Ferroportin in monocytes of hemodialysis patients and its associations with hepcidin,inflammation, markers of iron status and resistance to erythropoietin

Purpose

Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Increased hepcidin, which downregulates the iron exporter ferroportin, has been incriminated. However, other factors also control ferroportin expression in mononuclear phagocyte system. Ferroportin in monocytes, as well as serum hepcidin, interleukin-6 (IL-6) and common markers of iron status were measured and correlations with rHuEpo resistance index (ERI) were evaluated.

Methods

After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of western blotting, whereas hepcidin and IL-6 with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured.

Results

Ferroportin in monocytes of HD patients was decreased. Serum hepcidin and IL-6 were increased, whereas serum iron and TSAT were decreased. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with hepcidin.

Conclusion

Decreased ferroportin in monocytes of HD patients accompanies increased hepcidin, inflammation, decreased iron availability and is correlated with resistance to rHuEpo treatment.     

Serum copper and ferroportin in monocytes of hemodialysis patients are both decreased but unassociated

Purpose

Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Although increased hepcidin, which downregulates the iron exporter ferroportin, had been incriminated, such an association has not been confirmed. Albeit not universally accepted, it has been supported that in case of copper deficiency, decreased activity of multicopper oxidases induces endocytosis and degradation of ferroportin. Ferroportin in monocytes, serum copper, ceruloplasmin and markers of iron status were measured, and associations with rHuEpo resistance index (ERI) were evaluated.

Methods

After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of Western blotting, copper colorimetrically, whereas ceruloplasmin with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured.

Results

Ferroportin in monocytes of HD patients was decreased. Serum copper, ceruloplasmin, iron and TSAT were decreased. No correlation between copper or ceruloplasmin and ferroportin was detected. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with copper or ceruloplasmin.

Conclusion

Although copper deficiency and decreased ferroportin are common in HD patients, copper might not play role in ferroportin level in monocytes and in iron metabolism in this population.     

The Relationship of Visfatin Levels to Inflammatory Cytokines and Left Ventricular Hypertrophy in Hemodialysis and Continuous Ambulatory Peritoneal Dialysis Patients

Visfatin was recently defined as an adipocytokine; however, the pathophysiological role of visfatin is not completely understood. A few studies suggest that visfatin may be a new proinflammatory adipocytokine. The aim of the present study was to compare serum visfatin levels between hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients and evaluate the relationship between visfatin levels to IL-6, TNF-α, and left ventricular hypertrophy. Serum visfatin, IL-6, and TNF-α levels were measured by using the ELISA method, and echocardiographic evaluations were performed in 31 hemodialysis patients, 30 CAPD patients, and 21 healthy volunteers. Serum visfatin levels were higher in the CAPD group (265.27 ± 387.86 ng/mL) than hemodialysis (97.68 ± 244.96 ng/mL,) and control (41.33 ± 48.87 ng/mL) groups (p = 0.04, p = 0.01, respectively). No significant difference was observed between the hemodialysis and control groups. In univariate analysis, visfatin levels were positively correlated with IL-6 (r = 0.24, p = 0.03), TNF-α (r = 0.34, p = 0.002), and BMI (r = 0.26, p = 0.03) and negatively correlated with some left ventricular diastolic parameters [Em and Em/Am (r = ?0.305, p = 0.01), (r = ?0.251, p = 0.03), respectively]. No relationship was found between visfatin and left ventricular mass index. In the linear regression analysis, visfatin levels independently related with TNF-( (β = 0.369, p = 0.001) and IL-6 (β = 0.284, p = 0.015). This study has found significantly higher levels of serum visfatin in CAPD patients when compared to healthy individuals. Increased visfatin levels seem to associate with proinflammatory cytokines such as IL-6 or TNF-α. As for the effects of on left ventricular structure and functions, visfatin might have negative effects on left ventricular diastolic function parameters but have no effects on left ventricular mass index.     

