Leukopenia and thrombocytopenia in hemodialysis patients with hepatitis B or C virus infection and non-hemodialysis patients with hepatitis cirrhosis

AIMS: To investigate the relation of leukopenia and thrombocytopenia in hemodialysis (HD) patients with hepatitis C virus (HCV) infection. MATERIALS AND METHODS: The study included 86 HD patients with hepatitis B surface antigen-negative and hepatitis C antibody-negative, 28 HD patients with hepatitis C antibody-positive, 22 HD patients with hepatitis B surface antigen-positive, 78 non-HD patients with hepatitis B-induced liver cirrhosis and 38 non-hemodialysis patients with hepatitis C-induced liver cirrhosis. The following parameters were checked: anti-HCV, hepatitis B surface antigen, hemoglobin, hematocrit, white blood cells, platelets, calcium, phosphate, iron, ferritin, albumin, globulin, aspartate transaminase (AST), alanine transaminase (ALT) and C-reactive protein. The history of blood transfusions, medications, erythropoietin doses and adequate dialysis (KTNV) for 6 consecutive months was also recorded from charts. RESULTS: The HD patients with positive serum anti-HCV and non-HD patients with hepatitis B- or C-induced liver cirrhosis had higher prevalences of leukopenia (39.3%, 43.6% and 50% vs. 15.1%; p < 0.001) and thrombocytopenia (67.9%, 89.7% and 81.6% vs. 34.9%: p < 0.001) than HD patients with serum anti-HCV(-)HbsAg(-). The WBC (4,432 +/- 1,394, 4,792 +/- 2,263 and 4,624 2,446 vs. 5,590 +/- 1,500/mm3; p < 0.001) and platelet counts (140 +/- 45, 80 +/- 50 and 89 +/- 65 vs. 186 +/- 62 x 10(3)/mm3; p < 0.001) of HD patients with positive serum anti-HCV and non-HD patients with hepatitis B- or C-induced cirrhosis were also lower than HD patients without anti-HCV antibody. The liver cirrhosis patients had more thrombocytopenia than the HD patients with anti-HCV(+). The WBC and platelet counts did not vary between HD patients with HbsAg(+) and HD patients with anti-HCV(-)HBsAg(-). The durations of HD, hepatitis and liver cirrhosis were not related to the leukopenia or thrombocytopenia (p > 0.05). CONCLUSIONS: HCV infection associated with leukopenia and/or thrombocytopenia in HD patients is as common as in non-HD patients with liver cirrhosis. This may be due to the direct effect of hemopoiesis rather than the hyperspleenism of liver cirrhosis patients. There is a need for further prospective investigation to ascertain the clinical significance of leukopenia and thrombocytopenia in HD patients with anti-HCV(+). The prevalence of leukopenia and thrombocytopenia was higher in HD patients with hepatitis C than in HD patients with hepatitis B and HD patient without hepatitis.     

High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied

AIMS: Some studies have reported that ALT determination is of little value in the study of chronic hepatitis C in hemodialysis (HD) patients. This could be due to the fact that ALT values are lower in HD patients than in healthy individuals; ALT in HCV infection follows a fluctuating pattern and the HCV viremia may be intermittent. The aim of this study was to establish the reference ALT values in a large group of hepatitis-free HD patients, and to determine their role in predicting viremia in anti-HCV-positive HD patients. METHODS: Four subject groups were studied: group I, patients with normal renal function (n = 88); group II, hepatitis-free HD patients (n = 218); group III, non-viremic anti-HCV+ HD patients (n = 9); and group IV, viremic anti-HCV+ HD patients (n = 24). The ALT used for calculation purposes was the mean value of the twelve previous months for each individual patient. PCR screening for HCV-RNA was performed at least twice for anti-HCV+ patients; these were deemed viremic (HCV-RNA+) if at least one screening was positive, and non-viremic (HCV-RNA) if all PCR results were negative. RESULTS: Mean ALT in group II was lower than in subjects with normal renal function (15.6 +/- 12 vs. 22.7 +/- 18 IU/l, p < 0.05). No significant differences were observed between group III and group II (17.7 +/- 6 vs. 15.6 +/- 6 IU/l, ns). ALT levels in group IV patients were higher than those of groups II and III (38.5 +/- 39 IU/l, p < 0.05). The upper limit (mean + 2 SD and 95th percentile) for ALT in hepatitis-free HD patients was 27 IU/l. Sensitivity of a mean ALT value > or = 27 IU/l in the diagnosis of HCV viremia was 50%, and specificity was 100%. The positive predictive value of this test in the diagnosis of hepatitis C viremia was 100%. CONCLUSIONS: ALT values are lower in HD patients and a high ALT level can constitute an excellent tool in predicting viremia in anti-HCV-positive HD patients once other causes of liver disease have been excluded.     

