Plasma NGAL levels in stable kidney transplant recipients and the risk of allograft loss.

BACKGROUND: The objective of this study was to investigate the utility of neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR). METHODS: A total of 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss was evaluated during a 58-month follow-up. RESULTS: Among biomarkers, pNGAL showed the best predictive ability for graft loss and was the only biomarker with an area under the curve (AUC) > 0.7 for graft loss within 5 years. Patients with graft loss within 5 years (n = 49) had a median pNGAL of 304 [interquartile range (IQR) 235-358] versus 182 (IQR 128-246) ng/mL with surviving grafts (P < .001). Time-dependent receiver operating characteristic analyses at 58 months indicated an AUC for pNGAL of 0.795, serum creatinine-based Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for graft loss with death as competing risk (age, transplant age, presence of donor-specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with graft loss {subdistribution hazard ratio (sHR) for binary log-transformed pNGAL [log2(pNGAL)] 3.4, 95% confidence interval (CI) 2.24-5.15, P < .0001}. This association was substantially attenuated when eGFR was added to the model [sHR for log2(pNGAL) 1.63, 95% CI 0.92-2.88, P = .095]. Category-free net reclassification improvement of a risk model including log2(pNGAL) in addition to conventional risk factors and eGFR was 54.3% (95% CI 9.2%-99.3%) but C-statistic did not improve significantly. CONCLUSIONS: pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared with baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted.

Care Bundle for Acute Kidney Injury in Cardiac Patients: A Cluster-Randomized Trial.

Detection and timely intervention of acute kidney injury (AKI) is a major challenge worldwide. Electronic alerts for AKI may improve process- and patient-related endpoints. The present study evaluated the efficacy of an AKI electronic alert system and care bundle. This is a two-arm, prospective, cluster-randomized, controlled trial enrolling patients with AKI (KDIGO criteria) and cardiac diseases. Patients were randomly assigned to a routine care group or intervention group (DRKS-IDDRKS00017751). Two hundred patients (age 79 years, 46% female) were enrolled, with 100 patients in each group. The primary endpoint did not differ between patients in the routine care group 0.5 (-7.6-10.8) mL/min/1.73 m2 versus patients in the intervention group 1.0 (-13.5-15.1) mL/min/1.73 m2, p = 0.527. Proportions of patients in both study groups with hyperkalemia, pulmonary edema, and renal acidosis were comparable. The stop of antihypertensive medication during hypotensive periods was more frequent in patients in the intervention group compared to patients in the control group, p = 0.029. The AKI diagnosis and text module for AKI in the discharge letter were more frequently documented in patients in the intervention group (40%/48% vs. 25%/34%, p = 0.034; p = 0.044, respectively). Continued intake of RAAS inhibitors and the presence of a cardiac device were independently associated with a less pronounced decrease in eGFR from admission to the lowest value. In this RCT, electronic alerts for AKI and a care bundle improved process- but not patient-related endpoints.

NT-proBNP/urine hepcidin-25 ratio and cardiorenal syndrome type 1 in patients with severe symptomatic aortic stenosis.

Background: This study aimed to determine whether novel and conventional cardiorenal biomarkers in patients before transcatheter aortic valve implantation may be associated with cardiorenal syndrome (CRS) type 1. Methods: Serum NT-proBNP and urine biomarkers (hepcidin-25, NGAL, IL-6) were measured before and 24 h after transcatheter aortic valve implantation. Results: 16/95 patients had CRS type 1. Those patients had longer length of stay in hospital (12.5 [9.0-16.0] vs 9.0 [8-12] days; p = 0.025) and were more frequently readmitted to hospital within 6 months after discharge (46.7 vs 15.6%; odds ratio: 4.7; 95% CI: 1.5-15.5; p = 0.007). The NT-proBNP/urine hepcidin-25 ratio (odds ratio: 2.89; 95% CI: 1.30-6.41; p = 0.009) was an independent modifier of CRS type 1. Conclusion: The NT-proBNP/urine hepcidin-25 ratio appears to be a modifier of risk of CRS type 1.

Neutrophil Gelatinase-Associated Lipocalin Cutoff Value Selection and Acute Kidney Injury Classification System Determine Phenotype Allocation and Associated Outcomes.