High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients

Background: The resistence to recombinant human erythropoietin (rHuEpo) therapy in haemodialysis (HD) patients has multifactorial aetiologies; erythropoietin insufficiency, dialysis insufficiency, iron deficiency, and secondary hyperparathyroidism. Angiotensin-converting enzyme (ACE) inhibitors induce anaemia in patients with essential hypertension, congestive heart failure, chronic renal insufficiency, and renal transplants. Data exist suggesting that ACE inhibitors impair erythropoiesis in HD patients. Therefore the aim of this study was to investigate the impact of enalapril on rHuEpo requirement. Methods: In the present prospective non-randomized study of 12 months, we compared the effects of enalapril and nifedipine on rHuEpo requirement in 40 hypertensive patients receiving rHuEpo for more than 6 months on maintenance haemodialysis. Twenty normotensive rHuEpo-dependent patients served as a control group. All patients with severe hyperparathyroidism or iron deficiency were excluded. The mean (±SD) haemoglobin concentration was >10 g/dl in all groups. The mean weekly rHuEpo dose increased in the enalapril group (P<0.0001 vs before) and remained constant in the nifedipine and control groups (P=NS vs before). Statistically, there was no differences with regard to iPTH levels, dialysis parameters, iron status, and underlying renal diseases among all groups. Conclusion: High-dose enalapril increases rHuEpo requirement and should be reserved for dialysis patients with hypertension uncontrollable with other antihypertensive medications or dialysis patients with cardiac failure.     

Transfusion and recombinant human erythropoietin requirements differ between dialysis modalities

Background: Before the routine use of recombinant human erythropoietin (rHuEpo), patients dialysed by peritoneal dialysis (PD) received fewer blood transfusions than patients on haemodialysis (HD). We compared transfusion practices in these groups now that the use of rHuEpo has become standard, while controlling for variables known to influence anaemia of end-stage renal disease (ESRD). Maintenance rHuEpo doses were also compared. Methods: Data were examined for 157 HD and 126 PD patients during a 2-year period. Potential confounders included age, gender, albumin, iron deficiency, parathyroid hormone (PTH), underlying renal disease, cormorbid illness, renal transplant, dialysis adequacy and duration. An intent-to-treat analysis was used, with sensitivity analyses to account for change in treatment and transplant. Results: Mean haemoglobin (Hb) was not different (10.47 g/dl for HD, 10.71 G/DL for PD; P=0.45). Mean monthly transfusion rate was higher for HD (0.47 units per month vs 0.19; P<0.01). More HD patients received at least one transfusion (52.9 vs 40.9%; P<0.01). The maintenance rHuEpo dose was higher for HD (7370 U/week vs 5790 U/week; P=0.01). The only factors associated with risk of being transfused were dialysis duration and mode of dialysis (less risk for PD, odds-ratio 0.57; 95% confidence interval 0.35-0.92). Conclusions: Despite the routine use of rHuEpo, HD patients received more blood and rHuEpo than PD patients to achieve the same Hb. No patient factors were identified to account for this difference. The use of fewer transfusions and less rHuEpo in PD represents an advantage over HD in terms of both cost and safety.     

Body mass index and resistance to recombinant human erythropoietin therapy in maintenance hemodialysis patients

Abstract

The aim of this work was to contribute to a better understanding of the relationship between resistance to recombinant human erythropoietin (rhEPO) therapy and body mass index (BMI) in hemodialysis (HD) patients. We evaluated 191 HD patients and 25 healthy individuals. Complete blood count, reticulocyte count, and circulating levels of ferritin, transferrin, iron, soluble transferrin receptor (sTfR), transferrin saturation, hepcidin, C-reactive protein (CRP), interleukin 6 (IL-6), albumin, and adiponectin were measured in all patients and controls. Non-responder patients (n?=?16), as compared with responder patients (n?=?175), showed statistically significant lower BMI values, an enhanced inflammatory and higher adiponectin levels, associated with disturbances in iron metabolism. Analyzing the results according to BMI, we found that underweight patients required higher rhEPO doses than normal, overweight, and obese patients, and a higher percentage of non-responders patients were found within the underweight group of HD patients. Moreover, underweight patients presented lower levels of transferrin and higher levels of adiponectin compared to overweight and obese patients, and lower levels of iron compared with normal weight patients. Multiple regression analysis identified the sTfR, hemoglobin, BMI, and albumin as independent variables associated with rhEPO doses. In conclusion, our work showed that HD patients resistant to rhEPO therapy present a functional iron deficiency and a higher degree of inflammation, despite their lower BMI values and higher levels of adiponectin. Actually, BMI is poorly related with markers of systemic inflammation, such as IL-6 and CRP, while adiponectin works a fairly good indirect marker of adiposity within HD patients.     

