SARS-CoV-2 Neutralization Capacity in Hemodialysis Patients with and without a Fifth Vaccination with the Updated Comirnaty Original/Omicron BA.4-5 Vaccine.

BACKGROUND: Hemodialysis patients have reduced serologic immunity after SARS-CoV-2 vaccination compared to the general population and an increased risk of morbidity and mortality when exposed to SARS-CoV-2. METHODS: Sixty-six hemodialysis patients immunized four times with the original SARS-CoV-2 vaccines (BNT162b2, mRNA-1273) either received a booster with the adapted Comirnaty Original/Omicron BA.4-5 vaccine 8.3 months after the fourth vaccination and/or experienced a breakthrough infection. Two months before and four weeks after the fifth vaccination, the live-virus neutralization capacities of Omicron variants BA.5, BQ.1.1, and XBB.1.5 were determined, as well as neutralizing and quantitative anti-SARS-CoV-2 spike-specific IgG antibodies. RESULTS: Four weeks after the fifth vaccination with the adapted vaccine, significantly increased neutralizing antibodies and the neutralization of Omicron variants BA.5, BQ.1.1, and XBB.1.5 were observed. The increase was significantly higher than after the fourth vaccination for variants BQ.1.1 and BA.5. Of all analyzed variants, BA.5 was neutralized best after the fifth vaccination. We did not see a difference in humoral immunity between the group with an infection and the group with a vaccination as a fifth spike exposure. Fivefold-vaccinated patients with a breakthrough infection showed a significantly higher neutralization capacity of XBB.1.5. CONCLUSION: A fifth SARS-CoV-2 vaccination with the adapted vaccine improves both wild-type specific antibody titers and the neutralizing capacity of the current Omicron variants BA.5, BQ.1.1, and XBB.1.5 in hemodialysis patients. Additional booster vaccinations with adapted vaccines will likely improve immunity towards current and original SARS-CoV-2 variants and are, therefore, recommended in hemodialysis patients. Further longitudinal studies must show the extent to which this booster vaccination avoids a breakthrough infection.

Potential and Uncertainties of RejectClass in Acute Kidney Graft Dysfunction: An Independent Validation Study.

BACKGROUND: Kidney graft rejections are classified based on the Banff classification. The RejectClass algorithm, initially derived from a cohort comprising mostly protocol biopsies, identifies data-driven phenotypes of acute rejection and chronic pathology using Banff lesion scores. It also provides composite scores for inflammation activity and chronicity. This study independently evaluates the performance of RejectClass in a cohort consisting entirely of indication biopsies. METHODS: We retrospectively applied RejectClass to 441 patients from the German TRABIO (TRAnsplant BIOpsies) cohort who had received indication biopsies. The primary endpoint was death-censored graft failure during 2 y of follow-up. RESULTS: The application of RejectClass to our cohort demonstrated moderately comparable phenotypic features with the derivation cohort, and most clusters indicated an elevated risk of graft loss. However, the reproduction of all phenotypes and the associated risks of graft failure, as depicted in the original studies, was not fully accomplished. In contrast, adjusted Cox proportional hazards analyses substantiated that both the inflammation score and the chronicity score are independently associated with graft loss, exhibiting hazard ratios of 1.7 (95% confidence interval, 1.2-2.3; P = 0.002) and 2.2 (95% confidence interval, 1.8-2.6; P < 0.001), respectively, per 0.25-point increment (scale: 0.0-1.0). CONCLUSIONS: The composite inflammation and chronicity scores may already have direct utility in quantitatively assessing the disease stage. Further refinement and validation of RejectClass clusters are necessary to achieve more reliable and accurate phenotyping of rejection.

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.

Rescue Allocation Modes in Eurotransplant Kidney Transplantation: Recipient Oriented Extended Allocation Versus Competitive Rescue Allocation-A Retrospective Multicenter Outcome Analysis.

BACKGROUND: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries. METHODS: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods. RESULTS: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y. CONCLUSIONS: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.

Longitudinal SARS-CoV-2 neutralization of Omicron BA.1, BA.5 and BQ.1.1 after four vaccinations and the impact of breakthrough infections in haemodialysis patients.

