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BACKGROUND: An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.METHODS: This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed.FINDINGS: Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 × mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0·4% (-16 to 15; p=0·96) for 2 × mRNA-1273 and -6% (-21 to 10; p=0·49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0·15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; pINTERPRETATION: Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.FUNDING: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.

Background The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. Methods The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. Results The total KT rate in the 40 participating countries increased with 1.9% annually [95% confidence interval (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East–West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). Conclusions The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries.

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C0) and abbreviated area under the curve from zero to 12 hours (AUC0-12h) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC0-12h (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30–0.50, P < 0.001), Tac-C0 (HR: 0.46, 95% CI: 0.38–0.57, P < 0.001) and MPA-AUC0-12h at 1 year (HR: 0.80, 95% CI: 0.68–0.94, P = 0.006), as well as repeated measurements of Tac-C0 (HR: 0.70, 95% credibility interval (CrI): 0.61–0.82, P < 0.001), and of MPA-AUC0-12h (HR: 0.75, 95% CrI: 0.62–0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC0-12h at 1 year would be 75–95 ng*hour/mL and a Tac-C0 5–7 ng/mL. The Tac-AUC0-12h predicted BPAR better than Tac-C0 and identified KTRs with over- or underexposure despite supposedly adequate Tac-C0. We did not find evidence to recommend another target than the consensus range of 30–60 mg*hour/L for MPA-AUC0-12h after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.

Background Health-related quality of life (HRQOL) is an increasingly important patient-reported outcome in kidney transplant recipients (KTRs). This study explored relationships between symptom prevalence and burden with HRQOL, and age and gender differences in symptom experience. Methods Eligible Dutch KTRs transplanted in Leiden University Medical Center were invited for this cross-sectional study. HRQOL, and occurrence and burden of 62 symptoms were measured using validated questionnaires. Univariate and multivariate regression analysis were used for investigating the associations of symptom experience with mental and physical HRQOL, and differences in symptom experience between genders and KTRs of diverse age groups. Results A total of 631 KTRs were analyzed; the mean (standard deviation) age was 61.3 (11.3) years, and 62% were male. The median (interquartile range) number of symptoms was 14 (7–22), with a burden of 20 (8–37; range 0–244). Per extra symptom, physical and mental HRQOL decreased [–0.41 (–0.50; –0.31) and –0.51 (–0.59; –0.42), respectively, P 50–65 ≥65 years) feelings of depression and both female and younger KTRs reported higher symptom prevalence concerning changes in physical appearance. Conclusion KRTs’ symptom experience differed depending on gender and age, highlighting the need to develop tailored treatment strategies to reduce symptom experience and subsequently improve HRQOL.

After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single‐center, open‐label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation., TRITON, a randomized, prospective, single‐center, open‐label study, shows that autologous mesenchymal stromal cell therapy and early tacrolimus withdrawal was feasible and safe, without increased rejection and with preserved renal function.

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI’s in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

Background Hospital readmission after transplantation is common in kidney transplant recipients (KTRs). In this study, we aim to compare the risk of 3-month hospital readmission after kidney transplantation with different donor types in the overall population and in both young ( Methods We included all first-time adult KTRs from 2016 to 2018 in the Netherlands Organ Transplant Registry. Multivariable logistic regression models were used to estimate the effect while adjusting for baseline confounders. Results Among 1917 KTRs, 615 (32.1%) had at least one hospital readmission. Living donor kidney transplantation (LDKT) recipients had an adjusted OR of 0.76 (95%CI, 0.61 to 0.96; p = 0.02) for hospital readmission compared to deceased donor kidney transplantation (DDKT) recipients. In the young and elderly, the adjusted ORs were 0.69 (95%CI, 0.52 to 0.90, p = 0.01) and 0.93 (95%CI, 0.62 to 1.39, p = 0.73) and did not differ significantly from each other (p-value for interaction = 0.38). In DDKT, the risk of hospital readmission is similar between recipients with donation after cardiac death (DCD) or brain death (DBD) and the risk was similar between the young and elderly. Conclusion A lower risk of post-transplant 3-month hospital readmission was found in recipients after LDKT compared to DDKT, and this benefit of LDKT might be less dominant in elderly patients. In DDKT, having either DCD or DBD donors is not associated with post-transplant 3-month hospital readmission, regardless of age. Tailored patient management is needed for recipients with DDKT and elderly KTRs.

