Restriction of interleukin-6 alters endothelial cell immunogenicity in an allogenic environment.

The microvascular endothelium of the renal transplant is the first site of graft interaction with the host immune system and is often injured in chronic Antibody Mediated Rejection (AMR). Microvascular inflammation is an independent determinant of AMR and heightens endothelial expression of HLA molecules thereby increasing the possibility of Donor Specific Antibody (DSA) binding. Endothelial cells produce IL-6 in the steady-state and this is increased by inflammation or by HLA-DR antibody binding in an allogeneic setting. Because IL-6 has been implicated in AMR, IL-6 blockade is currently under investigation as a therapeutic target. To further understand the role of IL-6 in endothelial cell immunogenicity, we have examined whether humanized antibody blockade of IL-6 altered endothelial cell interactions with allogeneic PBMC and after anti-HLA or DSA binding to endothelial cells in an in vitro human experimental model. Soluble factors, endothelial phenotype, Stat-3 activation, CD4+ -T differentiation, and C4d deposition were examined. Blockade of IL-6 reduced endothelial cell secretion of IL-6 and of the monocyte chemoattractant MCP-1. Pre-activation of endothelial cells by anti-HLA or DSA binding increased IL-6 secretion, that was further increased by concurrent binding of both antibodies and this was inhibited by IL-6 blockade. Activation of Stat-3 in CD4+ -T mediated by soluble factors produced in endothelial-PBMC interactions, and endothelial differentiation of CD4+ -T cell subsets (Th1, Th17, Treg), were impaired whereas activation of Complement by anti-HLA antibody binding remained unchanged by IL-6 blockade. Together, these data identify EC-mediated pro-inflammatory responses (T cell expansion, EC auto-activation, chemokine secretion) targeted by IL-6 blockade.

A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

Restriction of interleukin-6 alters endothelial cell immunogenicity in an allogenic environment.

The microvascular endothelium of the renal transplant is the first site of graft interaction with the host immune system and is often injured in chronic Antibody Mediated Rejection (AMR). Microvascular inflammation is an independent determinant of AMR and heightens endothelial expression of human leukocyte antigen (HLA) molecules thereby increasing the possibility of Donor Specific Antibody (DSA) binding. Endothelial cells (ECs) produce IL-6 in the steady-state that is increased by inflammation or by HLA-DR antibody binding in an allogeneic setting. Because IL-6 has been implicated in AMR, IL-6 blockade is currently under investigation as a therapeutic target. To further understand the role of IL-6 in EC immunogenicity, we have examined whether humanized antibody blockade of IL-6 altered EC interactions with allogeneic PBMC and after anti-HLA or DSA binding to ECs in an in vitro human experimental model. Soluble factors, endothelial phenotype, Stat-3 activation, CD4+ -T differentiation and C4d deposition were examined. Blockade of IL-6 reduced EC secretion of IL-6 and of the monocyte chemoattractant MCP-1. Pre-activation of ECs by anti-HLA or DSA binding increased IL-6 secretion, that was further increased by concurrent binding of both antibodies and this was inhibited by IL-6 blockade. Activation of Stat-3 in CD4+ -T mediated by soluble factors produced in endothelial-PBMC interactions, and endothelial differentiation of CD4+ -T cell subsets (Th1, Treg), were impaired whereas activation of Complement by anti-HLA antibody binding remained unchanged by IL-6 blockade. Together, these data identify EC-mediated pro-inflammatory responses (T cell expansion, EC auto-activation, chemokine secretion) targeted by IL-6 blockade.

Emergency department interventions for frailty (EDIFY): improving functional outcomes in older persons at the emergency department through a multicomponent frailty intervention.

