Publications by authors named "Mark A Hardy"

89 Publications

Manifestation of Nonuremic Calciphylaxis in the Extremities: Case Report and Review.

J Foot Ankle Surg 2021 Oct 27. Epub 2021 Oct 27.

Kent State University College of Podiatric Medicine, Independence, OH.

Nonuremic calciphylaxis is a rare condition presenting with peripheral ischemic ulcerations. Calciphylaxis is the deposition of calcium and phosphate into arteriolar walls caused by exceeding their solubility range in the blood. It is most commonly seen in patients with end-stage renal disease; however, nonuremic calciphylaxis occurs in patients with normal or mildly impaired renal function. Risk factors for nonuremic calciphylaxis include Coumadin therapy, obesity, and diabetes mellitus. Histopathologic examination of deep skin biopsy containing subcutaneous adipose tissue reveals medial calcification of dermal and subcutaneous arterioles. This diagnosis must be managed locally with wound care and systemically by control of blood calcium solubility. Avoidance of infection is critical to survival. Here we report a case of calciphylaxis in a patient with normal renal function and serum levels of calcium and phosphorus who presented with gangrene of the extremities. Increased awareness of this debilitating disease will lead to earlier diagnosis, proper treatment and improved patient outcomes.
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http://dx.doi.org/10.1053/j.jfas.2021.10.024DOI Listing
October 2021

Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting.

J Clin Med 2021 Jun 29;10(13). Epub 2021 Jun 29.

Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, FL 33136, USA.

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.
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http://dx.doi.org/10.3390/jcm10132878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269003PMC
June 2021

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

Mod Pathol 2021 09 13;34(9):1795-1805. Epub 2021 May 13.

Surgery, Division of Transplantation, Columbia University Irving Medical Center, New York, NY, USA.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.
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http://dx.doi.org/10.1038/s41379-021-00815-9DOI Listing
September 2021

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Am J Transplant 2021 04 10;21(4):1365-1375. Epub 2021 Feb 10.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.
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http://dx.doi.org/10.1111/ajt.16397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016716PMC
April 2021

Authors' Reply to Letter to the Editor.

J Foot Ankle Surg 2020 May - Jun;59(3):645

Division Head and Associate Professor, Division of Foot & Ankle Surgery/Biomechanics, Kent State University College of Podiatric Medicine, Independence, OH.

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http://dx.doi.org/10.1053/j.jfas.2019.09.020DOI Listing
July 2020

Acute Deltoid Ligament Repair in Ankle Fractures: Five-year Follow-up.

Clin Podiatr Med Surg 2020 Apr 3;37(2):295-304. Epub 2020 Feb 3.

Private Practice, Orange County Foot and Ankle Surgeon, 16405 Sand Canyon Avenue, Suite 270, Irvine, CA 92618, USA.

Direct repair of deep deltoid ruptures after traumatic ankle fracture is not commonly performed. Previous studies overlook the contributions of the medial deltoid to overall ankle stability and long-term patient satisfaction. Historically, deep deltoid injuries have been addressed indirectly through syndesmotic ligament repair. This technique fails to restore, however, the anatomic function of the primary medial stabilizing structure. The oversight of direct deltoid repair may be one contributing factor to the less than optimal outcomes after ankle fractures with syndesmotic injuries. This article reports a positive response with direct deep deltoid repair, at average 5-year follow-up, with 93% positive return to normal function.
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http://dx.doi.org/10.1016/j.cpm.2019.12.004DOI Listing
April 2020

Intrinsic Fixation of the Tibial Sesamoid in First Metatarsophalangeal Joint Arthrodesis: A Cadaveric Study.

Clin Podiatr Med Surg 2020 Apr 31;37(2):287-293. Epub 2020 Jan 31.

Division of Surgery and Biomechanics, Kent State University College of Podiatric Medicine, 6000 Rockside Woods Boulevard, Independence, OH 44131, USA.