Objectives: This study aims to investigate the separate contributions of liver fat and visceral fat on microalbuminuria and impaired renal function, and second, to examine whether non-alcoholic fatty liver disease is causally related to microalbuminuria and/or impaired renal function.Methods: Associations between visceral adipose tissue (VAT), hepatic triglyceride content (HTGC), and risk of microalbuminuria and renal function were studied cross-sectionally in the Netherlands Epidemiology of Obesity study. Mendelian randomization using GWAS meta-analysis data was performed to estimate the causal effect of non-alcoholic fatty liver disease (PNPLA3, LYPLAL1, NCAN, GCKR) on eGFR (N-max 118,460), microalbuminuria (N-max 54,116), and impaired renal function (N-max 118,147).Results: In total, 2,023 participants (mean age 55.5 +/- 6.0 years, 53% women) were included of which 29% had fatty liver and 2.0% chronic kidney disease stage >= 3. In joint models, VAT was associated with a 2-fold increased risk of microalbuminuria which was mainly driven by the association in women (total population: per standard deviation [SD] = 55.4 cm(2), odds ratio [OR] 2.02, 95% confidence interval [CI] 1.18-3.47; women: OR 2.83, 95% CI 1.44, 5.56), but HTGC was not (total population: per SD = 7.9%, OR 1.20, 95% CI 0.85, 1.70). No associations were found for VAT and HTGC with eGFR (VAT: per SD = 55.4 cm(2), OR 1.25, 95% CI 0.83, 1.87; HTGC: per SD = 7.9%, OR 0.65, 95% CI 0.42, 0.99). No causal effect of NAFLD on microalbuminuria or impaired renal function was found.Conclusions: In observational analyses, visceral fat was associated with microalbuminuria in women. Liver fat was not associated with microalbuminuria or renal function, which was supported by Mendelian randomization. Visceral fat might be more important than liver fat in the etiology of microalbuminuria. (C) 2019 by the National Kidney Foundation, Inc. All rights reserved.

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.

Contains fulltext : 245148.pdf (Publisher’s version ) (Open Access) Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P

Background Health-related quality of life (HRQOL) is becoming an increasingly important outcome in kidney transplantation (KT). To describe HRQOL in kidney transplant recipients (KTRs), this systematic review summarizes literature that compared HRQOL among KTRs and other relevant populations [i.e. patients receiving dialysis, patients on the waiting list (WL) for KT, patients with chronic kidney disease (CKD) not receiving renal replacement therapy (RRT), the general population (GP) and healthy controls (HCs)] and themselves before KT. Methods The literature search was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Eligible studies published between January 2000 and October 2020 were included. Results Forty-four studies comprising 6929 KTRs were included in this systematic review. Despite the study heterogeneity, KTRs reported a higher HRQOL after KT compared with pre-transplantation and compared with patients receiving dialysis with or without being on the WL, especially in disease-specific domains (i.e. burden and effects of kidney disease). Additionally, KTRs had similar to marginally higher HRQOL compared with patients with CKD Stages 3–5 not receiving RRT. When compared with HCs or the GP, KTRs reported similar HRQOL in the first 1 or 2 years after KT and lower physical HRQOL and lower to comparable mental HRQOL in studies with longer post-transplant time. Conclusions The available evidence suggests that HRQOL improves after KT and can be restored to but not always maintained at pre-CKD HRQOL levels. Future studies investigating intervention targets to improve or maintain post-transplant HRQOL are needed.

