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Background/aims: Zonulin is the only known regulator of intestinal permeability. It is also considered as a potential inflammatory marker in several conditions such as diabetes and inflammatory bowel syndrome. The aim of the study was to investigate zonulin levels in patients with early stages of CKD and its possible correlation with inflammation, anemia and iron status parameters., Methods: Eighty-eight patients with early stages of CKD and 23 healthy volunteers were enrolled in the study. Zonulin, hepcidin-25, soluble transferrin receptor, interleukin-6 and high-sensitivity C-reactive protein were measured using commercially available assays., Results: Zonulin was significantly lower among patients with CKD in comparison with healthy volunteers. There were no statistically significant differences in zonulin concentration between patients with and without inflammation. Zonulin was significantly correlated with hepcidin only in patients with inflammation. Zonulin was neither related to iron nor related to ferritin., Conclusions: Zonulin cannot be considered as an inflammatory marker in CKD. It does not play a role in the disturbances of iron metabolism in CKD. Its physiological role remains to be elucidated.

Aim: Visfatin is an adipocytokine that has recently generated much interest. The aim of the study was to assess visfatin in correlation with markers of endothelial damage and inflammation in haemodialyzed and peritoneally dialyzed patients., Methods: Visfatin, leptin, apelin and adiponectin, markers of coagulation (thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2 (F1+2)), fibrinolysis (tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1)), endothelial function/injury (Von Willebrand factor (vWF), thrombomodulin, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), CD146) and inflammation (high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6) were assessed., Results: Triglycerides, hsCRP, creatinine, IL-6, TNF-alpha, vWF, F1+2, TAT, thrombomodulin, ICAM, VCAM, CD146, PAI-1, leptin, adiponectin and visfatin were elevated in dialyzed patients over controls. Visfatin correlated significantly, in univariate analysis, in haemodialyzed patients with markers of endothelial damage/inflammation (CD146, ICAM, IL-6), other adipocytokines, Kt/V and dialysis vintage, and tended to correlate with hsCRP. In peritoneally dialyzed patients, visfatin correlated significantly with haemoglobin, and markers of endothelial damage. In the healthy volunteers visfatin correlated significantly with ICAM, creatinine and IL-6. In multiple regression analysis in HD patients visfatin was only independently related to Kt/V, dialysis vintage and IL-6., Conclusion: Elevated visfatin related to markers of inflammation might represent a novel link between inflammation and adipocytokines in dialyzed patients. Time on dialyses and dialysis adequacy may influence visfatin in dialyzed patients due to the decreased clearance of visfatin.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) binds small, iron-carrying molecules - siderophores. On the other hand, hepcidin is a small defensin-like peptide produced by hepatocytes, modulated in response to anaemia, hypoxia, or inflammation. We tested the hypothesis that NGAL may be related to hepcidin, not only to iron metabolism, in 182 prevalent haemodialysed patients., Methods: Iron status (iron, total iron-binding capacity, ferritin, total saturation of transferrin, TSAT), complete blood count, creatinine, albumin, serum lipids were assessed using standard laboratory methods. Soluble receptor of transferrin, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha, interleukin-6, prohepcidin, hepcidin and NGAL were measured in serum using commercially available kits., Results: Serum NGAL, prohepcidin, hepcidin levels were significantly higher in haemodialysed patients over healthy volunteers (579.11 +/- 213.95 vs. 78.43 +/- 32.21 ng/ml, p < 0.001, 320.54 +/- 182.65 vs. 98.65 +/- 34.32 ng/ml, p < 0.01, 155.30 +/- 94.05 vs. 23.65 +/- 12.76 ng/ml, p < 0.001, respectively). Serum NGAL correlated strongly with residual renal function (r = -0.54, p < 0.001), Kt/V (r = 0.41, p < 0.001), hepcidin (r = -0.28, p < 0.01), serum creatinine (r = 0.63, p < 0.001), iron (r = 0.25, p < 0.01), TSAT (r = 0.30, p < 0.001), ferritin (r = 0.33, p < 0.001), hsCRP (r = 0.32, p < 0.001). In multiple regression analysis, residual renal function, hepcidin, creatinine and hsCRP were predictors of serum NGAL in haemodialysed patients., Conclusions: NGAL is highly induced in dialysed patients. NGAL could reflect both kidney function and iron metabolism. Taking into account the antimicrobial properties of NGAL, further studies are needed to address the role of NGAL in iron metabolism and inflammation in renal failure., ((c) 2010 S. Karger AG, Basel.)

