Vascularized Composite Allotransplantation in Burn Reconstruction: Systematic Review and Meta-analysis

3281 Management of Acute Rejection in Penile Allotransplantation

Approximately 7 million individuals (over 1 million amputees) require complex reconstructive procedures in the United States each year. The recent success of clinical composite tissue allotransplantation, attests to the fact that composite tissue allografts have tremendous potential in these life-enhancing reconstructions. This review summarizes the initial outcomes of the first four human hand transplants, together with those of the first larynx, bone, knee, nerve and tendon transplants, with special emphasis on the operative technique, graft survival and functional outcomes. The May 2000 Louisville symposium, where these results were presented was undoubtedly a milestone in the history of modern composite tissue allotransplantation. It set the stage for reconstructive and transplant surgeons, researchers, physiotherapists, patients and patient advocates and members of the community to convene and discuss major advances in current composite tissue allotransplantation. The symposium underscored the vital importance of objective evaluation of the status of composite tissue allotransplantation by frank dissemination of details of clinical results and complications of the transplants performed thus far. The composite tissue allotransplantation area is among the newest of transplant areas. The immunology of composite tissue allografts is complex, making tolerance more difficult to achieve than organ tolerance. It needs to be emphasized that any episodes of acute rejection should be prevented for perfect restoration of function and to minimize the risk of chronic rejection in composite tissue allografts. Efficacious, safe and ethical clinical tolerance protocols could improve patient acceptance of composite tissue allografts by providing an alternative to chronic immunosuppression.

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

Brenner, Michael J. MD; Tung, Thomas H. MD; Jensen, John N. MD; Mackinnon, Susan E. MD Author Information

Tumor necrosis factor-alfa (TNF-α) gene polymorphism is supposed to have a significant influence on the incidence of acute rejection in renal transplantation. The monocyte chemoattractant protein-1 (MCP-1) is another factor supposed to modulate graft rejection. We studied TNF-α and MCP-1 gene polymorphisms in 84 kidney allograft recipients with polymerase chain reaction and restriction fragment length polymorphism and their serum levels by enzyme-linked immunosorbent assay. The patients were classified into two groups based on their outcomes: Group I (n = 47) recipients with stable graft function as the control group and group II (n=37) recipients who experienced acute graft rejection episodes in the first 30 days post-transplantation. A significantly higher incidence of TNF 2 /TNF 2 genotype was observed among patients with acute graft rejection in comparison with the control group (40.5% and 19.2% respectively, P <0.05), while no statistically significant differences were observed in the TNF 1 /TNF 1 genotype between the groups (59.4% and 80.8%, respectively, P >0.05). A significant elevation of serum TNF-α levels was found in group II than group I and between TNF 2 genotype compared with that of TNF1 genotype within group II recipients. Distribution of MCP-1 genotypes in patients with and without acute rejection episodes was not significantly different (70.2% and 76.6% for MCP-1 A/A and 29.7% and 23.4% for MCP-1 G/G, respectively, P >0.05). The serum MCP-1 levels were not significantly different between the groups and between MCP-1 G/G genotype and MCP-1 A/A genotype in group II recipients. In conclusion, TNF-α gene polymorphism or its serum levels may identify patients at risk of acute rejection, where patients with TNF 2 /TNF 2 genotype or high serum TNF-α levels are more likely to have acute rejection episodes, while there was no relation between MCP-1 genotype or its serum levels and acute rejection.

Donor age was identified recently as a major factor that determines long-term outcome after transplantation, but the mechanism that is responsible for increased graft loss of old donor kidneys is unknown. The influence of donor age on graft survival was assessed retrospectively in 514 consecutive first cadaveric transplants that were treated with cyclosporine maintenance immunosuppression. Donor age > or =50 yr (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.2 to 2.6), acute rejection (RR = 2.0; 95% CI, 1.3 to 3.0), and type of rejection (RR = 3.3; 95% CI, 2.0 to 5.3) had a significant impact on graft survival. However, when subsets of patients who entered subsequent intervals after transplantation were analyzed, donor age was not an independent predictive factor of graft loss. Donor age (RR = 1.53; 95% CI, 1.19 to 1.98), human leukocyte antigen-DR mismatch (RR = 2.28; 95% CI, 1.78 to 2.92), and recipient age (RR = 1.34; 95% CI, 1.05 to 1.72) were associated significantly with acute rejection episodes. Delayed graft function alone was not associated independently with the occurrence of early acute rejection (RR = 1.24; 95% CI, 0.96 to 1.61). The timing of the rejection episodes of old donor kidneys was not different, and the excess rejection prevalence was attributable entirely to interstitial (grade I) types of rejection. Interstitial rejection episodes in kidneys from old donors had a significant (P < 0.05) negative impact on graft survival. Beyond the first year, poor renal function and proteinuria were significant risk factors for graft loss, regardless of rejection. Our data fit best the hypothesis that increased graft loss of older donor kidneys results from an increased incidence of acute interstitial rejection episodes in the early posttransplantation months. It is proposed that kidneys from older donors are more immunogenic than kidneys from young donors and that acute rejection episodes result in functional deterioration. Contrary to interstitial rejection in kidneys from younger donors, kidneys from old donors seem to have an impaired ability to restore tissue.

