Alicja E. Grzegorzewska

Antibodies to hepatitis B virus surface antigen and interleukin 12 and interleukin 18 gene polymorphisms in hemodialysis patients

BackgroundThe interleukin (IL)18 rs360719 CC genotype is associated with the development of antibodies to hepatitis B virus surface antigen (anti-HBs) in hemodialysis (HD) patients. IL18 shares biological properties with IL12 in promoting the T-hepler 1 (Th1) system. We studied whether polymorphisms in the IL12A 3` untranslated region (UTR) and IL12B 3`UTR may contribute to anti-HBs development (titre ≥ 10 IU/L) in HD patients either individually or jointly with the IL18 polymorphism.MethodsIn 518 HD patients and 240 controls the IL12A rs568408 3’UTR G > A polymorphism was genotyped by high-resolution melting curve analysis. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL12B rs3212227 3’UTR A > C and IL18 -1297 T > C rs360719 polymorphisms. The associations between the IL12A, IL12B and IL18 genotypes and the risk of impaired anti-HBs development were estimated by computing the odds ratios and their 95% confidence intervals using logistic regression analysis.ResultsIn the logistic regression analysis, the higher frequency of rs360719 CC individually (2.9% in 207 patients without anti-HBs development vs 8.0% in 311 patients with anti-HBs development, p = 0.009) and of rs360719 CC combined with rs568408 GG (p = 0.048), rs568408 GA (p = 0.035), rs568408 GG/AA (p = 0.034) or rs3212227 AA (p = 0.046) was associated with an increased chance for the development of anti-HBs in HD patients. Patients bearing both rs568408 AA and rs360719 TT had a 10.9-fold or 8.9-fold lower chance, respectively, to develop anti-HBs compared with those carrying any other genotype (p = 0.005) or those who had both wild-type rs568408 GG and rs360719 TT (p = 0.011). Carriers of both rs3212227 CC and rs360719 TC had a 4.6-fold lower chance for anti-HBs development than carriers of any other genotype (p = 0.042).ConclusionDevelopment of anti-HBs in HD patients is associated with gene polymorphisms of interleukins involved in the Th1 system.

Interleukin-18 Promoter Polymorphism and Development of Antibodies to Surface Antigen of Hepatitis B Virus in Hemodialysis Patients

Background: Interleukin (IL)-18 is involved in hepatitis B virus (HBV) clearance and augments antibodies against surface antigen of HBV (anti-HBsAg) production during DNA vaccination. The IL-18 –1297C>T (rs360719) polymorphism may modulate the IL-18 expression. Aim: To determine the potential association of IL-18 –1297C>T polymorphism with development of anti-HBsAg in hemodialysis (HD) patients. Methods: The frequency of IL-18 –1297C>T alleles and genotypes was identified by polymerase chain reaction restriction fragment length polymorphism in 435 HD patients. Group 1 (n = 219) developed an anti-HBsAg titer >10 IU/l as a result of vaccination or HBV transmission. Group 2 (n = 216) included patients who did not develop an anti-HBsAg titer >10 IU/l in response to at least one full series of vaccination or HBV transmission. The significance of genotype frequency was tested using the Fisher exact test. Results: In group 1, the frequencies of –1297CC, –1297CT and –1297TT genotypes were 7.3, 39.7 and 53.0%, respectively, and in group 2 they were 1.9, 42.1 and 56.0%, respectively. The odds ratio for CC versus CT + TT was 0.239 (95% CI 0.079–0.728, p = 0.010), and for CC versus TT it was 0.240 (95% CI 0.078–0.738, p = 0.009). Conclusion: In HD patients, the IL-18 –1297CC genotype may play a role in anti-HBsAg development in response to HBV surface antigen.

