The Effect of Erythropoietin Therapy and Hemoglobin Levels on the Immune Response to Engerix-B Vaccination in Chronic Kidney Disease

Background.?Patients undergoing chronic hemodialysis have an increased risk of acquiring hepatitis B infection. Only 43–66% of dialysis patients develop effective anti-HBs titers after vaccination. Aim.?To evaluate the effect of recombinant erythropoietin (rEPO) therapy and basal hemoglobin levels on the outcome of the immune response to four doses of IM 40 µg Engerix-B vaccination in hemodialysis and chronic kidney disease (CKD) patients before starting replacement therapy. Subjects and methods.?One hundred and three patients were included in the study: 34 hemodialysis patients treated with rEPO (Group A), 36 predialytic patients who did not treated with rEPO (Group B) and 33 predialytic patients treated with rEPO (Group C). Plasma creatinine in predialytic patients was 2–7 mg/dL. All patients' HBsAg and anti-HBs antibodies were negative. Patients were immunized with IM 40 µg Engerix-B at 0, 1, 3, and 6 months. Anti-HBs titers were measured at 7th month. Results.?Eighty seven point one percent of patients from group C developed protective anti-HBs titers compared with 69.4% from group B and 44.1% from group A (p = 0.001). Patients from all groups with baseline hemoglobin levels above 11 gr/dL developed protective anti-HBs titers significantly more than patients with baseline hemoglobin levels below 11 gr/dL (p<0.05). Conclusion.?Predialytic patients treated with rEPO and with hemoglobin levels higher than 11 gr/dL had significantly better immune response outcomes to Engerix-B vaccination. Immunization against hepatitis B infection should be considered at early stages of CKD prior to the deterioration in kidney functions and the development of renal anemia.     

Hepatitis B vaccination in human immunodeficiency virus-infected adults receiving hemodialysis

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends hepatitis B virus (HBV) immunization for all hemodialysis (HD) patients because they are at high risk of infection. Several studies have shown that the development of protective antibody titers after HBV vaccination is much lower in HD patients. We hypothesized that human immunodeficiency virus (HIV) infection in patients with end-stage renal disease (ESRD) would further impair the immune response to hepatitis B vaccination. METHODS: We performed a retrospective cohort study of patients undergoing long-term hemodialysis from 1990 to 2002 at the United States-based dialysis facilities of Gambro Corporation, North America. The response rate defined as an increase in anti-HBs levels >/=10 mIU/L after a month of the third dose of HBV vaccination was determined in HIV-infected and a randomly selected group of ESRD patients. The demographic information, laboratory data, and hepatitis B surface antibody (anti-HBs) titers were recorded from the Gambro Corporation database on these patients. RESULTS: Of the 347 adult HIV ESRD patients, 116 received three doses of recombinant hepatitis B vaccination. Seventy percent were male, and the majority (86%) were black. Of the 116 patients who received three doses of HBV vaccination, 62 (53.4%) developed protective antibody titers. This was comparable to the response rate of 50.4% in the randomly selected 220 non-HIV hemodialysis patients. Among HIV ESRD patients, the mean hemoglobin (Hgb) was higher in patients who developed protective antibody titers (Hgb 11.61 +/- 2 vs. 10.55 +/- 1.86, P value <0.01). On multivariate logistic regression analysis, higher Hgb was associated with protective antibody titers (odds ratio: 1.34, 95% CI 0.99-1.72). Seventy percent of the HIV-infected responders maintained protective antibody titers 6 months after vaccination. CONCLUSION: Hepatitis B vaccination should be offered to all HIV-infected ESRD patients because over half of the patients with HIV and ESRD can develop protective antibodies.     

