Bilateral Transplantation Research Articles

Early Bilateral Amniotic Membrane Transplantation in the Management of Severe Ocular Involvement from Acute Toxic Epidermal Necrolysis in a Chinese Pediatric Patient

Introduction: Toxic Epidermal Necrolysis (TEN) is a rare but potentially life-threatening muco-cutaneous condition associated with idiosyncratic hypersensitivity to certain drugs. Ophthalmic involvement is common, typically affecting the ocular surface and eyelids. Survivors often suffer from resulting bilateral blindness and ocular dryness or pain. Objective: To report the successful management of severe ocular surface disease during the acute stage of toxic epidermal necrolysis using early amniotic membrane transplantation on both eyes in a Chinese paediatric patient. Design: Interventional case report Case report: A 15 year-old Chinese girl was transferred to the intensive care unit of Queen Mary Hospital, Hong Kong with TEN after taking oral cefuroxime and diclofenac. She developed bilateral keratoconjunctivitis, diffuse corneal epithelial defects (80-90% of cornea surface) and later bilateral symblephara. After initial treatment with daily rodding, topical lubricants, steroids and antibiotics, there was no improvement in her condition. Bilateral amniotic membrane transplantation (AMT) was performed over the cornea, fornix, tarsal and bulbar conjunctiva on day 10 of illness. On discharge from the hospital (post-operative week 7), the patient had pinhole visual acuity of 6/7.5 in the right eye and 6/6 the left eye. She was eventually weaned off all topical medication Visual acuity eventually recovered to 6/6 in both eyes by week 20 after surgery. There was mild residual forniceal symblepharon and eyelid margin keratinization. She continues to require regular lubricants for her chronic ocular surface condition. Conclusion: Early use of AMT minimized ocular damage and prevented severe vision loss in a Chinese pediatric patient with severe bilateral ocular surface inflammation secondary to TEN. Effective management is dependent on early and active communication between the patient’s family, pediatricians, intensive care physicians and ophthalmologists.

Large-sized Fetal Striatal Grafts in Huntington's Disease Do Stop Growing: Long-term Monitoring in the Florence Experience.

Development of six large nodules of solid tissue after bilateral human fetal striatal transplantation in four Huntington’s disease patients has raised concern about the safety of this experimental therapy in our setting. We investigated by serial MRI-based volumetric analysis the growth behaviour of such grafts. After 33-73 months from transplantation the size of five grafts was stable and one graft showed a mild decrease in size. Signs neither of intracranial hypertension nor of adjuctive focal neurological deficit have ever been observed. This supports long-term safety of the grafting procedure at our Institution.

Stereotactic planning software for human neurotransplantation: Suitability in 22 surgical cases of Huntington's disease

Intrastriatal neural transplantation using multiple grafts is an experimental approach to the treatment of Huntington's disease (HD). Brain atrophy makes stereotactic plans in these patients a tedious procedure with a risk of suboptimal spatial distribution of the grafts in transplantation procedures. Here we present a self-developed software to optimize the surgical stereotactic planning for bilateral neurotransplantation procedures. It allows close to symmetrical distribution of the stereotactic coordinates in relation to the mid-commissural point (MCP), proposing automatically the planning coordinates for the first transplanted hemisphere and mirrored coordinates to be used in the contra-lateral hemisphere. Twenty-two consecutive HD patients underwent bilateral stereotactic striatal transplantation. Two caudate nucleus and four putaminal tracks were planned bilaterally. For the second, contra-lateral transplantation, the coordinates were mirrored in order to determine contralateral targets and trajectories. Intra-individual comparison between software given coordinates and finally used coordinates was performed. No statistical significance was found comparing a) the differences between coordinates proposed by the software and the final coordinates and b) the distribution of the transplantation sites in relation to the midline for the right vs. left hemisphere. No intra- or postoperative transplantation-related adverse events occurred. The use of model-based and mirrored coordinates allowed optimal spatial distribution of the grafts. Minor changes were required comparing right to left coordinates giving proof-of principle. The initial use of the software suggests that it may be useful in experimental transplantation trials where neural cell grafts are to be implanted into predefined target sites in the human brain, whether unilateral or bilateral.

