B Cell-Attracting Chemokine-1 and Progranulin in Bronchoalveolar Lavage Fluid of Patients with Advanced Non-small Cell Lung Cancer: New Prognostic Factors.

Progranulin is a growth and survival factor implicated in tumorigenesis and drug resistance. Several studies showed that progranulin is expressed in breast cancer tissue and inversely correlates with survival. B lymphocyte chemoattractant, also known as B cell-attracting chemokine 1 (BCA-1), is a member of the CXC subtype of the chemokine superfamily. BCA-1 is critical for secondary lymphoid tissue development and navigation of lymphocytes within the microcompartments of the tissue. There are no data on the content of progranulin and BCA-1 in bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients. To study this issue, we measured BALF content of progranulin and BCA-1 in 46 NSCLC patients before chemotherapy and 15 healthy subjects. Both markers were elevated in cancer patients compared to healthy subjects (progranulin: 61.4 (1.6-384.0) vs. 6.5 (0.6-12.9) ng/ml, p = 0.001 and BCA-1: 30.8 (24.3-70.8) vs. 15.4 (13.3-19.5) pg/ml, p = 0.0001). The cut-off BALF level concerning NSCLC vs. controls, investigated using the receiver-operating characteristic (ROC) curve, yielded 6.5 ng/ml for progranulin and 15.4 pg/ml for BCA-1. We failed to find any association between the BALF content of progranulin or BCA-1 and the stage of tumor or prospectively assessed treatment response. However, BALF progranulin associated with time to tumor progression (r = 0.61; p = 0.04). In addition, a higher BALF content of BCA-1 in NSCLC patients associated with shorter overall survival. We conclude that progranulin and BCA-1 in BALF of NSCLC patients before chemotherapy may be prognostic factors of cancer progression.

Prognostic Value of Osteoprotegerin and sRANKL in Bronchoalveolar Lavage Fluid of Patients with Advanced Non-small Cell Lung Cancer.

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (sRANKL). OPG promotes endothelial cell survival and neoangiogenesis. Dysregulation of the OPG/RANKL system has been detected in several tumors. In the present study, we evaluated the clinical usefulness of OPG and sRANKL assessment in bronchoalveolar lavage fluid (BALF) of patients with advanced non-small cell lung cancer (NSCLC). We measured the concentration of OPG and sRANKL in BALF of 44 NSCLC patients and 15 healthy volunteers taken as control subjects. The OPG content was higher in the NSCLC group than that in controls [0.48 (0.12-1.45) vs. 0.23 (0.14-0.75) pmol/l; p = 0.0001]. There were no significant differences in sRANKL content between the NSCLC and control groups [1.22 (0.74-23.00) vs. 1.12 (0.79-4.39) pmol/l; p = 0.67]. However, we found that the greater the level of sRANKL in NSCLC patients, the shorter the overall survival. We found a correlation between the content of sRANKL and the percentage of lymphocytes in BALF of NSCLC patients (r = 0.52; p = 0.041). We conclude that NSCLC patients have a higher content of OPG in BALF than healthy people. A high level of sRANKL in BALF of NSCLC patients may predict worse survival.

Osteoprotegerin/sRANKL Signaling System in Pulmonary Sarcoidosis: A Bronchoalveolar Lavage Study.

