Patients receiving hemodialysis are at high risk for both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe coronavirus disease 2019. A lifesaving vaccine is ...available, but sensitivity to vaccines is generally lower in patients on dialysis. Little is yet known about antibody responses after coronavirus disease 2019 (COVID-19) vaccination in this vulnerable group.
In this prospective single-center study, we included 22 patients on dialysis and 46 healthy controls from Heidelberg University Hospital between December 2020 and February 2021. We measured anti-S1 IgG with a threshold index for detection greater than one, neutralizing antibodies with a threshold for viral neutralization of ≥30%, and antibodies against different SARS-CoV2 fragments 17-22 days after the first dose and 18-22 days after the second dose of the mRNA vaccine BNT162b2.
After the first vaccine dose, four of 22 (18%) patients on dialysis compared with 43 of 46 (93%) healthy controls developed positive anti-S1 IgG, with a median anti-S1 IgG index of 0.2 (interquartile range, 0.1-0.7) compared with nine (interquartile range, 4-16), respectively. SARS-CoV2 neutralizing antibodies exceeded the threshold for neutralization in four of 22 (18%) patients on dialysis compared with 43 of 46 (93%) healthy controls, with a median percent inhibition of 11 (interquartile range, 3-24) compared with 65 (interquartile range, 49-75), respectively. After the second dose, 14 of 17 (82%) patients on dialysis developed neutralizing antibodies exceeding the threshold for viral neutralization and antibodies against the receptor binding S1 domain of the spike protein, compared with 46 of 46 (100%) healthy controls, respectively. The median percent inhibition was 51 (interquartile range, 32-86) compared with 98 (interquartile range, 97-98) in healthy controls.
Patients receiving long-term hemodialysis show a reduced antibody response to the first and second doses of the mRNA vaccine BNT162b2. The majority (82%) develop neutralizing antibodies after the second dose but at lower levels than healthy controls.
To study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 ...AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving
≥
7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6;
p
< 0.001), including urinary tract infection (
p
= 0.007), pneumonia (
p
= 0.003), opportunistic pneumonia (
p
= 0.022) and sepsis (
p
= 0.008). Especially pneumonia during the first 24 months after disease onset hazard ratio, 3.0 (95% CI 1.5 − 6.1) led to more deaths from infection (
p
= 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with
≥
7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.
Seroconversion after COVID‐19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an ...increasing threat to these patients. In this observational cohort study, we measured anti‐S1 IgG, surrogate neutralizing, and anti‐receptor‐binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age‐matched healthy controls. In addition, vaccine‐induced neutralization of SARS‐CoV‐2 wild‐type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live‐virus assay. After a third vaccine dose, anti‐S1 IgG, surrogate neutralizing, and anti‐receptor‐binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS‐CoV‐2 wild‐type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine‐induced cross‐neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti‐S1 IgG, surrogate neutralizing, and/or anti‐RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS‐CoV‐2 wild‐type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all).
A third mRNA vaccine dose increases immunogenicity in most kidney transplant recipients but, in comparison to healthy controls, kidney recipients have significantly reduced cross‐neutralizing antibody activity against the immune‐escaping B.1.1.529 (omicron) variant.
Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR).
In this study, we separately ...investigated the differentiation of CD8
regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing
NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7
CD45RA
CD31
recent thymic emigrant (RTE) cells differentiate
CD45RA
CD31
memory (CD31
memory) cells,
resting mature naïve (MN) cells or
direct proliferation into CD45RA
CD31
memory (CD31
memory) cells, consisting of both CCR7
CD45RA
central memory (CM) and CCR7
CD45RA
effector memory (EM) cells.
We found that both RTE Treg and Tresp differentiation
CD31
memory Tregs/Tresps was age-independently increased in KTR, who developed
NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8
Treg/Tresp ratio, suggesting this ratio as a reliable marker for
NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained
conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence.
In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8
Tregs more than that of CD8
Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.
Overhydration is a common problem in peritoneal dialysis patients and has been shown to be associated with mortality. However, it still remains unclear whether overhydration per se is predictive of ...mortality or whether it is mainly a reflection of underlying comorbidities. The purpose of our study was to assess overhydration in peritoneal dialysis patients using bioimpedance spectroscopy and to investigate whether overhydration is an independent predictor of mortality.
We analyzed and followed 54 peritoneal dialysis patients between June 2008 and December 2014. All patients underwent bioimpedance spectroscopy measurement once and were allocated to normohydrated and overhydrated groups. Overhydration was defined as an absolute overhydration/extracellular volume ratio > 15%. Simultaneously, clinical, echocardiographic and laboratory data were assessed. Heart failure was defined either on echocardiography, as a reduced left ventricular ejection fraction, or clinically according to the New York Heart Association functional classification. Patient survival was documented up until December 31st 2014. Factors associated with mortality were identified and a multivariable Cox regression model was used to identify independent predictors of mortality.
Apart from higher daily peritoneal ultrafiltration rate and cumulative diuretic dose in overhydrated patients, there were no significant differences between the 2 groups, in particular with respect to gender, body mass index, comorbidity and cardiac medication. Mortality was higher in overhydrated than in euvolemic patients. In the univariate analysis, increased age, overhydration, low diastolic blood pressure, raised troponin and NTproBNP, hypoalbuminemia, heart failure but not CRP were predictive of mortality. After adjustment, only overhydration, increased age and low diastolic blood pressure remained statistically significant in the multivariate analysis.
Overhydration remains an independent predictor of mortality even after adjustment for heart failure in peritoneal dialysis patients and should therefore be actively sought and managed in order to improve survival in this population.