Soluble transferrin receptor is correlated with erythropoietin sensitivity in dialysis patients.

BACKGROUND: Iron deficiency is the most common cause of erythropoietin (EPO) resistance in dialyzed patients with renal anemia. Subclinical or functional iron deficiency is difficult to diagnose in these patients. The soluble transferrin receptor (sTf-R) is considered as a sensitive and specific indicator of bone marrow iron availability. PATIENTS AND METHODS: To evaluate the clinical usefulness of this novel marker, we investigated relationships between EPO requirements and various hematological and biochemical parameters of erythropoiesis in 27 pediatric end-stage renal failure patients treated by hemodialysis (HD, n = 11) or chronic peritoneal dialysis (PD, n = 16). Iron was substituted intravenously once or twice per week in HD, and by daily oral administration to PD patients. Serum sTf-R concentrations were measured by an enzyme-linked immunosorbent assay. Serum ferritin and transferrin concentrations were determined using nephelometric assays. Hemoglobin and iron levels were estimated by automated procedures. RESULTS: While neither transferrin saturation nor serum ferritin concentrations were indicative of EPO requirements, a highly significant correlation between the EPO efficacy index (EPO dose divided by hemoglobin concentration) and sTf-R was observed (r = 0.65, p = 0.001). The intravenous iron substitution in HD patients was associated with higher ferritin concentrations compared to the orally substituted PD patients (280+/-100 ng/ml vs. 124+/-83 ng/ml, p<0.002). In contrast, sTf-R concentrations were similar in both treatment groups (25.7+/-7.7 nM vs. 27+/-10.8 nM, n.s.), as were hemoglobin concentrations and EPO requirements. CONCLUSION: Our results suggest that sTf-R is a more sensitive indicator of functional iron deficiency and impaired EPO responsiveness than serum ferritin or transferrin saturation in dialyzed patients. Intensified iron substitution to patients with elevated sTf-R concentrations may considerably improve the cost efficacy of EPO treatment.     

Current management of renal anemia in patients with chronic kidney disease at the predialysis stage

OBJECTIVE: Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence. MATERIALS & METHODS: The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks. RESULTS: The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points. CONCLUSION: The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted.     

Trace elements and lipid peroxidation abnormalities in patients with chronic renal failure

Plasma selenium (Se), zinc (Zn) and copper (Cu) levels and antioxidant metalloenzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), were studied in 17 patients on maintenance hemodialysis (HD) (group I), 14 uremic patients (group II) and 14 healthy subjects (group III). Plasma Se levels and erythrocyte GPX were significantly lower in the HD group (for Se: 0.69 +/- 0.12 vs. 1.05 +/- 0.13 mumol/l in controls; for erythrocyte GPX: 34.4 +/- 6.4 vs. 49.2 +/- 9 IU/g hemoglobin in controls) and a significant correlation was found between the two parameters (r = 0.66, p less than 0.005). There was also a correlation between decreased plasma Zn and erythrocyte SOD activity (r = 0.58, p less than 0.02) and between decreased plasma Cu and erythrocyte SOD (r = 0.60, p less than 0.02). Plasma malondialdehyde levels were augmented in HD patients (5.08 +/- 0.26 vs. 2.55 +/- 0.15 mumol/l in controls and 2.79 +/- 0.40 mumol/l in the uremic group). The catalase activity was increased in HD patients (202 +/- 24 vs. 140 +/- 40 IU/mg hemoglobin in group III). A defective antioxidant activity may thus contribute to increased peroxidative damage to cells in the course of dialysis.     

Does hepatitis C virus infection increase hematocrit and hemoglobin levels in hemodialyzed patients?

