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Keywords:

  • C-reactive protein;
  • cardiovascular risk;
  • dialysis;
  • fibrinogen;
  • inflammation;
  • uremia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Abstract. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Stancanelli B, Nicocia G, Buemi M (Institute of Biomedicine, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Cal; University of Catania; and University of Messina, Italy). Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure. J Intern Med 2003; 254: 132–139.

Objective. Fibrinogen is an established predictor of cardiovascular events in the general population but the relationship between fibrinogen, mortality and incident cardiovascular complications has been very little investigated in patients with end-stage renal disease (ESRD).

Design and subjects. We investigated the relationship between fibrinogen and all cause mortality and cardiovascular outcomes in a prospective cohort study in 192 patients on chronic haemodialysis treatment (follow-up: 34 ± 16 months).

Results. Fibrinogen was significantly higher in patients who died during the follow-up than in those who survived. Similarly, fibrinogen was higher in patients who had fatal or nonfatal cardiovascular events than in event free patients. On multivariate Cox regression analysis fibrinogen was an independent predictor of survival [hazard ratio (1 g L−1 increase in plasma fibrinogen): 1.19, 95% confidence interval (CI): 1.05–1.35, P = 0.006] and a highly significant (P = 0.0008), independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g L−1 increase in plasma fibrinogen): 1.25, 95% CI: 1.10–1.43] in a model including traditional risk factors and serum C-reactive protein (CRP) and plasma homocysteine.

Conclusions. Fibrinogen is as an independent risk factor for overall and cardiovascular mortality in patients with ESRD. Intervention studies are required to see whether reducing plasma fibrinogen may help to curb the exceedingly high cardiovascular risk of the uremic population.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Fibrinogen is an established predictor of cardiovascular events in the general population [1–6] and a recent meta-analysis has further highlighted the strong link between this key element of the coagulation cascade and cardiovascular complications in patients with ischaemic heart disease [7]. The plasma level of this protein is influenced by several conventional risk factors like smoking, hypertension and diabetes [8] and by emerging risk factors like inflammation [9]. Thus, fibrinogen may represent not only a risk factor on its own [10] but also a common pathway through which risk factors interact in promoting arterial disease.

End-stage renal disease (ESRD) is a growing problem of alarming dimensions. It has been estimated that by 2010 more than two million patients in the USA will suffer from ESRD [11]. These patients have an exceedingly high cardiovascular risk [12]. The high prevalence of hypertension, diabetes and other traditional risk factors in patients with advanced renal failure only in part explains the high cardiovascular risk of this population [13]. Low grade, persistent inflammation [14– 18] and hyperhomocysteinaemia [19, 20] are now emerged as risk factors of primary importance in ESRD. Since inflammation increases the plasma concentration of this coagulation protein while hyperhomocysteinaemia has a marked thrombogenic effect [20], fibrinogen can be a transducer and/or an amplifier of the pro-coagulant effect of both traditional and emerging risk factors in ESRD patients. However, the issue whether fibrinogen predicts survival and cardiovascular complications in ESRD has been very little investigated. Since the question is of epidemiological and clinical importance, we have prospectively studied the relationship between fibrinogen, mortality and incident cardiovascular events in a large cohort of patients on chronic dialysis. The principal aim of the study was that of establishing whether the plasma concentration of this protein is associated to mortality and cardiovascular outcomes and to see whether this link is dependent or independent of classical and emerging risk factors.

Protocol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

The protocol was in conformity to the ethical guidelines of our Institutions and informed consent was obtained from each participant. All studies were performed during a nondialysis day, between 8 a.m. and 1 p.m.

Study cohort

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

A total of 192 patients with ESRD (108 M and 84 F) who had been on regular dialysis treatment (RDT) for at least 6 months (median duration of RDT 45 months, interquartile range 21–112 months) without history of congestive heart failure and without intercurrent illnesses, were eligible for the study. These patients represented about the 70% of those on treatment in our dialysis centres. The remaining 30% of patients were excluded because of the presence of circulatory congestion or major infections (20%) or because they were hospitalized for intercurrent illnesses or for logistic reasons/unwillingness to participate in the study (10%). The main demographic and clinical characteristics of the patients included in the study are detailed in Table 1. The prevalence of diabetes mellitus in this cohort was 14% (i.e. 26 patients of 192).

