Effects on inflammatory and nutritional markers of haemodiafiltration with online regeneration of ultrafiltrate (HFR) vs online haemodiafiltration: a cross-over randomized multicentre trial.

BACKGROUND: HFR [double chamber haemodiafiltration (HDF) with reinfusion of regenerated ultrafiltrate] is a novel dialytic method which combines the processes of diffusion, convection and adsorbance. In this technique an adsorbent cartridge of resin and charcoal may regenerate the ultrafiltrate suggesting its use as an endogenous substitution fluid. The aim of this multicentre randomized cross-over study was to compare HFR to online HDF in terms of inflammatory and nutritional parameters. METHODS: After a 1 month run-in period of standard bicarbonate dialysis (HD) with a synthetic membrane, 25 chronic dialytic patients were randomized (A-B or B-A) to be treated by HFR (A) with a two-chamber filter (SG 8 Plus - high permeability Polysulphone HF 0.7 m2 + SMC 1.95 sqm; Bellco, Mirandola, Italy) or by online sterile bicarbonate HDF. Each study period of 4 months was separated by 1 month of HD and the entire length of the study was 10 months. CRP levels were measured by a highly sensitive nephelometric assay (Dade, Behring) with a sensitivity of 0.1 microg/ml. Cytokine concentrations were determined by EIA [Interleukin (IL) 6, Biosource, USA and IL-10 Bender MED-Systems, Vienna]. The sensitivity thresholds were < 5 pg/ml for IL-6 and < 8 pg/ml for IL-10. Serum leptin was determined with a ELISA method (Biosource, USA). All parameters were determined monthly in patients starting a midweek dialytic session. RESULTS: Plasma CRP and IL-6 were significantly reduced during the 4 months of HFR and HDF: CRP from 8.0 +/- 3.2 to 5.6 +/- 3.4 mg/l with HFR (P < 0.05) and from 9.4 +/- 4.3 to 5.9 +/- 3.9 mg/l with HDF (P < 0.05). IL-6 decreased from 14.8 +/- 6.3 to 10.1 +/- 3.2 with HFR (P < 0.02) and from 12.1 +/- 4.2 to 9.6 +/- 3.7 with HDF (P = ns) with a percentage decrease after 4 months of 32% with HFR vs 21% with HDF. During the 1 month wash-out period with HD, CRP increased from 5.7 +/- 3.6 to 8.7 +/- 3.9 mg/l (P < 0.01) and IL-6 from 10 +/- 3.4 to 13.5 +/- 5.2 pg/ml (P < 0.01). A significant increase in IL-10 was detected either in HFR (from 4.8 +/- 2.1 to 6.89 +/- 1.7 pg/ml) and in HDF (from 3.3 +/- 1.7 to 8.95 +/- 4.3 pg/ml; P < 0.05) after 4 months. No significant variation in serum leptin levels were observed during the study. CRP and IL-6 were highly correlated (r = 0.54; P < 0.001) as was serum albumin and prealbumin (r = 0.39; P < 0.001). Serum albumin was negatively correlated with CRP (r = -0.26; P < 0.01) and IL-6 (r = -0.19; P < 0.05); serum prealbumin was correlated with IL-6 (r = 0.37; P < 0.001) and with CRP (r = 0.24; P < 0.01). CONCLUSIONS: Haemodiafiltration with online regeneration of ultrafiltrate and online HDF are highly biocompatible techniques and no significant difference between HFR and online HDF was observed in terms of reduction of inflammatory markers. Further studies with a longer follow-up are needed to evaluate the clinical relevance of the online endogenous reinfusion to counteract the chronic inflammatory state of the uraemic patient.     

持续性非卧床腹膜透析患者容量超负荷与大动脉僵硬度的关系

目的探讨持续性非卧床腹膜透析（CAPD）患者细胞外液（ECW）与总体水（TBW）的比率（E／T）与脉搏波速度（PWV）的关系。方法选取56例CAPD患者为研究对象。自动PWV分析仪测定PWV。多频生物电阻抗分析仪对患者的容量状态进行评估。对相应指标进行相关及多元回归分析，筛选出PWV的影响因素。结果结果显示E／T（β=0．472．P=0．001）、脉压（β=0．442，P=0．001）、C反应蛋白（β=0．246，P=0．05）是PWV增加的独立危险因素。3者一起决定了PWV变化的58．1％，其中E／T决定37．8％。结论在透析患者中容量超负荷可能是通过动脉硬化程度的加重导致心血管疾病发生率和病死率增加的。     

Relationship of peritoneal membrane transport characteristics to the nutritional status in CAPD patients.

