Primary Cause Of Graft Failure Research Articles

Incidence of Complications Related to Corneal Graft in a Group of 758 Patients.

Purpose: this study aimed to assess the frequency of complications related to corneal grafts, including epithelialization disorders, wound dehiscence, infectious keratitis, recurrence of herpetic keratitis, graft rejection, late graft failure, and infectious and noninfectious corneal melting, while also considering risk factors, particularly indications. Methods: this retrospective analysis of corneal graft failure included a chart review of the hospital records of patients who underwent penetrating keratoplasty (PK) between January 2016 and December 2020 at the Department of Ophthalmology of the District Railway Hospital, Katowice, Poland. Results: Between 2016 and 2020, a total of 758 PK procedures were carried out at the ophthalmology department. Bullous keratopathy (20.58%), keratoconus (18.07%), and corneal perforation (13.32%) were the primary indications for keratoplasty. Secondary glaucoma was diagnosed in 99 patients (13.06%). The success rate of PK was 72.43% (494). The most frequent treatment complication was secondary glaucoma (13.06%), followed by late endothelial failure, perforation (4.1%), and bacterial keratitis (3.23%). Patients in the high-risk group were 4.65 times more likely to develop complications than those in the low-risk group. Multivariate regression analysis showed that concomitant ophthalmic diseases (odds ratio (OR): 3.12, confidence interval (CI): 1.60−6.08, p = 0.00) and connective tissue diseases (OR: 7.76, CI: 2.40−25.05, p = 0.00) were significant factors associated with the occurrence of complications. Diabetes, dermatological diseases, primary glaucoma, and sex were not associated with corneal graft failure (p > 0.05). Conclusion: Chronic loss of the endothelium was the primary cause of graft failure in individuals who underwent PK. The high-risk transplant has up to 4.65 times higher risk of complications compared to the indications with a good prognosis.

P1333: PLASMA EXCHANGE, IMMUNOGLOBULIN & PRE-TRANSPLANT IMMUNOSUPPRESSION: AN EFFECTIVE DESENSITISATION STRATEGY FOR DSA ALLOANTIBODIES IN HAPLOIDENTICAL HCT FOR PAEDIATRIC RED CELL DISORDERS

Background: Near universal availability of HCT is possible due to the feasibility of haploidentical transplantation [haplo HCT] with the use of post-transplantation cyclophosphamide or TCRαβ CD+19 depletion, enabling HCT for haemoglobinopathies and rare inherited anaemias for whom donors are underrepresented in registries. Patients with these disorders are at increased risk of developing anti-HLA antibodies having often received multiple transfusions pre-transplantation. HLA antibodies constituting donor specific antigens [DSA] affect approximately 15% of haplo HCT [Leffel, 2013] representing a significant cause of primary graft failure [Ciurea, 2009]. An effective desensitisation strategy is necessary as alternative donors for haploidentical HCT are often lacking. Several desensitisation approaches have been developed based on strategies used for solid organ transplantation, yet there exists no consensus in their application to haplo HCT for paediatric haemoglobinopathies where there is a particularly high risk of graft failure [de la Fuente, BBMT 2019, de la Fuente, ASH 2020]. Aims: To assess the efficacy of plasma exchange, high dose immunoglobulin and pre-transplant immunosuppression as a desensitisation strategy for DSA alloantibodies in paediatric patients undergoing haploidentical HCT for red cell disorders. Methods: Seven [17.5%] patients were found to have HLA class I DSA in 40 consecutive related reduced-intensity conditioning haplo HCT with post-transplant cyclophosphamide for red cell disorders performed at St Mary’s Hospital from 2013 to December 2021. The MFI cut off used was 2,000U. Transplant indications included homozygous sickle cell disease [n=5], HbSβ0 thalassaemia [n=1] and Diamond-Blackfan anaemia [n=1]. Median age was eight years [range 3-15 years]. Five children were female. Two patients had two different DSA. Each patient received a regimen based on the John Hopkins protocol [Leffel, 2013], comprising a single dose of rituximab 375mg/kg, four alternate day cycles of single volume plasmapheresis [replacing 100% volume with 5% albumin] and anti-CMV hyperimmune immunoglobulin 100mg/kg on days -16, -14, -12 and -10 before the initiation of the conditioning regimen and a further cycle of single volume plasmapheresis on D -1 and anti-CMV hyperimmune immunoglobulin 100mg/kg, and immunosuppression with tacrolimus and MMF to Day 0. HLA antibodies were measured on Day 0 prior to HSC infusion. If the MFI had not decreased <2000U, two further cycles of single volume plasmapheresis and anti-CMV hyperimmune immunoglobulin 100mg/kg were given on D+1 and D+2. Results: The median MFI at baseline was 5,974 U [range 1,544-22806U]. The protocol was well tolerated and completed without serious adverse events in all patients. Four patients required additional cycles on days +1 and +2. Median MFI at protocol completion was 230U [range 0-769U]. No patient suffered primary graft failure. Median time to neutrophil engraftment was 21 days [range 15-24]. All patients achieved full donor whole blood chimerism on D+28 and wheras there was mixed chimerism in the T cell fraction in three of the patients, this improved over time in all patients and no patient suffered secondary graft failure. Summary/Conclusion: The use of a desensitisation protocol comprising the combination of plasma exchange, high dose immunoglobulin and pre transplant immunosuppression constitutes an effective desensitisation strategy for DSA and abrogates the risk of graft failure in multiply transfused paediatric patients undergoing haploidentical HCT for red cell disorders, enabling HCT where no alternative donor exists.

