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.

Factors associated with early catheter-related complications in peritoneal dialysis.

PURPOSE: It is advocated to delay the start of peritoneal dialysis (PD) at least 10-14 days after insertion of peritoneal catheter. The aim of this study was to investigate factors associated with catheter-related complications (CRC) in patients starting PD early (1-13 days) (ES) and late (14 days or more) (LS) after catheter implantation. MATERIAL/METHODS: Single center, retrospective analysis of CRC occurring within 14 days of follow up after peritoneal dialysis initiation in ES and LS group of patients. RESULTS: A total of 97 patients were analyzed. Seventy percent of them were ES. There were significantly more CRC in ES vs. LS (31% vs. 3%, p=0.01). Significantly more mechanical CRC occurred in ES than in LS (21% vs. 0%, p=0.01). Occurrence of infectious CRC did not differ between the groups. In multivariate analysis the only predictor of CRC development was the time elapsed between catheter insertion and beginning of PD (Odds Ratio [OR] 0.80 95% Confidence Interval [95% CI] 0.70-0.91; p=0.001). CONCLUSIONS: Each day of delay of PD initiation following peritoneal catheter insertion decreases the odds for development of mechanical CRC.

Thrombin activatable fibrinolysis inhibitor in hypertensive kidney transplant recipients.

Kidney transplant recipients are prone to hypertension, dyslipidemia, and cardiovascular death. Hypertension is associated with hemostatic abnormalities. Thrombin activatable fibrinolysis inhibitor (TAFI) is a glycoprotein that links coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations in renal transplant recipients in relation to blood pressure. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex [TAT], prothrombin fragments 1+2 [F1+2]), thrombomodulin (TM), and the degree of plasmin generation (plasmin-antiplasmin complex [PAP]) using commercially available kits. The studies were performed on 86 renal allograft recipients (48 women, 38 men) at age range 26 to 73 years. The immunosuppressive regimen consisted of cyclosporine (CsA), prednisone, and azathioprine (n = 58) or mycophenolate mofetil (MMF; n = 28). All patients maintained sufficient and stable graft function, showing no clinical signs of rejection. In patients with hypertension (n = 68), we observed significantly higher concentrations of TAFI and of markers of thrombin generation (F1+2, TAT), and of thrombomodulin with significantly prolonged euglobulin clot lysis time (ECLT), which reflects overall fibrinolytic activity and lower fibrinolytic activity index (FAI). Both groups did not differ with respect to age, creatinine clearance, body mass index, time after transplantation, albumin, fibrinogen, and PAP. Diastolic blood pressure correlated significantly with TAFI concentrations, uric acid, and prednisone dose, whereas systolic blood pressure correlated with urea, uric acid, creatinine clearance, and MCV. Elevated TAFI concentrations and enhanced thrombin generation in hypertensive kidney transplant recipients may contribute to the hypofibrinolysis and progressive atherosclerosis in this population. Blood pressure was related to kidney function, maintenance prednisone dose, and TAFI concentration.

Intima media thickness of common carotid arteries is associated with traditional risk factors and presence of ischaemic heart disease in hemodialysis patients.

Patients with chronic renal failure are prone to cardiovascular complications. The mechanisms and the assessment of the risk of cardiovascular diseases (CVD) in this population are of interest. The purpose of this study was to investigate the traditional and potential risk factors for the development of CVD and their contribution to ischemic heart disease (IHD) and variation in carotid intima media thickness (IMT) in hemodialyzed patients (HD). Twenty-one chronically HD patients and nineteen healthy volunteers were recruited. Studied parameters were intima-media thickness, body mass index (BMI), mean arterial blood pressure (MAP), hemoglobin, fibrinogen (Fbg), serum lipids, lipoprotein (a) [Lp(a)], total homocysteine (tHcy). Mean carotid IMT, tHcy, Fbg and Lp(a) were higher in HD patients compared to the control group. There were no differences in cholesterol (tCh) and triglycerides between these groups. Patients with ischemic heart disease were older and they had higher values of carotid IMT, tCh, triglycerides, Fbg and Lp(a). There were no differences in MAP, time on dialysis and tHcy between the two subgroups (with vs without IHD). Carotid IMT correlated positively with age (r = 0.68, p = 0.001), BMI (r = 0.50, p = 0.02), tCh (r = 0.58, p < 0.01), LDL- cholesterol (r = 0.55, p = 0.01) and Fbg (r = 0.57, p < 0.01) but not with tHcy or Lp(a) in the patients group. Carotid intima media thickness thus reflects the risk for ischemic heart disease in hemodialyzed patients. Elevated fibrinogen concentration and dyslipidemia influence arterial remodelling.

