Serum α1-Antitrypsin But Not Complement C3 and C4 Predicts Chronic Inflammation in Hemodialysis Patients

Background.?We studied whether predialysis serum levels of positive acute phase markers such as α₁-antitrypsin (AT), and complement components C3 and C4 could identify the presence of chronic inflammation in maintenance hemodialysis (HD) patients. Methods/Results.?In 103 stable HD patients, AT directly correlated with C-reactive protein (CRP) (P<0.005), α₁ acid-glycoprotein (P<0.005), fibrinogen (P<0.05), lipoprotein (a) (P<0.01) and von Willebrand factor antigen (P<0.05), while C3 and C4 were not related to any of these inflammatory markers. In the patients with elevated CRP and hypoalbuminemia, the mean AT value of 1.74 ± 0.50 g/L was higher (P = 0.008) than that of 1.38 ± 0.27 g/L in the subjects with normal CRP and albumin. Using the above cut-off levels, the positive and negative predictive values of AT on the presence of severe inflammation were 0.86 and 0.62, respectively, and the sensitivity and specificity were 86% and 73%, respectively. Conclusion. Serum AT levels above 1.74 g/L and below 1.38 g/L may select the HD patients with severe inflammation from those without. Measurements of C3 and C4 are not helpful in this situation.     

Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events.

BACKGROUND: Increased levels of circulating adhesion molecules and chemokines have been reported in haemodialysis (HD) patients but the influence of the HD membranes on their secretion, as well as their pathophysiological implications, remains largely unknown. METHODS: Circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured by immunosorbent assay (ELISA) in 81 HD patients (45 male, mean age 57+/-13 years) and 35 normal subjects. All patients had been stabilized on renal replacement therapy for >3 months and were free of active infection. Thirty-three patients (40.7%) were routinely dialysed with modified cellulose membranes and 48 patients (59.3%) were dialysed with polysulfone membranes. Blood samples were taken directly from the arteriovenous fistula immediately before and at the end of a routine HD session. RESULTS: Pre-dialysis levels were significantly elevated in HD patients compared with controls (ICAM-1 515+/-177 vs 238+/-664 ng/ml, P<0.0001; VCAM-1 2107+/-648 vs 1012+/-115 ng/ml, P<0.0001; MCP-1 427+/-148 vs 125+/-42 pg/ml, P<0.0001). The HD session resulted in a significant increase in the levels of all three molecules measured (515+/-177 vs 679+/-187 ng/ml, P<0.0001; 2107+/-648 vs 2662+/-800 ng/ml, P<0.0001; 427+/-148 vs 567+/-153 pg/ml, P<0.0001, respectively). There was no difference in pre- or post-dialysis levels of the above molecules between patients routinely dialysed with either modified cellulose or polysulfone membranes. MCP-1 levels had a positive correlation with ICAM-1 levels (r=0.41, P<0.0005). VCAM-1 levels had a negative correlation with HDL levels (r=-0.30, P<0.01) and were significantly elevated in patients with HDL <35 mg/dl compared with patients with HDL > or = 35 mg/dl (2300+/-606 vs 1890+/-633 ng/ml, P<0.005). Log-transformed exact C-reactive protein (CRP) values were significantly correlated with ICAM-1 and VCAM-1 levels (r=0.41, P<0.005 and r=0.43, P<0.005, respectively). In addition, compared with patients with normal CRP values, patients with elevated CRP had significantly increased levels of ICAM-1 (466+/-166 vs 580+/-172 ng/ml, P<0.005). Patients with cardiovascular, cerebrovascular, or peripheral vascular diseases had significantly increased serum CRP and ICAM-1 levels compared with patients with no evidence of vascular disease (19.2+/-12.9 vs 7.9+/-11.8 mg/l, P<0.001 and 608+/-189 vs 474+/-155 ng/ml, P<0.005 respectively). CONCLUSIONS: Serum levels of ICAM-1, VCAM-1, and MCP-1 are increased in HD patients and probably result from either inadequate clearance or enhanced synthesis and release. HD session resulted in a significant increase of the above molecule levels but the exact mechanism(s) responsible for these alterations are yet to be fully elucidated. Increased levels of adhesion molecules are associated with inflammation, dyslipidaemia, and cardiovascular events. However, the potential link between these processes and its clinical significance warrants further investigation.     

