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Abstract Background Since the implementation of universal antiretroviral therapy, kidney transplantation (K-Tx) has become a valuable option for treatment of end-stage kidney disease for people with HIV (PWH) with similar patient and graft survival as compared to HIV-uninfected patients. Little is known about the hazards and manifestations of infectious disease (ID) events occurring in kidney transplant recipients with HIV. Methods Using linked information collected in the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), we described in-depth demographical and clinical characteristics of PWH who received a K-Tx since 2008. Further, we performed recurrent time to event analyses to understand whether HIV was an independent risk factor for ID events. Results Overall, 24 PWH with 57 ID events were included in this study (100% match of SHCS to STCS). Of these, 17 (70.8%) patients had at least one ID event: 22 (38.6%) viral (HIV not counted), 18 (31.6%) bacterial, one (1.8%) fungal and 16 (28.1%) probable infections. Most ID events affected the respiratory tract (25, 37.3%) or the urinary tract (13, 19.4%). Pathogen types and infection sites were similar in PWH and a matched control group of HIV-uninfected patients. HIV was not an independent risk factor for ID events (adjusted hazard ratio 0.94, p = 0.9). Conclusion By linking data from two large national Swiss cohorts, we provided in-depth information on ID events in PWH receiving a K-Tx in Switzerland. HIV infection was not associated with an increased hazard for ID events after K-Tx.

BackgroundIn kidney transplant (KT) patients, magnesium (Mg2+) deficiency is widespread. It is often encountered early after KT, may persist longer, and is frequently promoted by calcineurin inhibitors (CNIs) and tubular leakage. Studies demonstrated an association between post-KT hypomagnesemia and allograft dysfunction. The concentration of the active form, the ionized Mg2+ (iMg2+), is not measured clinically, and total Mg2+ (tMg2+) and iMg2+ correlations are conflicting. We assess the cross-sectional prevalence of hypomagnesemia in KT patients. The correlation of demographic and anthropometric parameters was also studied.MethodsA prospective, single-center analysis of KT patients was conducted at the University Hospital of Bern, Switzerland (March 2023–August 2023). Blood samples were collected at least twice for the majority of patients. tMg2+ has been quantified from a plasma sample at the Clinical Chemistry Department of the University Hospital of Bern. The PRIME® ES analyzer (Nova Biomedical, USA) provided results for iMg2+. The following co-variables were considered: age, comorbidities, kidney disease, KT history, estimated glomerular filtration rate (eGFR), and treatment (including Mg2+ supplementation and immunosuppression).ResultsA total of 208 measurements in 104 patients were performed [once in 9/104 patients (8.7%), twice in 86/104 (82.7%), and three times in 9/104 (8.7%)]. Compared to that in healthy volunteers (51 measurements in 51 participants), mean iMg2+ was significantly lower in KT patients {KT: 0.46 mmol/L [interquartile range (IQR): 0.40–0.50], volunteers: 0.57 mmol/L (IQR 0.54–0.61), p < 0.01}. Overall, iMg2+ and tMg2+ showed strong category agreement (r2 = 0.93, p < 0.01). In linear regression, low iMg2+ correlated with CNI exposure. For 110/208 measurements (52.9%), a reduced iMg2+ (cutoff: 0.42 mmol/L) was shown. In 58/208 (27.9%), both values were reduced, and 52/208 (25%) had isolated reduced iMg2+. In principal component analysis, patients with isolated low iMg2+ clustered with patients with low iMg2+ and tMg2+.ConclusioniMg2+ and tMg2+ were strongly correlated. A substantial proportion of patients show isolated low iMg2+. Currently, it is unclear if these patients suffer from Mg2+ deficiency.