The Relationship of Visfatin Levels with Insulin Resistance and Left Ventricular Hypertrophy in Peritoneal Dialysis Patients

Background/objectives: Cardiovascular abnormalities are common in patients with chronic kidney disease. Visfatin influences lipid metabolism, insulin sensitivity, and cardiovascular health. The aim of this study was to explore the relation of serum visfatin to cardiovascular risk factors in nondiabetic peritoneal dialysis (PD) patients. Patients and methods: Eighty-seven nondiabetic patients (mean age 48 ± 15 years, 39 males) under PD were enrolled. Weight, anthropometric measurements, blood pressure, biochemical parameters, and insulin resistance (homeostatic model assessment-insulin resistance—HOMA-IR) were measured. Visfatin was measured and left ventricular mass index (LVMI) was calculated by echocardiography. Results: LVMI was correlated with body mass index (BMI; r = 0.47, p = 0.01), systolic blood pressure (SBP; r = 0.62, p = 0.04), and serum visfatin levels (r = 0.49, p = 0.03). According to HOMA-IR levels patients were grouped as insulin-resistant (IR) (HOMA-IR ≥2.0, n = 35) and noninsulin-resistant (non-IR) (HOMA-IR <2.0, n = 52) groups. The IR group had longer PD duration and higher BMI, total cholesterol, uric acid, and serum visfatin levels (p < 0.05). The study patients were divided into three groups according to their serum visfatin levels. Group 1 (≤34 ng/mL, n = 22) was considered as the lowest tertile of low visfatin and group 2 (35–42 ng/mL, n = 43) and group 3 (≥43 ng/mL, n = 22) in the upper tertile. Considering the visfatin groups, group 3 patients had significantly higher BMI (p = 0.00), total cholesterol (p = 0.03), C-reactive protein (CRP) (p = 0.03), HOMA-IR (p = 0.03), and LVMI (p = 0.02). In regression analysis, SBP (β = 0.19, p < 0.05) and serum visfatin levels (β = 0.74, p < 0.05) were independent variables affecting LVMI. Conclusion: Serum visfatin might be a sensitive marker than HOMA-IR evaluations for cardiac performance in nondiabetic PD patients.     

Visfatin and endothelial function in dialyzed patients

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‐α (TNF‐α) and interleukin (IL)‐6) were assessed. Results: Triglycerides, hsCRP, creatinine, IL‐6, TNF‐α, 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.     

Percentage of hypochromic red blood cells as predictor of erythropoietic and iron response after i.v. iron supplementation in maintenance haemodialysis patients

Background. The percentage of hypochromic red blood cells (RBC), defined as those with a cellular haemoglobin <28 g/dl has been suggested to be a sensitive marker of functional iron deficiency in maintenance haemodialysis (HD) patients. Thus, during rHuEpo therapy an increase in hypochromic RBC to >10% would indicate that more intensive iron supplementation may be required. Methods. We investigated 70 HD patients 57.1±15.3 years old and on maintenance HD for 66.3±47.9 months without blood loss from gastrointestinal bleeding or from the vascular access, without surgery and without infectious disease or malignancy. During the study period of 12 weeks, each patient received an i.v. dose of 800 mg ferrogluconate. Haemoglobin, haematocrit, and the percentage of hypochromic RBC were measured before and every 4 weeks after the start of the study; serum ferritin, zinc protoporphyrin (ZPP) and C-reactive protein (CRP) were measured at the beginning (baseline) and end of the study. Results. At baseline the percentage of hypochromic RBC was ⩽5.0% in 28 patients, >5.0 and ⩽10.0% in 25 patients and >10.0% in 17 patients, suggesting functional iron deficiency in at least 42 patients, suggesting functional iron deficiency in at least 42 patients. Nine patients had serum ferritin values <100 &mgr;g/l; nonetheless in these patients the median percentage of hypochromic RBC was 5.9% (range 0.9-14.3%), indicating that an absolute iron deficiency can occur in the presence of normal amounts of hypochromic RBC. There was a significant correlation between serum ferritin levels and hypochromic RBC at the end, but not at the beginning, of the study. However, there was no correlation between ZPP and hypochromic RBC at any time during the study. During i.v. iron supplementation the rHuEpo dose could be reduced by 8.5% in patients with hypochromic RBC ⩽5.0%, by 11.3% in patients with hypochromic RBC>5.0 and ⩽10.0% and by 23.4% in patients with hypochromic RBC>10.0%, demonstrating the benefit of i.v. iron in patients with functional iron deficiency. In HD patients in whom serum ferritin levels remained below 290 &mgr;g/l until the end of the study, a significant reduction of the rHuEpo dosage could be obtained during i.v. iron therapy. This was not the case in patients with serum ferritin >290 &mgr;g/l after iron supplementation. We found that the percentage of hypochromic RBC is the most sensitive parameter for predicting hyporesponsiveness in CPR-positive patients. Finally our data indicate that HD patients with hypochromic RBC>6% and low to moderate increases in serum ferritin levels after i.v. iron supplementation significantly benefit from i.v. iron therapy. Conclusions. Two different aspectsshould be taken into consideration in HD patients treated with rHuEpo and concomitant i.v. iron therapy: (1) response of the erythropoietic system to rHuEpo, and (2) adequate delivery of the supplemented iron to the erythropoietic system. The patient's percentage of hypochromic RBC and increase in serum ferritin after i.v. iron supplementation should be used to decide whether or no i.v. iron should be given and to monitor this type of therapy in HD patients.     