Elevated plasma F2-isoprostanes in patients on long-term hemodialysis

BACKGROUND: End-stage renal disease (ESRD) patients on long-term hemodialysis (HD) may be under increased oxidative stress, caused by either HD or renal failure. Plasma F2-isoprostanes have been established as an important indicator of in vivo oxidative stress. METHODS: Plasma esterified F2-isoprostanes were measured in 25 HD patients and 23 controls with normal renal function, employing gas chromatography-mass spectrometry with negative chemical ionization (GC-MS-NCI). C-reactive protein (CRP) was determined concurrently in patients and controls by enzyme-linked immunosorbent assay (ELISA). alpha-Tocopherol, retinol, albumin and creatinine were also determined. RESULTS: The average total esterified F2-isoprostanes in the ESRD patients was 1.62 +/- 0.73 vs. 0.27 +/- 0.10 ng/mL in controls (P < 0.001), with no overlap between patients and controls. Plasma F2-isoprostanes in diabetic ESRD patients were similar to F2-isoprostanes in patients with other causes for renal failure. In a subset of 10 of these ESRD patients evaluated eight months after the initial measurement, plasma-esterified F2-isoprostanes were not altered by an individual dialysis session. Average plasma CRP values were also higher in HD patients (P < 0.02), but some patients had CRP values that were similar to controls. In the HD patients, total plasma F2-isoprostanes and plasma CRP were correlated (r = 0.48, P = 0.015). Plasma alpha-tocopherol did not differ between patients and controls, but plasma retinol was higher in patients (3.15 +/- 1.71 micromol/L) than in controls (1.97 +/- 0.51 micromol/L, P < 0.05). CONCLUSIONS: These results are consistent with the hypothesis that oxidative stress in ESRD patients contributes to increased values of esterified plasma F2-isoprostanes, with concurrent increases in plasma CRP levels in some patients. Impaired clearance of esterified F2-isoprostanes may contribute to the elevated levels in renal failure. Plasma esterified F2-isoprostanes may be a useful indicator to evaluate effectiveness of interventions to decrease oxidative stress and associated inflammation.     

Inflammatory markers and platelet aggregation tests as predictors of hemoglobin and endogenous erythropoietin levels in hemodialysis patients

BACKGROUND/AIMS: Chronic inflammation is a common cause of severe anemia and hyporesponsiveness to recombinant erythropoietin (EPO) therapy in maintenance hemodialysis (HD) patients. We compared various acute-phase markers and ex vivo platelet aggregation tests in relation to clinical conditions in order to find factors predictive of hemoglobin (Hb) and endogenous EPO levels in a cross-section of clinically stable HD patients. METHODS: In 100 subjects, pre-HD blood levels of C-reactive protein (CRP), alpha(1)-acid-glycoprotein (AGP), alpha(1)-antitrypsin (AT), immunoglobulin (Ig) M and G (by nephelometry), antigens of endothelial von Willebrand factor (vWF), type 1 plasminogen activator inhibitor and thrombomodulin, interleukin-6, lipoprotein(a) [Lp(a)] and EPO (by ELISA), and albumin, fibrinogen, iron metabolism indices, thyroid-stimulating hormone, phosphorus, parathormone, total cholesterol, triglycerides, viral hepatitis B/C markers, liver enzyme, and aluminium were determined. Platelet aggregations in response to ristocetin (RIPA), adenosine diphosphate, and collagen were measured in whole blood (electric impedance method) and platelet-rich plasma (optical aggregometry). RESULTS: Hb levels inversely correlated with IgM, Lp(a), soluble vWF antigen, phosphorus, and all platelet aggregations in whole blood, but not in platelet-rich plasma. HD duration and triglycerides were positive correlates of anemia. In a multivariable analysis, increased IgM, short HD duration, increased Lp(a) and enhanced whole blood RIPA (in descending order of significance) were independent predictors of low Hb levels. In 51 patients not treated with recombinant EPO, serum levels of this hormone inversely correlated with whole blood RIPA, AT, age, vWF antigen, AGP, and positively with viral hepatitis marker. Anemia and EPO levels were not affected by gender, body mass index, cause of renal failure, residual renal function, HD dose, protein catabolic rate, use of different heparins or dialysate buffers, ACE inhibitor therapy, and parathyroid or thyroid function. In additional 10 patients, single HD session resulted in an increase in IgM levels associated with a fall in total lymphocyte counts. CONCLUSION: Subclinical inflammation is an important determinant of anemia in maintenance HD patients. Increased serum IgM reflecting a microinflammatory effect of HD procedures, enhanced whole blood RIPA as a surrogate of vascular endothelial damage, and Lp(a) as its promoter could be markers of such impaired erythropoiesis.     

Inflammation as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis in haemodialysis patients: the role of chlamydia and cytomegalovirus infection

OBJECTIVES: Atherosclerotic vascular disease is the most frequent complication seen in haemodialysis (HD) patients. Evidence suggests that inflammation may play a role in the pathogenesis and progression of atherosclerosis. Our aim was to evaluate the causative role of inflammation in atherosclerosis among HD patients. METHODS: Intima-media thickness (IMT) in carotid arteries was determined in 54 HD patients and 52 controls. Plasma levels of lipids, glucose, albumin and several acute phase proteins, and immunoglobulin G titres against chlamydia and cytomegalovirus were measured in all subjects. RESULTS: Mean carotid IMT was significantly greater in HD patients than in controls (0.75 mm vs 0.56 mm, P < 0.005). While plasma levels of C-reactive protein (CRP), serum amyloid A (SAA), lipoprotein (a) Lp(a), fibrinogen and ferritin were higher in HD patients, albumin levels were lower. In HD patients, carotid IMT was correlated positively with CRP (R = 0.29, P = 0.019), SAA (R = 0.69, P < 0.001), Lp(a) (R = 0.42, P = 0.001), fibrinogen (R = 0.57, P < 0.001) and chlamydia pneumonia immunoglobulin G titres (R = 0.50, P < 0.001), and negatively with albumin levels (R = -0.33, P = 0.02); there was no relationship between carotid IMT and hypertension, plasma lipid levels and cytomegalovirus. In multivariate regression analysis, these variables still showed a significant relationship with IMT (R(2) = 0.694 and P < 0.001). CONCLUSION: We conclude that atherosclerotic changes are more common in HD patients than in controls, and that inflammatory processes may play a role in the pathogenesis of atherosclerosis.     