Nonunion rate of first metatarsophalangeal joint (MTP) joint arthrodesis is reportedly less than 6%, regardless of fixation type. Robust modern plating constructs aim to decrease incidence of nonunion while also allowing early postoperative weight-bearing. Quicker transition to weight-bearing postoperatively increases patient adherence, decreases adjacent joint stiffness, and reduces risk of deep vein thrombosis in the postoperative period. The purpose of this study was to investigate the effect tibial sesamoid fixation has on first MTP joint arthrodesis.
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http://dx.doi.org/10.1016/j.cpm.2019.12.003DOI Listing
April 2020

Ultra-low-contrast angiography in patients with advanced chronic kidney disease and previous coronary artery bypass surgery.

Coron Artery Dis 2019 08;30(5):346-351

Center for Interventional Vascular Therapy, Division of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center.

Objective: We sought to describe a technique for ultra-low-contrast angiography (ULCA) in patients with advanced chronic kidney disease (CKD) and previous coronary artery bypass surgery (CABG).

Background: Patients with advanced CKD and previous CABG are at high risk of developing contrast-induced nephropathy (CIN) because of the additional contrast often required to identify bypass grafts. Apart from hydration, reduced contrast administration is the only established method to minimize the risk of CIN.

Patients And Methods: Ten patients underwent ULCA, whereby an intracoronary injection of saline and coronary guidewires were used instead of test injections of contrast for engagement of bypass grafts with catheters. Estimated glomerular filtration rate (eGFR) before and 30 days following angiography were recorded as was the need for renal replacement therapy 1 year after the procedure.

Results: All patients completed a diagnostic angiogram without complications. The median volume of contrast delivered was 13.5 ml (interquartile range: 10.5-17.8). The median eGFR was 18.3 ml/min/1.73 m (interquartile range: 16.5-28.2). There was no statistically significant difference in eGFR before the procedure and 30 days after the procedure (P=0.79). No patient required dialysis 30 days after the procedure. Two patients required initiation of dialysis at 1 year after the procedure.

Conclusion: In patients with advanced CKD and previous CABG, ULCA may be performed with high procedural success and without complications, minimizing the risk of CIN in these high-risk patients.
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http://dx.doi.org/10.1097/MCA.0000000000000741DOI Listing
August 2019

Charcot Pathogenesis: A Study of In Vivo Gene Expression.

J Foot Ankle Surg 2018 Nov - Dec;57(6):1067-1072

Assistant Professor, Exercise Physiology, Kent State University, Kent, OH.

Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.
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http://dx.doi.org/10.1053/j.jfas.2018.03.023DOI Listing
February 2019

State of the Art: Role of the Dendritic Cell in Induction of Allograft Tolerance.

Transplantation 2018 10;102(10):1603-1613

Department of Surgery, Columbia University Medical Center, New York, NY.

Despite decades of research, the induction and maintenance of long-term allograft tolerance without immunosuppression remains an elusive goal in the field of solid organ and cell transplantation. Immunosuppressive medications frequently prevent or minimize acute cellular rejection but have failed to halt antidonor antibody production and chronic organ rejection. Past efforts aimed at promoting lasting allograft tolerance have focused primarily on peripheral T-cell depletion, augmentation of regulatory T cells, or induction via simultaneous hematopoietic stem cell transplantation and facilitation of donor chimerism. So far, none of these methods have led to consistently safe, feasible and long lasting donor organ acceptance. Over the course of the past 4 decades, the study of a unique population of antigen-presenting cells known as dendritic cells has shown promise for breaking new ground in achieving indefinite allograft survival without immunosuppression and its associated adverse effects. In this review, we discuss the discovery and early investigations of dendritic cells and chronicle some of the key studies demonstrating their role in transplantation, particularly in indirect allorecognition, the immunologic pathway thought to drive chronic rejection and perhaps tolerance induction.
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http://dx.doi.org/10.1097/TP.0000000000002239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153030PMC
October 2018

The Use of Pediatric Flexible Intramedullary Nails for Minimally Invasive Fibular Fracture Fixation.

J Foot Ankle Surg 2018 Jul - Aug;57(4):844-849. Epub 2018 Apr 13.