Combining enriched environment and induced pluripotent stem cell therapy results in improved cognitive and motor function following traumatic brain injury.

Despite advances towards potential clinically viable therapies there has been only limited success in improving functional recovery following traumatic brain injury (TBI). In rats, exposure to an enriched environment (EE) improves learning and fosters motor skill development. Induced pluripotent stem cells (iPSC) have been shown to survive transplantation and influence the recovery process. The current study evaluated EE and iPSC as a polytherapy for remediating cognitive deficits following medial frontal cortex (mFC) controlled cortical impact (CCI) injury. Sixty adult male rats received a midline mFC CCI or sham injury and were randomly placed in either EE or standard environment (SE). Seven days post-injury rats received bilateral transplantation of iPSCs or media. Behavioral measures were conducted throughout the remainder of the study. Following behavioral analysis, brains were extracted and prepared for histological analysis. Open-field data revealed that combined therapy resulted in typical Sham/EE activity rearing patterns by the conclusion of the study. On the Vermicelli Handling task, rats with EE/iPSC polytherapy performed better than media-treated rats. Furthermore, rats treated with polytherapy performed equivalently to Sham/EE rats on the Morris water maze. Proficiency on the Rotarod was consistently better in EE when compared to SE counterparts. Confocal microscopy confirmed that iPSCs survived and migrated away from the transplantation site. Overall, EE or iPSC therapy improved cognition and motor performance, however, full cognitive restoration was seen only with the EE/iPSC treatment. These data suggest that EE/iPSC therapy should be explored as a potential, clinically relevant, treatment for TBI.

Editorial introductions

Editorial introductions

Rehabilitation After Bilateral Hand Transplantation in the Quadrimembral Patient

The hand transplantation is a unique entity in the fields of medicine and rehabilitation. Hand therapy and rehabilitation programs are consistently reported as essential to a successful functional outcome for the hand transplant patient. In September 2011, our medical center performed their first bilateral hand and forearm transplant on a 28-year-old female 4 years after losing her lower extremities and upper extremities due to multiorgan system failure and pressure-induced extremity ischemia. She participated in 4 months of hand therapy, occupational therapy, and physical therapy at our institution, and then returned to her hometown to continue with an intensive therapy program. At 16 months after transplantation, she had sensory return to diminished protective level and motor return to all transplanted muscles except for intrinsics. Our hand therapy team established a treatment program based on literature, collaboration with other transplant centers, and clinical experience. Now, 2 years after our first hand transplant case, we assess our plan and program, offer suggestions for developing a treatment program and encourage therapist to collaborate with their own transplant team and others around the United States and the world.

Technical Implications in Proximal Forearm Transplantation

The field of vascularized composite allotransplantation has developed for more than a decade. Investigators are defining patient selection criteria, transplant indications, immunologic regimens, and tolerance. The majority of the current reported hand transplantations have been for treatment of distal forearm or hand amputations. In more proximal amputees, the functional outcome of the transplanted arm has some unique variables that require a different surgical approach. We present a single case of bilateral proximal forearm transplantation in effort to describe the unique technical considerations in this complex procedure. The surgical procedure is described in detail. At 19 months, our patient had 4/5 strength of finger and thumb flexors and protective extensor as well as 4/5 wrist flexors and extensors. Our patient had recovery of sensation. Our patient now lives independently and does her lower extremity prosthesis independently using her hands. These results are expected to continue to improve with more time. In hand transplantation, functional results have been very promising. The described approach of forearm transplantation allows the transfer of the entire functional unit, which should optimize the ultimate outcome for these more proximal injuries.