Loss of hepatitis B immunity in hemodialysis patients acquired either naturally or after vaccination

AIM: The aim of our study was the long-term evolution of hepatitis B immunity and the titers of antibodies against the surface antigen (anti-HBs) acquired either naturally or after vaccination in hemodialysis (HD) patients with no history of hepatitis C virus (HCV) infection. METHODS: 36 HD patients were vaccinated with 4 doses of 40 microg recombinant B vaccine (Engerix, Rixensart, Belgium), intramuscularly at 0, 1, 2 and 6 months. 21 patients (60%) seroconverted developing anti-HBs titers > or = 10 IU/ml. Two patients were transferred to another unit before completion of 6 months after the last vaccine dose. We followed-up 19 HD patients who were immune against HBV after vaccination (Group A), and 30 immune patients (anti-HBs titers > or = 10 IU/ml) who had never been vaccinated and had antibodies against the core antigen (anti-HBc), diagnostic of natural HBV infection (Group B). In all patients of Groups A and B, anti-HBs were determined every 6 months, starting 6 months after the last dose in the vaccinated patients. Follow-up period lasted from October 2002 - April 2006. RESULTS: The mean follow-up in Group A was 21 +/- 12 months (range 6 - 36) and in Group B 29 +/- 12 months (range 6 - 42). Age, sex, presence of diabetes mellitus and duration of dialysis did not differ between the two groups. Five patients in Group A (26%) and 2 patients in Group B (9%) lost immunity (anti-HBs < 10 IU/ml) (p = 0.07). The median time to loss of immunity in Group A patients was 12 months (interquartile range 6 - 18 months), while in Group B patients it was 15 months (interquartile range 12 - 18 months). No booster dose was administered during the study. The 2 patients of Group B who lost immunity were the oldest of the group and redeveloped anti-HBs 6 and 12 months after they had lost it. During the first 6 months of the follow-up period, Group A had significantly higher anti-HBs titers than Group B (p < 0.05). However, this difference was lost later on, and after the first year of follow-up, anti-HBs titers were decreased significantly in Group A (p < 0.05), but remained unchanged in Group B throughout the follow-up period. CONCLUSIONS: In conclusion, HD patients lost hepatitis B immunity both after natural infection or vaccination, but naturally infected patients easily redeveloped protective anti-HBs titers. Anti-HBs titers decreased faster in vaccinated patients than in those with natural acquired immunity who held stable titers for a longer period. It is suggested that HD patients should be followed-up regularly for loss of HBV immunity after vaccination and receive a boosting dose when this occurs. In contrast, patients who acquired natural immunity do not need any anamnestic vaccination.     

Comparative immunogenicity of 2 recombinant hepatitis B vaccines (GeneVac-B and Engerix-B) in adult patients with chronic renal failure

BACKGROUND: Hepatitis B virus infection is often fatal or results in a carrier state with uremia. Vaccination protects against infection, but immune response may remain low. We aimed to study immune responses to 2 recombinant hepatitis B vaccines (Engerix-B and GeneVac-B) in patients with end-stage chronic renal failure. METHODS: Patients initially negative for hepatitis B (HB) surface antigen (HBsAg), and with core antibody (anti-HBc) and nonprotective anti-HBs titers (<100 mIU/mL) were selected. Four doses of 40 microng of either vaccine were administered intramuscularly, further doses being given 1, 2 and 6 months after the first dose. Seroconversion and seroprotection were defined as anti-HBs level above 10 mIU/mL and 100 mIU/mL, respectively. RESULTS: A total of 11 and 9 subjects receiving GeneVac-B and Engerix-B, respectively, completed the protocol. Seroconversion was achieved in 100% for both vaccines. Seroprotection occurred in 78% and 82% of the Engerix-B and the GeneVac-B recipients, respectively. Geometric mean titers 1 month after the fourth dose were 274 mIU/mL (95% confidence interval [95% CI], 71-1,057 mIU/mL) and 322 mIU/mL (95% CI, 142-730 mIU/mL), respectively. CONCLUSIONS: Both vaccines are highly immunogenic in renal failure and did not show significant differences between each other.     

