monthly calculation of Kt/V formula and the urea reduction ratio (URR) for all cases. Single pool Kt/V (spKt/V) was assessed using the Daugirdas second-generation formula.15 Recombinant human erythropoietin and intravenous iron were prescribed to maintain Hb from 105 to 120 g/L, transferring saturation >20%, and serum ferritin >100 ng/mL. Phosphate binders were used to maintain predialysis serum phosphate below 1.78 mmol/L, and serum calcium from 2.1 to 2.37 mmol/L. Vitamin D was prescribed to maintain intact parathyroid hormone between 15.9 and 31.8 pmol/L. All tunneled catheters were locked with heparin to prevent thrombosis between HD treatments; citrate or antibiotic locks were not used. All exit sites were cleaned with a standard Betadine solution after each treatment before re-dressing, and patients were monitored for fever/signs of infection throughout the study period.
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therapy was 2.92 ± 2.08 years (range 1–11 years), mean body mass index (BMI) was 25.75 ± 5.04 kg/m2, 15 patients have diabetes, and 58 patients were negative and only 9 patients were positive for HCV-abs in the serum. In the fistula group, the mean age was 52.22 ± 15.84 years (range 19–80 years), mean BMI was 26.87 ± 5.22 kg/m2, 19 patients have diabetes, 78 patients were seronegative and 8 patients were seropositive for HCV-abs, and the mean duration of HD therapy was 3.51 ± 1.87 years (range 10 months–12 years). In both groups, no statistically significant differences as regard the demographic data were observed (Table 1). In the studied groups (catheter and fistula), there was no statistically difference as regard the biochemical variables apart from CRP levels (they were followed up prospectively every 2 months for a period of 6 months). In the catheter group, median (IQR) serum CRP levels were 0.79 (0.55, 1.78), 0.68 (0.52, 1.04), and 0.86 (0.58, 1.20) mg/dL, respectively, compared with the fistula group, which had median (IQR) serum CRP levels of 0.48 (0.20, 0.93), 0.38 (0.19, 0.85), and 0.39 (0.20, 0.87) mg/dL, respectively (P = 0.000) (Table 1; Figure 1).
Demographic and biochemical data
Hemodialysis adequacy
In the catheter group, the mean age was 52.15 ± 16.36 years (range 18–80 year), the mean duration of HD
The mean and SD of URR and Kt/V values for the whole group were 70.18 ± 4.95% and 1.40 ± 0.15, respectively.
Patients were also subjected to the following biochemical tests: hemoglobin, calcium (corrected), phosphorus, PTH, Kt/V, URR, and albumin.
Statistical analysis The results were summarized as mean ± standard deviation (SD) and median (interquartile range [IQR]). Person chi-square test, independent-sample t test, and MannWhitney U test were used for testing the significance of the differences in values measured between the two groups as appropriate. Multivariate analyses for repeated measures were performed (using mixed effects models) to evaluate the independent association between access type and CRP concentrations (log-transformed). Covariates that were included in the model were age, gender, diabetes status, URR, calcium-phosphate product, and dialysis vintage. P value ≤ 0.05 (two-tailed) was taken as statistically significant. All analysis was performed using the Statistical Package for Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA).