OBJECTIVE: Some case reports indicated that red cell status increased after hepatitis C viral infection. The aim of study was to define the influence of hepatitis C infection (HCV) on red cell status in hemodialyzed patients. MATERIALS AND METHODS: A total of 49 (21 anti-HCV-positive and 28 anti-HCV-negative) patients with ESRD were included in this study. Exclusion criteria were blood transfusion and massive blood loss in the last 6 months preceding the study. None of the patients used any drug containing aluminum. RESULTS: The prevalence of anti-HCV antibody was 42.8%. Mean age was 51.6 +/- 14.3 in anti-HCV (+) group and 50.4 +/- 17.0 in anti-HCV (-) group. There was no statistically significant difference between the ages of the 2 groups. Mean duration time of hemodialysis was significantly longer in patients with anti-HCV antibody (+) group (54.9 +/- 34.2 months) compared to anti-HCV-negative group (12.5 +/- 9.0 months) (p < 0.001). Mean hemoglobin (Hb) and hematocrit (Htc) levels were significantly higher in anti-HCV-positive patients than in anti-HCV-negative patients (Hb: 10.4 +/- 1.8 g/dl, Htc: 30.5 +/- 5.5% vs Hb: 8.8 +/- 1.7 g/dl, Htc: 26.1 +/- 5.3%) (for Hb p < 0.005, for Htc p < 0.007). There was no significant difference regarding the usage ofrHuEPO between the 2 study groups (57.1% in anti-HCV antibody (+)/59.3% in anti-HCV antibody (-)) (p > 0.05). All patients not receiving rHuEPO did so because of economical reasons. Serum AST and ALT levels were significantly higher in the anti-HCV antibody-positive group compared with the anti-HCV antibody-negative group. (AST p < 0.04, ALT p < 0.04). CONCLUSION: Anti-HCV antibody-positive ESRD patients have higher hemoglobin and hematocrit levels compared to HCV-negative patients.     

Endothelial function is more impaired in hemodialysis patients than renal transplant recipients

BACKGROUND: Endothelial dysfunction (ED) is a common precursor and denominator of cardiovascular events including development of atherosclerosis. In this cross-sectional, controlled study, we aimed to investigate ED measured by ischemia-induced forearm vasodilatation in chronic hemodialysis (HD) patients and renal transplant recipients (rTX). PATIENTS AND METHODS: Thirty-nine HD patients, 39 rTX and 38 normotensive healthy controls were included. There was no difference in age and gender distribution among the study groups. The mean time spent on dialysis and transplantation were 74 +/- 46 and 68 +/- 39 months. Serum high sensitive C-reactive protein (hs-CRP) and plasma fibrinogen levels were measured. Endothelium dependent post-ischemic vasodilatation of brachial artery was used to evaluate ED. RESULTS: The hs-CRP and plasma fibrinogen levels were significantly increased in HD patients when compared with rTX. On high resolution ultrasonographic examination, post-ischemic vasodilatation values in HD patients (9.55 +/- 6.47%) were significantly lower than rTX (14.39 +/- 8.06%, p = 0.007) and controls (20.42 +/- 6.10%, p < 0.001). Renal transplant recipients also had significantly lower post-ischemic vasodilatation values than controls (p = 0.001). The hs-CRP levels were negatively correlated with endothelium-dependent dilatations in TX (r = -0.59, p = 0.001), however, this correlation was not detected in HDp. CONCLUSION: Patients with end-stage renal disease have ED. Endothelial function is more impaired in HD patients than rTX. Different mechanisms might be responsible for ED in HD patients and rTX.     

Serum erythropoietin levels and hematocrit in end-stage renal disease: influence of the mode of dialysis

Serum erythropoietin (Ep) levels were measured by radioimmunoassay in 70 patients with end-stage renal disease (ESRD) to evaluate the influence of the mode of dialysis on the relationship between serum Ep levels and the severity of anemia. Thirty-five patients were on hemodialysis (HD), seven were on intermittent peritoneal dialysis (IPD), and 28 were on continuous ambulatory peritoneal dialysis (CAPD). Compared to HD, CAPD patients had higher serum Ep (CAPD), 46.1 +/- 13.4 v HD, 16.9 +/- 2.2 mU/mL) and hematocrit (CAPD, 33.9 +/- 2.5 v HD, 24.8 +/- 1.4%; P less than 0.05). The Ep and Hct values for IPD patients were intermediate between the other two groups. Serum Ep levels were higher in CAPD patients in the first 4 weeks of initiation of CAPD (144 +/- 35 mU/mL, n = 6) than later (39 +/- 6.4 mU/mL, n = 24). A significant fluctuation in serum Ep and Hct values was noted in patients on all three modes of dialysis, when multiple samples were obtained at different time intervals. There was a weak correlation between serum Ep and Hct in the three groups of dialysis patients; r = 0.36, P less than 0.005. The data suggest that CAPD provides a better biochemical milieu for Ep production and responsiveness than HD treatment of ESRD.     

Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to lower hematocrit and erythropoietin (EPO), but a direct link between angiotensin II (Ang II) and EPO in humans has not been shown. METHODS: Placebo or Ang II was infused for six hours in nine healthy male volunteers with and without blockade of the Ang II subtype 1 receptor (AT1R). EPO concentrations were measured 3, 6, 12, and 24 hours after the start of the infusion. RESULTS: Ang II raised the mean arterial pressure by about 20 mm Hg. Consistent with the known diurnal variation, EPO levels rose significantly (P < or = 0.02) during the day in all groups. During Ang II infusion, EPO levels rose to significantly higher levels after 6 and 12 hours compared with placebo [9.9 +/- 3.5 vs. 7.2 +/- 3.1 mU/mL (3 h, P = NS); 16.9 +/- 4.5 vs. 8.8 +/- 3.7 mU/mL (6 h, P = 0.01); 17.0 +/- 8.6 vs. 11.1 +/- 4.7 mU/mL (12 h, P = 0.01)] and returned to baseline after 24 hours (7.9 +/- 3.8 vs. 10.6 +/- 8.6 mU/mL, P = NS). With AT1R blockade, blood pressure remained normal during Ang II infusion, and EPO levels were never significantly different from placebo [6.8 +/- 4.8, 10.5 +/- 5.6, 13.1 +/- 9.0, and 12.4 +/- 10.1 mU/mL at 3, 6, 12, and 24 h after infusion, respectively, P = NS]. CONCLUSIONS: Ang II increases EPO levels in humans. This increase requires the participation of AT1R.     

Erythropoietin requirements: a comparative multicenter study between peritoneal dialysis and hemodialysis

BACKGROUND: The management of anemia with erythropoietin (EPO) is important in the global treatment of dialysis patients. There is a general impression that anemia control with EPO is obtained more easily in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients. The EPO administration route has to be the same to compare the two techniques adequately. METHODS: To compare EPO action by subcutaneous (SC) route in HD and PD, 132 stable patients were recruited (HD: 69, PD: 63) from six centers, with adequate dialysis criteria (Kt/V in HD >1.3; weekly Kt/V in PD >1.8). In a cross-sectional study, the EPO dose/week, the number of EPO doses/week, hemoglobin (Hb), ferritin, transferrin saturation index (TS), albumin and intact parathyroid hormone (iPTH) were analyzed. Iron treatment, comorbidity and ACE inhibitors (ACEI) and angiotensin II antagonist (AIIA) treatment were recorded. A multivariate regression model was used in the statistical analysis. RESULTS: The mean Hb level was the same in both groups, HD 11.6 (1.3) g/dL, PD 11.4 (1.4) g/dL, p=0.3. The SC, EPO doses required to obtain the Hb levels were higher in HD than in PD patients, with a difference of 64.3 u/Kg/week, statistically significant in the multivariate regression model (p=0.001, 95% CI 42.6-86.0). The number of EPO doses/week was also higher in HD patients (65% of HD patients with > or = 3 doses, 19% of PD patients with three or more doses, p<0.001). TS was similar in both groups, while ferritin was higher in HD patients, with a higher percentage of HD patients using intravenous (i.v.) iron (HD 77% vs. PD 49%, p=0.001). Serum albumin and iPTH were lower in PD patients (p<0.001 and p=0.04, respectively), but the percentage of patients with intact parathyroid hormone (iPTH) >500 pg/mL was similar in both groups (HD 17%, PD 14%). CONCLUSIONS: With the same administration route, PD patients showed a reduced EPO requirement, and less frequent EPO administration than HD patients, to obtain the same Hb level. No other factors, except those involved in better depuration of erythropoiesis inhibitors in PD, seemed responsible for the different EPO requirements.     