Type of Renal Replacement Therapy and Residual Renal Function May Affect Prohepcidin and Hepcidin

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.     

Importance of iron supply for erythropoietin therapy

BACKGROUND.: rHuEpo and iron therapy corrects renal anaemia. However, dosage,route of administration, and monitoring of iron and rHuEpo therapyin uraemic patients remains controversial. METHODS.: Therefore a 22-month i.v. iron substitution trial, subdividedinto four study periods, was initiated in 64 iron-depleted chronichaemodialysis (HD) patients receiving i.v. rHuEpo therapy. Withinthe first period (6 months) patients were treated with high-doseiron (100mg at the end of HD treatment, mean cumulative i.v.iron saccharate dosage was 2538±810 mg per patient) inorder to replete the iron stores. During the 2nd period (6 months)the available iron pool was maintained with low-dose iron byadministration of 10, 20, or 40 mg iron at each HD, dependingon haemoglobin, serum ferritin and transferrin saturation levels.During the 3rd period (4 months), the iron-replete patientswere randomized to i.v. or s.c. route of rHuEpo administration.During the 4th period (3 months) iron substitution was omittedto exclude severe iron overload. RESULTS.: In the first study period, high-dose iron therapy dramaticallyreduced the weekly rHuEpo requirement by 70% of the initialdose (from 217±179 to 62.6±70.2 U/kg/week). Inthe 2nd period iron storage pools were easily maintained. Serumferritin and transferrin saturation levels remained stable duringthis study period. Randomization for thrice-weekly i.v. or s.c.administration of rHuEpo in the 3rd study period revealed comparableefficacy for both administration routes in iron-replete patients.In well-nourished patients (serum albumin >40 g/1) withouthyperparathyroidism (parathyroid hormone levels < 100 pg/ml),50–60 U/kg/week rHuEpo were required in contrast to >100 U/kg/week in patients with hyperparathyroidism. In the 4thstudy period, withdrawal of iron administration led to a rapiddecrease of serum ferritin and transferrin saturation levels,indicating the absence of severe iron overload. CONCLUSIONS.: Long-term thrice-weekly i.v. low-dose iron therapy (10–20mg per HD treatment) proved to be a very effective, economicaland safe treatment schedule for iron-replete HD patients. Intravenousand s.c. rHuEpo therapy was equally efficacious in iron-replete,well-nourished patients. HD patients with increased parathyroidhormone levels require significantly more rHuEpo than HD patientswith parathyroid hormone levels values <100 pg/ml).     

Is hemojuvelin a possible new player in iron metabolism in hemodialysis patients?

Introduction

Hemojuvelin (HJV) is highly expressed in the liver, skeletal muscles, and heart, seems to play a role in iron absorption and release from cells, and has anti-inflammatory properties. Moreover, HJV plays an essential role in the regulation of hepcidin expression, specifically in the iron-sensing pathway. Hepcidin has emerged as a key regulator of iron homeostasis. In this study we tested for the first time the hypothesis that HJV is related to iron metabolism in hemodialysis (HD) patients.

Methods

Iron status, complete blood count, and serum creatinine, albumin, and lipids were assessed, using standard laboratory methods. Serum levels of soluble transferrin receptor (sTFR), high-sensitivity CRP, IL-6, hepcidin, and HJV were measured using commercially available kits.