Osteoprotegerin (OPG), a soluble tumor necrosis factor receptor family molecule, protects endothelial cells from apoptosis in vitro and promotes neovascularization in vivo. Angiogenesis may be crucial for the course and outcome of sarcoidosis. In this study, we evaluated the clinical usefulness of OPG and its ligand, a soluble receptor activator of nuclear factor-kappaB (sRANKL), in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis (BBS, Besniera-Boeck-Schaumann disease). We studied 22 BBS patients and 15 healthy volunteers as a control group. The levels of OPG, sRANKL, and interleukin-18 (IL-18) were measured by the Elisa method. The BALF levels of sRANKL and IL-18 were higher in the BBS patients compared with controls [sRANKL: 2.12 (0.82-10.23) vs. 1.12 (0.79-4.39) pmol/l, p = 0.03; IL-18: 34.29 (12.50-133.70) vs. 13.05 (12.43-25.88) pg/ml, p = 0.001]. There were no significant differences between the concentration of OPG in the BBS patients and healthy controls [0.22 (0.14-0.81) vs. 0.23 (0.14-0.75) pmol/l]. In the BBS patients we found correlations between sRANKL and IL-18 in BALF (r = 0.742, p = 0.0001) and between OPG and lung diffusing capacity for carbon monoxide (DLCO) (r = -0.528, p = 0.029). Receiver-operating characteristic (ROC) curve was applied to find the cut-off for the BALF level of sRANKL (BBS vs. healthy: 1.32 pmol/l). We conclude that OPG and sRANKL may have usefulness in clinical evaluation of BBS patients.

Clinical Implications of Hepatocyte Growth Factor, Interleukin-20, and Interleukin-22 in Serum and Bronchoalveolar Fluid of Patients with Non-Small Cell Lung Cancer.

Hepatocyte growth factor (HGF) is involved in tumorigenesis, interleukin-20 (IL-20) is an inhibitor of angiogenesis, and interleukin-22 (IL-22) stimulates tumor growth. The aim of this study was to determine the level of HGF, IL-20, and IL-22 in both serum and bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients before onset of chemotherapy, the nature of the interrelationships between these markers, and their prognostic significance regarding post-chemotherapy survival time. We studied 46 NSCLC patients and 15 healthy subjects as a control group. We found significantly higher serum levels of HGF and IL-22 in the NSCLC patients than those in controls [pg/ml: HGF - 1911 (693-6510) vs. 1333 (838-3667), p = 0.0004; IL-22 - 10.66 (1.44-70.34) vs. 4.69 (0.35-12.29), p = 0.0007]. In contrast, concentrations of HGF and IL-22 in BALF were lower in NSCLC patients than those in controls [pg/ml: HGF - 72 (6-561) vs. 488 (14-2003), p = 0.0002; IL-22 - 2.28 (0.70-6.52) vs. 3.72 (2.76-5.64), p = 0.002]. In the NSCLC patients, there was a negative correlation between the serum level of IL-20 and time to tumor progression (r = -0.405, p = 0.04) and between the serum level of HGF and survival time (r = -0.41, p = 0.005). In addition, a higher serum level of HGF and a higher BALF level of IL-22 in patients were linked with a shorter overall survival. We conclude that HGF, IL-20, and IL-22 in the serum and BALF of NSCLC patients before chemotherapy may be a prognostic of cancer progression.

Renal Handling of Sclerostin in Response to Acute Glomerular Filtration Decline.

Deterioration of glomerular filtration rate (GFR) is associated with alterations of bone metabolism. It translates clinically to bone fragility and increased fractures rate among patients with impaired GFR. Recently, sclerostin (SCL) gained much attention as an important factor in pathogenesis of mineral and bone disturbances in patients with renal diseases. There is no data about SCL behaviour in patients with acute GFR decline. The aim of this study was to evaluate the renal handling of SCL. This is a prospective, single-centre observational study in patients undergoing nephrectomy due to urological indications. Serum and urinary SCL levels were measured prior and after nephrectomy. 25 patients were enrolled. After surgery, eGFR significantly declined (from 87.4±19.7 to 67.7±25.7 ml/min/1.73 m(2), p<0.0001). Nephrectomy caused more than 20 times higher renal fractional excretion of SCL [0.15 (interquartile range, IQR 0.09-0.40) vs. 2.78 (IQR 1.51-4.02)%, p<0.001], while its serum level remained intact [0.69 (IQR 0.57-0.90 vs. 0.65 (IQR 0.53-0.88) ng/ml, p=0.4]. The magnitude of eGFR reduction was associated inversely with change in urinary SCL fractional excretion (r=-0.6, p=0.001) and with alteration in serum SCL level (r=-0.5, p=0.01). Our results suggest that increased serum SCL concentrations at moderately reduced GFR are not due to diminished renal clearance. At more severely decreased GFR, elevated SCL concentration results from both increased production and reduced renal elimination.