During the first episode of acute cellular rejection (ACR) after liver transplantation, centrilobular changes in liver biopsy specimens may be possible indicators of subsequent episodes of ACR, early chronic rejection, or acute graft loss. The purpose of this study was to identify differences between the histopathological findings in liver biopsy specimens obtained during the first rejection episode in patients who subsequently developed further episodes of ACR and those who did not. The histopathological findings in 22 patients who had a single episode of acute rejection (group 1) were compared with those in 23 patients who had multiple episodes of acute rejection (group 2). Only the first liver biopsy samples of the latter group were taken into consideration. We assessed the predictive value of centrilobular necrosis, central vein endothelialitis, pericentral inflammation, hepatocellular ballooning, cholestasis, hepatocellular apoptosis, lobular inflammation, the degree of portal eosinophilia, and characteristic portal tract features in poor responders to antirejection treatment. The time to the first episode of ACR and the rejection activity index were similar in patients in both groups. Hepatocellular apoptosis, hepatocellular ballooning, and central vein endothelialitis were common features of both groups. The incidences of pericentral inflammation, centrilobular necrosis, and portal eosinophilia were significantly higher in patients in group 2 than in those in group 1 (P < 0.05). Patients with pericentral inflammation, centrilobular necrosis, and marked portal eosinophilia during an initial episode of acute rejection may be more likely to develop subsequent episodes of ACR.

Known since antiquity, rickets was a common disease until the beginning of the 20th century. It took many years and the collaborative effort of several laboratories to identify the compound present in cod liver oil responsible for the therapeutic effect against rickets. The vitamin D structure was finally described in 1936 by the German chemist Adolf Windaus (1876–1959). Since then, we have come to understand the synthesis of 1α,25(OH)2-vitamin D3 (calcitriol) and its mechanism of action through a nuclear receptor, VDR, to regulate calcium homeostasis and bone mineralization. VDR is expressed not only in intestinal cells and osteoblasts but also constitutively in monocytes and in activated macrophages, dendritic cells, natural killer cells, T and B cells, which suggests immunomodulatory functions for calcitriol. Calcitriol acts as an inhibitor of the adaptive immune system. It has inhibitory effects on macrophages and dendritic cells. Calcitriol enables dendritic cells with tolerogenic properties (1) and acts directly in Th cells to enhance the development of a Th2 phenotype (2). These features could be of benefit in the transplantation setting. In retrospective studies, the administration of calcitriol to kidney transplant recipients improved graft function, graft survival and decreased episodes of acute rejection (3–5). Similar results have been published for heart transplantation. Low post-operative calcitriol serum concentrations are independently associated with high 1-year mortality in cardiac transplant recipients (6). Patients receiving low-dose calcitriol after cardiac transplantation required substantially lower cumulative doses of cyclosporin for organ rejection without any detectable change in the episodes of rejection (7). What about liver transplantation and calcitriol? We investigated the effect of calcitriol as an immunosuppressive agent in an experimental model for liver transplantation (8). Calcitriol increased the survival of vascularized liver allografts in rats when compared with controls. Vitamin D reduced the concentration of interleukin (IL)-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity after transplantation was significantly lower in treated rats compared with vehicle-treated controls. In this issue of Liver International, Bitetto et al. (9) present a highly anticipated clinical study that investigates whether vitamin D has beneficial immune properties after liver transplantation. Based on a collection of 133 liver transplantation recipients, the authors report that a low pretransplant serum 25-OH vitamin D is independently associated with rejection episodes (Banff score ≥6) in the first 2 months following liver transplantation and that the introduction of vitamin D3 supplementation in the first month after liver transplantation is associated with a decreased risk for acute rejection (Banff score ≥3) in the following 3–8 months. These results are not surprising, but are important nonetheless. It is estimated that two-third of patients with cirrhosis and 96% of patients awaiting liver transplantation have low serum vitamin D levels (10) and the present study found optimal vitamin D levels (>30 ng/ml) in only 7.5% of the patients tested. Osteoporosis, which increases the risk of vertebral fractures, occurs in 12–55% of patients with cirrhosis (10). In the months following liver transplantation, further bone loss occurs in most liver recipients and exacerbates pre-existing osteopenia with a high incidence of fracturing (10). Patients listed for a liver transplantation should then receive vitamin D before and after transplantation. This supplementation is safe, well tolerated and appears to have additional non-negligible immune effects. Acute rejection is rarely a serious issue after liver transplantation today. Nevertheless, immunosuppressive drugs have side effects, which limit the long-term benefit of liver transplantation. Calcineurin inhibitors impair renal function and every large liver transplantation centre must provide dialysis for some of their transplant recipients and some even receive kidney transplantation. The hope that mTOR inhibitors could serve as renal protective immunosuppressors is vanishing. A retrospective, controlled study showed that the administration of sirolimus after orthotopic liver transplantation did not protect against renal dysfunction (11). Another case–control retrospective series suggested that the choice of sirolimus for liver transplant patients with chronic renal insufficiency is associated with the stabilization of renal function but conferred no additional benefit over low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of <30 ml/min (12). In this context, vitamin D as a calcineurin inhibitor sparing immunosuppressant in liver transplantation is an attractive option. The retrospective nature of the work of Bitetto is a disadvantage as are the arbitrarily chosen endpoints. It is imperative that prospective randomized studies be designed in the liver transplantation field to establish definitively the immunosuppressive role of vitamin D as it is already the case in the renal transplantation field (13). We should not miss the opportunity to treat the bones and get less rejection!

