Complement activation and long-term graft function in ABO-incompatible kidney transplantation

BACKGROUND: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.METHODS: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.RESULTS: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.</p

Complement activation during OKT3 treatment: A possible explanation for respiratory side effects

Complement activation during OKT3 treatment: A possible explanation for respiratory side effects. Respiratory side effects that sometimes occur during treatment with anti-CD3 MAb OKT3 might result from pulmonary sequestration of activated neutrophils. Therefore, we studied complement activation in relation to activation and pulmonary sequestration of neutrophils during antirejection treatment with OKT3. In each of nine patients studied, plasma C3a-desarg and C4b/c levels increased compared with pretreatment values already in the first sample taken 15 minutes after the first dose of OKT3 (P < 0.05), with peak values at 15 and 30 minutes, respectively. Levels of neutrophil degranulation product elastase (complexed to α1-antitrypsin) also increased already at 15 minutes after the first dose of OKT3 (P < 0.05), which is before elevated levels of the cytokines TNFα, IL-6 or IL-8 were detectable. In contrast, upon subsequent OKT3 administrations or in the control group treated with methylprednisolone, neither complement activation, cytokine release nor neutrophil degranulation occurred. In five studied patients treated with OKT3, pulmonary sequestration of radiolabeled granulocytes was observed from 3 until 15 minutes after the first dose of OKT3, together with peripheral blood granulocytopenia, which lasted at least 30 minutes. In conclusion, we demonstrate a simultaneous activation of complement and pulmonary sequestration of activated granulocytes immediately following the first dose of OKT3. These phenomena may be involved in the development of respiratory side effects complicating this therapy

Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients

Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response. METHODS. Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome. RESULTS. The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA); chronic lung disease, heart failure, and diabetes; increased age; shorter time after transplantation; lower body mass index; lower kidney function; no alcohol consumption; ≥2 transplantations; and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations. CONCLUSIONS. In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies

Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay

HCMV infection, reinfection or reactivation occurs in 60% of untreated solid organ transplant (SOT) recipients. Current clinical approaches to HCMV management include pre-emptive and prophylactic antiviral treatment strategies. The introduction of immune monitoring to better stratify patients at risk of viraemia and HCMV mediated disease could improve clinical management. Current approaches quantify T cell IFNγ responses specific for predominantly IE and pp65 proteins ex vivo, as a proxy for functional control of HCMV in vivo. However, these approaches have only a limited predictive ability. We measured the IFNγ T cell responses to an expanded panel of overlapping peptide pools specific for immunodominant HCMV proteins IE1/2, pp65, pp71, gB, UL144, and US3 in a cohort of D+R– kidney transplant recipients in a longitudinal analysis. Even with this increased antigen diversity, the results show that while all patients had detectable T cell responses, this did not correlate with control of HCMV replication in some. We wished to develop an assay that could directly measure anti-HCMV cell-mediated immunity. We evaluated three approaches, stimulation of PBMC with (i) whole HCMV lysate or (ii) a defined panel of immunodominant HCMV peptides, or (iii) fully autologous infected cells co-cultured with PBMC or isolated CD8+ T cells or NK cells. Stimulation with HCMV lysate often generated non-specific antiviral responses while stimulation with immunodominant HCMV peptide pools produced responses which were not necessarily antiviral despite strong IFNγ production. We demonstrated that IFNγ was only a minor component of secreted antiviral activity. Finally, we used an antiviral assay system to measure the effect of whole PBMC, and isolated CD8+ T cells and NK cells to control HCMV in infected autologous dermal fibroblasts. The results show that both PBMC and especially CD8+ T cells from HCMV seropositive donors have highly specific antiviral activity against HCMV. In addition, we were able to show that NK cells were also antiviral, but the level of this control was highly variable between donors and not dependant on HCMV seropositivity. Using this approach, we show that non-viraemic D+R+ SOT recipients had significant and specific antiviral activity against HCMV

Employment and ability to work after kidney transplantation in the Netherlands:The impact of preemptive versus non-preemptive kidney transplantation

Background: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. Methods: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). Results: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6 +/- 11.3 vs. PKT 31.1 +/- 9.6, L-nPKT 30.1 +/- 9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. Conclusions: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole

Communion by extension : discrepancies between policy and practice

The growing practice of Communion by Extension was given formal authorisation by the Church of England General Synod in 2000 with the expectation that it would be used in particular circumstances, including explicitly the rural multi-church benefice. This paper reviews the historical origins of the practice of Communion by Extension and clarifies the intentions of the authorisation given in 2000. Then the intentions of the 2000 authorisation are compared and contrasted with current parochial practice within one English diocese. Considerable divergence is found. Five main themes are identified and discussed: the relationship between worship and mission; the pressures on clerical time; sacramental self-sufficiency; the value given to familiarity; and the choice between reservation and congregationalism

