BackgroundAn increased risk of severe infectious disease and acute antibody-mediated rejection (AMR) has been described after ABOi renal transplantation. We performed a prospective renal transplant study up to 5 years posttransplant to detect long-term immunological effects of rituximab administration.MethodsMononuclear cell subsets in peripheral blood, regional lymph nodes and protocol biopsies, in-vitro T and B cell responses, serum sCD30 and neopterin were assessed in 85 renal transplant recipients (living donation: n=25 ABOi, n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible), and IgG anti-HLA antibodies by single antigen assay in ABOc and ABOi patients.ResultsAn increased frequency of severe infectious diseases in ABOi recipients (doubled versus ABOc within 2 years, P = 0.042) coincided with profoundly downregulated peripheral blood B cell subsets for at least 2 years, impaired in-vitro B cell responses (T-dependent: 2 years, versus ABOc: P = 0.004) and significantly lower CD4+ and CD8+ T cell counts (versus ABOc; 6 months, P = 0.046 and 3 months, P = 0.011, respectively). In regional lymph nodes, we found a significant downregulation of naive B cells (P = 0.031) and short lived plasma cells (P<0.0005) at the time of transplantation. In protocol graft biopsies, rituximab induced B cell depletion at 3 months (P<0.001), but counter-regulatory enhanced counts of T cells (P = 0.041), macrophages (P = 0.021) and plasma cells (P = 0.033) at 1 year. This immune activation was associated with a temporary rise in neopterin levels (P ≤ 0.024 versus ABOc, day 14 until 1 year), CD4 helper activity (P = 0.019 versus ABOc at 2 years) and NK cell counts (P = 0.034 versus ABOc, 4 years; P ≤ 0.040 versus DD, 3–5 years), a missing impact of rituximab on sCD30 levels and HLA antibody formation, and an increased frequency of biopsy-proven acute rejection (3–12 months, P = 0.003) and AMR (P = 0.008 within 5 years).ConclusionsAn increased frequency of severe infectious diseases in ABOi renal transplant recipients may be explained by rituximab-induced long-term immunological effects on CD4+ and CD8+ T cell counts and the prolonged depletion of B cell subsets together with compromised B cell responses. In protocol graft biopsies, rituximab induced early B cell depletion but counter-regulatory proinflammatory effects coinciding with an increased acute rejection frequency.Registration DetailsClinicalTrials.gov, identifier NCT01136395; EudraCT, identifier No.: 2009-012198-36.

It is important to learn more about the prevalence, severity and characteristics (i.e., which cognitive abilities are especially affected) of cognitive impairment in kidney transplant patients. Furthermore, the impact of living vs. deceased donor renal transplantation on cognitive outcome in this patient group needs further studies. Fifty-nine patients (43 men, age 55 ± 13 years) who received a deceased donor or living donor kidney transplant, completed a comprehensive neuropsychological test assessment. Neuropsychological tests explored the cognitive domains of verbal and visual memory, attention, and executive functions. Fifteen percent of the patients had mild, 25

Background. Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. Methods. The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. Results. Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. Conclusions. REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.

Purpose The association between sarcopenia of kidney transplant recipients and outcome after kidney transplantation (KT) has not yet been fully understood and is still considered controversial. The aim of our study was to analyze the impact of pre-transplant sarcopenia on graft function, postoperative complication rates, and survival of the patients after renal transplantation. Methods In this retrospective single-center study, all patients who underwent KT (01/2013–12/2017) were included. Demographic data, rejection rates, delayed graft function, and graft and patient survival rates were analyzed. Sarcopenia was measured in computed tomography images by the sex-adjusted Hounsfield unit average calculation (HUAC). Results During the study period, 111 single KTs (38 women and 73 men) were performed. Living donor kidney transplants were performed in 48.6%. In total, 32.4% patients had sarcopenia. Sarcopenic patients were significantly older (59.6 years vs. 49.8 years; p < 0.001), had a higher body mass index (BMI = 27.6 kg/m 2 vs. 25.0 kg/m 2 ; p = 0.002), and were more likely to receive deceased donor kidneys (72.2% vs. 41.3%; p = 0.002). Interestingly, 3 years after KT, the creatinine serum levels were significantly higher (2.0 mg/dl vs. 1.5 mg/dl; p = 0.001), whereas eGFR (39.9 ml/min vs. 53.4 ml/min; p = 0.001) and graft survival were significantly lower ( p = 0.004) in sarcopenic transplant recipients. Sarcopenic patients stayed in hospital significantly longer postoperatively than those who were non-sarcopenic. Conclusions At the time of kidney transplantation, sarcopenia was found to predict reduced long-term graft function and diminished graft survival after KT. The early identification of sarcopenic patients can not only enable an optimized selection of recipients, but also the initiation of pre-habilitation programs during the waiting period.

