Kidney transplantation after rescue allocation-meticulous selection yields the chance for excellent outcome.

BACKGROUND: The small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date. METHODS: We conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients. RESULTS: RA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well. CONCLUSIONS: Facing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.

STAT1 regulates macrophage number and phenotype and prevents renal fibrosis after ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) leads to acute kidney injury or delayed allograft function, which predisposes to fibrosis in the native kidney or kidney transplant. Here we investigated the role of the signal transducer and activator of transcription 1 (STAT1) in inflammatory responses following renal IRI. Our study showed that a subsequent stimulation of Janus-activated kinase 2/STAT1 and Toll-like receptor 4 pathways led to greater STAT1 activation followed by increased cytokine transcription compared with single-pathway stimulation in murine renal tubular cells. Moreover, we observed increased activation of STAT1 under hypoxic conditions. In vivo, STAT1-/- mice displayed less acute tubular necrosis and decreased macrophage infiltration 24 h after renal ischemia. However, investigation of the healing phase (30 days after IRI) revealed significantly more fibrosis in STAT1-/- than in wild-type kidneys. In addition, we demonstrated increased macrophage infiltration in STAT1-/- kidneys. Flow cytometry analysis revealed that STAT1 deficiency drives an alternatively activated macrophage phenotype, which is associated with downregulated cluster of differentiation 80 expression, decreased intracellular reactive oxygen species production, and enhanced ability for phagocytosis. Furthermore, we detected immunohistochemically enhanced STAT1 expression in human renal allograft biopsies with no interstitial fibrosis/tubular atrophy (IF/TA) compared with specimens with severe IF/TA without specific etiology. Thus, STAT1 activation drives macrophages toward an alternatively activated phenotype and enhances fibrogenesis indicating a potential STAT1-driven protective mechanism in tissue repair after ischemic injury.

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.

A complex pattern of autonomic dysfunction in familial Mediterranean fever. Results from a controlled cross-sectional study.

OBJECTIVES: Autonomic dysfunction (AD) has been described in various chronic inflammatory diseases. Studies of AD in patients with familial Mediterranean fever (FMF) are inconclusive. We aimed to assess AD in a cohort of FMF patients. METHODS: Signs and symptoms of AD were investigated in patients with FMF and compared to age and gender matched healthy controls. Symptoms of AD were assessed by COMPASS-31, a validated questionnaire to evaluate orthostatic, vasomotor, secretomotor, gastrointestinal, pupillomotor and bladder function domains. Assessment of objective AD comprised heart rate variability during deep breathing, skin conductance changes during mental arithmetic, blood pressure response to pain and dynamic infrared pupillometry. RESULTS: 25 patients and 25 healthy controls were included and evaluated by COMPASS-31 and objective testing of AD. FMF patients had higher median COMPASS-31 total scores than controls (23.7 vs. 1.6, p=0.024). Significant differences were also found in the secretomotor and gastrointestinal sub-domains (4.2 vs. 0.0; p<0.001 and 8.0 vs. 0.0; p=0.004, respectively). Symptoms of autonomic dysfunction were correlated with patient reported global disease activity (r=0.71; p<0.001) and pain level (r=0.68; p<0.001). There were no differences in heart rate variability (HRV), skin conductance, blood pressure response to pain or sympathetic pupillomotor function between patients and controls. FMF patients revealed impaired parasympathetic pupillomotor function that was not associated with clinical parameters. However, patients that were on IL-1-blocking therapy had better parasympathetic pupillary function than patients on conventional treatment. CONCLUSIONS: FMF patients have AD in terms of symptoms and parasympathetic pupillomotor function. Dynamic pupillometry can provide additional information on autonomic regulation in patients with FMF.

Mortality prediction in stable hemodialysis patients is refined by YKL-40, a 40-kDa glycoprotein associated with inflammation.