BACKGROUND: The study was carried out to evaluate the role of individual peritoneal membrane transport characteristics in the nutritional status expressed as the composite nutritional index (CNI) METHODS: Cross-sectional analyses of the overall nutritional status of 147 continuous ambulatory peritoneal dialysis (CAPD) patients were performed using the CNI. CNIs based on a scoring system of 10 nutritional indices including subjective global assessment, biochemical parameters and anthropometry were compared according to the results of a standard peritoneal equilibration test (PET) RESULTS: Patients were classified as low (n = 16, 10.9%), low average (n=59, 40.2%), high average (n=54, 36.7%) and high (n=18, 12.2%) transporters based on the D/P(Cr) after 4 h dwells. The mean 4 h D/P(Cr) was 0.65 +/- 0.12 (0.34-0.95), and there was no significant correlation between D/P(Cr) and other demographic parameters such as age, duration of peritoneal dialysis and body surface area. D/P(Cr) was correlated with dialytic albumin loss (r=0.47, P<0.001), serum albumin (r=-0.46, P<0.001), serum creatinine (r= -0.38, P<0.001), serum TGF-1 (r=-0.37, P<0.01) and LBM(Cr) (r= -0.26, P<0.05). In high transporters, the serum albumin was significantly lower while dialysate protein and albumin losses were significantly greater compared with low transporters. Serum creatinine and IGF-1 concentrations as well as LBM(Cr) were also decreased in higher transporters. The mean CNI score was 8.1 +/- 4.9, with a range of 0-24. CNI was positively correlated with age, duration of peritoneal dialysis, incidence of peritonitis, CRP and dialytic protein loss, whereas it was inversely correlated with ultrafiltration volume, haemoglobin and NPNA. The CNI score was significantly higher in high transporters compared with low transporters (11.7 +/- 4.3 vs. 5.9 +/- 1.6, P < 0.01). There was also a significant correlation between D/P(Cr) and CNI (r = 0.29, P < 0.05). Multiple regression analysis revealed that the incidence of peritonitis, duration of CAPD, CRP and D/P(Cr) were the independent factors affecting the CNI. CONCLUSION: Peritoneal membrane transport characteristics correlate with the overall nutritional status of peritoneal dialysis patients assessed by the scoring system of the CNI, although it is associated with a different impact on the individual nutritional indices. The results of this cross-sectional study also suggest that a high permeability state is a risk factor for malnutrition in CAPD patients. Prospective studies evaluating the changes in nutritional parameters among patients with different membrane transport rates are needed to understand better the relationship of peritoneal membrane characteristics to the nutritional status of CAPD patients.     

Thyroid function tests in patients undergoing maintenance dialysis: characterization of the 'low-T4 syndrome' in subjects on regular hemodialysis and continuous ambulatory peritoneal dialysis

Thyroid function tests were evaluated in 38 patients on regular hemodialysis (HD), in 36 on continuous ambulatory peritoneal dialysis (CAPD) and in 39 healthy controls. A significant reduction in total thyroxine (TT4), total triiodothyronine (TT3), reverse (rT3), and free T4 (fT4) mean levels and normal TSH, free T3, TBG and albumin concentrations was found in both HD and CAPD patients. A 'low-T4 syndrome' (serum T4 less than 5 micrograms/dl) was found in 9 CAPD (25%) and 20 HD (53%) patients, but none of them had fT4 levels below the normal laboratory range. The only striking difference between low-T4 HD and low-T4 CAPD patients was the significantly lower TBG and albumin serum levels in CAPD group. Low-T4 HD displayed normal TBG levels but enhanced fT4/TT4 and fT4/TT4 X TBG ratios. We concluded that: the abnormalities in thyroid function tests in patients on long-term dialysis (HD and CAPD) do not express the existence of a true hypothyroidism; a different pathogenesis of the low-T4 syndrome in the CAPD and HD groups may be hypothesized: in the former it could be attributed to a reduction in serum-binding capacity for thyroid hormones, in the latter the relative increase in fT4 percentage despite normal TBG levels suggests either the presence of T4-TBG-binding inhibitor(s), or structural abnormalities of thyroid-hormone-binding proteins.     

