Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.

All eyes on PCS: analysis of the retinal microvasculature in patients with post-COVID syndrome-study protocol of a 1 year prospective case-control study.

Since widespread vaccination against COVID-19, the development of effective antiviral drugs, and the decreasing number of patients with COVID-19 in intensive care, the risk from SARS-CoV-2 infection appears less threatening. However, studies show that a significant number of patients suffer from long-term sequelae, even months after SARS-CoV-2 infection. The so-called post-COVID syndrome (PCS) often presents a diagnostic and treatment challenge for physicians. This study protocol describes the "All Eyes on PCS" study, which aims to investigate the retinal microvasculature in PCS patients and COVID-19-recovered patients to provide new insights into the pathophysiology of PCS. "All Eyes on PCS" is a prospective, case-control study with the primary objective of detecting endothelial dysfunction (ED) in patients with PCS. Therefore, we intend to recruit patients with PCS, fully SARS-CoV-2-infection-recovered (CR) participants, and SARS-CoV-2-infection-naïve (CN) participants. Baseline measurements will include: (1) patient-specific characteristics, (2) biochemistry, (3) retinal vessel analysis (RVA), (4) survey questionnaires as patient-reported outcomes measurements (PROMs), (5) optical coherence tomography (OCT), OCT angiography (OCTA), and adaptive optics (AO), (6) blood pressure recordings, (7) handgrip strength test. After 6 months, baseline measurements will be repeated in the PCS cohort, and after 1 year, a telephone query will be conducted to assess residual symptoms and treatment needs. The aim of this study is to gain insight into the pathophysiology of PCS and to provide an objective biomarker for diagnosis and treatment, while also creating a comprehensive clinical database of PCS patients.ClinicalTrials.gov Identifier: NCT05635552; Date: 2.12.2022.

Public information needs and preferences on COVID-19: a cross-sectional study.

BACKGROUND: Right from the beginning of the SARS-CoV-2 pandemic the general public faced the challenge to find reliable and understandable information in the overwhelming flood of information. To enhance informed decision-making, evidence-based information should be provided. Aim was to explore the general public's information needs and preferences on COVID-19 as well as the barriers to accessing evidence-based information. METHODS: We performed a cross-sectional study. Nine hundred twenty-seven panel members were invited to an online survey (12/2020-02/2021). The HeReCa-online-panel is installed at the Martin Luther University Halle-Wittenberg to assess regularly the general public's view on health issues in five regions in Germany. The survey was set up in LimeSurvey, with nine items, multiple-choice and open-ended questions that allowed to gather qualitative data. Quantitative data were analysed descriptively and a content analysis was carried out to categorise the qualitative data. RESULTS: Six hundred thirty-six panel members provided data; mean age 52 years, 56.2% female, and 64.9% with higher education qualifications. Asked about relevant topics related to COVID-19, most participants selected vaccination (63.8%), infection control (52%), and long-term effects (47.8%). The following 11 categories were derived from the qualitative analysis representing the topics of interest: vaccination, infection control, long-term effects, therapies, test methods, mental health, symptoms, structures for pandemic control, infrastructure in health care, research. Participants preferred traditional media (TV 70.6%; radio 58.5%; newspaper 32.7%) to social media, but also used the internet as sources of information, becoming aware of new information on websites (28.5%) or via email/newsletter (20.1%). The knowledge question (Which European country is most affected by the SARS-CoV-2 pandemic?) was correctly answered by 7.5% of participants. The Robert Koch Institute (93.7%) and the World Health Organization (78%) were well known, while other organisations providing health information were rarely known (< 10%). Barriers to accessing trustworthy information were lack of time (30.7%), little experience (23.1%), uncertainty about how to get access (22.2%), complexity and difficulties in understanding (23.9%), and a lack of target group orientation (15,3%). CONCLUSIONS: There are extensive information needs regarding various aspects on COVID-19 among the general population. In addition, target-specific dissemination strategies are still needed to reach different groups.