Hepatitis B vaccination in chronic kidney disease patients: a call for novel vaccines

The protective immunization rates in response to hepatitis B vaccination in chronic kidney disease (CKD) patients are lower than response rates in the general population because of genetic and CKD-related factors as well as logistic problems with a proper providing of the recommended vaccination schedules. This review focuses on third-generation vaccines and adjuvanted vaccines commercially introduced in some countries, investigated in clinical trials, especially involving CKD patients or used only in the experimental studies. In order to improve the immunization rate, the use of third-generation vaccines (yeast-derived pre-S2/S HBV vaccines, mammalian cell-derived pre-S2/S HBV vaccines, mammalian cell-derived pre-S1/pre-S2/S HBV vaccines), novel adjuvants (AS04, AS02, phosphorothioate oligodeoxyribonucleotide, hemokinin-1, a polysaccharide based on delta inulin, nano-complex Hep-c, cyclic diguanylate) or immunostimulants for enhancement of immunogenicity of existing recombinant hepatitis B vaccines is tried to improve results of hepatitis B vaccination prior to dialysis commencement or already on renal replacement therapy.

Seroconversion rate to positivity for antibodies against core antigen of hepatitis B virus and duration of renal replacement therapy

BACKGROUND Prevalence of total antibodies against core antigen (anti-HBc) of hepatitis B virus (HBV) is greater in longer dialysed patients, but there are no data indicating a relationship between the higher seroconversion rate to anti-HBc positivity and longer renal replacement therapy (RRT) vintage prior to seroconversion. Our aim was to evaluate the association between RRT duration and seroconversion to anti-HBc positivity. METHODS An incidence of anti-HBc was evaluated in 425 anti-HBc-negative intermittent haemodialysis (IHD) patients: Group I included patients who underwent first anti-HBc testing 31 days from first IHD session, and Group II or III included patients with RRT duration < 3 or ≥ 3 years, respectively. Anti-HBc testing was repeated every 6-12 months. Sex, age, RRT duration, anti-HCV, HCV RNA, ALT, ASP, GGT, full vaccination series against HBV with developed anti-HBs titre > 10 IU/L, hepatitis history and underlying kidney diseases were used as independent variables predicting seroconversion to anti-HBc positivity. RESULTS Seroconversion rate to anti-HBc positivity was 2.59, 2.12 and 2.44 episodes/100 patient-years in Group I (n = 174), II (n = 170) and III (n = 80), respectively. In the entire group, there were 15 seroconversions to anti-HBc and one seroconversion to HBsAg positivity. The only variable predicting seroconversion in all HBsAg-negative patients (n = 424) was the lack of full vaccination series against HBV with developed anti-HBs titre > 10 IU/L maintained during the study (β - 0.112, P = 0.04). CONCLUSIONS Seroconversion rate to anti-HBc positivity is not related to duration of RRT treatment but to ineffective vaccination against HBV.

IL4R and IL13 polymorphic variants and development of antibodies to surface antigen of hepatitis B virus in hemodialysis patients in response to HBV vaccination or infection

We searched for an association between the interleukin 4 receptor gene (IL4R) rs1805015 and interleukin 13 gene (IL13) rs20541 polymorphisms and the development of antibodies to hepatitis B surface antigen (anti-HBs) in the case of hepatitis B virus (HBV) vaccination or infection in hemodialysis (HD) patients. HD patients who failed to respond to HBV vaccination did not differ in genotype frequencies of IL4R (TT 72.7%, CT 22.6%, CC 4.7%) and IL13 (CC 59.0%, CT 34.2%, TT 6.8%) from vaccine responders (IL4R TT 68.0%, CT 27.3%, CC 4.7%; IL13 CC 55.0%, CT 38.5%, TT 6.5%). HD patients who did not develop anti-HBs despite HBV infection also did not differ in genotype frequencies of IL4R (TT 67.8%, CT 26.8%, CC 5.4%) and IL13 (CC 60.7%, CT 33.9%, TT 5.4%) from HD patients who developed an anti-HBs response (IL4R TT 65.4%, CT 30.8%, CC 3.8%; IL13 CC 60.5%, CT 34.6%, TT 4.9%). In HD patients, neither the IL4R nor IL13 polymorphism is associated with anti-HBs development irrespective of whether an immunization is provoked by HBV vaccination or HBV infection.

