A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection.

BACKGROUND: Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels. RESULTS: A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. CONCLUSIONS: Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.).

Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation.

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.

Natural Killer Cell Presence in Antibody-Mediated Rejection.

Transcript analyses highlight an important contribution of natural killer (NK) cells to microvascular inflammation (MVI) in antibody-mediated rejection (ABMR), but only few immunohistologic studies have quantified their spatial distribution within graft tissue. This study included 86 kidney transplant recipients who underwent allograft biopsies for a positive donor-specific antibody (DSA) result. NK cells were visualized and quantified within glomeruli and peritubular capillaries (PTC), using immunohistochemistry for CD34 alongside CD16/T-bet double-staining. Staining results were analyzed in relation to histomorphology, microarray analysis utilizing the Molecular Microscope Diagnostic System, functional NK cell genetics, and clinical outcomes. The number of NK cells in glomeruli per mm2 glomerular area (NKglom) and PTC per mm2 cortical area (NKPTC) was substantially higher in biopsies with ABMR compared to those without rejection, and correlated with MVI scores (NKglom Spearman's correlation coefficient [SCC] = 0.55, p < 0.001, NKPTC 0.69, p < 0.001). In parallel, NK cell counts correlated with molecular classifiers reflecting ABMR activity (ABMRprob: NKglom 0.59, NKPTC 0.75) and showed a trend towards higher levels in association with high functional FCGR3A and KLRC2 gene variants. Only NKPTC showed a marginally significant association with allograft function and survival. Our immunohistochemical results support the abundance of NK cells in DSA-positive ABMR.

Morphologic and Molecular Features of Antibody-Mediated Transplant Rejection: Pivotal Role of Molecular Injury as an Independent Predictor of Renal Allograft Functional Decline.

Current knowledge about the factors correlating with functional decline and subsequent failure of kidney allografts in antibody-mediated rejection (ABMR) is limited. We conducted a cohort study involving 75 renal allograft recipients diagnosed with late ABMR occurring at least 6 months after transplantation. The study aimed to examine the correlation of molecular and histologic features with estimated glomerular filtration rate (eGFR) trajectories and death-censored graft survival. We focused on sum scores reflecting histologic ABMR activity versus chronicity and molecular scores of ABMR probability (ABMRProb), injury-repair response (IRRAT) and fibrosis (ciprob). In multivariable Cox analysis, a Banff lesion-based chronicity index (ci+ct+cg[x2]; hazard ratio per interquartile range [IQR]: 1.97 [95% confidence interval: 0.97 to 3.99]) and IRRAT (1.93 [0.96 to 3.89]) showed the strongest associations with graft failure. Among biopsy variables, IRRAT exhibited the highest relative variable importance and emerged as the sole independent predictor of eGFR slope (change per IQR: -4.2 [-7.8 to -0.6] mL/min/1.73 m2/year). In contrast, morphologic chronicity associated with baseline eGFR only. We conclude that the extent of molecular injury is a robust predictor of renal function decline. Transcriptome analysis has the potential to improve outcome prediction and possibly identify modifiable injury, guiding targeted therapeutic interventions.

International Validation of the Canadian Syncope Risk Score : A Cohort Study.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation. OBJECTIVE: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score. DESIGN: Prospective cohort study. SETTING: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents. PARTICIPANTS: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope. MEASUREMENTS: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome). RESULTS: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome). LIMITATION: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge. CONCLUSION: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain. PRIMARY FUNDING SOURCE: Swiss National Science Foundation & Swiss Heart Foundation.

Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased.

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Evaluation of iron stores in hemodialysis patients on maintenance ferric Carboxymaltose dosing.

BACKGROUND: Iron is administered intravenously (IV) to many dialysis patients at regular intervals and iron stores are evaluated through periodic measurements of ferritin and transferrin saturation (TSAT). In patients without kidney diseases, large single doses of IV iron lead to a transient rise in serum ferritin that does not reflect iron stores. It is not known whether and to what extent smaller IV iron doses used to maintain adequate stores in hemodialysis patients lead to transient spurious elevations of ferritin and TSAT. METHODS: Ferritin and TSAT were serially determined over four weeks after the administration of ferric carboxymaltose (FCM) in hemodialysis patients on a stable maintenance FCM dosing regimen of 100 mg or 200 mg every four weeks. RESULTS: Ferritin values increased by 113 ± 72.2 µg/l (P < 0.001) from baseline to the peak value and remained significantly elevated until two weeks after the administration of 100 mg FCM (n = 19). After the administration of 200 mg FCM (n = 12), ferritin values increased by 188.5 ± 67.56 µg/l (P < 0.001) and remained significantly elevated by the end of week three. TSAT values increased by 12.0 ± 9.7% (P < 0.001) and 23.1 ± 20.4% (P = 0.002) in patients receiving 100 or 200 mg FCM, respectively, and returned to baseline within four days. CONCLUSIONS: IV administration of FCM at doses of 100 or 200 mg in hemodialysis patients leads to dose-dependent transient ferritin elevations of extended duration. Temporal coordination of blood sampling for iron status evaluation with the maintenance IV iron dosing schedule is advisable. TRIAL REGISTRATION: ISRCTN12825165 (retrospectively registered 01/02/2019).