Measurement of des-gamma-carboxy prothrombin levels in hemodialysis patients positive for anti-hepatitis virus C antibody

BACKGROUND: The prevalence of anti-hepatitis virus C (HCV) antibody is much higher in hemodialysis (HD) patients than in the normal population. Recently, blood des-gamma-carboxy prothrombin (PIVKA-II) has been demonstrated as a sensitive marker for the early detection of hepatocellular carcinoma (HCC). In this study, we measured blood PIVKA-II in HD patients positive for anti-HCV antibody or hepatitis B virus surface (HBs) antigen to examine if HD therapy may affect the measurement of PIVKA-II. PATIENTS AND METHODS: Ninety-four stable HD patients who had anti-HCV antibodies (n = 86) or HBs antigen (n = 8) without any evidence of HCC were enrolled in the study (age: 60 +/- 11 years, duration of HD: 17 +/- 10 years, male/female = 63/31). Five patients had liver cirrhosis and another 5 patients received warfarin treatment. We simultaneously measured serum PIVKA-II and alpha-fetoprotein (AFP), and compared the association between these markers and HCV RNA titer and laboratory parameters. RESULTS: Serum PIVKA-II became positive (> or = 40 mAU/ml) in only 5.6% (5/89) of patients without warfarin administration, ranging from 47 to 71 mAU/ml. Seventy out of 89 patients (78.7%) were below 20 mAU/ml. Serum PIVKA-II did not correlate with biochemical parameters including HCV RNA, while serum AFP was significantly correlated with serum AST (r = 0.21, p < 0.05), gamma-GTP (r = 0.21, p < 0.01) and platelet counts (r = -0.29, p < 0.01), respectively. In contrast, 5 patients receiving warfarin had an extremely high PIVKA-II value ranging from 1,930 to 19,900 mAU/ml. PIVKA-II was significantly and inversely correlated with the thrombotest value (r = -0.72, p = 0.01). CONCLUSION: The positivity of blood PIVKA-II in HD patients with hepatitis viremia was identical to that in patients without renal failure. Warfarin treatment dramatically increased serum PIVKA-II more than 1,000 mAU/ml. These findings suggested that HD treatment itself did not affect the measurement of PIVKA-II, but vitamin K deficiency can readily influence the PIVKA-II level in dialysis patients.     

Infection of hepatitis C virus in patients with chronic renal failure undergoing hemodialysis therapy and staff members]

The prevalence of antibody to hepatitis C virus (anti-HCV) was determined in 564 patients and 145 staff members of nine hemodialysis (HD) units in Nagano Prefecture using an enzyme-linked immunosorbent assay based on the C 100 HCV antigen (the first generation anti-HCV assay). And also serum HBV markers were tested in these subjects. One hundred patients (18%) were anti-C100 HCV positive, indicating that this figure represents a much higher prevalence than that (0.9%) among general population in the same geographical area. Out of 141 patients without history of blood transfusion, 17 (12%) were positive for anti-C 100 HCV, suggesting that blood-transfusions-unrelated acquisition of HCV infection can occur. Anti-HCV prevalence correlated with both the blood units transfused and the duration of HD treatment. There was a significant difference in the prevalence of anti-C 100 HCV in individual dialysis units ranging from 0% to 53%. In the dialysis unit with prevalence of 53%, approximately half of the anti-HCV positive patients were found to have chronic liver disease. The prevalence of hepatitis B virus (HBV) markers among HD patients, on the other hand, was 36% (202/564). Fifty one (51%) of 100 anti-C 100 HCV positive patients and 151 (33%) of 464 anti-C 100 HCV negative patients were positive for HBV markers, with significant difference in HBV infection rate between the 2 groups. The prevalence of chronic liver disease, defined as abnormal serum transaminase levels for more than 6 months was significantly higher in anti-HCV positive patients than in anti-HCV negative ones (39% vs 10%, p less than 0.05), suggesting that HCV infection may contribute to chronic liver disease in HD patients. Among 145 staff members, only 3 (2%) were positive for anti-HCV, whereas 25 (17%) were positive for hepatitis B core antibody (anti-HBc), indicating prior HBV infection. With applying the second generation anti-HCV assay, which can detect antibodies to both capsid and nonstructural products of HCV gene, anti-HCV prevalence increased by two times in HD patients, but didn't change in HD staff members.(ABSTRACT TRUNCATED AT 400 WORDS)     

The influence of hepatitis C and iron replacement therapy on plasma pentosidine levels in haemodialysis patients.