Valganciclovir (VGC) is administered as prophylaxis to kidney transplant recipients (KTR) CMV donor (D)+/recipient (R)− and CMV R+ after thymoglobulin-induction (R+/TG). Although VGC dose adjustments based on renal function are recommended, there is paucity of real-life data on VGC dosing and associations with clinical outcomes. This is a retrospective Swiss Transplant Cohort Study-embedded observational study, including all adult D+/R− and R+/TG KTR between 2010 and 2020, who received prophylaxis with VGC. The primary objective was to describe the proportion of inappropriately (under- or over-) dosed VGC week-entries. Secondary objectives included breakthrough clinically significant CMV infection (csCMVi) and potential associations between breakthrough-csCMVi and cytopenias with VGC dosing. Among 178 KTR, 131 (73.6%) patients had ≥2 week-entries for the longitudinal data of interest and were included in the outcome analysis, with 1,032 VGC dose week-entries. Overall, 460/1,032 (44.6%) were appropriately dosed, while 234/1,032 (22.7%) and 338/1,032 (32.8%) were under- and over-dosed, respectively. Nineteen (14.5%) patients had a breakthrough-csCMVi, without any associations identified with VCG dosing (p = 0.44). Unlike other cytopenias, a significant association between VGC overdosing and lymphopenia (OR 5.27, 95% CI 1.71–16.22, p = 0.004) was shown. VGC prophylaxis in KTR is frequently inappropriately dosed, albeit without meaningful clinical associations, neither in terms of efficacy nor safety.

BackgroundEnterobacterales are often responsible for urinary tract infection (UTI) in kidney transplant recipients. Among these, Escherichia coli or Klebsiella species producing extended-spectrum beta-lactamase (ESBL) are emerging. However, there are only scarce data on frequency and impact of ESBL-UTI on transplant outcomes.MethodsWe investigated frequency and impact of first-year UTI events with ESBL Escherichia coli and/or Klebsiella species in a prospective multicenter cohort consisting of 1,482 kidney transplants performed between 2012 and 2017, focusing only on 389 kidney transplants having at least one UTI with Escherichia coli and/or Klebsiella species. The cohort had a median follow-up of four years.ResultsIn total, 139/825 (17%) first-year UTI events in 69/389 (18%) transplant recipients were caused by ESBL-producing strains. Both UTI phenotypes and proportion among all UTI events over time were not different compared with UTI caused by non-ESBL-producing strains. However, hospitalizations in UTI with ESBL-producing strains were more often observed (39% versus 26%, p = 0.04). Transplant recipients with first-year UTI events with an ESBL-producing strain had more frequently recurrent UTI (33% versus 18%, p = 0.02) but there was no significant difference in one-year kidney function as well as longer-term graft and patient survival between patients with and without ESBL-UTI.ConclusionFirst-year UTI events with ESBL-producing Escherichia coli and/or Klebsiella species are associated with a higher need for hospitalization but do neither impact allograft function nor allograft and patient survival.

BackgroundLiving donor (LD) kidney transplantation in the setting of ABO blood group incompatibility (ABOi) has been previously reported to be associated with increased risk for antibody-mediated rejection (ABMR). It is however unclear if the presence of pre-transplant donor specific antibodies (DSA) works as an additive risk factor in the setting of ABOi and if DSA positive ABOi transplants have a significantly worse long-term outcome as compared with ABO compatible (ABOc) DSA positive transplants.MethodsWe investigated the effect of pre-transplant DSA in the ABOi and ABOc setting on the risk of antibody-mediated rejection (ABMR) and graft loss in a cohort of 952 LD kidney transplants.ResultsWe found a higher incidence of ABMR in ABOi transplants as compared to ABOc transplants but this did not significantly affect graft survival or overall survival which was similar in both groups. The presence of pre-transplant DSA was associated with a significantly increased risk of ABMR and graft loss both in the ABOi and ABOc setting. We could not detect an additional risk of DSA in the ABOi setting and outcomes were comparable between DSA positive ABOi and ABOc recipients. Furthermore, a combination of DSA directed at both Class I and Class II, as well as DSA with a high mean fluorescence intensity (MFI) showed the strongest relation to ABMR development and graft loss.ConclusionThe presence of pre-transplant DSA was associated with a significantly worse long-term outcome in both ABOi and ABOc LD kidney transplants and our results suggests that the risk associated with pre-transplant DSA is perhaps not augmented in the ABOi setting. Our study is the first to investigate the long-term effects of DSA in the ABOi setting and argues that pre-transplant DSA risk could potentially be evaluated similarly regardless of ABO compatibility status.

BackgroundCalcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients.MethodSingle-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations.ResultsIn total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: −0.22–1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible.ConclusionMeasuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.