Attending, Private Practice, Orange County Foot and Ankle Surgeon, Irvine, CA.

Fibular fractures in the setting of an unstable ankle joint require surgical fixation; however, several factors contradict open surgical correction. Severe soft tissue compromise can delay adequate fracture reduction and preclude the standard incisional approach. The soft tissue envelope in the setting of obesity, diabetes, and/or peripheral vascular disease further complicates definitive treatment. Poorly timed open fixation can lead to delayed healing of the incision site, with wound breakdown and the potential for hardware failure. Proximal fibular fractures are also at unique risk of neurovascular compromise with open reduction and internal fixation. Surgical fixation has now focused on minimizing the soft tissue insult using percutaneous techniques in the comorbid patient. We present a case that highlights a minimally invasive technique that provides dynamic stable internal fixation of fibular fractures with the use of flexible pediatric intramedullary nails, typically used in long bone fractures of children.
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http://dx.doi.org/10.1053/j.jfas.2017.11.024DOI Listing
December 2018

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes.

Kidney Int 2018 05 13;93(5):1227-1239. Epub 2018 Mar 13.

Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.
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http://dx.doi.org/10.1016/j.kint.2017.12.015DOI Listing
May 2018

RGDfK-Peptide Modified Alginate Scaffold for Cell Transplantation and Cardiac Neovascularization.

Tissue Eng Part A 2018 05 13;24(9-10):740-751. Epub 2017 Nov 13.

1 Department of Surgery, Columbia University Medical Center , New York, New York.

Cell implantation for tissue repair is a promising new therapeutic strategy. Although direct injection of cells into tissue is appealing, cell viability and retention are not very good. Cell engraftment and survival following implantation are dependent on a sufficient supply of oxygen and nutrients through functional microcirculation as well as a suitable local microenvironment for implanted cells. In this study, we describe the development of a porous, biocompatible, three-dimensional (3D) alginate scaffold covalently modified with the synthetic cyclic RGDfK (Arg-Gly-Asp-D-Phe-Lys) peptide. Cyclic RGDfK peptide is protease resistant, highly stable in aqueous solutions, and has high affinity for cellular integrins. Cyclic RGDfK-modified alginate scaffolds were generated using a novel silicone sheet sandwich technique in combination with freeze-gelation, resulting in highly porous nonimmunogenic scaffolds that promoted both human and rodent cell survival in vitro, and neoangiogenesis in vivo. Two months following implantation in abdominal rectus muscles in rats, cyclic RGDfK-modified scaffolds were fully populated by host cells, especially microvasculature without an overt immune response or fibrosis, whereas unmodified control scaffolds did not show cell ingrowth. Importantly, modified scaffolds that were seeded with human mesenchymal precursor cells and were patched to the epicardial surface of infarcted myocardium induced myocardial neoangiogenesis and significantly improved cardiac function. In summary, purified cyclic RGDfK peptide-modified 3D alginate scaffolds are biocompatible and nonimmunogenic, enhance cell viability, promote angiogenesis, and may be used as a means to deliver cells to myocardial infarct areas to improve neovascularization and cardiac function.
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http://dx.doi.org/10.1089/ten.TEA.2017.0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963542PMC
May 2018

The immunologic considerations in human head transplantation.

Int J Surg 2017 May 24;41:196-202. Epub 2017 Jan 24.

Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe-University, Friedrichsheim Orthopedic Hospital, Haus 97 B, 1OG, Marienburgstr. 2, 60528, Germany Frankfurt/Main, Germany. Electronic address:

The idea of head transplantation appears at first as unrealistic, unethical, and futile. Here we discuss immunological considerations in human head transplantation. In a separate accompanying article we discuss surgical, ethical, and psychosocial issues concerned in body-to-head transplantation (BHT) [1]. The success of such an unusual allograft, where the donor and the recipient can reject each other, depends on prevention of complex immunologic reactions, especially rejection of the head by the body (graft-vs-host) or probably less likely, the possibility of the head rejecting the total body allograft (host-vs-graft). The technical and immunologic difficulties are enormous, especially since rapid nerve and cord connections and regeneration have not yet been possible to achieve. In this article we begin by briefly reviewing neuro-immunologic issues that may favor BHT such as the blood brain barrier (BBB) and point out its shortcomings. And we touch on the cellular and humoral elements in the brain proper that differ in some respects from those in other organs and in the periphery. Based on recent successes in vascular composite allografts (VCAs), we will elaborate on potential specific advantages and difficulties in BHT of various available immunosuppressive medications already utilized in VCAs. The risk/benefit ratio of these drugs will be emphasized in relation to direct brain toxicity such as seizure disorders, interference, or promotion of nerve regeneration, and potentiation of cerebral viral infections. The final portion of this article will focus on pre-transplant immunologic manipulation of the deceased donor body along with pretreatment of the recipient.
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http://dx.doi.org/10.1016/j.ijsu.2017.01.084DOI Listing
May 2017

Surgical, ethical, and psychosocial considerations in human head transplantation.

Int J Surg 2017 May 19;41:190-195. Epub 2017 Jan 19.

Frankfurt Initiative for Regenerative Medicine, Experimental Orthopedics & Trauma Surgery, J.W. Goethe-University, Friedrichsheim Orthopedic Hospital, Haus 97 B, 1OG, Marienburgstr. 2, 60528, Frankfurt/Main, Germany. Electronic address:

Transplanting a head and brain is perhaps the final frontier of organ transplantation. The goal of body-to-head transplantation (BHT) is to sustain the life of individuals who suffer from terminal disease, but whose head and brain are healthy. Ideally BHT could provide a lifesaving treatment for several conditions where none currently exists. BHT is no ordinary experiment, to transfer a head to another body involves extraordinarily complex medical challenges as well as ethical and existential dilemmas that were previously confined to the imagination of writers of fiction. The possibility of replacing an incurably ill body with a healthy one tests not only our surgical limits, but also the social and psychological boundaries of physical life and alters what we recognize life to be. The purpose of this target article, the complementary manuscript focused on immunological issues in BHT, and the accompanying Commentaries by scholars and practitioners in medicine, immunology, and bioethics is to review major surgical and psychosocial-ethical and immunological considerations surrounding body-to-head transplantation. We hope that together these ideas will provide readers with a comprehensive overview of the possibilities and challenges associated with BHT and initiate professional discussion and debate through which this new frontier in medicine is considered and approached.
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http://dx.doi.org/10.1016/j.ijsu.2017.01.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490488PMC
May 2017

Direct oral anticoagulant considerations in solid organ transplantation: A review.

Clin Transplant 2017 01 28;31(1). Epub 2016 Dec 28.

Department of Pharmacy, Hackensack University Medical Center, Hackensack, NJ, USA.

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter- and intrapatient variability, much shorter half-lives, and less known drug-drug and drug-food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug-drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.
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http://dx.doi.org/10.1111/ctr.12873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490493PMC
January 2017

Imaging- and physiology-guided percutaneous coronary intervention without contrast administration in advanced renal failure: a feasibility, safety, and outcome study.

Eur Heart J 2016 Oct 7;37(40):3090-3095. Epub 2016 Mar 7.

Division of Cardiology, Center for Interventional Vascular Therapy, New York Presbyterian Hospital and Columbia University, New York, NY, USA.

Aims: The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown. In this series, we investigated a specific strategy for 'zero contrast' PCI with the aims of preserving renal function and preventing the need for renal replacement therapy (RRT) in patients with advanced CKD.

Methods And Results: A total of 31 patients with advanced CKD [creatinine = 4.2 mg/dL, inter-quartile range (IQR) 3.1-4.8, estimated glomerular filtration rate = 16 ± 8 mL/min/1.73 m] who had clinical indication for PCI based on a prior minimal contrast coronary angiogram were included. Zero contrast PCI was performed at least 1 week after diagnostic angiography using real-time intravascular ultrasound (IVUS) guidance, with pre- and post-PCI measurements of fractional flow reserve and coronary flow reserve to confirm physiological improvement. This approach resulted in successful PCI, no major adverse cardiovascular events and preservation of renal function without the need for RRT within a follow-up time of 79 days (IQR 33-207) in all patients.