Interleukin-33 as a New Marker of Pulmonary Sarcoidosis.

The mechanisms of sarcoidosis (Besniera-Boeck-Schaumann disease, BBS) remain incompletely understood, although recent observations suggested an important contribution of interleukin-33 (IL-33). So far, there are no data about bronchoalveolar lavage fluid (BALF) concentration of IL-33 in patients with BBS. In the present study we attempted to relate the concentration of IL-33 to IL-18, a well-known marker of BBS activity, in BALF of BBS patients. We examined 24 BBS patients (stage II). The age-matched control group consisted of 24 healthy subjects. The levels of IL-33 and IL-18 in BALF were higher in BBS patients than in the control group [IL-33: 4.8 (0.1-12.5) vs. 3.4 (0.6-56.9) pg/ml, p=0.024; IL-18: 33.2 (5.7-122.0) vs. 10.8 (1.9-45.8) pg/ml, p=0.002]. In the BBS group, the correlations between IL-33 and IL-18 (r=0.606, p=0.002), and between IL-33 and diffusion lung capacity for carbon monoxide (DLCO) (r=-0.500, p=0.035) were found. The receiver-operating characteristic curves were applied to find the cut-off serum levels of IL-33 and IL-18 in BALF (BBS vs. healthy: IL-33 2.7 pg/ml and IL-18 16.4 pg/ml). We conclude that IL-33 appears an important factor of pulmonary BBS activity.

Expression of macrophage markers in cryoglobulinemic glomerulonephritis - a possible role of CXCL9.

PURPOSE: Cryoglobulinemic glomerulonephritis (CGGN) is a type of membranoproliferative glomerulonephritis (MPGN) that develops in patients with systemic cryoglobulinemia. To date the exact pathogenesis of CGGN remains unclear. It has been suggested that macrophages may be significant contributors to the glomerular injury in this disease. In our study we attempt to characterize the macrophages in human CGGN using classical activation and regulatory macrophage markers. MATERIAL AND METHOD: We searched our database for renal biopsy cases of CGGN. Macrophages were detected using a monoclonal anti-CD68 antibody. Two groups of macrophage markers were used: classical activation markers, including iNOS, CXCL9 and CCL20, and regulatory markers: SPHK1 and LIGHT. The stains were performed using immunohistochemical method. RESULTS: Five patients with CGGN were identified. Four patients had systemic cryoglobulinemia and two had a serological evidence of hepatitis C virus infection. In all cases the glomeruli contained numerous macrophages. Staining for activatory macrophage markers revealed a strong nuclear staining for CXCL9 in numerous cells, including those corresponding to the macrophage location. Staining for the other activatory markers, as well as staining for regulatory markers, was not significant. CONCLUSION: In this study of human CGGN we showed a striking expression of cytokine CXCL9, a classical macrophage activation marker, by the macrophages and possibly other cell types within the glomeruli. This observation points to the possible role of classically activated macrophages in the pathogenesis of MPGN. If this observation is confirmed on a larger group of patients, the cytokine CXCL9 could become a potential therapeutic target for human CGGN.

Age and gender predict OPG level and OPG/sRANKL ratio in maintenance hemodialysis patients.

