The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Scoring donor lungs for graft failure risk: The Lung Donor Risk Index (LDRI).

Lung transplantation lags behind other solid organ transplants in donor lung utilization due, in part, to uncertainty regarding donor quality. We sought to develop an easy-to-use donor risk metric that, unlike existing metrics, accounts for a rich set of donor factors. Our study population consisted of n = 26 549 adult lung transplant recipients abstracted from the United Network for Organ Sharing Standard Transplant Analysis and Research file. We used Cox regression to model graft failure (GF; earliest of death or retransplant) risk based on donor and transplant factors, adjusting for recipient factors. We then derived and validated a Lung Donor Risk Index (LDRI) and developed a pertinent online application (https://shiny.pmacs.upenn.edu/LDRI_Calculator/). We found 12 donor/transplant factors that were independently predictive of GF: age, race, insulin-dependent diabetes, the difference between donor and recipient height, smoking, cocaine use, cytomegalovirus seropositivity, creatinine, human leukocyte antigen (HLA) mismatch, ischemia time, and donation after circulatory death. Validation showed the LDRI to have GF risk discrimination that was reasonable (C = 0.61) and higher than any of its predecessors. The LDRI is intended for use by transplant centers, organ procurement organizations, and regulatory agencies and to benefit patients in decision-making. Unlike its predecessors, the proposed LDRI could gain wide acceptance because of its granularity and similarity to the Kidney Donor Risk Index.

Frailty and Cardiovascular Outcomes in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes in adults with kidney failure requiring dialysis. However, this relationship has not been thoroughly evaluated among those with non-dialysis-dependent CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,539 adults in the Chronic Renal Insufficiency Cohort Study. EXPOSURE: Frailty status assessed using 5 criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss. OUTCOME: Atherosclerotic events, incident heart failure, all-cause death, and cardiovascular death. ANALYTICAL APPROACH: Cause-specific hazards models. RESULTS: At study entry, the participants' mean age was 62 years, 46% were female, the mean estimated glomerular filtration rate was 45.4mL/min/1.73m2, and the median urine protein was 0.2mg/day. Frailty status was as follows: 12% frail, 51% prefrail, and 37% nonfrail. Over a median follow-up of 11.4 years, there were 393 atherosclerotic events, 413 heart failure events, 497 deaths, and 132 cardiovascular deaths. In multivariable regression analyses, compared with nonfrailty, both frailty and prefrailty status were each associated with higher risk of an atherosclerotic event (HR, 2.03 [95% CI, 1.41-2.91] and 1.77 [95% CI, 1.35-2.31], respectively) and incident heart failure (HR, 2.22 [95% CI, 1.59-3.10] and 1.39 [95% CI, 1.07-1.82], respectively), as well as higher risk of all-cause death (HR, 2.52 [95% CI, 1.84-3.45] and 1.76 [95% CI, 1.37-2.24], respectively) and cardiovascular death (HR, 3.01 [95% CI, 1.62-5.62] and 1.78 [95% 1.06-2.99], respectively). LIMITATIONS: Self-report of aspects of the frailty assessment and comorbidities, which may have led to bias in some estimates. CONCLUSIONS: In adults with CKD, frailty status was associated with higher risk of cardiovascular events and mortality. Future studies are needed to evaluate the impact of interventions to reduce frailty on cardiovascular outcomes in this population. PLAIN-LANGUAGE SUMMARY: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes. We sought to evaluate the association of frailty status with cardiovascular events and death in adults with CKD. Frailty was assessed according to the 5 phenotypic criteria detailed by Fried and colleagues. Among 2,539 participants in the CRIC Study, we found that 12% were frail, 51% were prefrail, and 37% were nonfrail. Frailty status was associated with an increased risk of atherosclerotic events, incident heart failure, and death.

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

SIGNIFICANCE STATEMENT: eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. BACKGROUND: The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. METHODS: We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. RESULTS: SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. CONCLUSIONS: This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Selective Electrocatalytic Degradation of Ether-Containing Polymers.