OBJECTIVES: emergency department interventions for frailty (EDIFY) delivers frailty-centric interventions at the emergency department (ED). We evaluated the effectiveness of a multicomponent frailty intervention (MFI) in improving functional outcomes among older persons. DESIGN: a quasi-experimental study. SETTING: a 30-bed ED observation unit within a 1,700-bed acute tertiary hospital. PARTICIPANTS: patients aged ≥65 years, categorised as Clinical Frailty Scale 4-6, and planned for discharge from the unit. METHODS: we compared patients receiving the MFI versus usual-care. Data on demographics, function, frailty, sarcopenia, comorbidities and medications were gathered. Our primary outcome was functional status-Modified Barthel Index (MBI) and Lawton's iADL. Secondary outcomes include hospitalisation, ED re-attendance, mortality, frailty, sarcopenia, polypharmacy and falls. Follow-up assessments were at 3, 6 and 12 months. RESULTS: we recruited 140 participants (mean age 79.7 ± 7.6 years; 47% frail and 73.6% completed the study). Baseline characteristics between groups were comparable (each n = 70). For the intervention group, MBI scores were significantly higher at 6 months (mean: 94.5 ± 11.2 versus 88.5 ± 19.5, P = 0.04), whereas Lawton's iADL scores experienced less decline (change-in-score: 0.0 ± 1.7 versus -1.1 ± 1.8, P = 0.001). Model-based analyses revealed greater odds of maintaining/improving MBI in the intervention group at 6 months [odds ratio (OR) 2.51, 95% confidence interval (CI) 1.04-6.03, P = 0.04] and 12 months (OR 2.98, 95% CI 1.18-7.54, P = 0.02). This was similar for Lawton's iADL at 12 months (OR 4.01, 95% CI 1.70-9.48, P = 0.002). ED re-attendances (rate ratio 0.35, 95% CI 0.13-0.90, P = 0.03) and progression to sarcopenia (OR 0.19, 95% CI 0.04-0.94, P = 0.04) were also lower at 6 months. CONCLUSIONS: the MFI delivered to older persons at the ED can possibly improve functional outcomes and reduce ED re-attendances while attenuating sarcopenia progression.

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism.

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4-weekly doses; 12 weeks), followed by a 9-month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose-adjusted C0 levels (C0 /D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4-weekly intervals. IL-6 and C-reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL-6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21-7.84] versus 4.22 [1.99-8.18] µg/ml*h, P = 0.36) or calcineurin inhibitor C0 /D ratios (tacrolimus: 1.49 [1.17-3.20] versus 1.37 [0.98-2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57-0.85] versus 1.08 [0.52-1.38] ng/ml/mg, P = 0.47). We conclude that IL-6 blockade in ABMR - in absence of systemic inflammation - may have no meaningful effect on CYP metabolism.

Pharmacodynamic Effects of Sucroferric Oxyhydroxide and Sevelamer Carbonate on Vitamin D Receptor Agonist Bioactivity in Dialysis Patients.

BACKGROUND: Many patients with chronic kidney disease are prescribed vitamin D receptor agonists (VDRAs) for the management of secondary hyperparathyroidism. Oral phosphate binders may interact with, and potentially reduce the therapeutic activity of, oral VDRAs. This post hoc analysis of a Phase 3 study evaluated the pharmacodynamic effects of the iron-based phosphate binder sucroferric oxyhydroxide (SFOH) and sevelamer (SEV) carbonate on VDRA activity in dialysis patients. METHODS: One thousand and fifty nine patients were randomized to SFOH 1.0-3.0 g/day (n = 710) or SEV 2.4-14.4 g/day (n = 349) for up to 52 weeks. Potential interactions of SFOH and SEV with VDRAs were assessed using serum intact parathyroid hormone (iPTH) concentrations as a pharmacodynamic biomarker. Three populations of SFOH- and SEV-treated patients were analyzed: Population 1 (n = 187), patients taking concomitant stable doses of oral VDRAs only; Population 2 (n = 250), patients taking no concomitant VDRAs; Population 3 (n = 68), patients taking concomitant stable doses of intravenous paricalcitol only. Populations were compared using a mixed-effects model to obtain the least squares mean change in iPTH from baseline to Week 52. Differences between treatment groups were also compared. RESULTS: In Population 1, iPTH decreased from baseline to Week 52 in the SFOH group (-25.3 pg/ml) but increased in the SEV group (89.8 pg/ml) (p = 0.02). In Population 2, iPTH increased to a similar extent in both treatment groups. In Population 3, iPTH concentrations in both treatment groups decreased to a similar degree (-29.6 and -11.4 pg/ml for SFOH and SEV, respectively; p = 0.87). CONCLUSIONS: In contrast with SEV, SFOH did not appear to impact the iPTH-lowering effect of oral VDRAs.

Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients.

BACKGROUND: Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. METHODS: In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0 g/day (2-6 tablets/day; n = 710) or sevelamer 2.4-14.4 g/day (3-18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. RESULTS: Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 ± 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 ± 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13-1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 ± 1.5) versus sevelamer (10.1 ± 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time. CONCLUSIONS: The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation.

Identifying phenomenological differences and recovery of cognitive and non-cognitive symptomatology among delirium superimposed upon dementia patients (DsD) versus those without dementia (DaD) in an acute geriatric care setting.

BACKGROUND: Phenomenological differences between delirium superimposed on dementia (DsD) versus delirium in the absence of dementia (DaD) remain poorly understood. We aimed to identify phenomenological differences in delirium symptoms (cognitive and non-cognitive) and compare delirium recovery trajectories between DsD and DaD. METHODS: We conducted a prospective observational study on individuals admitted to the Geriatric Monitoring Unit (GMU), a five-bed unit specializing in managing older adults with delirium, between December 2010 and August 2012 (n = 234; mean age 84.1 ± 7.4). We collected data on demographics, comorbidities, severity of illness, cognitive and functional scores, and number of precipitants. Cognitive status was assessed using locally validated Chinese Mini-Mental State Examination (CMMSE) and delirium severity assessed using Delirium Rating Scale-Revised-98 (DRS-R98). Delirium disease trajectory was plotted over five days. RESULTS: DsD patients had a longer duration of delirium with slower recovery in terms of cognition and delirium severity scores compared with DaD patients (0.33 (0.0-1.00) vs. 1.0 (0.36-2.00) increase in CMMSE per day, p < 0.001, and 1.49 ± 1.62 vs. 2.63 ± 2.28 decrease in DRS-R98 severity per day, p < 0.001). When cognitive and non-cognitive sub-scores of DRS-R98 were examined separately, we observed steeper recovery in both sub-scores in DaD patients. These findings remained significant after adjusting for significant baseline differences. CONCLUSIONS: Our findings of slower cognitive symptom recovery in DsD patients suggest cognitive reserve play a role in delirium syndrome development and recovery. This merits further studies to potentially aid in appropriate discharge planning and to identify potential pharmacological and non-pharmacological cognitive interventions for hospitalized older persons with delirium.

A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients.

Efficacy of PA21 (sucroferric oxyhydroxide), a novel calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder, was compared with that of sevelamer carbonate in an open-label, randomized, active-controlled phase III study. Seven hundred and seven hemo- and peritoneal dialysis patients with hyperphosphatemia received PA21 1.0-3.0 g per day and 348 received sevelamer 4.8-14.4 g per day for an 8-week dose titration, followed by 4 weeks without dose change, and then 12 weeks maintenance. Serum phosphorus reductions at week 12 were -0.71 mmol/l (PA21) and -0.79 mmol/l (sevelamer), demonstrating non-inferiority of, on average, three tablets of PA21 vs. eight of sevelamer. Efficacy was maintained to week 24. Non-adherence was 15.1% (PA21) vs. 21.3% (sevelamer). The percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer. A higher proportion of patients withdrew owing to treatment-emergent adverse events with PA21 (15.7%) vs. sevelamer (6.6%). Mild, transient diarrhea, discolored feces, and hyperphosphatemia were more frequent with PA21; nausea and constipation were more frequent with sevelamer. After 24 weeks, 99 hemodialysis patients on PA21 were re-randomized into a 3-week superiority analysis of PA21 maintenance dose in 50 patients vs. low dose (250 mg per day (ineffective control)) in 49 patients. The PA21 maintenance dose was superior to the low dose in maintaining serum phosphorus control. Thus, PA21 was effective in lowering serum phosphorus in dialysis patients, with similar efficacy to sevelamer carbonate, a lower pill burden, and better adherence.

Functional dependency as a marker for positive SARC-F screen among older persons at the emergency department.