Background Iohexol plasma clearance-based glomerular filtration rate (GFR) determination provides an accurate method for renal function evaluation. This technique is increasingly advocated for clinical situations that dictate highly accurate renal function assessment, as an alternative to conventional serum creatinine-based methods with limited accuracy or poor feasibility. In the renal transplantation setting, this particularly applies to living renal transplant donor eligibility screening, renal transplant function monitoring and research purposes. The dependency of current iohexol GFR estimation techniques on extensive sampling, however, has limited its clinical application. We developed a population pharmacokinetic model and limited sampling schedules, implemented in the online InsightRX precision dosing platform, to facilitate pragmatic iohexol GFR assessment. Methods Iohexol concentrations (n = 587) drawn 5 min to 4 h after administration were available from 67 renal transplant recipients and 41 living renal transplant donor candidates with measured iohexol GFRs of 27–117 mL/min/1.73 m2. These were split into a model development (n = 72) cohort and an internal validation (n = 36) cohort. External validation was performed with 1040 iohexol concentrations from 268 renal transplant recipients drawn between 5 min and 4 h after administration, and extended iohexol curves up to 24 h from 11 random patients with impaired renal function. Limited sampling schedules based on one to four blood draws within 4 h after iohexol administration were evaluated in terms of bias and imprecision, using the mean relative prediction error and mean absolute relative prediction error. The total deviation index and percentage of limited sampling schedule-based GFR predictions within ± 10% of those of the full model (P10) were assessed to aid interpretation. Results Iohexol pharmacokinetics was best described with a two-compartmental first-order elimination model, allometrically scaled to fat-free mass, with patient type as a covariate on clearance and the central distribution volume. Model validity was confirmed during the internal and external validation. Various limited sampling schedules based on three to four blood draws within 4 h showed excellent predictive performance (mean relative prediction error < ± 0.5%, mean absolute relative prediction error < 3.5%, total deviation index < 5.5%, P10 > 97%). The best limited sampling schedules based on three to four blood draws within 3 h showed reduced predictive performance (mean relative prediction error < ± 0.75%, mean absolute relative prediction error < 5.5%, total deviation index < 9.5%, P10 ≥ 85%), but may be considered for their enhanced clinical feasibility when deemed justified. Conclusions Our online pharmacometric tool provides an accurate, pragmatic, and ready-to-use technique for measured GFR-based renal function evaluation for clinical situations where conventional methods lack accuracy or show limited feasibility. Additional adaptation and validation of our model and limited sampling schedules for renal transplant recipients with GFRs below 30 mL/min is warranted before considering this technique in these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-00998-z.

The membrane attack complex—also known as C5b-9—is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.

Graft function and patient survival are traditionally the most used parameters to assess the objective benefits of kidney transplantation. Monitoring graft function, along with therapeutic drug concentrations and transplant complications, comprises the essence of outpatient management in kidney transplant recipients (KTRs). However, the patient’s perspective is not always included in this process. Patients’ perspectives on their health after kidney transplantation, albeit subjective, are increasingly acknowledged as valuable healthcare outcomes and should be considered in order to provide patient-centred healthcare. Such outcomes are known as patient-reported outcomes (PROs; e.g. health-related quality of life and symptom burden) and are captured using PRO measures (PROMs). So far, PROMs have not been routinely used in clinical care for KTRs. In this review we will introduce PROMs and their potential application and value in the field of kidney transplantation, describe commonly used PROMs in KTRs and discuss structural PROMs implementation into kidney transplantation care.

Human leukocyte antigen (HLA) antibodies are induced by pregnancy, transfusion, or transplantation. Serum from transplant recipients is regularly screened for IgG HLA antibodies because of their clinical relevance for transplant outcome. While other isotypes of HLA antibodies, such as IgA may also contribute to the alloimmune response, validated detection assays for IgA HLA antibody detection are lacking. Therefore, we modified the commonly used luminex screening assay for IgG HLA antibody detection (IgG-LMX) into an IgA HLA antibody screening assay (IgA-LMX). Optimization and validation was performed with IgG, IgA1, and IgA2 isotype variants of HLA-specific human recombinant monoclonal antibodies (mAbs). Reactivity patterns of IgA1 and IgA2 isotype HLA-specific mAbs in IgA-LMX were identical to those of the IgG isotype. Cross-reactivity with IgG and IgM antibodies and nonspecific binding to the beads were excluded. Further assay validation showed the absence of IgA HLA antibodies in serum from individuals without alloantigen exposure (n = 18). When the IgA-LMX assay was applied to sera from 289 individuals with known alloantigen exposure through pregnancy (n = 91) or kidney transplantation (n = 198), IgA HLA antibodies were detected in 3.5% of individuals; eight patients on the kidney retransplant waitlist and two women immunized through pregnancy. The majority (90%) of IgA HLA antibodies were directed against HLA class II and were always present in conjunction with IgG HLA antibodies. Results of this study show that this validated IgA-LMX method can serve as a screening assay for IgA HLA antibodies and that the incidence of IgA HLA antibodies in alloantigen exposed individuals is low.