Impaired Retinal Vessel Dilation Predicts Mortality in End-Stage Renal Disease.

RATIONALE: Patients with end-stage renal disease (ESRD) are characterized by increased cardiovascular (CV) and all-cause mortality due to advanced remodeling of the macro- and microvascular beds. OBJECTIVE: The aim of this study was to determine whether retinal microvascular function can predict all-cause and CV mortality in patients with ESRD. METHODS AND RESULTS: In the multicenter prospective observational ISAR (Risk Stratification in End-Stage Renal Disease) study, data on dynamic retinal vessel analysis (DVA) was available in a sub-cohort of 214 dialysis patients (mean age 62.6{plus minus}15.0; 32% female). Microvascular dysfunction was quantified by measuring maximum arteriolar (aMax) and venular dilation (vMax) of retinal vessels in response to flicker light stimulation. During a mean follow-up of 44 months, 55 patients died, including 25 CV and 30 non-CV fatal events. vMax emerged as a strong independent predictor for all-cause mortality. In the Kaplan-Meier analysis, individuals within the lowest tertile of vMax showed significantly shorter three-year survival rates than those within the highest tertile (66.9{plus minus}5.8% vs 92.4{plus minus}3.3%). Uni- and multivariate hazard ratios for all-cause mortality per SD increase of vMax were 0.62 [0.47;0.82] and 0.65[0.47;0.91], respectively. aMax and vMax were able to significantly predict nonfatal and fatal CV events (HR 0.74[0.57;0.97] and 0.78[0.61;0.99], respectively). CONCLUSIONS: Our results provide the first evidence that impaired retinal venular dilation is a strong and independent predictor of all-cause mortality in hemodialyzed ESRD patients. DVA provides added value for prediction of all-cause mortality and may be a novel diagnostic tool to optimize CV risk stratification in ESRD and other high-risk CV cohorts. CLINICAL TRIAL REGISTRATION: NCT01152892.

Exome Sequencing and Identification of Phenocopies in Patients With Clinically Presumed Hereditary Nephropathies.

RATIONALE & OBJECTIVE: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. STUDY DESIGN: Cross-sectional cohort study. SETTING & PARTICIPANTS: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other." RESULTS: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n=5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases. LIMITATIONS: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). CONCLUSIONS: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.

Comparison of 24-hour and Office Pulse Wave Velocity for Prediction of Mortality in Hemodialysis Patients.

BACKGROUND: Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV). METHOD: This study cohort contains patients from the "Risk stratification in end-stage renal disease - the ISAR study," a multicenter prospective longitudinal observatory cohort study. We examined and compared the predictive value of ambulatory 24-hour PWV (24 h-PWV) and Office-PWV on mortality in a total of 344 hemodialysis patients. The endpoints of the study were all-cause and cardiovascular mortality. Survival analysis included Kaplan-Meier estimates and Cox regression analysis. RESULTS: During a follow-up of 36 months, a total of 89 patients died, 35 patients due to cardiovascular cause. Kaplan-Meier estimates for tertiles of 24 h-PWV and Office-PWV were similarly associated with mortality. In univariate Cox regression analysis, 24 h-PWV and Office-PWV were equivalent predictors for all-cause and cardiovascular mortality. After adjustment for common risk factors, only 24 h-PWV remained solely predictive for all-cause mortality (hazard ratio 2.51 [95% CI 1.31-4.81]; p = 0.004). CONCLUSIONS: Comparing both measurements, 24 h-PWV is an independent predictor for all-cause-mortality in hemodialysis patients beyond Office-PWV.

Association of Ambulatory Blood Pressure with All-Cause and Cardiovascular Mortality in Hemodialysis Patients: Effects of Heart Failure and Atrial Fibrillation.