Interleukin-17 Promotes Early Allograft Inflammation

What is happening with hand transplants?

BackgroundVascularized composite allotransplantation (VCA) offers unique reconstructive solutions for severe tissue loss, restoring form and function. Acute and chronic rejection remains a significant barrier, with acute episodes occurring in most recipients and chronic rejection persisting as the leading cause of graft failure. Unlike solid organ transplantation, VCA involves highly immunogenic tissues, like skin and mucosa, making rejection more frequent and challenging to manage.MethodsA systematic review was conducted following PRISMA 2020, searching PubMed/MEDLINE, EMBASE, and Web of Science for original human VCA studies reporting immunosuppressive protocols and outcomes in acute or chronic rejection. Quality was assessed using the Newcastle–Ottawa Scale and Level of Evidence; extracted data included demographics, regimens, rejection episodes, treatments, and graft survival.ResultsFourty-six studies (136 recipients) met inclusion criteria: upper extremity (n=69; 51%), face (n=33; 24%), abdominal wall (n=33; 24%), scalp and penile (each n=1; 0.7%). Acute rejection occurred in 81/136 (60%) within year 1, most often at POW 1–2 (n=52), 5–12 (n=42), and 13–52 (n=30). Severity was Banff grade I (n=49; 36%), II (n=73; 54%), III (n=50; 37%), and severe IV (n=1; 0.7%). Common symptoms included skin lesions (n=43; 32%), edema (n=32; 24%), erythema (n=29; 21%), and rash (n=15; 11%), with some experiencing numbness (n=4; 2.9%), tingling (n=5; 3.7%), or burning sensations (n=5; 3.7%). Corticosteroids were the mainstay (n=98; 72%)—methylprednisolone (n=31; 23%), clobetasol (n=15; 11%), and prednisone (n=11; 8.1%); tacrolimus was used in 49 (36%), including topical in 29 (21%). Other immunosuppressants included antithymocyte globulin (n=19; 14%), alemtuzumab (n=11; 8.1%), mycophenolate mofetil (n=11; 8.1%), and rituximab (n=6; 4.4%); basiliximab (n=4; 2.9%), sirolimus (n=2; 1.5%), and plasmapheresis (n=4; 2.9%) were used selectively. Monotherapy was used in 42 episodes, and dual therapy in 51, most commonly methylprednisolone plus topical tacrolimus (n=26).ConclusionThis review underscores the ongoing challenge of rejection in VCA and the need for improved treatment strategies, with corticosteroids, calcineurin inhibitors, and mycophenolate mofetil remaining standard while emerging biologicals offer promise. Acute rejection is often manageable yet threatens graft survival, whereas chronic rejection is less reported, likely under-recognized and harder to treat, underscoring need for novel immunomodulators, standardized protocols, and prevention to improve outcomes.

Increased expression of graft intraepithelial T-Cell pro-inflammatory cytokines compared with native lung during episodes of acute rejection