PURPOSE: Cardiovascular disease (CVD) is a major cause of death among chronic hemodialysis (HD) patients. Gender and age belong to its classical risk factors. OPG/RANK/sRANKL (Osteoprotegerin/ Receptor Activator of Nuclear Factor κB/ soluble Receptor Activator of Nuclear Factor κB Ligand) axis constitute a system connecting bone and vascular remodeling. METHODS: We aimed to evaluate the plasma levels of OPG, sRANKL and OPG/sRANKL ratio in 21 HD patients and 16 healthy volunteers in relation to gender, age and the other clinical parameters. RESULTS: OPG and OPG/sRANKL ratio were significantly higher in HD patients than in controls whereas sRANKL was similar in both groups. Adjusted for gender, in controls OPG were higher in women whereas sRANKL did not differ between men and women. In HD group OPG and sRANKL were higher in women whereas OPG/sRANKL ratio was similar in both genders. Female patients compared to healthy women revealed 56% higher OPG concentration and 54% higher OPG/ sRANKL ratio. Comparison of male patients and controls revealed 61% higher level of OPG and 75% higher OPG/sRANKL ratio in HD group. Interestingly, OPG and OPG/sRANKL ratio positively correlated with age only in male patients. Contrary, the association between OPG/sRANKL ratio and age was negative in HD women. CONCLUSION: Higher OPG levels in HD women comparing to age matched HD men indicate the necessity of more careful screening towards the presence of CVD and bone-mineral disorders. The negative association between age and OPG/ sRANKL ratio in HD women warrant in-depth study for thorough understanding of this complex interrelationship.

Over-dialysis plasma RANTES increase depends on heparin dose and cardiovascular disease status.

PURPOSE: The lifespan of maintenance hemodialysis patients is reduced mainly because of cardiovascular complications due to accelerated atherosclerosis and impaired angiogenesis. We aimed to compare the effect of unfractionated heparin (UFH) and enoxaparin used as anticoagulants during hemodialysis (HD) on circulating levels of heparin-binding, anti-angiogenic Endostatin, pro-inflammatory RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted), and MCP-1 (Monocyte Chemoattractant Protein-1). METHODS: We enrolled 22 chronic HD patients, who were randomly assigned to either enoxaparin (n=11) or UFH (n=11) anticoagulation, and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. The factors were measured (ELISA) at the start, 10 and 180 min of HD, and compared to 20 healthy volunteers. RESULTS: The baseline Endostatin, RANTES, and MCP-1 levels in patients were higher than in controls and comparable during enoxaparin and UFH treatment. RANTES significantly increased during both enoxaparin and UFH anticoagulated HD, while over-HD Endostatin and MCP-1 levels remained stable regardless of the heparin sort. About 25% RANTES increase after 10 min of HD positively correlated with the dose of both heparins and HD duration. The switch from enoxaparin to UFH treatment had no impact on the levels of parameters studied. Patients with ischemic heart disease had less RANTES increase after 180 min of HD especially during enoxaparin treatment. CONCLUSION: RANTES is dose-depended and transitory increased in response to both UFH and enoxaparin administration during HD. Cardiovascular disease status occurred to be the most important predictor of its over-HD level.

Angiogenic axis angiopoietin-1 and angiopoietin-2/Tie-2 in non-small cell lung cancer: a bronchoalveolar lavage and serum study.

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), ligands for the Tie-2 receptor expressed on endothelial cells, play a critical role in angiogenesis, in concert with vascular endothelial growth factor (VEGF). Angiogenesis is important for tumor growth and development and also is implicated in the pathogenesis of interstitial lung diseases. The aim of this study was to evaluate the concentration of Ang-1, Ang-2, Tie-2, interleukin-18 (IL-18), transforming growth factor beta-1 (TGF ß1), and VEGF domain in both serum and bronchoalveolar lavage fluid (BALF) of lung cancer patients before chemotherapy. We studied 45 non-small cell lung cancer (NSCLC) patients (M/F; 38/7; mean age 62 ± 4 years). The age-matched control groups consisted of 15 sarcoidosis (BBS), 15 hypersensivity pneumonitis (HP), and 15 healthy subjects. The patients with NSCLC had a significantly higher level of Ang-1 compared with the BBS and healthy subjects, and a higher level of Ang-2 compared with the healthy subjects in both serum and BALF. BALF level of IL-18 was lower in the NSCLC than that in the HP group, but higher than that in the BBS patients. Serum level of IL-18 was higher in the NSCLC than in the healthy subjects. The NSCLC group had lower VEGF in BALF than that in healthy subjects. Receiver-operating characteristics (ROC) curves were applied to find the cut-off the serum levels of Ang-1 and Ang-2 levels in BALF. We did not find any correlation between the levels of Ang-1, Ang-2, Tie-2, and the stage of tumor or treatment response (prospectively). We conclude that the angiogenic axis Ang-1 and Ang-2/Tie-2 may play an important role in lung cancer development and their concentrations may be a useful marker at the time of initial diagnosis of lung cancer.

