Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients.

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients.

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

PURPOSE: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. METHODS: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. RESULTS: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. CONCLUSION: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

High altitude trekking after lung transplantation: a prospective study using lung ultrasound to detect comets tails for interstitial pulmonary edema in lung transplant recipients and healthy volunteers.

The intensity of physical activity which can be tolerated after lung transplantation and the tolerance to prolonged exercise at high altitude are poorly investigated. Lung ultrasound comet tails have been used in the diagnosis of interstitial pulmonary edema and high pulmonary altitude edema. The aim was to assess the number of lung ultrasound comet tails and to monitor changes in the optic nerve sheath diameter (ONSD) during a climb to the top of Mount Kilimanjaro in 10 lung transplant recipients and 10 healthy controls at three different altitude levels: 1360, 3505, 4900 m. Lung transplant recipients showed a constant increase in comet tail scores with altitude, whereas control subjects only showed an increase at the highest measurement point. Differences between groups (transplant versus control) reached significance only after the first ascend: 0.9 (95% CI: -0.41; 2.21) vs. 0.1 (95% CI: -0.12; 0.32) (P = 0.2; 1360 m), 2.33 (95% CI: 0.64; 4.02) vs. 0.3 (95% CI: -0.18; 0.78) (P = 0.04; 3505 m), and 4.11 (95% CI: 0.13; 0.34) vs. 2.9 (95% CI: 0.49; 5.31) (P = 0.15; 4900 m); ONSD increased significantly in both groups from 3.53 (95% CI: 0.34; 0.66) at 1360 m to 4.11 (95% CI: 0.36; 0.71) at 4900 m (P < 0.05). Lungs of transplant recipients are able to adapt to altitude and capable of performing prolonged exercise at high altitude after slow ascend.

A Pilot Assessment of Carotid and Brachial Artery Blood Flow Estimation Using Ultrasound Doppler in Cardiac Surgery Patients.

OBJECTIVES: To estimate carotid and brachial artery blood flow with Doppler ultrasound in cardiac surgery patients and relate such estimates to cardiac index, lactate levels, and markers of renal function. DESIGN: A prospective observational study. SETTING: A teaching hospital. PARTICIPANTS: Twenty-five elective cardiac surgery patients. INTERVENTIONS: The authors measured bilateral carotid and brachial artery blood flows using Doppler ultrasound and, simultaneously, cardiac index using a pulmonary artery catheter; lactate and serum creatinine levels; and urine output. The relationship between these indices and biomarkers was assessed statistically. MEASUREMENTS AND MAIN RESULTS: Median carotid arterial blood flow was estimated at 0.323 L/min (interquartile ratio [IQR], 0.256-0.429 L/min) on the right and 0.308 L/min (IQR, 0.247-0.376 L/min) on the left at baseline. Median brachial arterial blood flow was estimated at 0.063 L/min (IQR, 0.039-0.115 L/min) on the right and 0.063 L/min (IQR, 0.039-0.081 L/min) on the left at baseline. There was a weak correlation between right- and left-sided flows (brachial: rho = 0.285; carotid: rho = 0.384) and between brachial and carotid flow (right: rho = 0.135, left: rho = 0.225). There also was a weak correlation between cardiac index and brachial flow (right: rho = 0.215; left: rho = 0.320) and carotid flow (left: rho = 0.159) immediately after surgery, and no correlation 1 day after surgery (right brachial: rho = -0.010; left brachial: rho = -0.064; left carotid: rho = -0.060). There were no significant correlations between carotid or brachial flows and lactate and serum creatinine levels or urine output. CONCLUSIONS: In cardiac surgery patients, Doppler-estimated carotid and brachial arterial blood flows have only a weak correlation with cardiac index and no correlation with lactate or creatinine levels or urine output. Thus, Doppler estimation of these blood flows cannot be used to provide noninvasive estimates of cardiac index in patients after cardiac surgery.

Effect of Preload Alterations on Left Ventricular Systolic Parameters Including Speckle-Tracking Echocardiography Radial Strain During General Anesthesia.