High-grade preoperative osteoarthritis of the index compartment is a major predictor of meniscal allograft failure.

Preoperatively available predictors of meniscal allograft failure would help in patient counseling and surgical indication for meniscal allograft transplantation (MAT). It was hypothesized that young patient age, high posterior tibial slope (PTS), and high-grade osteoarthritis (OA) are predictors of meniscal allograft failure. Patients undergoing MAT with a minimum follow-up of 2years were included in this retrospective study. Demographic and surgical data, and causes of meniscal allograft failure were collected. PTS and degree of OA (low-grade: Kellgren-Lawrence 0, 1, and 2; high-grade: Kellgren-Lawrence 3 and 4) of the index and opposite tibiofemoral compartments were determined on preoperative radiographs. This study included 77 patients with a mean age of 25.7 ± 10.1years at the time of MAT. After a mean follow-up of 7.6 ± 5.6years, meniscal allograft failure was observed in 26 patients (34%). The median time from MAT to meniscal allograft failure was 1.3years (inter-quartile range, 2.5years). Meniscal allograft tears (88%) were the primary cause of graft failure, followed by high-grade OA (12%). Patients experiencing meniscal allograft failure were an average of 2.7years (95% CI [2.2, 7.5], p = 0.202) older at the time of MAT than patients without failure. PTS was not found to be a predictor of meniscal allograft failure (odds ratio, 0.884 (95% CI [0.727, 1.073], p = 0.212)). Patients with high-grade preoperative OA of the index compartment had 28 times higher odds of experiencing meniscal allograft failure than patients with low-grade preoperative OA (p = 0.008). High-grade preoperative OA of the index compartment was found to be a significant and clinically relevant predictor of meniscal allograft failure. Surgeons should be aware of the impact of OA on meniscal allograft survival, which needs to be considered in patient counseling and surgical indication for MAT in patients.

Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection.

Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.

Pancreas allograft biopsies procedure in the management of pancreas transplant recipients.

Pancreas transplantation is an effective therapy for diabetic patients, which can significantly improve the survival rate and quality of life of diabetic patients. According to the international registration of pancreas transplantation center, the global total pancreas transplantation has reached more than 80,000 cases by 2017, including pure pancreas transplantation and simultaneous pancreas-kidney transplantation (SPK). With the development and application of a new type of immunosuppressant, with the gradual maturity of organ preservation technology and surgical technology, the pancreas transplantation has rapidly on a global scale. However, pancreas transplantation still has more problems than limit its development compared with other organ transplantation. For example, the early diagnosis and treatment of pancreatic rejection are of considerable significance to the prognosis of pancreas transplantation. Some surveillance methods of diagnosis have been used increasingly, among which the histopathological diagnosis is particularly important. The first Banff schema for the histological diagnosis of pancreas rejection has been published, which primarily dealt with the diagnosis of acute T-cell-mediated rejection (ACMR). In recent years, antibody-mediated rejection (AMR) has been more emphasized as the primary cause of graft failure. The Banff pancreas allograft rejection grading schema was updated in 2011 by a broad-based multidisciplinary panel, presenting comprehensive guidelines for the diagnosis of AMR.