Soluble Fas: a novel marker of inflammation in uremia

BACKGROUND: Inflammation has been associated with atherosclerotic cardiovascular disease (CVD) and anemia in patients with end-stage renal disease (ESRD). Recent studies have shown that serum levels of soluble Fas (sFas), an antiapoptotic and proinflammatory molecule, are elevated in patients with cardiac disease and patients with ESRD. We therefore sought to investigate serum levels of sFas in uremic patients and its correlation with known markers of inflammation, anemia and CVD. METHODS: The study included 25 ESRD patients (14 on hemodialysis, 11 on CAPD), 27 patients with chronic kidney disease (CKD; creatinine clearance <50 ml/min/1.73 m2), and 14 normal control subjects. We measured serum levels of sFas, C-reactive protein (CRP), and albumin. We also investigated the association of serum sFas levels with the presence of CVD and with erythropoietin (EPO) dosage. RESULTS: Levels of sFas were elevated in CKD and ESRD patients compared to controls. sFas levels correlated negatively with creatinine clearance. In the dialysis patients, we observed that sFas levels were higher among those with CVD. Serum levels of sFas correlated with serum levels of CRP (r=0.31; P=0.03), serum levels of albumin (r=-0.35, P=0.02), and EPO dosage (r=0.51; P=0.009). CONCLUSION: These results suggest that sFas may be a marker of inflammation in CKD and ESRD patients.     

Leptin in CAPD patients: serum concentrations and peritoneal loss.

BACKGROUND: To determine whether serum leptin concentrations in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are influenced by peritoneal loss of leptin and to compare serum leptin levels of normal subjects with those of patients receiving renal replacement therapy such as haemodialysis (HD), CAPD, or kidney transplantation. SUBJECTS AND METHODS: Eighty-four individuals were investigated: six females and 14 males on standard CAPD; 13 females and 13 males on chronic HD; 10 female and eight male kidney transplant recipients, and 10 female and 10 male subjects as controls. Morning serum, 8-h and 24-h samples of peritoneal fluid concentrated to 6-20-fold by Centricon 3 (cutoff 3000 daltons), and 24-h urinary concentrations of leptin were measured with commercial RIA (Linco Research, Inc., USA). Venous blood and peritoneal fluid samples of albumin, beta2-microglobulin, glucose, urea, and creatinine were determined by standard laboratory techniques. Serum insulin levels were measured by radioimmunoassay. RESULTS: Patients (men and women) on CAPD and after kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/BMI ratios than control subjects. These increased values did not reach statistical significance in HD patients. Serum leptin concentrations were correlated very significantly with BMI in all cases (r=0.380, P<0.001). Moreover, in CAPD patients (r=0.630, P<0.007) and in HD patients (r=0.668, P<0.005), but not in kidney transplant recipients or control subjects, significant correlations were observed between serum leptin and insulin concentrations. Residual renal function (RRF) in the range 0-12.8 ml/min and serum beta2-microglobulin levels in the range 7.9-47.1 mg/l did not influence serum leptin levels in CAPD and HD patients. As expected, leptin was detected in the peritoneal fluid of CAPD patients. Twenty-four-hour peritoneal loss (30.95+/-21.05 ng/min) and 24-h peritoneal clearance (0.01+/-0.01 ml/kg/min) of leptin account for only 3.9% of estimated whole-body leptin production rate and 0.7% of leptin clearance from plasma respectively. Twenty-four-hour urinary losses of leptin in CAPD patients were negligible, accounting for 5.6+/-1.8% (range 0.3-15.2%) of total (peritoneal and urinary) loss of this hormone. CONCLUSIONS: These findings suggest that serum leptin levels are not affected by continuous peritoneal loss of leptin during CAPD and that insulin resistance and hyperinsulinaemia contribute to elevated serum leptin concentrations in CAPD and HD patients. The aetiology of increased serum leptin levels in kidney transplant recipients is probably different from that in dialysis patients.     

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.     

