Assessment of Tocilizumab (Anti–Interleukin‐6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody‐Mediated Rejection and Transplant Glomerulopathy in HLA‐Sensitized Renal Allograft Recipients

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor‐specific antibodies (DSAs) posttransplantation leads to chronic active antibody‐mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL‐6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti–IL‐6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long‐term outcomes. Tocilizumab‐treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long‐term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL‐6–IL‐6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.     

Ferret Lung Transplant: An Orthotopic Model of Obliterative Bronchiolitis

Obliterative bronchiolitis (OB) is the primary cause of late morbidity and mortality following lung transplantation. Current animal models do not reliably develop OB pathology. Given the similarities between ferret and human lung biology, we hypothesized an orthotopic ferret lung allograft would develop OB. Orthotopic left lower lobe transplants were successfully performed in 22 outbred domestic ferrets in the absence of immunosuppression (IS; n = 5) and presence of varying IS protocols (n = 17). CT scans were performed to evaluate the allografts. At intervals between 3–6 months the allografts were examined histologically for evidence of acute/chronic rejection. IS protects allografts from acute rejection and early graft loss. Reduction of IS dosage by 50% allowed development of controlled rejection. Allografts developed infiltrates on CT and classic histologic acute rejection and lymphocytic bronchiolitis. Cycling of IS, to induce repeated episodes of controlled rejection, promoted classic histologic hallmarks of OB including fibrosis‐associated occlusion of the bronchiolar airways in all allografts of long‐term survivors. In conclusion, we have developed an orthotopic lung transplant model in the ferret with documented long‐term functional allograft survival. Allografts develop acute rejection and lymphocytic bronchiolitis, similar to humans. Long‐term survivors develop histologic changes in the allografts that are hallmarks of OB.     

Composite Tissue Vasculopathy and Degeneration Following Multiple Episodes of Acute Rejection in Reconstructive Transplantation

Transplant vasculopathy has not been systematically investigated in composite tissue allotransplantation (CTA). The impact of multiple acute rejections (ARs) on long‐term graft outcomes in reconstructive transplantation remains unknown. This study in a rat hind‐limb allotransplantation model systematically analyzes vasculopathy and tissue‐specific pathological changes secondary to multiple AR episodes. LEW rats were transplanted with BN rat hind limbs and treated as follows: Group 1 (Iso): isografts. Group 2 (CsA): Cyclosporine (CsA) qd; Group 3 (mult AR): CsA and dexamethasone only when AR was observed. No AR was observed in Groups 1 and 2. Multiple AR were observed in Group 3, and each episode was completely reversed (clinically) with pulsed CsA + dexamethasone treatment. Group 3 animals demonstrated significant vascular lesions along with skin and muscle atrophy, upregulation of profibrotic gene expression and fibrosis when compared to Groups 1 and 2. In addition, allograft bone was sclerotic, weak and prone to malunion and nonunion. Interestingly, vasculopathy was a late finding, whereas muscle atrophy with macrophage infiltration was seen early, after only a few AR episodes. Taken together, multiple AR episodes lead to vasculopathy and tissue‐specific pathology in CTA. This is the first evidence of ‘composite tissue vasculopathy and degeneration (CTVD)’ in CTA.     

