Research Spotlight

Zhang, J., M. K. Fallahzadeh and P. A. McCullough (2016). “Aging male spontaneously hypertensive rat as an animal model for the evaluation of the interplay between contrast-induced acute kidney injury and cardiorenal syndrome in humans.” Cardiorenal Med 7(1): 1-10.

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BACKGROUND: Although there are some animal models for biomarkers of contrast-induced acute kidney injury (CI-AKI), for cardiorenal syndrome (CRS) and for acute renal failure, the interplay between CI-AKI and CRS has yet to be evaluated. Insight into the pathogenesis of CRS is urgently needed from animal models in order to foster the discovery and implementation of novel biomarkers for this disease. Specially designed animal models for type 1 and 3 CRS, particularly CI-AKI, have not yet emerged. SUMMARY: We hypothesize that the aging male spontaneously hypertensive rat (SHR) is likely to be a suitable model. The SHR model is able to mimic risk factors for preclinical CRS that appears in the clinical setting, specifically hypertension, age, preexisting damage and dysfunction of the heart and kidney, endothelial dysfunction, increased level of reactive oxygen species, decreased level and bioavailability of nitric oxide (NO), impairment of the L-arginine-NO pathway, and insulin resistance. In the SHR, CI-AKI results in a different profile of AKI biomarkers than is seen with preexisting chronic kidney injury. KEY MESSAGES: The SHR model can be used to evaluate the interaction between CI-AKI and CRS type 1 and 3 and to verify neutrophil gelatinase-associated lipocalin (NGAL) as a reliable CI-AKI biomarker for clinical application. Further research is warranted with a large number of aging male SHRs to prove NGAL as a sensitive, specific, highly predictive, early biomarker for CI-AKI.

Packer, M. (2016). “Angiotensin neprilysin inhibition for patients with heart failure: What if sacubitril/valsartan were a treatment for cancer?” JAMA Cardiol.

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Oncologists would adopt the new drug as the standard of care in a heartbeat, but US physicians who treat patients with heart failure often do little. Heart failure is a fatal disorder, and current drugs achieve only a brief clinical remission. Twoyears ago, sacubitril/valsartanwas shown to be superior to a conventional inhibitor of the renin-angiotensin system in reducing the risk of cardiovascular death,1 and it received expedited US Food and Drug Administration approval for treatment of chronic heart failure. Owing to cost, third-party payors discouraged the use of the drug by requiring high patient copays and administrative preapprovals. Oncologists are accustomed to overcoming these distractions, but other physicians are not. Consequently, uptake of sacubitril/ valsartan by US practitioners has been slow.

Morris, M. S., L. A. Graham, J. S. Richman, R. H. Hollis, C. E. Jones, T. Wahl, K. M. Itani, H. J. Mull, A. K. Rosen, L. Copeland, E. Burns, G. Telford, J. Whittle, M. Wilson, S. J. Knight and M. T. Hawn (2016). “Postoperative 30-day readmission: Time to focus on what happens outside the hospital.” Ann Surg 264(4): 621-631.

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OBJECTIVE: The aim of this study is to understand the relative contribution of preoperative patient factors, operative characteristics, and postoperative hospital course on 30-day postoperative readmissions. BACKGROUND: Determining the risk of readmission after surgery is difficult. Understanding the most important contributing factors is important to improving prediction of and reducing postoperative readmission risk. METHODS: National Veterans Affairs Surgical Quality Improvement Program data on inpatient general, vascular, and orthopedic surgery from 2008 to 2014 were merged with laboratory, vital signs, prior healthcare utilization, and postoperative complications data. Variables were categorized as preoperative, operative, postoperative/predischarge, and postdischarge. Logistic models predicting 30-day readmission were compared using adjusted R and c-statistics with cross-validation to estimate predictive discrimination. RESULTS: Our study sample included 237,441 surgeries: 43% orthopedic, 39% general, and 18% vascular. Overall 30-day unplanned readmission rate was 11.1%, differing by surgical specialty (vascular 15.4%, general 12.9%, and orthopedic 7.6%, P < 0.001). Most common readmission reasons were wound complications (30.7%), gastrointestinal (16.1%), bleeding (4.9%), and fluid/electrolyte (7.5%) complications. Models using information available at the time of discharge explained 10.4% of the variability in readmissions. Of these, preoperative patient-level factors contributed the most to predictive models (R 7.0% [c-statistic 0.67]); prediction was improved by inclusion of intraoperative (R 9.0%, c-statistic 0.69) and postoperative variables (R 10.4%, c-statistic 0.71). Including postdischarge complications improved predictive ability, explaining 19.6% of the variation (R 19.6%, c-statistic 0.76). CONCLUSIONS: Postoperative readmissions are difficult to predict at the time of discharge, and of information available at that time, preoperative factors are the most important.

Sapisochin, G., M. Facciuto, L. Rubbia-Brandt, J. Marti, N. Mehta, F. Y. Yao, E. Vibert, D. Cherqui, D. R. Grant, R. Hernandez-Alejandro, C. H. Dale, A. Cucchetti, A. Pinna, S. Hwang, S. G. Lee, V. G. Agopian, R. W. Busuttil, S. Rizvi, J. K. Heimbach, M. Montenovo, J. Reyes, M. Cesaretti, O. Soubrane, T. Reichman, J. Seal, P. T. Kim, G. Klintmalm, C. Sposito, V. Mazzaferro, P. Dutkowski, P. A. Clavien, C. Toso, P. Majno, N. Kneteman, C. Saunders and J. Bruix (2016). “Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.” Hepatology 64(4): 1178-1188.

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The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very early” iCCA (single tumors 2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results.

Packer, M. (2016). “Data sharing: Lessons from copernicus and kepler.” Bmj 354: i4911.

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To understand the workings of science, pick up a copy of De Revolutionibus Orbium Coelestium. Published with great reluctance by the astronomer Nicolaus Copernicus in 1543, the book puts forth a compelling argument for a heliocentric universe. Turn the pages and you will see the book is filled with data. Whose data? Copernicus relied on the data collected by others in addition to his own to formulate his revolutionary theory. Publication of these data subsequently allowed Johannes Kepler to identify discrepancies, which led to his innovative proposal in 1605 that the planets moved in an ellipse (rather than in a circle), an idea that he had previously assumed to be too simple for earlier astronomers to have overlooked. Of course, Kepler presented his data at the same time that he published his conclusions. In contrast, Tycho Brahe (who opposed Copernicus) famously withheld his astronomical data from Kepler because he knew they could be used to confirm Copernicus’s heliocentric model.