Chronic inflammation contributes to increased mortality in hemodialysis (HD) patients. YKL-40 is a novel marker of inflammation, tissue remodeling, and highly expressed in macrophages inside vascular lesions. Elevated levels of YKL-40 have been reported for HD patients but how it integrates into the proinflammatory mediator network as a predictor of mortality remains elusive. We studied serum YKL-40, Interleukin-6 (IL-6), high-sensitivity C-reactive protein, monocyte chemotactic protein-1 (MCP-1), and interferon-gamma induced protein-10 (IP-10) in 475 chronic hemodialysis patients. Patients were followed for mortality for a median of 37 [interquartile range: 25-49] months and checked for interrelation of the measured mediators. To plot cumulative incidence functions, patients were stratified into terciles per YKL-40, IL-6, MCP-1, and IP-10 levels. Multivariable Cox regression models were built to examine associations of YKL-40, IP-10, and MCP-1 with all-cause and cause-specific mortality. Net reclassification improvement was calculated for the final models containing YKL-40 and IL-6. Increased YKL-40 was independently associated with age, IP-10, and IL-6 serum levels. After adjustment for demographic and laboratory parameters, comorbidities, and IL-6, only YKL-40 significantly improved risk prediction for all-cause (hazard ratio 1.4; 95% confidence interval 1.1-1.8) and cardiovascular mortality (hazard ratio 1.5; 95% confidence interval 1.03-2.2). Thus, in contrast to other biomarkers of aberrant macrophage activation, YKL-40 reflects inflammatory activity, which is not covered by IL-6. Mechanistic and prospective studies are needed to test for causal involvement of YKL-40 and whether it might qualify as a therapeutic target.

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.

Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes.

Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1ß and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.

Tixagevimab/Cilgavimab for COVID-19 Pre-Exposure Prophylaxis in Hematologic Patients-A Tailored Approach Based on SARS-CoV-2 Vaccine Response.

Patients with hematologic malignancies still face a significant risk of severe coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-neutralizing monoclonal antibody combination tixagevimab/cilgavimab (TIX/CGB) could be administered to immunocompromised patients for pre-exposure prophylaxis (PrEP) before the emergence of TIX/CGB-resistant COVID-19 Omicron variants. TIX/CGB application could be carried out regardless of the host's immune response to previous active SARS-CoV-2 vaccinations or infections. Because the efficacy of COVID-19 PrEP remains unclear, especially in SARS-CoV-2-seropositive patients, German national guidelines recommended TIX/CGB PrEP only for SARS-CoV-2-seronegative patients in addition to an intensified active vaccination schedule. Having followed these guidelines, we now report the characteristics and outcomes of 54 recipients of TIX/CGB PrEP in SARS-CoV-2-seronegative patients with hematological disease from a German tertiary medical center and compare them to 125 seropositive patients who did not receive any PrEP. While the number of patients with B-cell lymphomas was significantly higher in the seronegative cohort (33 (61%) vs. 18 (14%) cases, p < 0.01), patients with myeloid diseases were significantly more frequent in the seropositive cohort (51 (41%) vs. 5 (9%) cases, p < 0.01). Strikingly, patients who had undergone allogeneic hematopoietic stem cell transplantation were significantly more likely (forty-nine (39%) vs. six (11%) cases, p < 0.01) to be SARS-CoV-2 seropositive. We observed that prophylactic application of TIX/CGB PrEP to a highly vulnerable group of SARS-CoV-2-seronegative patients resulted in a similar number of COVID-19 breakthrough infections compared to the untreated seropositive control group (16 (32%) vs. 39 (36%), p = 0.62) and comparable COVID-19-related outcomes like hospitalization and oxygen requirement throughout an extended follow-up period of 12 months. In conclusion, our results support the tailored approach of administering TIX/CGB PrEP only to SARS-CoV-2-seronegative patients during the COVID-19 pandemic and might provide a rationale for similar strategies during future outbreaks/diseases, especially in times of initial limited availability and/or financial constraints.

Effectiveness, Immunogenicity and Harms of Additional SARS-CoV-2 Vaccine Doses in Kidney Transplant Recipients: A Systematic Review.