Development and Validation of a Risk Model for Primary Graft Failure after Heart Transplantation and Comparison to the RADIAL Risk Score

Purpose Primary graft failure (PGF) is the leading cause of early mortality following heart transplantation (HTx). Many risk factors and scores for the development of PGF have been defined, e.g. the RADIAL score. Since then a new ISHLT consensus paper was published and took new risk factors and pathological consideration into account. Therefore, the aim of this study is to develop and validate a new risk score based on the ISHLT Transplant Registry Database (TRD). Methods The ISHLT TRD (time-period 2005-June 2017) was used. Pediatric pts. (n = 6944) and pts. who underwent repeat-HTx or multi-organ transplantation (n = 2134) were excluded. Pts. with complete available data on donor/recipient age, sex, height, weight and recipient mean PA, PCW and CO were included. A dataset of 23,004 pts. was used including PGF (within first 30 d after HTx) as the primary cause of graft failure, death, or retransplant in 644 pts. Since RA pressure was not recorded in the ISHLT TRD, a modified RADIAL risk score excluding RA pressure was applied. At first, 173 variables were defined as potential predictors of PGF. Based on the year of HTx, the final database was split in a derivation (17229 pts.; 2005-2014; 532 PGF cases) and validation cohort (5775 pts.; 2015-2017; 112 PGF cases),followed by the application of a LASSO algorithm for variable selection. A logistic regression model was built by using the prior selected variable. The performance of the model (measured by AUC) was assessed in the validation and derivation dataset, and compared to the performance of the modified RADIAL score. Based on the regression coefficients, a point-based score was built. Results A model including 27 predictors was derived in the derivation cohort. The AUC of this model was calculated with 0.69. After correcting for overoptimism, the AUC was 0.67. The AUC in the validation cohort was similar with 0.72 (p Conclusion Based on the ISHLT TRD we developed a new score model with a higher predictive value than the RADIAL score. This new model has the advantage of including donor and recipient characteristics, and might therefore improve the outcome by early treatment of primary graft failure in patients at risk.

Primary graft failure following cardiac transplantation—our experience over 18 months

Primary graft failure (PGF) remains the strongest determinant of perioperative mortality after heart transplantation (HT). It manifests as a severe systolic dysfunction of the graft—left, right, or biventricular—requiring high inotropic doses with or without mechanical circulatory support. PGF was defined by four criteria reflecting significant myocardial dysfunction, severe hemodynamic impairment, and early onset after heart transplantation, and absence of secondary causes of graft dysfunction. This study looks at the incidence and outcomes of PGF at our center after we started heart transplant 18 months ago. Eleven orthotopic heart transplants were done at this center from May 2013 till November 2014. All patients were included in the study. All transplants were done in the same standard biatrial technique and by the same surgeon. PGF was defined as echocardiographic finding of dysfunction of either or both ventricles; cardiogenic shock lasting more than 1 h in the form of systolic blood pressure less than 90 despite adequate filling pressures of 15 mm CVP; or requirement of mechanical circulatory devices like IABP, ECMO, or VAD. Secondary causes of PGF like hyper acute rejection or cardiac tamponade were excluded. Four patients out of 11 had PGF (36 %). One had isolated LV dysfunction in the form of sluggish LV on echocardiogram requiring IABP support for 48 h. Three patients required ECMO in the immediate post operative period and only one could be successfully weaned off. Mortality was two patients (18 %). PGF is the lone cause of mortality in our series and results are improving with increasing understanding of the causes and better and judicious use of mechanical circulatory devices.