BACKGROUND: Chronic liver disease and intravenous (i.v.) iron therapy can enhance oxidative stress. The aim of this study was to assess the influence of hepatitis C virus (HCV) and i.v. iron administration on oxidative stress in chronic haemodialysis (HD) patients. METHODS: A total of 115 HD patients (47% males, age 47 +/- 13 years) were placed in two groups according to the presence (HCV(+)) or absence (HCV(-)) of serum antibodies against HCV. Plasma pentosidine, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and alanine aminotransferase (ALT) levels were measured. The patients were also analysed according to the tertiles of serum levels of ferritin: group 1 (ferritin <380 ng/ml), group 2 (ferritin 380-750 ng/ml) and group 3 (ferritin >750 ng/ml). The cumulative iron dose was recorded during 6 months prior to the study. RESULTS: HCV(+) patients had significantly higher levels of plasma pentosidine and ALT than HCV(-) patients. Age, gender, serum albumin, IL-6 and hsCRP did not differ according to HCV serology. The levels of pentosidine were related to the ferritin levels and were significantly higher in group 3 compared with group 1. Moreover, the cumulative dose of iron was significantly higher in group 3 than in group 1. Plasma pentosidine showed a positive correlation with age, HCV and ferritin. In a stepwise backward multiple regression model, age and HCV were independent predictors of pentosidine levels. CONCLUSION: HCV in HD patients is associated with increased pentosidine levels, possibly reflecting increased oxidative stress. The association between pentosidine and ferritin levels may suggest an impact of i.v. iron therapy.     

Ultrapure dialysate improves iron utilization and erythropoietin response in chronic hemodialysis patients - a prospective cross-over study

BACKGROUND: The impact of ultrapure dialysis on dialysate-related chronic inflammatory status and anemia in uremic patients on maintenance hemodialysis (HD) remains uncertain. We evaluated ultrapure dialysate effects on erythropoietin (EPO) response and inflammatory status in a prospective, randomized, cross-over study. METHODS: Thirty-four HD patients were divided into two groups. One group was treated with conventional dialysate and the other group with ultrapure dialysate for 6 months and crossed over for another 6 months. Bacteria growth and dialysate endotoxin were examined. Parameters including C-reactive protein (CRP), recombinant human erythropoietin (rHuEPO) dose, ferritin, iron saturation and serum albumin were measured at the start, and at 6 and 12 months. RESULTS: The endotoxin levels reduced significantly in the ultrapure dialysate by adding a dialysate ultrafilter. After a 6-month treatment with ultrapure dialysate, there were statistically significant differences in the systemic inflammation markers between both groups. Changing from conventional to ultrapure dialysis fluid significantly reduced CRP (7.01 +/- 5.059 to 4.461 +/- 3.754 mg/L, p<0.05), and resulted in reduced rHuEPO doses (12500 +/- 7060 to 10440 +/- 7050 U/month, p<0.05). Continuous conventional dialysate use was not associated with significant alternations in CRP (from 5.849 +/- 7.744 to 6.187 +/- 7.997 mg/L, p=0.456) and rHuEPO dose (14060 +/- 6210 to 15060 +/- 7250U/month, p>0.05). The ferritin level reduced significantly (422 +/- 183 to 272 +/- 162 mcg/L, p<0.05) in the ultrapure dialysate group. After another 6-month cross-over, the study parameters were reversed among the two groups indicating the beneficial effect of ultrapure dialysis. CONCLUSIONS: Through endotoxin reduction in conventional dialysate, ultrapure dialysis in dialysis patients manifested a reduced inflammatory parameter, reduced rHuEPO dose and improved iron utilization; and therefore, could be beneficial in anemia treatment.     

Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients.

BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.     

Oxidative stress markers in hepatitis C infected hemodialysis patients

BACKGROUND: Oxidative stress in hemodialysis (HD) patients or hepatitis C virus (HCV) infections may be related to increased production of free radicals. We assessed the effect of HCV infection on the oxidative stress markers, malondialdehyde (as TBARS), protein carbonyl content and protein sulfhydryl groups, in chronic HD patients. METHODS: Twenty HCV infected patients (9 men and 11 women, age 44.8 +/- 14.3 years) and 10 non-HCV infected patients (6 men and 4 women, age 55.6 +/- 14.3 years) receiving regular HD were recruited. The average hemodialysis duration was 30 +/- 8 months for HCV (+) patients and 14 +/- 8 months for HCV (-) patients. Controls consisted of healthy subjects. RESULTS: Serum TBARS and carbonyl content were significantly elevated in HCV(-) patients (p<0.001, p<0.05) and in HCV(+) patients (p<0.001, p<0.001) vs. Controls. There was also a significant difference in serum TBARS and carbonyl content between HCV(-) patients and HCV(+) patients (p<0.001, p<0.05). Serum protein sulfhydryl groups in HCV(-) and HCV(+) patients were the same, but significantly lower than in Controls (p<0.001, p<0.001). When HCV(+) patients were divided into two sub-groups, one with shorter (13.4 +/- 8 months; n=7) and the other with longer (40.3 +/- 8 months; n=13) duration of HD treatment, no differences were found between subgroups. CONCLUSION: HCV infection may aggravate oxidative stress in HD patients.     

