Research Spotlight

Wahl, T. S., L. A. Graham, M. S. Morris, J. S. Richman, R. H. Hollis, C. E. Jones, K. M. Itani, T. H. Wagner, H. J. Mull, J. C. Whittle, G. L. Telford, A. K. Rosen, L. A. Copeland, E. A. Burns and M. T. Hawn (2018). “Association Between Preoperative Proteinuria and Postoperative Acute Kidney Injury and Readmission.” JAMA Surg 153(9): e182009. [Epub ahead of print Sep 19].

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Importance: Proteinuria indicates renal dysfunction and is a risk factor for morbidity among medical patients, but less is understood among surgical populations. There is a paucity of studies investigating how preoperative proteinuria is associated with surgical outcomes, including postoperative acute kidney injury (AKI) and readmission. Objective: To assess preoperative urine protein levels as a biomarker for adverse surgical outcomes. Design, Setting, and Participants: A retrospective, population-based study was conducted in a cohort of patients with and without known preoperative renal dysfunction undergoing elective inpatient surgery performed at 119 Veterans Affairs facilities from October 1, 2007, to September 30, 2014. Data analysis was conducted from April 4 to December 1, 2016. Preoperative dialysis, septic, cardiac, ophthalmology, transplantation, and urologic cases were excluded. Exposures: Preoperative proteinuria as assessed by urinalysis using the closest value within 6 months of surgery: negative (0 mg/dL), trace (15-29 mg/dL), 1+ (30-100 mg/dL), 2+ (101-300 mg/dL), 3+ (301-1000 mg/dL), and 4+ (>1000 mg/dL). Main Outcomes and Measures: Primary outcome was postoperative predischarge AKI and 30-day postdischarge unplanned readmission. Secondary outcomes included any 30-day postoperative outcome. Results: Of 346676 surgeries, 153767 met inclusion criteria, with the majority including orthopedic (37%), general (29%), and vascular procedures (14%). Evidence of proteinuria was shown in 43.8% of the population (trace: 20.6%, 1+: 16.0%, 2+: 5.5%, 3+: 1.6%) with 20.4%, 14.9%, 4.3%, and 0.9%, respectively, of the patients having a normal preoperative estimated glomerular filtration rate (eGFR). In unadjusted analysis, preoperative proteinuria was significantly associated with postoperative AKI (negative: 8.6%, trace: 12%, 1+: 14.5%, 2+: 21.2%, 3+: 27.6%; P < .001) and readmission (9.3%, 11.3%, 13.3%, 15.8%, 17.5%, respectively, P < .001). After adjustment, preoperative proteinuria was associated with postoperative AKI in a dose-dependent relationship (trace: odds ratio [OR], 1.2; 95% CI, 1.1-1.3, to 3+: OR, 2.0; 95% CI, 1.8-2.2) and 30-day unplanned readmission (trace: OR, 1.0; 95% CI, 1.0-1.1, to 3+: OR, 1.3; 95% CI, 1.1-1.4). Preoperative proteinuria was associated with AKI independent of eGFR. Conclusions and Relevance: Proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative eGFR. Simple urine assessment for proteinuria may identify patients at higher risk of AKI and readmission to guide perioperative management.

Zhang, Q., A. T. Agoston, T. H. Pham, W. Zhang, X. Zhang, X. Huo, S. Peng, M. Bajpai, K. Das, R. D. Odze, S. J. Spechler and R. F. Souza (2018). “Acidic Bile Salts Induce Epithelial to Mesenchymal Transition via VEGF Signaling in Non-Neoplastic Barrett’s Cells.” Gastroenterology Sep 27. [Epub ahead of print].