Background: We explored the extent to which neutrophil gelatinase-associated lipocalin (NGAL) cutoff value selection and the acute kidney injury (AKI) classification system determine clinical AKI-phenotype allocation and associated outcomes. Methods: Cutoff values from ROC curves of data from two independent prospective cardiac surgery study cohorts (Magdeburg and Berlin, Germany) were used to predict Kidney Disease: Improving Global Outcome (KDIGO)- or Risk, Injury, Failure, Loss of kidney function, End-stage (RIFLE)-defined AKI. Statistical methodologies (maximum Youden index, lowest distance to [0, 1] in ROC space, sensitivity≍specificity) and cutoff values from two NGAL meta-analyses were evaluated. Associated risks of adverse outcomes (acute dialysis initiation and in-hospital mortality) were compared. Results: NGAL cutoff concentrations calculated from ROC curves to predict AKI varied according to the statistical methodology and AKI classification system (10.6-159.1 and 16.85-149.3 ng/mL in the Magdeburg and Berlin cohorts, respectively). Proportions of attributed subclinical AKI ranged 2%-33.0% and 10.1%-33.1% in the Magdeburg and Berlin cohorts, respectively. The difference in calculated risk for adverse outcomes (fraction of odds ratios for AKI-phenotype group differences) varied considerably when changing the cutoff concentration within the RIFLE or KDIGO classification (up to 18.33- and 16.11-times risk difference, respectively) and was even greater when comparing cutoff methodologies between RIFLE and KDIGO classifications (up to 25.7-times risk difference). Conclusions: NGAL positivity adds prognostic information regardless of RIFLE or KDIGO classification or cutoff selection methodology. The risk of adverse events depends on the methodology of cutoff selection and AKI classification system.

Laboratory Diagnostic of Acute Kidney Injury and Its Progression: Risk of Underdiagnosis in Female and Elderly Patients.

Acute kidney injury (AKI) is a common disease, with high morbidity and mortality rates. In this study, we investigated the potential influence of sex and age on laboratory diagnostics and outcomes. It is known that serum creatinine (SCr) has limitations as a laboratory diagnostic parameter for AKI due to its dependence on muscle mass, which may lead to an incorrect or delayed diagnosis for certain patient groups, such as women and the elderly. Overall, 7592 cases with AKI, hospitalized at the University of Leipzig Medical Center (ULMC) between 1st January 2017 and 31st December 2019, were retrospectively analyzed. The diagnosis and staging of AKI were performed according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, based on the level and dynamics of SCr. The impact of sex and age was analyzed by the recalculation of a female to male and an old to young SCr using the CKD-EPI equation. In our study cohort progressive AKI occurred in 19.2% of all cases (n = 1458). Female cases with AKI were underrepresented (40.4%), with a significantly lower first (-3.5 mL/min) and last eGFR (-2.7 mL/min) (p < 0.001). The highest incidence proportion of AKI was found in the [61-81) age group in female (49.5%) and male (52.7%) cases. Females with progressive AKI were underrepresented (p = 0.04). By defining and staging AKI on the basis of relative and absolute changes in the SCr level, it is more difficult for patients with low muscle mass and, thus, a lower baseline SCr to be diagnosed by an absolute SCr increase. AKIN1 and AKIN3 can be diagnosed by a relative or absolute change in SCr. In females, both stages were less frequently detected by an absolute criterion alone (AKIN1 ♀ 20.2%, ♂ 29.5%, p < 0.001; AKIN3 ♀ 13.4%, ♂ 15.2%, p < 0.001). A recalculated SCr for females (as males) and males (as young males) displayed the expected increase in AKI occurrence and severity with age and, in general, in females. Our study illustrates how SCr, as the sole parameter for the diagnosis and staging of AKI, bears the risk of underdiagnosis of patient groups with low muscle mass, such as women and the elderly. A sex- and age-adapted approach might offer advantages.

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

Progression of Chronic Kidney Disease and All-Cause Mortality in Patients with Tricuspid Regurgitation.