持续性非卧床腹膜透析患者肝肾阴虚证与低T3综合征的关系

目的:探讨持续性非卧床腹膜透析(CAPD)患者本虚证候与血清游离三碘甲腺原氨酸(FT3)水平的关系。方法:对2009年3月～4月在北京大学第三医院肾内科接受持续性非卧床腹膜透析的患者进行横断面调查。检测血清甲状腺激素(TT3、TT4、FT3、FT4、TSH)水平及生化项目。采用均数比较及多因素分析等统计学方法探讨肝肾阴虚证与FT3水平的关系。结果:共纳入正常促甲状腺素(TSH)的CAPD患者89例,分为肝肾阴虚证组(19例),非阴虚证组(70例),结果显示肝肾阴虚证组血清TT3、TT4与FT3均明显低于非阴虚证组[TT3(0.96±0.23)μg/mlvs(1.13±0.22)μg/ml,P<0.01;TT4(7.59±1.69)μg/mlvs(8.65±1.55)μg/ml,P<0.01;FT3(2.35±0.35)pg/mlvs(2.57±0.33)pg/ml,P<0.01)];多因素分析结果示在矫正性别、年龄、糖尿病、透析龄等因素后,肝肾阴虚、血清白蛋白、C反应蛋白与残肾Kt/V是FT3的独立影响因素(R2=0.396,P<0.01)。结论:本研究表明肝肾阴虚证可能与CAPD患者低T3综合征的发生密切相关。     

Ceruloplasmin and acute phase protein levels are associated with cardiovascular disease in chronic dialysis patients

BACKGROUND: The most frequent cause of death in hemodialysis (HD) patients is cardiovascular disease (CVD), and chronic inflammation has been identified as an epidemiologically important risk factor for CVD. Elevated levels of minor acute phase reactants, such as ceruloplasmin (Cp) and transferrin, have been related to an increased cardiovascular risk in the general population, but little information is available regarding dialysis patients. We investigated the correlation between Cp and copper concentration (Cu) with major acute phase reactants such as C-reactive protein (CRP) and interleukin-6 (IL-6) in a population of chronic dialytic patients. Furthermore, we evaluated the relationship between long-lasting acute phase proteins such as Cp and nutritional markers. PATIENTS AND METHODS: CRP (Berhing Diagnostic, high sensitivity modified nephelometric technique, detection limit 0.1 mcg/mL), IL-6 (EIA, RD Systems), serum albumin, prealbumin, Cp (Berhing, nephelometric assay), copper (mass spectrometry, Varian) and standard laboratory routine analysis were determined in 75 stable chronic dialysis patients (age 60 +/- 16 yrs; dialytic age 65 +/- 50 months ) starting a midweek dialytic session. RESULTS: Thirty-seven patients (49%) had clinical signs of cerebrovascular, cardiovascular or peripheral vascular disease. Fifty-one patients (67%) showed biochemical inflammation markers as suggested by elevated CRP levels (mean 12.4 mg/L, SD 11.5) and IL-6 (mean 21.3 pg/mL, SD 19.7) with a positive correlation (r=0.65; p<0.001) between CRP and IL-6. CRP and IL-6 also related negatively to nutritional markers such as albumin and prealbumin (r=-0.42; p<0.01). Cp related significantly to CRP (r=0.4; p<0.001) and IL-6 (r=0.41; p<0.001), and as expected to copper (r=0.96; p<0.001), but not with serum albumin and prealbumin. In a multivariate logistic regression analysis, age (p<0.001), dialytic age (p>0.01), IL-6 (p=0.04) and Cp (p=0.02) were the strongest risk factors for cardio-vascular disease (CVD). CONCLUSION: These data suggest that serum Cp could be useful in monitoring the "chronic inflamed" patient and support the suggestion that elevated metalloprotein levels are associated with an increased cardiovascular risk in a population of stable dialysis patients.     

Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patient.