Table 1.  Somatometric, haemodynamic and biochemical data of the study population
 Plasma fibrinogenP-value
I tertile (<3.09 g L−1)II tertile (3.09–4.69 g L−1)III tertile (>4.69 g L−1)
  1. Data are mean ± SD, median (interquartile range) or percentage frequency.

Age (years)59.3 ± 16.858.2 ± 15.658.6 ± 13.20.91
Male sex n (%)34 (54)38 (59)36 (55)0.82
Diabetics n (%)7 (11)11 (17)8 (12)0.57
Smokers n (%)18 (29)29 (45)28 (43)0.11
Patients with previous coefficient of variation (CV) events n (%)23 (37)24 (37)35 (54)0.08
Haemodynamic data
 Systolic pressure (mmHg)138.8 ± 25.1141.3 ± 26.7142.8 ± 23.30.66
 Diastolic pressure (mmHg)76.3 ± 14.177.7 ± 13.375.1 ± 12.60.55
Biochemical data
 Haemoglobin (g L−1)106.7 ± 20.2107.7 ± 19.4105.2 ± 17.00.74
 Serum albumin (g L−1)42.4 ± 4.741.9 ± 4.240.8 ± 6.00.18
 Serum total cholesterol (mmol L−1)5.09 ± 1.205.34 ± 1.425.57 ± 1.580.16
 Serum calcium (mmol L−1)2.28 ± 0.202.25 ± 0.312.30 ± 0.250.45
 Serum phosphate (mmol L−1)2.00 ± 0.381.92 ± 0.422.08 ± 0.560.16
 Serum C-reactive protein (mg L−1)4.4 (3.4–14.4)7.4 (3.4–15.6)11.8 (3.8–20.3)0.02
 Plasma homocysteine (μmol L−1)24.6 (17.6–34.3)27.8 (19.3–47.6)26.8 (20.4–42.1)0.38

All patients were virtually anuric (24 h urine volume <200 mL day−1) and were being treated thrice weekly with standard bicarbonate dialysis (Na 138 mmol L−1, HCO3 35 mmol L−1, K 1.5 mmol L−1, Ca 1.25 mmol L−1, Mg 0.75 mmol L−1) and cuprophan or semi-synthetic membranes (dialysis filters surface area: 1.1–1.7 m2). The average urea Kt/V in these patients was 1.23 ± 0.27. Seventy-five patients (39%) were habitual smokers (22 ± 16 cigarettes day−1). One hundred and six patients were on treatment with erythropoietin. Seventy-six patients were being treated with anti-hypertensive drugs (53 on monotherapy with angiotensin converting enzyme (ACE) inhibitors, AT-1 antagonists, Calcium-channel blockers, alpha and beta-blockers and 23 on double or triple therapy with various combinations of these drugs).

Follow-up

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

After the initial assessment patients were followed up for an average time of 34 months (range 0.8–52.0 months). During the follow-up cardiovascular events [electrocardiogram (ECG) documented anginal episodes and myocardial infarction, ECG documented arrhythmia, heart failure [21], transient ischaemic attacks (TIA) and stroke [22] and other thrombotic events] and death were accurately recorded. Each death was reviewed and assigned an underlying cause by a panel of five physicians. As a part of the review process, all available medical information about each death was collected. This information always included study and hospitalization records. In the case of an out-of-hospital death family members were interviewed by telephone to better ascertain the circumstances surrounding death.

Laboratory measurements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Blood sampling was performed after an overnight fast between 8.00 a.m. and 10.00 a.m. always during a nondialysis day. After 20–30 min of quiet resting in semi-recumbent position samples were taken into chilled ethylenediaminetetraacetic acid (EDTA) vacutainers, placed immediately on ice, centrifuged within 30 min at −4°C and the plasma stored at −80°C before assay. No patient had intercurrent acute coronary syndromes at the time of the study. Serum lipids, albumin, calcium, phosphate, and haemoglobin measurements were made using standard methods in the routine clinical laboratory. Plasma fibrinogen was measured by a commercially available kit (Multifibren U, Dade Behring Marburg, Germany). The intra-assay coefficient of variation of this method is 1.5–6.0%. The upper limit of the normal range of this assay in a group of 144 healthy subjects is 3.50 g L−1. C-reactive protein (CRP) and plasma homocysteine were measured as reported elsewhere [16].