Endotoxemia and acute-phase proteins in major abdominal surgery

BACKGROUND: Translocation of endotoxin is a controversial issue. The ability of plasma to inactivate endotoxin is an indirect measure of endotoxemia. Endotoxin is a potent stimulator of the inflammatory response and affects the innate immune system. OBJECTIVE: To elucidate the kinetics of endotoxemia and the ability of plasma to inactivate endotoxin in patients with major abdominal operations. To demonstrate the early time course of the acute-phase proteins C-reactive protein (CRP), serum amyloid A (SAA), alpha(1)-antitrypsin, alpha(2)-macroglobulin, transferrin, and interleukin 6 (IL-6), and to correlate them with the amount of endotoxemia. METHODS: Twenty patients with elective major abdominal operation and 10 healthy controls were investigated. Blood was collected preoperatively, during the operation and regularly up to 12 days after surgery. Endotoxin was measured by Limulus amebocyte lysate test (LAL), the ability of plasma to inactivate endotoxin by modified LAL, the acute-phase proteins nephelometrically, and IL-6 by enzyme-linked immunosorbent assay (ELISA). RESULTS: Preoperative endotoxin plasma level (0.026 +/- 0.004 EU/mL) did not differ from healthy volunteers but increased during operation (0.09 +/- 0.02 EU/mL, P = 0.02). Endotoxemia peaked 1 hour after the surgical procedure (0.16 +/- 0.03 EU/mL; P <0.0001 versus preoperative) and decreased to almost normal values after 48 hours. The capability of plasma to inactivate endotoxin was significantly reduced during (recovery, 0.16 +/- 0.03 EU/mL), 1 hour (0.25 +/- 0.04 EU/mL) and 24 hours (0.16 +/- 0.02 EU/mL) after the operation compared with preoperative (0.068 +/- 0.01 EU/mL) values. Plasma IL-6 was significantly increased for 48 hours with a peak 1 hour after surgery (470 +/- 108 pg/mL). CRP peaked at 210 +/- 19 mg/L (P <0.0001 versus preoperative) 48 hours after operation and was significantly elevated for the rest of the observation period. SAA was significantly increased 24 hours after surgery (249 +/- 45 mg/L) and peaked additional 48 hours later (456 +/- 86 mg/L). alpha(1)-Antitrypsin, although a positive acute-phase protein, decreased initially to 1.38 +/- 0.1 g/L (preoperative, 2.33 +/- 0.18 g/L; P <0.0001) and increased thereafter until day 12 (3.05 +/- 0.35 g/L, P = 0.11 versus preoperative). The same was true for alpha(2)-macroglobulin (preoperative, 2.2 +/- 0.16 g/L; intraoperative, 1.36 +/- 0.13 g/L; day 5, 2.8 +/- 0.4 g/L). Transferrin decreased already during surgery (1.6 +/- 0.1 g/L versus preoperative 2.8 +/- 0.17 g/L, P <0.0001) and remained on this level for 5 days. Correlation analysis revealed a relationship between endotoxemia and the ability of plasma to inactivate endotoxin (r = 0.67, P <0.0001) and also a relation between intraoperative endotoxemia on one hand and alpha(2)-macroglobulin (-0.53 > r > -0.6, P <0.05) as well as alpha(1)-antitrypsin (0.64 > r >0.55, P <0.05) on the other. CONCLUSION: Major abdominal surgery is associated with transient endotoxemia and a transient reduced endotoxin inactivation capacity of the plasma. Endotoxemia correlates with the endotoxin inactivation capacity. The surgical procedure causes substantial changes in plasma concentrations of acute-phase proteins. alpha(2)-Macroglobulin and alpha(1)-antitrypsin correlate moderately with endotoxemia.     

Reduced Plasma Zinc Levels,Lipid Peroxidation,and Inflammation Biomarkers Levels in Hemodialysis Patients: Implications to Cardiovascular Mortality

Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(–)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty-five HD patients (28 men, 54.2 ± 12.7 years, 62.2 ± 51.4 months on dialysis and BMI 24.3 ± 4.1 kg/m²) were studied and compared to 20 healthy individuals (9 men, 51.6 ± 15.6 years, BMI 25.2 ± 3.9 kg/m²) and followed for 24 months to investigate the risks for CV mortality. LDL(–) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 ± 16.1 μg/dL) and high-LDL(–) (0.18 ± 0.12 U/L) and TNF-α (5.5 ± 2.2 pg/mL) levels when compared to healthy subjects (78.8 ± 9.4μ g/dL, 0.10 ± 0.08U/L, 2.4 ± 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-α (r = –0.49; p = 0.0001) and LDL(–) (r = –0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-α, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death.     