Cilostazol, Not Aspirin, Prevents Stenosis of Bioresorbable Vascular Grafts in a Venous Model.

Despite successful translation of bioresorbable vascular grafts for the repair of congenital heart disease, stenosis remains the primary cause of graft failure. In this study, we investigated the efficacy of long-term treatment with the antiplatelet drugs, aspirin and cilostazol, in preventing stenosis and evaluated the effect of these drugs on the acute phase of inflammation and tissue remodeling. C57BL/6 mice were fed a drug-mixed diet of aspirin, cilostazol, or normal chow during the course of follow-up. Bioresorbable vascular grafts, composed of poly(glycolic acid) mesh sealed with poly(l-lactide-co-ε-caprolactone), were implanted as inferior vena cava interposition conduits and followed up for 2 weeks (n=10 per group) or 24 weeks (n=15 per group). Both aspirin and cilostazol suppressed platelet activation and attachment onto the grafts. On explant at 24 weeks, well-organized neotissue had developed, and cilostazol treatment resulted in 100% graft patency followed by the aspirin (67%) and no-treatment (60%) groups (P<0.05). Wall thickness and smooth muscle cell proliferation in the neotissue of the cilostazol group were decreased when compared with that of the no-treatment group at 24 weeks. In addition, cilostazol was shown to have an anti-inflammatory effect on neotissue at 2 weeks by regulating the recruitment and activation of monocytes. Cilostazol prevents stenosis of bioresorbable vascular graft in a mouse inferior vena cava implantation model up to 24 weeks and is accompanied by reduction of smooth muscle cell proliferation and acute inflammation.

Standardized DMEK Technique: Reducing Complications Using Prestripped Tissue, Novel Glass Injector, and Sulfur Hexafluoride (SF6) Gas.

To report low complication rates in Descemet membrane endothelial keratoplasty (DMEK) using sulfur hexafluoride (SF6) gas, a novel glass injector, and donor tissue prestripped by an eye bank technician. A standardized technique of DMEK was performed in 80 consecutive Fuchs corneal dystrophy cases using technician-prestripped tissue, a novel glass injector, a modified Yoeruek tap technique, and an SF6 gas (20% concentration) bubble for prolonged tissue support. Twenty-five donors were premarked with an "S" stamp for intraoperative orientation. Surgery was performed by 2 experienced DMEK surgeons and 2 inexperienced cornea fellows. Complications were recorded, and the percent endothelial cell loss was calculated at 6 months postoperatively. There were 5 cases that received an air bubble injection postoperatively (6% rebubble rate). There were 6 grafts that immediately failed, 2 because of excessive surgical trauma, and 4 because of upside-down graft placement documented by optical coherence tomography. None of the 25 cases with an S stamp failed. Recipient corneas cleared quickly with no clinical evidence of toxicity from the SF6 gas bubble, and the grafts experienced a mean endothelial cell loss of 27% at 6 months. Tissue prestripped by an eye bank technician can be safely used for DMEK surgery. SF6 gas for prolonged tissue support may reduce the rebubble rate in DMEK, with no apparent acute toxic effect. An unrecognized upside-down graft was the primary cause of graft failure in this series. Upside-down grafts may be eliminated by the use of donor tissue premarked by the eye bank with an S orientation stamp.

Case series: Revision anterior cruciate ligament reconstructions using patellar tendon autografts