Aim: The impact of chronic kidney disease (CKD) on patient-related outcomes in patients with tricuspid regurgitation (TR) is well known. However, the impact of the progression of CKD in patients with TR and potentially modifiable risk factors of progressing CKD is unknown. Methods: 444 consecutive adult patients with TR and CKD stage 1−4 admitted in an inpatient setting between January 2010 and December 2017 were included. During a median follow-up of two years, eGFR and survival status were collected. Independent risk factors for CKD progression and all-cause mortality were determined. Patient survival statuses were grouped according to different combinations of the presence or absence of CKD progression and the TR grade. Results: Progression of CKD (OR 2.38 (95% confidence interval 1.30−4.35), p = 0.005), the grade of TR (OR 2.38 (1.41−4.00), p = 0.001) and mitral regurgitation (OR 1.72 (1.20−2.46), p = 0.003) were independent risk factors for all-cause mortality. Haemoglobin at admission (OR 0.80 (0.65−0.99), p = 0.043) and the presence of type 2 diabetes (OR 1.67 (1.02−2.73), p = 0.042) were independent risk factors for CKD progression. The combination of the status of CKD progression and the TR grade showed a stepwise pattern for all-cause mortality (p < 0.001). Patients with CKD progression and TR grade 1 had comparable all-cause mortality with patients without CKD progression but with TR grade 2 or 3. Even in patients with TR grade 1, the risk for all-cause mortality doubled if CKD progression occurred (OR 2.49 (95% CI 1.38−4.47), p = 0.002). Conclusion: CKD progression appears to be a risk factor for all-cause mortality in patients with TR. Anaemia and diabetes are potential modifiers of CKD progression.

Improved immunologic response to COVID-19 vaccine with prolonged dosing interval in haemodialysis patients.

Vaccination against 2019 coronavirus disease (COVID-19) can reduce disease incidence and severity. Dialysis patients demonstrate a delayed immunologic response to vaccines. We determined factors affecting the immunologic response to COVID-19 vaccines in haemodialysis patients. All patients within a Swedish haemodialysis network, vaccinated with two doses of COVID-19 vaccine 2-8 weeks before inclusion, were eligible for this cross-sectional study. Severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibody levels were determined by EliA SARS-CoV-2-Sp1 IgG test (Thermo Fisher Scientific, Phadia AB) and related to clinical and demographic parameters. Eighty-nine patients were included. Patients were vaccinated with two doses of Comirnaty (BNT162b2, 73%) or Spikevax (mRNA-1273, 23,6%). Three patients received combinations of different vaccines. Response rate (antibody titres >7 U/mL) was 89.9%, while 39.3% developed high antibody titres (>204 U/mL), 47 (43-50) days after the second dose. A previous COVID-19 infection associated with higher antibody titres (median (25th-75th percentile) 1558.5 (814.5-3,763.8) U/mL vs 87 (26-268) U/mL, P = .002), while time between vaccine doses did not differ between groups (P = .7). Increasing SARS-CoV-2 antibody titres were independently associated with increasing time between vaccine doses (B 0.241, P = .02), decreasing serum calcium levels (B -0.233, P = .007) and previous COVID-19 (B 1.078, P < .001). In conclusion, a longer interval between COVID-19 mRNA vaccine doses, lower calcium and a previous COVID-19 infection were independently associated with a stronger immunologic vaccination response in haemodialysis patients. While the response rate was good, only a minority developed high antibody titres, 47 (43-50) days after the second vaccine dose.

Distribution of RET proto-oncogene variants in children with appendicitis.

BACKGROUND: In addition to patient-related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%-50% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the RET proto-oncogene. We thus hypothesized that RET variants contribute to the etiology of AP. METHODS: DNA from paraffin-embedded appendices and clinical data of 264 children were analyzed for the RET c.135A>G variant (rs1800858, NC_000010.11:g.43100520A>G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for RET sequencing. RESULTS: Germline mutations were found in 13% of GAP, whereas no RET mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A>T). In GAP, the polymorphic G-allele in rs2435352 (NC_000010.11:g.43105241A>G) in intron 4 was underrepresented (p = 0.0317). CONCLUSION: Our results suggest an impact of the RET proto-oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including RET germline mutations with phenotypic heterogeneity and incomplete penetrance.

Humoral immunogenicity and tolerability of heterologous ChAd/BNT compared with homologous BNT/BNT and ChAd/ChAd SARS-CoV-2 vaccination in hemodialysis patients : A multicenter prospective observational study.