Plasma tissue-type plasminogen activator, fibrinogen, and time on dialysis prior to transplantation are related to carotid intima media thickness in renal transplant recipients.

The majority of deaths among patients after renal transplantation is attributed to cardiovascular disease (CVD). Intima media thickness (IMT) of the common carotid artery is related to coronary and cerebrovascular arterial disease. One of the major causes of death due to CVD is acute coronary syndrome, which is precipitated by coronary plaque rupture and subsequent thrombosis. The aim of the study was to evaluate associations between some fibrinolytic factors: antigens of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI), and IMT in a population of renal transplant recipients. The study was performed on 33 Caucasian, clinically stable kidney transplant recipients (11 women, mean age 43 years, range 26 to 62 years). All the patients were on triple immunosuppressive regimen (cyclosporine, prednisone, and azathioprine) and had stable graft function (serum creatinine 1.7 +/- 0.7 mg/dL). The mean time since transplantation was 49.9 months (range 4.1 to 131.8 months). In univariate analysis IMT correlated significantly with age (r =.5; P =.001), pulse pressure (PP) (r =.4; P =.05), time on dialysis prior to transplantation (r =.6; P =.001), fibrinogen (r =.4; P =.02), and t-PA (r =.6; P =.001). Multiple regression analysis showed that t-PA antigen concentration (P =.001), fibrinogen (P <.05), and time on dialysis prior to transplantation (P <.05) were positive independent predictors of IMT. These data support the concept of the coincidence of disturbances in fibrinolysis and arterial remodelling in patients after kidney transplantation. On the other hand the study shows that the duration of dialysis therapy before transplantation is detrimental to the arterial vasculature.

Some aspects of hemostasis in kidney transplant recipients maintained on cyclosporine, azathioprine, and prednisone in comparison to patients treated with cyclosporine and prednisone.

Cyclosporine (CyA) has been implicated to increase cardiovascular morbidity and mortality after renal transplantation. Impairment of the fibrinolytic system is one factor involved in the development of thrombotic complications. The aim of this study was to compare hematological and hemostatic parameters among patients on CyA, azathioprine, and prednisone (n = 31) versus CyA and steroids (n = 14). Using commercially available kits we evaluated thrombin activity as thrombin-antithrombin complexes (TAT), prothrombin fragments (1 + 2), thrombin activatable fibrinolysis inhibitor-(TAFI), TAFI activator, thrombomodulin (TM)-a marker for endothelial cell injury,-plasmin generation (plasmin-antiplasmin complex PAP), a glycoprotein linking coagulation and fibrinolysis. We observed that patients not treated with azathioprine displayed longer prothrombin times and activated partial thromboplastin times; higher fibrinogen, platelet counts and fibrinolytic activity index (FAI); shorter euglobulin clot lysis time; as well as lower thrombin generation markers namely, prothrombin fragments 1 + 2 and thrombin-antithrombin complexes. Although patients in the non-AZA group tended to have been engrafted for a longer time (P =.086), the groups did not differ with regard to age, BMI, erythrocyte count, hematocrit, leukocyte count, creatinine clearance, alanine and asparagine aminotransferase activities mean arterial blood pressure, fibrinogen, TAFI, thrombomodulin, or plasmin-antiplasmin complexes. These findings suggest that kidney transplant recipients on triple therapy are at greater risk of cardiovascular disease than those without azathioprine treatment, despite the lower fibrinolytic activity.

Thrombin-activatable fibrinolysis inhibitor in kidney transplant recipient with dyslipidemia.

Kidney transplant recipients are not only prone to dyslipidemia but also have a high risk of cardiovascular death. Impairment of the fibrinolytic system is thought to be one factor playing a role in development of thrombotic complications. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations and activities in renal transplant recipients stratified based upon serum cholesterol values above 220 mg/dL or below 200 mg/dL. The groups did not differ regarding age, creatinine clearance, BMI, time after transplantation, albumin, fibrinogen, thrombomodulin, or PAP. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex TAT, prothrombin fragments 1 + 2); TAFI activator; thrombomodulin (TM), catalyzer of TAFI activation; and the degree of plasmin generation (plasmin-antiplasmin complex PAP) using commercially available kits. In patients with hyperlipidemia significantly higher TAFI concentrations and activities may contribute to prolonged ECLT and lowered fibrinolytic activity index (FAI). Increased levels of F1 + 2 and TAT were observed in hypercholesterolemic patients, indicating enhanced thrombin generation. Elevated TAFI concentration, and activities and enhanced thrombin generation observed in hypercholesterolemic kidney transplant recipients may contribute to hypofibrinolysis and progression of atherosclerosis in this group of patients.