Conclusion: In patients with advanced CKD who require revascularization, PCI may safely be performed without contrast using IVUS and physiological guidance with high procedural success and without complications.
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http://dx.doi.org/10.1093/eurheartj/ehw078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279210PMC
October 2016

Irreducible Ankle Fracture Dislocation Due to Tibialis Posterior Tendon Interposition: A Case Report.

J Foot Ankle Surg 2016 Nov - Dec;55(6):1276-1281. Epub 2015 Aug 1.

Foot and Ankle Surgery, Mercy Health, Cleveland, OH.

Traumatic ankle fractures and dislocations that fail closed reduction present a challenging set of circumstances that can potentially lead to unnecessary complications and require surgical intervention. Interposition of adjacent tendons occurs rarely and can obstruct the anatomic realignment. Because of the potential for neurovascular compromise and possible skin tension necrosis, an irreducible fracture dislocation must be addressed with open reduction and internal fixation. The present case details an unusual, low-energy, external rotation ankle fracture and dislocation that was incapable of skeletal traction relocation. The present report also details the intraoperative finding of a complex injury pattern.
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http://dx.doi.org/10.1053/j.jfas.2015.06.014DOI Listing
July 2017

Optimization of alginate purification using polyvinylidene difluoride membrane filtration: Effects on immunogenicity and biocompatibility of three-dimensional alginate scaffolds.

J Biomater Appl 2016 10 25;31(4):510-520. Epub 2016 Apr 25.

Department of Surgery, Columbia University Medical Center, USA.

Sodium alginate is an effective biomaterial for tissue engineering applications. Non-purified alginate is contaminated with protein, lipopolysaccharide, DNA, and RNA, which could elicit adverse immunological reactions. We developed a purification protocol to generate biocompatible alginate based on (a) activated charcoal treatment, (b) use of hydrophobic membrane filtration (we used hydrophobic polyvinylidene difluoride membranes to remove organic contaminants), (c) dialysis, and finally (d) ethanol precipitation. Using this approach, we could omit pre-treatment with chloroform and significantly reduce the quantities of reagents used. Purification resulted in reduction of residual protein by 70% down to 0.315 mg/g, DNA by 62% down to 1.28 µg/g, and RNA by 61% down to less than 10 µg/g, respectively. Lipopolysaccharide levels were reduced by >90% to less than 125 EU/g. Purified alginate did not induce splenocyte proliferation in vitro. Three-dimensional scaffolds generated from purified alginate did not elicit a significant foreign body reaction, fibrotic overgrowth, or macrophage infiltration 4 weeks after implantation. This study describes a simplified and economical alginate purification method that results in alginate purity, which meets clinically useful criteria.
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http://dx.doi.org/10.1177/0885328216645952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479495PMC
October 2016

Characteristics and Outcomes of Renal Transplant Recipients with Hemolytic Uremic Syndrome in the United States.

Transplant Direct 2015 Nov 18;1(10). Epub 2015 Nov 18.

Department of Surgery, Columbia University College of Physicians & Surgeons, New York, NY.

Background: Hemolytic uremic syndrome (HUS) accounts for <1% of renal transplants in the US. There are limited data on the characteristics and outcomes of HUS in pediatric and adult kidney transplant recipients in the US.

Methods: This study included all renal transplant recipients identified with HUS (N=1,233) as a cause of end-stage renal disease between 1987 and 2013 using the UNOS/OPTN database. The cohort was divided into two age groups: pediatric (N=447) and adult (N=786). Main outcomes were acute rejection rate at one-year, allograft and patient survival, and recurrence of HUS post-transplant. Both age groups were then compared with a propensity score (1:2 ratio) matched control group with an alternative primary kidney disease (non-HUS cohort: pediatric [N= 829] and adult [N=1,547]).