Antibody-mediated rejection in hand transplantation

Clinical relevance of antibody-mediated rejection (ABMR) in vascularized composite allotransplantation (VCA) has not been defined. We herein describe a novel type of donor-specific antibody (DSA) and B-cell-associated rejection in hand transplantation. In 2003, a bilateral forearm transplantation was performed on a 42-year-old male patient. In 2012, the patient presented with edematous hands and forearms without skin lesions. Punch skin biopsies revealed rejection grade Banff II. Immunohistochemical analysis identified large aggregates of CD20 + lymphocytes with an architecture resembling lymph nodes. De novo DSA was found at a high level. Steroid treatment was ineffective, but administration of rituximab resulted in complete remission of clinical symptoms, evaporation of B-cell aggregates, and disappearance of DSA. We herein report the first case of what we suggest is an ABMR in VCA occurring at 9 years after forearm transplantation. Rituximab therapy successfully reversed the event.

Coronary Revascularization in Lung Transplant Recipients With Concomitant Coronary Artery Disease

Coronary artery disease (CAD) is not uncommon among lung transplant candidates. Several small, single-center series have suggested that short-term outcomes are acceptable in selected patients who undergo coronary revascularization prior to, or concomitant with, lung transplantation. Our objective was to evaluate perioperative and intermediate-term outcomes in this patient population at our institution. We performed a retrospective, observational cohort analysis of 898 lung transplant recipients between 1997 and 2010. Pediatric, multivisceral, lobar or repeat transplantations were excluded, resulting in 791 patients for comparative analysis, of which 49 (median age 62, 79.6% bilateral transplant) underwent concurrent coronary artery bypass and 38 (median age 64, 63.2% bilateral transplant) received preoperative percutaneous coronary intervention (PCI). Perioperative mortality, overall unadjusted survival and adjusted hazard ratio for cumulative risk of death were similar among both revascularization groups as well as controls. The rate of postoperative major adverse cardiac events was also similar among groups; however, concurrent coronary artery bypass was associated with longer postoperative length of stay, more time in the intensive care unit and more postoperative days requiring ventilator support. These results suggest that patients with CAD need not be excluded from lung transplantation. Preferential consideration should be given to preoperative PCI when feasible.

Post-chemotherapy bilateral limbal stem cell deficiency

We report an extremely rare case of bilateral total limbal stem cell deficiency (LSCD) induced by long-term systemic chemotherapy for squamous cell carcinoma of the lung, and the outcomes of bilateral keratolimbal allograft transplantation (KLAT) in such a case. A 34-year-old male patient had underlying disease of squamous cell carcinoma in the right upper lung with extensive mediastinum and lymph node metastasis and received a series of systemic chemotherapy, including a combination of vinorelbine and cisplatin and a combination of gemcitabine, cisplatin, and docetaxel. According to clinical manifestations of ocular surface disorder, pathology findings, and immunostaining of cytokeratin 13 (CK13), LSCD secondary to systemic chemotherapy was diagnosed. KLAT was performed in both eyes. Although graft rejection developed in the right eye, complete re-epithelialization with favorable visual acuity occurred in the left eye 3 years after limbal transplantation.

Greffe de main : quelles implications ?

The first hand allograft transplantation was performed in 1998 by a French surgeons team and has opened the era of functional allotransfers. In France, the authorized preliminary study included five patients who sustained traumatic amputation of both hands. All patients had bilateral hand allograft transplantation. Long-term results (follow-up ranging from 3 to 12 years) undoubtedly show a useful daily function, a good psychological acceptance and a physiological integration. Despite several obstacles as the need of immunosuppressive therapy for life, hand allograft transplantation is worthy of interest in some outstanding situations.

Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions

Atypical haemolytic uraemic syndrome (aHUS) is associated with dysfunction of the alternative pathway of complement. Disease activity subsides as renal failure progresses but recurs upon renal transplantation, indicating that viable renal tissue contributes to disease activity. We present evidence of cerebrovascular occlusive disease indicating that vascular injury may occur in the absence of kidneys. A currently 12-year-old girl developed renal failure at the age of 20 months. She underwent bilateral nephrectomy and renal transplantation but lost the transplant due to recurrences. She was on haemodialysis for 7 years. At 10 years of age she developed a transient ischaemic attack. Imaging, genetic investigation and mutation characterization were performed. Imaging demonstrated occlusion and stenosis of the carotid arteries. Two complement mutations, a novel mutation in factor B and a previously described mutation in factor I, and the H3-factor H haplotype, were identified. The factor B mutation, L433S, did not induce excessive complement activation in vitro. Measurement of C3 degradation products indicated ongoing complement activation. In spite of the patient being anephric, treatment was initiated with eculizumab, a humanized anti-C5 antibody that blocks terminal complement activation. She underwent a successful kidney transplant 9 months later and has not developed a recurrence or progression of vascular stenosis 1 year later. The course of disease in this patient with aHUS suggests that complement-mediated vascular injury may occur in the total absence of renal tissue and overt recurrences. To our knowledge, this is the first description of eculizumab treatment in an anephric aHUS patient.