OBJECTIVES: Frequently used parameters for evaluation of left ventricular systolic function are load-sensitive. However, the impact of preload alterations on speckle-tracking echocardiographic parameters during anesthesia has not been validated. Therefore, two-dimensional (2D) speckle-tracking echocardiography radial strain (RS) was assessed during general anesthesia, simulating 3 different preload conditions. DESIGN: Single-center prospective observational study. SETTING: University hospital. PARTICIPANTS: Thirty-three patients with normal left ventricular systolic function undergoing major surgery. INTERVENTIONS: Transgastric views of the midpapillary level of the left ventricle were acquired at 3 different positions. MEASUREMENTS AND MAIN RESULTS: Fractional shortening (FS), fractional area change (FAC), and 2D speckle-tracking echocardiography RS were analyzed in the transgastric midpapillary view. Considerable correlation above 0.5 was found for FAC and FS in the zero and Trendelenburg positions (r = 0.629, r = 0.587), and for RS and FAC in the anti-Trendelenburg position (r = 0.518). In the repeated-measures analysis, significant differences among the values measured at the 3 positions were found for FAC and FS. For FAC, there were differences up to 2.8 percentage points between the anti-Trendelenburg position and the other 2 positions. For FS, only the difference between position zero and anti-Trendelenburg was significant, with an observed change of 1.66. Two-dimensional RS was not significantly different at all positions, with observed changes below 1 percentage point. CONCLUSIONS: Alterations in preload did not result in clinically relevant changes of RS, FS, or FAC. Observed changes for RS were smallest; however, the variation of RS was larger than that of FS or FAC.

The effect of a bolus dose of intravenous lidocaine on the minimum alveolar concentration of sevoflurane: a prospective, randomized, double-blinded, placebo-controlled trial.

BACKGROUND: The anesthetic effect of volatile anesthetics can be quantified by the minimum alveolar concentration (MAC) of the drug that prevents movement in response to a noxious stimulus in 50% of patients. The underlying mechanism regarding how immobilization is achieved by volatile anesthetics is not thoroughly understood, but several drugs affect MAC. In this study, we investigated the effect of a single IV bolus dose of lidocaine on the MAC of sevoflurane in humans. METHODS: We determined the MAC for sevoflurane using the Dixon "up-and-down" method in 3 groups of patients, aged 30 to 65 years, who underwent elective surgery (30 patients per group). Study medication (placebo, 0.75 mg·kg(-1) lidocaine or 1.5 mg·kg(-1) lidocaine) was administered 3 minutes before skin incision after a 15-minute equilibration period and the response to skin incision was recorded (movement versus no movement). RESULTS: MAC was 1.86% ± 0.40% in the placebo and 1.87% ± 0.45% in the 0.75 mg·kg(-1) lidocaine group (P = 1.00). MAC was 1.63% ± 0.24% in the 1.5 mg·kg(-1) lidocaine group, which was significantly lower than that of the placebo group (mean difference of 0.23% sevoflurane [95% adjusted confidence interval {CI}, 0.03-0.43]; P = 0.022). No significant difference was observed between the 0.75 mg·kg(-1) lidocaine and the placebo groups (mean difference of -0.01% sevoflurane [95% adjusted CI, -0.27 to 0.25]; P = 1). CONCLUSIONS: IV 1.5 mg·kg(-1) lidocaine decreased the MAC by at least 0.03% sevoflurane (mean difference 0.23% sevoflurane [95% adjusted CI, 0.03-0.43]). We did not observe a significant reduction in the MAC of sevoflurane with the IV administration of 0.75 mg·kg(-1) lidocaine.

Risk Factors for Hepatitis E Virus Infection and Eating Habits in Kidney Transplant Recipients.