Levamisole treatment enhances protective antibody response to hepatitis B vaccination in hemodialysis patients

Hemodialysis shows a high risk for hepatitis B infection, and hepatitis B virus (HBV) vaccination has now become a routine procedure. Unfortunately, 40% to 50% of hemodialysis patients do not have adequate protective antibodies against the HBV vaccination which is thought to be due to depressed cell mediated immunity. Levamisole has been reported to stimulate depressed T-cell activity and enhance B lymphocyte function and restore delayed hypersensitivity reactions in immune-depressed patients. We studied the effects of levamisole, an immunomodulatory agent, on the protective antibody response of hemodialysis patients to the HBV vaccination. Our hemodialysis patients with negative anti-HBs antibody routinely received 40 microg doses of recombinant HBV vaccine intramuscularly at 0, 1, and 6 months, and we followed serum anti-HBs levels. Patients with a serum antibody level of >10 mIU/ml were considered as responders. Study groups were classified as follows. Group 1 was comprised of 96 chronic hemodialysis patients with negative anti-HBs and HBV core antibody (52 male, 44 female, mean age of 45 +/- 15 years and mean hemodialysis duration of 46 +/- 40 months) who received HBV vaccination; 55 patients (57%) were found to be responders. Group 2 was comprised of 19 randomly selected patients who had never received hepatitis B vaccine (13 male, 6 female, mean age of 42 +/- 14 years, mean duration of hemodialysis 31 +/- 27 months) and who were started on an HBV vaccination protocol with levamisole per os 80 mg after each hemodialysis session for 4 months and followed up on serum anti-HBs levels. Seventeen of the patients completed this levamisole treatment. Fourteen of the 17 patients had the levels of the protective serum antibody indicating a higher response rate when compared with patients who did not receive levamisole (82% versus 57%, respectively, p < 0.05). Group 3 was comprised of 19 patients randomly selected from persons who did not respond to previous vaccination programs (10 male, 9 female, mean age of 51 +/- 14 years, mean duration of hemodialysis 41 +/- 31 months). A second HBV vaccination program was started with the same levamisole protocol. In this group, 18 patients completed this treatment model. Fourteen of them responded to the vaccination model. In Group 4, a second HBV vaccination program was applied without levamisole to 20 randomly selected persons who did not respond to the previous routine vaccination program (12 male, 8 female, mean age of 53 +/- 17 years, mean duration of dialysis 51 +/- 38 months). Only 3 of them responded to a second vaccination program. Comparing Group 3 with Group 4, there was a higher responder rate to HBV vaccination (77% versus 15%, respectively, p < 0.0001). These results show that levamisole treatment increases the response rate to the first HBV vaccination and of the previously unresponsive cases by modulating possible cellular immune response.     

Comparison of Intramuscular and Intradermal Applications of Hepatitis B Vaccine in Hemodialysis Patients

This study compared the application of intramuscular recombinant hepatitis B vaccine in hemodialysis patients with the application of accelerated intradermal recombinant hepatitis B vaccine, which can be applied with one-tenth of the standard dose. Sixty seronegative patients for hepatitis B were randomly separated into two groups. Twenty μg of the recombinant hepatitis B vaccine was intramuscularly applied at 0-, 1-, 2-, and 6-month intervals to the first group (32 cases). One more dose was applied at month 12 to those whose anti-HBs titers remained below 100 mIU/mL at month 7. The same vaccine was intradermally applied at 2μg dose six times with one-month intervals to the second group (28 cases). Vaccine applications were continued in those whose anti-HBs titers remained below 100 mIU/mL at month 7 until antibody titers reached above this value or until the dose number became 12. Measurements of antibody titers were repeated at month 13 in both groups. As a result, in the vaccination of hemodialysis patients against hepatitis B, the accelerated ID application of hepatitis B vaccine with a dose reduced to one-tenth is more cost-effective than the standard dose vaccination schedules. Especially for hemodialysis patients, the time has come for routine application of ID hepatitis B vaccine as an alternative vaccination method.     

