Safety and efficacy of one and two booster doses of SARS-CoV-2 mRNA vaccines in kidney transplant recipients: A randomized clinical trial.

BACKGROUND: Kidney transplant recipients are at risk for a severe course of COVID-19 with a high mortality rate. A considerable number of patients remains without a satisfactory serological response after the baseline and adjuvant SARS-CoV-2 vaccination schedule. METHODS: In this prospective, randomized study, we evaluated the efficacy and safety of one and two booster doses of mRNA vaccines (either mRNA-1273 or BNT162b2) in 125 COVID-19 naive, adult kidney transplant recipients who showed an insufficient humoral response (SARS-CoV-2 IgG <10 AU/ml) to the previous 2-dose vaccination schedule. The primary outcome was the difference in the rate of a positive antibody response (SARS-CoV-2 IgG ≥10 AU/ml) between one and two booster doses at 1 month after the final booster dose. RESULTS: A positive humoral response was observed in 36 (62%) patients receiving two booster doses and in 28 (44%) patients receiving one booster dose (odds ratio [OR], 2.10, 95% confidence interval [CI], 1.02-4.34, p = .043). Moreover, median SARS-CoV-2 IgG levels were higher with two booster doses (p = .009). The number of patients with positive virus neutralizing antibody (VNA) levels was numerically higher with two booster doses compared to one booster dose, but without statistical significance (66% vs. 50%, p = .084). There was no significant difference in positive seroconversions rate and antibody levels between mRNA-1273 and BNT162b2. CONCLUSION: A higher number of kidney transplant recipients achieved a positive antibody response after two booster doses compared to one booster dose.

Insufficient response to mRNA SARS-CoV-2 vaccine and high incidence of severe COVID-19 in kidney transplant recipients during pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination may fail to sufficiently protect transplant recipients against coronavirus disease 2019 (COVID-19). We retrospectively evaluated COVID-19 in kidney transplant recipients (n = 226) after BNT162b2 mRNA vaccine administration. The control group consisted of unvaccinated patients (n = 194) during the previous pandemic wave. We measured anti-spike protein immunoglobulin G (IgG) levels and cellular responses, using enzyme-linked immunosorbent spot assay, in a prospective cohort after vaccination (n = 31) and recovery from COVID-19 (n = 19). COVID-19 was diagnosed in 37 (16%) vaccinated and 43 (22%) unvaccinated patients. COVID-19 severity was similar in both groups, with patients exhibiting a comparable need for hospitalization (41% vs. 40%, p = 1.000) and mortality (14% vs. 9%, p = .726). Short posttransplant periods were associated with COVID-19 after vaccination (p < .001). Only 5 (16%) patients achieved positive SARS-CoV-2 IgG after vaccination, and 17 (89%, p < .001) recovered from COVID-19 (median IgG levels, 0.6 vs. 52.5 AU/ml, p < .001). A cellular response following vaccination was present in the majority (n = 22, 71%), with an increase in interleukin 2 secreting T cells (p < .001). Despite detectable T cell immunity after mRNA vaccination, kidney transplant recipients remained at a high risk of severe COVID-19. Humoral responses induced by vaccination were significantly lower than that after COVID-19.

Substitution of citrate with tissue plasminogen activator (rt-PA) for catheter lock does not improve patency of tunnelled haemodialysis catheters in a randomised trial.

BACKROUND: The study aim was to establish if substitution of citrate with rt-PA for catheter lock once weekly can reduce the incidence of catheter-related blood stream infections (CR-BSI) or improve patency of tunneled haemodialysis catheters. METHODS: All incident patients undergoing insertion of a tunneled haemodialysis catheter were screened and included except those suffering infection or using oral anticoagulation. Study participants were randomized into two arms according to the solution applied as catheter lock: receiving either trisodium citrate (Citra-LockTM 4%) only or rt-PA (Actilyse® 1 mg/ml) on the middle session each week with citrate used on the first and third sessions. The incidence of CR-BSI (confirmed by positive blood culture), catheter non-function (complete obstruction), and malfunction (blood flow < 250 ml/min) was recorded. Statistical significance was tested with ANOVA, post hoc analysis was performed by means of multiple linear regression. RESULTS: Totally, 18 patients were included and followed during 655 haemodialysis sessions. No episode of CR-BSI was detected while 6 catheter non-functions (0.9% sessions) and 101 malfunctions (15.4% sessions) were recorded. The incidence of both events was equal between the study arms: 4 non-functions and 55 malfunctions in the rt-PA arm and 2 non-functions and 46 malfunctions in the citrate arm (p = 0.47 and p = 0.24, respectively). Additionally, the mean blood flow achieved did not differ significantly between the arms: 326 ± 1,8 and 326 ± 1,9 ml/min (p = 0.95) in rt-PA and citrate arms, respectively. Post hoc analysis identified time elapsed since previous session (ß = 0.12, p = 0.005) and malfunction on previous session (ß = 0.25, p < 0.001) as significant factors affecting the occurrence of malfunction. By contrast, the study arm, rt-PA application on previous session, and catheter vintage did not enter the model. CONCLUSION: Substitution of citrate with rt-PA for catheter lock does not reduce the incidence of catheter malfunction neither does it affect the blood flow achieved during haemodialysis. Catheter patency is related rather to the time interval between sessions and to previous malfunction (thus probably reflecting undefined individual factors). The incidence of CR-BSI within pre-selected haemodialysis population is sporadic (less than 1 per 4.3 patient years in our sample). TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12612000152820 . Retrospectively registered 03/02/2012.