Statistical analysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Data are reported as mean ± SD (normally distributed data) or as median and interquartile range (non-normally distributed data). Comparisons between groups were made by the t-test, the Mann–Whitney or the chi-square tests, as appropriate.

Survival was analysed by the Kaplan–Meier product-limit method and by the Mantel (log-rank) test. For patients who experienced multiple events, survival analysis was restricted to the first event. The independent prognostic power of plasma fibrinogen for survival and cardiovascular events (fatal and nonfatal) was analysed by the Cox's proportional hazards method considering a series of traditional and nontraditional cardiovascular risk factors in dialysis patients (age, male sex, previous cardiovascular events, smoking, diabetes, systolic pressure, albumin, haemoglobin, cholesterol, calcium and phosphate, homocysteine and CRP). Starting from the saturated model a reduced model was developed by using a stepwise backward approach. Furthermore, to control for the potential confounding effect of covariates that differed (P ≤ 0.10) in the three fibrinogen tertiles (see Table 1) we always forced such covariates into the final models. By this strategy the constructed models of adequate statistical power (at least 10 patients for each variable in the model). The assumption of linearity for the Cox models was examined through visual inspection and no violation of proportional hazards was found. Hazard ratios and their 95% confidence intervals (CI) were calculated using the estimated regression coefficients and their SE in the Cox regression analysis. All calculations were made using a standard statistical package (SPSS for Windows Version 9.0.1; SPSS, Chicago, IL, USA, 11 March 1999).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Plasma fibrinogen (median 2.82 g L−1, interquartile range 2.59–5.38 g L−1) was above the upper limit of the normal range (cut-off >3.50 g L−1) in the majority of dialysis patients (n = 107, i.e. 56%). As shown in Table 1 patients in the third tertile of plasma fibrinogen had a significantly higher level of serum CRP when compared with remaining patients. The proportion of patients with previous cardiovascular complications was higher in the third fibrinogen tertile than in the other two tertiles but the difference failed to reach the statistical significance (P = 0.08).

Plasma fibrinogen, survival and cardiovascular events

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

During the follow-up period (34 ± 16 months) 117 fatal and nonfatal cardiovascular events occurred in 75 patients. Seventy-three patients died, 50 deaths (i.e. 67% of all deaths) were attributable to cardiovascular causes (Table 2).

Table 2.  Cardiovascular events (fatal and nonfatal) and causes of death in the study cohort
Cardiovascular events (fatal and nonfatal)nCauses of deathn
  Cardiovascular
Stroke26 Stroke16
Arrhythmia22 Heart failure11
Heart failure18 Myocardial infarction10
Angina15 Mesenteric infarction5
Myocardial infarction14 Arrhythmia4
Transient ischemic attack8 Sudden death2
Mesenteric infarction5 Pulmonary embolism2
Major episodes of venous thrombosis3Other causes
Sudden death2 Cachexia6
Pulmonary embolism2 Sepsis/infection5
Retinal artery thrombosis1 Neoplasia4
Peripheral artery disease1 Hyperkalaemia4
   Gastrointestinal haemorrhage1
   Chronic obstructive pulmonary disease1
   Diabetes, hyperosmolar coma1
   Treatment withdrawal1
Total117Total73

Fibrinogen was significantly higher (P = 0.04) in patients who died during the follow-up (median 4.04 g L−1, interquartile range 3.21–5.56 g L−1) than in those who survived (3.46 g L−1, 2.43–5.34 g L−1). By the same token, fibrinogen was higher (P = 0.047) in patients who had fatal or nonfatal cardiovascular events (4.29 g L−1, 2.96–5.76 g L−1) than in event free patients (3.67 g L−1, 2.48–5.05 g L−1). Event free survival curves in patients divided into three tertiles on the basis of the plasma concentration of fibrinogen are shown in Fig. 1. All cause mortality (Fig. 1a) and incident fatal and nonfatal cardiovascular events (Fig. 1b) in patients in the third fibrinogen tertile were significantly higher (P ≤ 0.02) than in those in the other two tertiles.

image

Figure 1. Kaplan–Meier survival curves for all cause death (a) and for fatal and nonfatal cardiovascular events (b). Patients was divided into three tertiles on the basis of individual level of plasma fibrinogen. In more detail: I tertile: <3.09 g L−1; II tertile: 3.09–4.69 g L−1; III tertile: >4.69 g L−1.