Results: In pediatric cohort, when compared to the PS matched controls, acute rejection, death censored allograft and patient survival was similar in the HUS group. However, in the adult cohort, the graft and patient survivals were significantly worse in the HUS group. HUS was associated with allograft loss (HR=1.40, 95%CI 1.14-1.71) in adult recipients. Patients with HUS recurrence had significantly lower allograft and patient survival rates compared to the non-recurrent group in both age groups. Acute rejection was one of the major predictor of HUS recurrence in adults (OR=2.64, 95%CI 1.25-5.60). Calcineurin inhibitors (CNI) were not associated HUS recurrence in both age groups.

Conclusion: Pediatric HUS-patients, unlike adult recipients, have similar outcomes compared to the PS matched controls. Recurrence of HUS is associated with poor allograft and patient survival in pediatric and adult patients. Use of CNIs seem to be safe as a part of maintenance immunosuppression post-transplantation. A comprehensive national registry is urgently needed.
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http://dx.doi.org/10.1097/TXD.0000000000000555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775084PMC
November 2015

"Treating Lungs": The Scientific Contributions of Dr. Theodor Kolobow.

ASAIO J 2016 Mar-Apr;62(2):203-10

From the *Extracorporeal Life Support Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan; †Department of Surgery, Columbia University Medical Center, New York, NY; and ‡Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.

We are fortunate to live in an age in which biomedical technology has provided us with unprecedented ability to supplant the functions of organs and support the physiologic processes of the human body. Ingenious doctors, physiologists, and engineers helped create these advances with new and innovative ideas. One of these pioneers was Dr. Theodor Kolobow. He is best known for one of his earliest inventions, the spiral coil membrane lung. His contributions to medical innovation, however, are diverse, as he also contributed to advances in hemodialysis, improvements in extracorporeal life support technology/circuit components, and through his laboratory experiments helped shape our current understanding of cardiopulmonary pathophysiology. In retrospect, much of Kolobow's work was unified by the theme of preventing iatrogenic lung injury caused by mechanical ventilation. This tenet became more obvious as his later studies progressed to developing techniques and devices intended to limit ventilator pressures, and prevent bacterial colonization of the lungs. Although he formally retired from his research endeavors in 2009, the impact of his contributions remains prominent in our everyday use of techniques and equipment that he either originated or helped to develop.
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http://dx.doi.org/10.1097/MAT.0000000000000323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790827PMC
December 2016

Recommendations for including surgery on the public health agenda.

J Surg Res 2015 Jul 9;197(1):112-7. Epub 2015 Apr 9.

Surgeons OverSeas (SOS), New York, New York; Department of Surgery, Intermountain Health Care, Salt Lake City, Utah; Department of Surgery, University of Utah, Salt Lake City, Utah.

Background: Surgical care has made limited inroads on the public health and global health agendas despite increasing data showing the enormous need. The objective of this study was to survey interested members of a global surgery community to identify patterns of thought regarding barriers to political priority.

Materials And Methods: All active members of the nongovernmental organization Surgeons OverSeas were surveyed and asked why surgical care is not receiving recognition and support on the public health and global health agenda. Responses were categorized using the Shiffman framework on determinants of political priority for global initiatives by two independent investigators, and the number of responses for each of the 11 factors was calculated.

Results: Seventy-five Surgeons OverSeas members replied (75 of 176; 42.6% response rate). A total of 248 individual reasons were collected. The most common responses were related to external frame, defined as public portrayals of the issue (60 of 248; 24.2%), and lack of effective interventions (48 of 248; 19.4%). Least cited reasons related to global governance structure (4 of 248; 2.4%) and policy window (4 of 248; 1.6%).

Conclusions: This survey of a global surgery community identified a number of barriers to the recognition of surgical care on the global health agenda. Recommendations include improving the public portrayal of the problem; developing effective interventions and seeking strong and charismatic leadership.
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http://dx.doi.org/10.1016/j.jss.2015.04.020DOI Listing
July 2015

Live Donor Renal Anatomic Asymmetry and Posttransplant Renal Function.

