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Peritubular capillaritis (ptc) is a hallmark lesion of antibody-mediated rejection (AMR), but the grading of its extent is historically based on arbitrary defined cut-offs. Molecular AMR diagnosis via intragraft gene expression measurements may provide evidence to challenge established ptc categories. We retrospectively included 38 renal allograft biopsies from clinical routine, performed because of suspicion of AMR. Biopsies were re-assessed by an experienced nephropathologist and intragraft gene expression was measured using the NanoString nCounter® platform. Ptc categories were correlated with AMR gene expression to identify a ptc extent cut-off with optimal prediction of molecular diagnosis of AMR [gene expression levels above first quartile (AMRQ>1)]. Finally, an independent validation cohort (n = 25, Erasmus MC, Rotterdam, The Netherlands) was included to reproduce the results. Re-assessment of biopsies revealed AMR in 26/68.4%, mixed rejection in 5/13.2%, and T-cell-mediated rejection in 3/7.9%. Biopsies with diffuse ptc had significantly higher AMR gene expression compared to biopsies with focal ptc and biopsies with no ptc (64.0/53.3–84.0 vs. 31.5/27.0–49.5, p = 0.023 and 27.0/14.3–31.8, p = 0.003, median/IQR). Sensitivity analysis revealed that a ≥35% ptc cut-off resulted in higher AUCs for predicting AMRQ>1 compared to ptc50% (AUC 0.78, 95% CI: 0.63–0.93, p = 0.009 versus AUC: 0.74, CI: 0.56–0.90, p = 0.03). In the validation cohort, only the ptc35–, but not the ptc50%, cut-off significantly predicted AMRQ>1 (AUC 0.75, 95% CI: 0.54–0.96 p = 0.04 vs. AUC 0.69, CI: 0.46–0.93, p = 0.13). Using intragraft gene expression measurement, we identified a new ptc extent threshold with better prediction of molecular AMR. The newly proposed cut-off of ≥35% could potentially improve diagnostic evaluation and prognostication in cases with suspected or diagnosed AMR.

Polyomavirus nephropathy (BKPyVAN) is a major cause of allograft dysfunction after kidney transplantation (KTX). While plasma BKPyV-PCR is the diagnostic gold standard, it may not fully reflect tissue injury. We conducted a prospective observational proof-of-concept study in 30 KTX recipients with BKPyV reactivation (November 2022–February 2024); 21 underwent kidney biopsy, 11 were diagnosed with biopsy-proven (BP)-BKPyVAN. Urine samples were analyzed by flow cytometry to quantify the potential of VP1-positive reno-urinary epithelial cells as a novel non-invasive marker of active tubular damage. The control cohort included 21 virology-negative patients. Median urinary VP1-positivity was higher in BP-BKPyVAN (33%, IQR 27–46) vs. non-BKPyVAN patients (5%, IQR 1–13; p < 0.001). The assay achieved an AUC of 0.98 (95% CI 0.93–1.00, p = 0.0003; cut-off: 11.7%; sensitivity = 91%, specificity = 89%) for BP-BKPyVAN. Longitudinally, median VP1-burden declined from 13% (IQR 4–29) at baseline to 0% (IQR 0–0.4). BKPyV-DNAemia declined rapidly, but plateaued at ∼4 × 10 2 –7 × 10 2 copies/mL, whereas urinary VP1-positive cells became undetectable. Our preliminary results suggest that combining urinary VP1-positivity with plasma BKPyV-PCR may help distinguish BP-BKPyVAN from non-BKPyVAN within a BKPyV-reactivation cohort. Longitudinal VP1 tracking may indicate resolution of viral infection earlier than DNAemia. These findings are hypothesis-generating and require validation in larger independent cohorts.