Comparison of intramuscular and intradermal applications of hepatitis B vaccine in hemodialysis patients

This study compared the application of intramuscular recombinant hepatitis B vaccine in hemodialysis patients with the application of accelerated intradermal recombinant hepatitis B vaccine, which can be applied with one-tenth of the standard dose. Sixty seronegative patients for hepatitis B were randomly separated into two groups. Twenty mug of the recombinant hepatitis B vaccine was intramuscularly applied at 0-, 1-, 2-, and 6-month intervals to the first group (32 cases). One more dose was applied at month 12 to those whose anti-HBs titers remained below 100 mIU/mL at month 7. The same vaccine was intradermally applied at 2 microg dose six times with one-month intervals to the second group (28 cases). Vaccine applications were continued in those whose anti-HBs titers remained below 100 mIU/mL at month 7 until antibody titers reached above this value or until the dose number became 12. Measurements of antibody titers were repeated at month 13 in both groups. As a result, in the vaccination of hemodialysis patients against hepatitis B, the accelerated ID application of hepatitis B vaccine with a dose reduced to one-tenth is more cost-effective than the standard dose vaccination schedules. Especially for hemodialysis patients, the time has come for routine application of ID hepatitis B vaccine as an alternative vaccination method.     

The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients

BACKGROUND: The introduction of recombinant human erythropoietin for the treatment of anemia of chronic renal failure provided the opportunity to correct anemia in this patient population. The optimal target hemoglobin for patients with end-stage renal disease (ESRD) remains controversial. A large database of hemodialysis patients was analyzed to determine whether increasing hemoglobin level above the current Kidney Dialysis Outcomes Quality Initiative (K/DOQI) recommendations was associated with increased risk of mortality and hospitalization. METHODS: A longitudinal study of hemodialysis patients in Fresenius Medical Care-North America facilities was performed. Selection was restricted to patients in the census for 6 consecutive months from July 1, 1998 through June 30, 2000. Patient mean hemoglobin and other covariates measured during the initial 6 months were related to survival, number of hospitalizations, and length of stay over the subsequent 6 months of follow-up. RESULTS: Patients with hemoglobin <9 g/dL had an adjusted relative risk of death of 2.11 compared to those patients with 11 /=13 g/dL had an adjusted length of stay of 9.6 days compared to 10.9 days for those with 11 12 g/dL.     

Low response to HBsAg vaccine in chronic renal failure patients is not due to intrinsic defect of B cells

OBJECTIVE: The aim of this study was to investigate whether the inability of chronic renal failure patients to mount an adequate antibody response following hepatitis B vaccination was due to an inherent defect in the antibody producing capacity of their B cells. MATERIAL AND METHODS: Peripheral blood mononuclear cells of end stage renal disease (ESRD) patients, who were not on maintenance hemodialysis (CRF) and those undergoing long-term hemodialysis (HD) were stimulated in vitro with pokeweed mitogen, a B cell mitogen or hepatitis B surface antigen. The total immunoglobulin (IgG, IgM and IgA) levels and anti-HBs specific IgM and IgG were quantitiated by sandwich ELISA and levels between patients who had a good antibody response in vivo and those who failed to mount an antibody response were compared. RESULTS: Spontaneous IgG production was significantly higher than normals in CRF and HD group; PWM induced IgM, IgG and IgA production was comparable to normals in both groups of patients. The spontaneous IgG and PWM stimulated IgM and IgG production was significantly higher in HD patients as compared to CRF. The in vitro Ig levels in the vaccine responders and non-responders was comparable except for the spontaneous IgG which was highest in the responders. The in vitro anti-HBs production was comparable in HB vaccine responders and non-responders; the in vivo and in vitro anti-HBs titers showed a significant correlation coefficient thereby indicating that the in vitro assay reflects the in vivo functional status of B cells. CONCLUSION: Our results demonstrate that the B cells in ESRD patients are functionally normal and cannot be the cause of the compromised vaccine response in these patients.     

Immune response after vaccination with recombinant hepatitis surface antigen in maintenance hemodialysis patients and healthy controls.