Simvastatin and markers of endothelial function in patients undergoing continuous ambulatory peritoneal dialysis.

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. The aim of this study was to assess the effects of a 6-month treatment with simvastatin (10 mg at bedtime) on markers of endothelial cell injury in 12 hypercholesterolemic CAPD patients. Cholesterol and low-density lipoprotein cholesterol fell significantly after 1 month of therapy. Simvastatin treatment significantly decreased concentrations of vascular cell adhesion molecule and intracellular adhesion molecule after 3 and 6 months of the therapy, respectively. Thrombomodulin decreased significantly after 6 months of the treatment, whereas von Willebrand's factor, P-selectin and E-selectin remained unaltered during simvastatin therapy. Simvastatin, an effective hypolipemic agent, favorably affects endothelial function and may potentially slow the progression of atherosclerosis and confer protection from thrombotic complications in patients with hypercholesterolemia undergoing CAPD.

Patients on peritoneal dialysis but not on hemodialysis have elevated concentration and activity of thrombin-activatable fibrinolysis inhibitor.

Cardiovascular disease (CVD) is a leading cause of death in patients on dialysis. Increased concentration of fibrinogen, dyslipidemia and impaired fibrinolysis are regarded as important risk factors for CVD. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently discovered inhibitor of the fibrinolytic system. The aim of this study was to investigate whether peritoneal dialysis (PD) and hemodialysis (HD) patients differ with regard to TAFI concentration and/or its activity. We also measured albumin, cholesterol, triglycerides and fibrinogen. The study was performed on 35 chronically dialyzed patients (14 on PD and 21 on HD) and 18 healthy volunteers. TAFI antigen and its activity were measured with commercially available kits. Albumin, cholesterol, triglycerides and fibrinogen were measured using standard laboratory methods. Only PD patients had significantly elevated level of TAFI antigen and its activity compared to control subjects. Differences in TAFI concentration and its activity between PD and HD were at the level of statistical significance (P=.09 and P=.07, respectively). PD patients had significantly higher concentration of cholesterol and triglycerides than HD group. Fibrinogen was elevated significantly in PD patients compared to HD and controls. There was no difference in albumin concentration between PD and HD. Significant positive correlations were found between fibrinogen or triglycerides and TAFI activity only in PD patients. We conclude that the above phenomenon may predispose PD patients to suppression of fibrinolysis.

Effects of long-term treatment with simvastatin on some hemostatic parameters in continuous ambulatory peritoneal dialysis patients.

BACKGROUND/AIM: Disturbances in serum lipids, hemostasis and platelet functions are frequent features in uremia and may contribute to the progression of atherosclerosis and its thrombotic complications. Recently, attention has been paid to beneficial effects of statins on serum lipids and hemostasis in uremic patients. Peritoneally dialyzed (continuous ambulatory peritoneal dialysis; CAPD) subjects are particularly prone to dyslipidemia and have a high risk of cardiovascular death. The purpose of this work was to assess platelet functions, some hemostatic parameters and serum lipids in 8 hyperlipidemic CAPD patients treated with simvastatin (Zocor, MSD) for 6 months. METHODS: Platelet aggregation in whole blood and in platelet-rich plasma (PRP) induced by collagen (2 microg/ml for whole blood and PRP), arachidonic acid (0.75 mM for whole blood and PRP), ADP (10 microM for whole blood and 5 microM for PRP) and ristocetin (0.75 mg/ml for whole blood and 1.5 mg/ml for PRP) was studied before and after 1, 3 and 6 months of simvastatin (dose: 10 mg at bedtime) treatment. RESULTS: Whole-blood platelet aggregation induced by collagen decreased significantly after 3 and 6 months of the therapy, whereas in PRP, platelet aggregation induced by collagen and ADP decreased significantly after 6 months. Ristocetin-induced platelet aggregation in PRP decreased significantly after 3 and 6 months of simvastatin therapy. P-selectin remained unaltered by 6 months of simvastatin therapy. The fibrinolytic activity index was significantly higher after 3 months of the therapy when compared to the baseline values. Thrombomodulin, a marker of endothelial cell injury, was significantly lower after 3 and 6 months of the therapy. Prothrombin fragments 1 + 2 did not change significantly during 6 months of simvastatin administration. Cholesterol and LDL fell significantly as early as after 1 month and remained lowered during further months of the therapy. CONCLUSION: Simvastatin is an effective hypolipemic agent and favorably affects platelet aggregation, endothelial function and fibrinolysis in CAPD patients.