Transplantation 2015 Aug;99(8):e66-74

1 Division of Nephrology, UT Southwestern Medical Center, Dallas, TX. 2 Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, NY. 3 Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY. 4 Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY. 5 Booth School of Business, University of Chicago, Chicago, IL. 6 Renal Transplantation, New York Presbyterian Hospital, New York, NY. 7 Renal and Pancreatic Transplantation, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY.

Background: Relationship between live donor renal anatomic asymmetry and posttransplant recipient function has not been studied extensively.

Methods: We analyzed 96 live kidney donors, who had anatomical asymmetry (>10% renal length and/or volume difference calculated from computerized tomography angiograms) and their matching recipients. Split function differences (SFD) were quantified with technetium-dimercaptosuccinic acid renography. Implantation biopsies at time 0 were semiquantitatively scored. A comprehensive model using donor renal volume adjusted to recipient weight (Vol/Wgt), SFD, and biopsy score was used to predict recipient estimated glomerular filtration rate (eGFR) at 1 year. Primary analysis consisted of a logistic regression model of outcome (odds of developing eGFR>60 mL/min/1.73 m(2) at 1 year), a linear regression model of outcome (predicting recipient eGFR at one-year, using the chronic kidney disease-epidemiology collaboration formula), and a Monte Carlo simulation based on the linear regression model (N=10,000 iterations).

Results: In the study cohort, the mean Vol/Wgt and eGFR at 1 year were 2.04 mL/kg and 60.4 mL/min/1.73 m(2), respectively. Volume and split ratios between 2 donor kidneys were strongly correlated (r = 0.79, P < 0.001). The biopsy scores among SFD categories (<5%, 5%-10%, >10%) were not different (P = 0.190). On multivariate models, only Vol/Wgt was significantly associated with higher odds of having eGFR > 60 mL/min/1.73 m (odds ratio, 8.94, 95% CI 2.47-32.25, P = 0.001) and had a strong discriminatory power in predicting the risk of eGFR less than 60 mL/min/1.73 m(2) at 1 year [receiver operating curve (ROC curve), 0.78, 95% CI, 0.68-0.89].

Conclusions: In the presence of donor renal anatomic asymmetry, Vol/Wgt appears to be a major determinant of recipient renal function at 1 year after transplantation. Renography can be replaced with CT volume calculation in estimating split renal function.
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http://dx.doi.org/10.1097/TP.0000000000000599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549234PMC
August 2015

Use of a flexible implant and bioabsorbable anchor for deltoid rupture repair in bimalleolar equivalent Weber B ankle fractures.

J Foot Ankle Surg 2015 May-Jun;54(3):513-6. Epub 2014 Aug 14.

Chief, Department of Foot and Ankle Surgery, HealthSpan Physicians Group, Cleveland, OH. Electronic address:

Supination external rotation ankle fractures are the most common ankle fracture subtype. Deltoid ligament injuries have often been associated with this type of injury pattern. A missed injury can lead to post-traumatic arthritis and persistent pain. The current data do not support acute deltoid rupture repair. This has been based primarily on level III and IV studies in which less than satisfactory results were reported. We believe that acute deltoid rupture repair could be indicated in select cases. We have outlined a new deltoid repair technique for use with bimalleolar, equivalent supination external rotation ankle fractures using a flexible implant and bioabsorbable anchor.
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http://dx.doi.org/10.1053/j.jfas.2014.06.025DOI Listing
March 2016

Preformed donor-specific antibodies and risk of antibody-mediated rejection in repeat renal transplantation.

Transplantation 2014 Mar;97(6):642-7

1 Department of Pharmacy, NewYork-Presbyterian Hospital, Columbia University Medical Center, New York, NY. 2 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY. 3 Division of Nephrology, Department of Medicine, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY. 4 Department of Quality, NewYork-Presbyterian Hospital, Columbia University Medical Center, New York, NY. 5 Division of Transplantation, Department of Surgery, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY. 6 Address correspondence to: Demetra S. Tsapepas, Pharm.D., B.C.P.S., Department of Pharmacy, NewYork-Presbyterian Hospital, Columbia University Medical Center, 622 West 168th Street, Room VCB, New York, NY.