Background: Functional dependency may serve as a marker for positive SARC-F screen among older adults at the Emergency Department (ED). We compared functional dependency between SARC-F- (<4) and SARC-F+ (≥4) groups at the ED. Methods: A secondary analysis of cohorts from two quasi-experimental studies among patients aged ≥65 years old presenting to the ED of a 1700-bed tertiary hospital. We compared both groups for baseline characteristics using univariate analyses, and performed multiple linear regression to examine the association between Modified Barthel Index (MBI) and Lawton's instrumental activities of daily living (IADL) against SARC-F, and binary logistic regression to examine the associations between individual ADL domains and SARC-F+. We compared the area under receiver operating characteristic curves (AUC) to detect SARC-F+ for MBI, IADL, frailty, age, cognition and comorbidity. Results: SARC-F+ patients were older (86.4±7.6 years), predominantly female (71.5%) and frail (73.9%), more dependent on walking aids (77.2%), and had lower premorbid MBI[90.0(71.0-98.0)] and IADL[4.0(2.0-5.0)] (both p<.001). MBI (ß -0.07, 95%CI:-0.086 to -0.055] and IADL (ß -0.533,95%CI:-0.684 to -0.381) were significantly associated with SARC-F. Dependency in finances [Odds Ratio(OR):14.7,95%CI:3.57-60.2, p<.001], feeding (OR:12.4,95%CI:1.45-106, p=0.022), and stair-climbing (OR:10.49,95%CI:4.96-22.2, p<.001) were the top 3 functional items associated with SARC-F. MBI (AUC:0.82,95%CI:0.77-0.84) and IADL (AUC:0.78,95%CI:0.72-0.84) showed superior discrimination for SARC-F+ compared to other measures (AUC:0.58-0.70). Conclusion: Functional dependency is strongly associated with positive SARC-F screen among older adults at the ED. This highlights the need for increased vigilance, especially in the presence of dependency in relevant domains such as managing finances, feeding, and stair-climbing.

Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Renal Allograft Rejection: Accumulation of Antibody-neutralized Interleukin-6 Without Signs of Proinflammatory Rebound Phenomena.

BACKGROUND: Blockade of interleukin-6 (IL-6) has emerged as a promising therapeutic option for antibody-mediated rejection. Subtherapeutic anti-IL-6 antibody level or treatment cessation following prolonged cytokine neutralization may result in proinflammatory rebound phenomena via accumulation of IL-6 and/or modulated gene expression of major components of the IL-6/IL-6 receptor (IL-6R) axis. METHODS: We evaluated biologic material obtained from a randomized controlled, double-blind phase 2 trial designed to evaluate the safety and efficacy of the anti-IL-6 monoclonal antibody clazakizumab in late antibody-mediated rejection. Twenty kidney transplant recipients, allocated to clazakizumab or placebo, received 4-weekly doses over 12 wks, followed by a 40-wk extension where all recipients received clazakizumab. Serum proteins were detected using bead-based immunoassays and RNA transcripts using quantitative real-time polymerase chain reaction (peripheral blood) or microarray analysis (serial allograft biopsies). RESULTS: Clazakizumab treatment resulted in a substantial increase in median total (bound and unbound to drug) serum IL-6 level (1.4, 8015, and 13 600 pg/mL at 0, 12, and 52 wks), but median level of free (unbound to drug) IL-6 did not increase (3.0, 2.3, and 2.3 pg/mL, respectively). Neutralization of IL-6 did not boost soluble IL-6R or leukocyte or allograft expression of IL-6, IL-6R, and glycoprotein 130 mRNA. Cessation of treatment at the end of the trial did not result in a meaningful increase in C-reactive protein or accelerated progression of graft dysfunction during 12 mo of follow-up. CONCLUSION: Our results argue against clinically relevant rebound phenomena and modulation of major components of the IL-6/IL-6R axis following prolonged IL-6 neutralization with clazakizumab.

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design.

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

Heterogeneity in functional status among moderately frail older adults: improving predictive performance using a modified approach of subgrouping the Clinical Frailty Scale.