Leveraging electrochemistry to degrade robust polymeric materials has the potential to impact society's growing issue of plastic waste. Herein, we develop an electrocatalytic oxidative degradation of polyethers and poly(vinyl ethers) via electrochemically mediated hydrogen atom transfer (HAT) followed by oxidative polymer degradation promoted by molecular oxygen. We investigated the selectivity and efficiency of this method, finding our conditions to be highly selective for polymers with hydridic, electron-rich C-H bonds. We leveraged this reactivity to degrade polyethers and poly(vinyl ethers) in the presence of polymethacrylates and polyacrylates with complete selectivity. Furthermore, this method made polyacrylates degradable by incorporation of ether units into the polymer backbone. We quantified degradation products, identifying up to 36 mol % of defined oxidation products, including acetic acid, formic acid, and acetaldehyde, and we extended this method to degrade a polyether-based polyurethane in a green solvent. This work demonstrates a facile, electrochemically-driven route to degrade polymers containing ether functionalities.

Hydrazine-Catalysed Ring-Opening Metathesis Polymerization Of Cyclobutenes.

Materials formed by the ring-opening metathesis polymerization (ROMP) of cyclic olefins are highly valued for industrial and academic applications but are difficult to prepare free of metal contaminants. Here we describe a highly efficient metal-free ROMP of cyclobutenes using hydrazine catalysis. Reactions can be initiated via in situ condensation of a [2.2.2]-bicyclic hydrazine catalyst with an aliphatic or aromatic aldehyde initiator. The polymerizations show living characteristics, achieving excellent control over molecular weight, low dispersity values, and high chain-end fidelity. Additionally, the hydrazine can be used in substoichiometric amounts relative to the aldehyde chain-end while maintaining good control over molecular weight and low dispersity values, indicating that a highly efficient chain transfer mechanism is occurring.

Acute respiratory failure-related excess mortality in pediatric sepsis.

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 - 98.9) and sensitivity of 70.5% (CI 44.0 - 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 - 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.

Prospective associations of health literacy with clinical outcomes in adults with CKD: findings from the CRIC study.

BACKGROUND: Limited health literacy is associated with significant morbidity and mortality in the general population but the relation of health literacy with long-term clinical outcomes among adults with chronic kidney disease (CKD) is less clear. METHODS: Prospective data from the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3715) were used. Health literacy was assessed with the Short Test of Functional Health Literacy in Adults (dichotomized as limited/adequate). Cox proportional hazards models were used to separately examine the relations of health literacy with CKD progression, cardiovascular event (any of the following: myocardial infarction, congestive heart failure, stroke or peripheral artery disease), and all-cause, cardiovascular and non-cardiovascular mortality. Poisson regression was used to assess the health literacy-hospitalization association. Models were sequentially adjusted: Model 1 adjusted for potential confounders (sociodemographic factors), while Model 2 additionally adjusted for potential mediators (clinical and lifestyle factors) of the associations of interest. RESULTS: In confounder-adjusted models, participants with limited (vs adequate) health literacy [555 (15%)] had an increased risk of CKD progression [hazard ratio (HR) 1.34; 95% confidence interval (CI) 1.06-1.71], cardiovascular event (HR 1.67; 95% CI 1.39-2.00), hospitalization (rate ratio 1.33; 95% CI 1.26-1.40), and all-cause (HR 1.54; 95% CI 1.27-1.86), cardiovascular (HR 2.39; 95% CI 1.69-3.38) and non-cardiovascular (HR 1.27; 95% CI 1.01-1.60) mortality. Additional adjustments for potential mediators (Model 2) showed similar results except that the relations of health literacy with CKD progression and non-cardiovascular mortality were no longer statistically significant. CONCLUSIONS: In the CRIC Study, adults with limited (vs adequate) health literacy had a higher risk for CKD progression, cardiovascular event, hospitalization and mortality-regardless of adjustment for potential confounders.

Validity of self-reported migraine in adolescents and children.