C reactive protein in patients with chronic renal diseases

Base-line serum levels of plasma C-reactive protein (CRP) are predictive of future myocardial infarction and sudden cardiac death in apparently healthy subjects, suggesting the hypothesis that chronic inflammation might be important in the pathogenesis of atherothrombosis. CRP production is mediated by several inflammatory mediators: interleukin 6 (IL-6) is currently felt to be the major cytokine influencing the acute phase response. CRP and other acute phase proteins are elevated in dialysis patients and cardiovascular diseases represent the single largest cause of mortality in chronic renal failure patients. Little information is available, however regarding CRP and IL-6 plasma levels in pre-dialysis renal failure. Plasma CRP was determined by a modification of the laser nephelometry technique; IL-6 by immunoassay (RD System); and fibrinogen, serum albumin, cholesterol, triglycerides, hematocrit, white blood cell count, erythrocytic sedimentation rate (ESR) and urinary protein levels by standard laboratory techniques. Results were obtained in 102 chronic pre-dialysis patients whose mean age was 53+/-5.8 years with a mean creatinine clearance (C(Cr)) of 52+/-37 mL/min). CRP was greater than 5 mg/L in 25% of the global population. CRP and IL-6 were 4.0+/-4.6 mg/L and 5.8+/-5.6 pg/mL, respectively and were not significantly correlated (r=0.11, p=n.s.). CRP and IL-6 were however related with renal function (CRP versus C(Cr) r=-0.40 p <0.001; IL- 6 versus C(Cr) r=-0.45; p <0.001). When patients were divided in two groups according to renal function, CRP resulted 7.4+/-6.3 mg/L in the group of patients with a C(Cr) lower than 20 mL/min (n=32) and 2.76+/-4.35 in the group of patients with a C(Cr) higher than 20 mL/min (n = 70) (p <0.0001). CRP and IL-6 were positively related with ESR (r=0.32 and 0.46 respectively). Serum albumin levels were not significantly different in the two groups of patients (3.2+/-0.4 versus 3.0+/-0.5 g/dL). CRP and serum albumin were not significantly related (r=0.17). CRP and IL-6 correlated positively with ESR (r=0.32 and 0.46 respectively). In pre-dialysis patients we have demonstrated an increase in both CRP and IL-6 that occurs as renal function decreases. These data provided evidence of the activation - even in the predialysis phase of renal failure - of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome.     

Increased albumin and fibrinogen synthesis in hemodialysis patients with normal nutritional status

This study compared the rates of whole-body proteolysis and of albumin and fibrinogen synthesis of seven hemodialysis patients (HD) with those of seven normal matched control subjects (C). HD patients had a normal nutritional and inflammatory status and serum albumin levels >3.5 g/dl. Endogenous leucine flux, albumin and fibrinogen fractional synthesis rate (FSR), and absolute intravascular synthesis rate (ASR) of albumin and fibrinogen all were evaluated by a primed/continuous infusion of 5,5,5-D3-L-leucine. Plasma volume was determined by the Evans blue dye dilution method. Endogenous leucine flux was significantly increased in HD (2.64 +/- 0.08 micromol/kg per min) compared with C (2.17 +/- 0.07 micromol/kg per min, P: < 0.05). Serum albumin concentrations were similar in HD and C. Plasma fibrinogen levels were significantly increased in HD compared with C (P: < 0.05). Plasma volume was greater in HD than in C (P: < 0.05). As a result, total intravascular pool of both albumin (141 +/- 7 versus 114 +/- 3 g/1.73 m(2), P: < 0.05) and fibrinogen (11.7 +/- 1 versus 6.7 +/- 0.5 g/1.73 m(2), P: < 0.05) were greater in HD than in C. Albumin FSR was not statistically different in HD and C. However, albumin ASR was significantly increased in HD than in C (13.7 +/- 2 versus 10.3 +/- 1 g/1.73 m(2) per d, P: < 0.05). Similarly, FSR of fibrinogen did not differ in HD and C groups, whereas ASR of fibrinogen was significantly higher in HD than in C (3.31 +/- 0.6 versus 1.94 +/- 0.3 g/1.73 m(2) per d, P: < 0.05). In summary, normoalbuminemic HD patients have an increased intravascular pool with a greater absolute synthesis rate of both albumin and fibrinogen and an increased rate of whole-body leucine flux.     

Association of cardiac valve calcification and inflammation in patients on hemodialysis