Table 1 Demographic and biochemical data of both groups Parameters Number Male/female ratio Age (mean ± SD; y) BMI (mean ± SD; kg/m2) Duration of HD (mean ± SD; y) CRP1 (median, IQR; mg/dL), after 2 months CRP2 (median, IQR; mg/dL), after 4 months CRP3 (median, IQR; mg/dL), after 6 months Hemoglobin (mean ± SD; gm/L) Darbepoetin dose (median, IQR; μg/wk) iPTH (median, IQR; pmol/L) Serum corrected calcium (mean ± SD; mmol/L) Serum phosphate (mean ± SD; mmol/L) Ca × Phosphorus product (mean ± SD; mmol2/L2) ALP (median, IQR; IU/L) Iron saturation (mean ± SD; %) Serum ferritin (median, IQR; ng/mL) Serum albumin (mean ± SD; gm/L) Kt/V (mean ± SD) URR (mean ± SD, %)
Fistula group
Catheter group
P value
86 57/29 52.22 ± 15.84 26.87 ± 5.22 3.51 ± 1.87 0.48 (0.20, 0.93) 0.38 (0.19, 0.85) 0.39 (0.20, 0.87) 109.15 ± 12.48 31.25 (20.00, 40.00) 30 (19.06, 51.98) 2.17 ± 0.21 1.51 ± 0.32 3.29 ± 0.75 129 (78.75, 169.50) 24.65 ± 5.14 358 (218.70, 729.23) 32.86 ± 3.48 1.39 ± 0.15 69.88 ± 5.25
67 44/23 52.15 ± 16.36 25.75 ± 5.04 2.92 ± 2.08 0.79 (0.55, 1.78) 0.68 (0.52, 1.04) 0.86 (0.58, 1.20) 106.84 ± 21.95 35.16 (20.00, 58.59) 30 (18.73, 49.20) 2.13 ± 0.22 1.50 ± 0.44 3.16 ± 0.88 112 (75.00, 160.00) 25.14 ± 5.33 324 (214.00, 608.00) 32.10 ± 4.74 1.42 ± 0.15 70.55 ± 4.55
0.937 0.977 0.184 0.068 0.000 0.000 0.000 0.413 0.398 0.871 0.172 0.840 0.336 0.292 0.684 0.481 0.256 0.232 0.409
ALP = alkaline phosphatase; BMI = body mass index; CRP = C-reactive protein; HD = hemodialysis; iPTH = intact parathormone; IQR = interquartile range; URR = urea reduction ratio.
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CRP in HD
Figure 1 C-reactive protein (CRP) levels in the catheter and fistula groups.
The mean URR and kt/V in the fistula group were not significantly different from that in the catheter group (69.88 ± 5.25% vs. 70.55 ± 4.55%, P value = 0.409 and 1.39 ± 0.15 vs. 1.42 ± 0.15, P value = 0.232, respectively) (Table 1). In multivariate analysis using mixed effects models, only access type (tunneled catheters use, P value = 0.000) was a significant predictor of an elevated CRP concentration independent of age, gender, diabetes status, URR, calcium-phosphate product, and dialysis vintage (P values > 0.05).
DISCUSSION This study aimed to provide an analysis of inflammatory response as assessed by CRP measurements in prevalent (HD) patients every 2 months for a period of 6 months. Our results show that high-grade and persistent inflammation are prevalent in HD patients with noninfected catheters compared with patients who receive dialysis via AVF. The data further confirm our hypothesis that HD patients subsist within a state of chronic inflammation as reflected by our results. The presence of a HD catheter was a major determinant of the inflammatory response in our cohort. Consistent with our study, Movilli et al. reported in a cross-sectional analysis of 79 HD patients that the mean CRP for HD patients with catheters was 20 mg/L vs. 8 mg/L for patients with AVG and 5 mg/L for those with AVF.13 The clinical relevance of this observation is also obvious because HD catheter utilization has increased by 50% in the United States between 1998 and 2004, and for the year 2004, catheter placement rate was 447/1000 patient years as opposed to the low fistula placement rate of 96.8/1000 patient years. Needless to say, catheters have been associated with increased rates of infections, complication, and death.1 Moreover, Goldstein et al.16 reported
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that a change of dialysis access from a catheter to a fistula is accompanied by a significant fall in the serum level of CRP and reduction of inflammation. These findings were in patients who did not have evident catheter infections. This should provide yet further impetus to use fistulas rather than catheters in HD patients. Some issues remain, however. The first is that in this report, information on long-term outcome is not provided, either for morbidity and mortality or for quality of life. One can assume that a fall in the CRP level is a good thing, and that such a drop may reduce cardiovascular morbidity and mortality, but assumption is not a fact. A second point is that there can be substantial variation in the CRP level in a given patient, and single values of CRP were used by Goldstein et al.16 rather than multiple ones. Still, the patterns of change in CRP levels are distinct and differ between those who got a fistula and those who remained with a dialysis catheter. Apparently, most HD patients suffer from chronic inflammation. Sachdeva et al.17 observed, in an adjusted analysis, that CRP levels are