Abstract Background Many potential prognostic factors for predicting kidney transplantation outcomes have been identified. However, in Switzerland, no widely accepted prognostic model or risk score for transplantation outcomes is being routinely used in clinical practice yet. We aim to develop three prediction models for the prognosis of graft survival, quality of life, and graft function following transplantation in Switzerland. Methods The clinical kidney prediction models (KIDMO) are developed with data from a national multi-center cohort study (Swiss Transplant Cohort Study; STCS) and the Swiss Organ Allocation System (SOAS). The primary outcome is the kidney graft survival (with death of recipient as competing risk); the secondary outcomes are the quality of life (patient-reported health status) at 12 months and estimated glomerular filtration rate (eGFR) slope. Organ donor, transplantation, and recipient-related clinical information will be used as predictors at the time of organ allocation. We will use a Fine & Gray subdistribution model and linear mixed-effects models for the primary and the two secondary outcomes, respectively. Model optimism, calibration, discrimination, and heterogeneity between transplant centres will be assessed using bootstrapping, internal-external cross-validation, and methods from meta-analysis. Discussion Thorough evaluation of the existing risk scores for the kidney graft survival or patient-reported outcomes has been lacking in the Swiss transplant setting. In order to be useful in clinical practice, a prognostic score needs to be valid, reliable, clinically relevant, and preferably integrated into the decision-making process to improve long-term patient outcomes and support informed decisions for clinicians and their patients. The state-of-the-art methodology by taking into account competing risks and variable selection using expert knowledge is applied to data from a nationwide prospective multi-center cohort study. Ideally, healthcare providers together with patients can predetermine the risk they are willing to accept from a deceased-donor kidney, with graft survival, quality of life, and graft function estimates available for their consideration. Study registration Open Science Framework ID: z6mvj

BackgroundEsophageal atresia (EA) is a rare congenital anomaly characterized by a discontinuity of the esophagus. Following surgical repair, survival rates have improved dramatically the past decenniums and today exceed 90%, but the children commonly present with esophageal and respiratory morbidity. In 2018, a condition-specific quality-of-life questionnaire for children with esophageal atresia (EA) aged 2–7 in Sweden-Germany was finalized (The EA-QOL questionnaire). The study aim was to describe the evaluation of the new translations across 12 new countries in Europe, Asia, Africa, Central-and North America.MethodsFollowing forward-backward translation into the new languages, the 17-item EA-QOL questionnaire was tested in cognitive debriefing interviews with parents of children with EA aged 2–7. Parents rated if each item was easy to understand (clarity) and sensitive to answer (interference with personal integrity). They could skip responding to a non-applicable/problematic item and give open comments. Predefined psychometric criteria were used; item clarity ≥80%/item sensitive to answer ≤20%/item feasibility ≤5% missing item responses. The decision to modify the translation was based on native expert, patient stakeholder, and instrument developer review, and the need for harmonization between translations.ResultsSimilar to findings in the Swedish-German cognitive debriefing, the cross-cultural analysis of input from 116 parents from 12 new countries (4–14 parents, median 9 parents/country) showed that all items in the EA-QOL questionnaire fulfilled the criteria for item clarity ≥80% and sensitive to answer (ranging from 1%-4.5%), although results varied between countries. Four items had missing responses between 5.2% and 13.4%, three within the same domain and were in line with parents’ explanations. Poor translations and feasibility were improved.ConclusionsBased on parent input, the collaboration between native experts, patient stakeholders, and instrument developers, a linguistic version of the EA-QOL questionnaire for children aged 2–7 for use in and across 14 countries has been established. These efforts have set the conditions for a cross-cultural field test of the EA-QOL questionnaire and will open the doors for a new chapter in outcome research, registries, and clinical practice concerning children with EA. In the long-term, this will help increase knowledge of the disease's burden, promote patient-centeredness, exchange of information between nations, and strengthen evidence-based treatments for children born with EA.

IntroductionThe demographics of donor and recipient candidates for kidney transplantation (KT) have substantially changed. Recipients tend to be older and polymorbid and KT to suboptimal recipients is associated with delayed graft function (DGF), prolonged hospitalization, inferior long-term allograft function, and poorer patient survival. In parallel, donors are also older, suffer from several comorbidities, and donations coming from circulatory death (DCD) predominate, which in turn leads to early and late complications. However, it is unclear how donor and recipient risk factors interact.MethodsIn this retrospective cohort study, we assess the impact of a KT from suboptimal donors to suboptimal recipients. We focused on: 1) DGF; 2) hospital stay and number of dialysis days after KT and 3) allograft function at 12 months.Results and discussionAmong the 369 KT included, the overall DGF rate was 25% (n = 92) and median time from reperfusion to DGF resolution was 7.8 days (IQR: 3.0–13.8 days). Overall, patients received four dialysis sessions (IQR: 2–8). The combination of pre-KT anuria (