OBJECTIVE: To assess agreement for migraine day between self-report and diagnostic guidelines for children and adolescents using a headache diary. BACKGROUND: Trial guidelines recommend prospective collection of headache features and adoption of migraine day as an outcome measure, but there is no clear consensus on the definition of migraine day. METHODS: This is a secondary analysis of data from two projects-a prospective cohort study validating a pediatric scale of treatment expectancy and a clinical trial of occipital nerve blocks to treat status migrainosus. Participants completed a text message-based diary for 4 or 12 weeks (depending on treatment), and a detailed headache assessment on a random 20% of headache days. Using this assessment, we determined whether a headache day qualified for migraine or probable migraine, based on the International Classification of Headache Disorders, 3rd edition (ICHD-3). RESULTS: Of 122 enrolled children and adolescents, 106 (86.9%) completed ≥1 detailed headache assessment (438 entries). We found moderate agreement between self-reported and ICHD-derived migraine day, with a Cohen's Kappa of 0.50 (positive predictive value [PPV]: 0.66; negative predictive value [NPV]: 0.85; correlation: 0.51). Allowing for ICHD-derived probable migraine significantly increased PPV (0.66 vs. 0.94; 95% CI: 0.57-0.74 vs. 0.90-0.97), but decreased NPV (0.85 vs. 0.293; CI: 0.77-0.90 vs. 0.199-0.40), Cohen's Kappa (0.50 vs. 0.237; CI: 0. 389-0.60 vs. 0.139-0.352), and correlation (r = 0.51 vs. 0.302; CI: 0.41-0.61 vs. 0.192-0.41). Pain severity (OR: 5.7; CI: 2.39-13.8), photophobia (OR: 4.1; CI: 1.02-16.6), and phonophobia (OR: 7.5; CI: 1.95-29.3) were significantly associated with participants' perception of migraine. CONCLUSION: We found only moderate agreement between self-reported and ICHD-derived migraine day, suggesting both measures are not equal but may represent overlapping aspects of migraine as a disease. This highlights the difficulty of applying ICHD criteria to individual attacks. We recommend greater methodological transparency in future research to avoid readers conflating both measures.

Patient headache questionnaires can improve headache diagnosis and treatment in children.

OBJECTIVE: To examine trends in diagnosis of headache and migraine in a large pediatric neurology cohort, and test whether an electronic health record (EHR)-integrated headache questionnaire can increase specificity of diagnosis and likelihood of prescribing migraine treatment. BACKGROUND: Under-diagnosis of migraine contributes to the burden of disease. As we founded our Pediatric Headache Program in 2013, we recognized that the proportion of patients with headache who were given a diagnosis of migraine was much lower than expected. METHODS: We developed a patient headache questionnaire, initially on paper (2013-2014), then in an electronic database (2014-2016), and finally integrated into our electronic health record (pilot: 2016, full: May 2017). We compared diagnoses and prescribed treatments for new patients who were given a headache diagnosis, looking at trends in the proportion of patients given specific diagnoses (migraine, etc.) versus the non-specific diagnosis, "headache." Next, we conducted a prospective cohort study to test for association between provider use of the form and the presence of a specific diagnosis, then for an association between specific diagnosis and prescription of migraine treatment. RESULTS: Between July 2011 and December 2022 the proportion of new headache patients who were given a diagnosis of migraine increased 9.7% and non-specific headache diagnoses decreased 21.0%. In the EHR cohort (June 2017-December 2022, n = 15,122), use of the provider form increased the rate of specific diagnosis to 87.2% (1839/2109) compared to 75.5% (5708/7560) without a patient questionnaire, nearly doubling the odds of making a specific diagnosis (odds ratio [OR] 1.90, 95% confidence interval [CI]: 1.65-2.19). Compared to those given only a non-specific headache diagnosis who were prescribed a migraine therapy 53.7% (1766/3286) of the time, 75.3% (8914/11836) of those given a specific diagnosis received a migraine therapy, more than doubling the odds of prescription (OR 2.39, 95% CI: 2.20-2.60). CONCLUSIONS: Interventions to improve specificity of diagnosis were effective and led to increased rates of prescription of migraine treatments. These results have been sustained over several years. This headache questionnaire was adapted into the Foundation system of EpicCare, so it is broadly available as a clinical and research tool for institutions that use this EHR software.

Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

Acute Kidney Injury Associates with Long-Term Increases in Plasma TNFR1, TNFR2, and KIM-1: Findings from the CRIC Study.