BACKGROUND/AIMS: This study investigates the possible relationship between inflammation and cardiac valve calcification (VC) in patients on hemodialysis (HD), and identifies risk factors for VC in this patient group. METHODS: Seventy-nine patients on HD (mean age, 52.2 +/- 13.6 years; mean HD duration, 46.8 +/- 34.3 months) were assessed echocardiographically for the presence of VC. Systolic and diastolic blood pressure (BP) values were determined. The blood parameters studied in each case were hemoglobin, blood urea nitrogen, creatinine, calcium, phosphate, calcium-phosphorous (Ca x P) product, albumin, alkaline phosphatase, intact parathyroid hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, lipoprotein(a), fibrinogen, and C-reactive protein (CRP). The number of patients receiving vitamin D and calcium-containing phosphate binder was determined from records, and presence of diabetes mellitus was noted. RESULTS: Cardiac VC was detected in 36 patients (46%). Five of these patients (6%) had mitral VC, 11 (14%) had aortic VC, and 20 (25%) had calcification of both valves. The patients with VC were significantly older than those without VC (60 +/- 11 vs. 43 +/- 15 years, respectively; P=.001). Compared with the group without VC, the group with calcification had significantly higher systolic (145.1 +/- 14.7 vs. 124.3 +/- 20.7 mmHg, P=.001) and diastolic BP (91.3 +/- 10.3 vs. 75.09 +/- 14.9 mmHg, P=.001); significantly higher phosphate (5.1 +/- 1.4 vs. 4.5 +/- 1.4 mg/dL, P=0.04), CaxP product (48.6 +/- 16.2 vs. 39.8 +/- 11.8, P=.01), lipoprotein(a) [28 (15, 45) vs. 16 (5,42) mg/dL, P=.04], fibrinogen (4.2 +/- 1.2 vs. 3.5-0.9, P=.005), and CRP levels [9 (4, 19) vs. 5 (3, 11) mg/L, P=.05]; and significantly longer HD duration [49 (27, 99) vs. 26 (17, 52) month, P=.01). Apart from age, duration of HD, systolic and diastolic BP, and Ca x P product, VC was associated with CRP (odds ratio, 1.151; P=.007) and fibrinogen (odds ratio, 1.119; P=.005). CONCLUSIONS: The results confirm well-known risk factors for cardiac VC in HD patients, such as older age, longer HD duration, elevated BP, and high Ca x P product. In addition, they suggest that elevated levels of CRP and fibrinogen were associated with VC in the HD population.     

Malnutrition and inflammation in peritoneal dialysis patients

BACKGROUND: Malnutrition, cardiovascular disease, and heightened inflammation are highly prevalent in dialysis patients, and major contributors to morbidity and mortality. We have investigated the inter-relationship between malnutrition and inflammation, and their impact on morbidity and mortality in peritoneal dialysis (PD) patients. METHOD: We enrolled 63 PD patients beginning in November 2000, and measured C-reactive protein (CRP) and various nutritional markers, including prealbumin. RESULTS: CRP level was elevated in 29% of the PD patients. Diabetics had higher CRP than non-diabetics (24 vs. 9.3 mg/L, P = 0.016). Patients who were hospitalized during the study had higher enrollment CRP (16 vs. 12.5 mg/L, P = 0.05) and lower enrollment albumin (3.5 vs. 3.9 g/dL, P = 0.002), blood urea nitrogen (BUN) (40 vs. 49 mg/dL, P = 0.034), and protein catabolic rate (nPCR) (0.88 vs. 1.0 g/kg/day, P = 0.02) than those who were not hospitalized. Enrollment level of CRP was inversely correlated with nutritional markers prealbumin (r = -0.5, P < 0.0001) and creatinine (r =-0.35, P < 0.01). After adjusting for age, race, gender, diabetes, and CRP level, prealbumin continued to correlate with other nutritional markers. There was a trend toward association of elevated CRP with all-cause mortality in PD patients. CONCLUSION: It is useful to incorporate prealbumin and CRP in the regular assessment of PD patients, whose survival may be improved by better management of malnutrition and inflammation.     

Comparison of C-reactive protein and high-sensitivity C-reactive protein levels in patients on hemodialysis

Chronic inflammation is highly prevalent in patients on hemodialysis (HD), as evidenced by increased levels of C-reactive protein (CRP). We compared CRP to high-sensitivity C-reactive protein (hs-CRP) to determine whether it has any clinical implications and prognostic significance in terms of mortality. CRP was measured using a standard immunoturbidometric assay on the COBAS? INTEGRA system and hs-CRP was measured using the Dade Behring on the Konelab Nephelometer in 50 patients on HD. CRP (≥6 mg/L) and hs-CRP (≥3 mg/L) levels were elevated in 30% and 54% of the patients, respectively. A significant correlation was noted between hs-CRP and CRP levels (r = 0.98, P <0.001). Deming regression analysis showed that the slope was near one (r = 0.90; 0.83-0.94) and that the intercept was small. Multivariate regression confirmed that age above 40 years (RR = 3.69, P = 0.027) and duration on HD greater than five years (RR = 3.71, P = 0.028) remained significant independent predictors of serum hs-CRP. Thirteen patients died during follow-up (26%). Multivariate Cox regression demonstrated that hs-CRP (RR = 1.062, P = 0.03) and CRP levels (RR = 1.057, P = 0.009) and age (RR = 1.078, P = 0.001) were the most powerful predictors of mortality. The CRP standard assay presents a reasonable alternative to the hs-CRP assay in patients on HD. The advantages of the CRP standard assay are its online and real-time availability as well as lower costs, particularly in developing countries.     