IntroductionThe type of donation may affect how susceptible a donor kidney is to injury from pre-existing alloimmunity. Many centers are, therefore, reluctant to perform donor specific antibody (DSA) positive transplantations in the setting of donation after circulatory death (DCD). There are, however, no large studies comparing the impact of pre-transplant DSA stratified on donation type in a cohort with a complete virtual cross-match and long-term follow-up of transplant outcome.MethodsWe investigated the effect of pre-transplant DSA on the risk of rejection, graft loss, and the rate of eGFR decline in 1282 donation after brain death (DBD) transplants and compared it to 130 (DCD) and 803 living donor (LD) transplants.ResultsThere was a significant worse outcome associated with pre-transplant DSA in all of the studied donation types. DSA directed against Class II HLA antigens as well as a high cumulative mean fluorescent intensity (MFI) of the detected DSA showed the strongest association with worse transplant outcome. We could not detect a significant additive negative effect of DSA in DCD transplantations in our cohort. Conversely, DSA positive DCD transplants appeared to have a slightly better outcome, possibly in part due to the lower mean fluorescent intensity (MFI) of the pre-transplant DSA. Indeed when DCD transplants were compared to DBD transplants with similar MFI (

cSCC (cutaneous squamous cell carcinoma) and its precursors are a major cause of morbidity, especially in immunosuppressed patients, and are frequently associated with human papillomavirus (HPV) infections. The purpose of this study is to investigate the therapeutic potential of alpha-HPV vaccination for immunosuppressed patients with established cSCC and its precursors. In this retrospective study, all patients who received Gardasil-9®, a nonavalent HPV vaccine, as secondary prophylaxis were examined. Dermatologic interventions in both the pre- and post-vaccination periods were analyzed with zero-inflated Poisson regression and a proportional intensity model for repeated events with consideration of the clinically relevant cofactors. The hazard ratio for major dermatologic interventions was 0.27 (CI 0.14–0.51, p < 0.001) between pre- and post-Gardasil-9® intervention. Gardasil-9® vaccination showed good efficacy in reducing major dermatologic interventions even after correction of relevant cofactors and national COVID-19 caseloads during the observational period. Alpha-HPV vaccination may potentially cause a significant decrease in dermatologic interventions and overall mortality as well as healthcare costs in immunosuppressed patients with high skin tumor burden.

In allograft monitoring of solid organ transplant recipients, liquid biopsy has emerged as a novel approach using quantification of donor-derived cell-free DNA (dd-cfDNA) in plasma. Despite early clinical implementation and analytical validation of techniques, direct comparisons of dd-cfDNA quantification methods are lacking. Furthermore, data on dd-cfDNA in urine is scarce and high-throughput sequencing-based methods so far have not leveraged unique molecular identifiers (UMIs) for absolute dd-cfDNA quantification. Different dd-cfDNA quantification approaches were compared in urine and plasma of kidney and liver recipients: A) Droplet digital PCR (ddPCR) using allele-specific detection of seven common HLA-DRB1 alleles and the Y chromosome; B) high-throughput sequencing (HTS) using a custom QIAseq DNA panel targeting 121 common polymorphisms; and C) a commercial dd-cfDNA quantification method (AlloSeq® cfDNA, CareDx). Dd-cfDNA was quantified as %dd-cfDNA, and for ddPCR and HTS using UMIs additionally as donor copies. In addition, relative and absolute dd-cfDNA levels in urine and plasma were compared in clinically stable recipients. The HTS method presented here showed a strong correlation of the %dd-cfDNA with ddPCR (R2 = 0.98) and AlloSeq® cfDNA (R2 = 0.99) displaying only minimal to no proportional bias. Absolute dd-cfDNA copies also correlated strongly (τ = 0.78) between HTS with UMI and ddPCR albeit with substantial proportional bias (slope: 0.25; 95%-CI: 0.19–0.26). Among 30 stable kidney transplant recipients, the median %dd-cfDNA in urine was 39.5% (interquartile range, IQR: 21.8–58.5%) with 36.6 copies/μmol urinary creatinine (IQR: 18.4–109) and 0.19% (IQR: 0.01–0.43%) with 5.0 copies/ml (IQR: 1.8–12.9) in plasma without any correlation between body fluids. The median %dd-cfDNA in plasma from eight stable liver recipients was 2.2% (IQR: 0.72–4.1%) with 120 copies/ml (IQR: 85.0–138) while the median dd-cfDNA copies/ml was below 0.1 in urine. This first head-to-head comparison of methods for absolute and relative quantification of dd-cfDNA in urine and plasma supports a method-independent %dd-cfDNA cutoff and indicates the suitability of the presented HTS method for absolute dd-cfDNA quantification using UMIs. To evaluate the utility of dd-cfDNA in urine for allograft surveillance, absolute levels instead of relative amounts will most likely be required given the extensive variability of %dd-cfDNA in stable kidney recipients.