Background: Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail.

Design: This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function.

Results: Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7 ± 1.1 vs. 4.1 ± 1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8 ± 13.1 vs. 47 ± 20.2 mL/min/1.73 m(2), P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients.

Conclusions: This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients.
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http://dx.doi.org/10.1097/01.TP.0000440954.14510.6aDOI Listing
March 2014

An update to managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline.

Clin Transplant 2013 Sep-Oct;27(5):647-8. Epub 2013 Aug 8.

Department of Pharmacy, New-York Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA.

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http://dx.doi.org/10.1111/ctr.12204DOI Listing
May 2014

Managing renal transplant ischemia reperfusion injury: novel therapies in the pipeline.

Clin Transplant 2013 Jul-Aug;27(4):484-91. Epub 2013 Apr 25.

Department of Pharmacy, New York Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA.

Ischemia reperfusion injury (IRI) is an early, non-specific inflammatory response that follows perfusion of warm blood into a cold asanguinous organ following transplantation. The occurrence of IRI may have a pivotal impact on acute and long-term renal allograft function. Initially, IRI contributes to delayed graft function (DGF), a term typically defined as the need for dialysis within one wk after renal transplantation. DGF frequently leads to prolonged hospital stay, increased healthcare costs, and potentially worse prognosis. Strategies to prevent IRI have so far been fairly limited, poorly defined, inadequately studied, and mostly anecdotal. The purpose of this review is to summarize the existing and novel therapies, which may mitigate IRI in renal transplantation. Agents currently in the pipeline include: Diannexin, which reduces endothelial cell injury by shielding phosphatidylserine; YSPSL, which mimics the binding portion of P-selectin glycoprotein ligand-1 to competitively inhibit translocation of P-selectin and recruitment of polymorphonuclear leukocytes to the surface of endothelial cells; and I5NP, a synthetic small interfering ribonucleic acid that results in the inhibition of p53 expression. These agents represent an exciting frontier in transplant pharmacotherapy; they are in various phases of investigation and may have broader benefits in reducing complications of DGF.
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http://dx.doi.org/10.1111/ctr.12121DOI Listing
March 2014

The benefits of international rotations to resource-limited settings for U.S. surgery residents.

Surgery 2013 Apr 27;153(4):445-54. Epub 2012 Dec 27.

Surgeons OverSeas, New York, NY, USA.

Background: U.S. surgery residents increasingly are interested in international experiences. Recently, the Residency Review Committee approved international surgery rotations for credit toward graduation. Despite this growing interest, few U.S. surgery residency programs offer formal international rotations. We aimed to present the benefits of international surgery rotations and how these rotations contribute to the attainment of the 6 Accreditation Council for Graduate Medical Education (ACGME) competencies.

Methods: An e-mail-based survey was sent in November 2011 to the 188 members of Surgeons OverSeas, a group of surgeons, residents, fellows, and medical students with experience working in resource-limited settings. They were asked to list 5 benefits of international rotations for surgery residents. The frequency of benefits was qualitatively grouped into 4 major categories: educational, personal, benefits to the foreign institution/Global Surgery, and benefits to the home institution. The themes were correlated with the 6 ACGME competencies.

Results: The 58 respondents (31% response rate) provided a total of 295 responses. Fifty themes were identified. Top benefits included learning to optimally function with limited resources, exposure to a wide variety of operative pathology, exposure to a foreign culture, and forming relationships with local counterparts. All ACGME competencies were covered by the themes.

Conclusion: International surgery rotations to locations in which resources are constrained, operative diseases vary, and patient diversity abound provide unique opportunities for surgery residents to attain the 6 ACGME competencies. General surgery residency programs should be encouraged to establish formal international rotations as part of surgery training to promote resident education and assist with necessary oversight.
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http://dx.doi.org/10.1016/j.surg.2012.10.018DOI Listing
April 2013
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