Vaccination and chronic kidney disease

Infectious diseases are the second most common cause of death in end-stage renal disease (ESRD) patients [ 1 ]. Patients with chronic kidney disease (CKD) are immunocompromised and haemodialysis (HD) patients are at high risk for several infections, due to exposure to blood products [ 2 ]. CKD patients present impaired cell-mediated and humoral immunity, reducing activities of the immune system cells (B-cell, T-cell, monocytes, macrophages,…) leading to a lower seroconversion rate, a lower peak of antibody titers and a quicker decline of antibody levels in these patients as compared with healthy subjects [ 2 ]. Usual schedules of vaccination may thus be ineffective. The aim of this paper is to review the studies on the use of vaccines in ESRD patients, in order to determine whether dosage adjustment is necessary in these patients. Hepatitis B is one of the most serious infectious diseases in the world. It is estimated that 200–500 million of people are infected. The virus can be transmitted by blood, other corporal fluids, vertically or horizontally among high-risk groups including CKD patients. These patients are exposed to blood products, internally contaminated dialysis equipment and cross-contamination from environmental surfaces [ 2 ]. The use of HBV vaccine and preventive measures have helped reduce the annual incidence of HBV infection in patients on dialysis, from 3% to 0.05% between 1976 and 1997 in the USA [ 3 ]. It is thus important and useful to vaccinate these patients. The usual vaccination schedule in healthy adults ranged from 10 to 20 μg per dose in a three- or four-shot schedule (0, 1, 2, 12 or 0, 1, 6 months). The effectiveness of HBV vaccination was found to be lower in ESRD patients than in subjects without CKD [ 2 ]. Those patients commonly presented lower seroconversion rates, lower peak antibody titers and a rapid decline of antibody levels [ 4 ]. Furthermore, some ‘negative factors’ affected seroconversion rates among these patients (age, gender, obesity, nutritional status and smoking) [ 5 ]. In order to improve the response to the vaccine, various methods were tested. Many studies ( Table 1 ) have tested the effectiveness of higher doses of vaccine with 40 μg in a four-shot schedule. Seroconversion rates were found in 60–90.5% of ESRD patients [ 5–9 ]. Studies on hepatitis B vaccination and ESRD patients HD: haemodialysis patients, PD: peritoneal dialysis patients, CKD: chronic kidney disease patients, IM: intramuscular vaccination, ID: intradermal vaccination. a Antibody level >10 UI/l. Studies on hepatitis B vaccination and ESRD patients HD: haemodialysis patients, PD: peritoneal dialysis patients, CKD: chronic kidney disease patients, IM: intramuscular vaccination, ID: intradermal vaccination. a Antibody level >10 UI/l. All of these studies tried to improve the immune response by vaccinating with higher doses than the standard 10– 20 μg. One study compared 40 μg versus 20 μg in 121 patients with moderate renal insufficiency (at Months 0, 1, 6 in a three-shot schedule). Seroconversion rate was superior in patients with a high dose of 40 μg than in patients with a standard dose of 20 μg. However, this was not statistically significant for the three- or four-shot vaccination schedule. The authors recommended the use of three doses of 20 μg in patients with renal impairment. A fourth dose could be administered in patients who failed to respond [ 10 ]. Another study compared intradermal (ID) and intramuscular (IM) vaccination in ESRD patients. The ID group of patients received 5 μg of vaccine on a bimonthly schedule, while the IM group of patients were administered 40 μg on a four-dose vaccination schedule. Most patients reached a high seroconversion rate, 97.6% for the ID group and 90.5% for the IM group. The authors recommended using 5 μg every 2 weeks up to a peakantibody titer >1000 IU/l or for a total duration of administration of 18 months [ 8 ]. Another suggestion was to use standard 20 μg doses repeatedly. One study tried to raise the protective rate among ESRD patients by using 20 μg every month until they reached 100 UI/l of antibody titers, or up to 10 doses. After 5 months, seroconversion rate reached 42%; after 12 months it was 70% [ 11 ]. Early vaccination of patients before they start dialysis has been used in order to improve the response rate. One of the largest studies performed on this topic included 61 RI patients. The authors concluded that patients not yet on dialysis had a better immune response to HBV vaccine than dialysis patients [ 12 ]. These studies suffer from relative disparities. Some authors reported that certain factors could influence the antibody levels, considered as being protective. Elderly ESRD patients seemed to have a lower rate of seroconversion than younger patients [ 10,11 , 13 ]. Unexpectedly, there was no apparent correlation between the seroconversion rate and severity of RI in one study that included patients with mild to moderate CKD [ 10 ]. However, another study found an association (not statistically significant) between the glomerular filtration rate (GFR) and the seronconversion rate in patients with severe renal impairment (GFR < 30 ml/ min) [ 9 ]. These different results may be due to diverse inclusion criteria. Indeed, DaRoza's [ 9 ] patients had worse renal dysfunction than in the other study. [ 10 ]. HBV vaccination is a critical issue in ESRD patients because they are a high-risk group for developing infection. Thus, patients with CKD must be immunized as soon as possible and before starting dialysis, where possible. The trends in all studies are characterized by a huge disparity; this may be due to certain factors influencing the immunogenic response of patients to the vaccine. Advanced age, male gender, previous blood transfusions are associated with poor seroconversion rates [ 2 ]. Several ways of improving seroconversion have been tested with various results. The recommended vaccination schedule is four doses of 40 μg of Engerix B® (GlaxoSmithKline) vaccine at 0, 1, 2 and 6 months or three doses 20 μg of Recombivax HB® (Merck) vaccine at 0, 1 and 6 months [ 14–16 ]. Booster doses can be given to patients whose antibody titers fall under 10 UI/l [ 4 ]. However, ID administration of HBV vaccine may also represent an alternative and cost-effective method [ 8 ]. Nevertheless, Tong's study [ 17 ] tested Fendrix® (GlaxoSmithKline), a new hepatitis B vaccine containing HBsAg adjuvanted with 3- O -desacyl-4′-monophosphoryl lipid A (MPL) and aluminium phosphate in predialysis and dialysis patients. This study showed an increased geometric mean titer of HBs antibody, but not an increased number of patients with seroconversion with single 20 μg doses of Fendrix® administered at 0, 1, 2 and 6 months compared to Engerix® (40 μg with the same vaccine schedule). Furthermore, Fendrix® is recommended for pre-haemodialysis and haemodialysis patients in its SmPC. In conclusion, HBV vaccination in patients with kidney disease remains highly recommendable. The sooner they are vaccinated, the better the response. Dose recommendation is four 40 μg doses of Engerix B®, three doses of Recombivax HB® or four 20 μg doses of Fendrix® (see Table 1 ). HAV vaccination among the general population has been used for decades. It is a safe and effective vaccine. However, data in ESRD patients are limited. The recommended vaccination schedule in healthy adult subjects is one dose of 1440 Elisa units (ELU) at 0 and between 6 and 12 months. One study tested HAV vaccination with Havrix® (GlaxoSmithKline, 720 ELU at 0, 1 and 6 months) in ESRD patients. The 1440 ELU Havrix® was not available at the time of the study. The authors concluded that the vaccine was safe and effective, in accordance with the safety and efficiency profiles reported in healthy subjects [ 18 ]. In conclusion, HAV vaccination in ESRD patients is well tolerated and immunogenic [ 18,19 ]. The Advisory Committee on Immunisation Practices (ACIP) recommends using the standard dose and schedule in adult ESRD patients (1440 ELU, 1 ml) of Havrix® at 0 and between 6 and 12 months [ 15 ]. Varicella is a common benign infectious disease in the paediatric population. However, it may be severe and even fatal in immunocompromised ESRD children. Furthermore, zoster disease, the reactivation form of varicella usually seen in the adult and elderly population, can occur. Again, effective vaccination is a critical issue for these patients. The usual vaccine schedule for healthy subjects older than 13 years is two doses of 1350 plaque-forming units (PFU) with an interval of 4 to 8 weeks or two doses of 10 3,7 PFU with an interval of 6 to 8 weeks. Response to varicella vaccination was tested in children with CKD and dialysis patients waiting for kidney transplantation. It was generally well-tolerated and protective antibody titers were obtained for almost all children. However, a second and a third booster dose (1350 to 2000 PFU for each dose [ 20,21 ]) were necessary, in order to obtain a high rate of seroconversion and a persistence of protective antibody titers. Some of these children underwent renal transplantation thereafter; zoster or varicella infections were minimal [ 20–22 ]. Furthermore, varicella infection was more frequent and more serious among non-immunized post-transplant patients than vaccinated post-transplant patients [ 22 ]. In conclusion, varicella vaccination is safe and effective in ESRD patients and is thus recommended in these patients. However, sometimes an additional booster dose of vaccine may be necessary, to reach appropriate antibody levels in children with ESRD. Webb