Seasonal influenza is a major global health problem causing substantial morbidity and health care costs. Yet, in many countries, the rates of influenza vaccination remain low. Chronic kidney or liver diseases (CKLD) predispose patients to severe influenza infections, but data on vaccination acceptance and status is limited in this risk population. We investigated the influenza vaccination awareness considering sociodemographic factors in CKLD patients. This cross-sectional, questionnaire-based study recruited CKLD patients managed at three Viennese tertiary care centers between July and October 2020. CKLD was defined as chronic kidney- (all stages) or compensated/decompensated liver disease, including kidney/liver transplant recipients. Questionnaires assessed sociodemographic and transplant- associated parameters, patients vaccination status and the individuals self-perceived risks of infection and associated complications. In total 516 patients (38.1% female, mean age 56.4 years) were included. 43.9% of patients declared their willingness to be vaccinated in the winter season 2020/2021, compared to 25.4% in 2019/2020 and 27.3% in 2016-2018. Vaccination uptake was associated with the self-perceived risks of infection (OR: 2.8 (95%CI: 1.8-4.5), p<0.001) and associated complications (OR: 3.8 (95%CI: 2.3-6.3), p<0.001) as well as with previously received influenza vaccination (2019/2020: OR 17.1 (95%CI: 9.5-30.7), p<0.001; season 2016-2018: OR 8.9 (95%CI: 5.5-14.5), p<0.001). Most frequent reasons for not planning vaccination were fear of a) graft injury (33.3%), b) complications after vaccination (32.4%) and c) vaccine inefficiency (15.0%). While influenza vaccination willingness in patients with CKLD is increasing in the 2020/2021 season, vaccination rates may still remain <50%. Novel co-operations with primary health care, active vaccination surveillance and financial reimbursement may substantially improve vaccination rates in high-risk CKLD patients.

Urolithiasis is one of the most common diseases worldwide, characterized by high morbidity and significant treatment-related costs, with a rising prevalence of up to 20%. The relapse rate within the first 10 years after initial treatment is estimated to be about 60%. Given the increasing prevalence, healthcare-related costs associated with urinary tract stones in the USA are expected to reach up to US $1.24 billion annually by 2030. Current prophylactic therapy for urolithiasis recurrence includes lifestyle modifications, citrate supplementation, and pharmaceuticals. However, a high number of cases remain unresponsive to available pharmacological therapies. Though initially developed for the treatment of Diabetes mellitus, SGLT-2 inhibitors have shown promise in decreasing cardiac and renal endpoints across multiple indications. Recent registry studies have indicated that patients receiving SGLT-2 inhibitors exhibit lower rates of urolithiasis incidence, suggesting a potential reduction in recurrence rates and associated mortality. We hypothesize that SGLT-2 inhibitors (Dapagliflozin), owing to their multiple pleiotropic effects, may offer a viable treatment option for the prophylaxis of high-risk calcium oxalate kidney stones and reduce urinary calcium oxalate output. This study will proceed in two phases: an exploratory phase and a randomized controlled phase. In the exploratory phase, 22 participants with indications for dapagliflozin treatment will be evaluated before and after treatment initiation to ascertain the concrete effect size regarding oxalate and calcium-sparing effects. This data will inform the calculation of the study sample size (ranging from 17 to 104 participants) to include high-risk calcium oxalate kidney stone formers in a randomized controlled crossover study design. Treatment phases-one with dapagliflozin and one with placebo-will alternate with wash-out phases involving placebo. The primary outcome is the reduction of oxalate excretion in 24-hour urine samples compared to baseline values after 8 weeks of therapy. Secondary objectives include analysing effects on kidney function, the frequency of urolithiasis, and treatment tolerance. Additionally, in-depth metabolomics analyses will explore pathophysiological pathways during treatment. Investigators, patients, and research staff will be blinded to the randomization list. This study was initially registered under EudraCT (Nr:2022-000994-13) and has been transitioned to CTIS (Nr: 2024-519371-25-00) to comply with EU Regulation 536/2014, ensuring streamlined management and transparency. Dapagliflozin's pleiotropic effects may provide a novel prophylactic treatment option for urolithiasis. This study aims to evaluate potential treatment effects in a prospective RCT and elucidate potential pathophysiological pathways through in-depth metabolomics analyses. SGLT-2 inhibitors have the potential to transform the landscape of urolithiasis treatment, reduce the healthcare burden on individuals and the system, and significantly improve patient quality of life.

Introduction: The absolute BK viral load is an important diagnostic surrogate for BK polyomavirus associated nephropathy (PyVAN) after renal transplant (KTX) and serial assessment of BK viremia is recommended. However, there is no data indicating which particular viral load change, i.e., absolute vs. relative viral load changes (copies/ml; percentage of the preceding viremia) is associated with worse renal graft outcomes. Materials and Methods: In this retrospective study of 91 biopsy proven PyVAN, we analyzed the interplay of exposure time, absolute and relative viral load kinetics, baseline risk, and treatment strategies as risk factors for graft loss after 2 years using a multivariable Poisson-model. Results: We compared two major treatment strategies: standardized immunosuppression (IS) reduction ( n = 53) and leflunomide ( n = 30). The median viral load at the index biopsy was 2.15E+04 copies/ml (interquartile range [IQR] 1.70E+03–1.77E+05) and median peak viremia was 3.6E+04 copies/ml (IQR 2.7E+03–3.3E+05). Treatment strategies and IS-levels were not related to graft loss. After correction for baseline viral load and estimated glomerular filtration rate (eGFR), absolute viral load decrease/unit remained an independent risk factor for graft loss [incidence rate ratios [IRR] = 0.77, (95% CI 0.61–0.96), p = 0.02]. Conclusion: This study provides evidence for the prognostic importance of absolute BK viremia kinetics as a dynamic parameter indicating short-term graft survival independently of other established risk factors.