significantly elevated only in the first week following access surgery, but, similar to the HEMO study, CRP levels were not elevated at 1 month or other points throughout the following year. These investigators reported significantly higher CRP values associated with AVGs, not present with AVFs. In the HEMO study, AVFs and AVGs were combined into one “AV access” group for the analysis, which may have obscured differences between the AV access and TC group and differences within the AV access group (AVFs vs. AVGs). Similar to the findings of the current study, Goldstein et al.16 and Sachdeva et al.17 reported that tunneled catheter usage was significantly associated with elevated CRP, independent of age and diabetes status. There was no significant association between gender and elevated CRP in Goldstein et al.’s16 study and ours, but, this is in contradistinction to the findings reported by Sachdeva et al.17 in which female sex was associated with higher CRP values, which was observed in multivariate model adjusting for differences in vascular access type. The relationship between gender and CRP levels is unclear and requires further investigation. It is also important to point out that some of the potential determinants included in the analysis are part of the acute-phase response; more specifically, albumin and transferrin are negative acutephase proteins (APPs) and white blood cell count is a positive acute-phase reactant and they are expected to change as a consequence of inflammation, but not in our study as it shows no difference between the two groups. While the actual cause-and-effect relationship between inflammation and variables examined in this study still needs to be sorted out, it is obvious that this cohort of
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patients with a background of inflammatory response requires attention, as studies in the general population have clearly shown that if persistent, even low-grade inflammation is associated with an increased risk for cardiovascular events.9,14,18 A unique aspect of our study is the use of longitudinal data every 2 months over an extensive period of time. There has been growing interest in using serial measurements of CRP to predict outcome in HD patients. Kaysen et al.19 reported that the levels of APPs and albumin varied considerably over time. Furthermore, because the variations in albumin were small, serial measurements of APPs were considered to provide a greater insight into the dynamics of clinically relevant processes. A relatively small, short-term study by Tsirpanlis et al. using serial measurements of CRP described episodes of high inflammation that responded to clinical events along with persistent microinflammation20 in HD population. Also, Snaedal et al.21 reported widely fluctuating CRP values in 68% of patients, indicating that frequent serial CRP measurements are superior to a single measurement. Our study adds important information to these earlier observations, providing information on changes of CRP over time. The result of this study should be interpreted with certain caveats. Most importantly, we do not report the predictive power of our study results in terms of hard clinical outcomes, such as hospitalization and death. The primary goals of this study were to provide a comprehensive analysis of the inflammatory response in HD patients over time and to identify the clinical and demographic determinants of the inflammatory state, including the contributions of a HD catheter toward the inflammatory response. Future studies examining specific CRP cut-off levels in relation to hospitalization and death are critically important in order to support clinical practice guidelines that include monitoring and management of inflammation in ESRD. Other important limitations include the lack of information on comorbidities and the fact that this was only a two-center study, which limit the generalizability of the results. Nevertheless, our results provide clinically relevant information with immediate applicability.
CONCLUSION Hemodialysis patients have a particular pattern of inflammation, usually of low grade. Serial determinations of CRP can provide a better prediction of the inflammatory state of HD patients than scatter single time-point measurements. Catheters are to be avoided, then, not just because they are associated with worse outcomes but also because they are a proinflammatory stimulus whenever possible.
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CONFLICT OF INTEREST The authors have declared that no conflict of interest exists.
Manuscript received September 2013; revised December 2013.
