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Background: Hemodialysis patients are at high risk for severe COVID-19 disease. Despite a high early seropositivity rate, dialysis patients mount a dampened immune response following two doses of an mRNA vaccine. This study aimed to evaluate the serologic response to a booster dose of BNT162b2 vaccine, 6 months after the second dose, among hemodialysis patients., Methods: This prospective study included 80 hemodialysis patients and 56 healthcare workers serving as controls. Serologic samples were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were the seropositivity rate and the log-transformed anti-SARS-COV-2 S1 (RBD) IgG as a continuous variable after the third dose. Secondary outcomes were the proportion of participants with "high response," defined as antibody levels >1,000 AU/mL, and "robust response," defined as antibody levels >4,160 AU/mL, according to prespecified cutoff values associated with neutralizing antibodies. Univariate and multivariate analyses were conducted to identify predictors of antibody response., Results: Among 80 hemodialysis patients, seropositivity rates improved from 78% (62/80) before the third dose, up to 96% (77/80) after the booster dose. The S1-RBD log-transformed antibody level increased significantly following the third dose from 2.15 ± 0.75 to 3.99 ± 0.83 compared with 2.65 ± 0.4 to 4.31 ± 0.42 in the control group. Among the hemodialysis patients, 88% (70/80) became "high responders" (>1,000 AU/mL), and of these, 79% (63/80) mounted a "robust response" (>4,160 AU/mL). Baseline antibody level, dialysis therapy, and hypoalbuminemia were independent predictors of impaired antibody response., Conclusions: A third dose of BNT162b2 COVID-19 vaccine, 6 months after the standard two-dose vaccination regimen, substantially improved humoral response in hemodialysis patients., (© 2022 S. Karger AG, Basel.)

Background: The emergence of new SARS-CoV-2 variants, which evade immunity, has raised the urgent need for multiple vaccine booster doses for vulnerable populations. In this study, we aimed to estimate the BNT162b2 booster effectiveness against the spread of coronavirus variants in a hemodialysis population. Methods: We compared humoral and cell-mediated immunity in 100 dialysis patients and 66 age-matched volunteers, before and 2-3 weeks following the first booster vaccine dose. Participants were assessed for anti-spike (RBD) antibody titer, neutralizing antibodies against B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants, spike-specific T-cell responses by FACS and infection outbreak after the first and second booster. Results: Anti-spike antibody titer was significantly increased following the booster, with reduced humoral and cellular response in the dialysis patients. Neutralizing antibody levels increased significantly after the booster dose, with an inferior effect (≤2 fold) against Omicron compared with the Delta variant. Furthermore, CD4+ and CD8+ T-cell activation by Delta spike protein was preserved in 70% of PBMCs from the dialysis patients. A second booster dose tended to reduce breakthrough infections in the dialysis patients. Conclusions: Until the release of an updated vaccine, BNT162b2 booster doses will improve the humoral and cell-mediated immunity against variants. These findings support the importance of repetitive booster doses for hemodialysis patients.

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yahav, Rahamimov, Mashraki, Ben-Dor, Steinmetz, Agur, Zingerman, Herman-Edelstein, Lichtenberg, Ben-Zvi, Bar-Haim, Cohen, Rotem, Elia, Margalit and Zvi.)

Background: End-stage kidney disease substantially increases the risk of severe COVID-19. However, despite early robust immunogenicity of the mRNA-SARS-CoV-2 vaccination in patients with hemodialysis, the longevity of humoral response in this high-risk population is still unknown., Methods: A prospective cohort study aimed to evaluate the longevity of serologic response in patients with hemodialysis, compared with a control group, 6 months following the second dose of the BNT162b2 vaccine. We assessed antibody response by quantitative measurement of IgG antibodies against the receptor-binding domain of the Spike protein (anti-S1-RBD IgG). Study outcomes were defined as a seropositivity rate and log-transformed anti-S1-RBD IgG levels at 6 months, and the change in antibody levels between 3 and 6 months., Findings: The cohort included 104 patients with hemodialysis and 84 controls. At a median time of 184 days (IQR, 183-188) following the second dose of the vaccine, 83/104 (79.8%) patients with hemodialysis maintained seropositivity for the anti-S1-RBD IgG level compared to 83/84 (98.8%) in the control group ( p < 0.001). The log-transformed antibody level was significantly lower in the hemodialysis group (2.23 ± 0.39 log AU/ml vs. 2.69 ± 0.65 log AU/ml, respectively, p < 0.001). Older age and hypoalbuminemia were the only variables that were found to be associated with reduced log-transformed antibody levels in univariate and multivariate analysis. There was no interaction between dialysis status and an antibody-level decline rate ( p = 0.972)., Conclusion: Among patients with hemodialysis, a seropositivity rate and anti-S1-RBD antibody titers were substantially reduced compared with a control group, at 6 months following the second dose of the BNT162b2 vaccine. These findings support the prioritization of patients with hemodialysis for a third "booster" dose., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Agur, Ben-Dor, Herman-Edelstein, Steinmetz, Lichtenberg, Schneider, Yahav, Rozen-Zvi and Zingerman.)