Download figure to PowerPoint

On multivariate analysis (Cox proportional hazard model) plasma fibrinogen was an independent predictor of survival (Table 3a) and it maintained its predictive power for this outcome [hazard ratio (1 g L−1 increase in plasma fibrinogen): 1.14, 95% CI: 1.00–1.30, P = 0.05] also in a model including serum CRP (see also legend to Table 3a). Of note fibrinogen resulted to be a highly significant, independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g L−1 increase in plasma fibrinogen): 1.25, 95% CI: 1.10–1.43, P = 0.0008] in a Cox model including serum CRP and plasma homocysteine as well as other conventional risk factors (Table 3b).

Table 3.  Cox proportional hazard models
 Units of increaseHazard ratio (95% CI)P-value
  1. 1The association between fibrinogen and survival remained significant [hazard ratio (1 g L−1 increase in plasma fibrinogen): 1.14, 95% confidence interval (CI): 1.00–1.30, P = 0.05] also when serum CRP [hazard ratio (10 mg L−1 increase in serum CRP): 1.08, 95% CI: 0.98–1.18, P = 0.11] was introduced into the model.

  2. Data are expressed as hazard ratio, 95% CI and P-value. The method used to construct multivariate models is described in detail in the Methods section.

(a) Cox proportional hazard model for all cause death
 Age1 year1.05 (1.03–1.07)<0.0001
 Male sex 2.77 (1.61–4.77)0.0002
 Diabetes 2.45 (1.40–4.30)0.002
 Fibrinogen11 g L−11.19 (1.05–1.35)0.006
 Previous coefficient of variation (CV) events 1.97 (1.20–3.22)0.007
 Albumin1 g L−10.94 (0.89–0.99)0.02
 Cholesterol1 mmol L−11.28 (1.05–1.57)0.02
(b) Cox proportional hazard model for fatal and nonfatal cardiovascular events
 Age1 year1.04 (1.02–1.06)0.0003
 Homocysteine10 μmol L−11.15 (1.06–1.25)0.0005
 Fibrinogen1 g L−11.25 (1.10–1.43)0.0008
 Previous CV events 2.27 (1.37–3.76)0.001
 Diabetes 2.08 (1.17–3.71)0.01
 C-reactive protein10 mg L−10.89 (0.78–1.02)0.09

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

In this study fibrinogen predicted all-cause mortality and cardiovascular events in patients with ESRD. Furthermore, the predictive power of fibrinogen was largely independent of a large series of traditional and emerging risk factors and of risk factors peculiar to ESRD.

The high rate of cardiovascular complications is a major factor limiting rehabilitation and long-term survival in ESRD patients. Cardiovascular mortality is very high in these patients and observational and intervention studies aimed at clarifying the causes of such high risk are deemed an absolute research priority [12]. Notwithstanding hypertension is a pervasive consequence of ESRD, the large majority of cardiovascular events in these patients are thrombotic in nature (myocardial infarction, stroke, peripheral vascular disease) [23], an observation which is further confirmed in the present study (see Table 2).

Risk factors in ESRD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

Patients with ESRD in many ways represent a selected population with a high burden of classical risk factors. Indeed the prevalence of diabetes, hypertension and of alterations in the lipid profile is exceedingly high in incident and prevalent ESRD patients. Yet traditional risk factors only in part account for the high cardiovascular mortality of this population. Anaemia [24] and high phosphate and calcium × phosphate product [25] have been associated with cardiovascular complications in ESRD but these factors are insufficient to explain the large difference in cardiovascular mortality rate between this population and the general population [13]. Recently particular attention has been focused on inflammation as a cardiovascular risk factor [18] and it has been noted that high serum CRP is frequently associated with malnutrition and hypoalbuminaemia in ESRD [14–18, 26]. Several studies have documented that acute phase reactants such as serum CRP [14, 17] and serum Amyloid A [14] predict all cause and cardiovascular mortality in these patients suggesting that inflammation may trigger thrombotic events via the link with the coagulation cascade. Furthermore, hyperhomocysteinaemia has been identified as an independent risk factor for cardiovascular complications in ESRD [19], particularly for thrombotic events [20]. However, there is evidence that a pro-thrombotic situation occurs early in renal failure [27] and that in ESRD endothelial dysfunction [28], high levels of fibrinogen and fibrin degradation products, defective platelet function and altered fibrinolysis all concur to increase substantially thrombotic risk [29].