Background: Individuals on haemodialysis (HD) are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the general population due to end-stage kidney disease-induced immunosuppression. Methods: A total of 26 HD patients experiencing SARS-CoV-2 infection after a third vaccination were matched 1:1 with 26 of 92 SARS-CoV-2-naïve patients by age, sex, dialysis vintage and immunosuppressive drugs receiving a fourth vaccination with a messenger RNA-based vaccine. A competitive surrogate neutralization assay was used to monitor vaccination success. To determine infection neutralization titres, Vero-E6 cells were infected with SARS-CoV-2 variants of concern (VoCs), Omicron sublineage BA.1, BA.5 and BQ.1.1. The 50% inhibitory concentration (IC50, serum dilution factor 1:x) was determined before, 4 weeks after and 6 months after the fourth vaccination. Results: A total of 52 HD patients received four coronavirus disease 2019 (COVID-19) vaccinations and were followed up for a median of 6.3 months. Patient characteristics did not differ between the matched cohorts. Patients without a SARS-CoV-2 infection had a significant reduction of real virus neutralization capacity for all Omicron sublineages after 6 months (P < .001 each). Those patients with a virus infection did not experience a reduction in real virus neutralization capacity after 6 months. Compared with the other Omicron VoC, the BQ.1.1 sublineage had the lowest virus neutralization capacity. Conclusions: SARS-CoV-2-naïve HD patients had significantly decreased virus neutralization capacity 6 months after the fourth vaccination, whereas patients with a SARS-CoV-2 infection had no change in neutralization capacity. This was independent of age, sex, dialysis vintage and immunosuppression. Therefore, in infection-naïve HD patients a fifth COVID-19 vaccination might be reasonable 6 months after the fourth vaccination.

High RIPK3 expression is associated with a higher risk of early kidney transplant failure.

Renal ischemia-reperfusion injury (IRI) is associated with reduced allograft survival, and each additional hour of cold ischemia time increases the risk of graft failure and mortality following renal transplantation. Receptor-interacting protein kinase 3 (RIPK3) is a key effector of necroptosis, a regulated form of cell death. Here, we evaluate the first-in-human RIPK3 expression dataset following IRI in kidney transplantation. The primary analysis included 374 baseline biopsy samples obtained from renal allografts 10 minutes after onset of reperfusion. RIPK3 was primarily detected in proximal tubular cells and distal tubular cells, both of which are affected by IRI. Time-to-event analysis revealed that high RIPK3 expression is associated with a significantly higher risk of one-year transplant failure and prognostic for one-year (death-censored) transplant failure independent of donor and recipient associated risk factors in multivariable analyses. The RIPK3 score also correlated with deceased donation, cold ischemia time and the extent of tubular injury.

Extracorporeal light-chain elimination in myeloma with simple medium cutoff membrane hemodialysis: a retrospective cohort study.

Background: We determined the efficacy of free light chain (FLC) removal by regular dialysis equipment (high-flux filtration) with medium cutoff (MCO) membrane hemodialysis (HD) as an adjuvant treatment to standard chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM) and its impact on further dialysis dependency. Methods: Sixty patients with acute dialysis-dependent renal failure secondary to MM were treated with MCO-HD (55 patients) or HCO (high cutoff)-HD (5 patients) as a control. FLC serum concentration, total protein, immunoglobulins, and LDH were measured throughout the dialysis therapy. The kidney function of the patients was followed up for 1 year. Results: The median age was 69 years; 25 female and 35 male patients were enrolled. HD significantly reduced FLC kappa levels in the MCO/HCO group by 58%/84% (MCO/HCO group; p < 0.05) and FLC lambda by 39%/33% (MCO/HCO group; p < 0.05). Single HD data (MCO) showed a relative reduction of 70% in kappa and 37% in lambda FLC concentration, as expected by the different sizes of the light chains. Renal function improved significantly and continuously from starting creatinine 5.7/3.8 mg/dl (MCO/HCO group) before HD to 1.4/2.0 mg/dl (MCO/HCO group; p < 0.001) after 1 year. No significant alteration of total protein, immunoglobulins, and LDH concentrations by HD (HCO and MCO group) was observed. After 1 year, 37 of 60 patients were alive and 34 of them were off dialysis. Conclusion: FLC elimination with MCO-HD is effective, technically easy, and less cost-intensive as compared with HCO-HD. Kidney function recovery in MM patients is achievable.

Locating Medical Information during an Infodemic: Information Seeking Behavior and Strategies of Health-Care Workers in Germany.