BACKGROUND: Bolus calcitriol (CTR) is used for the treatment of secondary hyperparathyroidism in dialysis patients. Although CTR treatment reduces parathyroid hormone (PTH) levels in many dialysis patients, a significant number fail to respond. METHODS: To learn whether or not an analysis of parathyroid function could further illuminate the response to CTR, a PTH-calcium curve was performed before and after at least two months of CTR treatment in 50 hemodialysis patients with a predialysis intact PTH of greater than 300 pg/ml. RESULTS: For the entire group (N = 50), CTR treatment resulted in a 24% reduction in predialysis (basal) PTH from 773 +/- 54 to 583 +/- 71 pg/ml (P < 0.001), whereas ionized calcium increased from 1.10 +/- 0.02 to 1.22 +/- 0.02 mM (P < 0.001); however, maximal and minimal PTH did not change from pre-CTR values. Based on whether or not the basal PTH decreased by 40% or more during CTR treatment, patients were divided into responders (Rs, N = 25) and nonresponders (NRs, N = 25). Before CTR, the NR group was characterized by a greater basal (959 +/- 80 vs. 586 +/- 51 pg/ml, P < 0.001) and maximal (1899 +/- 170 vs. 1172 +/- 108 pg/ml, P < 0. 001) PTH and serum phosphorus (6.14 +/- 0.25 vs. 5.14 +/- 0.34 mg/dl, P < 0.01). Logistical regression analysis showed that the pre-CTR basal PTH was the most important predictor of the post-CTR basal PTH, and a pre-CTR basal PTH of 750 pg/ml represented a 50% probability of a response. Basal PTH correlated with the ionized calcium in the NR group (r = 0.59, P = 0.002) but not in the R group (r = 0.06, P = NS). In the R group, an inverse correlation was present between ionized calcium and the basal/maximal PTH ratio, an indicator of whether calcium is suppressing basal PTH secretion relative to the maximal secretory capacity (maximal PTH) r = -0.55, P = 0.004; in the NR group, this correlation approached significance but was positive (r = 0.34, P = 0.09). After CTR treatment, serum calcium increased in both groups, and despite marked differences in basal PTH (Rs, 197 +/- 25 vs. NRs, 969 +/- 85 pg/ml), an inverse correlation between ionized calcium and basal/maximal PTH was present in both groups (Rs, r = -0.61, P = 0.001, and NRs, r = -0.60, P = 0.001). CONCLUSIONS: (a) Dynamic testing of parathyroid function provided insights into the pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of hyperparathyroidism was the most important predictor of the response to CTR. (c) Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium, calcium suppressed basal PTH relative to maximal PTH in both groups.     

Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function.

BACKGROUND: Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined. METHODS: Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed. RESULTS: Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P < 0.001), 4.1+/-0.6 (P < 0.001), 2.6+/-0.4 (P < 0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P < 0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P < 0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P < 0.001), while body mass index (T = 7.83, P < 0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM Nx > IgAN > T1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P < 0.001) > 663+/-34 (P = 0.001) > 601+/-21 (P < 0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P < 0.001) > 313+/-13 (P < 0.001) > 307+/-8 (P < 0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P < 0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P < 0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001). CONCLUSIONS: Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.     

Changes in quality of life after renal transplantation

Studies were performed to investigate the relationship between serum interleukin-6 (IL-6) and the nutritional status in chronic hemodialysis patients. Serum IL-6 in 45 patients (21 men and 24 women), each with chronic renal failure and having undergone hemodialysis for more than 3 years, was measured before and after a dialysis session. The nutritional status of each patient was evaluated by measuring body mass index (BMI), body weight loss for 3 years, midarm muscle area (MAMA), serum albumin, prealbumin, and insulin-like growth factor-1. Serum IL-6 was significantly higher in the patients undergoing hemodialysis (11.7 +/- 2.8 pg/mL) than in healthy volunteers (< 0.6 pg/mL). There was no further increase in serum IL-6 after a dialysis session when the extracellular water volume was corrected by the ultrafiltrate volume. Predialytic serum IL-6 was significantly correlated with serum albumin (r = -0.4, P = 0.006), cholinesterase (r = -0.51, P = 0.001), body weight change for 3 years (r = -0.48, P = 0.001) and MAMA r = -0.39, P = 0.05). With the patients divided into two groups, a high serum IL-6 (>10 pg/mL) group and low serum IL-6 (<10 pg/mL) group, the body weight loss for 3 years (-4.60% +/- 1.39% v 0.76 +/- 0.75%, P < 0.01) was significantly higher, and the serum albumin level (3.66 +/- 0.10 g/dL v 3.96 +/- 0.05 g/dL, P < 0.05) was significantly lower in those patients with high serum IL-6 than in those with low serum IL-6. The results of a multiple regression analysis indicated that the serum IL-6 level was dependent on the duration of hemodialysis, age, and the dialysis membrane properties. These results suggest that the nutritional status in chronic hemodialysis patients was affected, at least in part, by the circulating IL-6 level. Multiple factors, such as long-term hemodialysis, aging, and the use of a regenerated cellulose membrane dialyzer, were associated with this increased level of IL-6.     

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.     