Citrate-Buffered Dialysis Solution (Citrasate) Allows Avoidance of Anticoagulation During Intermittent Hemodiafiltration-At the Cost of Decreased Performance and Systemic Biocompatibility.

Reportedly, citrate-based dialysis solution enables heparin dose tapering or even complete exclusion, particularly in postdilution hemodiafiltration (HDF). The aim of the study was to verify this strategy in predilution setting and to assess its short-term safety, efficacy, and biocompatibility. Ten regular hemodialysis patients were assigned to predilution HDF on acetate- and citrate-based dialysis solutions (0.8 mmol/l trisodium citrate) at random order. Acetate HDF was performed using routine dose of heparin while citrate HDF was heparin free. Plasma calcium, thrombin-antithrombin complexes (TAT), and citrate levels were measured at 0, 30, 60, 120, and 240 min. Following each session, a semiquantitative dialyzer clotting score (DCT 1-5) was assessed and HDF adequacy was determined as spKt/V. Statistical relevance was tested by ANOVA with pP < 0.05 held significant, data are given as means ± standard deviations. All sessions were accomplished successfully, premature termination or circuit re-setting was not necessary. However, DCT was significantly higher in citrate-HDF compared to acetate-HDF regimen (3.4 ± 0.65 and 1.8 ± 0.79, respectively, P = 0.002) as well as TAT generation rate (increase per session by factor 11.0 ± 8.43 and 2.1 ± 1.26, respectively, P = 0.004 between regimens). Ionized calcium declined only by the end of citrate-HDF (from 1.09 ± 0.086 to 0.99 ± 0.030 mmol/L, P = 0.002) yet without accompanying clinical symptoms. Systemic citrate levels increased along the citrate-HDF session but stayed an order of magnitude below concentrations needed to establish citrate anticoagulation (peak at 0.276 ± 0.112 mmol/L). Dialysis adequacy estimated by spKt/V was found lower in citrate-HDF vs. acetate-HDF (1.48 ± 0.163 and 1.58 ± 0.165, respectively, P = 0.006). Although predilution HDF using citrate-based dialysate is feasible without heparin, both dialysis adequacy and biocompatibility is significantly compromised. Therefore, this approach can be adopted for a single procedure but is not acceptable on a regular basis.

Previous Vaccination and Age are More Important Predictors of Immune Response to Influenza Vaccine than Inflammation and Iron Status in Dialysis Patients.

BACKGROUND/AIMS: The immune response to influenza vaccine may be influenced by many factors, e.g. age, comorbidities or inflammation, and iron status. METHODS: We studied the vaccine-induced production of hemagglutination-inhibition antibodies (HI) in 133 hemodialysis patients (HD) and 40 controls. To identify variables associated with the immune response, uni- and multivariate regression analyses were performed with seroconversion in HI titers as a dependent variable, with demographics, comorbidities, previous vaccination, inflammation, and iron status as independent variables. RESULTS: Seroconversion rates were lower in HD than in controls [43% versus 73% (H1N1 strain; p < 0.05); 43% versus 53% (H3N2; P=NS); 36% versus 62% (B; p < 0.05)]. In both HD and control groups, the predictors of the inferior HI production were pre-vaccination seroprotection, vaccination in the previous season, and old age. We did not find associations between seroconversion rates and inflammation and iron status in the studied populations. This was also true for a subanalysis of patients without pre-vaccination seroprotection. CONCLUSION: The influenza vaccine-induced antibody production was lower in HD than in controls and was independent of inflammation and iron status in both groups. Besides dependence on dialysis, the variables associated with inferior seroconversion rates included pre-vaccination seroprotection, previous vaccination, and old age.

