Research Spotlight

Posted April 15th 2017

Cell-Free DNA and Active Rejection in Kidney Allografts.

Bernard Fischbach M.D.

Bernard Fischbach M.D.

Bloom, R. D., J. S. Bromberg, E. D. Poggio, S. Bunnapradist, A. J. Langone, P. Sood, A. J. Matas, S. Mehta, R. B. Mannon, A. Sharfuddin, B. Fischbach, M. Narayanan, S. C. Jordan, D. Cohen, M. R. Weir, D. Hiller, P. Prasad, R. N. Woodward, M. Grskovic, J. J. Sninsky, J. P. Yee and D. C. Brennan (2017). “Cell-Free DNA and Active Rejection in Kidney Allografts.” J Am Soc Nephrol: 2017 Mar [Epub ahead of print].

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Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types >/=IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types >/=IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type >/=IB or ABMR) and levels >1% indicate a probability of active rejection.


Posted April 15th 2017

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Hughes, D. A., K. Nicholls, S. P. Shankar, G. Sunder-Plassmann, D. Koeller, K. Nedd, G. Vockley, T. Hamazaki, R. Lachmann, T. Ohashi, I. Olivotto, N. Sakai, P. Deegan, D. Dimmock, F. Eyskens, D. P. Germain, O. Goker-Alpan, E. Hachulla, A. Jovanovic, C. M. Lourenco, I. Narita, M. Thomas, W. R. Wilcox, D. G. Bichet, R. Schiffmann, E. Ludington, C. Viereck, J. Kirk, J. Yu, F. Johnson, P. Boudes, E. R. Benjamin, D. J. Lockhart, C. Barlow, N. Skuban, J. P. Castelli, J. Barth and U. Feldt-Rasmussen (2017). “Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in fabry disease: 18-month results from the randomised phase iii attract study.” J Med Genet 54(4): 288-296.

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BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in alpha-galactosidase (alpha-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of alpha-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of alpha-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.


Posted April 15th 2017

Hospital Readmissions after Surgery: How Important Are Hospital and Specialty Factors?

Laurel A. Copeland Ph.D.

Laurel A. Copeland Ph.D.

Hollis, R. H., L. A. Graham, J. S. Richman, M. S. Morris, H. J. Mull, T. S. Wahl, E. Burns, L. A. Copeland, G. L. Telford, A. K. Rosen, K. F. Itani, J. Whittle, T. H. Wagner and M. T. Hawn (2017). “Hospital readmissions after surgery: How important are hospital and specialty factors?” J Am Coll Surg 224(4): 515-523.

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BACKGROUND: Hospital readmission rates after surgery can represent an overall hospital effect or a combination of specialty and patient effects. We hypothesized that hospital readmission rates for procedures within specialties were more strongly correlated than rates across specialties within the same hospital. STUDY DESIGN: For general, orthopaedic, and vascular specialties at Veterans Affairs hospitals during 2008 to 2014, 30-day risk-adjusted readmission rates were estimated for 6 high-volume procedures and each specialty. Relationships were assessed using the Pearson correlation coefficient. RESULTS: At 84 hospitals, 64,724 orthopaedic, 24,963 general, and 10,399 vascular inpatient procedures were performed; mean readmission rates were 6.3%, 13.6%, and 16.4%, respectively. There was no correlation between specialty-specific adjusted hospital readmission rates: general and orthopaedic (r = 0.21; p = 0.06), general and vascular (r = 0.15; p = 0.19), and vascular and orthopaedic surgery (r = 0.07; p = 0.55). Within specialties, we found modest correlations between knee and hip arthroplasty readmission rates (r = 0.39; p < 0.01) and colectomy and ventral hernia repair (r = 0.24; p = 0.03), but not between lower-extremity bypass and endovascular aortic repair (r = 0.13; p = 0.26). Overall, controlling for patient-level factors, 1.9% of the variation in readmissions was attributable to specialty-level factors; only 0.6% was attributable to hospital-level factors. CONCLUSIONS: Hospital readmission rates for orthopaedic, vascular, and general surgery were not correlated between specialties; within each of the 3 specialties, modest correlations were found between 2 procedures within 2 of these specialties. These findings suggest that hospital surgical readmission rates are primarily explained by patient- and procedure-specific factors and less by broader specialty and/or hospital effects.


Posted April 15th 2017

Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial.

Priscilla A. Hollander M.D.

Priscilla A. Hollander M.D.

Hollander, P., H. E. Bays, J. Rosenstock, M. E. Frustaci, A. Fung, F. Vercruysse and N. Erondu (2017). “Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: A randomized clinical trial.” Diabetes Care: 2017 Mar [Epub ahead of print].

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OBJECTIVE: To assess the efficacy and safety of coadministration of canagliflozin (CANA) and phentermine (PHEN) compared with placebo (PBO) and CANA or PHEN monotherapies in individuals who were overweight and obese without type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, phase 2a, randomized, double-blind, PBO-controlled, multicenter, parallel-group study enrolled individuals who were obese or overweight without type 2 diabetes (N = 335, age 18-65 years, BMI >/=30 to <50 kg/m2 or BMI >/=27 to <50 kg/m2 with hypertension and/or dyslipidemia). Participants were randomized (1:1:1:1) to receive PBO, CANA 300 mg, PHEN 15 mg, or coadministration of CANA 300 mg and PHEN 15 mg (CANA/PHEN) orally once daily. The primary end point was percent change in body weight from baseline to week 26; key secondary end points were the proportion of participants achieving weight loss >/=5% and change from baseline in systolic blood pressure. RESULTS: CANA/PHEN provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference -6.9% [95% CI -8.6 to -5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss >/=5% and reduction in systolic blood pressure compared with PBO. CANA/PHEN was generally well tolerated, with a safety and tolerability profile consistent with that of the individual components. CONCLUSIONS: CANA/PHEN produced meaningful reductions in body weight and was generally well tolerated in individuals who were overweight or obese without type 2 diabetes. Further studies are warranted to evaluate potential use of this combination for long-term weight management.


Posted April 15th 2017

Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies.

J. Theodore Phillips M.D.

J. Theodore Phillips M.D.

Havrdova, E., G. Giovannoni, R. Gold, R. J. Fox, L. Kappos, J. T. Phillips, M. Okwuokenye and J. L. Marantz (2017). “Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: Integrated analysis of the phase iii define and confirm studies.” Eur J Neurol: 2017 Mar [Epub ahead of print].

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BACKGROUND AND PURPOSE: Significant effects on clinical/neuroradiological disease activity have been reported in patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate (DMF) in phase III DEFINE/CONFIRM trials. We conducted a post hoc analysis of integrated data from DEFINE/CONFIRM to evaluate the effect of DMF on achieving no evidence of disease activity (NEDA) in patients with relapsing-remitting multiple sclerosis. METHODS: The analysis included patients randomized to DMF 240 mg twice daily, placebo or glatiramer acetate (CONFIRM only) for