Unlabelled: Neutrophil gelatinase-associated lipocalin (NGAL) has recently been proved useful in the quantitation of chronic kidney disease. A cross-sectional study was performed to assess NGAL in serum, urine and ultrafiltrate in relation to the type of renal replacement therapy and NGAL correlations with renal function and markers of inflammation., Methods: NGAL, hsCRP, TNFalpha, and IL-6 were measured using commercially available kits in 200 patients on hemodialysis (HD), 17 on hemodiafiltration (HDF)., Results: Patients on HDF had lower serum NGAL than those on HD. In hemodialyzed patients with residual renal function, serum NGAL was significantly lower than in anuric patients. NGAL was significantly higher in patients dialyzed on modified cellulose dialyzers versus polysulphone dialyzers. NGAL correlated with age, residual renal function, hsCRP, IL-6, TNF-alpha, time on HD, ferritin, TSAT, creatinine, urea, urea reduction ratio, and Kt/V in hemodialyzed patients. In multiple regression analysis, residual renal function and hsCRP were predictors of NGAL in hemodialyzed patients. NGAL correlated with hsCRP and creatinine in HDF patients., Conclusions: Residual renal function seems to play a pivotal role in NGAL levels in dialyzed patients. Low-grade inflammation, more pronounced in anuric patients may also contribute to elevated NGAL. Removal of NGAL with ultrafiltrate may also partially explain its lower concentration after dialysis., (Copyright 2009 S. Karger AG, Basel.)

Aim: Resistin is an adipocytokine that recently generated much interest. Because of the fact that inflammation, endothelial cell damage or injury is invariably associated with such clinical conditions as thrombosis, atherosclerosis and their major clinical consequences, that is, cardiovascular disease and resistin play a role in linking inflammation and cardiovascular disease, the aim of the study was to assess resistin in correlation with markers of inflammation, endothelial cell injury and residual renal function in haemodialysed (HD) patients., Methods: We assessed resistin, markers of coagulation: thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2; fibrinolysis: tPA, plasminogen activator inhibitor type 1, plasmin-antiplasmin complexes (PAP); endothelial function/injury: von Willebrand factor (vWF), thrombomodulin, intracellular adhesion molecule (ICAM); inflammation: high sensitivity C-reactive protein (hsCRP), tumour necrosis factor alpha and interleukin-6 (IL-6)., Results: Healthy volunteers and HD patients did not differ significantly regarding age, leucocyte count, serum iron, aspartate and alanine aminotransferases activities, calcium, cholesterol, tPA concentration. Triglycerides, CRP (assessed by high sensitivity method), phosphate, urea, creatinine, IL-6, tumour necrosis factor alpha, vWF, prothrombin fragments 1+2, TAT, PAP, thrombomodulin, ICAM, plasminogen activator inhibitor type 1 and resistin, were elevated in HD patients when compared with the control group. Serum albumin, total protein, haemoglobin and haematocrit were significantly lower in HD patients when compared with the control group. In HD patients with hsCRP 0e; 6 mg/L, resistin, IL-6, vWF and F1+2 were significantly higher, whereas tPA was significantly lower than in patients with hsCRP<6 mg/L. Moreover, HD patients with residual renal function have significantly lower resistin when compared with patients without it. Resistin was significantly higher in diabetics. In HD patients, resistin correlated significantly, in univariate analysis, with calcium, phosphate, PTH, TIBC, vWF residual renal function, urea, hsCRP, IL-6 and tended to correlate with tPA and ferritin. In the healthy volunteers, resistin was related to IL-6 and hsCRP. In multiple regression analysis, resistin was independently related to hsCRP, IL-6, residual renal function in HD patients., Conclusion: Elevated resistin related to markers of inflammation may represent a novel link between inflammation and adipocytokines in HD patients. Impaired renal function and inflammation are responsible for elevated resistin in HD patients.

Maintaining the correct iron balance is crucial for health. Our understanding of the molecular control of iron metabolism has increased dramatically over the past 5 years due to the discovery of hepcidin. This is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its mobilization from macrophages and hepatic stores. Inflammation causes an increase of production of hepcidin, which is a potent mediator of anemia of chronic diseases. Anemia in chronic kidney disease is mainly due to erythropoietin deficiency but these patients often have a chronic inflammatory state. The aim of this review is to summarize the current knowledge dealing with a possible role of hepcidin in iron metabolism and its regulation, particularly in kidney disease. In addition, current methods of determination of hepcidin are reviewed., (Copyright 2007 S. Karger AG, Basel.)