Novel cytokines: IL-27, IL-29, IL-31 and IL-33. Can they be useful in clinical practice at the time diagnosis of lung cancer?

UNLABELLED: There are several antiproliferative and angiogenic factors, recently have been discovered (IL-27, IL-29, IL-31 and IL-33), but they have not been tested yet in lung cancer patients. The aim of this pilot study was to assess the clinical usefulness of determination of IL-27, IL-29, IL-31 and IL-33 in advanced stages of lung cancer. PATIENTS AND METHODS: The study included 45 patients (38 males; mean age 62 years; 45 with advanced NSCLC). Serum and BALF cytokine concentrations were evaluated by ELISA method before chemotherapy. The comparative groups consisted of patients with sarcoidosis (BBS, n = 15), hypersensivity pneumonitis (HP, n = 8) and healthy subjects (n = 15). RESULTS: The serum IL-29 levels were higher in NSCLC patients than in the sarcoidosis group. However, serum IL-27, IL-31 and IL-33 did not differ markedly between: NSCLC, BBS, HP and the control group. Concentrations of IL-29 and IL-31 in BALF did not differ significantly between investigated groups. In all groups levels of IL-27 and IL-29 are significantly higher in serum than in BALF. Concentrations of IL-31 in BBS, HP and control groups tended to higher in BALF than in serum. These differences were significantly in NSCLC patients. Patients in stage IIIB of NSCLC had higher serum levels of IL-29 than these in stage IV. Lung cancer patients with partial remission (PR) after chemotherapy had significantly higher concentration of IL-27 in BALF than patients with SD. However, patients with SD had higher levels of IL-29 in BALF than patients with PD. A negative correlation was found between serum IL-31 levels before therapy and time to progression of NSCLC. CONCLUSION: Determination of IL-27, IL-29 and IL-31 in serum and BALF can be useful in clinical practice, but their practical significance needs further studies.

The status of BK polyomavirus replication in adult renal transplant recipients in northeastern Poland.

PURPOSE: BK polyomavirus (BKV) infection and BKV-associated nephropathy (BKVAN) are among the most important problems in renal transplantation. We aimed to determine the incidence of BK viruria, viremia, and BKVAN in renal transplant recipients in the northeastern part of Poland. METHODS: Urine and blood samples from 126 cadaveric renal transplant recipients were analyzed for BK viruria and viremia using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The diagnosis of BKVAN was established on the allograft biopsy. RESULTS: Based on the BKV DNA analysis, the patients were divided into three groups: group 1 (n=89; 70.6%) without viruria or viremia, group 2 (n=24; 19.1%) with isolated viruria, and group 3 (n=13; 10.3%) with both viruria and viremia. The presence of BK viremia negatively correlated with time after the transplantation. BK viruria was associated with mycophenolate mofetil daily dose. In group 3 there were four patients (3.2%) with high viremia (>10(4) genome equivalents [gEq]/mL) and viruria (>10(7) gEq/mL) loads. Only one patient from this group developed clinical symptoms and had BKVAN in allograft biopsy. In all four cases, the maintenance immunosuppression therapy was based on tacrolimus and steroids. CONCLUSION: Prevalence of BKV infection in renal transplant recipients in the northeastern part of Poland is similar to that reported by studies from other countries. We confirm that BK viremia could be predicted by the presence of intense viruria. Time after transplantation and the type of immunosuppression strategy are the most important predictors of BK viremia and viruria in patients after renal transplantation.

Fungaemia due to Cryptococcus laurentii as a complication of immunosuppressive therapy--a case report.