Results

Serum HJV, hepcidin, ferritin, IL-6, hsCRP, and serum creatinine were significantly higher (all P?<?0.001), whereas serum iron, sTFR, transferrin, hemoglobin, and erythrocyte count were significantly lower in HD patients, compared to healthy volunteers (all P?<?0.001). In univariate analysis, HJV was strongly correlated (P?<?0.001) with ferritin, transferrin saturation, and TIBC, as well as with hsCRP, hepcidin, Kt/V (P?<?0.01) and residual renal function, the presence of diabetes, APKD, and coronary heart disease. Predictors of HJV level in multiple regression analysis were ferritin (beta value was 0.50, P?=?0.00004) and transferrin saturation (beta value was 0.47, P?=?0.0002), explaining 81% of the HJV variations.

Conclusions

Serum HJV is elevated in HD patients and related predominantly to kidney function and iron metabolism. However, HJV is probably not correlated to inflammation. HJV appears to be a new player in iron metabolism in these patients.     

Changes of endogenous erythropoietin level and iron status during a 30-month hemodialysis treatment of a group of patients

In our earlier paper [1] we found that among 50 hemodialysis patients(HD pts) 48% (24 pts) control anemia with hemoglobin (Hb)concentration >9.5 g/dl and hematocrit (Hct) >30%without recombinant human erythropoietin (rHuEpo) therapy. These HD ptshad significantly higher mean endogenous erythropoietin (eEpo) level andlower iron reserves (IR) than HD pts who need rHuEpo therapy. The aim ofthis study was to judge whether the possibility to control anemia in ptsnot requiring rHuEpo therapy changes during a 30-month HD treatment.Serum eEpo and ferritin were measured every 6 months. After 30 months ofHD treatment 18 pts remained in this group – 5 pts died, Iunderwent transplantation. During the study period 4/18 ptspermanently had a very low level of eEpo (under detection limit),7/18 had the level of eEpo within normal range for healthy control,7/18 pts had a high level of eEpo (up to 3 times higher than themean for healthy control). Pts who had the highest level of eEpo had thelowest IR. After 30 months IR were significantly lower than at thebeginning of observation (292 ± 87 vs 143 ± 127 mg).Important negative correlation between eEpo and IR was observedthroughout the whole period of study: r = –0.4820,p < 0.02 at the start of the study, and r =–0.6126, p < 0.007 after 30 months of treatment. Thestudy shows that the possibility to control anemia in pts not treatedwith rHuEpo did not change significantly during 30 months of HDtreatment. Endogenous Epo level in HD pts not treated with rHuEpo variedbetween different pts: it was permanently low in some pts, permanentlyhigh in others and stayed normal in remaining pts.     

The Impact of Chronic Inflammation on Bone Turnover in Hemodialysis Patients

Background. Renal osteodystrophy is very common in hemodialysis (HD) patients. HD is a chronic inflammatory state. Studies in other pathological entities have shown an impact of chronic inflammation on bone metabolism. In the present study, the impact of chronic inflammation on bone turnover in HD patients was evaluated.?Patients and methods. Thirty-three anuric HD patients free of other pathological conditions or medications that affect immune system or bone metabolism and 30 healthy volunteers enrolled into the study. Intact parathyroid hormone (iPTH), the markers of inflammation IL-6 and CRP, as well as the markers of bone turnover osteocalcin (OCN) and beta-isomerized C-terminal cross-linked peptide of collagen type I (β-CTx) were measured in the serum.?Results. All evaluated factors were increased in HD patients. In the HD group, the serum marker of osteoblastic activity OCN was related inversely to patients' age (r?=??0.469, p?=?0.006), CRP (rho?=??0.460, p?=?0.007), and IL-6 (r?=??0.485, p?=?0.004) but positively to iPTH (r?=?0.707, p < 0.001). Similarly, the serum marker of osteoclastic activity β-CTx was related inversely to patients' age (r?=??0.383, p?=??0.028), CRP (rho?=?–0.466, p?=?0.006), and IL-6 (r?=??0.460, p?=?0.007) but positively to iPTH (r?=?0.657, p < 0.001). Multiple linear regression analysis revealed that IL-6 affects bone turnover independently of PTH and to the opposite direction.?Conclusion. Chronic inflammation has a negative impact on bone turnover in HD patients. Certainly, further research and large clinical trials are needed for definite conclusions and for clarifying the exact molecular mechanisms implicated in the interaction between the immune system and bone metabolism in HD patients.     