Background. Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. Methods. We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. Results. Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3–30.2%] in kidney transplant and 25.0% (95% CI 20.2–30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59–1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation Conclusions. The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Background The COVID-19 pandemic has markedly affected renal transplant care. During this time of social distancing, limited in-person visits, and uncertainty, patients and donors are relying more than ever on telemedicine and web-based information. Several factors can influence patients’ understanding of web-based information, such as delivery modes (instruction, interaction, and assessment) and social-epistemological dimensions (choices in interactive knowledge building). Objective The aim of this study was to systemically evaluate the content, delivery modes, and social-epistemological dimensions of web-based information on COVID-19 and renal transplantation at time of the pandemic. Methods Multiple keyword combinations were used to retrieve websites on COVID-19 and renal transplantation using the search engines Google.com and Google.nl. From 14 different websites, 30 webpages were examined to determine their organizational sources, topics, delivery modes, and social-epistemological dimensions. Results The variety of topics and delivery modes was limited. A total of 13 different delivery modes were encountered, of which 8 (62%) were instructional and 5 (38%) were interactional; no assessment delivery modes were observed. No website offered all available delivery modes. The majority of delivery modes (8/13, 62%) focused on individual and passive learning, whereas group learning and active construction of knowledge were rarely encountered. Conclusions By taking interactive knowledge transfer into account, the educational quality of eHealth for transplant care could increase, especially in times of crisis when rapid knowledge transfer is needed.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) pandemic has led to a stepwise scale‐down of transplant care with an observed increase in waitlist mortality for patients with end‐stage‐renal‐disease (ESRD).[1] Reports on coronavirus disease‐2019 (COVID‐19) populations suggest that organ transplant recipients have an age‐adjusted hazard of more than four for COVID‐19 mortality but specific vulnerabilities and risk factors are missing.[2]

BACKGROUND The COVID-19 pandemic has markedly affected renal transplant care. During this time of social distancing, limited in-person visits, and uncertainty, patients and donors are relying more than ever on telemedicine and web-based information. Several factors can influence patients’ understanding of web-based information, such as delivery modes (instruction, interaction, and assessment) and social-epistemological dimensions (choices in interactive knowledge building). OBJECTIVE The aim of this study was to systemically evaluate the content, delivery modes, and social-epistemological dimensions of web-based information on COVID-19 and renal transplantation at time of the pandemic. METHODS Multiple keyword combinations were used to retrieve websites on COVID-19 and renal transplantation using the search engines Google.com and Google.nl. From 14 different websites, 30 webpages were examined to determine their organizational sources, topics, delivery modes, and social-epistemological dimensions. RESULTS The variety of topics and delivery modes was limited. A total of 13 different delivery modes were encountered, of which 8 (62%) were instructional and 5 (38%) were interactional; no assessment delivery modes were observed. No website offered all available delivery modes. The majority of delivery modes (8/13, 62%) focused on individual and passive learning, whereas group learning and active construction of knowledge were rarely encountered. CONCLUSIONS By taking interactive knowledge transfer into account, the educational quality of eHealth for transplant care could increase, especially in times of crisis when rapid knowledge transfer is needed.