Procalcitonin as a marker of micro-inflammation in hemodialysis

In searching for a rapid and sensitive test to detect micro-inflammation in patients on hemodialysis (HD), we measured serum procalcitonin (PCT) levels and made a comparison with other traditional markers such as C-reactive protein (CRP), serum amyloid (SAA) and homocysteine, considered related to vascular damage. We investigated 51 HD patients, without signs of infection, in basal conditions (during standard bicarbonate dialysis and unselected filters: X) and after 4 months of possibly more biocompatible treatments (on-line hemofiltration (HF) or HD with ultra-pure dialysate and biocompatible membranes: Y). Serum PCT (measured by immunoluminometric assay), CRP and SAA (nephelometric assay) and plasma homocysteine (measured by high performance liquid chromatography) concentrations were assessed at the beginning of dialysis (T0) and after 4 hr (T4). Patients on unselected dialysis displayed mean PCT values significantly increased after 4 hr of dialysis in comparison to those at the start of the sessions (XT4 1.56 +/- 3.93 vs. XT0 0.4 +/- 0.34 ng/mL; p < 0.05). The PCT levels detected after 4 hr of biocompatible treatments were significantly lower than those detected after 4 hr of unselected treatments (YT4 0.78 +/- 0.34 ng/mL; p < 0.05), even though the percentage of patients with positive PCT values (> 0.5 ng/mL) remained almost unchanged. No significant modification in mean levels or in the frequency of positive values was observed for CRP, SAA and homocysteine. After 4 months of highly biocompatible treatments, a reduction in intradialytic enhancements of all inflammation markers was detected. Our data support the conclusion that PCT is a more precise marker than other traditional tests to evaluate micro-inflammation and biocompatibility in HD.     

Thyroid function, endothelium, and inflammation in hemodialyzed patients: possible relations?

OBJECTIVE: Renal function affects the thyroid gland in many ways. Disturbances in hemostasis and inflammation are common complications of kidney diseases. Endothelial dysfunction may link these two processes. DESIGN AND PATIENTS: A cross-sectional study on thyroid hormones in relation to markers of endothelial damage and inflammation in 96 hemodialyzed (HD) patients and 39 healthy volunteers was performed. SETTING: The study took place in the dialysis unit at a university hospital. INTERVENTION: Thyroid hormones, markers of endothelial damage (von Willebrand factor, thrombomodulin, intracellular adhesion molecule, and CD146), markers of inflammation (high-sensitivity C-reactive protein, tumor necrosis factor alpha), other hemostatic parameters (thrombin-antithrombin complexes, prothrombin fragments 1 + 2 - F1 + 2, plasmin-antiplasmin complexes, tissue plasminogen activator and its inhibitor, tissue factor pathway inhibitor, and platelet glycoprotein V) were measured using commercially available kits. RESULTS: Free T3 and total T3 were lower in HD patients compared with controls. Markers of endothelial dysfunction and inflammation were significantly elevated in HD patients compared with controls. In multiple regression analysis T3 was independently related to time on dialyses, albumin, iron, ferritin, C-reactive protein (CRP), and F1 + 2 in HD patients. Free T3 was also independently related to total protein, total calcium, and triglycerides. In patients with CRP less than 6 mg/L in multiple regression analysis the only correlates of T3 were albumin and ferritin, whereas the only correlates of free T3 were albumin and time on dialyses. Multiple regression analysis showed that in HD patients with CRP greater than equal to 6 mg/L predictors of free T3 were CRP, F1 + 2, and dose of erythropoietin. In healthy volunteers T3 was related to tissue factor pathway inhibitor and platelet glycoprotein V was related to thyroid-stimulating hormone. CONCLUSIONS: We described novel relations between thyroid hormones and markers of endothelial dysfunction and inflammation in HD patients. Thyroid dysfunction is related to time on dialyses, endothelial damage, and inflammatory state, frequently encountered in uremia. Therefore, the relations between thyroid axis and endothelium in HD subjects merit additional studies.     

Differential diagnosis of bacterial infection and inflammatory response in kidney diseases using procalcitonin