BackgroundPre-transplant donor specific antibodies (DSA), directed at non-self human leukocyte antigen (HLA) protein variants present in the donor organ, have been associated with worse outcomes in kidney transplantation. The impact of the mean fluorescence intensity (MFI) and the target HLA antigen of the detected DSA has, however, not been conclusively studied in a large cohort with a complete virtual cross-match (vXM).MethodsWe investigated the effect of pre-transplant DSA on the risk of antibody-mediated rejection (ABMR), graft loss, and the rate of eGFR decline in 411 DSA positive transplants and 1804 DSA negative controls.ResultsPre-transplant DSA were associated with a significantly increased risk of ABMR, graft loss, and accelerated eGFR decline. DSA directed at Class I and Class II HLA antigens were strongly associated with increased risk of ABMR, but only DSA directed at Class II associated with graft loss. DSA MFI markedly affected outcome, and Class II DSA were associated with ABMR already at 500-1000 MFI, whereas Class I DSA did not affect outcome at similar low MFI values. Furthermore, isolated DSA against HLA-DP carried comparable risks for ABMR, accelerated eGFR decline, and graft loss as DSA against HLA-DR.ConclusionOur results have important implications for the construction and optimization of vXM algorithms used within organ allocation systems. Our data suggest that both the HLA antigen target of the detected DSA as well as the cumulative MFI should be considered and that different MFI cut-offs could be considered for Class I and Class II directed DSA.

Methylation sequencing is a promising approach to infer the tissue of origin of cell-free DNA (cfDNA). In this study, a single- and a double-stranded library preparation approach were evaluated with respect to their technical biases when applied on cfDNA from plasma and urine. Additionally, tissue of origin (TOO) proportions were evaluated using two deconvolution methods. Sequencing cfDNA from urine using the double-stranded method resulted in a substantial within-read methylation bias and a lower global methylation (56.0% vs. 75.8%, p ≤ 0.0001) compared to plasma cfDNA, both of which were not observed with the single-stranded approach. Individual CpG site-based TOO deconvolution resulted in a significantly increased proportion of undetermined TOO with the double-stranded method (urine: 32.3% vs. 1.9%; plasma: 5.9% vs. 0.04%; p ≤ 0.0001), but no major differences in proportions of individual cell types. In contrast, fragment-level deconvolution led to multiple cell types, with significantly different TOO proportions between the two methods. This study thus outlines potential limitations of double-stranded library preparation for methylation analysis of cfDNA especially for urinary cfDNA. While the double-stranded method allows jagged end analysis in addition to TOO analysis, it leads to significant methylation bias in urinary cfDNA, which single-stranded methods can overcome.

IntroductionThere is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known.MethodsBased on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared.ResultsA reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response.ConclusionIn caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT03430414].

Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells.Methods: To measure a compound’s potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed.Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo.Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A’s activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.