We evaluated anti-HBs titers 2 months after vaccination with recombinant hepatitis surface antigen (rDNA-HBsAg) in 43 maintenance hemodialysis patients (MHP). Of these, 34 had not undergone hepatitis B virus vaccination previously (NV-MHP) and 9 had shown negative response to vaccination with plasma-derived HBsAg (HEVAC Pasteur; V-MHP). 120 healthy workers from the same hospital undergoing rDNA-HBsAg immunization were used as controls. All low responders (LR) (anti-HBs less than 100 mIU/ml) and nonresponders (NR; anti-HBs less than 10 mIU/ml) were given a booster dose 3 months after the last dose of vaccine. Seroconversion rates were lower in NV-MHP (52.9%) than in controls (98.4%). V-MHP showed higher seroconversion rates (88.9%) than NV-MHP. In each group, the number of responders (R; anti-HBs greater than or equal to 100 mIU/ml), LR and NR was as follows: controls 101, 17, 2; NV-MHP 6, 12, 16; V-MHP 8, 0, 1. After booster dose, 17/17 controls LR and no NV-MHP LR showed a rise in anti-HBs titers over 100 mIU/ml. Six months after the last dose of vaccine or the booster dose, anti-HBs titer fell under 10 mIU/ml in 4/12 MHP LR and under 100 mIU/ml in 6/14 MHP R. To achieve high seroconversion rates and to avoid the decline of anti-HBs to nonprotective titers in MHP, a booster injection should be made at different dates after the first vaccination.     

Prevalence of anemia in erythropoietin-treated pediatric as compared to adult chronic dialysis patients

BACKGROUND: Recent guidelines recommend a target hemoglobin range of 11 to 12 g/dL in pediatric and adult dialysis patients. We compared anemia prevalence in United States Medicare pediatric and adult dialysis patients. METHODS: Prevalent hemodialysis patients (0 to 19 years, pediatric: N= 1692; adult: N= 352,291) and peritoneal dialysis patients (pediatric: N= 597; adult: N= 39,136) treated with recombinant human erythropoietin (rHuEPO) from 1996 to 2000 were selected. Mean annual hemoglobin values were calculated by modality, age, sex, and race. RESULTS: Among hemodialysis patients, mean annual hemoglobin values less than 11 g/dL were present in pediatric and adult patients during 54.1% versus 39.8% patient years, respectively (P < 0.0001); for peritoneal dialysis patients, 69.5% versus 55.1% (P < 0.0001). Mean hemoglobin values increased over time and were 11.2, 11.5, 10.8, and 11.2 g/dL for pediatric and adult hemodialysis and peritoneal dialysis patients, respectively, in 2000. Pediatric hemodialysis patients received intravenous iron less frequently than adults (66.3% vs. 82.5% patient years; P < 0.0001). CONCLUSION: Hemoglobin values in rHuEPO-treated pediatric dialysis patients lagged behind those of adult patients, with pediatric patients achieving target hemoglobin values only a minority of the time (45.9% and 30.5% patient years, respectively, for hemodialysis and peritoneal dialysis). Trends show recent improvement in anemia treatment of children on dialysis. Still, further attention to and analysis of rHuEPO and iron therapy in pediatric dialysis patients is warranted.     

Long-term immunogenicity and efficacy of hepatitis B vaccine in hemodialysis patients.

Although the efficacy of hepatitis B vaccines in patients under chronic hemodialysis treatment has been well documented, the persistence of immunity in this population remains largely unknown. In this study we have followed 60 hemodialysis patients up to 3 years after primary hepatitis B vaccination (four doses of recombinant hepatitis B vaccine; Engerix B, 20 mg/dose) to evaluate the persistence of immunity (as indicated by serum levels of antibody to hepatitis B surface antigen-anti-HBs-higher than or equal to 10 mIU/ml). Fourty-four (73%) patients developed anti-HBs levels above 10 mIU/ml after vaccination; the remaining 16 (27%) vaccinees were considered nonresponders and were given a booster dose that again failed to elicit an immunoresponse. After 3 years of follow-up, 18 out of 44 (41%) responders had no detectable anti-HBs levels in the serum (antibody loss occurring within 8 and 12 months in 3 cases, within 1 and 2 years in 13, and within 2 and 3 years in 2 other cases). When compared with the responders that lost their antibodies during the follow-up period, those who remained immunoreactive 3 years after vaccination was initiated were younger and had higher anti-HBs levels at 8 months of follow-up. Two hepatitis B virus infections were detected among nonresponders during the follow-up period. Based on these data, we conclude that patients undergoing chronic hemodialysis therapy not only have lower response rates to hepatitis B vaccination than healthy adults, but also that these are frequently transient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Occult hepatitis B virus infection in hemodialysis patients with chronic HCV infection