Iron,coronary artery calcification,and mortality in patients undergoing hemodialysis

ObjectiveA high coronary artery calcification score (CACS) may be associated with high mortality in patients undergoing hemodialysis (HD). Recently, effects of iron on vascular smooth muscle cell calcification have been described. We aimed to investigate the relationships between iron, CACS, and mortality in HD patients.MethodsWe studied 173 consecutive patients who were undergoing maintenance HD. Laboratory data and Agatston’s CACS were obtained at baseline for two groups of patients: those with CACS ≥400 (n = 109) and those with CACS <400 (n = 64). Logistic regression analyses for CACS ≥400 and Cox proportional hazard analyses for mortality were conducted.ResultsThe median (interquartile range) age and duration of dialysis of the participants were 67 (60–75) years and 73 (37–138) months, respectively. Serum iron (Fe) and transferrin saturation (TSAT) levels were significantly lower in participants with CACS ≥400 than in those with CACS <400, although the serum ferritin concentration did not differ between the groups. TSAT ≥21% was significantly associated with CACS ≥400 (odds ratio 0.46, p<0.05). TSAT ≥17%, Fe ≥63 µg/dL, and ferritin ≥200 ng/mL appear to protect against 5-year all-cause mortality in HD patients, independent of conventional risk factors of all-cause mortality (p < 0.05).ConclusionWe have identified associations between iron, CACS, and mortality in HD patients. Lower TSAT was found to be an independent predictor of CACS ≥400, and iron deficiency (low TSAT, iron, or ferritin) was a significant predictor of 5-year all-cause mortality in HD patients.     

Visfatin, a New Adipocytokine, Is Predominantly Related to Inflammation/Endothelial Damage in Kidney Allograft Recipients

Visfatin, a ubiquitous adipokine, was first described in 2005. It was found to be selectively up-regulated in the adipose tissue and to have insulin-mimetic effects. It has been reported that visfatin is associated with endothelial damage in chronic kidney disease. We investigated plasma visfatin levels (using commercially available kits) in 100 clinically stable kidney allograft recipients. We assessed visfatin markers of coagulation: thrombin-antithrombin complexes, prothrombin fragments 1 + 2; fibrinolysis: tissue plasminogen activator, plasminogen activator inhibitor, plasmin-antiplasmin complexes; endothelial function/injury: von Willebrand factor, thrombomodulin, intracellular adhesion molecule, vascular cell adhesion molecule (VCAM); inflammation: hsCRP and interleukin-6. Visfatin was significantly higher in kidney allograft recipients than in healthy volunteers. Visfatin did not differ significantly between diabetic and nondiabetics, hypertensives and normotensives, patients with and without coronary artery disease, and between male and female subjects. Type of immunosuppressive regimen (mycophenolate mofetil vs azathioprine) did not affect visfatin levels. On univariate analysis, visfatin correlated positively with prothrombin fragments 1 + 2, VCAM, creatinine, high-sensitivity C-reactive protein, and negatively with albumin. In multivariate analysis, only VCAM was associated with visfatin in kidney allograft recipients. Visfatin, which is related to markers of inflammation, may represent a novel link between inflammation and adipocytokines among long-term kidney transplant recipients.     

Alteration of mRNA expression of molecules related to iron metabolism in adenine-induced renal failure rats: a possible mechanism of iron deficiency in chronic kidney disease patients on treatment.

BACKGROUND: Recombinant human erythropoietin (rHuEpo) is a definitive treatment for anaemia in chronic kidney disease (CKD). During long-term rHuEpo treatment most patients develop and show persistent iron deficiency in spite of oral iron supplementation. Abnormalities of iron absorption and transport in the duodenum may contribute to this deficiency. METHODS: To investigate changes in iron absorption and transport in CKD and iron deficiency against the background of rHuEpo treatment, we used severely anaemic rats with adenine-induced renal failure (adenine rats) and sham-treated control rats given only the vehicle. After 4 weeks on adenine or the vehicle, the rats were divided into four groups according to whether or not they received rHuEpo for the next 4 weeks: rHuEpo(-)-adenine, rHuEpo(-)-control, rHuEpo(+)-adenine and rHuEpo(+)-control. We evaluated the effects of rHuEpo treatment on iron balance, duodenal mRNA expression of molecules related to iron absorption and transport and hepatic mRNA expression of hepcidin. RESULTS: Treatment with rHuEpo improved anaemia and induced iron deficiency only in the adenine rats, in whom the expression of mRNAs for ferroportin 1 and hephaestin 1 increased and for divalent metal transporter 1 (DMT1) was unchanged. In contrast, control rats treated with rHuEpo showed no changes. Hepcidin mRNA expression was greater in adenine rats than in control rats. CONCLUSIONS: In the adenine rats, rHuEpo treatment improved renal anaemia and induced persistent iron deficiency. An alteration of mRNA expression of molecules related to iron metabolism in renal insufficiency may be one of the reasons for this iron deficiency.     