BACKGROUND: Evidence on the utility of ambulatory BP monitoring for risk prediction has been scarce and inconclusive in patients on hemodialysis. In addition, in cardiac diseases such as heart failure and atrial fibrillation (common among patients on hemodialysis), studies have found that parameters such as systolic BP (SBP) and pulse pressure (PP) have inverse or nonlinear (U-shaped) associations with mortality. METHODS: In total, 344 patients on hemodialysis (105 with atrial fibrillation, heart failure, or both) underwent ambulatory BP monitoring for 24 hours, starting before a dialysis session. The primary end point was all-cause mortality; the prespecified secondary end point was cardiovascular mortality. We performed linear and nonlinear Cox regression analyses for risk prediction to determine the associations between BP and study end points. RESULTS: During the mean 37.6-month follow-up, 115 patients died (47 from a cardiovascular cause). SBP and PP showed a U-shaped association with all-cause and cardiovascular mortality in the cohort. In linear subgroup analysis, SBP and PP were independent risk predictors and showed a significant inverse relationship to all-cause and cardiovascular mortality in patients with atrial fibrillation or heart failure. In patients without these conditions, these associations were in the opposite direction. SBP and PP were significant independent risk predictors for cardiovascular mortality; PP was a significant independent risk predictor for all-cause mortality. CONCLUSIONS: This study provides evidence for the U-shaped association between peripheral ambulatory SBP or PP and mortality in patients on hemodialysis. Furthermore, it suggests that underlying cardiac disease can explain the opposite direction of associations.

Acetate-free, citrate-acidified bicarbonate dialysis improves serum calcification propensity-a preliminary study.

Background: A novel in vitro test (T50 test) assesses ex vivo serum calcification propensity and predicts mortality in chronic kidney disease and haemodialysis (HD) patients. For the latter, a time-dependent decline of T50 was shown to relate to mortality. Here we assessed whether a 3-month switch to acetate-free, citrate-acidified, standard bicarbonate HD (CiaHD) sustainably improves calcification propensity. Methods: T50 values were assessed in paired midweek pre-dialysis sera collected before and 3 months after CiaHD in 78 prevalent European HD patients. In all, 44 were then switched back to acetate. Partial correlation was used to study associations of changing T50 and changing covariates. Linear mixed effect models were built to assess the association of CiaHD and covariates with changing T50. Results: A significant intra-individual increase of serum calcification resilience was found after 3 months on CiaHD (206 ± 56 to 242 ± 56 min; P < 0.001), but not after switching back to acetate (252 ± 63 to 243 ± 64 min; n = 44; P = 0.29). CiaHD, Δ serum phosphate and Δ albumin but not Δ ionized calcium and magnesium were the strongest determinants of changing T50. Beneath T50, only serum albumin but not phosphate changed significantly during 3 months of CiaHD. Conclusion: CiaHD dialysis favourably affected calcification propensity as measured by the T50 test. Whether this treatment, beyond established phosphate-directed treatments, has the potential to sustainably tip the balance towards a more anti-calcific serum milieu needs to be further investigated.

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.

BACKGROUND: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. METHODS: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. RESULTS: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. CONCLUSIONS: PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

Measures of wave intensity as a non-invasive surrogate for cardiac function predicts mortality in haemodialysis patients.

Background: Risk prediction in haemodialysis (HD) patients is challenging due to the impact of the dialysis regime on the patient's volume status and the complex interplay with cardiac function, comorbidities and hypertension. Cardiac function as a key predictor of cardiovascular (CV) mortality in HD patients is challenging to assess in daily routine. Thus the aim of this study was to investigate the association of a novel, non-invasive relative index of systolic function with mortality and to assess its interplay with volume removal. Methods: A total of 558 (373 male/185 female) HD patients with a median age of 66 years were included in this analysis. They underwent 24-hour ambulatory blood pressure monitoring, including wave intensity analysis [i.e. S:D ratio (SDR)]. All-cause and CV mortality served as endpoints and multivariate proportional hazards models were used for risk prediction. Intradialytic changes were analysed in tertiles according to ultrafiltration volume. During a follow-up of 37.8 months, 193 patients died (92 due to CV reasons). Results: The SDR was significantly associated with all-cause {univariate hazard ratio [HR] 1.36 [95% confidence interval (CI) 1.20-1.54], P < .001} and CV [univariate HR 1.41 (95% CI 1.20-1.67), P < .001] mortality. The associations remained significant in multivariate analysis accounting for possible confounders. Changes in the SDR from pre-/early- to post-dialytic averages were significantly different for the three ultrafiltration volume groups. Conclusion: This study provides well-powered evidence for the independent association of a novel index of systolic function with mortality. Furthermore, it revealed a significant association between intradialytic changes of the measure and intradialytic volume removal.