Introduction: Fibroblast growth factor 23 (FGF-23) levels are elevated in impaired renal function. Inflammation and iron are potential regulators of FGF-23. The aim of the study was to evaluate the association between FGF-23 concentration, novel iron status biomarkers and inflammatory parameters among patients with early stages of chronic kidney disease (CKD).Material and Methods: The study population included 84 patients with CKD in the early stage. Serum hemoglobin, fibrinogen, creatinine, iron, transferrin saturation and ferritin levels were measured using standard laboratory methods. Commercially available kits were used to measure: intact FGF-23, hepcidin, soluble transferrin receptor (sTfR), interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP).Results: In patients with CKD no differences in FGF-23 concentration according to iron status were observed. Lower iron concentration was associated with higher concentrations of hsCRP, IL-6 and fibrinogen. In univariate and multivariate analysis FGF-23 correlated with fibrinogen (r = -0.23, p < 0.05) and eGFR (r = -0.36, p < 0.05).Conclusions: FGF-23 is affected by kidney function and fibrinogen but not iron status parameters in the early stages of CKD. Our data are paving the way for further studies on the role of FGF-23 in iron metabolism, especially in early stages of CKD. [ABSTRACT FROM AUTHOR]

Introduction: All living organisms have evolved sophisticated mechanisms to maintain appropriate iron levels in their cells and within their body. Recently our understanding of iron metabolism has dramatically increased. Overt labile plasma iron (LPI) represents a component of non-transferrin bound iron (NTBI) that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload. The LPI measures the iron-specific capacity of a given sample to produce reactive oxygen species. We studied for the first time NTBI correlations with markers of iron status and inflammation in prevalent hemodialyzed patients. Material and methods: Complete blood count, urea, serum lipids, fasting glucose, creatinine, ferritin, serum iron, total iron binding capacity (TIBC) were studied by standard laboratory method. The NTBI was assessed commercially available kits from Aferrix Ltd in Tel Aviv, Israel. A test result of 0.6 units of LPI or more indicates a potential for iron-mediated production of reactive oxygen species in the sample. Results: Patients with LPI units ⩾ 0.6 had higher serum iron, erythropoiesis stimulating agents (ESA) dose, ferritin, high-sensitivity C-reactive protein (hsCRP), hepcidin and lower hemojuvelin. In hemodialyzed patients NTBI correlated with hsCRP (r = 0.37, p < 0.01), ferritin (r = 0.41, p < 0.001), IL-6 (r = 0.43, p < 0.001). In multivariate analysis predictors of NTBI were hemoglobin and alkaline phosphatase, explaining 58% of the variability Conclusions: Elevated NTBI in HD may be due to disturbed iron metabolism. Anemia and liver function might also contribute to the presence of NTBI in this population. [ABSTRACT FROM AUTHOR]

Hepcidin is a small defensin-like peptide, the production of which by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. Kidneys are involved in not only the synthesis of hepcidin, but they also may be involved in its elimination. A cross-sectional study was performed to assess prohepcidin and hepcidin in serum, urine, and ultrafiltrate/peritoneal effluent in relation to type of renal replacement therapy and prohepcidin and hepcidin correlations with renal function, iron status, and markers of inflammation. Methods. Prohepcidin and hepcidin high-sensitivity CRP, TNF alpha, and IL-6 were measured using commercially available kits in 102 patients on hemodialyses, 17 on hemodiafiltration, 44 on peritoneal dialyses, and 22 healthy volunteers. Results. In hemodialyzed and peritoneally dialyzed patients with residual renal function, serum prohepcidin (264.21 ± 95.84 vs. 341.84 ± 90.45 ng/mL, p < 0.01; 142.76 ± 57.87 vs. 238.42 ± 84.32 ng/mL, p < 0.01, respectively) and hepcidin (178.89 ± 89.87 vs. 295.76 ± 129.65 ng/mL, p < 0.01; 108.43 ± 75.49 vs. 186.53 ± 119.62 ng/mL, p < 0.01, respectively) were significantly lower than in anuric patients. In peritoneal effluent, prohepcidin level was significantly higher than in ultrafiltrate of HD/HDF patients. In multiple regression analysis, residual renal function, ferritin, and hsCRP were predictors of hepcidin in hemodialyzed patients, while residual renal function and ferritin were predictors of hepcidin in peritoneally dialyzed patients. Conclusions. Residual renal function seems to play a pivotal role in hepcidin levels in dialyzed patients. In addition, the presence of low-grade inflammation, more pronounced in anuric patients, and functional iron deficiency may also contribute to the elevated hepcidin. The removal of prohepcidin with ultrafiltrate/peritoneal effluent may partially explain its lower concentration in peritoneal dialysis and hemodiafiltration. [ABSTRACT FROM AUTHOR]