There is a significant risk for ongoing and treatment-resistant courses of hepatitis E virus (HEV) infection in patients after solid organ transplantation. The aim of this study was to identify risk factors for the development of hepatitis E, including the dietary habits of patients. We conducted a retrospective single-center study with 59 adult kidney and combined kidney transplant recipients who were diagnosed with HEV infection between 2013 and 2020. The outcomes of HEV infections were analyzed during a median follow-up of 4.3 years. Patients were compared with a control cohort of 251 transplant patients with elevated liver enzymes but without evidence of an HEV infection. Patients' alimentary exposures during the time before disease onset or diagnosis were assessed. Previous intense immunosuppression, especially treatment with high-dose steroids and rituximab, was a significant risk factor to acquire hepatitis E after solid organ transplantation. Only 11 out of 59 (18.6%) patients reached remission without further ribavirin (RBV) treatment. A total of 48 patients were treated with RBV, of which 19 patients (39.6%) had either viral rebounds after the end of treatment or did not reach viral clearance at all. Higher age (>60 years) and a BMI ≤ 20 kg/m2 were risk factors for RBV treatment failure. Deterioration in kidney function with a drop in eGFR (p = 0.046) and a rise in proteinuria was more common in patients with persistent hepatitis E viremia. HEV infection was associated with the consumption of undercooked pork or pork products prior to infection. Patients also reported processing raw meat with bare hands at home more frequently than the controls. Overall, we showed that the intensity of immunosuppression, higher age, a low BMI and the consumption of undercooked pork meat correlated with the development of hepatitis E.

COVID-19 Outcomes in Kidney Transplant Recipients in a German Transplant Center.

Kidney transplant recipients (KTRs) show higher morbidity and mortality from COVID-19 than the general population and have an impaired response to vaccination. We analyzed COVID-19 incidence and clinical outcomes in a single-center cohort of approximately 2500 KTRs. Between 1 February 2020 and 1 July 2022, 578 KTRs were infected with SARS-CoV-2, with 25 (4%) recurrent infections. In total, 208 KTRs (36%) were hospitalized, and 39 (7%) died. Among vaccinated patients, infection with the Omicron variant had a mortality of 2%. Unvaccinated patients infected with the Omicron variant showed mortality (9% vs. 11%) and morbidity (hospitalization 52% vs. 54%, ICU admission 12% vs. 18%) comparable to the pre-Omicron era. Multivariable analysis revealed that being unvaccinated (OR = 2.15, 95% CI [1.38, 3.35]), infection in the pre-Omicron era (OR = 3.06, 95% CI [1.92, 4.87]), and higher patient age (OR = 1.04, 95% CI [1.03, 1.06]) are independent risk factors for COVID-19 hospitalization, whereas a steroid-free immunosuppressive regimen was found to reduce the risk of COVID-19 hospitalization (OR = 0.51, 95% CI [0.33, 0.79]). This suggests that both virological changes in the Omicron variant and vaccination reduce the risk for morbidity and mortality from COVID-19 in KTRs. Our data extend the knowledge from the general population to KTRs and provide important insights into outcomes during the Omicron era.

Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation.

Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B-cell-specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B-cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL-10 production in primary stimulated B cells. In addition, B-cell co-cultures with pre-activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T-cell-dependent immunoglobulin production. Sotrastaurin did not inhibit B-cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B-cell functions in a dose-dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T-cell-dependent B-cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B-lymphocyte function and activation.

Declining Course of Humoral Immune Response in Initially Responding Kidney Transplant Recipients after Repeated SARS-CoV-2 Vaccination.

The immunogenicity of SARS-CoV-2 vaccines in kidney transplant recipients is limited, resulting in inadequately low serological response rates and low immunoglobulin (Ig) levels, correlating with reduced protection against death and hospitalization from COVID-19. We retrospectively examined the time course of anti-SARS-CoV-2 Ig antibody levels after up to five repeated vaccinations in 644 previously nonresponding kidney transplant recipients. Using anti SARS-CoV-2 IgG/IgA ELISA and the total Ig ECLIA assays, we compared antibody levels at 1 month with levels at 2 and 4 months, respectively. Additionally, we correlated the measurements of the used assays. Between 1 and 2 months, and between 1 and 4 months, mean anti-SARS-CoV-2 Ig levels in responders decreased by 14% and 25%, respectively, depending on the assay. Absolute Ig values and time course of antibody levels showed high interindividual variability. Ig levels decreased by at least 20% in 77 of 148 paired samples with loss of sufficient serological protection over time occurring in 18 out of 148 (12.2%). IgG ELISA and total Ig ECLIA assays showed a strong positive correlation (Kendall's tau = 0.78), yet the two assays determined divergent results in 99 of 751 (13.2%) measurements. IgG and IgA assays showed overall strong correlation but divergent results in 270 of 1.173 (23.0%) cases and only weak correlation of antibody levels in positive samples. Large interindividual variability and significant loss of serological response after 4 months supports repeated serological sampling and consideration of shorter vaccination intervals in kidney transplant recipients.