BACKGROUND: The COVID-19 pandemic has led to a flood of-often contradictory-evidence. HCWs had to develop strategies to locate information that supported their work. We investigated the information-seeking of different HCW groups in Germany. METHODS: In December 2020, we conducted online surveys on COVID-19 information sources, strategies, assigned trustworthiness, and barriers-and in February 2021, on COVID-19 vaccination information sources. Results were analyzed descriptively; group comparisons were performed using χ2-tests. RESULTS: For general COVID-19-related medical information (413 participants), non-physicians most often selected official websites (57%), TV (57%), and e-mail/newsletters (46%) as preferred information sources-physicians chose official websites (63%), e-mail/newsletters (56%), and professional journals (55%). Non-physician HCWs used Facebook/YouTube more frequently. The main barriers were insufficient time and access issues. Non-physicians chose abstracts (66%), videos (45%), and webinars (40%) as preferred information strategy; physicians: overviews with algorithms (66%), abstracts (62%), webinars (48%). Information seeking on COVID-19 vaccination (2700 participants) was quite similar, however, with newspapers being more often used by non-physicians (63%) vs. physician HCWs (70%). CONCLUSION: Non-physician HCWs more often consulted public information sources. Employers/institutions should ensure the supply of professional, targeted COVID-19 information for different HCW groups.

Comparable cellular and humoral immunity upon homologous and heterologous COVID-19 vaccination regimens in kidney transplant recipients.

Background: Kidney transplant recipients (KTRs) are at high risk for a severe course of coronavirus disease 2019 (COVID-19); thus, effective vaccination is critical. However, the achievement of protective immunogenicity is hampered by immunosuppressive therapies. We assessed cellular and humoral immunity and breakthrough infection rates in KTRs vaccinated with homologous and heterologous COVID-19 vaccination regimens. Method: We performed a comparative in-depth analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell responses using multiplex Fluorospot assays and SARS-CoV-2-specific neutralizing antibodies (NAbs) between three-times homologously (n = 18) and heterologously (n = 8) vaccinated KTRs. Results: We detected SARS-CoV-2-reactive T cells in 100% of KTRs upon third vaccination, with comparable frequencies, T-cell expression profiles, and relative interferon γ and interleukin 2 production per single cell between homologously and heterologously vaccinated KTRs. SARS-CoV-2-specific NAb positivity rates were significantly higher in heterologously (87.5%) compared to homologously vaccinated (50.0%) KTRs (P < 0.0001), whereas the magnitudes of NAb titers were comparable between both subcohorts after third vaccination. SARS-CoV-2 breakthrough infections occurred in equal numbers in homologously (38.9%) and heterologously (37.5%) vaccinated KTRs with mild-to-moderate courses of COVID-19. Conclusion: Our data support a more comprehensive assessment of not only humoral but also cellular SARS-CoV-2-specific immunity in KTRs to provide an in-depth understanding about the COVID-19 vaccine-induced immune response in a transplant setting.

Implication of FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain a proportion of cases. Aim of this study was to unravel the underlying molecular mechanism of syndromic CAKUT in two multiplex families with presumed autosomal recessive inheritance. Methods and Results: ES in the index individuals revealed two different rare homozygous variants in FOXD2, a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans with FOXD2 dysfunction. To study the pathomechanism of FOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology of Foxd2 KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Conclusions: In summary, our data implicate that FOXD2 dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.

Design and Transition of an Emergency E-Learning Pathology Course for Medical Students-Evaluation of a Novel Course Concept.

BACKGROUND: Around the world, the emergency brought about by the COVID-19 pandemic forced medical schools to create numerous e-learning supplements to provide instruction during this crisis. The question now is to determine a way in which to capitalize on this momentum of digitization and harness the medical e-learning content created for the future. We have analyzed the transition of a pathology course to an emergency remote education online course and, in the second step, applied a flipped classroom approach including research skills training. METHODS: In the summer semester of 2020, the pathology course at the Technical University of Munich was completely converted to an asynchronous online course. Its content was adapted in winter 2021 and incorporated into a flipped classroom concept in which research skills were taught at the same time. RESULTS: Screencasts and lecture recordings were the most popular asynchronous teaching formats. Students reported developing a higher interest in pathology and research through group work. The amount of content was very challenging for some students. CONCLUSION: Flipped classroom formats are a viable option when using pre-existing content. We recommend checking such content for technical and didactic quality and optimizing it if necessary. Content on research skills can be combined very well with clinical teaching content.

Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age.

X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in COL4A5 primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in COL4A5 compared to healthy controls. A total of 56 females with a heterozygous disease-causing COL4A5 variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort (rho = 0.403, p = 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the COL4A5 variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the COL4A5 variant carrying allele in female individuals with AS.