Platelet aggregation and beta-thromboglobulin levels in nephrotic patients with and without thrombosis

Platelet aggregation and beta-thromboglobulin levels were studied in 17 patients with the nephrotic syndrome. Thrombosis or thromboembolic complications occurred in 4 of these patients with serum albumin levels below 2 g/100 ml. Pathologic platelet aggregation assessed by estimating alpha 2-angle values derived from platelet aggregation curves was seen in the 4 patients with thromboembolic complications (alpha 2-angle 69.5 degrees +/- 10.1 degrees), whereas patients without thrombosis showed normal alpha 2-angle values (less than 30 degrees) with only one exception. In addition, patients with thromboembolic complications demonstrated significantly elevated beta-thromboglobulin levels, when compared with those not having thrombosis or thromboembolic complications (76.8 +/- 14.3 ng/ml vs 44.8 +/- 8.6 ng/ml, P less than 0.001). The decrease in serum albumin concentration showed an inverse relationship with both, alpha 2-angle values (r = -0.82, P less than 0.001) and beta-thromboglobulin levels (r = -0.83, P less than 0.001) indicating a regulatory role of serum albumin in platelet aggregation. We conclude, that altered platelet aggregation as well as hypercoagulability may be involved in the pathogenesis of thrombosis and thromboembolic complications in the course of the nephrotic syndrome.     

In vitro production of interleukin-1 receptor antagonist in chronic renal failure, CAPD and HD.

Dialysis-related symptoms are believed to be mediated, at least in part, by monocyte/macrophage-derived pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor (TNF). Measuring the production of interleukin-1 receptor antagonist (IL-Ra), a naturally occurring inhibitor of IL-1, opens avenues to study the balance between these two cytokines in patients. We studied the cell content and production of IL-1 beta and IL-Ra by unstimulated and endotoxin- or IgG-stimulated peripheral blood mononuclear cells (PBMC) in undialyzed patients with chronic renal failure (CRF), patients on continuous ambulatory peritoneal dialysis (CAPD) and patients on chronic hemodialysis with reuse cuprophan membranes (HD), and compared them to healthy controls. IL-1 beta and IL-Ra were measured by specific radioimmunoassay. IL-1 beta was undetectable in freshly harvested PBMC from healthy controls, CRF, CAPD or HD. In contrast, the content of IL-Ra in HD patients (2828 +/- 466 pg/ml) was significantly higher than that in healthy controls (643 +/- 53 pg/ml, P < 0.01), CRF (1097 +/- 320 pg/ml, P < 0.01) or CAPD (1398 +/- 390 pg/ml, P < 0.05). In endotoxin-stimulated PBMC, IL-1 beta production by HD patients (9375 +/- 1687 pg/ml) was not significantly different from healthy controls (8429 +/- 1621 pg/ml). However, endotoxin-stimulated IL-Ra production by HD patients (32,350 +/- 8276 pg/ml) was greater than that from healthy controls (11,284 +/- 1250 pg/ml, P < 0.001), CRF (12,263 +/- 2680 pg/ml, P < 0.01) or CAPD patients (11,822 +/- 1797 pg/ml, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting.

OBJECTIVE: It has been observed that a systemic inflammatory response after on-pump coronary artery bypass grafting (CABG) participates in the pathogenesis of postoperative atrial fibrillation (AF). In patients undergoing off-pump CABG, it is plausible that inflammation is associated with the development of postoperative AF. The present study examined relation of proinflammatory cytokines, which play an important role in the upstream of inflammatory cascade, to the development of AF after off-pump CABG. METHODS: The present study included 39 patients undergoing off-pump CABG. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8, were measured by enzyme-linked immunosorbent assay, on anesthetic induction, after sternotomy before anastomoses, at the completion of anastomoses, 3 and 6h thereafter, and on postoperative days (POD) 1-4. C-reactive protein (CRP) was also measured by turbidimetric immunoassay, preoperatively, and on POD 1, 2, 3, 6, 9, and 13. RESULTS: Eleven patients (28%) developed postoperative AF. Patients with postoperative AF were older (70+/-6.4 years vs 60+/-8.8 years, P=0.001); however, there was no difference in other pre- and perioperative variables. TNF-alpha level did not change during the study period. However, IL-8 and CRP levels significantly increased after the surgery, although there was no significant difference between the two groups. IL-6 level also increased after the surgery with its peak at 6h after the completion of anastomoses. IL-6 levels of 3 and 6h after anastomoses were significantly higher in patients with postoperative AF (360+/-143 pg/ml vs 230+/-94 pg/ml, P=0.0047, 435+/-175 pg/ml vs 247+/-102 pg/ml, P=0.0005, respectively). Logistic regression analysis indicated that the highest quartile of IL-6 level immediately after the surgery (odds ratio 7.63; 95% CI, 1.06-54.9; P=0.04) and age (odds ratio 1.18; 95% CI, 1.01-1.39; P=0.04) independently predict postoperative AF. Furthermore, the maximum level of IL-6 immediately after the surgery significantly correlated to age and intraoperative blood loss (r=0.04, P=0.01, and r=0.47, P=0.04, respectively). CONCLUSIONS: Advanced age was a major risk factor for postoperative AF. Furthermore, inflammatory response induced by surgical trauma was also associated with the development of AF after off-pump CABG.     