et al . thus recommended using a 2 × 2000 PFU-dose regimen and monitoring anti-VZV IgG titers in order to decide when to administer a third dose [ 20 ]. However, for ESRD patients older than 12 years, available guidelines recommend two doses of 0.5 ml with no booster doses [ 15,16 ]. Influenza is a common infection that is responsible for many deaths. From 1972 through 1992, influenza epidemics accounted for a total of 426 000 deaths in the United States [ 23 ]. Because of the virulence and the pathogenic power of this virus, influenza vaccination of the general population is very common, with a relative efficacy of a single dose injection of 15 μg. In the CKD population, the use of this vaccine is recommended. Indeed, the risk of hospitalization or death was decreased in vaccinated HD patients compared with non-vaccinated HD patients. Among patients on continuous ambulatory peritoneal dialysis (CAPD), those who were not vaccinated had a greater risk of hospitalization than immunized patients [ 24 ]. The usual dose for healthy adult subject is a single shot of 15 μg. Several studies showed comparable response rates between CKD patients and healthy subjects. These studies demonstrated that influenza vaccination was safe and effective in patients with CKD despite an impaired antibody response [ 25–28 ] ( Table 2 ). Some differences were observed according to the method of dialysis (peritoneal dialysis or haemodialysis), or the type of the viral antigen. Furthermore, correction of vitamin D deficiency among HD patients may improve immune response [ 25 ]. In order to obtain higher levels of antibodies, a booster immunization with a supplemental dose was tested, but with no success [ 27 ]. Studies on influenza vaccination and ESRD patients HD: haemodialysis patients, PD: peritoneal dialysis patients, CKD: chronic kidney disease patients. Studies on influenza vaccination and ESRD patients HD: haemodialysis patients, PD: peritoneal dialysis patients, CKD: chronic kidney disease patients. Because of the virulence and risks associated with influenza virus infection, vaccination is a universal health issue and is recommended all over the world. Injection of a single dose of 15 μg shows good efficacy in the CKD population. Vaccination against influenza decreases mortality and results in decreased hospitalization. In conclusion, influenza vaccination is highly recommended among ESRD patients. Antibody titers can be lower than those in healthy subjects. However, satisfactory protective rates can be reached by annual vaccination. It is thus recommended to vaccinate adult ESRD patients against influenz a each year, using a standard dose (15 μg annually) [ 15,16 ]. Data on the use of Haemophilus influenza type B vaccine among ESRD patients are limited. In a multicentre study, the safety and efficacy of the vaccine were determined in 10 CAPD children, where 90% of the patients reached a protective rate of antibodies [ 29 ]. ESRD patients should thus receive the same doses as for healthy subjects [ 15 ]. All children should be treated with measles, mumps and rubella vaccines (MMR), including dialysis patients. Seroconversion rates among this population were evaluated in 10 dialysis patients, 8 responded to measles vaccine, 5 to mumps vaccine and 8 to rubella vaccine alone. However, only three children responded to all three vaccines [ 30 ]. It is thus recommended to assess the seroconversion after vaccination (standard doses) among these patients [ 15 ]. The usual vaccination schedule begins with one shot at 1 year old and another between 3 and 6 years old. For adult patients, one single dose should be used [ 15 ]. Inactivated poliovirus vaccine is not very common because it is only recommended for specific groups of persons, and because the general population is not extensively exposed to the virus. However, for these specific exposed groups vaccination is recommended, including ESRD patients with inactivated poliovirus vaccine. The efficiency and safety of inactivated poliovirus vaccine was assessed in 49 chronic dialysis patients, resulting in 86% of patients having sufficient antibody levels [ 31 ]. It is thus recommended to vaccinate ESRD patients with a primary series of standard dose schedule (three doses with an interval of 1–2 months). [ 15 ]. Staphyloccocus aureus is a major cause of nosocomial and community-acquired infections. Patients undergoing dialysis represent a high-risk group of developing infection to S. aureus due to the violation of the skin barrier. It is an important cause of complications and death in patients on chronic HD [ 32 ]; however, there is no vaccine currently available for clinical use. Some studies have demonstrated that ESRD patients present an impaired immunological response, in comparison with healthy subjects, with a 50% reduction of IgG levels 6 