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BACKGROUND & AIMS: Metaplastic glands buried under squamous epithelium are frequently detected in patients with Barrett’s esophagus (BE). This sub-squamous intestinal metaplasia (SSIM) might be responsible for cancers that develop despite endoscopic surveillance, and for metaplasia recurrences after endoscopic ablation. To determine whether reflux induces BE cells to undergo epithelial to mesenchymal transition (EMT) that produces SSIM, we assessed EMT in BE cells exposed to acidic bile salts, and in rat and human esophageal tissues. METHODS: We compared markers of EMT and cell motility in transwell and 3-dimensional organotypic culture systems among dysplastic BE epithelial cell lines, nondysplastic telomerase-immortalized BE cell lines (BAR-T), and BAR-T cells exposed acutely or for 20 weeks (BEC-20W) to acidic bile salts. VEGFA was inhibited with a neutralizing antibody or CRISPR-Cas9n and VEGFR2 was inhibited with SU1498 or shRNA, and cells were analyzed by immunohistochemistry, quantitative PCR, or immunoblotting for markers of VEGF signaling and EMT; cell motility was assessed by transwell. We used immunohistochemistry and quantitative PCR to assess EMT markers in the columnar-lined esophagus of rats with surgically induced reflux esophagitis and in esophagectomy specimens from patients with BE. RESULTS: We detected features of EMT (decreased cadherin 1 [CDH1]; increased fibronectin 1, vimentin, and MMP2; and increased motility) in dysplastic BE epithelial cell lines and in BEC-20W cells, but not in unexposed BAR-T cells. Acute acidic bile salt exposure induced expression of the zinc finger E-box binding homeobox 1/2 (ZEB1/2) in BAR-T cells, which reduced their expression of CDH1 and increased motility; inhibitors of VEGF signaling blocked these effects. Columnar-lined esophagus of rats with reflux esophagitis had increased expression of ZEB1/2 and decreased expression of CDH1 compared with controls. Dysplastic BE tissues also had significantly increased levels of ZEB1 and significantly decreased levels of CDH1 compared with non-dysplastic BE tissues. CONCLUSIONS: In BE cell lines, acidic bile salts induce EMT via VEGF signaling, which increases expression of ZEB1/2, repressors of CDH1. These observations suggest that reflux induces EMT in metaplastic BE tissues, which promotes development of SSIM.

Yarlagadda, B., T. Deneke, M. Turagam, T. Dar, S. Paleti, V. Parikh, L. DiBiase, P. Halfbass, P. Santangeli, S. Mahapatra, J. Cheng, A. Russo, J. Edgerton, M. Mansour, J. Ruskin, S. Dukkipati, D. Wilber, V. Reddy, D. Packer, A. Natale and D. Lakkireddy (2018). “Temporal Relationships between Esophageal Injury Type and Progression in Patients Undergoing Atrial Fibrillation Catheter Ablation.” Heart Rhythm Sep 28. [Epub ahead of print].

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BACKGROUND: Currently very little is known about the onset, natural progression and management of esophageal injuries after atrial fibrillation (AF) ablation. OBJECTIVES: We sought to provide a systematic review on esophageal injury after AF ablation and identify temporal relationships between various types of esophageal lesions, their progression and outcomes. METHODS: A comprehensive search of PubMed and Web of science was conducted until September 21st, 2017. All AF ablation patients who underwent upper gastro-intestinal endoscopy within 1 week of the procedure were included. Patients with esophageal lesions were reclassified into 3 types using our novel Kansas City Classification. (Type 1: Erythema; Type 2a: Superficial ulcers; Type 2b: Deep ulcers; Type 3a: perforation without communication with the atria; Type 3b: perforation with Atrio-esophageal fistula). RESULTS: Thirty studies met our inclusion criteria. Of the 4,473 patients, 3921 underwent upper GI evaluation. The overall incidence of esophageal injuries was 15%. There were 206 (36%) type 1, 222 (39%) type 2a and 142 (25 %) type 2b lesions. Six type 2b lesions (6/142, 4.2%) progressed further to type 3, of which, 5 were type 3a and 1 was type 3b. All type 1, type 2a and most type 2b lesions resolved with conservative management. One type 3a and one 3b lesions were fatal. CONCLUSION: Based on our classification, all type 1 and most type 2 lesions resolved with conservative management. A small percentage (6/142, 4.2%) of type 2b lesions progressed to perforation and/or fistula formation and these patients need to be followed closely.