REFERENCES 1 Collins AJ, Foley R, Herzog C, et al. Excerpts from the United States Renal Data System 2007 annual data report. Am J Kidney Dis. 2008; 51(Suppl):1–320. 2 Wanner C, Zimmermann J, Schwedler S, et al. Inflammation and cardiovascular risk in dialysis patients. Kidney Int. 2002; 80(Suppl):99–102. 3 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336:973–979. 4 Lagrand LK, Visser CA, Hermens WT, et al. C-reactiveprotein as a cardiovascular risk more than an epiphenomenon. Circulation. 1999; 100:96–102. 5 Wanner C, Metzger T. C-reactive protein a marker for all-cause and cardiovascular mortality in haemodialysis patients. Nephrol Dial Transplant. 2002; 17:29–32. 6 Himmelfarb J, Stenvinkel P, Ikizler A, Hakim RM. The elephant of uremia oxidative stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002; 62:1524–1538. 7 Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome—the heart of the matter. Nephrol Dial Transplant. 2002; 17:28–31. 8 Panichi P, Migliori M, Pietro S, et al. The link of biocompatibility to cytokine production. Kidney Int Suppl. 2000; 58:96–103. 9 Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis. 2000; 35:469– 476. 10 Rehman R, Schmidt RJ, Moss AH. Ethical and legal obligation to avoid long-term tunneled catheter. Clin J Am Soc Neprol. 2009; 4:456–460. 11 Allon M, Daugirdas J, Depner TA, et al. Effect of change in vascular access on patient mortality in hemodialysis patients. Am J Kidney Dis. 2006; 47:469–477. 12 Nassar GM, Ayus JC. Infection complications of hemodialysis access. Kidney Int. 2001; 60:1–13. 13 Movilli E, Brunori G, Camerini C, et al. The kind of vascular access influences the baseline inflammatory status and epoetin response in chronic hemodialysis patients. Blood Purif. 2006; 24:387–393.
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14 Hung A, Pupim L, Yu C, et al. Determinants of C-reactive protein in chronic hemodialysis patients: Relevance of dialysis catheter utilization. Hemodial Int. 2008; 12:236– 243. 15 Daugirdas J. Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol. 1993; 4:1205–1213. 16 Goldstein SL, Ikizler TA, Zappitelli M, Silverstein DM, Ayus JC. Non-infected hemodialysis catheters are associated with increased inflammation compared to arteriovenous fistulas. Kidney Int. 2009; 76:1063–1069. 17 Sachdeva M, Hung A, Kovalchuk O, Bitzer M, Mokrzycki MH. The initial vascular access type contributes to inflammation in incident hemodialysis patients. Int J Nephrol. 2012; 2012:1–8. 18 Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk
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and mortality in hemodialysis patients. Kidney Int. 1999; 55:648–658. 19 Kaysen GA, Dubin JA, Müller HG, Rosales LM, Levin NW. The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients. The HEMO study group. Kidney Int. 2000; 58:346–352. 20 Tsirpanlis G, Bagos P, Ioannou D, et al. Exploring inflammation in hemodialysis patients: Persistent and superimposed inflammation. A longitudinal study. Kidney Blood Press Res. 2004; 27:63–70. 21 Snaedal S, Heimburger O, Qureshi AR, et al. Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: Implications for patient survival. Am J Kidney Dis. 2009; 53:1024– 1033.
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The level of C-reactive protein in chronic hemodialysis patients: A comparative study between patients with noninfected catheters and arteriovenous fistula in two large Gulf hemodialysis centers Alaa A. SABRY,1 Eid M. ELSHAFEY,2 Khalid ALSARAN,3 Medhat SHALABY,3 Sherrine ALSHERBEINY,3 Mohamed ABDELKADER3 1 Mansoura Urology and Nephrology Center, Mansoura University, Mansoura, Egypt; 2Nephrology Division, Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt; 3Prince Salman Center for Kidney Diseases, Riyadh, Kingdom of Saudi Arabia
Abstract Hemodialysis (HD) patients have greater morbidity and mortality when they have a central venous catheter (CVC) rather than an arteriovenous fistula (AVF) access. Inflammation associated with dialysis catheter use and resultant higher C-reactive protein (CRP) levels could have an independent adverse effect on patient outcomes. In this prospective study, we investigated whether HD catheters induce inflammation independent of infection. We compared the mean levels of the inflammatory marker (CRP) in 67 patients on maintenance HD using noninfected catheters with 86 HD patients using AVFs at Prince Salman Center for Kidney Diseases, Saudi Arabia (KSA), and Jahra Hospital, Kuwait, who met our inclusion criteria. C-reactive protein levels were measured every 2 months over a period of 6 months using immunoturbidimetric