BACKGROUND: The aim of this study was to determine the prevalence of occult hepatitis B infection in hemodialysis patients with chronic HCV infection and to compare it with that of HCV-infected patients with normal renal function. METHODS: Forty-nine patients on maintenance hemodialysis and 48 HCV-infected but otherwise normal patients, both groups HCV RNA-positive and HBsAg-negative and matched for age and sex, were evaluated for the presence of HBV DNA in serum by polymerase chain reaction (PCR). A proportion of patients (11/49 and 39/48, respectively) were also examined for HBV antigens in hepatocytes by immunohistochemistry. RESULTS: HBV DNA was detected by PCR in 10/49 (20.4%) hemodialysis patients and in 3/48 (6.3%) patients with normal renal function (p=0.041). HBV DNA concentrations were low (<10 3 copies/mL) in both groups. HBV DNA-positive hemodialysis patients had a significantly lower prevalence of past HBV vaccination and lower anti-HBs titers in serum than HBV DNA-negative patients of the same group. No positive staining for HBsAg or HbcAg was observed in the liver biopsies of either group. CONCLUSIONS: Occult HBV infection is more frequent in HCV-infected hemodialysis patients than otherwise normal patients with chronic HCV infection, probably because of impaired immune function in uremic patients and high risk of parenteral exposure to HBV. The clinical significance of this finding is unknown, but HBV vaccination of hemodialysis patients and staff could be an effective way of limiting the risk of transmission of HBV infection within dialysis units.     

Efficacy of GM-CSF as an adjuvant to hepatitis B vaccination in patients with chronic renal failure--results of a prospective,randomized trial

BACKGROUND: Chronic renal failure patients on hemodialysis are at an increased risk of acquiring hepatitis B infection. Hence vaccination against hepatitis B assumes great importance in these patients. However, the response to hepatitis B vaccination is poor, even when 4 double doses (40 microg) of the vaccine are given. This study was conducted to determine the efficacy of GM-CSF as an adjuvant to hepatitis B vaccine in CRF patients. METHODS: CRF patients including both hemodialysis (HD) and non-dialysis (ND) patients were randomized to receive either placebo or a single injection of GM-CSF (in varying doses of 50 microg, 100 microg, 150 microg) a day prior to the 1st dose of recombinant hepatitis B vaccine (40 microg). Three more doses of the vaccine were given at 1, 2, and 6 months. The anti-HBs antibody titres were measured by ELISA at 3 and 7 months. Patients having antibody titres less than 10 IU/L were considered non-responders. The response rate and mean antibody titers were compared between the control (I) and GM-CSF (II) groups. RESULTS: In group I, 31 and 27 patients were available for evaluation at 3 and 7 months respectively. In group II, 33 and 28 patients could be evaluated at the same time points. Within the control group (group I), the response rate in hemodialysis patients (63.6%) was lower as compared to non-dialysis patients (81.2%). The response rate in group II was higher than that in group I at both 3 months as well as 7 months (78.1% vs. 62.3% and 89.3% vs. 74.1%, p = ns). The best response rates in group II were observed when GM-CSF was used in a dose of 150 microg (90.9% at 3 months and 100% at 7 months). The mean antibody titers were also found to be higher in the group II as compared to group I (409.6 vs. 243.9 IU/L, p = 0.01). CONCLUSION: The results of this randomized, prospective study suggest that: 1. Patients with chronic renal failure should be vaccinated for hepatitis B as chronic renal insufficiency is established. 2. GM-CSF is an effective adjuvant to hepatitis B vaccine in these patients especially when a priming dose of 150 microg is used prior to 1st dose of hepatitis B vaccination.     