A Possible Role of Hepcidin in the Pathogenesis of Anemia Among Kidney Allograft Recipients

Hepcidin is a small, defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. We studied correlations of hepcidin concentrations with markers of iron status, erythropoietin therapy, and markers of inflammation among 130 kidney allograft recipients. In addition, we assessed the prevalence of anemia and its relation to hepcidin. Soluble receptor of transferrin (sTfR), high-sensitivity C-reactive protein (hsCRP), TNF-α, interleukin (IL)-6, prohepcidin, and hepcidin were measured using commercially available kits. According to the WHO definition, the prevalence of anemia was 28%. Among anemic recipients we found a significantly higher values of serum creatinine, serum prohepcidin, hepcidin, (hsCRP), TNF-α, IL-6, ferritin, and proteinuria in addition to more frequent use of rapamycin and significantly lower use of CSA with lower CSA concentrations, as well as lower cholesterol, hemoglobin, and estimated glomerular filtration rate (eGFR) (by the Modification of Diet in Renal Disease equation).Serum prohepcidin significantly correlated with creatinine, GFR, time after transplantation, albumin, hsCRP, IL-6, and TNF-α, whereas hepcidin-25 correlated with serum iron, ferritin, hsCRP, IL-6, hemoglobin, transferrin saturation (TSAT), creatinine, and GFR. Multiple regression analysis showed that prohepcidin was independently related only to GFR and ferritin. Upon multiple regression analysis, predictors of serum hepcidin were eGFR, ferritin, and hsCRP, explaining 79% of the variation of hepcidin values.In conclusion, the prevalence of anemia was relatively high among a population of kidney allograft recipients. The pathogenesis of anemia is mulitfactorial. Elevated hepcidin levels among kidney transplant recipients may be due to low-grade inflammation, which is frequently encountered in this population, and mainly to impaired renal function, but it did not seem to be a major pathogenetic factor for anemia in this population.     

The relationship of visfatin levels to inflammatory cytokines and left ventricular hypertrophy in hemodialysis and continuous ambulatory peritoneal dialysis patients

Visfatin was recently defined as an adipocytokine; however, the pathophysiological role of visfatin is not completely understood. A few studies suggest that visfatin may be a new proinflammatory adipocytokine. The aim of the present study was to compare serum visfatin levels between hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients and evaluate the relationship between visfatin levels to IL-6, TNF-alpha, and left ventricular hypertrophy. Serum visfatin, IL-6, and TNF-alpha levels were measured by using the ELISA method, and echocardiographic evaluations were performed in 31 hemodialysis patients, 30 CAPD patients, and 21 healthy volunteers. Serum visfatin levels were higher in the CAPD group (265.27 +/- 387.86 ng/mL) than hemodialysis (97.68 +/- 244.96 ng/mL,) and control (41.33 +/- 48.87 ng/mL) groups (p = 0.04, p = 0.01, respectively). No significant difference was observed between the hemodialysis and control groups. In univariate analysis, visfatin levels were positively correlated with IL-6 (r = 0.24, p = 0.03), TNF-alpha (r = 0.34, p = 0.002), and BMI (r = 0.26, p = 0.03) and negatively correlated with some left ventricular diastolic parameters [Em and Em/Am (r = -0.305, p = 0.01), (r = -0.251, p = 0.03), respectively]. No relationship was found between visfatin and left ventricular mass index. In the linear regression analysis, visfatin levels independently related with TNF-( (beta = 0.369, p = 0.001) and IL-6 (beta = 0.284, p = 0.015). This study has found significantly higher levels of serum visfatin in CAPD patients when compared to healthy individuals. Increased visfatin levels seem to associate with proinflammatory cytokines such as IL-6 or TNF-alpha. As for the effects of on left ventricular structure and functions, visfatin might have negative effects on left ventricular diastolic function parameters but have no effects on left ventricular mass index.