Michal Mysliwiec

Could neutrophil-gelatinase-associated lipocalin and cystatin C predict the development of contrast-induced nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine values?

The value of neutrophil-gelatinase-associated lipocalin (NGAL) was highlighted as a novel biomarker for the detection of acute renal failure. We tested the hypothesis whether NGAL could represent an early biomarker of contrast-induced nephropathy (CIN) in 100 patients with normal serum creatinine values undergoing percutaneous coronary interventions (PCI). In addition, we assessed serum and urinary NGAL in relation to cystatin C, estimated glomerular filtration rate, and serum and urinary creatinine in these patients. We measured urinary and serum NGAL values before and 2, 4, 8, 24, and 48 h after the PCI. We found a significant rise in serum NGAL levels 2, 4, and 8 h after the PCI and in urinary NGAL values 4, 8, and 24 h after a PCI procedure. Cystatin C rose significantly 24 h after the procedure. The prevalence of CIN was 11%. The NGAL levels were significantly higher 2 h after the PCI (serum NGAL) or 4 h after the PCI (urinary NGAL), whereas the cystatin C values were higher only 8 and 24 h after a PCI procedure in patients with CIN. In multivariate analysis, only serum creatinine was a predictor of serum NGAL before a PCI. NGAL may represent a sensitive early biomarker of renal impairment after PCI. Serum creatinine level, the presence of diabetes, and the duration of the PCI may affect serum NGAL values and kidney function following a PCI procedure.

Neutrophil gelatinase-associated lipocalin is a new and sensitive marker of kidney function in chronic kidney disease patients and renal allograft recipients.

BACKGROUND/AIMSnFew biomarkers exist to monitor chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL), a member of lipocalin family, has recently been proven useful to quantitate CKD. The aim of the study was to assess whether NGAL could represent a novel, sensitive marker of kidney function in adult patients with CKD and in kidney transplant recipients.nnnMETHODSnWe studied possible relations between serum NGAL, creatinine, and estimated glomerular filtration rate (eGFR) in 80 nondiabetic patients with CKD stages 2 to 4; 80 nondiabetic kidney transplant recipients on a calcineurin inhibitor mycophenolate mofetil, or azathioprine as well as prednisone and in healthy volunteers (n = 32, mean age 50 years).nnnRESULTSnSerum NGAL and creatinine values were significantly higher and eGFR significantly lower in kidney allograft recipients and patients with CKD compared with controls. NGAL rose gradually, reaching the higher value in stage 4 CKD. In univariate analysis serum NGAL was related to serum creatinine, hemoglobin, hematocrit, leukocyte count, and eGFR. Predictors of serum NGAL were creatinine and eGFR among patients with CKD. On univariate analysis serum NGAL was related to serum creatinine, urea, hemoglobin, hematocrit, white blood cell count, calcineurin concentration, eGFR, and albumin in kidney transplant recipients. On multiple regression analysis, predictors of NGAL were creatinine, calcineurin concentration, and high-sensitivity C-reactive protein. In healthy volunteers, serum NGAL correlated with age, serum creatinine, eGFR, and leukocyte count.nnnCONCLUSIONnNGAL should be investigated as a potential early, sensitive marker of kidney impairment/injury, which might provide an additional accurate measure of kidney impairment in CKD and among transplant recipients, particularly at advanced stages.

The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients

Since thromboembolic complications in transplanted patients are generally attributed to combined abnormalities in platelets and coagulo-lytic system, some hemostatic parameters tPA (tissue plasmogin activator):Ag and activity, its inhibitor-PAIAg and activity, tPA/PAI, thrombin-antithrombin (TAT) and plasmin-antiplasmin complexes (PAP), urokinase-uPA, euglobulin clot lysis time-ECLT, fibrinogen, plasminogen, protein C activity, D-dimer, prothrombin fragments1+2 (F1+2), fibrin monomers, fibronectin, lipoprotein-a, and von Willebrand factor(vWF), were evaluated using commercially available kits. The studies were performed on kidney transplant recipients treated with CsA, azathioprine and prednisone (n=21), and healthy volunteers (n=21). ECLT was significantly prolonged in kidney transplant recipients together with a rise in F1+2,lipoprotein-a, fibrinogen, fibronectin, and vWF when compared with controls. The TPA level was lower, whereas the PAI level was higher in kidney transplant recipients when compared with controls. In conclusion, CsA-treated kidney transplant recipients show evidence of pronounced impairment in fibrinolysis and endothelial damage in comparison with healthy volunteers.