Background and Aims Hospital readmission after kidney transplantation remains a burden not only for the kidney transplant recipients (KTRs) but also for the healthcare system. Therefore, it can also indicate the quality of care. The causes of hospital readmission in KTRs mainly include problematic graft function and complications caused by the invasive procedure or immunosuppressive regime. In the Netherlands, almost 1000 kidney transplantations are performed annually with an aging recipient population. In spite of the benefit of living donor transplantation, roughly half of the patients will receive a graft from a donor donating after cardiac death(DCD) or brain death(DBD). From 2000 to 2017 the DCD procedure accounted for 43% of all deceased donors in the Netherlands, which is the highest worldwide. With this analysis, we aim to investigate the effect of donor type on 3-month hospital readmission after kidney transplantation and also investigate this effect in different age groups. Method Our study was conducted with data abstracted from the Netherlands Organ Transplant Registry (NOTR). We retrieved data for all first-time KTRs over 18 years old from 1st Jan 2016 to 31st Dec 2018. A multivariate logistic regression model with multiple imputation for missing values was used to estimate the hazard ratio (HR) of post-transplant 3-month hospital readmission for different donor types and control for confounding. KTRs with living or deceased donors and KTRs with DCD or DBD donors were compared, respectively. Subgroup group analysis was conducted to investigate the effect of different donor types on 3-month hospital readmission within different recipient age groups( age below 65 vs 65 years or older). Results Among 1917 first-time KTRs surviving 3 months with a functioning graft, 941 (49,1%) had no hospital readmission, 371 (19,4%) had one readmission in this period, and 244 (12,7%) had two or more readmissions (361 (18,8%) with missingness in readmission). Within the cohort, 1163(60,7%) received a graft from a living donor, 281(14,7%) from DBD donors and 473(24,7%) from DCD donors. 259(23,3,%) recipients with living donor kidney transplantation were 65 years old or older while it is 104 (43,3%) for recipients with DBD donors and 172(41,5%) for recipients with DCD donors. KTRs with living donors were at lower risk of 3-month hospital readmission after transplantation compared to those with deceased donors (HR, 0,77; 95%CI, 0,61 to 0,95). The difference was consistent in KTRs under 65 years old (HR, 0,70; 95%CI, 0,53 to 0,92) but disappeared in KTRs above 65 years old(HR, 0,90; 95%CI: 0,60 to 1,35) in subgroup analysis. KTRs with DCD and DBD donors had a similar risk of 3-month hospital readmission. Conclusion Kidney transplant recipients younger than 65 years of age with a living donor have a lower risk of post-transplant 3-month hospital readmission compared to those with a deceased donor. KTRs at an age of 65 or above KTRs with either a DCD or DBD donor are similar with regard to 3-month hospital readmission across different age groups.

The current coronavirus disease 2019 (COVID‐19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35‐year‐old renal transplant recipient who suffered from a severe COVID‐19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence‐based COVID‐19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk‐benefit balance of experimental or off‐label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID‐19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug‐drug interactions associated with the various treatment options for COVID‐19 in renal transplant patients.

Objective: Ectopic lipid accumulation in the kidney (fatty kidney) is a potential driver of diabetic kidney disease, and tight glycemic control can reduce risk of diabetic nephropathy. We assessed whether glycemic control influences renal triglyceride content (RTGC). Furthermore, we compared glucagon-like peptide-1 receptor agonist liraglutide versus standard glucose-lowering therapy. Design andMethods: In this single-center parallel-group trial, patients with type 2 diabetes mellitus were randomized to liraglutide or placebo added to standard care (metformin/sulfonylurea derivative/insulin). Changes in RTGC after 26 weeks of glycemic control measured by proton spectroscopy and difference in RTGC between treatment groups were analyzed.Results: Fifty patients with type 2 diabetes mellitus were included in the baseline analysis (mean age, 56.5 +/- 9.1 years; range, 33-73 years; 46% males). Seventeen patients had baseline and follow-up measurements. Mean glycated hemoglobin was 7.8 +/- 0.8%, which changed to 7.3 +/- 0.9% after 26 weeks of glycemic control irrespective of treatment group (P = .046). Log-transformed RTGC was -0.68 +/- 0.30% and changed to -0.83 +/- 0.32% after 26 weeks of glycemic control irrespective of treatment group (P = .049). A 26-week-to-baseline RTGC ratio (95% confidence interval) was significantly different between liraglutide (-0.30 [-0.50, -0.09]) and placebo added to standard care (-0.003 [-0.34, 0.34]) (P = .04).Conclusion: In this exploratory study, we found that 26 weeks of glycemic control resulted in lower RTGC, in particular for liraglutide; however, larger clinical studies are needed to assess whether these changes reflect a true effect of glycemic control on fatty kidney. (C) 2020 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

Active maintenance of beta-cell identity through fine-tuned regulation of key transcription factors ensures beta-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human beta-cell maturity and beta-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress-activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key beta-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet-fed mice. Pharmacological inhibition of BMP signaling protects human beta-cells from tacrolimus-induced beta-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human beta-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.

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.

Background Despite growing waiting lists for renal transplants, hesitations persist with regard to the use of deceased after cardiac death (DCD) renal grafts. We evaluated the outcomes of DCD donations in The Netherlands, the country with the highest proportion of DCD procedures (42.9%) to test whether these hesitations are justified. Methods This study included all procedures with grafts donated after brain death (DBD) (n = 3611) and cardiac death (n = 2711) performed between 2000 and 2017. Transplant outcomes were compared by Kaplan Meier and Cox regression analysis, and factors associated with short (within 90 days of transplantation) and long-term graft loss evaluated in multi-variable analyses. Findings Despite higher incidences of early graft loss (+ 50%) and delayed graft function (+ 250%) in DCD grafts, 10-year graft and recipient survival were similar for the two graft types (Combined 10-year graft survival: 73.9% (95% CI: 72.5–75.2), combined recipient survival: 64.5% (95 CI: 63.0–66.0%)). Long-term outcome equivalence was explained by a reduced impact of delayed graft function on DCD graft survival (RR: 0.69 (95% CI: 0.55–0.87), p, Highlights • In the Netherlands, there is a frequent and liberal use of renal grafts donated after cardiac death. • Grafts donated after cardiac death present with high incidences of early graft loss and delayed graft function • Yet, grafts donated after cardiac and brain death show equivalent 10 year transplantation outcomes • Long-term outcome equivalence relates to a reduced impact of delayed graft function on graft survival of grafts donated after cardiac death.

Background Advanced renal disease is characterized by adverse changes in renal structure; however, noninvasive techniques to diagnose and monitor these changes are currently lacking. Purpose To evaluate the reproducibility of native T1 mapping for renal tissue characterization. Study type Reproducibility study. Population Fifteen healthy volunteers (mean age 31 years, range 19-63 years), and 11 patients with diabetic nephropathy (mean age 57 years, range 51-69 years). Field strength/sequence 3T, modified Look-Locker imaging (MOLLI) 5(3)3. Assessment Intra- and interexamination reproducibility of voxel-based T1 relaxation times of renal cortex and medulla was assessed in healthy human volunteers and diabetic nephropathy patients. Statistical tests Reproducibility was evaluated using Bland-Altman and intraclass correlation coefficients (ICCs). Results Intra- and interexamination reproducibility of renal native T1 mapping showed good-strong ICCs (0.83-0.89) for renal cortex and medulla, and moderate-good ICCs (0.62-0.81) for cortex-medulla ratio in both healthy volunteers and diabetic nephropathy patients. Intra- and interexamination limits of agreement were respectively (-124 msec, + 82 msec) and (-134 msec, + 98 msec) for renal cortex and (-138 msec, + 107 msec) and (-118 msec, + 151 msec) for medulla. Overall T1 values for renal cortex (P = 0.277) and medulla (P = 0.973) were not significantly different between healthy volunteers and diabetic nephropathy patients, in contrast to the cortex-medulla ratio (P = 0.003). Data conclusion Renal native T1 mapping is a technique with good-strong intra- and examination reproducibility in both healthy volunteers and diabetic nephropathy patients. Level of evidence 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:588-596.

Rationale & Objective: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2), is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women.Study Design: Retrospective cohort study.Setting & Participants: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium.Exposure: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source.Outcome: eGFR at the age of 45 to 65 years.Analytical Approach: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium.Results: At baseline, mean eGFR was 86 +/- 12.4 (SD) mL/min/1.73 m(2). After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/ min/1.73 m(2) lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR.Limitations: Birth weight was self-reported.Conclusions: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

