Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

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

SARS-CoV-2-specific immune responses converge in kidney disease patients and controls with hybrid immunity

Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens.</p

SARS-CoV-2-specific immune responses converge in kidney disease patients and controls with hybrid immunity

Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens.</p

Adherence to preventive measures after SARS-CoV-2 vaccination and after awareness of antibody response in kidney transplant recipients in the Netherlands:a nationwide questionnaire study

BACKGROUND: Kidney transplant recipients (KTRs) were advised to tightly adhere to government recommendations to curb the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) because of a high risk of morbidity and mortality and decreased immunogenicity after vaccination. The aim of this study was to analyse the change in adherence to preventive measures after vaccination and awareness of antibody response, and to evaluate its effectiveness.METHODS: In this large-scale, national questionnaire study, questionnaires were sent to 3531 KTRs enrolled in the Dutch RECOVAC studies, retrospectively asking for adherence to nine preventive measures on a 5-point Likert scale before and after SARS-CoV-2 vaccination and after awareness of antibody response. Blood samples were collected 28 days after the second vaccination. Antibody response was categorised as non-responder (≤50 BAU/mL), low-responder (&gt;50 ≤ 300 BAU/mL) or high-responder (&gt;300 BAU/mL), and shared with participants as a correlate of protection. Participants of whom demographics on sex and age, blood samples and completed questionnaires were available, were included. Our study took place between February 2021 and January 2022. The primary outcome of adherence before and after vaccination was assessed between August and October 2021 and compared via the Wilcoxon signed rank sum test. Logistic regression analysis was performed to estimate the association between antibody response and non-adherence, and adherence on acquiring SARS-CoV-2 infection. This study is registered at ClinicalTrials.gov (NCT04841785).FINDINGS: In 2939 KTRs (83%) who completed the first questionnaire on adherence to preventive measures, adherence was higher before than after vaccination (4.56, IQR 4.11-4.78 and 4.22, IQR 3.67-4.67, p &lt; 0.001). Adherence after awareness of antibody response was analysed in 2399 KTRs (82%) of whom also blood samples were available, containing 949 non-responders, 500 low-responders and 950 high-responders. Compared to non-responders, low- and high-responders reported higher non-adherence. Higher adherence was associated with lower infection rates before and after vaccination (OR 0.67 [0.51-0.91], p = 0.008 and OR 0.48 [0.28-0.86], p = 0.010).INTERPRETATION: Adherence decreased after SARS-CoV-2 vaccination and in KTRs who were aware of a subsequent antibody response compared with those without. Preventive measures in this vulnerable group seem to be effective, regardless of vaccination status. This study starts a debate on sharing antibody results with the patient and future studies should elucidate whether decreased adherence in antibody responders is justified, also in view of future pandemics.FUNDING: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.</p

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Publisher Copyright: © 2019, The Author(s).Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.Peer reviewe

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

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

Contains fulltext : 221518.pdf (publisher's version ) (Open Access

Spectrum of retinal abnormalities in renal transplant patients using chronic low-dose steroids

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