The multifaceted phenotypic and genotypic spectrum of type-IV-collagen-related nephropathy-A human genetics department experience.

Disease-causing variants in COL4A3-5 are associated with type-IV-collagen-related nephropathy, a genetically and phenotypically multifaceted disorder comprising Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) and autosomal, X-linked and a proposed digenic inheritance. Initial symptoms of individuals with AS are microscopic hematuria followed by proteinuria leading to kidney failure (90% on dialysis < age 40 years). In contrast, individuals with TBMN, an outdated histology-derived term, present with microscopic hematuria, only some of them develop kidney failure (>50 years of age). An early diagnosis of type-IV-collagen-related nephropathy is essential for optimized therapy and slowing of the disease. Sixty index cases, in whom exome sequencing had been performed and with disease-causing variant(s) in COL4A3-5, were evaluated concerning their clinical tentative diagnosis and their genotype. Of 60 reevaluated individuals with type-IV-collagen-related nephropathy, 72% had AS, 23% TBMN and 5% focal segmental glomerulosclerosis (FSGS) as clinical tentative diagnosis. The FSGS cases had to be re-classified as having type-IV-collagen-related nephropathy. Twelve percent of cases had AS as clinical tentative diagnosis and a monoallelic disease-causing variant in COL4A3/4 but could not be classified as autosomal dominant AS because of limited or conflicting clinical data. This study illustrates the complex clinical and genetic picture of individuals with a type IV-collagen-related nephropathy indicating the need of a refined nomenclature and the more interdisciplinary teamwork of clinicians and geneticists as the key to optimized patient care.

Improved SARS-CoV-2 Neutralization of Delta and Omicron BA.1 Variants of Concern after Fourth Vaccination in Hemodialysis Patients.

Hemodialysis patients are exposed to a markedly increased risk when infected with SARS-CoV-2. To date, it is unclear if hemodialysis patients benefit from four vaccinations. A total of 142 hemodialysis patients received four COVID-19 vaccinations until March 2022. RDB binding antibody titers were determined in a competitive surrogate neutralization assay. Vero-E6 cells were infected with SARS-CoV-2 variants of concern (VoC), Delta (B.1.617.2), or Omicron (B.1.1.529, sub-lineage BA.1) to determine serum infection neutralization capacity. Four weeks after the fourth vaccination, serum infection neutralization capacity significantly increased from a 50% inhibitory concentration (IC50, serum dilution factor 1:x) of 247.0 (46.3−1560.8) to 2560.0 (1174.0−2560.0) for the Delta VoC, and from 37.5 (20.0−198.8) to 668.5 (182.2−2560.0) for the Omicron VoC (each p < 0.001) compared to four months after the third vaccination. A significant increase in the neutralization capacity was even observed for patients with high antibody titers after three vaccinations (p < 0.001). Ten patients with SARS-CoV-2 breakthrough infection after the first blood sampling had by trend lower prior neutralization capacity for Omicron (p = 0.051). Our findings suggest that hemodialysis patients benefit from a fourth vaccination in particular in the light of the highly infectious SARS-CoV-2 Omicron-variants. A routinely applied four-time vaccination seems to broaden immunity against variants and would be recommended in hemodialysis patients.

Incidences of Infectious Events in a Renal Transplant Cohort of the German Center of Infectious Diseases (DZIF).

Background: Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods: In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results: Of 804 renal transplant recipients (65.2% male, 51 ± 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis, were rare. Conclusions: Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients.

The Kidney Donor Profile Index (KDPI) Correlates With Histopathologic Findings in Post-reperfusion Baseline Biopsies and Predicts Kidney Transplant Outcome.