BACKGROUND: After the reports of severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine, patients who had received one dose of ChAdOx1-S-nCoV-19 vaccine were recommended a second dose of Pfizer's BNT162b2 vaccine. In hemodialysis patients, we compared the humoral immunogenicity and tolerability of homologous vaccination with ChAdOx1-nCoV-19/ChAdOx1-nCoV-19 (ChAd/ChAd) and BNT162b2/BNT162b2 (BNT/BNT) with heterologous vaccination of first dose of ChAdOx1-nCoV-19 and a second dose with BNT162b2 (ChAd/BNT). METHODS: In a multicenter prospective observational study, SARS-CoV-2 spike-IgG antibody levels, Nucleocapsid-protein-IgG-antibodies, and vaccine tolerability were assessed 6 weeks after second SARS-CoV-2 vaccination in 137 hemodialysis patients and 24 immunocompetent medical personnel. RESULTS: In COVID-19-naïve hemodialysis patients, significantly higher median SARS-CoV-2-spike IgG levels were found after ChAd/BNT (N = 16) compared to BNT/BNT (N = 100) or ChAd/ChAd (N = 10) (1744 [25th-75th percentile 276-2840] BAU/mL versus 361 [25th-75th percentile 120-936] BAU/mL; p = 0.009; 1744 [25th-75th percentile 276-2840] BAU/mL versus 100 [25th-75th percentile 41-346] BAU/mL; p = 0.017, respectively). Vaccinated, COVID-19-naïve medical personnel had median SARS-CoV-2 spike-IgG levels of 650 (25th-75th percentile 217-1402) BAU/mL and vaccinated hemodialysis patients with prior COVID-19 7047 (25th-75th percentile 685-10,794) BAU/mL (N = 11). In multivariable regression analysis, heterologous vaccination (ChAd/BNT) of COVID-19-naïve hemodialysis patients was independently associated with SARS-CoV-2 spike-IgG levels. The first dose of ChAd and the second dose of BNT after the first vaccination with ChAd (heterologous vaccination, ChAd/BNT) were associated with more frequent but manageable side effects compared with homologous BNT. CONCLUSIONS: Within the limitations of this study, heterologous vaccination with ChAd/BNT appears to induce stronger humoral immunity and more frequent but manageable side effects than homologous vaccination with BNT/BNT or with ChAd/ChAd in COVID-19-naïve hemodialysis patients.

Time-dependent evolution of IgG antibody levels after first and second dose of mRNA-based SARS-CoV-2 vaccination in haemodialysis patients: a multicentre study.

BACKGROUND: Vaccination programs are essential for the containment of the coronavirus disease 2019 pandemic, which has hit haemodialysis populations especially hard. Early reports suggest a reduced immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in dialysis patients, in spite of a high degree of seroconversion. We aimed to identify risk factors for a reduced efficacy of an mRNA vaccine in a cohort of haemodialysis patients. METHOD: In a multicentre study, including 294 Portuguese haemodialysis patients who had received two doses of BNT162b2 with a 3-week interval, immunoglobulin G-class antibodies against the SARS-CoV-2 spike protein were determined 3 weeks after the first dose (M1) and 6 weeks after the second dose (M2). The threshold for seroconversion was 10 UR/mL. Demographic and clinical data were retrieved from a quality registry. Adverse events were registered using a questionnaire. RESULTS: At M2, seroconversion was 93.1% with a median antibody level of 197.5 U/mL (1.2-3237.0) and a median increase of 180.0 U/mL (-82.9 to 2244.6) from M1. Age [beta -8.9; 95% confidence interval (95% CI) -12.88 to -4.91; P < 0.0001], ferritin >600 ng/mL (beta 183.93; 95% CI 74.75-293.10; P = 0.001) and physical activity (beta 265.79; 95% CI 30.7-500.88; P = 0.03) were independent predictors of SARS-CoV-2 antibody levels after two vaccine doses. Plasma albumin >3.5 g/dL independently predicted the increase of antibody levels between both doses (odds ratio 14.72; 95% CI 1.38 to 157.45; P = 0.03). Only mild adverse reactions were observed in 10.9% of patients. CONCLUSIONS: The SARS-CoV-2 vaccine BNT162b2 is safe and effective in haemodialysis patients. Besides age, iron status and nutrition are possible modifiable modulators of the immunologic response to SARS-CoV-2 mRNA vaccines. These data suggest the need for an early identification of populations at higher risk for diminished antibody production and the potential advantage of the implementation of oriented strategies to maximize the immune response to vaccination in these patients.

NGAL/hepcidin-25 ratio and AKI subtypes in patients following cardiac surgery: a prospective observational study.