A Comparative Analysis of Bronchial Stricture After Lung Transplantation in Recipients With and Without Early Acute Rejection

Risk factors and outcomes of bronchial stricture after lung transplantation are not well defined. An association between acute rejection and development of stricture has been suggested in small case series. We evaluated this relationship using a large national registry. All lung transplantations between April 1994 and December 2008 per the United Network for Organ Sharing (UNOS) database were analyzed. Generalized linear models were used to determine the association between early rejection and development of stricture after adjusting for potential confounders. The association of stricture with postoperative lung function and overall survival was also evaluated. Nine thousand three hundred thirty-five patients were included for analysis. The incidence of stricture was 11.5% (1,077/9,335), with no significant change in incidence during the study period (P=0.13). Early rejection was associated with a significantly greater incidence of stricture (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.22-1.61; p<0.0001). Male sex, restrictive lung disease, and pretransplantation requirement for hospitalization were also associated with stricture. Those who experienced stricture had a lower postoperative peak percent predicted forced expiratory volume at 1 second (FEV1) (median 74% versus 86% for bilateral transplants only; p<0.0001), shorter unadjusted survival (median 6.09 versus 6.82 years; p<0.001) and increased risk of death after adjusting for potential confounders (adjusted hazard ratio 1.13; 95% CI, 1.03-1.23; p=0.007). Early rejection is associated with an increased incidence of stricture. Recipients with stricture demonstrate worse postoperative lung function and survival. Prospective studies may be warranted to further assess causality and the potential for coordinated rejection and stricture surveillance strategies to improve postoperative outcomes.

Lymphedema After Upper Limb Transplantation

Lymphatic vasculature is known to spontaneously reconnect after hand replantation. Nonetheless, lymphatic outflow has not been specifically studied in hand transplantation.Lymphedema was studied clinically and scintigraphically in 3 bilateral upper limb transplants performed in Valencia, Spain, since 2006. Case 1 was a radiocarpal level, case 2 midforearm and proximal forearm, and case 3 was a transhumeral transplantation. Follow-up was 5, 4, and 3 years, respectively. Clinically, in case 1, there was a left-sided moderate lymphedema, case 2 was normal, and a right-sided moderate lymphedema was present in case 3. Lymphoscintigraphy results were consistent with the clinical findings. It was normal in the 4 nonedematous limbs. In the 2 affected limbs, there were scintigraphic findings of lymphatic block and lymphangiectasia.The study demonstrates objectively that lymphatic circulation can reconnect spontaneously in hand transplantations, although not in a homogeneously efficient way.

Preoperative pulmonary artery pressure and mortality after lung transplantation

The purpose of this study was to determine the influence of changes in pulmonary artery pressure during the waiting period on survival after lung transplantation for pulmonary fibrosis. We identified 65 patients with pulmonary fibrosis who underwent lung transplantation from 2003 to 2010. Pulmonary artery pressure determined at listing was compared with intraoperative pressure. The primary outcome was overall survival. Co-variates included type of transplantation (single or bilateral), ischemic time, recipient and donor age and sex. The median age of the 65 patients undergoing transplantation was 58 years, and 27 (43%) underwent bilateral sequential transplantation. Twenty-two (35%) patients presented at transplantation with a mean pulmonary artery pressure increased by at least 10% compared to the initial pressure at the time of listing. Rising pulmonary artery pressure at transplantation was associated with increased mortality (p = 0.022). Other factors including type of operation, ischemic time, age, and sex, were not significantly associated with mortality. Post-transplantation survival was worse among recipients who had pulmonary artery pressure increased by at least 10% at transplantation (p = 0.003, logrank). Increasing pulmonary artery pressure while awaiting lung transplantation is associated with worse long-term survival following transplantation, and is a sign of progressively worsening disease for which greater urgency of donor organ allocation should be considered.