assay. One hundred fifty-three patients on maintenance HD for more than 6 months were included in the study, with mean age of 52.19 ± 16.06 years; 66% were males and 34% were females. Serial levels of mean CRP were statistically and significantly higher in group with noninfected catheters (1.33, 1.24, and 1.10 mg/ dL) compared to those with AVFs (0.65, 0.59, and 0.68 mg/dL) with P value of 0.000. In our study, we found no relation between CRP level and age, sex, hemoglobin, albumin, calcium, phosphorus, and iPTH level in both groups. Hemodialysis patients with a catheter have a heightened state of inflammation independent of infection, and thus our study supports the avoidance of catheters and a timely conversion to AVFs with catheter removal. Key words: CRP, access, inflammation, hemodialysis
INTRODUCTION Correspondence to: E. M. Elshafey, MD, Nephrology Division, Internal Medicine Department, Tanta University Hospitals, Tanta, Egypt. E-mail: [email protected]
The mortality rate for end-stage renal disease (ESRD) patients, especially for those on maintenance hemodialysis (HD), is 6 times higher than in the general population.1
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12145
674
CRP in HD
Factors associated with poor clinical outcomes in HD patients include the presence of increased inflammation.2 Chronic inflammation is an important component in the development and progression of atherosclerosis.3 C-reactive protein (CRP) has been shown to be both a marker and a mediator of atherosclerosis.4 In subjects undergoing HD, CRP is a potent, independent predictor of cardiovascular mortality as well as malnutrition.5–9 Central venous catheters are associated with infection and resultant higher CRP levels, suggesting that catheters may be an important determinant of the increased inflammatory response.10–14 Catheter utilization in HD patients has increased by an alternating rate of 50% between 1998 and 2004, and data from the United States Renal Data System indicate that 81% of the patients initiate HD through a catheter.1 Recent data showed that change from an arteriovenous access to catheter is associated with increased mortality in adult HD patients.11 Therefore, avoidance or removal of catheters may represent an effective strategy to limit the inflammatory response in HD patients. In fact, a recent review suggested that “nephrologists are ethically obliged to explain to patients the harms of tunneled catheters.”10 Although catheters might predispose to infection and result in inflammation,12 no much data exist to assess catheter-induced inflammation independent of infection. In this prospective, controlled study, HD patients were evaluated to determine the influence of persistent use of noninfected catheter vs. use of a matured arteriovenous fistula (AVF) on inflammation, using CRP as a marker. We hypothesized that the presence of persistent catheter use would be associated with higher CRP when compared with fistula use.
PATIENTS AND METHODS This prospective multicenter study was conducted at Prince Salman Center for Kidney Diseases (PSCKD), Saudi Arabia (KSA), and Jahrah Hospital, Kuwait, over a period of 6 months. One hundred fifty-three patients (101 males and 52 females) receiving maintenance HD for at least 6 months were enrolled in this study, after signing the informed written consent; their mean age was 52.19 ± 16.02 years. No patient died during the study period. In addition, all patients in the groups studied longitudinally completed 6 months of follow-up. C-reactive protein levels in all patients were followed prospectively with longitudinal analysis of laboratory values every 2 months for 6 months using turbidimetric immunoassay technique (fully automated chemistry analyzer). The following were exclusion criteria: (1) a clotted nonfunctional arteriovenous graft (AVG) in place; (2) a failed
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renal allograft in place; (3) patients who were hospitalized for infection during the month of scheduled blood draw; and (4) patients with fever in the week before scheduled blood draw (fever defined as equal to or greater than 37.5°C) throughout the study period. The study protocol was approved by the Institutional Review Board/Ethics Committee and adhered to the principles of Declaration of Helsinki.
Description of study groups Catheter group This group consisted of 67 patients (44 males and 23 females) on maintenance HD via only a tunneled internal jugular catheter for 6 months. Fistula-only group This group consisted of 86 patients (57 males and 29 females) on maintenance HD through only AVF for 6 months.