months after a 25-μg vaccination with a monovalent conjugated S. aureus type 5 capsular polysaccharide [ 33 ]. However, ESRD patients reached protective antibody levels (80 μg/ml) only for ∼6 months. In another study, the effectiveness and the good tolerance of a single injection of a bivalent conjugate vaccine containing S. aureus type 5 and 8 capsular polysaccharide (StaphVax®, Nabi, 25 μg of each capsular polysaccharide) have been it only a and in ESRD patients. The in vaccine efficacy after and the authors considered the study to be a because of those results [ ]. In order to the efficacy of the vaccine, a higher dose of the same vaccine (StaphVax®, Nabi, 100 μg of each capsular polysaccharide) was tested in ESRD patients. The vaccine was in these patients in comparison with patients 40 and it was well tolerated the study However, after the reduction of S. aureus in the group that received the vaccine as compared to the group was not statistically significant [ ]. Data are thus and there is no recommendation for the use of S. aureus vaccine in CKD patients. However, according to the response is and the levels of antibodies after several months. Seroconversion rate has been to be lower in dialysis patients than in healthy subjects after and vaccination [ ]. A study showed that vaccination booster in HD patients to of seroconversion rate but after 6 months [ ]. In one study, the immunological status after (40 and vaccination was tested among HD patients without before vaccination. years after the vaccination, 15 patients had a protective antibody level for and for . The authors thus recommended monitoring antibody levels and sufficient booster doses of vaccine [ ]. In conclusion, and infections can be by using vaccines in ESRD patients. However, because of impaired seroconversion rates, monitoring of antibody levels is recommended and a booster may be used in patients. vaccination is commonly used with success in healthy subjects and an appropriate level of antibodies may for several It is also well However, the immune response in patients with CKD decreases with than of dialysis patients have an response to the vaccine, but antibody levels are lower than those of healthy vaccinated adults and they decline 6 months to 5 while they sufficient in healthy subjects after 5 years [ ]. Vaccination is thus recommended in these patients with standard doses of polysaccharide vaccine, but should be performed years [ 15 ]. response to most vaccines in ESRD patients is higher of vaccine or supplemental are for these patients compared with patients with renal The of infection on the efficacy and safety of vaccination in CKD patients remains HBV vaccine has been in ESRD patients. the immunological response is to be more in those patients than in CKD patients or in patients with renal In some studies on renal patients showed that antibody titers are and protective antibody titers decline after vaccination against HBV μg of in patients compared to patients [ ]. A response to and vaccination in patients was also reported in patients without renal impairment [ ]. one study evaluated the of protective antibodies to HBV vaccine in patients on HD [ ]. patients protective antibodies after using the same doses and schedule as ESRD patients. The authors that HBV vaccination should be to all ESRD patients. vaccination should be performed at the of in the ESRD population with the (40 μg in a three- to four-shot and to use booster doses the antibody titers fall under 10 UI/l [ ]. for vaccines are available in the [ ]; however, clinical on this topic is and the use of vaccines in ESRD patients is to be or at the standard doses and schedule. patients are more to with certain than are healthy subjects. In to vaccination are Thus, these patients should be vaccinated against some pathogenic [ there is no available recommendation on the use of vaccine in ESRD patients. Another to improve the immunological response of vaccines in ESRD patients is to use an to vaccination, in order to the immune system of these patients. Several have been tested, One of the most was can the and of cells and Many studies have tested the association of with HBV vaccination in order to the immunological response to vaccination. 