A Comparison of Lipoatrophy and Aging: Volume Deficits in the Face

Background  Insight into the physical processes of aging can be gained by comparing the loss of facial volume that occurs during aging with the dramatic fat loss resulting from acquired lipoatrophy, including human immunodeficiency virus (HIV) treatment-associated lipoatrophy. The superficial effects of aging, such as rhytid formation, often are the focus of investigations into this phenomenon. However, age-related volume loss often is ignored. Methods  A review of the relevant literature was conducted to provide an overview of age-related lipoatrophy and its etiology and to compare it by facial region with HIV-associated facial lipoatrophy. Results  As a side effect of highly active antiretroviral therapy, HIV-associated lipoatrophy results in fat lipodystrophy (including both lipoatrophy and lipohypertrophy) and progresses toward nearly complete subdermal facial fat loss. Aging is accompanied by changes in the soft tissues of the face, leaving atrophic regions of generalized tissue ptosis. Some facial regions are affected differently by fat loss, depending on its cause. In the aging patient, certain parts of the face display only minimal fat loss. Conclusions  The role of fat loss in facial aging is slight compared with its considerable role in HIV-associated lipoatrophy. The losses of various facial tissues and the ptosis of some soft tissues are strong contributors to the appearance of the aged face. This regional anatomic assessment of the face engenders a more thorough understanding of the progression that characterizes volume changes associated with aging.     

Facial fat grafting: the search for predictable results

Since the majority of volume loss to the face is due to fat atrophy, autologous fat grafting with living fat cells represents the ideal tissue replacement. Recent technical improvements have led to excellent results utilizing fat grafting for cosmetic and reconstructive indications. The purpose of this article is to describe our clinical and laboratory experience with successful facial fat grafting for volume augmentation. Our laboratory experience with facial fat grafting centers around the results of multiple studies utilizing a nude mouse model of facial fat transplantation. Armed with the knowledge gained from our laboratory experience we present modified techniques to optimize fat grafting in the clinical setting. Furthermore, we present the results of several clinical studies examining a variety of recipient sites including nasolabial folds, glabella, lips, and lower eyelids. Lastly we describe our experience utilizing fat grafting to treat patients with hemifacial atrophy. When utilized in the appropriate areas, facial fat grafting can provide long-lasting aesthetically superior replacement for the soft tissues lost through aging or disease.     

Successful treatment of Parry-Romberg syndrome with autologous fat grafting: 14-year follow-up and review

Parry first described the syndrome of progressive facial atrophy in 1825, followed by Romberg in 1846. The clinical hallmark of the syndrome is atrophy of the facial soft tissues, including fat and muscle as well as underlying bone. Clinicians have classically reserved treatment until the end of the disease process, after the "burn out" stage. Various treatment modalities have been attempted with differing results. In this study, we present a case of Parry-Romberg syndrome treated with autologous fat grafting. This case report reviews the history of the disease, examines the safety and clinical outcomes of fat grafting as a treatment modality, and challenges the classic timing of that treatment. Additionally, long-term follow-up with photos and histological analysis of specimens are included.     

Autologous fat augmentation: a perfect fit in new and emerging technologies

The focus of recent cosmetic surgery is on the replacement of lost facial volume. Much of aging is a complex set of changes, including bone loss, muscle atrophy, and subcutaneous loss. For this reason, autologous fat augmentation is the perfect fit in the realm of new and emerging technologies. Although not necessarily a "new" technology, many advances have been made in the harvesting and infiltration of the fat, yielding much more consistent and long-lasting results. It also has the closest attributes of the "ideal filler."     

Restoration of Facial Form and Function After Severe Disfigurement from Burn Injury by a Composite Facial Allograft

Composite facial allotransplantation is emerging as a treatment option for severe facial disfigurements. The technical feasibility of facial transplantation has been demonstrated, and the initial clinical outcomes have been encouraging. We report an excellent functional and anatomical restoration 1 year after face transplantation. A 59‐year‐old male with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore midfacial form and function. An initial potent antirejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient demonstrated facial redness during the initial postoperative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life. Composite facial allotransplantation, along with minimal and well‐tolerated immunosuppression, was successfully utilized to restore facial form and function in a patient with severe disfigurement of the midface.     

Testing the Efficacy of Contrast‐Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation

One of the key unmet needs to improve long‐term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast‐enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High‐resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next‐generation imaging approaches to diagnose transplant rejection.     