BACKGROUND: Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown. METHODS: Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization). RESULTS: In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P<0.01), TNFR2 (10% versus 3%, P<0.01), and KIM-1 (13% versus -2%, P<0.01). CONCLUSIONS: Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult.

Direct Insertion Polymerization of Ionic Monomers: Rapid Production of Anion Exchange Membranes.

The limited number of methods to directly polymerize ionic monomers currently hinders rapid diversification and production of ionic polymeric materials, namely anion exchange membranes (AEMs) which are essential components in emerging alkaline fuel cell and electrolyzer technologies. Herein, we report a direct coordination-insertion polymerization of cationic monomers, providing the first direct synthesis of aliphatic polymers with high ion incorporations and allowing facile access to a broad range of materials. We demonstrate the utility of this method by rapidly generating a library of solution processable ionic polymers for use as AEMs. We investigate these materials to study the influence of cation identity on hydroxide conductivity and stability. We found that AEMs with piperidinium cations exhibited the highest performance, with high alkaline stability, hydroxide conductivity of 87 mS cm-1 at 80 °C, and a peak power density of 730 mW cm-2 when integrated into a fuel cell device.

Poly(2,3-Dihydrofuran): A Strong, Biorenewable, and Degradable Thermoplastic Synthesized via Room Temperature Cationic Polymerization.

Creation of strong and tough plastics from sustainable and biorenewable resources is a significant challenge in polymer science. This challenge is further complicated when attempting to make these materials using an economically viable process, which is often hindered by the production and availability of chemical feedstocks and the efficiency of the monomer synthesis. Herein, we report the synthesis and characterization of a strong thermoplastic made from 2,3-dihydrofuran (DHF), a monomer made in one step from 1,4-butanediol, a bioalcohol already produced on the plant scale. We developed a green, metal-free cationic polymerization to enable the production of poly(2,3-dihydrofuran) (PDHF) with molecular weights of up to 256 kg/mol at room temperature. Characterization of these polymers showed that PDHF possesses high tensile strength and toughness (70 and 14 MPa, respectively) comparable to commercial polycarbonate, high optical clarity, and good barrier properties to oxygen, carbon dioxide, and water. These properties make this material amenable to a variety of applications, from food packaging to high strength windows. Importantly, we have also developed a facile oxidative degradation process of PDHF, providing an end-of-life solution for PDHF materials.

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Acute Kidney Injury in Deceased Organ Donors and Kidney Transplant Outcomes: A National Cohort Study Using a Novel Data Source.

OBJECTIVE: The aim of this study was to determine graft function and survival for kidney transplants from deceased donors with acute kidney injury (AKI) that persists at the time of organ procurement. BACKGROUND: Kidneys from donors with AKI are often discarded and may provide an opportunity to selectively expand the donor pool. METHODS: Using Organ Procurement and Transplantation Network and DonorNet data, we studied adult kidney-only recipients between May 1, 2007 and December 31, 2016. DonorNet was used to characterize longitudinal creatinine trends and urine output. Donor AKI was defined using KDIGO guidelines and terminal creatinine ≥1.5 mg/dL. We compared outcomes between AKI kidneys versus "ideal comparator" kidneys from donors with no or resolved AKI stage 1 plus terminal creatinine <1.5mg/dL. We fit proportional hazards models and hierarchical linear regression models for the primary outcomes of all-cause graft failure (ACGF) and 12-month estimated glomerular filtration rate (eGFR), respectively. RESULTS: We identified 7660 donors with persistent AKI (33.2% with AKI stage 3) from whom ≥1 kidney was transplanted. Observed rates of ACGF within 3 years were similar between recipient groups (15.5% in AKI vs 15.1% ideal comparator allografts, P = 0.2). After risk adjustment, ACGF was slightly higher among recipients of AKI kidneys (adjusted hazard ratio 1.05, 95% confidence interval: 1.01-1.09). The mean 12-month eGFR for AKI kidney recipients was lower, but differences were not clinically important (56.6 vs 57.5 mL/min/1.73m 2 for ideal comparator kidneys; P < 0.001). There were 2888 kidneys discarded from donors with AKI, age ≤65 years, without hypertension or diabetes, and terminal creatinine ≤4 mg/dL. CONCLUSION: Kidney allografts from donors with persistent AKI are often discarded, yet those that were transplanted did not have clinically meaningful differences in graft survival and function.