Controlled trial of thymopentin in hemodialysis patients who fail to respond to hepatitis B vaccination

Uremic patients are at high risk of hepatitis B virus (HBV) infection and, despite the availability and efficacy of hepatitis B vaccine, a high rate of non responders has been reported. Forty uremic patients undergoing maintenance hemodialysis who failed to produce any measurable anti-HBs antibody response after 4 administrations of 5 micrograms of Hevac B Pasteur vaccine were admitted to a randomized controlled clinical trial. Group A (14 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals and 12 doses of 50 mg s.c. of thymopentin on alternate days between the first and the second vaccination. Group B (11 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals. Group C (15 patients) received 3 doses of 10 micrograms s.c. each of vaccine at monthly intervals. Immunization rates were 86% in group A (on both 1-month and 6-month checks), 36% on the 1-month and 27% on the 6-month check in group B, 53% on the 1-month and 47% on the 6-month check in group C. Anti-HBs antibody titers were similar in group A and C but notably lower in group B. Thymopentin seems as useful therapeutical tool for non responder patients. As it promotes T cell maturation and responsiveness, which are impaired in uremia, it could play a major part in the management of uremic immunodeficiency.     

Response to an experimental HBV vaccine permits withdrawal of HBIg prophylaxis in fulminant and selected chronic HBV-infected liver graft recipients.

Strategies using lamivudine and hepatitis B immunoglobulins (HBIg) for prevention of hepatitis B virus (HBV) reinfection after liver transplantation (LT) are expensive since life-long treatment is needed. We evaluated the possibility to obtain protective hepatitis B surface antigen (HBsAg) antibody (anti-HBs) titers after LT and to discontinue HBIg prophylaxis after a reinforced course of vaccination against HBV using an experimental adjuvant HBsAg / AS04 vaccine (GlaxoSmithKline Biologicals [GSK], Rixensart, Belgium) in patients transplanted for hepatitis B. Fifteen LT patients on stable low-level immunosuppression were vaccinated with a double dose of the vaccine at 0, 1, 2, 6, and 12 months: 5 patients were transplanted for nonviral diseases and 10 patients were transplanted for HBV on HBIg monotherapy. HBIg were continued during baseline vaccination (0, 1, and 2 months) and when anti-HBs titers determined every 6 weeks dropped below 150 IU/L. Overall follow-up was 18 months. Sustained long-term response to vaccination was defined as anti-HBs titers >500 IU/L without further need for HBIg administration during a follow-up period of at least 12 months. Overall sustained response to vaccination was 53% (8 / 15 patients); 80% (4 / 5 patients) in the nonviral disease group and 40% (4 / 10 patients) in the HBV group (2 /2 fulminant and 2/8 chronically infected patients) developed a sustained long-term response and were completely free of HBIg at the end of the 18-month follow-up. No HBV recurrence, rejection episodes, or side effects occurred during the follow-up. In conclusion, protective anti-HBs titers were obtained in a substantial number of LT patients following a reinforced course of HBV vaccination with vaccines containing new immunostimulating adjuvants. Vaccination seems well tolerated and safe and allows long-term discontinuation of HBIg.     

Treatment with recombinant human erythropoietin increases antibody titers after hepatitis B vaccination in dialysis patients

The effect of recombinant human erythropoietin (rHuEPO) on the immune system of hemodialysis patients has been studied by evaluating their response to hepatitis B (HB) vaccination. Fifty hemodialysis patients were given four doses of 20 micrograms recombinant DNA hepatitis B vaccine (SKF) at an interval of 0, 1, 2 and 6 months. Thirty-seven patients could be evaluated at one year. Twelve of 15 (80%) of the rHuEPO treated patients and 12 of 22 (54%) of non-rHuEPO treated dialysis patients developed anti-HBs antibodies. At the time of maximum immune response (8 months), the geometric mean anti-HBs titers (mIU/ml +/- SEM) of responders and all patients were five times (224.0 +/- 5.9 vs. 41.7 +/- 1.5, P less than 0.001), and eight times (57.6 +/- 8.7 vs. 6.7 +/- 1.8, P less than 0.05), respectively, higher in rHuEPO treated patients than in patients not receiving the drug. High antibody response (greater than 100 mIU/ml) prevailed in the group of rHuEPO treated patients and was associated with a high helper/suppressor ratio. Discriminant multivariate analysis (P = 0.038) revealed the influence of treatment with rHuEPO (40%) and helper/suppressor ratio (31%) on antibody concentration, while age, gender, duration of dialysis and previous blood transfusions were similar in both patient groups. Although changes in lymphocyte subsets observed in rHuEPO treated patients may be the result of a reduced administration of blood transfusions, immune reactivity seems also to be directly affected by the drug.     

Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin

BACKGROUND: Treatment with recombinant human erythropoietin (rHuEPO) has been a major advance for the management of anemia in patients on hemodialysis. Therapy, however, is often observed to be associated with recurrent cyclic fluctuations in hemoglobin levels. The purpose of this analysis was to describe the phenomenology of hemoglobin cycling during rHuEPO treatment. METHODS: Data were analyzed for 281 hemodialysis patients treated at Winthrop-University Hospital Dialysis Centers between 1998 and 2003. Eligible patients' first full 1-year period with less than 10 hospital days was studied. Hemoglobin cycling (cycles with amplitude >1.5 g/dL and duration >8 weeks) and excursions (half of one full cycle) were analyzed. RESULTS: Greater than 90% of patients experienced hemoglobin cycling. The mean number of hemoglobin excursions was 3.1 +/- 1.1 per patient/year. The mean amplitude per hemoglobin excursion was 2.51 +/- 0.89 g/dL. The mean duration of hemoglobin excursions was 10.3 +/- 5.1 weeks. Factors associated with initiation of up excursions included increases in rHuEPO dose (84%), intravenous iron treatment initiation or increase in dose (27%), posthospital discharge (36%), factors associated with down excursions included rHuEPO dose hold (15%) or dose reduction (62%), infection (6%), discontinuation of intravenous iron therapy (5%), and hospitalization (14%). Patients with frequent hemoglobin cycling (>two full cycles per year) were characterized as being more responsive to rHuEPO [index of EPO responsiveness (ERI) 1036 +/- 659 compared to 1992 +/- 701 for other patients] (P = 0.02). CONCLUSION: Hemoglobin cycling is a common occurrence in rHuEPO-treated hemodialysis patients. It is most closely associated with frequent rHuEPO dose changes, hospitalization, and iron treatment practices.     

Hepatitis B vaccination and interleukin 2 receptor expression in chronic renal failure

Only 50 to 60% of dialysis patients develop anti-HBs antibodies following hepatitis B vaccination. The nonresponder state correlates with impaired monocyte function, decreased interleukin-2 (IL-2) production of T cells, and an upregulation of the IL-2 receptor system. In the present study we examined anti-HBs production after hepatitis B vaccination and the in vitro expression of IL-2 receptors in nondialyzed patients with various degrees of chronic renal failure. Forty-four patients with impaired renal function were immunized with 2 micrograms recombinant hepatitis B vaccine and boostered after one and six months. Prior to the first injection IL-2 receptor expression of activated T cells was studied by an in vitro proliferation assay. Sixty-four healthy subjects served as controls. After completion of the third vaccination 55.0% of the patients acquired antibody titers greater than 10 U/liter. The seroconversion rate did not differ between patients with lower (less than 3.5 mg/dl) and higher (greater than 3.5 mg/dl) creatinine levels. In nonresponders IL-2 receptor expression (stimulation index, SI = 10.09 +/- 1.80) was elevated compared to healthy controls (SI = 4.62 +/- 0.35, P less than 0.002) or patients who responded with a high antibody titer (greater than 50 U/liter, SI = 3.12 +/- 0.43, P less than 0.001). Patients who produced low antibody titers (less than 50 U/liter) also presented with enhanced IL-2 receptor expression. These data show that an impaired antibody production following hepatitis B vaccination and an enhanced IL-2 receptor expression of T cells may already be present in early stages of chronic renal failure.     

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.