ObjectivesAlthough mRNA-based vaccines against SARS-CoV-2 induce a robust immune response and prevent infections and hospitalizations, there are limited data on the antibody response in individuals with humoral immunodeficiency. The aim of this study was to evaluate the humoral immune response after two vaccine doses with BNT162b2 or mRNA-1273 in patients with humoral immunodeficiency disease.MethodsThis cross-sectional study assessed 39 individuals with hypogammaglobulinemia under immunoglobulin replacement therapy. IgG anti-SARS-CoV-2 spike protein antibodies (anti-S) were measured 4 weeks to 4 months after two doses of an mRNA vaccine against SARS-CoV-2. The proportion of patients, who developed a humoral immune response to the spike protein were evaluated and compared to 19 healthy controls.ResultsAfter vaccination with two vaccine doses, 26/39 patients (66.7%) with humoral immunodeficiency disease and all healthy controls developed anti-S. In subjects with baseline IgG 5 g/l: 151.5 AU/ml (95%CI 109.0-400.0), healthy controls 250.0 AU/ml (95%CI 209.0-358.0), p = 0.007.ConclusionIn most patients with mild to moderate humoral immunodeficiency we found only slightly lower anti-S antibodies compared with healthy controls after two vaccine doses with BNT162b2 and mRNA-1273. However, in patients with a decreased baseline IgG below 3 g/l and/or under immunosuppressive drugs, we found severely impaired humoral immune responses.

Introduction As childhood mortality from infectious diseases falls across sub-Saharan Africa (SSA), the burden of disease attributed to surgical conditions is increasing. However, limited data exist on paediatric surgical outcomes in SSA. We compared the outcomes of five common paediatric surgical conditions in SSA with published benchmark data from high-income countries (HICs).Methods A multicentre, international, prospective cohort study was undertaken in hospitals providing paediatric surgical care across SSA. Data were collected on consecutive children (birth to 16 years), presenting with gastroschisis, anorectal malformation, intussusception, appendicitis or inguinal hernia, over a minimum of 1 month, between October 2016 and April 2017. Participating hospitals completed a survey on their resources available for paediatric surgery.The primary outcome was all-cause in-hospital mortality. Mortality in SSA was compared with published benchmark mortality in HICs using χ2 analysis. Generalised linear mixed models were used to identify patient-level and hospital-level factors affecting mortality. A p

The psychosocial aspect of various congenital anomalies like esophageal atresia (EA) with/or without a tracheoesophageal fistula (TEF) being the cause of Post-traumatic stress disorder (PTSD), depression, and anxiety in parents of these children, is often overlooked by medical professionals. Support groups may be useful to address a part of this problem and form an important aspect of emotional support for any rare or congenital disease. A cross-sectional descriptive study was conducted to assess the need for a formal support group for parents of patients born with EA and to emphasize the role of emotional support for these parents and children. A questionnaire was sent to members of an informal WhatsApp group which included participants with diverse demographics across private and public platforms, across South Africa. The questions focused on 3 main areas: demographic data, diagnosis and the surgery, and information about the participant’s emotional support. All the data were inserted in an excel datasheet and descriptive statistical analysis was used. Questions were sent to 14 members of an informal WhatsApp group. Eight were included in the study. All 8 participants were mothers of children born with an EA with a TEF. The questions about the need for emotional support focus on the time after the baby was born. The majority (87.5%) of the mothers felt that they could bond with their babies during pregnancy, but in contrast, 75% felt that they missed an opportunity to bond with their babies after birth, mainly because they were not allowed to hold their babies for up to 11 days after birth. Only 1 of the mothers were in contact with other families with children born with EA, and 6 of the remaining 7 agreed that this would have helped them during this emotionally challenging time. All 8 thought that sharing their stories with others could have helped them emotionally and all agreed that an EA/TEF support group was a good idea. The family, as another patient, ought to be treated and included in the overall treatment plan if we aim to improve the quality of life for both the patients and their families. Disease-specific support groups can play a major role in the emotional well-being of both the children born with EA and their families.

Background: Primary endorectal pull-through is becoming a standard of care across the globe. This study was done to compare the outcome of patients with Hirschsprung’s disease (HD) who underwent primary endorectal pull-through with patients who were treated with a staged approach. Methods: A retrospective data review was done of all patients diagnosed with Hirschsprung’s disease (HD) at Tygerberg Children’s Hospital, a tertiary hospital in Cape Town, during an 11-year period (2007 – 2018). The patients were divided into 2 groups: the primary Endorectal pull-through (ERP) group and the staged group and the two groups were compared. Results: Eighty patients with histologically confirmed Hirschsprung’s disease (HD) were seen at our institution during the study period (2007 – 2018). Four patients did not meet the inclusion criteria and were excluded. Of the remaining seventy-six who were included, forty-six patients (60.5%) had a primary endorectal-pull through (Primary group) and thirty patients (39.5%) had staged procedures (Staged group) with a stoma before the final ERP. The peri-operative complications were subdivided into major and minor complications. Minor perioperative complications in the primary group were less (13%) compared to the staged group (33%) with a p-value of 0.017, making the difference statistically significant. Anastomotic strictures were the most common complication in both groups with abdominal wound infection being more common in the staged group. The late complications were similar in both groups with a p-value of 0.43. Constipation was the most common complication in both groups, followed by soiling. Conclusion: The two groups had a similar outcome without statistically significant differences. We can safely conclude that the primary endorectal pull-through for HD is at least as safe as the staged approach in Sub- Saharan Africa. With this technique, we avoid a stoma and the necessity for two surgical procedures with added potential complications.