Hemojuvelin (HJV) is a membrane protein that is responsible for the iron overload condition known as juvenile hemochromatosis. HJV, highly expressed in the liver, skeletal muscle and heart, seems to play a role in iron absorption and release from cells and has anti-inflammatory properties. HJV is a bone morphogenetic protein (BMP) co-receptor and signals via the SMAD (human homolog of Drosophila mad – mother against decapentaplegic) pathway to regulate hepcidin expression. HJV acts as a BMP co-receptor. Moreover, HJV plays an essential role in the regulation of hepcidin expression, specifically in the iron-sensing pathway, although through unknown mechanisms. Dietary iron sensing and inflammatory pathways converge in the regulation of the key regulator hepcidin, but how these two pathways intersect remains unclear. Inflammation, through downregulation of hepatic HJV, might induce temporary elimination of iron sensing. Despite enormous scientific achievements in explaining the pathogenetic mechanisms of iron metabolism, many questions still remain unanswered: What is the functional role of HJV in iron metabolism? How it is related to hepcidin expression in different settings? How do iron-sensing and inflammatory pathways cooperate in hepcidin gene expression? Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background In patients after kidney transplantation, anemia is relatively common and is associated with impaired kidney function, subclinical inflammatory state, and immunosuppressive treatment. Zonulin-prehaptoglobin-2, a newly discovered protein, is necessary for integrity of intracellular tight junctions in the gut. Taking into consideration iron metabolism, including its absorption in the gut, we designed a cross-sectional study to look for the possible interactions among zonulin, iron status, and anemia in kidney transplant recipients. Methods The study was performed on 72 stable kidney transplant recipients and 22 healthy volunteers. Zonulin, iron status, and inflammatory markers were assessed with the use of commercially available kits. Results Zonulin was significantly lower in kidney allograft recipients than in healthy volunteers ( P < .001). Zonulin correlated with systolic blood pressure ( r = −0.33; P < .05), thyroid-binding globulin ( r = 0.24; P < .05), hematocrit ( r = 0.28; P < .005), hemoglobin ( r = 0.32; P < .01), total protein ( r = −0.33; P < .01), erythrocyte count ( r = 0.26; P < .05), and fasting glucose ( r = −0.25; P < .05). Zonulin was not affected by sex, type of immunosuppressive therapy, presence of diabetes, coronary artery disease, heart failure, hypertension, or cause of end-stage renal disease. Zonulin was not related to any of the iron parameters studied. In multiple regression analysis, predictors of zonulin were total protein and thyroglobulin-binding protein, explaining 46% of variation. Conclusions Zonulin, with its poorly defined function, does not seem to play a role in the anemia in kidney allograft recipients; however, it seems to be related to the absorption process in the gut. [ABSTRACT FROM AUTHOR]

Background YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction and expressed in macrophages in the earliest lesion of atherosclerosis. Because cardiovascular mortality is the main cause of death, there are no data on kidney transplant recipients, so the aim of the study was to assess YKL-40 in that population, with particular attention being paid to the relationship with endothelial damage. Methods We studied 68 patients after kidney transplantation. Complete blood count, creatinine, lipids, and fasting glucose were studied with the use of standard laboratory methods. We assessed YKL-40; markers of inflammation high-sensitivity C-reactive protein (hs-CRP), von Willebrand factor, thrombomodulin, interleukin-6, intracellular adhesion molecule, and vascular cell adhesion molecule; markers of hemostasis plasmin-antiplasmin complexes, thrombin-antithrombin complexes, prothrombin fragments 1+2; and marker of kidney function neutrophil gelatinase–associated lipocalin (NGAL) with the use of commercially available assays. Results Mean levels of YKL-40 were significantly higher in kidney allograft recipients than in the control group ( P < .001). YKL-40 was also significantly higher in patients with coronary artery disease, hypertension, and diabetes compared with their counterparts without these diseases. YKL-40, in univariate analysis, was related to NGAL, protein Z, plasmin-antiplasmin complex, mean corpuscular volume, cyclosporine level, and hs-CRP. YKL-40 was not related to serum lipids, markers of endothelial cell injury, or causes of end-stage renal failure. YKL-40 was predicted by cyclosporine level, NGAL, and hs-CRP, explaining 37% of the variation. Conclusions Elevated YKL-40 may contribute to enhanced risk of cardiovascular complication, mainly owing to endothelial cell injury and inflammation in patients after kidney transplantation treated with calcineurin inhibitors. [ABSTRACT FROM AUTHOR]