Fibrinogen as a cardiovascular risk factor in ESRD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References

High fibrinogen is a common finding in patients with moderate [27] and advanced chronic renal failure [29]. Hyperfibrinogenaemia is frequently observed in ESRD patients with malnutrition and increased CRP [26]. The relationship between fibrinogen and atherosclerosis, myocardial infarction and stroke has been examined in several cross-sectional studies in dialysis patients and an association was found in some studies [30–33] but negated in other studies [34, 35]. The present study confirms the inherent difficulty of establishing a relationship between fibrinogen and cardiovascular risk in cross-sectional investigations in ESRD patients. Indeed in the baseline assessment the prevalence of cardiovascular complications was only slightly higher in patients with high fibrinogen (third tertile, Table 1) than in those with relatively lower levels while in the prospective part of the study fibrinogen emerged as a strong and independent predictor of fatal and nonfatal cardiovascular events (see below). In a previous cohort study restricted to diabetic-uremics [36] fibrinogen was an independent predictor of overall and cardiovascular mortality. However, this study did not account for baseline risk and risk factors peculiar to ESRD or for emerging risk factors such as serum CRP and homocysteine.

Because fibrinogen is related to traditional [8] and nontraditional [9] risk factors it is important to account for these factors in statistical models aimed at assessing the independent link of this protein with mortality and cardiovascular events. Equally relevant is accounting for previous cardiovascular complications because these complications represent strong predictors of future events [37]. By multiple forms of analysis we found that high fibrinogen was independently associated with shorter survival. More importantly, fibrinogen emerged as a strong predictor of incident cardiovascular events and this association was independent of traditional risk factors, previous cardiovascular complications and of serum CRP and plasma homocysteine. This observation suggests that the link between fibrinogen and incident cardiovascular events only in part depends on the fact that fibrinogen is an acute phase protein. On the contrary, it is possible that fibrinogen reflects better than CRP the cardiovascular risk triggered by inflammation. Notably the independent risk associated with a 1 g L−1 increase in plasma fibrinogen in ESRD patients was of magnitude comparable to that associated with a 0.2–0.4 mmol L−1 decrease in serum high density lipoprotein and only slightly less than that conveyed by a 0.2–0.4 mmol L−1 increase in lipoprotein (a) in the general population [38]. It is noteworthy that the plasma levels of fibrinogen, like those of CRP [39] and other acute phase proteins, vary with time in ESRD patients. Because of regression dilution bias [40] this variability leads to an underestimation of the true risk associated with raised fibrinogen in these patients. Another factor that may lead to an underestimation of the association between fibrinogen and outcomes is the fact that in this study the cohort was composed by prevalent patients (patients who had been treated at least 6 months). Indeed excluding early deaths, i.e. cases at high risk may weaken the relationship of fibrinogen with adverse outcomes. Thus the cardiovascular risk of hyperfibrinogenaemia in ESRD may be higher than that observed in the present study. Furthermore, the observational nature of present findings precludes conclusions about causality.

In this study, fibrinogen emerges as an independent risk factor for overall mortality and cardiovascular outcomes in patients with ESRD. As this protein is a modifiable risk factor, intervention studies may be undertaken to see whether reducing plasma fibrinogen concentration may help to curb the exceedingly high cardiovascular risk of the uremic population.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Protocol
  6. Study cohort
  7. Follow-up
  8. Laboratory measurements
  9. Statistical analysis
  10. Results
  11. Plasma fibrinogen, survival and cardiovascular events
  12. Discussion
  13. Risk factors in ESRD
  14. Fibrinogen as a cardiovascular risk factor in ESRD
  15. Conflict of interest statement
  16. Acknowledgements
  17. References
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