Background: An increased frequency of severe infectious diseases and BK viremia has been described after ABOi renal transplantation. As rituximab induction may alter immunoregulation in these patients, we analyzed clinically relevant immune parameters in a prospective renal transplant study up to 5 years posttransplant. Materials and Methods: Mononuclear cell subsets (peripheral blood; lymph nodes taken during transplant surgery), intracellular cytokine responses, CD4 helper function and in-vitro B cell responses were assessed pretransplant and up to 5 years posttransplant in 85 renal transplant recipients (living donation: n=25 ABO incompatible (ABOi) and n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible). Results: Severe infectious diseases occurred more often in ABOi than ABOc recipients within 2 years posttransplant (11/24 (46%) versus 6/30 (20%), P=0.042) but not beyond. The incidence of BK viremia was significantly enhanced in rituximab versus non-rituximab treated patients (1 year: 9/29 (31%) versus 4/54 (7%), P=0.009; 5 years: 10/30 (33%) versus 7/53 (13%), P=0.029). After rituximab induction in ABOi recipients, counts of peripheral blood B cell subsets were profoundly downregulated even 3 years posttransplant and reached the level of non-ABOi recipients after 4 years (memory B cells after 5 years). T-dependent and T-independent B cell responses were significantly impaired in ABOi patients up to 2 years posttransplant (P=0.010 and P=0.053, respectively) whereas CD4 helper activity was not compromised. CD4+ T cell counts were significantly lower in ABOi compared to ABOc recipients at 3 and 6 months (P=0.025 and P=0.046, respectively), but showed no differences in the percentage of Tregs. In regional lymph nodes of ABOi patients, we found a significant downregulation of CD20+ but not CD19+ B cells (P<0.0005), of naive B cells (P=0.031) and short lived plasma cells (P<0.0005) at the time of transplantation. Conclusion: An increased frequency of severe infectious diseases and BK viremia in rituximab treated ABOi renal transplant recipients may be explained by significantly downregulated CD4+ T cell counts up to 6 months and a profoundly delayed B cell repopulation, most pronounced with regard to memory B cells, together with compromised B cell responses up to 2 years posttransplant. IL-10, as a key player in chronic BK virus infection, was not upregulated in rituximab-treated ABOi transplant recipients.

The shortage of organs for transplantation remains a global problem. The retransplantation of a previously transplanted kidney might be a possibility to expand the pool of donors. We provide our experience with the successful reuse of transplanted kidneys in the Eurotransplant region.

Patients receiving maintenance dialysis (MD) are vulnerable to COVID-19-related morbidity and mortality. Currently, data on SARS-CoV-2-specific cellular and humoral immunity post-vaccination in this population are scarce. We conducted a prospective single-center study exploring the specific cellular (interferon-γ and interleukin-2 ELISpot assays) and humoral immune responses (dot plot array and chemiluminescent microparticle immunoassay [CMIA]) at 4 weeks and 6 weeks following a single dose or a complete homologous dual dose SARS-CoV-2 vaccine regimen in 60 MD patients (six with a history of COVID-19). Our results show that MD patients exhibit a high seroconversion rate (91.7%) but the anti-spike IgG antibodies (CMIA) tend to wane rapidly after full immunization. Only 51.7% of the patients developed T cell immune response. High anti-spike IgG antibodies may predict a better cellular immunity. While patients with prior COVID-19 showed the best response after one, SARS-CoV-2-naïve patients may benefit from a third vaccine injection.