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination.

Predictors of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Patients: Baseline Characteristics, Immunosuppression, and the Role of IMPDH Monitoring.

Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m2), and responders were younger (53.0 vs. 57.4 years). Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose (AUC 0.84 vs. 0.62, p < 0.001). Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.

Comparison of two new generation pulse oximeters during emergency ambulance transportation.

OBJECTIVES: We wanted to test whether there is a difference between the total number and duration of malfunctions and a correlation between the oxygen saturation and pulse rate values of two new generation pulse oximeters (Masimo 'Radical 7' and Nellcor 'N 600') during emergency ambulance transportation. METHODS: Patients were monitored with two pulse oximeters ('Radical 7' and 'N 600') on different randomly selected fingers of the same hand during transportation. Data of both devices were recorded continuously by a laptop computer. RESULTS: Fifty-two patients with signs of peripheral vasoconstriction (including 22 patients with a blood pressure ≤100/60) were included. There were 0.21 ± 0.72 (0-4) malfunctions per patient lasting for a mean 113.55 ± 272.55 s in the 'Radical 7' and 0.13 ± 0.49 (0-3) malfunctions per patient with a mean duration of 301.0 ± 426.58 s in the 'N 600'. Oxygen saturation and pulse rate values correlated significantly [r² = 0.9608 (SpO2), r² = 0.9608 (pulse rate)] between the devices and showed a bias of -0.177770 (SpO2) and 0.310883 (pulse rate) with a standard deviation of 1.68367 (SpO2) and 4.46532 (pulse rate) in a Bland-Altman test. CONCLUSION: Although number and duration of malfunctions did not differ significantly between the devices, they showed a very low number of malfunctions even in hypotensive patients with peripheral vasoconstriction. Oxygen saturation correlated significantly in the two devices investigated at 49.409 time points. In addition, pulse rate also correlated significantly.

Estimation of pulmonary artery pressure with transesophageal echocardiography: An observer-blinded test accuracy study.

ABSTRACT: With the declining use of the pulmonary artery catheter (PAC), transesophageal echocardiography (TEE) has become an appealing alternative to obtain pulmonary artery pressure non-invasively using the simplified Bernoulli equation. The validation of this method in the perioperative setting has been scarce with no clear recommendations about which view is the most accurate to estimate right ventricular systolic pressure (RVSP).Therefore, we performed a prospective, observer-blinded, diagnostic test accuracy study to assess the difference in systolic pulmonary artery pressure (sysPAP) measuring both, invasively sysPAP and estimated RVSP with TEE in 3 different views: the mid-esophageal (ME) 4Chamber, the ME right ventricular (RV) inflow-outflow and the ME modified bicaval view.To show a clinically significant difference of at least 10% in RVSP, we included 40 cardiac surgical patients divided into 3 subgroups: Patients with mild to moderate tricuspid regurgitation (TR) and mean PAP <25 mm Hg, patients with mild to moderate TR and mean PAP≥ 25 mm Hg, and patients with severe TR.For the whole cohort, bias of estimated RVSP compared to measured sysPAP was 5.27 mm Hg, precision was 7.96 mm Hg, limits of agreement were -10.66 to 21.19 mm Hg. The best agreement between the 2 methods was found in patients with severe TR and in the ME RV inflow-outflow and the modified bicaval view. Good Doppler signals were available in 35% and 46% in these views, and in 20% in the ME 4 chamber view.The estimation of the sysPAP by TEE cannot be considered reliable in the clinical perioperative setting. Only measurements that provide a full Doppler envelope show sufficient precision to provide accurate estimations.

Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis.