Dialysis prescription and patient care The dialysis machines applied in the trial were 4008 and 5008 monitors (both Fresenius Medical Care, Bad Homburg, Germany) equipped with OCM, and enabling both HD and online HDF treatment modes. Patients were dialyzed according to their individual prescription with high-flux membranes (Nephral ST 500, HOSPAL Industrie, Meyzieu, France and FX 80 & FX 100, Fresenius Medical Care) with UFcoeff of 65 and 59 and 73 mL/h × mmHg, and effective surface areas of 2.15 m2 and 1.8 m2 and 2.2 m2, respectively. The dialysate flow (Qd) was 500 mL/min and effective blood flow (Qbeff) was 280– 300 mL/min. Dialysis adequacy was assessed by monthly calculation of Kt/V formula and the urea reduction ratio (URR) for all cases. Single pool Kt/V (spKt/V) was assessed using the Daugirdas second-generation formula.15 Recombinant human erythropoietin and intravenous iron were prescribed to maintain Hb from 105 to 120 g/L, transferring saturation >20%, and serum ferritin >100 ng/mL. Phosphate binders were used to maintain predialysis serum phosphate below 1.78 mmol/L, and serum calcium from 2.1 to 2.37 mmol/L. Vitamin D was prescribed to maintain intact parathyroid hormone between 15.9 and 31.8 pmol/L. All tunneled catheters were locked with heparin to prevent thrombosis between HD treatments; citrate or antibiotic locks were not used. All exit sites were cleaned with a standard Betadine solution after each treatment before re-dressing, and patients were monitored for fever/signs of infection throughout the study period.
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therapy was 2.92 ± 2.08 years (range 1–11 years), mean body mass index (BMI) was 25.75 ± 5.04 kg/m2, 15 patients have diabetes, and 58 patients were negative and only 9 patients were positive for HCV-abs in the serum. In the fistula group, the mean age was 52.22 ± 15.84 years (range 19–80 years), mean BMI was 26.87 ± 5.22 kg/m2, 19 patients have diabetes, 78 patients were seronegative and 8 patients were seropositive for HCV-abs, and the mean duration of HD therapy was 3.51 ± 1.87 years (range 10 months–12 years). In both groups, no statistically significant differences as regard the demographic data were observed (Table 1). In the studied groups (catheter and fistula), there was no statistically difference as regard the biochemical variables apart from CRP levels (they were followed up prospectively every 2 months for a period of 6 months). In the catheter group, median (IQR) serum CRP levels were 0.79 (0.55, 1.78), 0.68 (0.52, 1.04), and 0.86 (0.58, 1.20) mg/dL, respectively, compared with the fistula group, which had median (IQR) serum CRP levels of 0.48 (0.20, 0.93), 0.38 (0.19, 0.85), and 0.39 (0.20, 0.87) mg/dL, respectively (P = 0.000) (Table 1; Figure 1).
Demographic and biochemical data
Hemodialysis adequacy
In the catheter group, the mean age was 52.15 ± 16.36 years (range 18–80 year), the mean duration of HD
The mean and SD of URR and Kt/V values for the whole group were 70.18 ± 4.95% and 1.40 ± 0.15, respectively.
Patients were also subjected to the following biochemical tests: hemoglobin, calcium (corrected), phosphorus, PTH, Kt/V, URR, and albumin.
Statistical analysis The results were summarized as mean ± standard deviation (SD) and median (interquartile range [IQR]). Person chi-square test, independent-sample t test, and MannWhitney U test were used for testing the significance of the differences in values measured between the two groups as appropriate. Multivariate analyses for repeated measures were performed (using mixed effects models) to evaluate the independent association between access type and CRP concentrations (log-transformed). Covariates that were included in the model were age, gender, diabetes status, URR, calcium-phosphate product, and dialysis vintage. P value ≤ 0.05 (two-tailed) was taken as statistically significant. All analysis was performed using the Statistical Package for Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA).
