Debra Kukuruga

Positive Cross-Match Living Donor Kidney Transplantation: Longer-Term Outcomes

The long‐term graft outcomes after positive cross‐match (PXM) living donor kidney transplantation (LDKT) are unknown and the descriptive published data present short‐medium term results. We conducted a retrospective cohort study of LDKT with PXM by flow cytometry performed at our center during February 1999 to October 2006, compared to a control group, matched 1:1 for age, sex, race, retransplantation and transplant year. The PXM group was treated with a course of plasmapheresis/low‐dose intravenous immunoglobulin (IVIg) preoperatively, and OKT3 or thymoglobulin induction.

Total face, double jaw, and tongue transplantation: An evolutionary concept

Background: The central face high-energy avulsive injury has been frequently encountered and predictably managed at the R Adams Cowley Shock Trauma Center. However, despite significant surgical advances and multiple surgical procedures, the ultimate outcome continues to reveal an inanimate, insensate, and suboptimal aesthetic result. Methods: To effectively address this challenging deformity, a comprehensive multidisciplinary approach was devised. The strategy involved the foundation of a basic science laboratory, the cultivation of a supportive institutional clinical environment, the innovative application of technologies, cadaveric simulations, a real-time clinical rehearsal, and an informed and willing recipient who had the characteristic deformity. Results: After institutional review board and organ procurement organization approval, a total face, double jaw, and tongue transplantation was performed on a 37-year-old man with a central face high-energy avulsive ballistic injury. Conclusions: This facial transplant represents the most comprehensive transplant performed to date. Through a systematic approach and clinical adherence to fundamental principles of aesthetic surgery, craniofacial surgery, and microsurgery and the innovative application of technologies, restoration of human appearance and function for individuals with a devastating composite disfigurement is now a reality. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

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.

Antibody-mediated allograft rejection: morphologic spectrum and serologic correlations in surveillance and for cause biopsies.

Background Subclinical antibody-mediated allograft rejection (AMR) has been characterized in serial biopsies from presensitized recipients but has not been systematically studied in conventional renal transplants. Methods We evaluated 1101 consecutive kidney transplant biopsies (400 surveillance biopsies [SBx] and 701 for cause biopsies [FCBx]) with concurrent donor-specific antibody (DSA) studies, C4d staining, and ultrastructural examination. Results A comparison of AMR-related features (DSA and DSA class, C4d staining, and microvascular injury) demonstrated that these were qualitatively and quantitatively associated with each other and with graft dysfunction. A major difference between SBx and FCBx was that the complete AMR phenotype was more common in FCBx. Among SBx, 8.5% showed complete or incomplete AMR with predominance of an incomplete phenotype (according to the Banff schema, these were acute AMR [23.5%], chronic active AMR [14.7%], suspicious for acute AMR [41.1%], suspicious for chronic active AMR [2.9%], and only microvascular injury insufficient to consider AMR [17.5%]). Persistence or worsening of AMR in a subsequent biopsy occurred in 38.2% of cases independently of the strength of AMR findings in the first biopsy (e.g., progression to chronic AMR occurred also in cases with suspicious or nondiagnostic findings). Temporal progression from subclinical to clinically evident AMR is consistent with the fact that, overall, the biopsies with incomplete phenotype (DSA±C4d) occurred between 14.52 and 20.86 months, whereas the complete phenotype occurred much later (36.71 months). Conclusion An accurate diagnostic interpretation of the potentially important but incomplete, subclinical, AMR phenotype represents a serious challenge that may impact clinical management.

Relation Between Normal Rectal Methylation, Smoking Status, and the Presence or Absence of Colorectal Adenomas

Colorectal cancer (CRC) is 1 of the leading causes of death in the Western world. CRC develops from premalignant lesions, chiefly colorectal adenomas. Currently, the most accurate and recommended screening method for finding colorectal adenomas is colonoscopy performed on all individuals aged >50 years. However, the costs and risks associated with this procedure are relatively high. The objectives of the current study were to correlate epigenetic alterations that occur in normal rectal mucosa, smoking status, and age with the presence or absence of concomitant colorectal adenomas and to assess the potential clinical value of methylation in normal rectal biopsies as a screening assay for the presence of polyps and, hence, the need for a full colonoscopy.

Thymoglobulin dose optimization for induction therapy in high risk kidney transplant recipients

Backgound. Thymoglobulin (rATG) has become the agent of choice for induction therapy in high immunological risk kidney transplant recipients. However, its optimal dosing in this subgroup has not been studied. Methods. To evaluate the effect of total rATG dosing on graft outcomes in such patients, we conducted a retrospective cohort study of 96 adult patients who received repeat transplants (85%) or had panel reactive antibody more than 40% (19%) and were maintained on tacrolimus, mycophenolate mofetil, and steroid. Group 1 (n=33) received less than or equal to 7.5 and group 2 (n=63) received more than 7.5 mg/kg rATG. Graft and patient survival, incidence of acute rejection (AR), and 12-month serum creatinine (SCr) were examined. Results. The groups were comparable regarding demographics, donor source, retransplantation, panel reactive antibody, and human leukocyte antigen mismatch. Group 2 had more African Americans (44.4% vs. 21.2%, P=0.03). During the 25.4±18.0 months follow-up graft survival was 82.5% and 79.4%, respectively (P=0.54). Three in group 1 and four in group 2 died (P=0.65). The incidence of biopsy proven AR during the first 12-months did not differ between the groups (9.5% vs. 8.8%, respectively, P=0.9). SCr at 12 months was 1.6±0.7 in group 1 and 1.8±1.0 in group 2 (P=0.3). There was no independent association between rATG dose and graft survival (hazard ratio: 0.85, P=0.79, 95% CI: 0.26–2.7 for group 2 vs. 1) or 1-year SCr (regression coefficient=0.02 for ln(SCr), P=0.3; 95%CI: −0.01 to 0.6). Conclusion. Our results suggest that in high risk kidney transplant recipients total rATG doses less than or equal to 7.5 mg/kg are safe and effective in achieving a low rate of AR and graft outcomes comparable to higher doses.