Dysregulations in the differentiation of CD4+-regulatory-T-cells (Tregs) and CD4+-responder-T-cells (Tresps) are involved in the development of active systemic lupus erythematosus (SLE). Three ...differentiation pathways of highly proliferative inducible costimulatory molecule (ICOS)+- and less proliferative ICOS−-CD45RA+CD31+-recent-thymic-emigrant (RTE)-Tregs/Tresps via CD45RA−CD31+-memory-Tregs/Tresps (CD31+-memory-Tregs/Tresps), their direct proliferation via CD45RA+CD31−-mature naïve (MN)-Tregs/Tresps, and the production and differentiation of resting MN-Tregs/Tresp into CD45RA−CD31−-memory-Tregs/Tresps (CD31−-memory-Tregs/Tresps) were examined in 115 healthy controls, 96 SLE remission patients, and 20 active disease patients using six color flow cytometric analysis. In healthy controls an appropriate sequence of these pathways ensured regular age-dependent differentiation. In SLE patients, an age-independently exaggerated differentiation was observed for all Treg/Tresp subsets, where the increased conversion of resting MN-Tregs/Tresps particularly guaranteed the significantly increased ratios of ICOS+-Tregs/ICOS+-Tresps and ICOS−-Tregs/ICOS−-Tresps during remission. Changes in the differentiation of resting ICOS+-MN-Tresps and ICOS−-MN-Tregs from conversion to proliferation caused a significant shift in the ratio of ICOS+-Tregs/ICOS+-Tresps in favor of ICOS+-Tresps and a further increase in the ratio of ICOS−-Tregs/ICOS−-Tresps with active disease. The differentiation of ICOS+-RTE-Tregs/Tresps seems to be crucial for keeping patients in remission, where their limited production of proliferating resting MN-Tregs may be responsible for the occurrence of active disease flares.
Antibody response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is impaired in kidney transplant recipients. Emerging variants, such as B.1.617.2 (
), are of ...particular concern because of their higher transmissibility and partial immune escape. Little is known about protection against these variants in immunocompromised patients.
In this prospective two-center study, antispike 1 IgG and surrogate neutralizing antibodies were measured in 173 kidney transplant recipients and 166 healthy controls with different vaccination schedules. In addition, different SARS-CoV-2 epitope antibodies from 135 vaccinated kidney transplant recipients were compared with antibodies in 25 matched healthy controls after second vaccination. In 36 kidney transplant recipients with seroconversion, neutralization against B.1.1.7 (
), B.1.351 (
), and B.1.617.2 (
) was determined on VeroE6 cells and compared with neutralization in 25 healthy controls.
Kidney transplant recipients had significantly lower seroconversion rates compared with healthy controls. After the second vaccination, antispike 1, antireceptor-binding domain, and surrogate neutralizing antibodies were detectable in 30%, 27%, and 24% of kidney transplant recipients, respectively. This compares with 100%, 96%, and 100% in healthy controls, respectively (
<0.001). Neutralization against B.1.1.7 was detectable in all kidney transplant recipients with seroconversion, with a median serum dilution that reduces infection of cells by 50% of 80 (interquartile range, 80-320). In contrast, only 23 of 36 (64%) and 24 of 36 (67%) kidney transplant recipients showed neutralization against B.1.351 and B.1.617.2, respectively, with median serum dilutions that reduce infection of cells by 50% of 20 (interquartile range, 0-40) and 20 (interquartile range, 0-40), respectively. Neutralization against different variants was significantly higher in healthy controls (
<0.001), with all patients showing neutralization against all tested variants.
Seroconverted kidney transplant recipients show impaired neutralization against emerging variants of concern after standard two-dose vaccination.
Observational study to assess the SARS-CoV-2 specific immune response in kidney transplant recipients (COVID-19 related immune response), DRKS00024668.
Despite limited data on safety and immunogenicity, heterologous prime-boost vaccination is currently recommended for individuals with ChAdOx1 nCoV-19 prime immunization in certain age groups. In this ...prospective, single-center study we included 166 health care workers from Heidelberg University Hospital who received either heterologous ChAdOx1 nCoV-19/BNT162b2, homologous BNT162b2 or homologous ChAdOx1 nCoV-19 vaccination between December 2020 and May 2021. We measured anti-S1 IgG, SARS-CoV-2 specific neutralizing antibodies, and antibodies against different SARS-CoV-2 fragments 0–3 days before and 19–21 days after boost vaccination. Before boost, 55/70 (79%) ChAdOx1 nCoV-19-primed compared with 44/45 (98%) BNT162b2-primed individuals showed positive anti-S1 IgG with a median (IQR) anti-S1 IgG index of 1.95 (1.05–2.99) compared to 9.38 (6.26–17.12). SARS-CoV-2 neutralizing antibodies exceeded the threshold in 24/70 (34%) of ChAdOx1 nCoV-19-primed and 43/45 (96%) of BNT162b2-primed individuals. After boosting dose, median (IQR) anti-S1 IgG index in heterologous ChAdOx1 nCoV-19/BNT162b2 vaccinees was 116.2 (61.84–170), compared to 13.09 (7.03–29.02) in homologous ChAdOx1 nCoV-19 and 145.5 (100–291.1) in homologous BNT162b2 vaccinees. All boosted vaccinees exceeded the threshold for neutralization, irrespective of their vaccination scheme. Vaccination was well-tolerated overall. We show that heterologous ChAdOx1 nCoV-19/BNT162b2 vaccination is safe and induces a strong and broad humoral response in healthy individuals.
Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with ...significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G IgG), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.
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