Background Association of cognitive impairment with chronic kidney disease has been reported over the last decade. Individuals show better cognitive performance after kidney transplantation than individuals on dialysis but are more likely to be affected by cognitive impairment than age-matched comparison groups. Better knowledge of the prevalence as well as course and profile of cognitive impairment is important for the design of future studies assessing the clinical impact of cognitive impairment and developing management strategies. The goal of our study is to examine the extent of cognitive impairment before and after transplantation and to derive a distinct profile of cognitive function using standard neurocognitive tests. Furthermore, we aim to assess whether transplantation per se leads to an improvement in cognitive performance. Methods We are conducting a prospective single-center cohort study involving 100 kidney transplant individuals. Individuals who are wait-listed to receive a kidney transplantation or have already received one will be included in this study. Individuals will undergo a battery of detailed neurocognitive tests at baseline (in part before surgery), and then 3 and 12 months afterwards. Furthermore, the enrolled patients will complete a validated German version of the Cognitive Failure Questionnaire for self-assessment (s-CFQ) as well as the Hospital Anxiety and Depression Scale -Deutsche (HADS-D), a self-report screening instrument with two scales that capture anxiety and depression. In addition, a hair sample will be taken at each measurement time point for the determination of hair cortisol levels as a parameter for the cumulative hypothalamic-pituitary-adrenocortical axis activity over the previous three months. The primary outcome measure will be (a) the effect of kidney transplantation on the cognitive performance up to 12 months after transplantation and (b) the course of cognitive performance following kidney transplantation over time. Discussion The results of our study have potentially important implications for the prevention and treatment of cognitive impairment in kidney transplant individuals. By increasing our knowledge of the neurocognitive profile and assigning the corresponding deficits, it might be possible to create an individualized training program to positively impact cognitive deficits in kidney transplant patients.

Compared with the general population, patients receiving maintenance dialysis are at increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19). Currently, data on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-specific immunity post-vaccination in patients on maintenance dialysis are scarce given that the effectiveness of the vaccines has not been explicitly tested in this population due to their common exclusion from SARS-CoV-2 vaccination trials. We herein present data of the specific cellular (interferon-γ and interleukin-2 ELISpot assays) and humoral immune responses (dot plot array and chemiluminescent microparticle immunoassay) at 4 weeks and 6 weeks following a single dose or a complete homologous dual dose SARS-CoV-2 vaccine regimen in 60 adult patients on maintenance dialysis (six with a history of COVID-19). The data was produced in a framework of a project focused on a) quantifying the immune response after full vaccination, b) evaluating the short-term durability of immune response, and c) examining the reactogenicity of SARS-CoV-2 vaccine regimens in patients on maintenance dialysis.

IntroductionGaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week–3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients.MethodsWe recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios.ResultsWe found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, p=0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, p = 0.021, n=37; r=-0.43, p=0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (p=0.001 and p <0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months (p = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months (p = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs.ConclusionThese findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.

BACKGROUND:At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA.METHODS:Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018.RESULTS:Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program.CONCLUSIONS:Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.

Background: In a randomized prospective renal transplant study, we found that IL-10 plays a key role in chronic BKV infection. Tacr/ERL treatment significantly downregulated IL-10 responses and resulted in the lowest BK viremia incidence compared to CsA/MMF and Tacr/MMF treatment. As IL-10 acts as a potent B cell growth and differentiation factor, we wondered whether increased IL-10 responses in chronic BK-virus infection might promote HLA antibody formation. Materials and Methods: We analyzed intracellular cytokine responses, CD4+ T helper function and in-vitro B cell responses pretransplant and up to 24 months posttransplant. 105 renal transplant recipients were randomized to a CsA/MMF (n=35), Tacr/MMF (n=37) and Tacr/ERL (n=33) regimen, respectively. 18 drop-outs were excluded from analysis. Luminex-based HLA class I and II and MICA antibody screening was performed pretransplant and 1 and 2 years posttransplant. Results: In patients developing BK viremia, posttransplant HLA and MICA antibody formation was not increased compared to patients without BK viremia (P≥0.256). However, pretransplant increased CD4, CD8 and CD14 cell IL-10 production was significantly related to HLA class I antibody formation in CsA/MMF or Tacr/MMF treated patients (CD4 and CD8 cells: 1 year and 2 years, p<0.0005; CD14 cells: 1 year, p=0.013) but not in Tacr/ERL treated patients. Compared to CsA/MMF and Tacr/MMF patients, Tacr/ERL patients showed downregulated IL-10 responses (CD4 cells: p=0.009, 1 year; CD19 cells: p=0.002, 4 months; CD14 cells: p=0.048, 2 years) and increased T-dependent B cell responses (p=0.004, 4 months; p=0.019, 1 year) posttransplant. Only in Tacr/ERL patients, pretransplant CD8 cell IL-10R expression was significantly associated with HLA class I antibody formation (1 year and 2 years, p<0.0005). Conclusion: Patients developing BK viremia did not show a generally increased risk of HLA and MICA antibody formation within 2 years posttransplant. However, increased in-vitro IL-10 production pretransplant was significantly associated with posttransplant HLA class I antibody formation, with the exception of Tacr/ERL patients who showed downregulated IL-10 responses posttransplant. This study was supported by Astellas, Novartis and Roche Pharma.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008–2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and >= 4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for >= 4th DDRT.