BACKGROUND: Acute kidney injury (AKI) subtypes combining kidney functional parameters and injury biomarkers may have prognostic value. We aimed to determine whether neutrophil gelatinase-associated lipocalin (NGAL)/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) defined subtypes are of prognostic relevance in cardiac surgery patients. METHODS: We studied 198 higher-risk cardiac surgery patients. We allocated patients to four groups: Kidney Disease Improving Global Outcomes (KDIGO)-AKI-negative and NGAL/hepcidin-25 ratio-negative (no AKI), KDIGO AKI-negative and NGAL/hepcidin-25 ratio-positive (subclinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-negative (clinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-positive (combined AKI). Outcomes included in-hospital mortality (primary) and long-term mortality (secondary). RESULTS: We identified 127 (61.6%) patients with no AKI, 13 (6.6%) with subclinical, 40 (20.2%) with clinical and 18 (9.1%) with combined AKI. Subclinical AKI patients had a 23-fold greater in-hospital mortality than no AKI patients. For combined AKI vs. no AKI or clinical AKI, findings were stronger (odds ratios (ORs): 126 and 39, respectively). After adjusting for EuroScore, volume of intraoperative packed red blood cells, and aortic cross-clamp time, subclinical and combined AKI remained associated with greater in-hospital mortality than no AKI and clinical AKI (adjusted ORs: 28.118, 95% CI 1.465-539.703; 3.737, 95% CI 1.746-7.998). Cox proportional hazard models found a significant association of biomarker-informed AKI subtypes with long-term survival compared with no AKI (adjusted ORs: pooled subclinical and clinical AKI: 1.885, 95% CI 1.003-3.542; combined AKI: 1.792, 95% CI 1.367-2.350). CONCLUSIONS: In the presence or absence of KDIGO clinical criteria for AKI, the urinary NGAL/hepcidin-25-ratio appears to detect prognostically relevant AKI subtypes. TRIAL REGISTRATION NUMBER: NCT00672334, clinicaltrials.gov, date of registration: 6th May 2008, https://clinicaltrials.gov/ct2/show/NCT00672334 . Definition of AKI subtypes: subclinical AKI (KDIGO negative AND Ratio-positive), clinical AKI (KDIGO positive AND Ratio-negative) and combined AKI (KDIGO positive AND Ratio-positive) with urinary NGAL/hepcidin-25 ratio-positive cut-off at 85% specificity for in-hospital death. AKI, acute kidney injury. AUC, area under the curve. NGAL, neutrophil gelatinase-associated lipocalin. KDIGO, Kidney Disease Improving Global Outcomes Initiative AKI definition.

Discordance between estimated and measured changes in plasma volume among patients with acute heart failure.

AIMS: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF. METHODS AND RESULTS: We studied 36 AHF patients, who received two sequential assessments of mPV, measured red cell volume (mRCV) and measured total blood volume (mTBV) (48 h apart), during the course of diuretic therapy using a novel visible fluorescent injectate (VFI) technique based on the indicator dilution principle. Changes of ePV were calculated based on the Kaplan-Hakim or Strauss formula. AHF patients receiving diuretics (median intravenous furosemide equivalent 160 mg/48 h) displayed a wide range of changes of mPV (-25.4% to +37.0%). Changes in mPV were not significantly correlated with changes of Hb concentration [Pearson's r (r) = -0.241, P = 0.157], Hct (r = -0.307, P = 0.069), ePVKaplan-Hakim (r = 0.228, P = 0.182), or ePVStrauss (r = 0.237, P = 0.163). In contrast to theoretical assumptions, changes of mTBV were poorly correlated with changes of Hb concentrations and some patients displayed unanticipated variability of mRCV, suggesting an unstable intravascular red cell pool. CONCLUSIONS: Changes of Hb or Hct were not reflective of directly measured changes of intravascular volume status in AHF patients. Basing clinical assessment of decongestion on changes of Hb or Hct may misguide clinical decision-making on an individual patient level.

Immunogenicity and tolerability of COVID-19 vaccination in peritoneal dialysis patients-A prospective observational cohort study.