Table 1 Demographic and biochemical data of both groups Parameters Number Male/female ratio Age (mean ± SD; y) BMI (mean ± SD; kg/m2) Duration of HD (mean ± SD; y) CRP1 (median, IQR; mg/dL), after 2 months CRP2 (median, IQR; mg/dL), after 4 months CRP3 (median, IQR; mg/dL), after 6 months Hemoglobin (mean ± SD; gm/L) Darbepoetin dose (median, IQR; μg/wk) iPTH (median, IQR; pmol/L) Serum corrected calcium (mean ± SD; mmol/L) Serum phosphate (mean ± SD; mmol/L) Ca × Phosphorus product (mean ± SD; mmol2/L2) ALP (median, IQR; IU/L) Iron saturation (mean ± SD; %) Serum ferritin (median, IQR; ng/mL) Serum albumin (mean ± SD; gm/L) Kt/V (mean ± SD) URR (mean ± SD, %)
Fistula group
Catheter group
P value
86 57/29 52.22 ± 15.84 26.87 ± 5.22 3.51 ± 1.87 0.48 (0.20, 0.93) 0.38 (0.19, 0.85) 0.39 (0.20, 0.87) 109.15 ± 12.48 31.25 (20.00, 40.00) 30 (19.06, 51.98) 2.17 ± 0.21 1.51 ± 0.32 3.29 ± 0.75 129 (78.75, 169.50) 24.65 ± 5.14 358 (218.70, 729.23) 32.86 ± 3.48 1.39 ± 0.15 69.88 ± 5.25
67 44/23 52.15 ± 16.36 25.75 ± 5.04 2.92 ± 2.08 0.79 (0.55, 1.78) 0.68 (0.52, 1.04) 0.86 (0.58, 1.20) 106.84 ± 21.95 35.16 (20.00, 58.59) 30 (18.73, 49.20) 2.13 ± 0.22 1.50 ± 0.44 3.16 ± 0.88 112 (75.00, 160.00) 25.14 ± 5.33 324 (214.00, 608.00) 32.10 ± 4.74 1.42 ± 0.15 70.55 ± 4.55
0.937 0.977 0.184 0.068 0.000 0.000 0.000 0.413 0.398 0.871 0.172 0.840 0.336 0.292 0.684 0.481 0.256 0.232 0.409
ALP = alkaline phosphatase; BMI = body mass index; CRP = C-reactive protein; HD = hemodialysis; iPTH = intact parathormone; IQR = interquartile range; URR = urea reduction ratio.
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Figure 1 C-reactive protein (CRP) levels in the catheter and fistula groups.
The mean URR and kt/V in the fistula group were not significantly different from that in the catheter group (69.88 ± 5.25% vs. 70.55 ± 4.55%, P value = 0.409 and 1.39 ± 0.15 vs. 1.42 ± 0.15, P value = 0.232, respectively) (Table 1). In multivariate analysis using mixed effects models, only access type (tunneled catheters use, P value = 0.000) was a significant predictor of an elevated CRP concentration independent of age, gender, diabetes status, URR, calcium-phosphate product, and dialysis vintage (P values > 0.05).
DISCUSSION This study aimed to provide an analysis of inflammatory response as assessed by CRP measurements in prevalent (HD) patients every 2 months for a period of 6 months. Our results show that high-grade and persistent inflammation are prevalent in HD patients with noninfected catheters compared with patients who receive dialysis via AVF. The data further confirm our hypothesis that HD patients subsist within a state of chronic inflammation as reflected by our results. The presence of a HD catheter was a major determinant of the inflammatory response in our cohort. Consistent with our study, Movilli et al. reported in a cross-sectional analysis of 79 HD patients that the mean CRP for HD patients with catheters was 20 mg/L vs. 8 mg/L for patients with AVG and 5 mg/L for those with AVF.13 The clinical relevance of this observation is also obvious because HD catheter utilization has increased by 50% in the United States between 1998 and 2004, and for the year 2004, catheter placement rate was 447/1000 patient years as opposed to the low fistula placement rate of 96.8/1000 patient years. Needless to say, catheters have been associated with increased rates of infections, complication, and death.1 Moreover, Goldstein et al.16 reported
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that a change of dialysis access from a catheter to a fistula is accompanied by a significant fall in the serum level of CRP and reduction of inflammation. These findings were in patients who did not have evident catheter infections. This should provide yet further impetus to use fistulas rather than catheters in HD patients. Some issues remain, however. The first is that in this report, information on long-term outcome is not provided, either for morbidity and mortality or for quality of life. One can assume that a fall in the CRP level is a good thing, and that such a drop may reduce cardiovascular morbidity and mortality, but assumption is not a fact. A second point is that there can be substantial variation in the CRP level in a given patient, and single values of CRP were used by Goldstein et al.16 rather than multiple ones. Still, the patterns of change in CRP levels are distinct and differ between those who got a fistula and those who remained with a dialysis catheter. Apparently, most HD patients suffer from chronic inflammation. Sachdeva et al.17 observed, in an adjusted analysis, that CRP levels are significantly elevated only in the