Absolute blood volume (ABV) is a critical component of fluid status, which may inform target weight prescriptions and hemodynamic vulnerability of dialysis patients. Here, we utilized the changes in relative blood volume (RBV), monitored by ultrasound (BVM) upon intradialytic 240 mL dialysate fluid bolus-infusion 1 h after hemodialysis start, to calculate the session-specific ABV. With the main goal of assessing clinical feasibility, our sub-aims were to (i) standardize the BVM-data read-out; (ii) determine optimal time-points for ABV-calculation, \"before-\" and \"after-bolus\"; (iii) assess ABV-variation. We used high-level programming language and basic descriptive statistics in a retrospective study of routinely measured BVM-data from 274 hemodialysis sessions in 98 patients. Regarding (i) and (ii), we automatized the processing of RBV-data, and determined an algorithm to select the adequate RBV-data points for ABV-calculations. Regarding (iii), we found in 144 BVM-curves from 75 patients, that the average ABV ± standard deviation was 5.2 ± 1.5 L and that among those 51 patients who still had ≥2 valid estimates, the average intra-patient standard deviation in ABV was 0.8 L. Twenty-seven of these patients had an average intra-patient standard deviation in ABV <0.5 L. We demonstrate feasibility of ABV-calculation by an automated algorithm after dialysate bolus-administration, based on the BVM-curve. Based on our results from this simple \"abridged\" calculation approach with routine clinical measurements, we encourage the use of multi-compartment modeling and comparison with reference methods of ABV-determination. Hopes are high that clinicians will be able to use ABV to inform target weight prescription, improving hemodynamic stability.

Background: In hemodialysis patients, precise hemoglobin (Hb) monitoring is essential for anemia management. Point-of-care blood gas analyzers (BGAs), such as the ABL800 Flex, offer rapid Hb determinations, but their accordance and comparability with central laboratory measurements remains to be assessed in the hemodialysis setting. Methods: We performed a retrospective analysis (April 2017–February 2024) of 10,802 paired Hb measurements from 291 hemodialysis patients. BGA and laboratory values within 90 min were compared using paired t-tests, non-inferiority testing (margin 0.5 g/dL), a Bland–Altman analysis, and linear regression. Results: The mean ± standard deviation Hb (g/dL) values were 10.14 ± 1.64 (BGA) versus 9.90 ± 1.55 (laboratory). The overall mean difference (BGA—laboratory) was 0.24 ± 0.49 g/dL (95% CI: 0.23–0.25), demonstrating non-inferiority (p < 0.0001). Measurement delay correlated with increasing analysis discrepancies (mean difference in g/dL: 0.22 at <30 min vs. 0.27 at 60–90 min; p < 0.001). We derived the equation of laboratory Hb = 0.90 × BGA Hb + 0.72; a simplified correction (BGA−0.3 g/dL) produced a mean absolute error (MAE) of 0.30 g/dL and root mean square error (RMSE) of 0.50 g/dL, and patient-level 10-fold cross-validation yielded MAE ≈ 0.30 and RMSE ≈ 0.49 g/dL. The Bland–Altman analysis confirmed a small systematic bias of 0.24 g/dL with 95% limits of agreement ranging from −0.73 to +1.21 g/dL. Conclusions: BGA Hb measurements via the ABL800 Flex are non-inferior to central laboratory values across clinical scenarios, with minimal bias. After regression correction, the estimated total error was ≈0.78 g/dL. If hemodialysis centers accept this level of total error and apply confirmatory testing near decision points, BGA could be used to guide anemia management.