Single nucleotide polymorphisms of vitamin D binding protein, vitamin D receptor and retinoid X receptor alpha genes and response to hepatitis B vaccination in renal replacement therapy patients.

Aim: Vitamin D (VD) was recently associated with response to hepatitis B vaccination in chronic kidney disease. We investigated whether polymorphisms in VD binding protein (GC), VD receptor (VDR) and retinoid X receptor α (RXRA) genes were associated with response to hepatitis B vaccination in renal replacement therapy (RRT) patients. Method: The study was carried out on 692 responders and 223 non-responders. Results: After adjustment for gender, age at the RRT onset, RRT vintage, chronic glomerulonephritis as a cause of renal failure and mean serum parathyroid hormone level, VDR rs1544410 polymorphism was the only one significantly associated with response to hepatitis B vaccination: homozygotes AA (adjusted OR 1.50, 95% CI: 1.17–1.94, p = 0.002) had higher risk to be non-responders than GG homozygotes. Discussion: The VDR rs1544410 AA genotype may play a negative role (but not as an independent factor) in determining response to hepatitis B vaccination in RRT patients.

Monocyte chemoattractant protein-1 gene (MCP-1-2518 A/G) polymorphism and serological markers of hepatitis B virus infection in hemodialysis patients

Background The role of MCP1-2518 A/G in hepatitis B virus (HBV) infection is controversial. Our aim was to evaluate the frequency distribution of MCP1-2518 A/G (rs1024611) polymorphic variants in hemodialysis (HD) patients without or with type 2 diabetes in relation to serological markers of HBV infection. Material/Methods HD patients (n=170, 48 with diagnosis of type 2 diabetes), who tested positive for total antibodies to HBV core antigen (anti-HBc), underwent MCP1 genotyping using polymerase chain reaction-restriction fragment length polymorphism assay. Anti-HBc was accompanied by antibodies to HBV surface antigen (anti-HBs) in 127 individuals. In anti-HBc-positive/anti-HBs-negative patients, HBV surface antigen (HBsAg) was shown in 15 patients and isolated anti-HBc were present in 28 patients. The distribution of MCP1 genotypes in anti-HBc-positive patients was compared to that in healthy subjects (n=437) and anti-HBc-negative HD patients (n=754). Results There were no significant differences (Ptrend >0.05) in distribution of MCP1 genotypes between anti-HBc-positive patients, anti-HBc-negative subjects, and controls, regardless of anti-HBs or diabetic status. The MCP1-2518G allele prevalence was higher in HBsAg-positive/anti-HBs-negative patients defined as HBV carriers compared to MCP1-2518G allele frequency shown in groups composed of HBsAg-negative HD individuals and controls (50% vs. 28%, Ptrend 0.022). Conclusions A frequency distribution of MCP1 polymorphic variants is not associated with anti-HBs development in response to HBV infection in HD patients, independent of diabetic status, but the MCP1-2518G allele may predispose to HBsAg persistence (HBV carrier status).

Disseminated cutaneous Kaposi sarcoma in a patient receiving triptolide/tripdiolide for rheumatoid arthritis.