[Radiocontrast agents: wrongfully accused?] / Röntgenkontrastmittel ­ zu Unrecht verteufelt?

Radiocontrast agents: wrongfully accused? Abstract. Since its first description over half a century ago, contrast-induced nephropathy has been considered as one of the most common causes of acute kidney injury and as a major preventable health problem. Newer data now suggest that the incidence of contrast-induced nephropathy has been clearly overestimated and that prophylactic measures, such as the administration of N-acetylcysteine, sodium bicarbonate or intravenous hydration are largely useless. Indeed, the fear of contrast-induced nephropathy has prompted withholding of clinically indicated imaging procedures and interventions in many patients or the installation of unnecessary and potentially harmful prophylactic measures. The awareness of contrast-induced nephropathy has thus likely caused more harm than benefit.

Low tissue levels of miR-125b predict malignancy in solitary fibrous tumors of the pleura.

BACKGROUND: Solitary fibrous tumors of the pleura (SFTP) are rare neoplasia of the chest. A subset of SFTP follows a malignant course, sometimes several years after complete resection. Traditional scoring systems based on clinical and histological features are poor predictors of biological behavior. This study aimed to investigate tumor-associated miRNAs expression as novel biomarkers to predict the clinical behavior of SFTP. METHODS: Formalin-fixed and paraffin-embedded SFTP tissues blocks from patients surgically resected between 1992 and 2013 at two tertiary care teaching hospitals were included. SFTP tumors were categorized as either malignant or benign variants according to the WHO classification. Following miRNAs levels were measured: let-7a, miR-16b, miR-17, miR-21, miR-31, miR-34a, miR-92a, miR-125a, miR-125b, miR-195-5b, miR-203a, and miR-223. Differential gene expressions which were calculated with the threshold cycle (Ct) method were compared among the two variants. RESULTS: Thirty-eight patients (40% male, mean age 62.2 (±10.9) years) were included. Expression levels of miR-125b showed a significant difference between benign compared to malignant variants (-3.08 ± 0.93 vs. -2.22 ± 1.36, p = 0.0068). Furthermore, lower levels of miR-125b were found to be associated with increased tumor size (p = 0.0414). Thus, downregulation of miR-125b indicates malignant transformation. All other investigated miRNAs were not associated with grading of SFTP. CONCLUSIONS: Our data suggest a potential role of miR-125b in the pathogenesis of tumor growth and malignant transformation of SFTP, respectively. Further studies have to address the potential use of miRNA-125b as a biomarker or therapeutic target in SFTP.

Prognostic value of MIB-1 proliferation index in solitary fibrous tumors of the pleura implemented in a new score - a multicenter study.

BACKGROUND: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10-25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators. METHODS: In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value. RESULTS: In total, 78 patients (mean age 61 ± 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 ± 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) ≥10% (HR 12.3, CI 1.1-139.5, p = 0.043), ≥4 mitoses per 10 high power fields (HR 36.5, CI 1.2-1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7-4016.8, p = 0.027) were independently associated with adverse outcome. CONCLUSION: A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation.

Determinants of outcome of solitary fibrous tumors of the pleura: an observational cohort study.