Effectiveness of erythropoiesis on supervised intradialytic oral iron and vitamin C therapy is correlated with Kt/V and patient weight

BACKGROUND: Poor compliance to oral medication and diet is common in hemodialysis (HD) patients and limits the ability of oral iron therapy to support erythropoiesis. Intravenous (i.v.) iron may be associated with undesirable and sometimes life-threatening complications. PATIENTS AND METHODS: We hypothesized that intradialytic oral iron therapy can overcome compliance problems and support effective maintenance erythropoiesis, which will keep Hct in the range of 33% to 36% and EPO requirements up to 50 units/week/kg. In a prospective observational study, SC EPO-treated hospital-based HD patients without conditions known to cause EPO resistance, were managed on intradialytic oral administration of iron and vitamin C. The primary endpoints were EPO requirements and resistance to EPO which standardized EPO requirements by the Hct level. Secondary endpoints included parameters that might affect the primary endpoints. Exclusion criteria were refusal to take oral medication, prestudy Hct < 27%, recent i.v. iron therapy or transfusions, bleeding, clinical conditions obligating Hct > 30% and known causes of EPO resistance. Twelve patients completed minimal follow-up period of 9 months. RESULTS: Mean Hct was 34.4% (range: 31.8% - 40.2%). EPO requirements were 61.7 +/- 28.2 units/kg and below 52.5 units/kg in 50% of patients. Patients were classified into equal groups according to resistance to EPO, which was positively correlated (r = 0.71 p < 0.01) with body weight and Kt/V (r = -0.38, p < 0.05). CONCLUSION: In conclusion, intradialytic oral iron therapy can support effective maintenance erythropoiesis in 50% of patients without known causes for EPO resistance. High response to EPO and low EPO requirement are correlated with lower body weight and possibly improved dialysis.     

Recombinant human erythropoietin independence in chronic hemodialysis patients: clinical features, iron homeostasis and erythropoiesis

AIMS: Recombinant human erythropoietin (r-HuEPO) is widely used to correct renal anemia in uremic patients. Interestingly, some chronic hemodialysis (HD) patients can maintain high hemoglobin level without the need of r-HuEPO. The aim of this study is to investigate clinical features, iron metabolism and erythropoiesis of these r-HuEPO-independent HD patients. METHODS: r-HuEPO independence was defined in dialysis patients as hemoglobin greater than 12 g/dl and no use of r-HuEPO for at least 6 months. An age- and sex-matched group was selected for comparison. Their underlying diseases, duration of hemodialysis therapy, efficacy of dialysis (Kt/V), normalized protein catabolic rate (nPCR) and body mass index (BMI) were recorded. Laboratory data including: hemoglobin, albumin, high sensitivity C-reactive protein, serum iron, total iron binding capacity, transferrin saturation, ferritin, intact parathyroid hormone, soluble transferrin receptor (sTfR), serum EPO, cortisol, testosterone, aluminum and leptin levels were measured. Renal sonography was also performed in each patient to evaluate renal cyst formation. RESULTS: About 2.3% of all HD patients (21/888; M : F = 18 : 3) were r-HuEPO-independent. These patients had significantly longer HD duration and higher serum EPO and sTfR levels, and lower transferrin saturation rate than dependent groups. Correlation analysis revealed that hemoglobin level strongly correlated with HD duration, serum sTfR and EPO levels. Levels of sTfR were positively related with serum EPO levels and BMI. Multivariate regression analysis showed that level of sTfR was the only independent factor related to r-HuEPO independence. CONCLUSION: R-HuEPO independence is rare among chronic hemodialysis patients. Factors contributing to this dependence are complex and multiple. Level of serum sTfR parallels erythropoiesis and is the most significant factor associated with r-HuEPO independence in chronic HD patients.     