BACKGROUND: Kidney transplant recipients (KTRs) who have a highly impaired immune response are in need of intensified and safe vaccination strategies to achieve seroconversion and prevent severe disease. METHODS: We searched the Web of Science Core Collection, the Cochrane COVID-19 Study Register and the WHO COVID-19 global literature on coronavirus disease from January 2020 to 22 July 2022 for prospective studies that assessed immunogenicity and efficacy after three or more SARS-CoV-2 vaccine doses. RESULTS: In 37 studies on 3429 patients, de novo seroconversion after three and four vaccine doses ranged from 32 to 60% and 25 to 37%. Variant-specific neutralization was 59 to 70% for Delta and 12 to 52% for Omicron. Severe disease after infection was rarely reported but all concerned KTRs lacked immune responses after vaccination. Studies investigating the clinical course of COVID-19 found remarkably higher rates of severe disease than in the general population. Serious adverse events and acute graft rejections were very rare. Substantial heterogeneity between the studies limited their comparability and summary. CONCLUSION: Additional SARS-CoV-2 vaccine doses are potent and safe in general terms as well as regarding transplant-specific outcomes whilst the Omicron wave remains a significant threat to KTRs without adequate immune responses.

Immunophenotypic Characterization of Citrate-Containing A Concentrates in Maintenance Hemodialysis: A Pre-Post Study.

Introduction: Due to chronic inflammation, maintenance hemodialysis (MHD) patients continue to show excess mortality. Acetate-free citrate-buffered A concentrates could be a way to improve the biocompatibility of the procedure, reduce chronic inflammation, and thus in the long term improve the prognosis of patients. Methods: Using a pre-post design (3 months of acetate followed by 3 months of citrate-acidified A concentrates in standard bicarbonate-based dialysate hemodialysis, CiaHD) and linear mixed model analysis in 61 stable HD patients, we assessed the impact of CiaHD on counts and phenotypes of peripheral T cells and monocytes by flow cytometry. Results: Switching to CiaHD left C-reactive protein (CRP) levels and leucocyte counts unaffected. However, CiaHD increased lymphocyte counts ex vivo. Furthermore, we found a decrease in total CD3+CD4+CD69+ ((109/L), mean ± SD: acetate, 0.04 ± 1.0 versus citrate, 0.02 ± 0.01; P = 0.02) activated cells, while the number of CD28+ T cells remained stable. No differences were noted regarding T-cell exhaustion marker expression, CD14+CD16+ monocyte counts, and PMN-MDSCs. Conclusion: Compared with acetate, CiaHD has a minor impact on lymphocyte counts and CD4+T-cell activation, which was independent of systemic CRP and ionized magnesium, calcium levels, and other dialysis prescription modalities.

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.

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.

Pretransplant Serum Uromodulin and Its Association with Delayed Graft Function Following Kidney Transplantation-A Prospective Cohort Study.

Delayed graft function (DGF) following kidney transplantation is associated with increased risk of graft failure, but biomarkers to predict DGF are scarce. We evaluated serum uromodulin (sUMOD), a potential marker for tubular integrity with immunomodulatory capacities, in kidney transplant recipients and its association with DGF. We included 239 kidney transplant recipients and measured sUMOD pretransplant and on postoperative Day 1 (POD1) as independent variables. The primary outcome was DGF, defined as need for dialysis within one week after transplantation. In total, 64 patients (27%) experienced DGF. In multivariable logistic regression analysis adjusting for recipient, donor and transplant associated risk factors each 10 ng/mL higher pretransplant sUMOD was associated with 47% lower odds for DGF (odds ratio (OR) 0.53, 95% confidence interval (95%-CI) 0.30-0.82). When categorizing pretransplant sUMOD into quartiles, the quartile with the lowest values had 4.4-fold higher odds for DGF compared to the highest quartile (OR 4.41, 95%-CI 1.54-13.93). Adding pretransplant sUMOD to a model containing established risk factors for DGF in multivariable receiver-operating-characteristics (ROC) curve analysis, the area-under-the-curve improved from 0.786 [95%-CI 0.723-0.848] to 0.813 [95%-CI 0.755-0.871, p = 0.05]. SUMOD on POD1 was not associated with DGF. In conclusion, higher pretransplant sUMOD was independently associated with lower odds for DGF, potentially serving as a non-invasive marker to stratify patients according to their risk for developing DGF early in the setting of kidney transplantation.