BACKGROUND: Solitary fibrous tumors of the pleura (SFTP) are rare and their long-term outcome is difficult to predict, as there are insufficient data which allow accurate characterization of the malignant variant. Thus the aim of this study was to describe the outcome and possible determinants of malignant behavior of SFTPs. METHODS: Data were collected retrospectively from medical records of patients treated at the University Hospital Zurich from 1992 to 2012. Kaplan-Meier and Cox regression analysis were performed to define disease-free survival time (defined as survival without tumor-recurrence or tumor-related death) using the classical histo-morphological criteria (tumor size, localization, pedunculation, tumor necrosis or hemorrhage, mitotic activity and nuclear pleomorphism) and immunohistochemical parameters. RESULTS: 42 patients (20 males) with SFTP (median (IQR) age 62 (56-71) years) could be identified. SFTP were associated with symptoms in 50% of all cases. Complete resection was achieved by video-assisted thoracic surgery or thoracotomy in 20 and 22 patients, respectively. Three SFTP-related deaths (7.1%) and four tumor recurrences (9.5%) were observed. Mean disease-free survival time was 136.2 (± 13.1) months, and 2-, 5- and 10-year disease-free survival was 91%, 84%, and 67%, respectively. Mean disease-free survival inversely correlated with the mean tumor diameter, number of mitotic figures and proliferation rate (Ki-67 expression). Other criteria (tumor necrosis, atypical localization, sessile tumor, and pleomorphism) were not statistically significant prognostic parameters. CONCLUSIONS: Patients with large SFTP with a high mitotic index and high proliferation rate should be followed-up closely and over a prolonged time period in order to recognize recurrence of the SFTP early and at a treatable stage. Future research on this topic should focus on the prognostic role of immunohistochemistry including Ki-67 expression and molecular parameters.

Accuracy of Flash Glucose Monitoring in Hemodialysis Patients With and Without Diabetes Mellitus.

AIMS: Glucose and insulin metabolism are altered in hemodialysis patients, and diabetes management is difficult in these patients. We aimed to validate flash glucose monitoring (FGM) in hemodialysis patients with and without diabetes mellitus as an attractive option for glucose monitoring not requiring regular self-punctures. METHODS: We measured interstitial glucose using a FreeStyle Libre device in eight hemodialysis patients with and seven without diabetes mellitus over 14 days and compared the results to simultaneously performed self-monitoring of capillary blood glucose (SMBG). RESULTS: In 720 paired measurements, mean flash glucose values were significantly lower than self-measured capillary values (6.17±2.52 vs. 7.15±2.41 mmol/L, p=1.3 E-86). Overall, the mean absolute relative difference was 17.4%, and the mean absolute difference was 1.20 mmol/L. The systematic error was significantly larger in patients without vs. with diabetes (- 1.17 vs. - 0.82 mmol/L) and on dialysis vs. interdialytic days (-1.09 vs. -0.90 mmol/L). Compared to venous blood glucose (72 paired measurements), the systematic error of FGM was even larger (5.89±2.44 mmol/L vs. 7.78±7.25 mmol/L, p=3.74E-22). Several strategies to reduce the systematic error were evaluated, including the addition of +1.0 mmol/L as a correction term to all FGM values, which significantly improved accuracy. CONCLUSIONS: FGM systematically underestimates blood glucose in hemodialysis patients but, taking this systematic error into account, the system may be useful for glucose monitoring in hemodialysis patients with or without diabetes.

Urine CXCL10 to Assess BK Polyomavirus Replication After Kidney Transplantation.

BACKGROUND: Urine CXCL10 is a biomarker for renal allograft inflammation induced by rejection, urinary tract infection, or BK polyomavirus (BKPyV) replication. This study aimed to compare urine CXCL10 levels in different stages of BKPyV reactivation and to investigate urine CXCL10 as a biomarker for BKPyV replication. METHODS: We included 763 urine samples (235 patients) from an interventional, randomized trial obtained in the context of regular screening for urine CXCL10 levels. All urine samples had a complete urine sediment analysis, no rejection episode noted within 30 d before urine collection, and a urine decoy cell analysis was conducted within ±3 d. RESULTS: Urine CXCL10 levels were 2.31 ng/mmol in samples without BKPyV viruria, slightly rose to 4.35 ng/mmol with BKPyV viruria, and then markedly increased to 16.42 ng/mmol when decoy cells were detectable, but still in the absence of BKPyV DNAemia ( P < 0.001). The highest urine CXCL10 values were observed in samples with BKPyV DNAemia (median 42.59 ng/mmol). The area under the curve of urine CXCL10 levels to detect ≥3 decoy cells was 0.816. At a CXCL10 cutoff of 3 ng/mmol, the negative predictive value was 97%. The area under the curve of urine CXCL10 levels to detect BKPyV DNAemia was 0.882, with a negative predictive value of 99% at a CXCL10 cutoff of 3 ng/mmol. CONCLUSIONS: Urine CXCL10 levels are already significantly elevated in BKPyV viruria (especially with decoy cell shedding) and further increase with BKPyV DNAemia. Low urine CXCL10 values can rule out the presence of ≥3 decoy cells and BKPyV DNAemia with high certainty.