Data regarding immunogenicity of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among kidney transplant recipients in the months following vaccination are lacking. We aimed to investigate humoral immune response at 3-4 months post-vaccination among a cohort of kidney transplant recipients, compared with a control group of dialysis patients. Anti-spike antibodies were tested at 1 and 3-4 months after vaccination. Of 259 kidney transplant recipients tested at a median time of 110 days from second vaccine dose, 99 (38%) were seropositive, compared with 83% (101/122) of control patients. Younger age, better renal function and lower immunosuppression levels were associated with seropositivity. A total of 14% (13/94) of participants seropositive at 1 month became seronegative at follow-up and 11% (18/165) became seropositive. The latter were mainly individuals with higher antibody levels at 1 month. Antibody levels at 3-4 months were significantly reduced in both study groups, although the decline was more pronounced in the control group. Kidney transplant recipients present poor antibody response to mRNA SARS-CoV-2 vaccination, with only 38% seropositive at 3-4 months. Nevertheless, the decay in antibody response over time is modest, and some patients may present delayed response, reaching adequate antibody levels at 3-4 months. Low seropositivity rates in this group call for investigating other immunization strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Although congenital coronary artery anomalies are relatively rare, they are the second most common cause of sudden cardiac death among young athletes. When encountered in the cardiac catherization laboratory, they are often challenging to selectively engage, requiring multiple catheters, plus increased contrast volume and radiation exposure. In the setting of acute coronary syndromes, it is not infrequent that percutaneous intervention is delayed because of the inability to engage an anomalous coronary artery. The aim of this review is to provide a comprehensive and concise overview of coronary artery anomalies, with particular attention to diagnostic and guide catheter selection for each type of anomaly and recommendations on how to recognize the vessel course angiographically., Competing Interests: Funding Support and Author Disclosures Dr. Rogers is a proctor and consultant for Medtronic and Edwards Lifesciences; is an advisory board member for Medtronic; and holds equity interest in Transmural Systems. Dr. Slack is a proctor for Abbott. Dr. Pichard is medical director of Abbott Structural Heart. Dr. Waksman is an advisory board member for Amgen, Boston Scientific, Cardioset, Cardiovascular Systems, Medtronic, Philips, and Pi-Cardia; is a consultant for Amgen, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems, Medtronic, Philips, and Pi-Cardia; has received grant support from AstraZeneca, Biotronik, Boston Scientific, and Chiesi; is a member of the Speakers Bureaus for AstraZeneca and Chiesi; and is an investor in MedAlliance. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin-angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice., Methods: Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested., Results: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment., Conclusion: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.

Background: Proteinuria is common in kidney transplant recipients and has been established as a risk factor for graft-loss and mortality. In the general population, proteinuria has also been tied to a higher risk of cardiovascular disease. There is limited data exploring the association between changes in proteinuria over time and cardiovascular disease in kidney transplant recipients., Methods: In this retrospective cohort study we evaluated proteinuria as a time-varying covariate using urine dipstick protein values at 6 month intervals post-transplant. The primary outcome was the occurrence a major cardiovascular event (MACE). Univariate and multivariate time varying Cox model was used., Results: 579 patients were included in the final cohort. 120 episodes of MACE were documented in 98 patients. Time varying proteinuria was associated with MACE by univariate and multivariate analysis (HR 2.63, 95% CI 1.76-3.93, p < 0.001) and (HR 2.33, 95% CI 1.53-3.54, p < 0.001). Reduction of proteinuria to normal was associated with reduced risk of MACE compared with active proteinuria (HR 0.44, 95% CI 0.28-0.69, p < 0.001) and (HR 0.47, 95% CI 0.3-0.76, p = 0.002) for univariate and multivariate analyses. Exposure to proteinuria for more than 1 year was significantly associated with an increased risk of MACE for univariate and multivariate analysis (HR 2.33, 95% CI 1.48-3.68, p < 0.001) and (HR 2.18, 95% CI 1.37-3.45, p = 0.002) respectively, in comparison to exposure of less than 1 year., Conclusion: These findings may suggest that we should consider applying clinical interventions that are known to reduce cardiovascular morbidity in these patients.

Background: Acute kidney injury (AKI) was found to be associated with an increased risk of major adverse cardiovascular events (MACE) in the general population. Patients after kidney transplantation are prone to AKI events and are also at an increased risk of cardiovascular (CV) disease. The association between AKI and MACE in kidney transplant patients is yet to be studied., Methods: This retrospective single-center cohort study reviewed 416 adult renal allograft recipients transplanted between 2005 and 2010. AKI events were recorded starting 2 weeks after transplantation, or following discharge with a functioning graft. AKI was defined, according to the KDIGO criteria. The primary outcome was the composite of MACE starting 6 months after transplantation and all-cause mortality. For survival analysis, we used univariate and multivariate time varying Cox proportional hazard model., Results: One hundred and twenty-four patients (29.8%) had at least one episode of AKI. During the median follow-up time of 7.2 years (interquartile range 4.3-9.1), 144 outcome events occurred. By time varying Cox regression analysis, AKI was associated with an increased rate of CV outcomes or death (hazard ratio [HR] 1.96, 95% CI 1.36-2.81, p < 0.001), and the association remained significant by multivariate adjusted model (HR 1.76, 95% CI 1.18-2.63, p = 0.005). As for the different components of MACE, all-cause mortality and CV mortality were the only outcomes that were significantly associated with AKI. No interaction between AKI timing and MACE was found., Conclusion: AKI in kidney transplant recipient is associated with an increased risk of CV disease., (© 2019 The Author(s) Published by S. Karger AG, Basel.)