AIMS OF THE STUDY Primary maintenance immunosuppressive therapies for renal transplant recipients underwent significant changes in recent years. We aimed to assess time trends and the impact of immunosuppressive regimens in first renal transplant recipients without immunological risk (blood group incompatibility, pre-existing donor-specific antibodies, positive B/T cell cross-match) in a prospective national multicentre cohort. METHODS The Swiss Transplant Cohort Study (STCS) prospectively enrols all patients receiving solid organ transplants in Switzerland since 2008 and systematically collects high quality clinical and laboratory data using standardised definitions. The current STCS nested study enrolled all adult transplant-naïve normal-immunological risk renal transplant recipients up to the end of 2017 and investigated different immunosuppressive strategies across a variety of transplantation relevant outcomes. RESULTS Of 1191 recipients enrolled at six transplant centres, 115 (10%) died with a functioning allograft and 92 (8%) lost their allograft during a median follow-up time of 5.8 years. The predominant immunosuppressive therapy comprised tacrolimus, mycophenolate mofetil and prednisone (73.7%), whereas 24.3% were treated with ciclosporin instead of tacrolimus. Primary immunosuppression with an mTOR inhibitor (1.1%) or other immunosuppressive combinations (0.8%) was rare. In the years following 2011, ciclosporin-based immunosuppression decreased significantly. The incidence of graft loss was significantly higher in patients with ciclosporin-based than with tacrolimus-based immunosuppression (adjusted hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.29–2.14; p

Abstract Background Graft survival after kidney transplantation has significantly improved within the last decades but there is a substantial number of patients with declining transplant function and graft loss. Over the past years several studies have shown that metabolic acidosis plays an important role in the progression of Chronic Kidney Disease (CKD) and that alkalinizing therapies significantly delayed progression of CKD. Importantly, metabolic acidosis is highly prevalent in renal transplant patients and a recent retrospective study has shown that metabolic acidosis is associated with increased risk of graft loss and patient death in kidney transplant recipients. However, no prospective trial has been initiated yet to test the role of alkali treatment on renal allograft function. Methods The Preserve-Transplant Study is an investigator-initiated, prospective, patient-blinded, multi-center, randomized, controlled phase-IV trial with two parallel-groups comparing sodium bicarbonate to placebo. The primary objective is to test if alkali treatment will preserve kidney graft function and diminish the progression of CKD in renal transplant patients by assesing the change in eGFR over 2 years from baseline. Additionally we want to investigate the underlying pathomechanisms of nephrotoxicity of metabolic acidosis. Discussion This study has the potential to provide evidence that alkali treatment may slow or reduce the progression towards graft failure and significantly decrease the rate of end stage renal disease (ESRD), thus prolonging long-term graft survival. The implementation of alkali therapy into the drug regimen of kidney transplant recipients would have a favorable risk-benefit ratio since alkali supplements are routinely used in CKD patients and represent a well-tolerated, safe and cost-effective treatment. Trial registration ClinicalTrials.gov NCT03102996. Trial registration was completed on April 6, 2017.

Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.