Vascularized Bone Marrow‐Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates

Vascularized composite allograft (VCA) transplantation (also referred to as composite tissue allotransplantation) has demonstrated clinical success in cases of hand, arm and face transplantation despite prior belief that skin provides an insurmountable barrier to allograft rejection. These overall good outcomes are facilitated by substantial immunosuppressive requirements in otherwise healthy patients, yet still demonstrate frequent rejection episodes. We developed a nonhuman primate model of facial segment allotransplantation to elucidate the unique pathophysiology and immunosuppressive requirements of VCA with addition of concomitant vascularized bone marrow (VBM). Heterotopically transplanted facial segment VCA with VBM treated only with tacrolimus and mycophenolate mofetil (MMF) demonstrated prolonged rejection‐free survival, compared to VCA without VBM that demonstrated early rejection episodes and graft loss. While VCA with VBM demonstrated sporadic macrochimerism, acute and chronic rejection and graft loss occurred after discontinuation of immunosuppression. These data support an immunomodulatory role of VBM in VCA that reduces immunosuppressive requirements while providing improved outcomes.     

High-Tech Facelift

Recent technological advances in our specialty have made us reappraise the way we approach facial rejuvenation. Some of these technological interfaces have made it possible, in the author's exerpience, to improve results and to tackle difficult aesthetic problems. The purpose of this paper is to report how we combine these technological advances in an effort to improve the aesthetic outcomes. These technological advances are: laser skin resurfacing, endoscopy, newer fat grafting procedures, and new alloplastic materials for bone augmentation. Other technological advances are consultations via the Internet, computer imaging for simulation of possible outcomes, etc. Endoscopy is routinely used in our facial rejuvenative procedures, almost always for the forehead, often for the midface and less often for the neck. Fat grafting procedures using newly adapted concepts are used for the brow, glabella, tear trough deformity, cheeks, lips, chin, nasolabial folds, marionette lines, and other areas of soft tissue depressions apparent before or after the lifting procedures. This has allowed us to restore the tridimensional volume and treat the soft tissue atrophy. Patients with significant skeletal soft tissue disproportion due to aging, loss of dentition, prior trauma or congenital defects may receive one or more of the following implants: glabella, cheek, piriformis, angle of the mandible, mandibular body glove type of implant, prejawl implant, chin overlay or a glove type of implant. Our preference is for a porous polyethylene material because of its tissue ingrowth inductiveness. Individuals who have damaged skin due to solar exposure, aging, smoking, etc., may receive Ultrapulse CO₂ laser resurfacing at the same operative setting (more often) or in a delayed fashion. The Versapulse laser is also needed for the treatment of some skin changes secondary to aging such as telangiectasias (Variable Pulse Green) and brown spots (Q-Switch 532). The high-tech facelift has allowed us to treat the severely damaged skin, fat atrophy, bone atrophy in many patients, at the same time that the lifting procedure is performed. This provides a more comprehensive approach to facial rejuvenation. The combination of different techniques and technologies maximizes the effectiveness and minimizes the potential side effects of each one. Scars in the forehead and scalp are avoided. Incision and fat removal in the lower eyelid are often unnecessary. It provides a more precise vertical lifting with correction of the tear trough deformity and gives a tridimensional restoration of the facial volume. The facial disharmony is treated at every level starting from the facial skeletal support to the most external envelope (skin). Over 200 patients have been treated this way with a minimal rate of complications. The high-tech facial rejuvenation has allowed us to improve the surgical results of our patients compared with previous isolated techniques. The combination of each one of the techniques require a precise understanding of the limits and benefits of each. Case examples of the different combinations will be shown.     