Prolonged Survival of Composite Facial Allografts in Non-Human Primates Associated With Posttransplant Lymphoproliferative Disorder

Background. Composite tissue allotransplantation may have different immunosuppressive requirements and manifest different complications compared with solid organ transplantation. We developed a non-human primate facial composite tissue allotransplantation model to investigate strategies to achieve prolonged graft survival and immunologic responses unique to these allografts. Methods. Composite facial subunits consisting of skin, muscle, and bone were heterotopically transplanted to mixed lymphocyte reaction-mismatched Cynomolgus macaques. Tacrolimus monotherapy was administered via continuous intravenous infusion for 28 days then tapered to daily intramuscular doses. Results. Five of the six animals treated with tacrolimus monotherapy demonstrated rejection-free graft survival up to 177 days (mean, 113 days). All animals with prolonged graft survival developed posttransplant lymphoproliferative disorders (PTLD). Three animals converted to rapamycin after 28 days of rejection of their allografts, but did not develop PTLD. Genotypic analysis of PTLD tumors demonstrated donor origin in three of the five analyzed by short-tandem repeats. Sustained alloantibodies were detected in rejecting grafts and absent in nonrejecting grafts. Conclusions. Tacrolimus monotherapy provided prolonged rejection-free survival of composite facial allografts in a non-human primate model but was associated with the development of a high frequency of donor-derived PTLD tumors. The transplantation of a large volume of vascularized bone marrow in composite tissue allografts may be a risk factor for PTLD development.

Antibody‐mediated rejection of renal allograft in combined liver–kidney transplant

Barth RN, Campos L, Kukuruga DL, Drachenberg C, Philosophe B. Antibody‐mediated rejection of renal allograft in combined liver–kidney transplant.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01161.x
© 2009 John Wiley & Sons A/S.

Donor-recipient human leukocyte antigen matching practices in vascularized composite tissue allotransplantation: a survey of major transplantation centers.

Background: Vascularized composite tissue allotransplant recipients are often highly sensitized to human leukocyte antigens because of multiple prior blood transfusions and other reconstructive operations. The use of peripheral blood obtained from dead donors for crossmatching may be insufficient because of life support measures taken for the donor before donation. No study has been published investigating human leukocyte antigen matching practices in this field. Methods: A survey addressing human leukocyte antigen crossmatching methods was generated and sent to 22 vascularized composite tissue allotransplantation centers with active protocols worldwide. Results were compiled by center and compared using two-tailed t tests. Results: Twenty of 22 centers (91 percent) responded to the survey. Peripheral blood was the most commonly reported donor sample for vascularized composite tissue allotransplant crossmatching [78 percent of centers (n = 14)], with only 22 percent (n = 4) using lymph nodes. However, 56 percent of the 18 centers (n = 10) that had performed vascularized composite tissue allotransplantation reported that they harvested lymph nodes for crossmatching. Of responding individuals, 62.5 percent (10 of 16 individuals) felt that lymph nodes were the best donor sample for crossmatching. Conclusions: A slight majority of vascularized composite tissue allotransplant centers that have performed clinical transplants have used lymph nodes for human leukocyte antigen matching, and centers appear to be divided on the utility of lymph node harvest. The use of lymph nodes may offer a number of potential benefits. This study highlights the need for institutional review board–approved crossmatching protocols specific to vascularized composite tissue allotransplantation, and the need for global databases for sharing of vascularized composite tissue allotransplantation experiences.

Early Microchimerism After Face Transplantation Detected by Quantitative Real-time Polymerase Chain Reaction of Insertion/Deletion Polymorphisms.

V composite allografts (VCA), such as hand and face transplants, offer an alternative approach to complex reconstructive scenarios that otherwise require multiple complex operations. Multiple face transplants with various components of skin, muscle, and bone have been performed worldwide, with the most extensive including mandible and maxilla, tongue, and skin performed in 2012 at the University of Maryland Medical Center. Microchimerism, defined as the presence of low levels of donor-derived cells (<1%), has not been definitively associated with improved immunologic outcomes. We investigated the presence of chimerism in our clinical full-face VCA with upper and lower jaw vascularized bone marrow components using established techniques of flow cytometry and short tandem repeat analysis without detecting any evidence of macrochimerism. We subsequently analyzed postoperative whole blood samples from our face transplant recipient using a commercial assay (AlleleSEQR) that screens and quantifies DNA by quantitative polymerase chain reaction (PCR) using insertion/deletion (InDel) polymorphisms as genetic markers sensitive to 0.001%.