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.

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.

Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience.

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Automatic ECG-based detection of left ventricular hypertrophy and its predictive value in haemodialysis patients.

Objective.Left ventricular hypertrophy (LVH) is one of the most severe risk factors in patients with end-stage kidney disease (ESKD) regarding all-cause and cardiovascular mortality. It contributes to the risk of sudden cardiac death which accounts for approximately 25% of deaths in ESKD patients. Electrocardiography (ECG) is the least expensive way to assess whether a patient has LVH, but manual annotation is cumbersome. Thus, an automated approach has been developed to derive ECG-based LVH parameters. The aim of the current study is to compare automatic to manual measurements and to investigate their predictive value for cardiovascular and all-cause mortality.Approach.From the 12-lead 24 h ECG measurements of 301 ESKD patients undergoing haemodialysis, three different LVH parameters were calculated. Peguero-Lo Presti voltage, Cornell voltage, and Sokolow-Lyon voltage were automatically derived and compared to the manual annotations. To determine the agreement between manual and automatic measurements and their predictive value, Bland-Altman plots were created and Cox regression analysis for cardiovascular and all-cause mortality was performed.Main results.The median values for the automatic assessment were: Peguero-Lo Presti voltage 1.76 mV (IQR 1.29-2.55), Cornell voltage 1.14 mV (IQR 0.721-1.66), and Sokolow-Lyon voltage 1.66 mV (IQR 1.08-2.23). The mean differences when compared to the manual measurements were -0.027 mV (0.21 SD), 0.027 mV (0.13 SD) and -0.025 mV (0.24 SD) for Peguero-Lo Presti, Cornell, and Sokolow-Lyon voltage, respectively. The categorial LVH detection based on pre-defined thresholds differed in only 13 cases for all indices between manual and automatic assessment. Proportional hazard ratios only differed slightly in categorial LVH detection between manually and automatically determined LVH parameters; no differences could be found for continuous parameters.Significance.This study provides evidence that automatic algorithms can be as reliable in LVH parameter assessment and risk prediction as manual measurements in ESKD patients undergoing haemodialysis.

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.

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.

Mortality prediction of retinal vessel diameters and function in a long-term follow-up of haemodialysis patients.

AIM: Retinal vessel diameters are candidate biomarkers of mortality prediction in large population-based studies. We aimed to investigate the predictive value of retinal vessel diameters and flicker-induced retinal arteriolar and venular dilation on all-cause mortality in long-term follow-up of haemodialysis patients. METHODS AND RESULTS: Retinal vessel diameters as well as maximum arteriolar (aMax) and venular dilation (vMax) were investigated in 275 and 214 haemodialysis patients, respectively. Patients were observed in a long-term follow-up for a median period of 73 months. About 36% (76/214) and 41% (113/275) of patients died. Arteriolar and venular diameters were 175 ± 19 and 208 ± 20 µm, respectively. Median aMax and vMax were 1.6 (0.3-3.3) and 3.2 (2.0-5.1)%. Patients within the lowest tertile of vMax showed lower 5-year survival rates compared with the highest tertile (50.6 vs. 82.1%) and also exhibited a higher incidence of infection-related deaths (21.7 vs. 4.0%). Univariate hazard ratio (HR) per standard deviation increase of vMax for all-cause mortality was 0.69 (0.54-0.88) and was even more pronounced for infection-related mortality [HR 0.53 (0.33-0.83)]. Regarding all-cause mortality, multivariate adjustment for eight non-retinal mortality predictors including interleukin-6 did not attenuate the HR relevantly [0.73 (0.54-0.98)]. Arteriolar and venular diameters did not predict all-cause nor cardiovascular and infection-related mortality. CONCLUSIONS: Long-term follow-up of patients on haemodialysis demonstrated the potential of retinal venular dilation capacity for mortality prediction, which was most pronounced for infection-related mortality. In the same cohort, retinal arteriolar and venular diameters showed no predictive value for hard endpoints. Retinal venular dilation but not arteriolar and venular diameters is a valuable diagnostic biomarker for risk prediction in patients with end-stage renal disease and should be considered for monitoring of critically ill patients.