PURPOSE: Moderately frail individuals [Clinical Frailty Scale (CFS) 6] demonstrate heterogeneity in basic activities of daily living (bADL). We aimed to establish whether functional dependency in moderate frailty predicts poorer outcomes and examined the utility of subgrouping the CFS in predicting mortality and institutionalisation. METHODS: We prospectively studied 201 hospitalised frail patients (89.5 ± 4.7 years, female 70.1%). We examined Katz Index (KI) against adverse outcomes in CFS6 (n = 106). We then compared predictive performances of a modified CFS version 1 (mCFS-1; category 6A: CFS6 and KI ≥ 2; 6B: CFS6 and KI ≤ 1) and modified CFS version 2 (mCFS-2; category 6A: CFS6 and KI ≥ 2; 6B1: CFS6, KI ≤ 1 and feeding independent; 6B2: CFS6, KI ≤ 1 and feeding dependent) against the CFS. Multivariate analysis was used to compare each tool against mortality and institutionalisation. Receiver operator characteristic analysis was performed to determine area under curve and optimal cut-points for each tool. RESULTS: KI ≤ 1 in CFS6 was associated with higher 12-month mortality (39.3% vs. 15.6%, p = 0.01); amongst KI items, feeding dependent predicted 12-month mortality (p < 0.05). Using mCFS-1, category 6A did not increase 12-month mortality compared with category 5 (OR 1.83, 95% CI 0.52-6.47), unlike category 6B (OR 6.33, 95% CI 2.07-19.33). mCFS-2 produced higher mortality in category 6B1 (OR 5.19, 95% CI 1.30-20.69) and 6B2 (OR 6.92, 95% CI 2.14-22.35). Similar observations were seen for institutionalisation. Optimal cut-point for 12-month mortality was category 6 for CFS, and 6B and 6B1 for mCFS-1 and mCFS-2, respectively. CONCLUSION: This study corroborates the heterogeneity of functional status in moderately frail individuals and validates the use of a modified approach to subgrouping the CFS6 via bADL functional status for improved predictive performance.

Concurrent and Predictive Validity of FRAIL-NH in Hospitalized Older Persons: An Exploratory Study.

OBJECTIVES: The FRAIL-NH was originally developed for frailty assessment of nursing home (NH) residents. We aimed to compare concurrent, predictive, and known-groups validity between FRAIL-NH and FRAIL, using the Frailty Index (FI) as gold standard reference. We also examined for ceiling effect of both measures in the detection of severe frailty. DESIGN: A secondary analysis of a prospective cohort study. SETTING & PARTICIPANTS: Older adults (mean age 89.4 years) hospitalized for an acute medical illness in a 1300-bed tertiary hospital. MEASUREMENTS: Baseline data on demographics, comorbidities, severity of illness, functional status, and cognitive status were gathered. We also captured outcomes of mortality, length of stay (LOS), institutionalization, and functional decline. For concurrent validity, we compared areas under the operating characteristic curves (AUCs) for both measures against the FI. For predictive validity, univariate analyses and multiple logistic regression were used to compare both measures against the adverse outcomes of interest. For known-groups validity, we compared both measures against comorbidities and functional status via 1-way analysis of variance, and dementia diagnosis via independent t test. Box plots were also derived to investigate for possible ceiling effect. RESULTS: Both measures had good concurrent validity (both AUC > 0.8 and P < .001), with FRAIL-NH detecting more frailty cases (79.5% vs 50.0%). Although FRAIL-frail was superior for in-hospital mortality [6.7% vs 1.0%, P = .031, odds ratio (OR) 9.29, 95% confidence interval (CI) 1.09-79.20, P < .042] and LOS (10 vs 8 days, P = .043), FRAIL-NH-frail better predicted mortality (OR 6.62, 95% CI 1.91-22.94, P = .003) and institutionalization (OR 6.03, 95% CI 2.01-18.09, P = .001) up to 12 months postenrollment. Known-groups validity was good for both measures with FRAIL-NH yielding greater F values for functional status and dementia. Lastly, box plots revealed a ceiling effect for FRAIL in the severely frail group. CONCLUSIONS AND IMPLICATIONS: This exploratory study highlights the potential for expanding the role of FRAIL-NH beyond NH to acute care settings. Contrasted to FRAIL, FRAIL-NH had better overall validity with less ceiling effect in discrimination of severe frailty.

Change in Estimated GFR and Risk of Allograft Failure in Patients Diagnosed With Late Active Antibody-mediated Rejection Following Kidney Transplantation.

