Haemodialysis patients show a highly diminished antibody response after COVID-19 mRNA vaccination compared with healthy controls.

BACKGROUND: Haemodialysis (HD) patients are exposed to a high risk due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. They are prone to acquiring the infection and are threatened by high mortality rates in case of infection. However, HD patients were not included in the efficacy trials of the SARS-CoV-2 vaccines. Such efficacy data would have been critical because HD patients show decreased responses against various other vaccines and this could translate to the SARS-CoV-2 vaccines as well. METHODS: We conducted a prospective cohort study that contained a group of 81 HD patients and 80 healthy controls. All of them had been vaccinated with the BioNTech/Pfizer mRNA vaccine (two doses, as per the manufacturer's recommendation). The anti-SARS-CoV-2 spike (S) antibody response was measured for all participants 21 days after the second dose. The groups were compared using univariate quantile regressions and a multivariate analysis. The adverse events (AEs) of the vaccination were assessed via a questionnaire. Finally, a correlation between the HBs-antibody response and the SARS-CoV-2 antibody response in the HD patients was established. RESULTS: The HD patients had significantly lower anti-SARS-CoV-2 S antibody titres than the control patients 21 days after vaccination (median was 171 U/mL for dialysis patients and 2500 U/mL for the controls). Further, the HD group presented fewer AEs than the control group. No correlation was found between the antibody response to previous Hepatitis B vaccination and that of the SARS-CoV-2 vaccine. CONCLUSIONS: HD patients present highly diminished SARS-CoV-2 S antibody titres compared with a cohort of controls. Therefore, they could be much less protected by SARS-CoV-2 mRNA vaccinations than expected. Further studies to test alternative vaccination schemes should be considered.

Chronic kidney disease is more prevalent among women but more men than women are under nephrological care : Analysis from six outpatient clinics in Austria 2019.

BACKGROUND: A discrepancy between sex-specific treatment of kidney failure by dialysis (higher in men) and the prevalence of chronic kidney disease in the general population (higher in women) has been reported internationally, but the prevalence by sex has not been described for Austria. Sex disparity among nephrology outpatients has not been studied. METHODS: We employed two formulae (2009 CKD-EPI suppressing the race factor, and race-free 2021 CKD-EPI) to estimate the sex distribution of CKD in Austrian primary care, based on creatinine measurements recorded in a medical sample of 39,800 patients from general practitioners' offices (1989-2008). Further, we collected information from all clinic appointments scheduled at nephrology departments of 6 Austrian hospitals (Wien, Linz, Wels, St. Pölten, Villach, Innsbruck) during 2019 and calculated visit frequencies by sex. RESULTS: Using the 2009 CKD-EPI formula, the prevalence of CKD in stages G3-G5 (estimated glomerular filtration rate < 60 mL/min/1.73 m2) was 16.4% among women and 8.5% among men aged > 18 years who had attended general practitioners' offices in Austria between 1989 and 2008 and had at least one creatinine measurement performed. Using the 2021 CKD-EPI formula, the respective CKD prevalence was 12.3% among women and 6.1% among men. In 2019, 45% of all outpatients at 6 participating nephrology departments were women. The median of nephrology clinic visits in 2019 was two (per year) for both sexes. CONCLUSION: CKD is more prevalent among Austrian women than men. Men are more prevalent in nephrology outpatient services. Research into causes of this sex disparity is urgently needed.

SARS-CoV-2 Antibody and T Cell Response after a Third Vaccine Dose in Hemodialysis Patients Compared with Healthy Controls.

Hemodialysis (HD) patients have an increased risk of severe SARS-CoV-2 infection. In this study, we assess the impact of a third vaccine dose (3D) on antibody levels and T cell response in HD patients and a healthy control group in a prospective cohort study consisting of 60 HD patients and 65 healthy controls. Each participant received two doses of the BNT-162b2 mRNA vaccine and an mRNA vaccine 3D. The SARS-CoV-2 antibody response was measured 6 months after the second vaccine dose and 6 to 8 weeks after the 3D. We assessed INF-γ secretion 6-8 weeks post 3D in 24 healthy controls, 17 HD patients with a normal response, and 20 low responder HD patients. The groups were compared using univariate quantile regressions and multiple analyses. After the 3D, the SARS-CoV-2-specific antibody and INF-γ titers of most HD patients were comparable to those of healthy controls. A subgroup of HD patients who had shown a diminished antibody response after the first two vaccine doses developed a significantly lower antibody and INF-γ response compared to responder HD patients and controls even after the 3D. A new strategy is needed to protect low/non-responder HD patients from severe SARS-CoV-2 infection.

Alemtuzumab (Campath-1H) induction therapy and dendritic cells: Impact on peripheral dendritic cell repertoire in renal allograft recipients.

Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and are pivotal for initiating allograft immunity. Recently, particular DC subsets have been implicated also in allogeneic T cell hyporesponsiveness. Alemtuzumab (anti-CD52, Campath-1H) is a novel T cell depleting antibody that is currently under investigation for the use in allogeneic organ transplantation. While recent studies demonstrated a conspicuous effect of alemtuzumab on peripheral DC in clinical graft-versus-host disease, its efficiency in patients receiving allogeneic organ transplants is still undefined. In the present study we assessed the peripheral DC repertoire in kidney transplant recipients after either alemtuzumab induction therapy followed by FK506 monotherapy or after conventional immunosuppression (FK506, mycophenolate mofetil and steroids) without any induction agent. Induction with alemtuzumab caused a strong and sustained reduction of the total number of peripheral DC and a significant shift from myeloid to plasmacytoid DC subsets (mDC/pDC ratio) as early as 1 month post-transplantation. These data show that alemtuzumab induction targets the peripheral DC repertoire, which might add another mechanism allowing immunosuppressive drug minimization. Further studies are warranted to further elucidate the functional significance of these finding in the setting of allogeneic organ transplantation.

Inhibition of human dendritic cell maturation and function by the novel immunosuppressant FK778.

BACKGROUND: FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in the prevention of chronic allograft rejection. However, the cellular and molecular mechanisms underlying these effects of FK778 have not been investigated yet in detail. Because dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and are essential for the initiation of immune responses including acute and chronic allograft rejection, we investigated whether FK778 affects this particular cell type. METHODS: Allogeneic T cell stimulation by FK778-treated human monocyte-derived DCs was determined by mixed leukocyte cultures. Surface molecule expression was analyzed by flow-cytometric analysis and cytokine production by ELISA from culture supernatants. Activation of NF-kappaB in DCs was assessed by electrophoretic mobility shift assays. RESULTS: Treatment of DCs with FK778 inhibited their potency to stimulate allogeneic T cells. In line, LPS- and CD40L-induced upregulation of DC surface activation markers and production of IL-12 was significantly inhibited, irrespective of whether cells were treated during or after the monocyte to DC differentiation period. The effects of FK778 on DCs were not reversible by exogenous uridine indicating that FK778 acts independently of its action as an inhibitor of pyrimidine synthesis. On the signaling level, activation of NF-kappaB, the essential transcription factor involved in DC maturation and function, was markedly inhibited by FK778. CONCLUSIONS: Inhibition of activation and function of DCs as the central APCs may significantly contribute to the immunosuppressive profile of FK778 when applied after allogeneic organ transplantation.

The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function.

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-alpha was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-kappaB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA.