2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Early progression of chronic histologic lesions in kidney transplant biopsies is not associated with HLA histocompatibility.

BACKGROUND: Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. METHODS: We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at three and twelve months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores (i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR) were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. RESULTS: More than one third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the three to the twelve-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 (OR = 1.10, 95%-CI: 1.03-1.18). Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95-% CI: 1.19-22.57) could be confirmed in our cohort. CONCLUSIONS: These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.

Renin-angiotensin system inhibitor discontinuation in COVID-19 did not modify systemic ACE2 in a randomized controlled trial.

Despite the similar clinical outcomes after renin-angiotensin system (RAS) inhibitor (RASi) continuation or withdrawal in COVID-19, the effects on angiotensin-converting enzyme 2 (ACE2) and RAS metabolites remain unclear. In a substudy of the randomized controlled Austrian Corona Virus Adaptive Clinical Trial (ACOVACT), patients with hypertension and COVID-19 were randomized 1:1 to either RASi continuation (n = 30) or switch to a non-RASi medication (n = 29). RAS metabolites were analyzed using a mixed linear regression model (n = 30). Time to a sustained clinical improvement was equal and ACE2 did not differ between the groups but increased over time in both. Overall ACE2 was higher with severe COVID-19. ACE-S and Ang II levels increased as expected with ACE inhibitor discontinuation. These data support the safety of RASi continuation in COVID-19, although RASi were frequently discontinued in our post hoc analysis. The study was not powered to draw definite conclusions on clinical outcomes using small sample sizes.

A pan-tissue survey of mosaic chromosomal alterations in 948 individuals.

Genetic mutations accumulate in an organism's body throughout its lifetime. While somatic single-nucleotide variants have been well characterized in the human body, the patterns and consequences of large chromosomal alterations in normal tissues remain largely unknown. Here, we present a pan-tissue survey of mosaic chromosomal alterations (mCAs) in 948 healthy individuals from the Genotype-Tissue Expression project, augmenting RNA-based allelic imbalance estimation with haplotype phasing. We found that approximately a quarter of the individuals carry a clonally-expanded mCA in at least one tissue, with incidence strongly correlated with age. The prevalence and genome-wide patterns of mCAs vary considerably across tissue types, suggesting tissue-specific mutagenic exposure and selection pressures. The mCA landscapes in normal adrenal and pituitary glands resemble those in tumors arising from these tissues, whereas the same is not true for the esophagus and skin. Together, our findings show a widespread age-dependent emergence of mCAs across normal human tissues with intricate connections to tumorigenesis.

Prospective assessment of pre-existing and de novo anti-HLA IgE in kidney, liver, lung and heart transplantation.

Introduction: Antibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and de novo anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients. Methods: We prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an in vitro mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients. Results: Pre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed de novo anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no de novo IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils in vitro, demonstrating functionality of anti-HLA IgE. Discussion: These data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation.

Monitoring of Sotrovimab-Levels as Pre-Exposure Prophylaxis in Kidney Transplant Recipients Not Responding to SARS-CoV-2 Vaccines.

Background Sotrovimab, a monoclonal antibody against SARS-CoV-2, is used as a pre-exposition prophylaxis (PrEP) against COVID-19, but monitoring strategies using routine test systems have not been defined. Methods Twenty kidney transplant recipients without antibodies after vaccination received 500 mg Sotrovimab. Antibody levels were quantified over eight weeks using live-virus neutralization (BA1 and BA2), antibody binding assays (TrimericS, Elecsys, QuantiVAC) and surrogate virus neutralization tests (sVNTs; TECOmedical, cPass and NeutraLISA). Results Sotrovimab neutralized both Omicron subvariants (BA1 NT titer 90 (+-50) > BA2 NT titer 33 (+-15) one hour post infusion). Sotrovimab was measurable on all used immunoassays, although a prior 1:100 dilution was necessary for Elecsys due to a presumed prozone effect. The best correlation with live-virus neutralization titers was found for QuantiVAC and TrimericS, with a respective R2 of 0.65/0.59 and 0.76/0.57 against BA1/BA2. Elecsys showed an R2 of 0.56/0.54 for BA1/BA2, respectively. sVNT values increased after infusion but had only a poor correlation with live-virus neutralization titers (TECOmedical and cPass) or did not reach positivity thresholds (NeutraLISA). Conclusion Antibody measurements by the used immunoassays showed differences in antibody levels and only a limited correlation with neutralization capacity. We do not recommend sVNTs for monitoring SARS-CoV-2 neutralization by Sotrovimab.

Sex differences in the survival benefit of kidney transplantation: a retrospective cohort study using target trial emulation.

BACKGROUND: Kidney transplantation is the preferred treatment for eligible patients with kidney failure who need renal replacement therapy. However, it remains unclear whether the anticipated survival benefit from kidney transplantation is different for women and men. METHODS: We included all dialysis patients recorded in the Austrian Dialysis and Transplant Registry who were waitlisted for their first kidney transplant between 2000 and 2018. In order to estimate the causal effect of kidney transplantation on 10-year restricted mean survival time, we mimicked a series of controlled clinical trials and applied inverse probability of treatment and censoring weighted sequential Cox models. RESULTS: This study included 4408 patients (33% female) with a mean age of 52 years. Glomerulonephritis was the most common primary renal disease both in women (27%) and men (28%). Kidney transplantation led to a gain of 2.22 years (95% CI 1.88 to 2.49) compared with dialysis over a 10-year follow-up. The effect was smaller in women (1.95 years, 95% CI 1.38 to 2.41) than in men (2.35 years, 95% CI 1.92 to 2.70) due to a better survival on dialysis. Across ages the survival benefit of transplantation over a follow-up of 10 years was smaller in younger women and men and increased with age, showing a peak for both women and men aged about 60 years. CONCLUSIONS: There were few differences in survival benefit by transplantation between females and males. Females had better survival than males on the waitlist receiving dialysis and similar survival to males after transplantation.

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

[Diabetic kidney disease (update 2023) : Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology]. / Diabetische Nierenerkrankung (Update 2023) : Positionspapier der Österreichischen Diabetes Gesellschaft und der Österreichischen Gesellschaft für Nephrologie.

Epidemiological investigations have shown that approximately 2-3% of all Austrians have diabetes mellitus with renal involvement, leaving 250,000 people in Austria affected. The risk of occurrence and progression of this disease can be attenuated by lifestyle interventions as well as optimization of blood pressure, blood glucose control and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society of Nephrology for the diagnostic and treatment strategies of diabetic kidney disease.

Development and Validation of a Prediction Model for Future Estimated Glomerular Filtration Rate in People With Type 2 Diabetes and Chronic Kidney Disease.

Importance: Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking. Objective: To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts. Design, Setting, and Participants: This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of ≥30 mL/min/1.73 m2) were included. Data were analyzed between June 30, 2021, and January 31, 2023. Main Outcomes and Measures: Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A1c [mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated. Results: Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R2 ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5. Conclusions and Relevance: In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting kidney function decline up to 5 years after baseline. The results and prediction model are publicly available in an accompanying web-based application, which may open the way for improved prediction of individual eGFR trajectories and disease progression.

Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory. METHODS: We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models' predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation. RESULTS: The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an [Formula: see text] of 0.44 (95% credible interval 0.37-0.50) before, and 0.59 (95% credible interval 0.51-0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline. CONCLUSIONS: Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway.

Cardiovascular Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus and Reduced Calcineurin Inhibitor or Standard Triple Therapy: 24-month Post Hoc Analysis From TRANSFORM Study.

BACKGROUND: The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated. METHODS: The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation. RESULTS: MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of circulatory death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m 2 ; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms. CONCLUSIONS: Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.

Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy.