Correlation between carotid intima-media thickness and hematocrit and hemoglobin values in renal transplant recipients.

BACKGROUND: Cardiovascular diseases are the main causes of morbidity and mortality in kidney transplant recipients. Blood viscosity plays an important role in the development of arteriosclerosis in the general population. Since hematocrit (Ht) and hemoglobin (Hb) values are determinants of blood viscosity, we decided to perform a study to check the possible relevance between these hemorheological factors and carotid intima-media thickness (IMT) in renal transplant recipients. PATIENTS AND METHODS: The study was performed on 33 clinically stable renal transplant recipients and 19 healthy persons. All subjects underwent ultrasonographic measurements of IMT. Analyzed clinical parameters included: age, sex, body mass index (BMI), mean arterial blood pressure (MAP), pulse pressure (PP) time from renal transplantation, and time on dialysis. The following biochemical parameters were assessed: Hb, Ht, fibrinogen (Fbg), and homocysteine (tHcy) concentrations (estimated by enzyme immunoassay). RESULTS: The two analyzed groups did not differ in respect to age and BMI. Mean concentrations of Hb and Ht values were lower in the patients group. Mean carotid IMT, Fbg, tHcy, MAP, and PP were significantly higher in the renal transplant recipients group when compared to the control group. IMT was positively correlated with age (r=0.55; p=0.001), Hb (r=0.36; p=0.04), Ht (r=0.34; p<0.05), PP (r=0.35; p<0.05), Fbg (r=0.4; p=0.02), and time on dialysis prior to transplantation (r=0.50; p=0.003) in the patients group. Multiple regression analysis in renal transplant recipients showed that the IMT was independently related to age, Hb or Ht values, and Fbg. CONCLUSIONS: The results for the first time show positive association between IMT and Ht and Hb values in renal transplant recipients. The results may implicate the role of these rheological factors in progression and acceleration of arterial remodeling in renal transplant recipients.

A possible role of thrombin-activatable fibrinolysis inhibitor in disturbances of fibrinolytic system in renal transplant recipients.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of death in renal transplant recipients (RTR). Suppression of fibrinolysis plays a role in the progression of atherosclerosis. Accelerated progression of atherosclerosis and fibrinolytic system suppression has been observed in RTR. Despite many years of intensive research, the reason for impaired fibrinolysis in this patient population is not fully understood. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently discovered glycoprotein combining coagulation and fibrinolysis. This study was conducted to evaluate concentrations of TAFI, markers of thrombin generation, endothelial injury, and some standard laboratory parameters in RTR receiving triple immunosuppressive drug regimen. METHODS: The study was performed in 29 stable, non-diabetic kidney transplant recipients treated with cyclosporin A, azathioprine, and prednisone and in 18 age- and sex-matched healthy volunteers. Soluble thrombomodulin (sTM), prothrombin fragments F1+2 (F1+2), thrombin--antithrombin complexes (TAT), plasmin--antiplasmin complexes (PAP), and TAFI were measured with commercially available kits. RESULTS: The RTR group had significantly higher plasma levels of TAT, F1+2, sTM and TAFI than the healthy volunteers. There were no differences in PAP concentrations between the two groups. Plasma sTM correlated inversely with creatinine clearance, body mass index, haemoglobin, and albumin. Plasma TAT level was positively associated with total cholesterol. TAFI antigen influenced negatively PAP antigen concentration. CONCLUSIONS: On the basis of our research, we concluded that elevated circulating TAFI antigen might be a new link in the pathogenesis of impaired fibrinolysis in RTR, and thus atherosclerosis progression. In the patient group there is also evidence of endothelial injury, followed by secondary activation of the coagulation cascade. Hypercholesterolaemia in RTR is associated with enhanced thrombin activity.

[TAFI--thrombin activated fibrinolysis inhibitor ]. / TAFI--aktywowany przez trombine inhibitor fibrynolizy.