自体脂肪颗粒移植在面部年轻化中的临床应用

目的:探讨自体脂肪颗粒移植在面部塑形和改善面部衰老的方法和临床效果。方法:以标准自体脂肪注射器负压吸引法吸取大腿、腹部脂肪颗粒,纯化后根据术前设计用脂肪抽吸针将脂肪颗粒注射至额颞部、面颊、苹果肌、泪沟、鼻唇沟、上睑、下颏等需要填充部位。结果:本组58例求美者无明显术后并发症。随访3~6个月,仅1例行2次注射。填充后面部较术前丰满,质感同周围组织,形态自然,面部衰老得以改善。结论:采用自体脂肪颗粒移植可达到丰满塑形、改善面部衰老的效果,符合面部软组织特征。     

Autologous fat transfer: an in-depth look at varying concepts and techniques

Fat augmentation is safe, relatively inexpensive, and readily available. Now that cosmetic surgeons are recognizing that facial aging is not simply due to gravity but also to atrophy of tissues, the use of fat for volume restoration is becoming even more popular. Newer techniques of Lipostructure, facial fat rebalancing, and fat autograft muscle injection (FAMI) are targeted to achieve true full-face three-dimensional rejuvenation; however, practical means of objectively measuring outcome are lacking. Basic questions remain regarding the optimal harvesting site, processing technique, and most effective injection technique. Scientific research is emerging th address these issues.     

Short‐term kidney transplant outcomes among African American recipients do not predict long‐term outcomes: donor pair analysis

Keith D, Patrie JT. Short‐term kidney transplant outcomes among African‐American recipients do not predict long‐term outcomes: donor pair analysis.
Clin Transplant 2011: 25: 69–76. © 2010 John Wiley & Sons A/S. Abstract: African American (AA) renal transplant recipients have poorer graft survival compared to other racial and ethic groups. This study was undertaken to determine whether pre‐transplant factors and events occurring in the first six months post‐transplant were predictive of the poorer long‐term outcomes in AA recipients. To control for kidney quality, a paired analysis of deceased donor kidneys in which one donor kidney was transplanted into an adult AA recipient and the other was transplanted into an adult Caucasian was undertaken. Cox proportional hazard modeling was used to determine the impact of outcome variables at six months. Outcomes at six months among the paired recipients were very similar for graft and patient survival, and estimated glomerular filtration rate (GFR). Less than 10% of difference in long‐term outcomes was explained by differences in the pre‐transplant covariates and events in the first six months. Causes of graft failure after six months revealed a two to three times higher rate of chronic allograft nephropathy (CAN) and late acute rejection among AA. In conclusion, early outcomes after kidney transplant did not predict the poor long‐term graft survival among AA, and AA recipients appear to be more prone to graft loss because of CAN and late acute rejection.     

Preformed and De Novo Donor Specific Antibodies in Visceral Transplantation: Long‐Term Outcome With Special Reference to the Liver

Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long‐term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement‐dependent lymphocytotoxic crossmatch (CDC‐XM) with pre‐ and posttransplant solid phase HLA–DSA assay in 156 (80%). Grafts were ABO‐identical with random HLA‐match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus‐based with antilymphocyte recipient pretreatment in 150 (77%). CDC‐XM was positive in 55 (28%). HLA–DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class‐I whereas 74% of recipients with de novo antibodies had Class‐II. Gender, age, ABO blood‐type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA–DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti‐DSA strategies are required to further improve long‐term survival particularly of liver‐free allografts.     

Free latissimus dorsi perforator flap for reconstruction of hemifacial atrophy: case report

Progressive hemifacial atrophy (PHA) is characterized by slow and progressive atrophy usually of one side of the face. PHA affects primarily the subcutaneous fat and muscle tissues, but may involve the bone. The cause is unknown. The treatment is symptomatic and directed at augmentation of the deficient soft-tissue volume. The reconstructive procedures may combine fat grafts, dermis fat grafts, pedicle flaps, bone grafts, microvascular free flaps, and alloplastic implants. We report a patient with of PHA whose condition was treated with a free latissimus dorsi (LD) perforator flap. The LD perforator flap was suitable for the large defect of the patient. It could easily be tailored and thinned to follow the facial contour. Minor revisions were needed for esthetic reasons. There was neither significant downward gravitation nor wasting of the flap. 23 months later, the natural appearance of the face was maintained.     