Summary Background To date, Kaposi sarcoma has not been mentioned among the adverse effects of triptolide/tripdiolide, ethyl acetate extracts or polyglycosides of the Chinese herbal remedy Tripterygium wilfordii Hook F. Case Report A patient was diagnosed with rheumatoid arthritis at the age of 29 years. She underwent treatment with corticosteroids, methotrexate and gold sodium thiosulfate, and was chronically taking ketoprofen. At the age of 59 years she started to take a powder (≈2 g/day) from a Chinese physician for treatment of rheumatoid arthritis. This powder was supplied to her regularly for 10 years. At the age of 69 years, multiple soft, violaceous to dark-red patches, plaques, nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs, and later on her arms. Biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated Kaposi sarcoma. Triptolide (235 μg/1 g) and tripdiolide were found in the Chinese powder by the use of Liquid Chromatography Electrospray Ionization Mass Spectrometry. Administration of the powder was stopped and medication with paclitaxel was introduced. General condition of the patient improved and skin lesions diminished significantly. Conclusions This case indicates a possible association between triptolide/tripdiolide chronic intake and development of human herpesvirus 8-associated Kaposi sarcoma. Triptolide/tripdiolide could contribute to development of Kaposi sarcoma by reactivation of latent human herpesvirus 8, permitted by immunosuppression induced by triptolide.

Antibodies to core antigen of hepatitis B virus in patients on renal replacement therapy: association with demographic, clinical and laboratory data.

Background: Total antibodies to core antigen of hepatitis B virus (anti-HBc) are a marker for previous or current infection with hepatitis B virus (HBV). Our aim was to examine the prevalence and incidence of anti-HBc in relation to demographic, clinical and laboratory data of patients treated with intermittent hemodialysis (IHD). Methods: Predictors for anti-HBc positivity were evaluated in prevalence IHD patients with negative testing for surface antigen of HBV (HBsAg, n = 1,105) using the stepwise backward regression analysis. Patients starting IHD (n = 336) were introduced into the one-year prospective study evaluating seroconversion for anti-HBc. Results: Anti-HBc positivity (19.5% of all patients) was predicted by lack of vaccination against HBV with developed protective titer of antibodies to HBsAg (β = 0.592, p = 0.000), vintage of renal replacement therapy (RRT, β = 0.206, p = 0.000), history of hepatitis (β = 0.101, p = 0.000), and activity of alanine aminotransferase (β = 0.057, p = 0.037). In 85 prospective patients who finished first IHD year, seroconversion rate for anti-HBc was 1.23 episodes/100 patient-years. Conclusions: Lack of or not effective vaccination against HBV is the strongest predictor for prevalence of anti-HBc positivity in RRT patients. Periodical determination of anti-HBc, usually not required, may be helpful in evaluation of current epidemiological status and risk for further HBV infection in dialysis centers.

T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms in end-stage renal disease due to type 2 diabetes mellitus nephropathy: comparisons with health status and other main causes of end-stage renal disease.

Background. T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms were evaluated as possibly associated with end-stage renal disease (ESRD) resulting from type 2 diabetes mellitus (DM) nephropathy. Methods. Studies were conducted among hemodialysis (HD) patients with ESRD due to type 2 DM nephropathy, chronic glomerulonephritis, chronic infective tubulointerstitial nephritis, and hypertensive nephropathy as well as in healthy subjects. A frequency distribution of T-cell-related interleukin (IL) genes (IL18 rs360719, IL12A rs568408, IL12B rs3212227, IL4R rs1805015, IL13 rs20541, IL28B rs8099917, IL28B, and rs12979860) and vitamin D pathway genes (GC genes: rs2298849, rs7041, and rs1155563; VDR genes: rs2228570, rs1544410; and RXRA genes: rs10776909, rs10881578, and rs749759) was compared between groups. Results. No significant differences in a frequency distribution of tested polymorphisms were shown between type 2 DM nephropathy patients and controls. A difference was found in IL18 rs360719 polymorphic distribution between the former group and chronic infective tubulointerstitial nephritic patients (P trend = 0.033), which also differed in this polymorphism from controls (P trend = 0.005). Conclusion. T-cell cytokine and vitamin D pathway gene polymorphisms are not associated with ESRD due to type 2 DM nephropathy in Polish HD patients. IL18 rs360719 is probably associated with the pathogenesis of chronic infective tubulointerstitial nephritis.