Quantitative magnetic resonance imaging (MRI) is emerging as a non-invasive tool to measure tissue scarring in renal allografts. However, whether prolonged T 1 relaxation time results in lower transplant survival rates is unknown. This retrospective cohort study analyzed the capability to predict renal allograft dysfunction based on median T 1 time. Forty-six transplant recipients with non-contrast 1.5T MRI and allograft biopsy were included. The primary endpoint was the eGFR slope over 24 months. T 1 relaxation time correlated significantly with eGFR levels at all follow-up stages. Patients with T 1 relaxation time above the median (T 1 high ) had a consistent decline in kidney function as compared to the patient group below the median (T 1 low ): overall eGFR slope: 11.3 vs. 1.4 mL/min/1.73 m 2 over 24 months, p = 0.016. Graft survival rates at 24 months were 52% in the T 1 high vs. 87% in the T 1 low group, p = 0.0015. ROC analysis discovered a positive predictive value of 52% and a negative predictive value of 91% for graft loss. T 1 mapping identified patients with a persistent decline of allograft function and an increased risk of allograft loss. MRI could significantly influence monitoring strategies in transplant surveillance, offering a safe, non-invasive alternative to traditional diagnostic methods.

Introduction: Polyomavirus-associated nephropathy (BKPyVAN) is a common complication in kidney transplant recipients. The histological changes in the context of BKPyVAN and their association with the viral load and outcomes are still being investigated. Methods: This retrospective study involved 100 adult patients transplanted between 2000 and 2021, with available archived biopsy slides, aiming to analyze associations between viral load clearance in the blood (reduction in BKPyVAN-DNAemia below detection level) and histological features in biopsy-proven BKPyVAN. A kidney pathologist blinded to the clinical data reassessed the BANFF 2019 lesion scores in the BKPyVAN index biopsy. The primary endpoint was viral clearance three months after the diagnosis. Results: The presence of tubulointerstitial inflammation, peritubular capillaritis, and higher PVN Class at the diagnosis was linked to a reduced likelihood of viral clearance three months later (interstitial inflammation OR = 0.2, 95% CI [0.07–0.55], tubulitis OR = 0.39, 95% CI [0.21–0.73], peritubular capillaritis OR = 0.25, 95% CI [0.08–0.82], PVN Score OR = 0.1, 95% CI [0.03–0.4]), independently of other covariates. Combining the four lesions using the ROC analysis enhanced their capability to predict persistent BK viremia after 3 months with an AUC of 0.94. Conclusions: The presence of interstitial inflammation, tubulitis, and peritubular capillaritis, as well as the higher PVN Score, was associated with an up to 90% lower likelihood of viral load clearance three months post-diagnosis. These findings underscore the importance of histological evaluation as a surrogate of subsequent viral clearance and offer valuable insights for the management of BKPyVAN.

Despite the high prevalence of BK polyomavirus (BKPyV) and the associated risk for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant (KTX) recipients, many details on viral processes such as replication, maturation, assembly and virion release from host cells have not been fully elucidated. VP1 is a polyomavirus-specific protein that is expressed in the late phase of its replicative cycle with important functions in virion assembly and infectious particle release. This study investigated the localization and time-dependent changes in the distribution of VP1-positive viral particles and their association within the spectrum of differing cell morphologies that are observed in the urine of KTX patients upon active BKPyV infection. We found highly differing recognition patterns of two anti-VP1 antibodies with respect to intracellular and extracellular VP1 localization, pointing towards independent binding sites that were seemingly associated with differing stages of virion maturation. Cells originating from single clones were stably cultured out of the urine sediment of KTX recipients with suspected BKPyVAN. The cell morphology, polyploidy, virus replication and protein production were investigated by confocal microscopy using both a monoclonal (mAb 4942) and a polyclonal rabbit anti-VP1-specific antibody (RantiVP1 Ab). Immunoblotting was performed to investigate changes in the VP1 protein. Both antibodies visualized VP1 and the mAb 4942 recognized VP1 in cytoplasmic vesicles exhibiting idiomorphic sizes when released from the cells. In contrast, the polyclonal antibody detected VP1 within the nucleus and in cytoplasm in colocalization with the endoplasmic reticulum marker CNX. At the nuclear rim, VP1 was recognized by both antibodies. Immunoblotting revealed two smaller versions of VP1 in urinary decoy cell extracts, potentially from different translation start sites as evaluated by in silico analysis. Oxford Nanopore sequencing showed integration of BKPyV DNA in chromosomes 3, 4 and 7 in one of the five tested primary cell lines which produced high viral copies throughout four passages before transcending into senescence. The different staining with two VP1-specific antibodies emphasizes the modification of VP1 during the process of virus maturation and cellular exit. The integration of BKPyV into the human genome leads to high virus production; however, this alone does not transform the cell line into a permanently cycling and indefinitely replicating one.