Patients with kidney failure have notoriously weak responses to common vaccines. Thus, immunogenicity of novel SARS-CoV-2 vaccines might be impaired in this group. To determine immunogenicity of SARS-CoV-2 vaccination in patients with chronic dialysis, we analyzed the humoral and T-cell response after two doses of mRNA vaccine Tozinameran (BNT162b2 BioNTech/Pfizer). This observational study included 43 patients on dialysis before vaccination with two doses of Tozinameran 21 days apart. Overall, 36 patients completed the observation period until three weeks after the second dose and 32 patients were further analyzed at week 10. Serum samples were analyzed by SARS-CoV-2 specific IgG and IgA antibodies ~1, ~3-4 and ~10 weeks after the second vaccination. In addition, SARS-CoV-2-specific T-cell responses were assessed at ~3-4 weeks by an interferon-gamma release assay (IGRA). Antibody and T cell outcomes at this timepoint were compared to a group of 44 elderly patients not on dialysis, after immunization with Tozinameran. Median age of patients on chronic dialysis was 74.0 years (IQR 66.0, 82.0). The proportion of males was higher (69.4%) than females. Only 20/36 patients (55.6%, 95%CI: 38.29-71.67) developed SARS-CoV-2-IgG antibodies at the first sampling, whereas 32/36 patients (88.9%, 95%CI: 73.00-96.38) demonstrated IgG detection at the second sampling. In a longitudinal follow-up at ~10 weeks after the second dose, the proportion of dialysis patients reactive for anti-SARS-CoV-2-IgG decreased to 27/32 (84.37%, 95%CI: 66.46-94.10) The proportion of anti-SARS-CoV-2 S1 IgA decreased from 33/36 (91.67%; 95%CI: 76.41-97.82) at weeks 3-4 down to 19/32 (59.38; 95%CI: 40.79-75.78). Compared to a cohort of vaccinees with similar age but not on chronic dialysis seroconversion rates and antibody titers were significantly lower. SARS-CoV-2-specific T-cell responses 3 weeks after second vaccination were detected in 21/31 vaccinated dialysis patients (67.7%, 95%CI: 48.53-82.68) compared to 42/44 (93.3%, 95%CI: 76.49-98.84) in controls of similar age. Patients on dialysis demonstrate a delayed, but robust immune response three to four weeks after the second dose, which indicates effective vaccination of this vulnerable group. However, the lower immunogenicity of Tozinameran in these patients needs further attention to develop potential countermeasures such as an additional booster vaccination.

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.

Effects of the new immunosuppressive agent AEB071 on human immune cells.

UNLABELLED: BACKGROUND. The novel immunosuppressive agent AEB071 is currently being evaluated for its capability to prevent rejection after kidney transplantation as a potential adjunct to calcineurin inhibitor-based regimen. AEB071 is a selective protein kinase C inhibitor and has been shown to be well tolerated in humans. We here present extensive in vitro studies that contribute to the understanding of AEB071 effects on human lymphocyte, natural killer (NK) cell and dendritic cell (DC) action. METHODS: The impact of AEB071 on several T-cell activation and costimulatory markers was assessed. Furthermore, assays were performed to study the effect on T-cell proliferation and intracellular cytokine production. Additionally, the effect of AEB071 on DC maturation and their capacity to stimulate allogeneic T-cells was examined. Also, an evaluation of AEB071 effects on the lytic activity of human NK cells was performed. RESULTS: We were able to show that T-cell proliferation and cytokine production rates are significantly reduced after AEB071 administration. Also, mitogen-induced T-cell activation characterized by expression levels of surface markers could be significantly inhibited. In contrast, the T-cell stimulatory capacity of AEB071-treated mature monocyte-derived DC (Mo-DC) is not reduced, and AEB071 administration does not prevent lipopolysaccharide (LPS)-induced Mo-DC maturation. It could be demonstrated that AEB071 significantly inhibited the cytotoxic activity of NK cells. CONCLUSIONS: The promising immunosuppressive agent AEB071 has a strong impact on T-cell activation, proliferation and cytokine production as well as NK cell activity, but not DC maturation in vitro, and therefore, seems to function T-cell and NK cell specific via protein kinase C (PKC) inhibition.