Research Spotlight

O’Leary, J.G., Philippe, A., Freeman, R., Heidecke, H., Jennings, L.W., Catar, R., Klintmalm, G.B. and Dragun, D. (2021). “Non-HLA Autoantibodies at 1 Year Negatively Affect 5-Year Native Renal Function in Liver Transplant Recipients.” Transplant Proc 53(3): 1019-1024.

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BACKGROUND: Angiotensin II type-1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) autoantibodies, in addition to allograft injury, can bind native endothelial cells and cause vascular vasoconstriction and fibrosis progression in nontransplanted organs. Therefore, we investigated long-term native renal function in liver transplant (LT) recipients with and without anti-AT(1)R-Abs and/or anti-ET(A)R-Abs present in serum. METHODS: Primary LT recipients at our single center from January 2000 to April 2009 had their prospectively collected pre-LT (1269 patients) and year 1 post-LT (795 patients) serum tested retrospectively for anti-AT(1)R-Abs and/or anti-ET(A)R-Abs. Anti-AT(1)R-Abs and anti-ET(A)R-Abs testing was accomplished with a standardized solid phase assay in which >10 U was considered positive. RESULTS: Pretransplant anti-AT(1)R-Abs and/or anti-ET(A)R-Abs did not change the median delta creatinine from pretransplant to 1 year post-transplant. In multivariable analysis controlling for diabetes (DM) and calcineurin inhibitor (CNI) use, anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at 1-year remained statistically significantly associated with a decline in GFR (measured by Modification of Diet in Renal Disease-6) from years 1-5 post-LT (P = .04). In diabetic patients the association with a decline in renal function was more pronounced with (-9.29 mL/min) vs without (-2.28 mL/min) anti-AT(1)R-Abs and/or anti-ET(A)R-Abs at year 1, respectively (P = .004). CONCLUSION: At 1-year post-LT, the autoantibodies anti-AT(1)R-Abs and/or anti-ET(A)R-Abs are associated in multivariable analysis with an increased risk of native renal function decline especially in diabetic patients.

Nazif, T.M., Moses, J., Sharma, R., Dhoble, A., Rovin, J., Brown, D., Horwitz, P., Makkar, R., Stoler, R., Forrest, J., Messé, S., Dickerman, S., Brennan, J., Zivadinov, R., Dwyer, M.G. and Lansky, A.J. (2021). “Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.” JACC Cardiovasc Interv 14(5): 515-527.

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OBJECTIVES: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. BACKGROUND: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. METHODS: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method. RESULTS: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm(3) (-9.7%) and >1,000 mm(3) (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm(3)) and -82.9% (>1,000 mm(3)). CONCLUSIONS: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.

Nathani, A., Ghamande, S., Sanchez, J.F. and White, H.D. (2021). “Subclavian artery aneurysm: a rare cause of massive haemoptysis.” BMJ Case Rep 14(3).

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A 35-year-old man was admitted to the intensive care unit with massive haemoptysis. CT of the chest revealed a necrotic right upper lobe mass. Angiography of his thoracic vasculature revealed a pseudoaneurysm in the right subclavian artery with active contrast extravasation. This anatomic deformity was stented and coiled with the assistance of interventional radiology. Bronchoscopy with lavage and brushings of the right upper lobe mass revealed fungal hyphae and positive galactomannan, supporting that the patient developed invasive pulmonary aspergillosis leading to a mycotic pseudoaneurysm of the right subclavian artery followed by massive haemoptysis.

Moreno-Martinez, D., Aguiar, P., Auray-Blais, C., Beck, M., Bichet, D.G., Burlina, A., Cole, D., Elliott, P., Feldt-Rasmussen, U., Feriozzi, S., Fletcher, J., Giugliani, R., Jovanovic, A., Kampmann, C., Langeveld, M., Lidove, O., Linhart, A., Mauer, M., Moon, J.C., Muir, A., Nowak, A., Oliveira, J.P., Ortiz, A., Pintos-Morell, G., Politei, J., Rozenfeld, P., Schiffmann, R., Svarstad, E., Talbot, A.S., Thomas, M., Tøndel, C., Warnock, D., West, M.L. and Hughes, D.A. (2021). “Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.” Mol Genet Metab 132(4): 234-243.

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BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Moore, A.Y., Nguyen, M. and Moore, S. (2021). “Cyclic calcipotriene 0.005% foam and 1% 5-fluorouracil cream after cryotherapy in treatment of hyperkeratotic actinic keratosis: A retrospective study.” J Am Acad Dermatol 84(4): 1148-1150.

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Traditional treatments for actinic keratoses include cryotherapy, 5-fluorouracil cream, imiquimod, diclofenac, ingenol mebutate gel, and photodynamic therapy.1,2 Recent research suggests topical vitamin D3 as possibly efficacious by mounting a robust antitumor immunoresponse via T-cell recruitment.3 We hypothesized that these treatments may be synergistic and that vitamin D3 would enhance the efficacy of 5-fluorouracil cream in hyperkeratotic actinic keratoses treatment after cryotherapy. [No abstract; excerpt from article]