Preoperative Computed Tomography Morphological Features Indicative of Incisional Hernia Formation After Abdominal Surgery.

OBJECTIVE: To investigate key morphometric features identifiable on routine preoperative computed tomography (CT) imaging indicative of incisional hernia (IH) formation following abdominal surgery. BACKGROUND: IH is a pervasive surgical disease that impacts all surgical disciplines operating in the abdominopelvic region and affecting 13% of patients undergoing abdominal surgery. Despite the significant costs and disability associated with IH, there is an incomplete understanding of the pathophysiology of hernia. METHODS: A cohort of patients (n=21,501) that underwent colorectal surgery was identified, and clinical data and demographics were extracted, with a primary outcome of IH. Two datasets of case-control matched pairs were created for feature measurement, classification, and testing. Morphometric linear and volumetric measurements were extracted as features from anonymized preoperative abdominopelvic CT scans. Multivariate Pearson testing was performed to assess correlations among features. Each feature's ability to discriminate between classes was evaluated using 2-sided paired t testing. A support vector machine was implemented to determine the predictive accuracy of the features individually and in combination. RESULTS: Two hundred and twelve patients were analyzed (106 matched pairs). Of 117 features measured, 21 features were capable of discriminating between IH and non-IH patients. These features are categorized into three key pathophysiologic domains: 1) structural widening of the rectus complex, 2) increased visceral volume, 3) atrophy of abdominopelvic skeletal muscle. Individual prediction accuracy ranged from 0.69 to 0.78 for the top 3 features among 117. CONCLUSIONS: Three morphometric domains identifiable on routine preoperative CT imaging were associated with hernia: widening of the rectus complex, increased visceral volume, and body wall skeletal muscle atrophy. This work highlights an innovative pathophysiologic mechanism for IH formation hallmarked by increased intra-abdominal pressure and compromise of the rectus complex and abdominopelvic skeletal musculature.

Risk of Serious Infection With Low-dose Glucocorticoids in Patients With Rheumatoid Arthritis: An Instrumental Variable Analysis.

BACKGROUND: Low-dose glucocorticoids are commonly used in the treatment of rheumatoid arthritis (RA). Observational studies have found an increased risk of serious infection associated with low-dose glucocorticoids, but concerns about residual confounding remain. METHODS: We identified adults with RA on stable immunomodulatory therapy for >6 months receiving no glucocorticoids or ≤5 mg/day using Medicare data from 2006 to 2015. We used provider preference for glucocorticoids as an instrumental variable (IV) to assess associations between low-dose glucocorticoid use and the risk of infection requiring hospitalization using a cause-specific proportional hazards model. RESULTS: We identified 163,603 qualifying treatment episodes among 120,656 patients. Glucocorticoids ≤5 mg/day were used by 25,373/81,802 (31.0%) of patients seen by a rheumatologist with low provider preference for glucocorticoids and by 36,087/81,801 (44.1%) of patients seen by a rheumatologist with high provider preference for glucocorticoids (adjusted odds ratio 1.81, 95% confidence interval 1.77, 1.84 for association between provider preference and glucocorticoids). Chronic obstructive pulmonary disease, opioids, antibiotics, previous emergency department visits, hospitalizations, and infections requiring hospitalization infections were unbalanced with regard to exposure but not to the IV. The incidence of infection requiring hospitalization was 8.0/100 person-years among patients unexposed to glucocorticoids versus 11.7/100 person-years among those exposed. The association between glucocorticoids and infection requiring hospitalization from IV analysis (hazard ratio 1.26 [1.02-1.56]) was similar to results from a standard multivariable model (hazard ratio 1.24 [1.21-1.28]). CONCLUSIONS: Among patients with RA on stable immunomodulatory therapy, IV analysis based on provider preference demonstrated an increased risk of infection requiring hospitalization associated with low-dose glucocorticoids, similar to a traditional analysis.

A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.