first week following access surgery, but, similar to the HEMO study, CRP levels were not elevated at 1 month or other points throughout the following year. These investigators reported significantly higher CRP values associated with AVGs, not present with AVFs. In the HEMO study, AVFs and AVGs were combined into one “AV access” group for the analysis, which may have obscured differences between the AV access and TC group and differences within the AV access group (AVFs vs. AVGs). Similar to the findings of the current study, Goldstein et al.16 and Sachdeva et al.17 reported that tunneled catheter usage was significantly associated with elevated CRP, independent of age and diabetes status. There was no significant association between gender and elevated CRP in Goldstein et al.’s16 study and ours, but, this is in contradistinction to the findings reported by Sachdeva et al.17 in which female sex was associated with higher CRP values, which was observed in multivariate model adjusting for differences in vascular access type. The relationship between gender and CRP levels is unclear and requires further investigation. It is also important to point out that some of the potential determinants included in the analysis are part of the acute-phase response; more specifically, albumin and transferrin are negative acutephase proteins (APPs) and white blood cell count is a positive acute-phase reactant and they are expected to change as a consequence of inflammation, but not in our study as it shows no difference between the two groups. While the actual cause-and-effect relationship between inflammation and variables examined in this study still needs to be sorted out, it is obvious that this cohort of
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patients with a background of inflammatory response requires attention, as studies in the general population have clearly shown that if persistent, even low-grade inflammation is associated with an increased risk for cardiovascular events.9,14,18 A unique aspect of our study is the use of longitudinal data every 2 months over an extensive period of time. There has been growing interest in using serial measurements of CRP to predict outcome in HD patients. Kaysen et al.19 reported that the levels of APPs and albumin varied considerably over time. Furthermore, because the variations in albumin were small, serial measurements of APPs were considered to provide a greater insight into the dynamics of clinically relevant processes. A relatively small, short-term study by Tsirpanlis et al. using serial measurements of CRP described episodes of high inflammation that responded to clinical events along with persistent microinflammation20 in HD population. Also, Snaedal et al.21 reported widely fluctuating CRP values in 68% of patients, indicating that frequent serial CRP measurements are superior to a single measurement. Our study adds important information to these earlier observations, providing information on changes of CRP over time. The result of this study should be interpreted with certain caveats. Most importantly, we do not report the predictive power of our study results in terms of hard clinical outcomes, such as hospitalization and death. The primary goals of this study were to provide a comprehensive analysis of the inflammatory response in HD patients over time and to identify the clinical and demographic determinants of the inflammatory state, including the contributions of a HD catheter toward the inflammatory response. Future studies examining specific CRP cut-off levels in relation to hospitalization and death are critically important in order to support clinical practice guidelines that include monitoring and management of inflammation in ESRD. Other important limitations include the lack of information on comorbidities and the fact that this was only a two-center study, which limit the generalizability of the results. Nevertheless, our results provide clinically relevant information with immediate applicability.
CONCLUSION Hemodialysis patients have a particular pattern of inflammation, usually of low grade. Serial determinations of CRP can provide a better prediction of the inflammatory state of HD patients than scatter single time-point measurements. Catheters are to be avoided, then, not just because they are associated with worse outcomes but also because they are a proinflammatory stimulus whenever possible.
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CONFLICT OF INTEREST The authors have declared that no conflict of interest exists.
Manuscript received September 2013; revised December 2013.
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