The generation of electricity by hydropower plants meets the requirements for intermittent energy demand and for the production of renewable energy. However, the hydropower plant operation has important consequences for the biotic compartment of the river reaches downstream. Intermittent release of water causes sudden variations in discharge that increase bed shear stress and dislodge benthic organisms. Release from high-elevation reservoir can also affect the thermal regime of the river by causing sharp variations in water temperature. Because the hydrodynamic and thermal waves separate while propagating downstream, the benthic community is exposed to two distinct stressors that affect taxa differently based on their sensitivity and adaptations. We investigated separately the effects of a sudden variation in discharge or in water temperature on the small-scale swimming behavior of a widespread species of cyclopoid copepod in a laboratory flume that allows the tracking of organisms both in the water column and in a transparent sediment bed. We gradually varied the discharge or the temperature of the water to mimic the artificial changes caused by hydropower plants. We tracked copepods in three dimensions and quantified the kinematics of their motion. Copepods increased substantially their counter-current swimming effort in response to increasing flow velocity. This behavioral response seems to occur above a threshold in flow velocity of approx. 40 mm/s. It results in a substantial reduction in their downstream transport and hence opposes drift. Copepods reacted differently to warm and cold variations in temperature. Decreasing temperature resulted in a substantially lower counter-current swimming effort, which may therefore increase drift. Rising temperature had no clear effect on their behavior. Our study highlights the importance of understanding the behavioral traits that mediate the response of stream invertebrates to disturbances in the hydraulic and thermal regimes of their environment.

Late post-transplant Pneumocystis jirovecii pneumonia (PcP) has been reported in many renal transplant recipients (RTRs) centers using universal prophylaxis. Specific features of PcP compared to other respiratory infections in the same population are not well reported. We analyzed clinical, laboratory, administrative and radiological data of all confirmed PcP cases between January 2009 and December 2014. To identify factors specifically associated with PcP, we compared clinical and laboratory data of RTRs with non-PcP. Over the study period, 36 cases of PcP were identified. Respiratory distress was more frequent in PcP compared to non-PcP (tachypnea: 59%, 20/34 vs. 25%, 13/53, p = 0.0014; dyspnea: 70%, 23/33 vs. 44%, 24/55, p = 0.0181). In contrast, fever was less frequent in PcP compared to non-PcP pneumonia (35%, 11/31 vs. 76%, 42/55, p = 0.0002). In both cohorts, total lymphocyte count and serum sodium decreased, whereas lactate dehydrogenase (LDH) increased at diagnosis. Serum calcium increased in PcP and decreased in non-PcP. In most PcP cases (58%, 21/36), no formal indication for restart of PcP prophylaxis could be identified. Potential transmission encounters, suggestive of interhuman transmission, were found in 14/36, 39% of patients. Interhuman transmission seems to contribute importantly to PcP among RTRs. Hypercalcemia, but not elevated LDH, was associated with PcP when compared to non-PcP.

TWEAK is a TNF family member that binds the NFκB signalling receptor Fn14. Here the authors show that TWEAK is central to skin inflammation in mouse models of atopic dermatitis and psoriasis and causes similar pathology when injected subcutaneously into mice.

BACKGROUND:Accelerated bone loss occurs rapidly following renal transplantation due to intensive immunosuppression and persistent hyperparathyroidism. In renal transplant recipients (RTRs) due to the hyperparathyroidism the non-dominant forearm is often utilized as a peripheral measurement site for dual-energy x-ray absorptiometry (DXA) measurements. The forearm is also the site of previous created distal arteriovenous fistulas (AVF). Although AVF remain patent long after successful transplantation, there are no data available concerning their impact on radial bone DXA measurements. METHODS:In this cross-sectional study we performed DXA in 40 RTRs with preexisting distal AVF (RTRs-AVF) to assess areal bone mineral density (aBMD) differences between both forearms (three areas) and compared our findings to patients with chronic kidney disease (CKD, n = 40), pre-emptive RTRs (RTRs-pre, n = 15) and healthy volunteers (n = 20). In addition, we assessed relevant demographic, biochemical and clinical aspects. RESULTS:We found a marked radial asymmetry between the forearms in RTRs with preexisting AVF. The radial aBMD at the distal AVF forearm was lower compared to the contralateral forearm, resulting in significant differences for all three areas analyzed: the Rad-1/3: median (interquartile range) in g/cm2, Rad-1/3: 0.760 (0.641-0.804) vs. 0.742 (0.642, 0.794), p = 0.016; ultradistal radius, Rad-UD: 0.433 (0.392-0.507) vs. 0.420 (0.356, 0.475), p = 0.004; and total radius, Rad-total: 0.603 (0.518, 0.655) vs. 0.599 (0.504, 0.642), p = 0.001). No such asymmetries were observed in any other groups. Lower aBMD in AVF forearm subregions resulted in misclassification of osteoporosis. CONCLUSIONS:In renal transplant recipients, a previously created distal fistula may exert a negative impact on the radial bone leading to significant site-to-site aBMD differences, which can result in diagnostic misclassifications.