HEMOSTASIS, PLATELET FUNCTION AND SEROTONIN IN ACUTE AND CHRONIC RENAL FAILURE

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.

Accumulation of toxic products degradation of kynurenine in hemodialyzed patients

In patients that developed a chronic renal failure the augmentation intryptophan degradation is reflected in the increase in plasma metabolitesof kynurenine pathway. Hemodialaysis is one of therapeutic approachesthat significantly reduce all plasma kynurenine metabolites in uremicpatients. In spite of haemodialaysis, plasma concentration of kynurenine,kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenicacid and quinolinic acid were still elevated in uremic patients in comparisonwith healthy volunteers. These data shows significant disturbances inkynurenine metabolism in uremic patients. Accumulation of thesesubstances in uremic blood is capable to account for certain uremicsymptoms.

A STUDY OF PLATELET FUNCTIONS, SOME HEMOSTATIC AND FIBRINOLYTIC PARAMETERS IN RELATION TO SEROTONIN IN HEMODIALYZED PATIENTS UNDER ERYTHROPOIETIN THERAPY

Erythropoietin corrects anemia and improves hemostasis, but on the other hand bears a risk of thrombotic complications. Therefore in the present study an attempt has been made to evaluate bleeding time, platelet functions and some hemostatic and fibrinolytic parameters in relation to blood and platelet serotonin before and after 1, 2, 4, 8 and 12 weeks of treatment. 22 chronically hemodialyzed patients were administered with human recombinant erythropoietin (rHuEPO) in a dose of 2000 IU s.c. 3 times a week. Bleeding time was shortened significantly as early as after 1 week of the therapy, whereas hematocrit and hemoglobin increased after 2 weeks. These changes lasted throughout the study. Only a transient rise in platelet count, collagen-induced platelet aggregation, beta-thromboglobulin and VIII:C activity were observed during therapy relative to baseline values. ADP- and arachidonic acid-induced platelet aggregation seemed to be unaffected by rHuEPO treatment, whereas a gradual and progressive enhancement in platelet aggregation in response to ristocetin was found, starting from the 2nd week of the therapy. It lasted throughout the study and correlated inversely with the bleeding time and positively with a rise in both blood and platelet serotonin. rHuEPO did not alter plasminogen, fibrinogen, platelet factor 4, alpha 2 macroglobulin levels, protein C activity and euglobulin clot lysis time. A decline in protein C and S concentrations and antithrombin III activity observed during the therapy were counterbalanced by a fall in the activity of alpha 2 antiplasmin, C1 esterase inhibitor and plasminogen activator inhibitor. It is concluded that rHuEPO may improve platelet/vessel wall interactions possibly by means of serotonergic mechanisms. A lowered activity of inhibitors of fibrinolysis may be regarded as a protection against a general tendency to thrombosis during rHuEPO therapy.

Visfatin and apelin, new adipocytokines, and their relation to endothelial function in patients with chronic renal failure

PURPOSEnVisfatin and apelin are novel adipocytokines that have recently generated much interest. The aim of the study was to assess visfatin and apelin in correlation with markers of endothelial cell injury and inflammation in 22 patients with chronic kidney disease-CKD and 22 age- and sex-matched healthy volunteers.nnnMETHODSnWe assessed visfatin, apelin, markers of coagulation: TAT (thrombin-antithrombin complexes), prothrombin fragments 1+2; fibrinolysis: tPA (tissue plasminogen activator), PAI-1 (plasminogen activator inhibitor), PAP (plasmin-antiplasmin complexes); endothelial function/injury: vWF (von Willebrand factor), thrombomodulin, ICAM (intracellular adhesion molecule), VCAM (vascular cell adhesion molecule), CD146, CD40L, CD44, E-selectin, inflammation: hsCRP.nnnRESULTSnTriglycerides, hsCRP, creatinine, vWF, prothrombin fragments 1+2, TAT, thrombomodulin, ICAM, VCAM, CD146, CD44, CD40L, PAI-1, PAP, visfatin and E-selectin were elevated in chronic kidney disease patients when compared with the control group. Visfatin correlated significantly in patients with chronic kidney disease, in univariate analysis, with CD40L (r=-0.27, p<0.05), apelin (r=0.27, p<0.05), ICAM (r=0.26, p<0.05), VCAM (r=0.31, p<0.05) and tended to correlate with CD146 (r=0.21, p=0.10). Apelin correlated significantly with E-selectin (r=0.31, p<0.05) and VCAM (r=0.31, p<0.05). In the healthy volunteers visfatin correlated significantly with ICAM (r=-0.37, p<0.05) and serum creatinine (0.38, p<0.05).nnnCONCLUSIONSnElevated visfatin in CKD patients may be due to renal failure and/or inflammation. Adipocytokines related to adhesion molecules might support the importance of inflammation/endothelial cell injury in the pathogenesis of atherosclerosis and its consequences in CKD.