BackgroundUsing intra-operative findings and clinical results, including return to play (RTP) at the pre-injury level, this study investigated the causes of primary graft failure after revision anterior cruciate ligament (ACL) reconstruction with bone–patellar-tendon–bone (BPTB) autografts. MethodsA total of 54 patients were followed for a mean of 38.2±10.2months post-surgery. Subjective and objective results were evaluated using single assessment numeric evaluation (SANE) scores, Lachman tests, KT-2000 arthrometer results, and pivot-shift tests. The change in each patient's Tegner activity scale and RTP at the pre-injury level were also evaluated. ResultsInappropriate positioning of the tunnels was the most important reason (54%) for primary graft failure. After revision surgery, anterior knee stability was significantly improved (1.2 (mean)±1.2 (SD)mm vs 4.5(mean) ±1.9 (SD)mm; P<0.01). Two (4%) patients sustained revision graft ruptures while two (4%) sustained contralateral knee ACL tears. The rate of RTP at the pre-injury level was 67% (36 patients), and mean SANE scores at the time of RTP were higher than before surgery (74.8±13.8 points vs 24.1±16.4; P<0.001). The average time from primary graft failure to revision surgery was shorter (12.2 (mean)±4.0 (SD) vs 37.6 (mean)±8.8 (SD)months; P<0.01) and the ratio of major cartilage injury was lower (39% vs 83%; P<0.05) in the RTP group than that in the non-RTP group. ConclusionsThe time from primary graft failure to revision surgery and the extent of the cartilage injury are major factors in RTP after revision ACL reconstructions.

The innate immune system contributes to tissue‐engineered vascular graft performance

The first clinical trial of tissue-engineered vascular grafts (TEVGs) identified stenosis as the primary cause of graft failure. In this study, we aimed to elucidate the role of the host immune response in the development of stenosis using a murine model of TEVG implantation. We found that the C.B-17 wild-type (WT) mouse (control) undergoes a dramatic stenotic response, which is nearly completely abolished in the immunodeficient SCID/beige (bg) variant. SCID mice, which lack an adaptive immune system due to the absence of T and B lymphocytes, experienced rates of stenosis comparable to WT controls (average luminal diameter, WT: 0.071 ± 0.035 mm, SCID: 0.137 ± 0.032 mm, SCID/bg: 0.804 ± 0.039 mm; P < 0.001). The bg mutation is characterized by NK cell and platelet dysfunction, and systemic treatment of WT mice with either NK cell-neutralizing (anti-NK 1.1 antibody) or antiplatelet (aspirin/Plavix [clopidogrel bisulfate]; Asp/Pla) therapy achieved nearly half the patency observed in the SCID/bg mouse (NK Ab: 0.356 ± 0.151 mm, Asp/Pla: 0.452 ± 0.130 mm). Scaffold implantation elicited a blunted immune response in SCID/bg mice, as demonstrated by macrophage number and mRNA expression of proinflammatory cytokines in TEVG explants. Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs.

Brilliant blue FCF is a nontoxic dye for saphenous vein graft marking that abrogates response to injury

Injury to saphenous vein grafts during surgical preparation may contribute to the subsequent development of intimal hyperplasia, the primary cause of graft failure. Surgical skin markers currently used for vascular marking contain gentian violet and isopropanol, which damage tissue and impair physiologic functions. Brilliant blue FCF (FCF) is a nontoxic dye alternative that may also ameliorate preparation-induced injury. Porcine saphenous vein (PSV) was used to evaluate the effect of FCF on physiologic responses in a muscle bath. Cytotoxicity of FCF was measured using human umbilical venous smooth muscle cells. Effect of FCF on the development of intimal hyperplasia was evaluated in organ culture using PSV. Intracellular calcium fluxes and contractile responses were measured in response to agonists and inhibitors in rat aorta and human saphenous vein. Marking with FCF did not impair smooth muscle contractile responses and restored stretch injury-induced loss in smooth muscle contractility of PSV. Gentian violet has cytotoxic effects on human umbilical venous smooth muscle cells, whereas FCF is nontoxic. FCF inhibited intimal thickening in PSV in organ culture. Contraction induced by 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate and intracellular calcium flux were inhibited by FCF, oxidized adenosine triphosphate, KN-62, and brilliant blue G, suggesting that FCF may inhibit the purinergic receptor P2X7. Our studies indicated that FCF is a nontoxic marking dye for vein grafts that ameliorates vein graft injury and prevents intimal thickening, possibly due to P2X7 receptor inhibition. FCF represents a nontoxic alternative for vein graft marking and a potentially therapeutic approach to enhance outcome in autologous transplantation of human saphenous vein into the coronary and peripheral arterial circulation.