Temporal trends in the quality of deceased donor kidneys and kidney transplant outcomes in Europe:an analysis by the ERA-EDTA Registry

BACKGROUND: We investigated 10-year trends in deceased donor kidney quality expressed as the kidney donor risk index (KDRI) and subsequent effects on survival outcomes in a European transplant population. METHODS: Time trends in the crude and standardized KDRI between 2005 and 2015 by recipient age, sex, diabetic status and country were examined in 24 177 adult kidney transplant recipients in seven European countries. We determined 5-year patient and graft survival probabilities and the risk of death and graft loss by transplant cohort (Cohort 1: 2005–06, Cohort 2: 2007–08, Cohort 3: 2009–10) and KDRI quintile. RESULTS: The median crude KDRI increased by 1.3% annually, from 1.31 [interquartile range (IQR) 1.08–1.63] in 2005 to 1.47 (IQR 1.16–1.90) in 2015. This increase, i.e. lower kidney quality, was driven predominantly by increases in donor age, hypertension and donation after circulatory death. With time, the gap between the median standardized KDRI in the youngest (18–44 years) and oldest (>65 years) recipients widened. There was no difference in the median standardized KDRI by recipient sex. The median standardized KDRI was highest in Austria, the Netherlands and the Basque Country (Spain). Within each transplant cohort, the 5-year patient and graft survival probability were higher for the lowest KDRIs. There was no difference in the patient and graft survival outcomes across transplant cohorts, however, over time the survival probabilities for the highest KDRIs improved. CONCLUSIONS: The overall quality of deceased donor kidneys transplanted between 2005 and 2015 has decreased and varies between age groups and countries. Overall patient and graft outcomes remain unchanged

Improving outcomes for donation after circulatory death kidney transplantation:Science of the times

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects

Considerable Variability Among Transplant Nephrologists in Judging Deceased Donor Kidney Offers

Introduction: Transplant clinicians may disagree on whether or not to accept a deceased donor kidney offer. We investigated the interobserver variability between transplant nephrologists regarding organ acceptance and whether the use of a prediction model impacted their decisions.Methods: We developed an observational online survey with 6 real-life cases of deceased donor kidneys offered to a waitlisted recipient. Per case, nephrologists were asked to estimate the risk of adverse outcome and whether they would accept the offer for this patient, or for a patient of their own choice, and how certain they felt. These questions were repeated after revealing the risk of adverse outcome, calculated by a validated prediction model. Results: Sixty Dutch nephrologists completed the survey. The intraclass correlation coefficient of their estimated risk of adverse outcome was poor (0.20, 95% confidence interval [CI] 0.08–0.62). Interobserver agreement of the decision on whether or not to accept the kidney offer was also poor (Fleiss kappa 0.13, 95% CI 0.129–0.130). The acceptance rate before and after providing the outcome of the prediction model was significantly influenced in 2 of 6 cases. Acceptance rates varied considerably among transplant centers. Conclusion: In this study, the estimated risk of adverse outcome and subsequent decision to accept a suboptimal donor kidney varied greatly among transplant nephrologists. The use of a prediction model could influence this decision and may enhance nephrologists’ certainty about their decision.</p

A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss

Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the consequences of EGL. To gauge the consequence of EGL we systematically evaluated its impact in an observational study that included all 10,307 deceased-donor kidney transplantations performed in The Netherlands between 1990 and 2018. Incidence of EGL, defined as graft loss within 90 days, in primary transplantation was 8.2% (699/8,511). The main causes were graft rejection (30%), primary nonfunction (25%), and thrombosis or infarction (20%). EGL profoundly impacted short- and long-term patient survival (adjusted hazard ratio; 95% confidence interval: 8.2; 5.1-13.2 and 1.7; 1.3-2.1, respectively). Of the EGL recipients who survived 90 days after transplantation (617/699) only 440 of the 617 were relisted for re-transplantation. Of those relisted, only 298 were ultimately re-transplanted leading to an actual re-transplantation rate of 43%. Noticeably, re-transplantation was associated with a doubled incidence of EGL, but similar long-term graft survival (adjusted hazard ratio 1.1; 0.6-1.8). Thus, EGL after kidney transplantation is a medical catastrophe with high mortality rates, low relisting rates, and increased risk of recurrent EGL following re-transplantation. This implies that detrimental outcomes also involve convergence of risk factors in recipients with EGL. The 8.2% incidence of EGL minimally impacted population mortality, indicating this incidence is acceptable