Risk Factors of Nontunneled Noncuffed Hemodialysis Catheter Malfunction

Background: The use of noncuffed nontunneled central venous catheters is a widely accepted method of gaining temporary vascular access for hemodialysis. Malfunction and bacteremia are the main factors limiting catheter survival. Methods: We followed up prospectively 73 hemodialysis catheters (HC) (40 internal jugular, 33 femoral) in order to establish factors influencing HC malfunction. HC malfunction was defined as a catheter that was unable to attain and maintain blood flows of at least 150 ml/min. 73 HC were used for a total 1,100 days. Results: HC malfunction occurred in 23 cases (31.51%) during the study period, giving an overall rate of 21 episodes per 1,000 catheter days at risk. An analysis revealed a higher risk of HC malfunction with the catheterization of the femoral vein compared to the internal jugular vein (hazard ratio (HR) 6.3; 95% confidence interval (CI) 5.3–7.3). After correction for confounding factors in multivariate Cox analysis, the site of the catheterization remained a statistically significant predictor of HC malfunction (HR 5.03, 95% CI 3.83–6.23). After the first week malfunction rate was 42 and 8% for femoral and internal jugular site, respectively (relative risk (RR) for malfunction 5.3 (95% CI, 2.5–8). After the second and third week, the incidence of malfunction was 51 and 14% for femoral and internal jugular vein, respectively (RR 3.6, 95% CI 2.2–5.1). Conclusions: Catheterization of the internal jugular vein is associated with longer catheter survival when compared to the femoral vein. Hemodialysis catheters should be placed, if possible, in internal jugular vein to prevent their premature malfunction.

Peripheral serotonergic system in uremia.

Several data suggest that platelet-derived serotonin (5-HT), previously classified as a trivial modulator of blood-borne cardiovascular disease (1), may play a decisive role in various pathological processes, resulting from abnormal platelet-vessel wall interactions (2). Following platelet activation upon a contact with a damaged vessel wall, 5-HT, released from platelets upon the activation of 5-HT2 receptors, may amplify the action of other agents on vascular smooth muscle cells and platelets (3,4). Platelets play a unique role in 5-HT metabolism: they take it up, store in their dense granules and release upon stimulation. Platelet dysfunction, alteration in platelet count, their consumption and turnover are common in renal diseases (5). Storage pool deficiency regarding 5-HT and ADP was reported in renal failure (6). Previously we reported that 5HT2 receptor blockers may serve as potent antiplatelet drugs in uremic patients, which are prone to thrombotic complications (7,8). Up to date there have been a few reports dealing predominantly with 5-HT levels in renal patients. Thus, we focused on peripheral serotonergic mechanisms including 5-HT uptake and release and kinetics of its uptake in uremic patients.

Relationship between oxidative stress and extrinsic coagulation pathway in haemodialyzed patients

Enhanced oxidative stress (SOX), endothelial dysfunction and haemostatic abnormalities are common in end-stage renal failure patients undergoing maintenance haemodialysis (HD). We studied associations among circulating immunoreactive total lipid peroxides as a marker of short-time SOX, autoantibodies against oxidized LDL as a surrogate of prolonged SOX, copper/zinc superoxide dismutase (Cu/Zn SOD) as a major antioxidant enzyme, tissue factor (TF) as a principal initiator of extrinsic coagulation pathway counteracted by its inhibitor (TFPI), and prothrombin fragment 1+2 (F 1+2) as a surrogate of activated haemostasis.Pre-dialysis blood levels of all the markers studied were higher in 24 clinically stable HD patients compared to 11 healthy controls. Spearmans correlations among the three SOX markers were positive but nonsignificant in both HD patients and controls. In HD subjects, increased Cu/Zn SOD levels directly correlated with those of TF (rho=0.551, p=0.005) and TFPI (rho=0.501, p=0.001); the coagulation markers were also positively associated with each other (rho=0.663, p=0.0004). In healthy subjects, the relations between Cu/Zn SOD, TF and TFPI levels were inverse but not significant, and the direct association between TF and TFPI was nonsignificant either. In conclusion, increased plasma levels of Cu/Zn SOD, the antioxidant enzyme with emerging endothelial cell-protective and antithrombotic properties, may be a novel part of the system counteracting activated extrinsic coagulation system in maintenance HD patients.