Correlates of habitual physical activity in chronic haemodialysis patients.

BACKGROUND: Results of physical performance tests may not reflect the level of habitual physical activity and health status of the dialysis patients. The aim of our study was to assess interdialytic spontaneous physical activity in chronic haemodialysis (HD) patients in relation to their nutritional status, severity of anaemia, inflammation and dialysis adequacy. METHODS: Sixty HD patients [27 female, 33 male; mean age 60+/-13 years, time on dialysis 46.2+/-62.1 months and body mass index (BMI) 25.1+/-4.7 kg/m2] without physical and neurological disabilities and 16 healthy individuals (10 female, six male, mean age 56+/-6 years, BMI 26.6+/-4.9 kg/m2) were enrolled into the study. In all patients, spontaneous daily physical activity was measured during 48 h between mid-week dialysis sessions by pedometers. Nutritional status was estimated by anthropometric methods (BMI and mid-arm muscle circumference) and serum albumin concentration. Additionally, body composition was estimated using a multifrequency phase-sensitive bioimpedance analysis (BIA). Severity of anaemia was determined by blood haemoglobin level and haematocrit value, and the presence of inflammatory state was determined by high sensitivity plasma C-reactive (CRP) protein measurements. RESULTS: The total number of steps during daily activities in dialysis patients and in healthy individuals was 6896+/-2357 vs 14 181+/-5383 per 48 h, respectively (P<0.001). Dialysis patients showed typical signs of malnutrition in the BIA, i.e. high extracellular mass/body cell mass index (1.17+/-0.28 in dialysis patients vs 0.97+/-0.1 in controls; P<0.001), low percentage cell mass (46.7+/-5.6 and 51.0+/-3.6, respectively; P = 0.002) and low phase angle (5.1+/-0.9 and 5.8+/-0.7, respectively; P = 0.006). Dialysis patients also showed lower serum albumin and blood haemoglobin and higher serum CRP levels than healthy controls. In dialysis patients, the number of steps taken positively correlated with body water (R = 0.28, P = 0.03), fat mass (r = 0.29, P = 0.04), BMI (R = 0.25, P = 0.04), lean body mass (R = 0.26, P = 0.04), intracellular water (r = 0.30, P<0.01), phase angle (R = 0.40, P = 0.002), serum albumin (R = 0.32, P = 0.01), haematocrit (R = 0.46, P = 0.001) and haemoglobin (R = 0.44, P = 0.001). Furthermore, the number of steps taken correlated significantly with mid-arm muscle circumference (r = 0.35, P = 0.006). A negative correlation was found between the number of steps and extracellular mass/body cell mass index (R = -0.37; P = 0.004). No significant relationships were found between the measures of physical activity and high sensitivity CRP or adequacy of dialysis. Multiple regression analysis revealed the independent associations between the number of steps taken by the patients and haemoglobin concentration, age, total body water, extracellular mass/body cell mass index and phase angle. CONCLUSIONS: Low habitual physical activity assessed in HD patients with simple portable pedometers is strongly related to several factors of major clinical importance in this population.     

Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage

OBJECTIVE: Serum brain natriuretic peptide (BNP) is elevated after subarachnoid hemorrhage (SAH), causes diuresis and natriuresis (cerebral salt wasting), and may exacerbate delayed ischemic neurological deficits. We examined the temporal relationship between serum BNP elevation, hyponatremia, and the onset of delayed ischemic neurological deficits and determined whether serum BNP levels correlated with the 2-week outcome after SAH. METHODS: Serum BNP and sodium were measured prospectively every 12 hours for 14 days in 40 consecutive patients admitted with SAH. All patients remained euvolemic, underwent transcranial Doppler assessment every 48 hours, and underwent angiography at the onset of delayed neurological deficits. New-onset neurological deficits were attributed to vasospasm only in the absence of other causes and when supported by transcranial Doppler or cerebral angiography. RESULTS: Sixteen patients (40%) experienced symptomatic cerebral vasospasm after SAH. A more than threefold increase in admission serum BNP was associated with the onset of hyponatremia (P < 0.05). Mean BNP levels were similar between vasospasm and nonvasospasm patients fewer than 3 days after SAH (126 +/- 39 pg/ml versus 154 +/- 40 pg/ml; P = 0.61) but were elevated in the vasospasm cohort 4 to 6 days after SAH (285 +/- 67 pg/ml versus 116 +/- 30 pg/ml; P < 0.01), 7 to 9 days after SAH (278 +/- 72 pg/ml versus 166 +/- 45 pg/ml; P < 0.01), and 9 to 12 days after SAH (297 +/- 83 pg/ml versus 106 +/- 30 pg/ml; P < 0.01). BNP level remained independently associated with vasospasm adjusting for Fisher grade and Hunt and Hess grade (odds ratio, 1.28; 95% confidence interval, 1.1-1.6). In patients in whom vasospasm developed, mean serum BNP increased 5.4-fold within 24 hours after vasospasm onset and 11.2-fold the first 3 days after vasospasm onset. Patients with increasing BNP levels from admission demonstrated no change (0 +/- 3) in Glasgow Coma Scale score 2 weeks after SAH versus a 3.0 +/- 2 (P < 0.05) improvement in Glasgow Coma Scale score in patients without increasing serum BNP levels. CONCLUSION: Increasing serum BNP levels independently were associated with hyponatremia, significantly increased the first 24 hours after onset of delayed ischemic neurological deficits, and predicted the 2-week Glasgow Coma Scale score.     

Peritoneal transport status influence on atherosclerosis/inflammation in CAPD patients.

OBJECTIVE: Peritoneal transport status is one of the main determinants of dialysis adequacy and dialysis-related complications in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis (CAPD). In this study we aimed to investigate the relationship between peritoneal transport characteristics and known promoters of atherosclerosis in a group of patients receiving CAPD for a minimum of 36 months. DESIGN AND PARTICIPANTS: We performed a cross-sectional study of a cohort of 84 patients with end-stage renal disease (37 men, 47 women; age, 44.0 +/- 15.7 years; dialysis duration, 40.3 +/- 8.1 months) who were receiving CAPD for minimum 36 months. Peritoneal transport characteristics were identified after a peritoneal equilibration test (PET) determined at the third month of CAPD using Dialysate/Plasma (D/P) reference values. Patients were classified according to one of four peritoneal transport types: high (H), high-average (HA), low-average (LA), and low (L). After PET, patients were grouped as high (H/HA group, n = 51) or low (L/LA group, n = 33) transporters. The patient groups' clinical and laboratory data before dialysis and after initiation of the CAPD were collected retrospectively. The patients' follow-up data were retrieved for the diagnosis of any atherosclerosis-related event after the initiation of CAPD. The following events were collected, including myocardial infarction, having been diagnosed as having coronary artery disease by angiography or myocardium scintigraphy, cerebrovascular accident, and development of clinically evident peripheral arterial disease. RESULTS: A comparison of follow-up data revealed that the H/HA transport characteristic was associated with lower albumin (P < .01), higher C-reactive protein (CRP) (P < .0001) levels, and higher recombinant human erythropoietin (rHuEPO) needs (P < .001) when compared with the L/LA type. During follow-up, 28 patients showed an atherosclerosis-related event. Twenty-two of these were in the H/HA group (43.1%), whereas only six were in the L/LA group (18.1%, P < .01). Reanalysis of 18 patients with atherosclerosis-related events and high CRP levels (> 10 mg/L) showed that 15 were in the H/HA and 3 were in the L/LA group. Sixty-eight percent of the H/HA patients with atherosclerosis and 50% of the L/LA patients with an atherosclerotic event also had chronic inflammation (P < .001). A Pearson correlation analysis showed that there was a positive correlation between D/P creatinine levels and 36-month mean CRP levels (r = 0.608, P < .0001), and a negative correlation between D/P creatinine levels and 36-month mean albumin levels (r = -0.299, P < .005). CONCLUSIONS: This study shows that the high transporter peritoneal membrane characteristic is a risk factor for inflammatory state in patients with end-stage renal disease. High-transporter patients are at an increased risk of atherosclerosis when compared with their low-transporter counterparts through chronic inflammation.