Successful ICU Care of a 14-Year-Old With Total Artificial Circulation Using Two Ventricular Assist Devices for 118 Days

Within the first year following orthotopic heart transplantation, the patient is at risk of graft failure, rejection, and infection. Late mortality is often due to allograph vasculopathy. Most of the patients with primary graft failure will usually recover with temporary mechanical ventricular assist support; however, on occasion the patient must be retransplanted. For the patient who suffers primary graft failure necessitating explanation and bridging until a new suitable graft is found, there are several total artificial heart options. However, in the pediatric population these options are limited. The authors’ surgical colleagues were able to fashion a paracorporeal total artificial heart constructed with 2 ventricular assist devices. In this case report, the authors discuss a pediatric patient who had to be explanted and supported for an extended amount of time. This article describes the incidence of cardiomyopathy in juvenile rheumatoid arthritis patients, the choice of extracorporeal membrane oxygenation/extracorporeal complete life support versus ventricular assist devices for support, the major causes of primary graft failure, and the authors’ experience in caring for an adolescent with such a device for a protracted length of time (118 days).

Interleukin-10 Delivery via Mesenchymal Stem Cells: A Novel Gene Therapy Approach to Prevent Lung Ischemia–Reperfusion Injury

Ischemia-reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120 min of warm left lung ischemia, rats received approximately 15 x 10(6) vIL-10-engineered MSCs (MSC-vIL-10), empty vector-engineered MSCs (MSC-vec), or saline intravenously. Mean blood oxygenation (PaO(2)/FiO(2) ratio, mmHg) was measured at 4 hr, 24 hr, 72 hr, and 7 days. As early as 4 hr post-IR injury with MSC-vIL-10 treatment, blood oxygenation was significantly (p < 0.05) improved (319 +/- 94; n = 7) compared with untreated (saline) controls (63 +/- 19; n = 6). At 24 hr post-IR injury, in the MSC-vIL-10-treated group there was a further increase in blood oxygenation (353 +/- 105; n = 10) compared with the MSC-vec group (138 +/- 86; n = 9) and saline group (87 +/- 39; n = 10). By 72 hr, oxygenation reached normal (475 +/- 55; n = 9) in the MSC-vIL-10-treated group but not in the saline-treated and MSC-vec-treated groups. At 4 hr after IR injury, lungs with MSC-vIL10 treatment had a lower (p < 0.05) injury score (0.9 +/- 0.4) compared with lungs of the untreated (saline) group (2.5 +/- 1.4) or MSC-vec-treated group (2 +/- 0.4). Lung microvascular permeability and wet-to-dry weight ratios were markedly lower in the MSC-vIL10 group compared with untreated (saline) controls. ISOL (in situ oligonucleotide ligation for DNA fragmentation detection) and caspase-3 staining demonstrated significantly (p < 0.05) fewer apoptotic cells in MSC-vIL10-treated lungs. Animals that received MSC-vIL10 therapy had fewer (p < 0.05) CD4(+) and CD8(+) T cells in bronchoalveolar lavage fluid compared with untreated control animals. A therapeutic strategy using vIL-10-engineered MSCs to prevent IR injury in lung transplantation seems promising.

Resolution of Severe Ischemia–Reperfusion Injury Post–Lung Transplantation After Administration of Endobronchial Surfactant