17 studies on this topic concluded that the use of was and safe in ESRD patients patients [ ]. However, there was a in and vaccine μg to μg and from 20 μg × 1 to 40 μg × studies are to determine the doses of and HBV vaccine in ESRD patients. have been tested, to influence on HBV vaccination. Some as as they protective antibody response to hepatitis B vaccination in HD patients [ ]. However, no study was to the of other as an for HBV vaccination in ESRD patients [ ]. Several have in efficiency in immune response to and until more is vaccination against HBV should be performed according to the available data are available on the of on other and are to assess the efficacy of in other Most studies on the impaired efficacy of vaccines in ESRD patients were performed in HD patients and only a included patients. However, some studies the possible association between dialysis and the response to HBV or influenza patients presented a response rate to HD patients versus in and HD patients, in two studies in this review [ ]. Furthermore, et al . [ ] the differences in immunological response to HBV vaccine between HD and patients after 5 to 40 μg of various HBV vaccines on 3 to 5 dose vaccination concluded that dialysis not have an on the seroconversion rate after HBV vaccine in ESRD patients. In other where the of influenza vaccine was assessed in and HD patients, the authors reported some differences between the two groups of patients. using the standard dose and schedule of vaccine, patients reached better protective antibody titers than those of HD patients, but lower than those of patients without renal impairment [ 25 , ]. Because it is recommended to vaccinate HD patients with the standard dose of influenza vaccine each year [ 15 ] and because patients to have a better immunological response than HD patients, patients should receive the same dose regimen as HD patients. patients on peritoneal dialysis should be vaccinated with the same dose and schedule as patients on This recommendation is only for HBV vaccine. However, it possible to this recommendation to other vaccines and for those that not dosage adjustment in ESRD patients, as influenza vaccine. data are available on the use of vaccines in most of these studies included ESRD patients not yet on studies assessed the possible between and seroconversion rates in patients after HBV vaccine [ ]. from the results it was not possible to reach a as to the of between these two because the data were not no data are available on the vaccination of patients according to the level of renal it is to specific The with renal is not as as that of [ ]. Several studies have assessed the efficacy and safety of HBV and influenza vaccines in patients in comparison to healthy subjects and ESRD patients. patients had lower antibody response to vaccines and influenza ) than healthy patients [ , , ]. one study found a statistically significant antibody response to all the three and of influenza virus after annual vaccination in renal patients [ ]. Furthermore, influenza vaccine was well tolerated and no in patients [ ]. These are the same for HBV vaccination in patients. These patients had lower seroconversion rates than healthy subjects [ even with a high dose of vaccine [ ]. there are no on the vaccination on patients, available data that HBV and influenza vaccination can be performed in these patients. In conclusion, for influenza vaccine, annual vaccination with the standard dose should be performed in patients [ ]. For HBV vaccine, the should be to vaccinate before dialysis and to reach a protective antibody level in all patients before transplantation [ , ]. Furthermore, vaccines should not be given to patients, including varicella and poliovirus vaccines [ ]. Many vaccines have been used for years in ESRD However, some vaccines are in these patients. vaccines varicella and are generally because they present a risk of infection [ 15 ]. However, several studies the efficacy and safety profiles for some of these vaccines and in ESRD patients, with success varicella and In poliovirus should not be used in ESRD and patients [ 15 ]. ESRD patients who vaccination should receive the inactivated poliovirus vaccine. Vaccination against the most common pathogenic is used among the healthy population. it is common in patients with renal disease because of the risk of and as to efficacy in this population. These patients present impaired cell-mediated and humoral and activities of the immune system cells (B-cell, T-cell, monocytes, In this deficiency to lower seroconversion rates and a Because ESRD patients are they represent a high-risk group for developing infectious Furthermore, HD patients are extensively exposed to pathogenic to blood products, internally contaminated dialysis equipment and cross-contamination from environmental This review shows that vaccination of ESRD patients in well tolerated at standard doses or higher doses. Some vaccines may a seroconversion rate to against the disease influenza ). However, other vaccines sometimes not against the pathogenic In these higher supplemental booster doses are the more common to of the ESRD patients. Antibody levels must thus be in order to assess the protective of the immunization of ESRD patients is and vaccination should not be but Table 3 the for in adult dialysis patients. of for all vaccines in chronic dialysis patients not of for all vaccines in chronic dialysis patients not of .