Relationship between hepcidin and ferritin in haemodialysed patients.

BACKGROUND: Hepcidin is a key regulator of iron metabolism. It binds to ferroportin and causes the trapping of iron in cells, rendering it unavailable for erythropoiesis. The synthesis of hepcidin is upregulated by high iron stores and inflammation. Haemodialysed patients suffer from anaemia and impaired iron management, the cause of which is multifactorial. Our aim was to describe the relationship between hepcidin and other parameters of iron metabolism, erythropoiesis, and inflammation. PATIENTS, MATERIALS AND METHODS: Complete blood cell counts, hepcidin, parameters of iron metabolism, and inflammation were measured in samples from 164 dialysed patients and 37 control healthy volunteers. Patients were subdivided according to the time of dialysis session. RESULTS: According to the time of haemodialysis, iron levels showed an insignificant tendency for diurnal variability, whereas hepcidin levels were markedly different. Non-parametric correlations showed a weak, but statistically significant correlation between parameters of iron metabolism and inflammation in the entire group of patients. No correlation was found between hepcidin and other biochemical parameters in controls. Non-parametric correlations were also performed in the time subgroups of patients. CONCLUSION: It seems that the influence of inflammation on hepcidin levels in haemodialysed patients is not crucial and other factors (e.g. hepcidin retention) are involved.

Pharmacoeconomic impact of different regimens to prevent cytomegalovirus infection in renal transplant recipients.

BACKGROUND: The aim of this study was to determine the cost impact of four different strategies for prevention of cytomegalovirus (CMV) disease after renal transplantation. METHODS: Hospitalization data and medical resource utilization data were prospectively collected alongside two randomized trials. In the first trial, the patients were randomized to 3-month prophylaxis with either oral ganciclovir (1 g t.i.d., n = 36) or valacyclovir (2 g q.i.d., n = 35), and to the control group (n = 12) managed by deferred therapy. In the second trial, the patients were randomly assigned to 3-month valacyclovir prophylaxis (n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia. The cost analysis involved all real costs directly related to CMV during the first year after renal transplantation. RESULTS: The mean CMV-associated costs per patient were EUR 4,581, 2,577, 4,968, and 8,050 in patients in the ganciclovir, valacyclovir, preemptive, and deferred therapy groups, respectively (p < 0.001). Valacyclovir prophylaxis was significantly less expensive than any other regimen. The cost of one episode of CMV disease was EUR 7,510 per patient. Due to excessive incidence of CMV disease, deferred therapy was the most expensive strategy (p < 0.001). CONCLUSIONS: Valacyclovir prophylaxis is less expensive strategy compared with any other regimen.

High ferritin, but not hepcidin, is associated with a poor immune response to an influenza vaccine in hemodialysis patients.

BACKGROUND: The immune response to vaccination in hemodialysis (HD) patients can be influenced by disorders of iron metabolism, iron overload or chronic inflammatory state. Elevated levels of hepcidin are considered a new marker of iron metabolism impairment and anemia of inflammation in HD patients. METHODS: We studied the effects of hepcidin, other markers of iron status and intravenous iron (Fe(iv)) on the response to an influenza vaccine (Influvac(R) subunit 2008/2009) in 40 HD patients. The immune response of HD patients was compared with that of 46 controls without renal disease according to serum antihemagglutinin antibody titer (anti-HA). RESULTS: A total of 31 HD patients (responders) attained seroconversion (at least a 4-fold increase in anti-HA) to at least 1 of 3 vaccine strains; 9 patients (nonresponders) did not respond to any strain. Responders did not differ from nonresponders in hepcidin [99 microg/l (36-200) vs. 97 microg/l (23-216), p = 0.97]. Responders had lower ferritin (571 +/- 291 vs. 821 +/- 309 microg/l, p = 0.031) and were administered higher doses of Fe(iv) within the last 12 weeks prior to vaccination [625 mg (312-625) vs. 312 mg (0-625), p = 0.029]. The seroconversion to A(H1N1), A(H3N2) and B strains was noted in 20, 52 and 40% of HD and in 11, 39 and 48% of controls, respectively (HD vs. controls, p = nonsignificant). The rates of seroprotection (anti-HA > or =40) to vaccine strains in HD (27, 85 and 95%) and controls (24, 96 and 98%) were also comparable. CONCLUSION: Antibody production following influenza vaccination in HD patients may be suppressed by very high ferritin levels. Hepcidin does not correlate with immune response and high levels of hepcidin may reflect its retention in HD patients. Fe(iv) administration was not associated with a poorer immune response. The immunogenicity of the A(H1N1) strain was inadequate in HD patients and controls alike.