Background Renal steatosis (fatty kidney) is a potential biomarker for obesity-related renal disease; however, noninvasive assessment of renal fat content remains a technical challenge. Purpose To evaluate reproducibility and explore clinical application of renal metabolic imaging for the quantification of renal triglyceride content (TG) using proton magnetic resonance spectroscopy (1 H-MRS). Study type Reproducibility and clinical cohort study. Population Twenty-three healthy volunteers (mean age 30.1 ± 13.4 years) and 15 patients with type 2 diabetes mellitus (T2DM) (mean age 59.3 ± 7.0 years). Field strength/sequence 3T, single-voxel point resolved spectroscopy (PRESS). Assessment Intra- and interexamination reproducibility of renal TG was assessed in healthy volunteers, and compared to T2DM patients. Intraexamination differences were obtained by repeating the 1 H-MRS measurement directly after the first 1 H-MRS without repositioning of the subject or changing surface coil and measurement volumes. Interexamination variability was studied by repeating the scan protocol after removal and replacement of the subject in the magnet, and subsequent repositioning of body coil and measurement volumes. Statistical tests Reproducibility was determined using Pearson's correlation and Bland-Altman analyses. Differences in TG% between healthy volunteers and T2DM patients were assessed using the Mann-Whitney U-test. Results After logarithmic (log) transformation, both intraexamination (r = 0.91, n = 19) and interexamination (r = 0.73, n = 9) measurements of renal TG content were highly correlated with the first renal TG measurements. Intraexamination and interexamination limits of agreement of renal log TG% were respectively [-1.36%, + 0.84%] and [-0.77%, + 0.62%]. Backtransformed limits of agreement were [-0.89%,+0.57%] and [-0.55%, + 0.43%] multiplied by mean TG for intra- and interexamination measurements. Overall median renal TG content was 0.12% [0.08, 0.22; 25th percentile, 75th percentile] in healthy volunteers and 0.20% [0.13, 0.22] in T2DM patients (P = 0.08). Data conclusion Renal metabolic imaging using 3T 1 H-MRS is a reproducible technique for the assessment of renal triglyceride content. Level of evidence 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:507-513.

The main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV), a ubiquitous and non-pathogenic single-stranded DNA virus, has been proposed as a marker of functional immunity in immunocompromised patients. Here we investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients. In a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model. During follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01). In conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.

Purpose To assess the ophthalmological characteristics of asymptomatic patients with a renal transplant on chronic low-dose steroids for at least the last 2 years prior to examination. Methods Cross-sectional study. All patients underwent an extensive ophthalmological examination. Results Of the 37 included patients [25 male, 12 female; 59 ± 11 years (range, 38–77 years)] ophthalmological phenotyping revealed abnormalities in 22 patients (59%). Findings characteristic for (subclinical) central serous chorioretinopathy were detected in ten patients (27%), including two patients with serous subretinal fluid in the macula. An epiretinal membrane of the macula was present in six patients (16%). Mean subfoveal choroidal thickness was significantly increased in patients with ophthalmological abnormalities, in comparison with patients without abnormalities. Conclusions Retinal abnormalities are common in the majority of renal transplant patients using chronic low-dose steroids. These retinal changes may be associated with the renal disease and/or the effect of chronic steroid use on the choroid and retina.

Background Hepcidin is considered the master regulator of iron homoeostasis. Novel hepcidin antagonists have recently been introduced as potential treatment for iron-restricted anaemia. Meanwhile, serum hepcidin has been shown to be positively associated with cardiovascular disease and inversely with acute kidney injury. These properties may lead to contrasting effects, especially in renal transplant recipients (RTR), which are prone to cardiovascular diseases and graft failure. To date, the role of serum hepcidin in RTR is unknown. We, therefore, prospectively determined the association of serum hepcidin with risk of graft failure, cardiovascular mortality and all-cause mortality in RTR.Materials and methods Serum hepcidin was assessed in an extensively phenotyped RTR cohort by dual-monoclonal sandwich ELISA specific immunoassay. Statistical analyses were performed using univariate linear regression followed by stepwise backward linear regression. Cox proportional hazard regression models were performed to determine prospective associations.Results We included 561 RTR (age 51 +/- 12 years). Mean haemoglobin (Hb) was 8.6 +/- 1.0 mM. Median [IQR] serum hepcidin was 7.2 [3.2-13.4] ng/mL. Mean estimated glomerular filtration rate was 47 +/- 16 mL/min/ 1.73 m(2). In univariate Cox regression analyses, serum hepcidin was not associated with risk of graft failure, cardiovascular mortality or all-cause mortality. Notably, after adjustment for high sensitivity C-reactive protein and ferritin, serum hepcidin became negatively associated with all-cause mortality (hazard ratio 0.89; 95% confidence interval 0.80-0.99, P = 0.3).Conclusions In this study, we did not find an association between serum hepcidin and outcomes, that is graft failure, cardiovascular mortality or all-cause mortality. Based on our results, it is questionable whether serum hepcidin may be used to predict a beneficial effect of hepcidin antagonists.