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

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.

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

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.

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

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.

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

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.

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

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.

Charcot Pathogenesis: A Study of In Vivo Gene Expression.

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.

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

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.

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

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.

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

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.

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

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.

The immunologic considerations in human head transplantation.

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.

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

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.

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

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.

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

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.

Recommendations for including surgery on the public health agenda.

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.

Live Donor Renal Anatomic Asymmetry and Posttransplant Renal Function.

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.

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

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.

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

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.