Recently, infections caused by cryptococci non-neoformans have been increasingly recognized. Cryptococcus laurentii was previously considered saprophyte and thought to be non-pathogenic to humans. However, in favorable circumstances like diminished immunity, it seems to be an important pathogen. We present a case of fungaemia caused by Cryptococcus laurentii in a young man with membranoproliferative glomerulonephritis on aggressive immunosuppressive therapy. We also considered a tick-borne infection because of the endemic area of ticks' occurrence. Most cases of fungaemia caused by Cryptococcus laurentii were successfully treated with fluconazole. We still observed septic fever and positive microbiological blood tests after 3 weeks of treatment with fluconazole in our patient. Therefore, among the others, a computer tomography of abdomen was done, which revealed an inflammatory (presumably mycotic) focus near right lobe of the liver. Accordingly, we started treatment with itraconazole. Controlled microbiological blood tests after 5 weeks of itraconazole therapy were negative. Until now, only one case of fungaemia caused by Cryptococcus laurentii with use of itraconazole was reported. Such an unusual fungal infection needs guidelines dealing with earlier diagnosis, treatment and prophylaxis to protect immunocompromised hosts.

Comparison of serology assays and polymerase chain reaction for the monitoring of active cytomegalovirus infection in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is a common complication of renal transplantation. It can be diagnosed serologically, mainly based on seroconversion or by the detection of viral antigen via CMV-DNA amplification (polymerase chain reaction [PCR]). AIM: We sought diagnosis of an active CMV infection in renal transplant patients comparing serologic assays of CMV-IgM antibodies with CMV-DNA amplification. METHODS: We retrospectively studied renal transplant recipients 26 (including 15 women) hospitalized with clinical suspicion of CMV disease. The diagnosis of CMV infection was suspected on the basis of nonspecific symptoms, including fever, leukopenia, hyperbilirubinemia, and alanine aminotransferase elevation, alone or in combination. At the time of admission, all patients were screened for CMV-IgM antibody (immunoassays AxSYM/IMx) and CMV-DNA (qualitative PCR). RESULTS: The confirmation of CMV infection by the two methods (immunoassay and PCR) was obtained in only three patients (11.5%), its unambiguous exclusion--in four cases (15.4%). Nineteen patients (73.1%) were positive for CMV-IgM and negative for CMV-DNA. CONCLUSION: Detection of CMV-IgM antibodies by various immunoassays is not sensitive enough for diagnosis and cannot be used for monitoring during the active period in renal transplant recipients. This observation supported the prolonged presence of IgM antibodies after recent CMV infection in this patient group.

Endothelial dysfunction, atherosclerosis and thrombosis in uremia--possibilities of intervention.

Chronic renal failure is a state of prominent endothelial dysfunction, accelerated atherosclerosis, high incidence of thromboembolic complications and excess cardiovascular mortality. We reviewed up-to-date experimental and clinical data showing close and deleterious links between these entities. Emerging therapeutic interventions aimed at improvement of endothelial function and better clinical outcomes in chronic kidney disease patients were also discussed.

Endothelial dysfunction marker von Willebrand factor antigen in haemodialysis patients: associations with pre-dialysis blood pressure and the acute phase response.