U-Shaped Association of the Heart Rate Variability Triangular Index and Mortality in Hemodialysis Patients With Atrial Fibrillation.

Background: Atrial fibrillation (AF) is common in hemodialysis patients and contributes to increased mortality. We aimed to examine heart rate variability triangular index (HRVI) in hemodialysis patients with AF as it has recently been reported to predict mortality in AF patients without kidney disease. Methods: A total of 88 patients on hemodialysis with a medical history of AF or newly diagnosed AF underwent 24-h electrocardiography recordings. The primary endpoint of cardiovascular mortality was recorded during a median follow up of 3.0 years. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score. Results: Median age was 76 years, median dialysis vintage was 27 months. Altogether, 22 and 44 patients died due to cardiovascular and non-cardiovascular causes. In 55% of patients AF was present during the recording. Kaplan-Meier plots of HRVI quartiles suggested a non-linear association between HRVI, cardiovascular, and all-cause mortality which was confirmed in non-linear Cox regression analysis. Adjusted linear Cox regression revealed a hazard ratio of 6.2 (95% CI: 2.1-17.7, p = 0.001) and 2.2 (95% CI: 1.3-3.8, p = 0.002) for the outer quartiles (combined first and fourth quartile) for cardiovascular and all-cause mortality, respectively. Patients in the first quartile were more likely to have sinus rhythm whereas patients in the fourth quartile were more likely to have AF. Conclusions: We found a U-shaped association between HRVI and mortality in hemodialysis AF patients. The results might contribute to risk stratification independent of known risk scores in hemodialysis AF patients.

Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients.

Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

Urinary uromodulin independently predicts end-stage renal disease and rapid kidney function decline in a cohort of chronic kidney disease patients.

Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.Follow-up was 57.3 ±â€Š18.7 weeks, baseline age was 60 (18;92) years, and eGFR was 38 (6;156) mL/min/1.73 m. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria (ß = 0.554 and ß = -0.429, P < .001). In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002-12.992] and 5.409 (95% CI 1.444-20.269), respectively, in comparison to patients of the highest quartile (≥11.45 µg/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5 µg/mL and area under the curve of 0.786 (95% CI 0.712-0.860, P < .001).uUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment.

Worsening calcification propensity precedes all-cause and cardiovascular mortality in haemodialyzed patients.

A novel in-vitro test (T50-test) assesses ex-vivo serum calcification propensity which predicts mortality in HD patients. The association of longitudinal changes of T50 with all-cause and cardiovascular mortality has not been investigated. We assessed T50 in paired sera collected at baseline and at 24 months in 188 prevalent European HD patients from the ISAR cohort, most of whom were Caucasians. Patients were followed for another 19 [interquartile range: 11-37] months. Serum T50 exhibited a significant decline between baseline and 24 months (246 ± 64 to 190 ± 68 minutes; p < 0.001). With serum Δ-phosphate showing the strongest independent association with declining T50 (r = -0.39; p < 0.001) in multivariable linear regression. The rate of decline of T50 over 24 months was a significant predictor of all-cause (HR = 1.51 per 1SD decline, 95% CI: 1.04 to 2.2; p = 0.03) and cardiovascular mortality (HR = 2.15; 95% CI: 1.15 to 3.97; p = 0.02) in Kaplan Meier and multivariable Cox-regression analysis, while cross-sectional T50 at inclusion and 24 months were not. Worsening serum calcification propensity was an independent predictor of mortality in this small cohort of prevalent HD patients. Prospective larger scaled studies are needed to assess the value of calcification propensity as a longitudinal parameter for risk stratification and monitoring of therapeutic interventions.