Outcome of kidney transplantation from senior deceased donors: a single centre study.

BACKGROUND: Addressing the current demographic development, the efficacy and safety of kidney transplantations from very senior donors needs to be carefully evaluated. The aim of this study was to analyse patient and graft outcomes of kidney allograft recipients stratified by donor age. METHODS: We retrospectively investigated n = 491 patients from a prospective, observational renal transplant cohort. Patients with kidneys from very old donors (n = 75, aged >70 years), elderly donors (n = 158, between 60-70 years), and regular donors (n = 258, aged <60 years) were investigated. The primary outcome was death-censored graft survival within the predefined donor age groups. RESULTS: Overall, n = 57 death-censored graft losses occurred. Graft loss was proportionally highest in the very old donor group (n = 11/75), but this did not reach statistical significance when compared to the elderly (14/158) and regular donor groups (32/258); (p = 0.37). Kaplan-Meier analysis demonstrated that 3-year/5-year death-censored graft survival in the very old donor group was 96%/86% and did not differ from the other age groups (p = 0.44). Median estimated glomerular filtration rate (eGFR), calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (in ml/min/1.73 m2 of body surface) 12 months post-transplant did not differ between the elderly donor and very old donor groups (p = 0.53). However, patients who received regular donor kidneys had higher median eGFR compared to recipients in both the elderly and very old donor groups (p <0.0001). During follow-up, 31% of patients developed at least one acute rejection episode. Time-to-event analysis demonstrated no difference in occurrence of any acute rejection event across all three groups (p = 0.11). CONCLUSIONS: This study demonstrates that kidney transplantation from carefully selected very old donors seems a valid option with reasonable short- and mid-term outcomes.

Quantifying inflammation using interleukin-6 for improved phenotyping and risk stratification in acute heart failure.

AIMS: Systemic inflammation may be central in the pathophysiology of acute heart failure (AHF). We aimed to assess the possible role of systemic inflammation in the pathophysiology, phenotyping, and risk stratification of patients with AHF. METHODS AND RESULTS: Using a novel Interleukin-6 immunoassay with unprecedented sensitivity (limit of detection 0.01 ng/L), we quantified systemic inflammation in unselected patients presenting with acute dyspnoea to the emergency department in a multicentre study. One-year mortality was the primary prognostic endpoint. Among 2042 patients, 1026 (50.2%) had an adjudicated diagnosis of AHF, 83.7% of whom had elevated interleukin-6 concentrations (>4.45 ng/L). Interleukin-6 was significantly higher in AHF patients compared to patients with other causes of dyspnoea (11.2 [6.1-26.5] ng/L vs. 9.0 [3.2-32.3] ng/L, p < 0.0005). Elevated interleukin-6 concentrations were independently predicted by increasing N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T, as well as the clinical diagnosis of infection. Among the different AHF phenotypes, interleukin-6 concentrations were highest in patients with cardiogenic shock (25.7 [14.0-164.2] ng/L) and lowest in patients with hypertensive AHF (9.3 [4.8-21.6] ng/L, p = 0.001). Inflammation as quantified by interleukin-6 was a strong and independent predictor of 1-year mortality both in all AHF patients, as well as those without clinically overt infection at presentation (adjusted hazard ratio [95% confidence interval] 1.45 [1.15-1.83] vs. 1.48 [1.09-2.00]). The addition of interleukin-6 significantly improved the discrimination of the BIOSTAT-CHF risk score. CONCLUSION: An unexpectedly high percentage of patients with AHF have subclinical systemic inflammation as quantified by interleukin-6, which seems to contribute to AHF phenotype and to the risk of death.

Prognostic Value of Self-Reported Subjective Exercise Capacity in Patients With Acute Dyspnea.