BACKGROUND: Increased plasma soluble von Willebrand factor antigen (vWF : Ag) level, a marker of vascular endothelial cell dysfunction, is a strong predictor of atherosclerotic cardiovascular disease (CVD) in the general population. We studied cross-sectional associations between vWF : Ag level, prevalence of CVD, and related factors including pre-dialysis arterial blood pressure (BP) and some markers of inflammation in maintenance haemodialysis (HD) patients. Methods and results. Plasma vWF : Ag level measured by an enzyme-linked immunosorbent assay (ELISA) was higher in 110 HD patients than in 20 controls. On bivariate regression analysis, vWF : Ag level was directly associated with the presence of CVD, age, fibrinogen and the use of enoxaparin (vs unfractionated heparin) during HD procedures, and inversely with albumin and pre-dialysis BP. The patients with prevalent CVD were older, had higher vWF : Ag, white blood cell and platelet counts, fibrinogen and triglycerides, lower albumin levels, and were less frequently on combination antihypertensive therapy. Multivariable analyses identified low pre-dialysis BP, hypoalbuminaemia and hyperfibrinogenaemia (in descending order of significance) as independent predictors of high vWF : Ag level. There were no associations between vWF : Ag levels and gender, ABO blood type, smoking, body mass index, renal failure cause, duration of HD therapy, K(t)/V, normalized protein catabolic rate, dialysate buffers, dialysers, viral hepatitis, erythropoietin treatment, specific antihypertensive drugs, haemoglobin, white blood cell and platelet counts, liver enzymes, phosphorous, total cholesterol, and triglycerides. CONCLUSION: Elevated plasma levels of endothelial dysfunction marker vWF : Ag in maintenance HD patients are associated with established cardiovascular mortality risk factors such as low pre-dialysis blood pressure and the activated acute phase response.

Soluble thrombomodulin is associated with viral hepatitis, blood pressure, and medications in haemodialysis patients.

BACKGROUND: The level of soluble thrombomodulin (sTM), a traditional marker of endothelial injury, is also dependent on renal excretory function. We studied serum sTM in chronic haemodialysis (HD) patients to determine which factors are predictive of its levels in this population. METHODS AND RESULTS: sTM levels of 10.7 (5.72-30.7) ng/ml in 100 HD patients were higher than in 30 controls (P<0.0001). In a bivariate regression analysis, immunoreactive sTM was positively associated with the presence of hepatitis B virus surface antigen and/or anti-hepatitis C virus antibodies measured by third generation ELISAs (P<0.0001), and was related to certain markers of liver injury and biosynthetic dysfunction. sTM was also directly associated with time on dialysis (P=0.001), or use of unfractionated heparin (UFH) (vs enoxaparin) (P=0.0007), erythropoietin (P=0.008), ACE-inhibitors (P=0.034), acetate-buffered dialysate (vs bicarbonate) (P=0.040), pre-dialysis systolic (P=0.012), and diastolic blood pressure (P=0.043). It was negatively associated with lipoprotein(a) (P=0.029). sTM was not related to age, sex, smoking, cause of renal failure, prevalence of cardiovascular disease, amount of HD delivered, preserved residual renal function, ferritin, C-reactive protein, and other vasoactive medications used. In a multivariable analysis, a positive hepatitis marker (P=0.0002), the use of UFH (P=0.030) and erythropoietin (P=0.019), and raised pre-dialysis blood pressure (P=0.024) were positive independent predictors of high sTM level. CONCLUSION: These data indicate that, in addition to endothelial activation, elevated sTM levels in HD patients may be related to viral infection and/or liver dysfunction, and influenced by modifiable factors such as increased blood pressure, and the type of heparin and erythropoietin treatment used.

[The role of tissue factor and its inhibitor in hemostasis]. / Rola czynnika tkankowego i jego inhibitora w hemostazie.

TF (tissue factor) is a physiological inhibitor of blood coagulation in normal hemostasis and is a major initiator of clotting in thrombotic disease. TF functions as a protein cofactor for FVIIa. Coagulation at a site of injury is initiated by exposure of blood to cell-surface formation of TF/VIIa complex. The TF/VIIa complex then activates both factors IX and X leading to thrombin generation and fibrin formation. TFPI (tissue factor pathway inhibitor) appears to play a primary role in regulating TF-induced coagulation. Abnormal coagulation may contribute to the pathogenesis of many serious illnesses. In particular, induced expression of TF and TF-mediated coagulation occurs in atherosclerotic plaques, sepsis, malignancy, ARDS and glomerulonephritis. Several observations support the need for exogenous TFPI administration to effectively turn off the TF/VIIa complex in several clinical conditions with TF-induced coagulopathy. There are some reports about successful administration of rTFPI for antithrombotic therapy in humans.