BACKGROUND: Early diagnosis of bacterial infection in renal patients remains difficult. Common laboratory parameters, such as white blood cell (WBC) count, erythrocyte sedimentation rate, and C-reactive protein (CRP) may be affected by the underlying disease, uremia or its extracorporeal treatment, or by immunosuppressive drugs. Procalcitonin (PCT) may be useful for the detection of systemic bacterial infections in patients with end-stage renal disease (ESRD) undergoing renal replacement therapy, but elevated PCT concentrations have also been found in a significant number of uremic patients without signs of infection. METHODS: We tested whether measurements of PCT levels help distinguish the chronic inflammation in renal diseases from invasive bacterial infections. Serum levels of PCT were compared with the corresponding serum C-reactive protein (CRP) concentrations and WBC counts in 197 patients with different stages of renal disease: Group I) 32 patients with chronic renal failure (serum creatinine 2-6 mg/dL); group II) 31 patients with a functioning renal transplant receiving standard immunosuppressive regimens; group III) 76 clinically stable patients with ESRD undergoing hemodialysis (HD); group IV) 23 patients with chronic renal failure (CRF) due to systemic autoimmune disease; group V) 35 patients with proven systemic bacterial infection and CRF. RESULTS: PCT levels were within the normal range (< 0.5 ng/mL) in patients with CRF and renal transplant patients without any clinical evidence of bacterial infection, regardless of the degree of renal failure and the underlying disorders. In 22 out of 76 stable HD patients, PCT levels were above the upper limit of normal, but 97% of these values were below the proposed cut-off for chronic HD patients of < 1.5 ng/mL. CRP levels were elevated in 17 of 32 patients with CRF (mean +/- SD: 0.57 +/- 0.49 mg/dL), in 10 of 31 renal transplant patients (0.41 +/- 0.55 mg/dL), in 16 of 23 patients with autoimmune disorders (2.78 +/- 3.21 mg/dL) and in 42 of 76 patients treated by HD (0.64 +/- 0.58 mg/dL). In patients with CRF and systemic bacterial infections, both PCT and CRP were markedly elevated (PCT 61.50 +/- 115.4 ng/mL, CRP 14.50 +/- 10.36 mg/dL), but in contrast to PCT, CRP values overlapped in infected and non-infected patients. CONCLUSIONS: Our data indicate that PCT levels are not significantly affected by loss of renal function, immunosuppressive agents or autoimmune disorders. Thus, significantly elevated PCT concentrations offer good sensitivity and specificity for the early diagnosis of systemic bacterial infection in patients with CRF or patients with ESRD treated by HD. CRP concentrations may be useful indicators for inflammation in patients with renal diseases, but have low specificity for the diagnosis of bacterial infection.     

Association of advanced glycoxidation end products and inflammation markers with thrombosis of arteriovenous grafts in hemodialysis patients

BACKGROUND/AIMS: Intimal hyperplasia at the venous anastomosis of arteriovenous dialysis grafts (AVGs) is a common and costly complication in hemodialysis (HD) patients. Previous studies have shown significant accumulation of advanced glycation end products (AGEs) within the lesions, suggesting a pathogenic role for these compounds in this condition. METHODS: We retrospectively analyzed data from 139 HD patients, including 58 subjects with AVGs, to determine any relationship between serum AGEs and other circulating markers, e.g. C-reactive protein (CRP), tumor necrosis factor (TNF-alpha), vascular cell adhesion molecule-1 (VCAM-1), plasminogen activator inhibitor type 1 and vascular endothelial growth factor, with the presence of graft thrombosis, an index of venous intimal hyperplasia. RESULTS: Patients with previously thrombosed AVGs exhibited significantly higher levels of serum AGEs (42 +/- 18 vs. 28+/- 8 U/ml), CRP (1.4 +/- 1.1 vs. 0.6 +/- 0.4 mg/dl) and VCAM-1 (3,172 +/- 696 vs. 2,447 +/- 1,101 ng/ml) than those with uncomplicated AVGs, variances that were mostly attributed to diabetes difference. There was no difference regarding the levels of the parameters studied between patients with AVGs and other forms of vascular access. CONCLUSIONS: These results support an association between circulating AGEs, markers of inflammation and endothelial function and intimal hyperplasia at the venous anastomosis of AVGs in HD patients. The implication is that there may be a therapeutic role for anti-AGE interventions in the management of this common clinical condition.     

Impact of albumin synthesis rate and the acute phase response in the dual regulation of fibrinogen levels in hemodialysis patients

BACKGROUND: Fibrinogen is a risk factor for cardiovascular disease. It also is an acute phase protein (APP) and its plasma concentration increases with inflammation. Fibrinogen synthesis correlates with albumin synthesis in nephrotic patients and in patients with an expanded plasma volume even when serum albumin is normal and there is no inflammatory disease. The relationships among albumin synthesis, the acute phase response and plasma fibrinogen levels in hemodialysis patients are unknown. METHODS: In 74 hemodialysis patients, albumin synthesis, plasma volume (PV) and acute phase proteins (APPs) C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1 AG), ceruloplasmin (Cer), and interleukin 6 (IL-6) were measured in serum and fibrinogen in plasma, and the results analyzed by multiple regression analysis. CRP, IL-6, alpha1 AG, Cer and fibrinogen were measured monthly, which enabled us to determine whether changes in these APPs correlated with the levels of and variability in plasma fibrinogen over time using a longitudinal modeling approach. Length of follow-up for the 74 patients ranged from 3.25 to 67.5 months. RESULTS: Baseline fibrinogen (548.6 +/- 106. 4 mg/dL) was significantly greater than levels reported for normal adults and correlated positively with albumin synthesis (P < 0.001), age (P < 0.001) and log CRP (P = 0.002) and negatively with PV (P < 0.001). Longitudinally, fibrinogen varied positively with long-lived APPs, Cer and alpha1 AG, as well as the short-lived APP, CRP. CONCLUSION: Plasma fibrinogen concentration is high in HD patients and directly correlates with increased albumin synthesis rates and the serum levels of APPs. Fibrinogen levels also correlate negatively with PV. Fibrinogen levels vary over time in synchrony with levels of other long-lived APPs, supporting the hypothesis that fibrinogen is regulated in part as a component of the acute phase response and in part by factors that increase albumin synthesis.     