BACKGROUND: In peritoneal dialysis (PD) patients, information on the immunogenicity and tolerability of SARS-CoV-2 vaccination is still scarce. We compared the immunogenicity and tolerability of SARS-CoV-2 vaccination of PD patients with that of medical personnel. METHODS: In a prospective observational cohort study, PD patients and immunocompetent medical personnel were evaluated for SARS-CoV-2 spike-IgG- and Nucleocapsid-IgG-antibody-levels before, 2 weeks after the first, and 6 weeks after the second SARS-CoV-2 vaccination and vaccine tolerability after the first and second vaccination. RESULTS: In COVID-19-naïve PD patients (N = 19), lower SARS-CoV-2-spike-IgG-levels were found compared with COVID-19-naïve medical personnel (N = 24) 6 weeks after second vaccination (median 1438 AU/ml [25th-75th percentile 775-5261] versus 4577 [1529-9871]; p = 0.045). This finding resulted in a lower rate of strong vaccine response (spike-IgG ≥ 1000 AU/ml) of COVID-19-naïve PD patients compared with medical personnel (58% versus 92%; p = 0.013), but not for seroconversion rate (spike-IgG ≥ 50 AU/ml: 100% vs. 100%; p > 0.99). After first vaccination, COVID-naïve PD patients presented with significantly fewer side effects than medical personnel (number of any side effect: 1 [1-2] vs. 4 [1-7]; p = 0.015). A similar pattern with slightly decreased frequencies of side effects was observed for tolerability of second SARS-CoV-2 vaccination in PD patients and medical personnel (number of any side effects: 1 [1-1] vs. 2 [1-5]; p = 0.006). CONCLUSIONS: SARS-CoV-2 vaccination in COVID-19-naïve PD patients appeared to induce a very high rate of seroconversion but a substantially lower rate of patients with a strong response compared with medical personnel. Vaccination appeared to be safe in the PD patients studied.

Urinary biomarkers to predict severe fluid overload after cardiac surgery: a pilot study.

Aim: To assess the predictive ability of urinary and plasma biomarkers and clinical routine parameters for subsequent severe fluid overload. Patients & methods: In a pilot study, we studied 100 adult patients after cardiac surgery. On intensive care unit admission, we measured biomarkers in urine (midkine, IL-6, neutrophil gelatinase-associated lipocalin [NGAL], hepcidin-25) and plasma (creatinine, urea, B-type natriuretic peptide, lactate, C-reactive protein, leukocytes, IL-6, NGAL, hepcidin-25) to predict postoperative severe fluid overload. Results: Urinary midkine, IL-6, NGAL and hepcidin-25 (all AUCs ≥0.79) predicted postoperative severe fluid overload (n = 5 patients). Urinary NGAL/hepcidin-25 ratio (AUC 0.867) predicted postoperative severe fluid overload after adjustment to EuroScore and need for norepinephrine on surgery day (odds ratio: 2.4). Conclusion: Urinary biomarkers on intensive care unit admission might be helpful to predict subsequent severe fluid overload after cardiac surgery.

Lay abstract Aim: To assess whether proteins in the urine or blood or clinical routine laboratory parameters can predict severe body fluid overload after cardiac surgery. Patients & methods: In a pilot study, we studied 100 adult patients after cardiac surgery. After surgery, we measured proteins in the urine (midkine, IL-6, neutrophil gelatinase-associated lipocalin [NGAL], hepcidin-25) and blood (creatinine, urea, B-type natriuretic peptide, lactate, C-reactive protein, leukocytes, IL-6, NGAL, hepcidin-25) to predict postoperative severe fluid overload. Results: Urinary midkine, IL-6, NGAL and hepcidin-25 predicted postoperative severe fluid overload (n = 5 patients). Urinary NGAL/hepcidin-25 ratio predicted postoperative severe fluid overload after adjustment to important covariates. Conclusion: Urinary biomarkers might be helpful to predict subsequent severe fluid overload after cardiac surgery.

Syndecan-1 shedding by meprin ß impairs keratinocyte adhesion and differentiation in hyperkeratosis.

Dysregulation of proteolytic enzymes has huge impact on epidermal homeostasis, which can result in severe pathological conditions such as fibrosis or Netherton syndrome. The metalloprotease meprin ß was found to be upregulated in hyperproliferative skin diseases. AP-1 transcription factor complex has been reported to induce Mep1b expression. Since AP-1 and its subunit fos-related antigen 2 (fra-2) are associated with the onset and progression of psoriasis, we wanted to investigate if this could partially be attributed to increased meprin ß activity. Here, we demonstrate that fra-2 transgenic mice show increased meprin ß expression and proteolytic activity in the epidermis. To avoid influence by other fra-2 regulated genes, we additionally generated a mouse model that enabled tamoxifen-inducible expression of meprin ß under the Krt5-promotor to mimic the pathological condition. Interestingly, induced meprin ß expression in the epidermis resulted in hyperkeratosis, hair loss and mottled pigmentation of the skin. Employing N-terminomics revealed syndecan-1 as a substrate of meprin ß in skin. Shedding of syndecan-1 at the cell surface caused delayed calcium-induced differentiation and impaired adhesion of keratinocytes, which was blocked by the meprin ß inhibitor fetuin-B.

Urinary Neutrophil Gelatinase-Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial.

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.