Impact of anti-hepatitis C virus (HCV) antibody on outcomes in renal transplant recipients infected with HCV

OBJECTIVE: Hepatitis C virus (HCV) infection remains an important risk factor for mortality and morbidity in transplant recipients. In this study, we retrospectively analyzed the impact of pretransplantation hepatitis C antibody status in HCV-infected renal allograft recipients on graft and patient survivals. PATIENTS AND METHODS: From February 1998 to August 2007, 933 renal transplantations were performed at our center. Of these, 104 patients were identified to be harboring HCV infection: 59 (group I) were anti-HCV positive prior to transplantation and 45 (group II) were HCV RNA/antibody positive in the posttransplantation period. The patients transplanted in different eras received different immunosuppressive regimens. Complete follow-up data were available for 72.3% (43/59) in group I and 80% (36/45) in group II. Both groups had a similar number of patients on cyclosporine (62.8% vs 61.1%), tacrolimus (37.2% vs 38.8%), and mycophenolate mofetil (MMF; 58.1% vs 61.1%). These patients were analyzed for differences in patient and graft survivals by log-rank test. RESULTS: The overall mean ages were 35.1 +/- 10.4 and 32.4 +/- 10.4 years, male to female ratios 37:6 and 31:5, mean donor ages 41.5 +/- 10.9 and 41.2 +/- 13.1 years, and mean follow-up durations 29.4 +/- 24 (range, 1-107.7) and 32.6 +/- 24.2 (range, 3.1-97.2) months in groups I and II, respectively. The patients in group I had received a significantly greater number of blood transfusions compared with patients in group II (6.2 +/- 5.7 vs 2.1 +/- 2.9) and a significantly greater number of dialysis treatments prior to transplantation (84.5 +/- 62.0 vs 33.8 +/- 43.2), respectively. Liver function tests-SGOT (22.6 +/- 16.1 vs 18.3 +/- 12.1 IU/L) and SGPT (24.2 +/- 28.9 vs 20.4 +/- 20.2 IU/L)-were similar in the 2 groups in the pretransplantation period, respectively. The patient and graft survivals at 5 years were similar: 88.6% vs 82.3% (P = .81) and 60.1% vs 62.5% (P = .75) in groups I and II, respectively. The serum creatinine values at last follow-up were 1.38 +/- 0.6 vs 1.7 +/- 2.4 mg% (P = not significant), SGOT 33.4 +/- 25.6 vs 38.3 +/- 47 IU/L, and SGPT 39.3 +/- 46.7 vs 59.2 +/- 89 IU/L in groups I and II, respectively. Liver decompensation occurred in 4 patients, 2 in each group at a mean duration of 36.5 months. CONCLUSION: Absence of HCV antibody does not confer any survival disadvantage in HCV-infected renal allograft recipients undergoing renal transplantation.     

Pharmacokinetics and pharmacodynamics of subcutaneous and intraperitoneal administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis

The single-dose pharmacokinetics of 50 U/kg body weight of recombinant human erythropoietin (rHuEPO) given by either the subcutaneous (s.c.) or the intraperitoneal (i.p.) route were studied in 20 anemic patients maintained on continuous ambulatory peritoneal dialysis. Their baseline hemoglobin levels were less than 9 g/dl. The absorption of rHuEPO via the i.p. route was limited. The serum erythropoietin (EPO) level was only slightly elevated from a baseline value of 27 +/- 3 mU/l to a plateau of 36 +/- 4 mU/l at 12-24 hours. In comparison, after s.c. injection, a peak EPO level of 81 +/- 13 mU/l was obtained after 24 hours. The areas under the concentration-time curve from 0-24 hour were 803 +/- 67 and 1492 +/- 165 mU/l.h for the i.p. and s.c. group respectively (p less than 0.003). The same two groups of patients were then given rHuEPO by either the s.c. or the i.p. route over a period of 16 weeks. In the s.c. group, the hemoglobin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl (p less than 0.004). The mean rHuEPO dosage was 84 +/- 9 U/kg body wt/week. In the i.p. group, despite relatively higher rHuEPO dosage (133 +/- 7 u/kg body wt/week), the hemoglobin level did not increase significantly (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p = 0.09). Subcutaneous administration of rHuEPO is effective and convenient for patients maintained on continuous ambulatory peritoneal dialysis.