Ischemia-reperfusion injury (IRI) is a prominent cause of primary graft failure after lung transplantation and is associated with an altered surfactant profile. Experimental animal studies have found that replacement with exogenous surfactant administered via fiber-optic bronchoscopy (FOB) enhanced recovery from IRI with improved pulmonary compliance and gas exchange after lung transplantation. We report our clinical experience with FOB instillation of surfactant in severe IRI after human lung transplantation. This study is a retrospective review of 106 consecutive lung or heart-lung transplants performed at a single institution. Severe IRI was defined as diffuse roentgenographic alveolar infiltrates, worsening hypoxemia and decreased lung compliance within 72 hours of lung transplantation. One vial of surfactant (20 mg/ml phospholipid) was instilled into each segmental bronchus upon diagnosis of IRI. Six patients (5 bilateral sequential and 1 re-do heart-lung transplant), mean age 46 years, were diagnosed with IRI and surfactant was administered at a mean of 37 hours (range 2.3 to 98) post-transplant. Mean graft ischemia time was 376 minutes (range 187 to 625) and cardiopulmonary bypass time 174 minutes (range 0 to 210). Mean Pao(2) [mm Hg]/Fio(2) ratio before and 48 hours after surfactant instillation was 70 and 223, respectively. Significant resolution of radiologic infiltrates was evident in all cases within 24 hours. Successful extubation occurred at a mean of 13.5 days and survival is presently 100% at 19 months (range 3 to 54). Bronchoscopic instillation of surfactant improves oxygenation and prognosis after severe IRI in lung transplant recipients. It represents a cost-effective, relatively non-invasive therapeutic alternative to extracorporeal membrane oxygenation.

Recurrence of Membranoproliferative Glomerulonephritis Type II in Renal Allografts

Membranoproliferative glomerulonephritis type II (MPGN II) is an uncommon form of complement-dependent acquired renal disease. Although it has been recognized since the 1970s that MPGN II recurs almost universally in renal transplants, data regarding the long-term consequences of disease recurrence are limited. Therefore, a retrospective comparative analysis of 75 patients with MPGN II contained in the North American Pediatric Renal Transplant Cooperative Study transplantation database was performed. Five-year graft survival for patients with MPGN II was significantly worse (50.0 +/- 7.5%) compared with the database as a whole (74.3 +/- 0.6%; P < 0.001). Living related donor organs had a significantly better 5-yr survival (65.9 +/- 10.7%) compared with cadaveric donor organs (34.1 +/- 9.8%; P = 0.004). The primary cause of graft failure in 11 (14.7%) patients was recurrent disease. Supplemental surveys were obtained on 29 (38%) of 75 patients. Analysis of these data indicated that recurrent disease occurred in 12 (67%) of the 18 patients with posttransplantation biopsies. Although there was no correlation between pretransplantation presentation, pre- or posttransplantation C3 levels, and either disease recurrence or graft failure, there was a strong association between heavy proteinuria and disease recurrence. The presence of glomerular crescents in allograft biopsies had a significant negative correlation with graft survival. At last follow-up, patients with recurrent disease had significantly higher serum creatinine and qualitatively more proteinuria than patients without biopsy-proven disease. These data indicate that recurrent MPGN II has a significant negative impact on renal allograft function and survival.

Overexpression of Human Bcl-2 in Syngeneic Rat Donor Lungs Preserves Posttransplant Function and Reduces Intragraft Caspase Activity and Interleukin-1?? Production

A significant cause of primary graft failure in lung transplantation is ischemia-reperfusion (I/R). I/R injury generates proinflammatory cytokines, such as interleukin (IL)-1beta, and activates the caspase-mediated pathways of alveolar epithelial apoptosis. The authors investigated whether gene transfer of the human antiapoptotic protein Bcl-2 by means of intratracheal adenoviral administration would preserve posttransplant lung function and reduce intragraft activated caspase activity and IL-1beta production in syngeneic rat donor lung grafts. First, 1.0 x 10(9) plaque-forming units of AdvBcl-2 in phosphate-buffered saline (PBS), AdvNull empty vector in PBS, or PBS alone was administered intratracheally to ACI (RT1(a)) rats. Then, the left lungs were procured after 24 hr of in vivo incubation and orthotopically transplanted after 1 hr of cold ischemia into syngeneic recipients. After 2 hr of reperfusion, peak inspiratory pressures (PIP) and donor pulmonary vein PaO(2) was measured in all grafts; grafts were then excised and protein extracts were analyzed by enzyme-linked immunosorbent assay (ELISA) and activated caspase-3 and caspase-9 assays. Human Bcl-2 transgene overexpression in donor lung grafts was demonstrated by ELISA of tissue homogenates. Pretreatment of donor lungs with AdvBcl-2 resulted in reduced PIP and increased lung isograft pulmonary vein PaO(2) compared with AdvNull or PBS-alone treated controls. In addition, AdvBcl-2 pretreatment led to diminished cytochrome c release into cytosolic extracts and reduced intragraft IL-1beta production and inhibited intragraft caspase-3 and caspase-9 activity. Adenoviral overexpression of human Bcl-2 protein limits I/R injury in rat lung isografts. These data suggest that the use of Bcl-2 gene transfer to human lung donors may reduce the oxidative stress of pulmonary grafts after transplantation in clinical lung transplantation.

Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation: induction of tolerance and prevention of cardiac allograft vasculopathy.

Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation. We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 microg x kg(-1) x d(-1) HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3+/-4.1 days, P<0.001) compared with the controls (11.1+/-0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF treatment during acute rejection. In the long-term surviving allografts, HGF significantly inhibited the development of CAV and interstitial fibrosis. With respect to intragraft cytokine mRNA expression, HGF treatment reduced the early expression of interferon-gamma and enhanced the expression of transforming growth factor-beta1 during the acute phase and of interleukin-10 continuously through the acute phase to the chronic phase. Our findings demonstrate that HGF can prolong the survival of allografts by its cardioprotective and immunomodulative potencies. Thus, HGF administration may constitute a new therapeutic approach to preventing cardiac graft failure that has not been overcome by conventional immunosuppressive agents.

Human saphenous vein and coronary bypass surgery: ultrastructural aspects of conventional and "no-touch" vein graft preparations.

Coronary artery bypass graft surgery (CABG) is routinely used to restore blood flow to diseased cardiac muscle due to coronary artery disease. The patency of conventional grafts decreases with time, which is due to thrombosis and formation of neointima. A primary cause of graft failure is the mechanical damage inflicted to the graft during harvesting, including removal of surrounding tissue accompanied by high pressure saline distension to overcome vasospasm (both causing considerable mechanical trauma). The aim of this study was to compare the ultrastructural features of human saphenous vein (SV) grafts harvested conventionally and grafts prepared using an atraumatic 'no-touch' harvesting technique introduced by Souza (1996). The results of this study showed a better preservation of the lumenal endothelium and medial vascular smooth muscle (SM) in 'no-touch' versus conventional grafts. A 'fast' (within 30 min) response of SM cells to conventional harvesting was noted where features of both SM cell division and apoptosis were observed. It is concluded that the 'preserved' nature of the 'no-touch' aortocoronary SV grafts renders them less susceptible to thrombotic and atherosclerotic factors than grafts harvested conventionally. These features are suggested to contribute to the improved early patency rate described using the no-touch technique of SV harvesting.

Analyzing liver transplantation for fulminant hepatic failure at UCLA: a retrospective look at 18 years' experience.

Objective To analyze outcomes after liver transplantation (LT) in patients with fulminant hepatic failure (FHF) with emphasis on pretransplant variables that can potentially help predict posttransplant outcome. Summary background data FHF is a formidable clinical problem associated with a high mortality rate. While LT is the treatment of choice for irreversible FHF, few investigations have examined pretransplant variables that can potentially predict outcome after LT. Methods A retrospective review was undertaken of all patients undergoing LT for FHF at a single transplant center. The median follow-up was 41 months. Thirty-five variables were analyzed by univariate and multivariate analysis to determine their impact on patient and graft survival. Results Two hundred four patients (60% female, median age 20.2 years) required urgent LT for FHF. Before LT, the majority of patients were comatose (76%), on hemodialysis (16%), and bound for intensive care. The 1- and 5-year survival rates were 73% and 67% (patient) and 63% and 57% (graft). The primary cause of patient death was sepsis, and the primary cause of graft failure was primary graft nonfunction. Univariate analysis of pre-LT variables revealed that 19 variables predicted survival. From these results, multivariate analysis determined that the serum creatinine was the single most important prognosticator of patient survival. Conclusions This study, representing one of the largest published series on LT for FHF, demonstrates a long-term survival of nearly 70% and develops a clinically applicable and readily measurable set of pretransplant factors that determine posttransplant outcome. (Ann Surg 2003;237:666–676.)