Background: Self-reported exercise capacity is a well-established prognostic measure in stable ambulatory patients with cardiac and pulmonary disease. Objectives: The authors aimed to directly compare the prognostic accuracy of quantified self-reported exercise capacity using the Duke Activity Status Index (DASI) with the established objective disease-severity marker B-type natriuretic peptide (BNP) in patients presenting with acute dyspnea to the emergency department. Methods: The DASI was obtained in a prospective multicenter diagnostic study recruiting unselected patients presenting with acute dyspnea to the emergency department. The prognostic accuracy of DASI and BNP for 90-day and 720-day all-cause mortality was evaluated using C-index. Results: Among 1,019 patients eligible for this analysis, 75 (7%) and 297 (29%) patients died within 90 and 720 days after presentation, respectively. Unadjusted hazard ratios (HRs) and multivariable adjusted hazard ratios (aHRs) for 90- and 720-day mortality increased continuously from the fourth (best self-reported exercise capacity) to the first DASI quartile (worst self-reported exercise capacity). For 720-day mortality the HR of the first quartile vs the fourth was 9.1 (95% CI, 5.5-14.9) vs (aHR: 6.1, 95% CI: 3.7-10.1), of the second quartile 6.4 (95% CI: 3.9-10.6) vs (aHR: 4.4, 95% CI: 2.6-7.3), while of the third quartile the HR was 3.2 (95% CI: 1.9-5.5) vs (aHR: 2.4, 95% CI: 1.4-4.0). The prognostic accuracy of the DASI score was high, and higher than that of BNP concentrations (720-day mortality C-index: 0.67 vs 0.62; P = 0.024). Conclusions: Quantification of self-reported subjective exercise capacity using the DASI provides high prognostic accuracy and may aid physicians in risk stratification. (Basics in Acute Shortness of Breath EvaLuation [BASEL V] Study [BASEL V]; NCT01831115).

Diurnal Variations in Natriuretic Peptide Levels: Clinical Implications for the Diagnosis of Acute Heart Failure.

BACKGROUND: Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure. METHODS: In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals. RESULTS: Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18-110] versus 74 [27-168] ng/L; P<0.01) and NT-proBNP (median, 212 [72-581] versus 297 [102-902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95-0.98] and 0.95 [95% CI, 0.93-0.96] versus 0.94 [95% CI, 0.92-0.95] and 0.91 [95% CI, 0.90-0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01). CONCLUSIONS: BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.

Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure.

AIMS: Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF). METHODS AND RESULTS: This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT-proBNP plasma concentrations were applied: first, using currently recommended cut-offs; second, using cut-offs lowered by 33% with body mass index (BMI) of 30-34.9 kg/m2 and by 50% with BMI ≥ 35 kg/m2 . Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT-proBNP as quantified by the area under the receiver-operating characteristic curve was lower in obese versus non-obese patients (0.890 vs. 0.938). For rapid AHF rule-out in obese patients, the currently recommended cut-off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8-98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule-in, the age-dependent cut-off concentrations (age <50 years: 450 pg/ml; age 50-75 years: 900 pg/ml; age >75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8-88.9%). Proportionally lowering the currently recommended cut-offs by BMI increased sensitivity to 98.2% (95% CI 95.8-99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the 'gray zone' (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7-81.4%). CONCLUSIONS: Adjusting NT-proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF.

Acute kidney injury in patients with COVID-19: a retrospective cohort study from Switzerland.

BACKGROUND: Data about patients in Europe with corona virus disease-2019 (COVID-19) and acute kidney injury (AKI) are scarce. We examined characteristics, presentation and risk factors of AKI in patients hospitalised with COVID-19 in a tertiary hospital in Switzerland. METHODS: We reviewed health records of patients hospitalised with a positive nasopharyngeal polymerase chain reaction test for SARS-CoV2 between 1 February and 30 June 2020, at the University Hospital of Basel. The nadir creatinine of the hospitalisation was used as baseline. AKI was defined according the KDIGO guidelines as a 1.5× increase of baseline creatinine and in-hospital renal recovery as a discharge creatinine <1.25× baseline creatinine. Least absolute shrinkage and selection operator (LASSO) regression was performed to select predictive variables of AKI. Based on this a final model was chosen. RESULTS: Of 188 patients with COVID-19, 41 (22%) developed AKI, and 11 (6%) required renal replacement therapy. AKI developed after a median of 9 days (interquartile range [IQR] 5-12) after the first symptoms and a median of 1 day (IQR 0-5) after hospital admission. The peak AKI stages were stage 1 in 39%, stage 2 in 24% and stage 3 in 37%. A total of 29 (15%) patients were admitted to the intensive care unit and of these 23 (79%) developed AKI. In-hospital renal recovery at discharge was observed in 61% of all AKI episodes. In-hospital mortality was 27% in patients with AKI and 10% in patients without AKI. Age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.01­1.08; p = 0.024), history of chronic kidney disease (aOR 3.47, 95% CI 1.16­10.49;p = 0.026), C-reactive protein levels (aOR 1.09, 95% CI 1.03­1.06; p = 0.002) and creatinine kinase (aOR 1.03, 95% CI 1.01­1.06; p = 0.002) were associated with development of AKI. CONCLUSIONS: AKI is common in hospitalised patients with COVID-19 and more often seen in patients with severe COVID-19 illness. AKI is associated with a high in-hospital mortality.