BACKGROUND: There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx). METHODS: We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up. RESULTS: A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of -0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of -9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years. CONCLUSIONS: If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR.

Emergency Department Interventions for Frailty (EDIFY): Front-Door Geriatric Care Can Reduce Acute Admissions.

OBJECTIVES: The EDIFY program was developed to deliver early geriatric specialist interventions at the emergency department (ED) to reduce the number of acute admissions by identifying patients for safe discharge or transfer to low-acuity care settings. We evaluated the effectiveness of EDIFY in reducing potentially avoidable acute admissions. DESIGN: A quasi-experimental study. SETTING: ED of a 1700-bed tertiary hospital. PARTICIPANTS: ED patients aged ≥85 years. MEASUREMENTS: We compared EDIFY interventions versus standard care. Patients with plans for acute admission were screened and recruited. Data on demographics, premorbid function, frailty status, comorbidities, and acute illness severity were gathered. We examined the primary outcome of "successful acute admission avoidance" among the intervention group, which was defined as no ED attendance within 72 hours of discharge from ED, no transfer to an acute ward from subacute-care units (SCU) within 72-hours, or no transfer to an acute ward from the short-stay unit (SSU). Secondary outcomes were rehospitalization, ED re-attendance, institutionalization, functional decline, mortality, and frailty transitions at 1, 3, and 6 months. RESULTS: We recruited 100 participants (mean age 90.0 ± 4.1 years, 66.0% women). There were no differences in baseline characteristics between intervention (n = 43) and nonintervention (n = 57) groups. Thirty-five (81.4%) participants in the intervention group successfully avoided an acute admission (20.9% home, 23.3% SCU, and 44.2% SSU). All participants in the nonintervention group were hospitalized. There were no differences in rehospitalization, ED re-attendance, institutionalization and mortality over the study period. Additionally, we observed a higher rate of progression to a poorer frailty category at all time points among the nonintervention group (1, 3, and 6 months: all P < .05). CONCLUSIONS AND IMPLICATIONS: Results from our single-center study suggest that early geriatric specialist interventions at the ED can reduce potentially avoidable acute admissions without escalating the risk of rehospitalization, ED re-attendance, or mortality, and with possible benefit in attenuating frailty progression.

Validating a Standardised Approach in Administration of the Clinical Frailty Scale in Hospitalised Older Adults.

INTRODUCTION: We developed a Clinical Frailty Scale algorithm (CFS-A) to minimise inter-rater variability and to facilitate wider application across clinical settings. We compared the agreement, diagnostic performance and predictive utility of CFS-A against standard CFS. MATERIALS AND METHODS: We retrospectively analysed data of 210 hospitalised older adults (mean age, 89.4 years). Two independent raters assessed frailty using CFS-A. Agreement between CFS-A raters and with previously completed CFS was determined using Cohen's Kappa. Area under receiver operator characteristic curves (AUC) for both measures were compared against the Frailty Index (FI). Independent associations between these measures and adverse outcomes were examined using logistic regression. RESULTS: Frailty prevalence were 81% in CFS and 96% in CFS-A. Inter-rater agreement between CFS-A raters was excellent (kappa 0.90, P <0.001) and there was moderate agreement between CFS-A and standard CFS (kappa 0.42, P <0.001). We found no difference in AUC against FI between CFS (0.91; 95% CI, 0.86-0.95) and CFS-A (0.89; 95% CI, 0.84-0.95; P <0.001). Both CFS (OR, 3.59; 95% CI, 2.28-5.67; P <0.001) and CFS-A (OR, 4.31; 95% CI, 2.41-7.69; P <0.001) were good predictors of mortality at 12 months. Similarly, CFS (OR, 2.59; 95% CI, 1.81-3.69; P <0.001) and CFS-A (OR, 3.58; 95% CI, 2.13-6.02; P <0.001) were also good predictors of institutionalisation and/or mortality after adjusting for age, sex and illness severity. CONCLUSION: Our study corroborated the results on inter-rater reliability, diagnostic performance and predictive validity of CFS-A which has the potential for consistent and efficient administration of CFS in acute care settings.

Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial.

BACKGROUND: Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. METHODS: This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4-12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. DISCUSSION: Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03444103 . Registered on 23 February 2018 (retrospective registration).