Bilateral Transfemoral Lower Extremity Transplantation: Result at 1 Year

Upper limb transplantation has become a treatment option for upper limb amputees with good midterm results. Lower extremity transplantation has never been considered for fear of poor results. The authors present a bilateral transfemoral transplantation of lower extremities performed to a 22-year patient at 12 months of follow-up. The donor was a full HLA-mismatched female multiorgan donor. CMV status was D-/R-. A primary CMV infection coincident with an acute rejection occurred at 3 months and responded to treatment. At 1 year, the Tinel's sign is at malleolar level, there is active knee extension and active plantar flexion of the foot. The patient is walking between parallel bars. Further substantial improvements are expected with longer rehabilitation and follow-up.

Protein Expression Profiling Predicts Graft Performance in Clinical Ex Vivo Lung Perfusion

Purpose To study the impact of normothermic ex vivo lung perfusion (EVLP) on cytokines, chemokines and growth factors and their correlation with graft performance either during perfusion or after implantation. Methods and Materials High-risk brain death donors and donors after cardiac death underwent 4-6 hours EVLP with intent to transplant. Using a multiplex magnetic bead array assay we evaluated multiple analytes in perfusate samples. Donor lungs were divided into three grous: I. Control: bilateral transplantation with good early outcome (absence of PGD grade 3); II. PGD3: bilateral lung transplantation with PGD grade 3 anytime within 72 hours; III. Declined: lungs rejected following EVLP. Single-lung transplants and patients bridged to LTx with extracorporeal life support were excluded. Results Of 36 cases included in this study, 17 were in group I, 6 in group II and 13 in group III. Of a total of 51 analytes, 30 were measurable in perfusates. While markers from samples at 1 hour had higher capacity for discrimination between groups I and III, at the end of EVLP there were more analytes significantly higher in group II compared to I. The best markers to differentiate declined lungs from controls lungs were IL-1ra (p=0.005, AUC 0.80) and SCGF-b (p Figure ) Conclusions Perfusate protein expression can differentiate lungs with good outcome from lungs with a poor outcome (PGD 3) after transplantation as well as lungs that were declined during EVLP.

Endothelin-1 and Big-Endothelin-1 as Potential Biomarkers in Clinical Ex Vivo Lung Perfusion

Purpose Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment and improvement of donor lungs prior to transplantation. We hypothesized that the endothelin-1 (ET-1) axis is associated with donor lung performance during EVLP and recipient outcomes after transplantation. Methods and Materials We assessed levels of ET-1, big ET-1 and endothelin converting enzyme 1 (ECE-1) in the perfusates of donor lungs enrolled in a clinical trial EVLP. The trial included lungs from high-risk brain death donors (BDD) and lungs from donation after cardiac death (DCD). They were divided into three groups: I. Control: bilateral transplantation with good early outcomes (absence of PGD grade 3); II. PGD3: bilateral lung transplantation with PGD grade 3 whithin 72 hours; III. Declined: lungs rejected following EVLP. Single-lung transplants and patients bridged with extracorporeal life support were excluded. Results There were 25 cases in group I, 7 in group II and 16 in group III. At 1 hour of EVLP, perfusates of declined lungs had significantly higher levels of ET-1 (3.1±2.1 vs 1.8±2.3 pg/ml, p=0.01) and big ET-1 (15.8±14.2 vs 7.0±6.5, p=0.001) compared to control lungs. At the 4 hours of EVLP, declined lungs also had higher levels of ET-1 (2.7±2.2 vs 1.3±1.1 pg/ml, p=0.007) and big ET-1 (31.7±17.4 vs 19.4±9.5 pg/ml, p=0.007) compared to controls. In BDD lungs the ET-1 axis did not show significant differences between groups. However for DCD cases, groups II and III had higher ET-1 and big ET-1 levels at 4 hr perfusion when compared to group I (group II vs I: ET-1 p=0.03, big ET-1 p=0.01; group III vs I: ET-1 p=0.007, big ET-1 p=0.003). There were no differences in ECE-1 levels between groups. Conclusions In DCD lungs ET-1 and big ET-1 in perfusate predicted outcomes after lung transplantation. They were also associated with non-utilization of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of selection of donor lungs.