This is a review of literature data concerning Thrombin Activatable Fibrinolysis Inhibitor (TAFI) and its role in haemostatic system in vitro and in vivo. This is the glycoprotein, which was identified recently by three independent groups of researchers. TAFI is converted to its active form by thrombin-thrombomodulin complex. TAFIa removes lysine residues from fibrin net, making impossible formation of plasminogen, t-PA and fibrin complex. It causes impairment of plasmin generation, and by this way suppression of fibrinolysis.

[Homocysteine--new risk factor for progression of atherosclerosis and its complications]. / Homocysteina--nowy czynnik ryzyka rozwoju miazdzycy i jej powiklan.

The main cause of mortality and morbidity in Europe and United States are cardiovascular diseases. Besides well known atherogenic risk factors there has recently been a lot of attention paid to homocysteine. It is a sulfur aminoacid which is the demethylation product of methionine. Many facts support the role of this agent in development of arteriosclerosis and its sequelle. The relation of hyperhomocysteinemia with vascular complications, therapeutic options and potential atherogenic mechanisms are discussed in this paper. Special attention was paid to chronic renal failure patients.

Diverse effects of prolonged physical training on learning of the delayed non-matching to sample by rats.

The physiological effects of physical exercise have been extensively studied. Nevertheless, its influence on cognitive functioning remains a matter of controversy. In this study we have attempted to assess the effects of repeated exercise (6 weeks of daily treadmill running, meant to resemble human physical training), on parallel learning of a complex task [delayed non matching to sample (DNMS)] by rats. The trained rats appeared to learn the procedure slower and made a significantly lower percentage of correct choices (P<0.01) as compared to those in the non-trained control group. However, when only those rats, from both the groups, which reached the criterion of 80% correct choices in two consecutive sessions were compared, no significant differences were observed. These results suggest an adverse influence of long term physical exercise on rats' ability to learn complex tasks, but only by the 'poor performers'. The 'good performers' were insensitive to the deleterious effects of the exercise.

[Nephrolithiasis in a HIV infected patient treated with indinavir]. / Kamica nerkowa u zakazonego HIV leczonego indinavinem.

Protease inhibitors together with reverse transcriptase inhibitors are used in antiretroviral treatment. Indinavir, precipitating in renal tubules, quite often can cause nephrolithiasis. The case of a HIV infected patient with renal colic probably caused by indinavir, diagnostic and therapeutic options in such cases are described in the paper.

Leptin and serum erythropoietin in hemodialyzed and peritoneally dialyzed uremic patients during rHuEPO therapy.

Leptin produced by fat cell has an unanticipated role in hematopoietic system development. We examined the relationships between leptinemia and requirements of erythropoietin (Epo), endogenous Epo levels as well as markers of inflammation: C-reactive protein, tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) in rHuEPO-treated patients maintained on chronic hemodialyses or peritoneal dialyses. The studies were performed on 51 chronically hemodialyzed patients, 20 of them did not receive rHuEPO, 31 subjects received rHuEPO, and 22 patients on CAPD, 13 of them did not receive rHuEPO, 9 subjects were given rHuEPO. In hemodialyzed patients (Epo and Non-Epo group) leptin levels were significantly higher when compared to CAPD patients (Epo and Non-Epo group, respectively). Leptin in peritoneal fluid was significantly higher in the Non-Epo group. In ultrafiltrate, leptin levels were below the detection limit of 0.5 ng/ml. Epo levels in the HD + Epo group were significantly lower than in the HD + Non-Epo group and CAPD + Epo group. TNFalpha and IL-1 concentrations were significantly lower in both groups of CAPD patients when compared to respective HD groups. Treatment with rHuEPO resulted in nonsignificant decline in serum leptin (p = 0.07 in HD and p = 0.08 in CAPD) and significant leptin loss in peritoneal fluid. It may be of clinical relevance in dialyzed patients. In both groups of Epo-treated patients, positive physiological correlation between leptinemia and BMI disappeared. Leptin levels do not correlate with rHuEPO requirements and serum Epo in dialyzed patients.

[Calcium blockers and their their present application]. / Blokery kanalów wapniowych i obecne ich zastosowanie.

Use of calcium channel blockers in arterial hypertension and other cardiovascular diseases has increased substantially during the last decade. The biological role of calcium in contractile tissues mechanisms of action of calcium channel blockers and their present application are discussed.