Ralli Chiara1, Imperiali Patrizio1, Gabbrilelli Claudio2, Conti Paolo2, Lombardi Marco3, Sidoti Antonino4, Capitanini Alessandro5, Piluso Adriano5, Tekle Kiros Seble6, Duranti Diletta7 and Duranti Ennio1*
1UO Nephrology and Dialysis Hospital of Arezzo, Italy
2UO Nephrology and Dialysis Hospital of Grosseto, Italy
3UO Nephrology and Dialysis Hospital Bridge Niccheri Florence, Italy
4UO Nephrology and Dialysis Hospital Poggibonsi, Italy
5UO Nephrology and Dialysis Hospital of Pistoia, Italy
6UO Serology Laboratory AOU Careggi in Florence, Italy 7UO Serology Laboratory AOU Novara , Italy
Received: 10 December, 2015; Accepted: 20 January, 2016; Published: 21 January, 2016
Dr. Duranti Ennio, 1 UO Nephrology and Dialysis Hospital of Arezzo Italy, E-mail:
Chiara R, Patrizio I, Claudio G, Paolo C, Marco L, et al. (2016) Hemodialysis with Polymethylmethacrylate Restores the Response to Hepatitis B Vaccination in Chronic Dialysis Patients: Hypothesized Mechanism of Action. Arch Renal Dis Manag 2(1): 001-004. DOI: 10.17352/2455-5495.000006
© 2016 Chiara R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hemodialysis; Immune dysfunctions; Polymethylmethacrylate (PMMA) membrane; Hepatitis B vaccination; Soluble CD40
Patients undergoing hemodialysis often present with a reduced response to anti-hepatitis B virus (anti-HBV) vaccination. The soluble form of CD40 (sCD40) is elevated in hemodialysis patients and this has been shown to correlate with lack of response to anti-HBV vaccination. Due to its high molecular weight, conventional dialyzers cannot clear sCD40. Previous studies have demonstrated, that dialysis membranes in polymethylmethacrylate (PMMA) can reduce the levels of sCD40. We have studied the effect of dialysis with PMMA membranes in patients who were non-responders to anti-HBV vaccination after a complete cycle of vaccinations. Interestingly, we found that significantly more patients in the PMMA group were able to mount a response to vaccination, compared to the control group (P = 0.04).
Up to 50% of patients with end-stage renal disease (ESRD) undergoing dialysis therapy, present with a reduced response to anti-hepatitis B virus (anti-HBV) vaccination . Patients on hemodialysis have been shown to have higher levels of soluble CD40 (sCD40), compared to healthy subjects [2,3]. Soluble CD40 is produced by B-cells by alternative splicing of the CD40 gene and by proteolytic cleavage of membrane-bound CD40 . It has been shown experimentally that sCD40 reduces immunoglobulin (Ig) production and T cell activation and this molecule has therefore been hypothesized to have an immunodepressant effect . Soluble CD40 is a glycoprotein and exists as dimeric and higher oligomeric forms of 50 and 150 kDa . Due to its high molecular weight, sCD40 cannot be removed effectively by standard diffusive or convective dialysis therapy. Dialysis membranes in polymethylmethacrylate (PMMA) have been shown to effectively reduce the levels of sCD40 . Reduction of sCD40 levels by hemodialysis was shown to correlate with an improvement in the response rate to anti-HBV vaccination . We have shown previously, that dialysis with PMMA strengthens the response to anti-HBV vaccination and that this lasted effectively over time, even after discontinuation of PMMA .
The scope of the present study was to study the effect of dialysis treatment with PMMA on serum levels of sCD40 and the consequent response to anti-HBV vaccination in chronic hemodialysis patients who were non-responders to anti-HBV vaccination after a complete cycle of vaccinations.
Materials and Methods
Patients were included in this study if they had been on maintenance thrice-weekly dialysis treatment and had undergone at least one complete cycle of anti-hepatitis B virus vaccination (20 mg Fendrix, administered at 0, 1, 2 and 6 months) and were non-responders (e.g. anti-HBV antibody titre <10 UI/L). Patients were excluded from this study if they had undergone dialysis treatment with PMMA dialyzers prior to enrolment and/or if they had active neoplasia. All patients gave their informed consent to participate in the study. Following enrolment, patients were randomized into two groups, a control group that continued on the same dialysis treatment as previously, and a treatment group that was shifted to dialysis with PMMA series BK-F (1.3 to 2.1 m2). The treatment with PMMA continued until after the administration of the fourth vaccination. Patients underwent thrice-weekly dialysis for three months and were then administered the fourth vaccination dose. Immune response was evaluated hereafter.
Serum levels of sCD40 were measured every four weeks by enzyme-linked immunosorbent assay (ELISA) during the 12 weeks of study and again 4 weeks after anti-hepatitis B virus vaccination. ELISA was performed essentially as described by Contin et al. , all samples were measured in duplicates and the mean concentration was calculated. Blood urea nitrogen (BUN) concentrations, Kt/V and C-reactive protein (CRP) were evaluated every four weeks.
Data were analyzed using Excel. Quantitative data were presented in the form of mean and standard deviation. The Student t-test was used to compare data for the study group and the control group. Chi Square test was used to assess the independence of observed and expected data between the two groups. P was considered significant when <0.05.
Thirty-two patients fulfilled the inclusion criteria and were enrolled in the study (average age 73±12 years). Following randomization 17 patients underwent dialysis with PMMA filters, and 15 patients underwent dialysis with either polysulfone or polyamide filters (Table 1). Significantly more patients in the PMMA group were able to mount a response to vaccination, compared to the control group (χ2 test, p = 0.04). Of the 17 patients who were dialyzed with PMMA filters, eight patients (47%) were able to develop a protective immune response against HBV (anti-HBs antibody levels > 10UI/L), whereas only two patients out of 15 in the control group (13%) developed a protective response (Table 2). In the PMMA group six out of the eight responders had anti-HBs antibody levels ≥ 100UI/L (Figure 1), whereas only one of the responders in the control group had anti-HBs antibody levels ≥ 100UI/L (Figure 2). This is relevant, because anti-HBs antibody levels ≥ 100UI/L provide a very good seroprotection against HBV.