To study the complication incidence of 54 patients with chronic HBV infection following orthotopic liver transplantation (OLT) and risk factors associated with HBV recurrence and hepatocellular carcinoma (HCC) recurrence or metastasis post-OLT. The light-microscopic appearance of hepatic allograft biopsies in 54 patients with chronic HBV infection following OLT was examined. The related clinical data were analyzed. The incidence and occurrence time of post-OLT complications were studied. Furthermore, the relationship between hepatitis B virus recurrence and acute rejection and the relationship among HCC recurrence/metastasis, acute rejection, tumor diameter, and portal vein invasion were particularly studied. Frequent complications of patients with chronic HBV infection following OLT were acute rejection [38 (70.4%); occurrence time: 5-365 days], chronic rejection [1 (1.9%); occurrence time: 10.7months], bile duct complications [24 (44.4%);occurrence time: 7-940days], HBV recurrence [7 (13.0%); occurrence time: 1-540days], HCV infection [3 (5.6%); occurrence time: 60days, 60days, 33months], CMV infection [8 (14.8%); occurrence time: 67-90days], and HCC recurrence or metastasis [17 (31.5%); occurrence time: 2-41months]. At the end of 1year post-OLT, 95% of patients with post-hepatitis B cirrhosis were alive. At the end of 3years post-OLT, 85% of patients with post-hepatitis B cirrhosis were alive. However, at the end of 1year post-OLT, 67.6% of patients with post-hepatitis B HCC were alive. At the end of 3years post-OLT, 50% of patients with post-hepatitis B HCC were alive. The number of acute rejection episodes in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.86±1.46 times/patient and 1.07±0.90 times/patient, respectively (p>0.05); the number of moderate acute rejection episodes (RAI score ≥4) in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.29±0.49 times/patient and 0.50±0.63 times/patient (p>0.05). Incidence of patients with ≥3 episodes of acute rejection in patient with recurrent HBV infection and in those without recurrent HBV infection was 14.3 and 10.6% (p>0.05). Furthermore, the number of acute rejection episodes in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 1.12±0.93 times/patient and 1.06±1.39 times/patient, respectively (p>0.05). The number of moderate acute rejection episodes (RAI score ≥4) in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 0.65±0.79 times/patient and 0.65±1.06 times/patient, respectively (p>0.05). Incidence of patients with ≥3 episodes of acute rejection in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 5.9 and 17.6%, respectively (p>0.05). The tumor diameter in patients with HCC recurrence or metastasis was 6.72±3.40 cm; however, that in patients without HCC recurrence or metastasis was 3.55±2.17 cm (p=0.0047). The incidence of portal vein invasion in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 68.75 and 33.3%, respectively (p=0.006). There was no significant difference between HBV recurrence and acute rejection post-liver transplantation in patients with chronic HBV infection. There was no significant difference between HCC recurrence and acute rejection. The tumor diameter in patients with HCC recurrence or metastasis was significantly greater than that in patients with no HCC recurrence or metastasis. Portal vein invasion was significantly more frequent in patients with HCC recurrence or metastasis than in those with no HCC recurrence or metastasis.

Induction immunosuppression is now a common practice after intestinal and multivisceral transplantation. We report our experience in 27 adult recipients who received rituximab and rabbit antithymocyte globulin (rATG) in combination as induction agents. Twenty-seven adult patients received 29 intestinal transplants between July 2004 and March 2007. All patients received induction immunosuppression therapy with rATG, rituximab, and steroids. Tacrolimums and a steroid taper were used for maintenance therapy. Patient and graft survival, episodes of rejection as well as posttransplant lymphoproliferative disease (PTLD) and graft-versus-host disease were analyzed. One-year patient and graft survival was 81% and 76%, respectively. Thirteen patients (48%) experienced 19 episodes of acute rejection (9 mild episodes, 2 moderate, and 8 severe). Patients with a multivisceral graft experienced less episodes of severe acute rejection (1 of 19, 5%) when compared with isolated intestinal transplants and modified multivisceral transplants (7 of 10, 70%). Two patients had episodes of skin graft-versus-host disease that responded to steroid boluses. PTLD was not seen in our series. Two patients developed cytomegalovirus enteritis. The combination of rATG and rituximab was an effective induction therapy in our preliminary data. The number and severity of rejection episodes increased when the liver was not included as part of the graft. An immunosuppression regimen including rATG, rituximab, and steroids may have a protective effect against PTLD and chronic rejection.

Genetic factors other than HLA have been reported to be associated with the outcome of organ transplantations. Because binding of FasL to its receptor Fas could play an important role in tubulitis and in the death of graft tubular epithelial cells during kidney allograft rejection, a gene polymorphism recently identified in position -671 in the promoter of the TNFRSF6 gene coding for Fas was investigated in donors. A case-control study was performed within a cohort of non-hyperimmunized adult patients who had received cadaveric kidney transplants based on the occurrence or absence of acute cellular rejection in the first 6 months after renal transplantation. Each recipient from the acute rejection group (n = 35) was matched for age (+/- 5 years) and number of HLA-DR mismatches with two recipients within the non-acute rejection group (n = 70). The TNFRSF6-GG genotype was more frequent in donors in the group without rejection episodes. In contrast, patients who received a kidney from a TNFRSF6-A carrier were more likely to experience acute rejection episodes (relative risk nearly 2.1). This study suggests that donor TNFRSF6 polymorphism directly or indirectly influences acute kidney rejection episodes.