Background: The increasing organ shortage in kidney transplantation leads to the necessity to use kidneys previously considered unsuitable for transplantation. Numerous studies illustrate the need for a better decision guidance rather than only the classification into kidneys from standard or expanded criteria donors referred to as SCD/ECD-classification. The kidney donor profile index (KDPI) exhibits a score utilizing a much higher number of donor characteristics. Moreover, graft biopsies provide an opportunity to assess organ quality. Methods: In a single center analysis 383 kidney transplantations (277 after deceased and 106 after living donation) performed between January 1st, 2006, and December 31st, 2016, retrospectively underwent SCD/ECD and KDPI scoring. Thereby, the quality of deceased donor kidneys was assessed by using the KDPI and the living donor kidneys by using the living KDPI, in the further analysis merged as (L)KDPI. Baseline biopsies taken 10 min after the onset of reperfusion were reviewed for chronic and acute lesions. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards analysis within a 5-year follow-up. Results: The (L)KDPI correlated with glomerulosclerosis (r = 0.30, p < 0.001), arteriosclerosis (r = 0.33, p < 0.001), interstitial fibrosis, and tubular atrophy (r = 0.28, p < 0.001) as well as the extent of acute tubular injury (r = 0.20, p < 0.001). The C-statistic of the (L)KDPI concerning 5-year death censored graft survival was 0.692. Around 48% of ECD-kidneys were classified as (L)KDPI<85%. In a multivariate Cox proportional hazard analysis including (preformed) panel reactive antibodies, cold ischemia time, (L)KDPI, and SCD/ECD-classification, the (L)KDPI was significantly associated with risk of graft loss (hazard ratio per 10% increase in (L)KDPI: 1.185, 95% confidence interval: 1.033-1.360, p = 0.025). Survival analysis revealed decreased death censored (p < 0.001) and non-death censored (p < 0.001) graft survival in kidneys with an increasing (L)KDPI divided into groups of <35, 35-85, and >85%, respectively. Conclusion: With a higher granularity compared to the SCD/ECD-classification the (L)KDPI is a promising tool to judge graft quality. The correlation with chronic and acute histological lesions in post-reperfusion kidney biopsies underlines the descriptive value of the (L)KDPI. However, its prognostic value is limited and underlines the urgent need for a more precise prognostic tool adopted to European kidney transplant conditions.

COVID-19 Vaccines: Fear of Side Effects among German Health Care Workers.

(1) Background: Health care workers (HCWs) play a key role in increasing anti-COVID vaccination rates. Fear of potential side effects is one of the main reasons for vaccine hesitancy. We investigated which side effects are of concern to HCWs and how these are associated with vaccine hesitancy. (2) Methods: Data were collected in an online survey in February 2021 among HCWs from across Germany with 4500 included participants. Free-text comments on previously experienced vaccination side effects, and fear of short- and long-term side effects of the COVID-19 vaccination were categorized and analyzed. (3) Results: Most feared short-term side effects were vaccination reactions, allergic reactions, and limitations in daily life. Most feared long-term side effects were (auto-) immune reactions, neurological side effects, and currently unknown long-term consequences. Concerns about serious vaccination side effects were associated with vaccination refusal. There was a clear association between refusal of COVID-19 vaccination in one's personal environment and fear of side effects. (4) Conclusions: Transparent information about vaccine side effects is needed, especially for HCW. Especially when the participants' acquaintances advised against vaccination, they were significantly more likely to fear side effects. Thus, further education of HCW is necessary to achieve good information transfer in clusters as well.

Study protocol: the TRAnsplant BIOpsies (TRABIO) study - a prospective, observational, multicentre cohort study to assess the treatment of kidney graft rejections.

INTRODUCTION: Despite continued efforts, long-term outcomes of kidney transplantation remain unsatisfactory. Kidney graft rejections are independent risk factors for graft failure. At the participating centres of the TRAnsplant BIOpsies study group, a common therapeutic standard has previously been defined for the treatment of graft rejections. The outcomes of this strategy will be assessed in a prospective, observational cohort study. METHODS AND ANALYSIS: A total of 800 kidney transplantation patients will be enrolled who undergo a graft biopsy because of deteriorating kidney function. Patients will be stratified according to the Banff classification, and the influence of the treatment strategy on end points will be assessed using regression analysis. Primary end points will be all-cause mortality and graft survival. Secondary end points will be worsening of kidney function (≥30% decline of estimated Glomerular Filtration Rate [eGFR] or new-onset large proteinuria), recurrence of graft rejection and treatment response. Baseline data and detailed histopathology data will be entered into an electronic database on enrolment. During a first follow-up period (within 14 days) and subsequent yearly follow-ups (for 5 years), treatment strategies and clinical course will be recorded. Recruitment at the four participating centres started in September 2016. As of August 2020, 495 patients have been included. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the ethics committee of Kiel (AZ B 278/16) and was confirmed by the committees of Munich, Mainz and Stuttgart. The results will be reported in a peer-reviewed journal, according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. TRIAL REGISTRATION NUMBER: ISRCTN78772632; Pre-results.

Kidney Transplantation After Rescue Allocation-the Eurotransplant Experience: A Retrospective Multicenter Outcome Analysis.

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.