Villarreal, R., B. B. Wrobel, L. F. Macias-Valle, G. E. Davis, T. J. Prihoda, A. U. Luong, K. C. McMains, E. K. Weitzel, W. C. Yao, J. Brunworth, D. W. Clark, S. Nair, C. J. Valdes, A. Halderman, D. W. Jang, R. Sivasubramaniam, Z. Zhang and P. G. Chen (2018). “International assessment of inter- and intrarater reliability of the International Frontal Sinus Anatomy Classification system.” Int Forum Allergy Rhinol Sep 14. [Epub ahead of print].

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BACKGROUND: Inconsistencies in the nomenclature of structures of the frontal sinus have impeded the development of a validated “reference standard” classification system that surgeons can reliably agree upon. The International Frontal Sinus Anatomy Classification (IFAC) system was developed as a consensus document, based on expert opinion, attempting to address this issue. The purposes of this study are to: establish the reliability of the IFAC as a tool for classifying cells in the frontal recess among an international group of rhinologists; and improve communication and teaching of frontal endoscopic sinus surgery (ESS). METHODS: Forty-two computed tomography (CT) scans, each with a marked frontal cell, were reviewed by 15 international fellowship-trained rhinologists. Each marked cell was classified into 1 of 7 categories described in the IFAC, on 2 occasions separated by 2 weeks. Inter- and intrarater reliability were evaluated using Light’s kappa (kappa), the interclass correlation coefficient (ICC), and simple proportion of agreement. RESULTS: Interrater reliability showed pairwise kappa values ranging from 0.7248 to 1.0, with a mean of 0.9162 (SD, 0.0537). The ICC was 0.98. Intrarater reliability showed kappa values ranging from 0.8613 to 1.0, with a mean of 0.9407 (SD, 0.0376). The within-rater ICC was 0.98. CONCLUSION: Among a diverse sample of rhinologists (raters), there was substantial to almost perfect agreement between raters, and among individual raters at different timepoints. The IFAC is a reliable tool for classification of cells in the frontal sinus. Further outcome studies are still needed to determine the validity of the IFAC.

Tolia, V. N., K. Murthy, M. M. Bennett, R. G. Greenberg, D. K. Benjamin, P. B. Smith and R. H. Clark (2018). “Morphine vs Methadone Treatment for Infants with Neonatal Abstinence Syndrome.” J Pediatr Sep 14. [Epub ahead of print].

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OBJECTIVE: To estimate the relationship of initial pharmacotherapy with methadone or morphine and length of stay (LOS) in infants with neonatal abstinence syndrome (NAS) admitted to the neonatal intensive care unit (NICU). STUDY DESIGN: From the Pediatrix Clinical Data Warehouse database, we identified all infants born at >/=36 weeks of gestation between 2011 and 2015 who were diagnosed with NAS (International Classification of Diseases, Ninth Revision code 779.5) and treated with methadone or morphine in the first 7 days of life. We used multivariable Cox proportional hazards regression analysis to quantify the association between initial treatment and LOS after adjusting for maternal age, maternal race/ethnicity, maternal drug use, maternal smoking, gestational age, small for gestational age status, inborn status, and discharge year. RESULTS: We identified a total of 7667 eligible infants, including 1187 treated with methadone (15%) and 6480 treated with morphine (85%). Birth weight, gestational age, and sex were similar in the 2 groups. Methadone treatment was associated with a 22% shorter median LOS (18 days [IQR, 11-30 days] vs 23 days [IQR, 16-33]; P < .001) and a 19% shorter median NICU stay (17 days [IQR, 10-29 days] vs 21 days [IQR, 14-36 days]; P < .001). After adjustment, methadone was associated with a shorter LOS (hazard ratio for discharge, 1.24; 95% CI, 1.11-1.37; P < .001) CONCLUSION: Among infants born at >/=36 weeks of gestation with NAS, initial methadone treatment was associated with a shorter LOS compared with morphine treatment. Future prospective comparative effectiveness trials to treat infants with NAS are needed to verify this observation.