Urinary proteomics to diagnose chronic active antibody‐mediated rejection in pediatric kidney transplantation – a pilot study

Chronic antibody‐mediated rejection (cABMR) is the main cause of long‐term renal graft loss. Late‐stage diagnosis is made by detecting donor‐specific antibodies (DSA) in blood combined with typical histomorphological lesions in renal allografts. There is a need for noninvasive biomarkers for cABMR that might permit screening and earlier diagnosis. In a case control study of 24 pediatric renal transplant recipients, urine samples were analyzed using capillary electrophoresis and mass spectrometry. Patients were matched with 36 pediatric renal transplant patients without cABMR. Statistical analysis used the nonparametric Wilcoxon test to identify 79 significant biomarkers, which were combined to a support vector machine‐based classifier. After validation in an independent test cohort of eight pediatric patients with and 12 without cABMR, the area under the receiver operating characteristic (ROC) curve (AUC) for detection of cABMR was 0.92 (95% CI 0.71–0.99) with a sensitivity of 100% (95% CI 63–100%) and a specificity of 75% (95% CI 43–95%). Combining this classifier with the urinary proteomic marker CKD273 improved the detection of patients with cABMR with misclassification in only 2/20 of the patients. These data indicate that a biomarker pattern derived from urinary proteomics allows the detection of cABMR in pediatric renal transplant recipients with high sensitivity and moderate specificity.     

自体脂肪颗粒移植在面部年轻化的应用

目的探讨通过自体颗粒脂肪移植矫正面部老化的方法和临床效果。方法对178例,采用肿胀吸脂技术抽吸皮下脂肪,将抽吸出的自体颗粒脂肪经过离心、提纯后均匀注射于面部老化的标记区域,多层次多隧道注射,以补充面部丢失的软组织容量,改善老化面容。结果所有受术者随访3个月至3年,面部老化改善满意,无脂肪液化、感染、破溃等严重并发症发生,效果明显、持久。结论自体颗粒脂肪注射移植是一种安全有效的面部软组织填充手术技术,可以有效地取得改善面部老化、除皱的效果,值得临床推广应用。     

Learning Curve in Tracheal Allotransplantation

The first vascularized tracheal allotransplantation was performed in 2008. Immunosuppression was stopped after forearm implantation and grafting of the recipient mucosa to the internal site of the transplant. Nine months after forearm implantation, the allograft was transplanted to the tracheal defect on the radial blood vessels. Since then, four additional patients have undergone tracheal allotransplantation, three (patients 2–4) for long‐segment stenosis and one (patient 5) for a low‐grade chondrosarcoma. Our goal was to reduce the time between forearm implantation and orthotopic transplantation and to determine a protocol for safe withdrawal of immunosuppressive therapy. Following forearm implantation, all transplants became fully revascularized over 2 months. Withdrawal of immunosuppression began 4 months after graft implantation and was completed within 6 weeks in cases 2–4. Repopulation of the mucosal lining by recipient cells, to compensate for the necrosis of the donor mucosa, was not complete. This resulted in partial loss of the allotransplant in patients 2–4. In patient 5, additional measures promoting recipient cell repopulation were made. The trachea may be used as a composite tissue allotransplant after heterotopic revascularization in the forearm. Measures to maximize recipient cell repopulation may be important in maintaining the viability of the transplant after cessation of immunosuppression.     

Some Issues in Facial Transplantation

Human facial transplantation, a form of composite tissue allotransplantation, has now become a clinical reality. We carried out the world's second partial facial transplantation in April 2006. We reviewed some issues associated with facial transplantation, especially focusing on the individual who underwent the transplant in our department. We discussed surgical indications, techniques, risks versus benefits, informed consent and psychosocial, societal and financial issues of facial transplantation. In our opinion, with the progresses in composite tissue allotransplantation, partial or full facial transplantation is becoming a timely and effective remedy for the significantly disfigured patients. However, there are a lot of problems unsolved, and as we have performed the transplant on only three individuals, no long‐term outcome data are available. Facial transplantation needs further research.