Donor-Recipient Size Mismatch in Lung Transplantation Does Not Negatively Impact Survival: An Review of the UNOS Database

Purpose Depending on center preference, height or predicted total lung capacity (pTLC) is used for size matching in lung transplantation. However, there are conflicting reports regarding the impact of donor-recipient size mismatch on outcomes, and the interactions between lung size, recipient diagnosis, and single vs. bilateral transplantation have not been described. Methods and Materials We reviewed the UNOS database for all lung transplants performed for COPD or IPF from 1995-2011. Donor and recipient pTLC were calculated, and degree of mismatch was defined as donor/recipient height or pTLC. Lungs were considered mismatched if this ratio was ≤0.75 or ≥1.25. Within each diagnostic category, the effect of over- or under-sizing on 30-day, 1-, 3-, 5-, and 10-year mortality and rates of BOS were evaluated. Results In total, 10,375 patients were identified (COPD, n=6,113; IPF, n=4,262). Bilateral transplantation was more common in IPF (52% vs. 47%, p 0.199). The incidence of BOS (COPD, 12.2%; IPF 8.3%) and median time to BOS-related death (COPD 1,050; IPF 1,346 days) were independent of size mismatch. Subset analysis of oversized double lung transplant in IPF and undersized single lung transplant in COPD also showed no effect on overall or BOS-related mortality. Analyses using height for evaluating size mismatch yielded similar results. Conclusions In this study, significant donor-recipient size mismatch did not result in poorer overall or BOS-related mortality. These results suggest that acceptable outcomes can be achieved even in the setting of significant size mismatch, affording considerable flexibility in donor selection and increasing organ utilization.

CNE Article: Pain After Lung Transplant: High-Frequency Chest Wall Oscillation vs Chest Physiotherapy

Background Chest physiotherapy and high-frequency chest wall oscillation (HFCWO) are routinely used after lung transplant to facilitate removal of secretions. To date, no studies have been done to investigate which therapy is more comfortable and preferred by lung transplant recipients. Patients who have less pain may mobilize secretions, heal, and recover faster. Objectives To compare effects of HFCWO versus chest physiotherapy on pain and preference in lung transplant recipients. Methods In a 2-group experimental, repeated-measures design, 45 lung transplant recipients (27 single lung, 18 bilateral) were randomized to chest physiotherapy (10 AM, 2 PM) followed by HFCWO (6 PM, 10 PM; group 1, n=22) or vice versa (group 2, n=23) on postoperative day 3. A verbal numeric rating scale was used to measure pain before and after treatment. At the end of the treatment sequence, a 4-item patient survey was administered to assess treatment preference, pain, and effectiveness. Data were analyzed with χ(2) and t tests and repeated-measures analysis of variance. Results A significant interaction was found between mean difference in pain scores from before to after treatment and treatment method; pain scores decreased more when HFCWO was done at 10 AM and 6 PM (P =.04). Bilateral transplant recipients showed a significant preference for HFCWO over chest physiotherapy (11 [85%] vs 2 [15%], P=.01). However, single lung recipients showed no significant difference in preference between the 2 treatments (11 [42%] vs 14 [54%]). Conclusions HFCWO seems to provide greater decreases in pain scores than does chest physiotherapy. Bilateral lung transplant recipients preferred HFCWO to chest physiotherapy. HFCWO may be an effective, feasible alternative to chest physiotherapy. (American Journal of Critical Care. 2013;22:115-125).