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.

Cognitive impairment and microvascular function in end-stage renal disease.

OBJECTIVE: Hemodialysis patients show an approximately threefold higher prevalence of cognitive impairment compared to the age-matched general population. Impaired microcirculatory function is one of the assumed causes. Dynamic retinal vessel analysis is a quantitative method for measuring neurovascular coupling and microvascular endothelial function. We hypothesize that cognitive impairment is associated with altered microcirculation of retinal vessels. METHODS: 152 chronic hemodialysis patients underwent cognitive testing using the Montreal Cognitive Assessment. Retinal microcirculation was assessed by Dynamic Retinal Vessel Analysis, which carries out an examination recording retinal vessels' reaction to a flicker light stimulus under standardized conditions. RESULTS: In unadjusted as well as in adjusted linear regression analyses a significant association between the visuospatial executive function domain score of the Montreal Cognitive Assessment and the maximum arteriolar dilation as response of retinal arterioles to the flicker light stimulation was obtained. CONCLUSION: This is the first study determining retinal microvascular function as surrogate for cerebral microvascular function and cognition in hemodialysis patients. The relationship between impairment in executive function and reduced arteriolar reaction to flicker light stimulation supports the involvement of cerebral small vessel disease as contributing factor for the development of cognitive impairment in this patient population and might be a target for noninvasive disease monitoring and therapeutic intervention.

A randomized prospective cross over study on the effects of medium cut-off membranes on T cellular and serologic immune phenotypes in hemodialysis.

Extended cut-off filtration by medium cut-off membranes (MCO) has been shown to be safe in maintenance hemodialysis (HD). The notion of using them for the control of chronic low-grade inflammation and positively influencing cellular immune aberrations seems tempting. We conducted an open label, multicenter, randomized, 90 day 2-phase cross over clinical trial (MCO- vs. high flux-HD). 46 patients underwent randomization of which 34 completed the study. Dialysate- or pre- and post-dialysis serum inflammatory mediators were assayed for each study visit. Ex vivo T cell activation was assessed from cryopreserved leucocytes by flow cytometry. Linear mixed models were used to compare treatment modalities, with difference in pre-dialysis serum MCP-1 levels after 3 months as the predefined primary endpoint. Filtration/dialysate concentrations of most mediators, including MCP-1 (mean ± SD: 10.5 ± 5.9 vs. 5.1 ± 3.8 pg/ml, P < 0.001) were significantly increased during MCO- versus high flux-HD. However, except for the largest mediator studied, i.e., YKL-40, this did not confer any advantages for single session elimination kinetics (post-HD mean ± SD: 360 ± 334 vs. 564 ± 422 pg/ml, P < 0.001). No sustained reduction of any of the studied mediators was found neither. Still, the long-term reduction of CD69+ (P = 0.01) and PD1+ (P = 0.02) activated CD4+ T cells was striking. Thus, MCO-HD does not induce reduction of a broad range of inflammatory mediators studied here. Long-term reduction over a 3-month period was not possible. Increased single session filtration, as evidenced by increased dialysate concentrations of inflammatory mediators during MCO-HD, might eventually be compensated for by compartment redistribution or increased production during dialysis session. Nevertheless, lasting effects on the T-cell phenotype were seen, which deserves further investigation.