Clinical consequences of intermittent elevation of C-reactive protein levels in hemodialysis patients

An elevated C-reactive protein (CRP) level has been associated with malnutrition, with erythropoietin resistance during hemodialysis (HD) therapy, and with a higher risk of chronic transplant rejection. Meanwhile, the clinical consequences of intermittent elevations of CRP levels observed among a large group of HD patients are unclear. We sought to compare the inflammatory and nutritional parameters as well as the erythropoietin requirements for HD patients with persistent or intermittent CRP elevations versus subjects with CRP levels in the normal range. The 6-month retrospective clinical and laboratory data of 100 HD patients (age 48.4 +/- 14.3 years, HD duration 69.3 +/- 49.0 months) were divided into three groups on the basis of at least six monthly values of CRP: for persistent (group 1) or intermittent high (at least one level of CRP >/=10 mg/L); (group 2) versus normal CRP levels (group 3). We compared the estimates of fibrinogen, ICAM-1, VCAM-1, albumin, prealbumin, normalized protein catabolic rate (nPCR), interdialytic weight gain (IDWG), and rhuuEpo/kg/Htc. Significant differences, were observed in fibrinogen, albumin, prealbumin, ICAM-1, nPCR, IDWG, and rHUuEpo/kg/wk values. Like group 1, group 2 patients seemed to show inflammation and malnutrition, namely decreased albumin levels, nPCR, and rHUEpo resistance, when compared with group 3. Finally, intermittent elevations of CRP must be considered to reflect a state of chronic inflammatory response associated with malnutrition and erythropoietin resistance similar to that observed among hemodialysis patients with persistently high CRP levels.     

Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients.

BACKGROUND: Fetuin-A (alpha2-Heremans Schmid glycoprotein) has recently been identified as a circulating inhibitor of calcification and is regulated as a negative acute phase protein. However, its relationships with cardiac valvular calcification and atherosclerosis and outcome have not been evaluated in peritoneal dialysis (PD) patients. METHOD: We performed a prospective follow-up study in 238 PD patients with echocardiography done at baseline to detect cardiac valvular calcification and biochemical analysis performed for serum fetuin-A, albumin and C-reactive protein (CRP). RESULTS: Baseline serum fetuin-A concentration was (mean+/-SD) 0.309+/-0.068 g/l (normal range 0.4-0.95). Across the three tertiles of increasing serum fetuin-A, a significant trend effect was observed for age (P = 0.023), diabetes (P = 0.008), background atherosclerotic vascular disease (P = 0.010), cardiac valvular calcification (P = 0.002), serum albumin (P<0.001), subjective global assessment (P = 0.005) and CRP (P<0.001). Adjusting for CRP and calcium x phosphorus product, every 0.01 g/l increase in serum fetuin-A remained independently associated with a 6% decrease in the risk of valvular calcification (95% confidence intervals, 0.90-0.99; P = 0.028). Furthermore, serum fetuin-A showed a significant decrease across the four groups of patients with increasing components of the malnutrition, inflammation, atherosclerosis/calcification (MIAC) syndrome (P<0.001) and was the lowest among patients with all components of the MIAC syndrome (0.263+/-0.055 g/l) and highest among those who do not have the MIAC syndrome at all (0.338+/-0.063 g/l). Lower serum fetuin-A was associated with greater all-cause mortality (P = 0.0011) and fatal and non-fatal cardiovascular events (P = 0.0017), but its significance was lost when atherosclerotic vascular disease, valvular calcification, inflammation and malnutrition were included in the model. CONCLUSIONS: Serum fetuin-A showed important associations with valvular calcification, atherosclerosis, malnutrition and inflammation, and was linked to mortality and cardiovascular events in PD patients via its close relationships with the MIAC syndrome.     

Influence of oral vitamin E therapy on micro-inflammation and cardiovascular disease markers in chronic hemodialysis patients

BACKGROUND: The aim of this study was to evaluate the influence of oral vitamin E therapy on serum concentrations of several markers of micro-inflammation and cardiovascular disease in chronic hemodialysis (HD) patients. METHODS: 29 HD patients were randomized into two groups: 15 patients were treated orally with 400 mg of vitamin E daily for a period of five weeks, and 14 patients received no antioxidant supplementation. Before and after vitamin E therapy, serum concentrations of vitamin E (high-performance liquid chromatography), pregnancy-associated plasma protein-A (immunochemical--TRACE assay), C-reactive protein (nephelometry), intercellular adhesion molecule-1 (ELISA), and E-selectin (ELISA) were measured. HD patients were compared with 16 healthy controls. RESULTS: Baseline serum concentrations of PAPP-A and CRP were significantly higher in HD patients than in healthy controls (PAPP-A: 26.23+/-11.94 vs. 11.41+/-1.94 mIU/L, p<0.001; CRP: 5.20+/-3.50 vs. 3.40+/-3.80 mg/L, p<0.05). After five weeks of oral vitamin E intake, serum PAPP-A, CRP, ICAM-1, and E-selectin concentrations remained unchanged in both groups of HD patients. CONCLUSION: Chronic micro-inflammation in HD patients is documented by the elevation of CRP and PAPP-A. A daily oral dose of 400 mg of vitamin E does not seem to be able to reduce enhanced oxidative stress and micro-inflammation in chronic HD patients.