Reducing the recipient's T cell repertoire is considered to increase the efficacy of regulatory T cell (Treg) therapy. This necessitates timing the administration of antithymocyte globulin (ATG) early enough before adoptive cell therapy (ACT) so that residual serum ATG does not deplete the transferred Tregs. The optimum time point in this regard has not been defined. Herein, we report the effects of residual serum ATG on the viability of an in vitro expanded Treg cell product used in a clinical trial of ACT in kidney transplant recipients (NCT03867617). Patients received ATG monotherapy (either 6 or 3 mg/kg body weight) without concomitant immunosuppression 2 to 3 weeks before transplantation and Treg transfer. An anti-ATG immunoglobulin G (IgG) immune response was elicited in all patients within 14 days. In turn, the elimination of total and Treg-specific ATG was accelerated substantially over control patients receiving the same dose of ATG with concomitant immunosuppression. However, ATG serum concentrations of <1 µg/mL, which had previously been reported as subtherapeutic threshold, triggered apoptosis of Tregs in vitro. Therefore, ATG levels need to decline to lower levels than those previously thought for efficacious Treg transfer. In 5 of 6 patients, such low levels of serum ATG considered safe for Treg transfer were reached within 2 weeks after ATG administration.

The systemic renin-angiotensin system in COVID-19.

SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.

Survival Benefit of First Single-Organ Deceased Donor Kidney Transplantation Compared With Long-term Dialysis Across Ages in Transplant-Eligible Patients With Kidney Failure.

Importance: Kidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias. Objective: To compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods. Design, Setting, and Participants: In this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021. Exposures: A target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available. Main Outcomes and Measures: The primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach. Results: Among the 4445 included patients (2974 men [66.9%]; mean [SD] age, 52.2 [13.2] years), transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years (95% CI, -0.14 to 1.84 years) at age 20 years, 3.01 years (95% CI, 2.50 to 3.54 years) at age 60 years, and 2.48 years (95% CI, 1.88 to 3.04 years) at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time. Conclusions and Relevance: The findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times.

Development and validation of multivariable prediction models of serological response to SARS-CoV-2 vaccination in kidney transplant recipients.

Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response to third or fourth vaccination in KTR. We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in previously seronegative, COVID-19-naïve KTR. Using 20 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), least absolute shrinkage and selection operator (LASSO)-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 590 vaccinations were used. External validation was performed in four independent, international validation cohorts comprising 191, 184, 254, and 323 vaccinations, respectively. LASSO-regularized LR performed on the whole development dataset yielded a 20- and 10-variable model, respectively. External validation showed AUC-ROC of 0.840, 0.741, 0.816, and 0.783 for the sparser 10-variable model, yielding an overall performance 0.812. A 10-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions whether to modulate immunosuppressive therapy before additional active vaccination, or to perform passive immunization to improve protection against COVID-19 in previously seronegative, COVID-19-naïve KTR.

Corrigendum: Three-Month follow-up of heterologous vs. homologous third SARS-CoV-2 vaccination in kidney transplant recipients: Secondary analysis of a randomized controlled trial.

[This corrects the article DOI: 10.3389/fmed.2022.936126.].

[Nomenclature for kidney function and kidney diseases - Improving assessment and prognosis through precision and comprehensibility]. / Nomenklatur für Nierenfunktion und Nierenkrankheiten ­ Durch Präzision und Verständlichkeit zu besserer Erfassung und Prognose.

Kidney disease represents an increasing global health problem. Its mitigation requires effective communication between all stakeholders involved in assessment, diagnosis and therapy and individuals affected by kidney disease. However, as of today the nomenclature for kidney function and kidney disease is far from uniform. In 2019, the international non-profit organization Kidney Disease: Improving Global Outcomes (KDIGO) has implemented a consensus process to develop a glossary in English language to standardize the nomenclature for kidney function, kidney structure and kidney disease. Guiding principles for this process were (1) precision, (2) patient-centeredness and (3) consistency with KDIGO guidelines. The current position paper includes a translation of this nomenclature into German that was developed on behalf of the national societies for nephrology in Germany, Austria and Switzerland.