Robert J. Stratta

Vascular complications after orthotopic liver transplantation

Over a 57-month period, we performed 430 orthotopic liver transplants in 372 patients. A total of 38 vascular complications were identified including hepatic artery thrombosis (n = 24), portal vein thrombosis (n = 6), combined hepatic artery thrombosis/portal vein thrombosis (n = 3), and hepatic artery rupture (n = 5). A number of potential risk factors for the development of vascular thrombosis were evaluated with only children, weight less than 10 kg, and cold ischemia time found to be significant. The clinical presentation included fulminant hepatic failure, allograft dysfunction, biliary sepsis, and screening ultrasound. Duplex ultrasonography was diagnostic in nearly all cases. Therapeutic modalities included revascularization, revascularization followed by retransplantation, retransplantation alone, and observation. Five cases of hepatic artery rupture occurred in four patients. Infectious arteritis was present in four patients. The 6-month actuarial survival in patients with vascular complications was 70%. Early diagnosis is critical for graft salvage, with surgical intervention the mainstay of therapy.

Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation

BACKGROUND Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

The APOL1 Gene and Allograft Survival after Kidney Transplantation

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox‐proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow‐up was 26.4 ± 21.8 months. Twenty‐two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty‐five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long‐term renal allograft survival.

Production and implantation of renal extracellular matrix scaffolds from porcine kidneys as a platform for renal bioengineering investigations.

Background:It is important to identify new sources of transplantable organs because of the critical shortage of donor organs. Tissue engineering holds the potential to address this issue through the implementation of decellularization–recellularization technology. Objective:To produce and examine acellular renal extracellular matrix (ECM) scaffolds as a platform for kidney bioengineering. Methods:Porcine kidneys were decellularized with distilled water and sodium dodecyl sulfate–based solution. After rinsing with buffer solution to remove the sodium dodecyl sulfate, the so-obtained renal ECM scaffolds were processed for vascular imaging, histology, and cell seeding to investigate the vascular patency, degree of decellularization, and scaffold biocompatibility in vitro. Four whole renal scaffolds were implanted in pigs to assess whether these constructs would sustain normal blood pressure and to determine their biocompatibility in vivo. Pigs were sacrificed after 2 weeks and the explanted scaffolds were processed for histology. Results:Renal ECM scaffolds were successfully produced from porcine kidneys. Scaffolds retained their essential ECM architecture and an intact vascular tree and allowed cell growth. On implantation, unseeded scaffolds were easily reperfused, sustained blood pressure, and were tolerated throughout the study period. No blood extravasation occurred. Pathology of explanted scaffolds showed maintenance of renal ultrastructure. Presence of inflammatory cells in the pericapsular region and complete thrombosis of the vascular tree were evident. Conclusions:Our investigations show that pig kidneys can be successfully decellularized to produce renal ECM scaffolds. These scaffolds maintain their basic components, are biocompatible, and show intact, though thrombosed, vasculature.

Regenerative medicine and organ transplantation: past, present, and future.

This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.

A Randomized Trial of Alemtuzumab Versus Antithymocyte Globulin Induction in Renal and Pancreas Transplantation

Background. Alemtuzumab and rabbit antithymocyte globulin (rATG) are commonly used for induction of immunsuppression for kidney and pancreas transplantation, but the two agents have not been compared directly. Methods. We conducted a prospective randomized single-center trial comparing alemtuzumab and rATG induction in adult kidney and pancreas transplantation in patients treated with similar maintenance immunosuppression. Results. Between February 1, 2005, and September 1, 2007, 222 patients randomly received either alemtuzumab (n=113) or rATG (n=109) induction; 180 (81%) underwent kidney alone, 38 (17%) simultaneous pancreas-kidney, and 4 (2%) pancreas after kidney transplants. Of 180 kidney-alone transplants, 152 (84%) were from deceased donors, including 61 (34%) from expanded criteria donors. Retransplantation, human leukocyte antigen match, antibody titer, expanded criteria donors, race, cytomegalovirus status, delayed graft function, and immunologic risks were similar between the two induction groups. With a median follow-up of 2 years (minimum 1 year), overall patient, kidney, and pancreas graft survival rates were 96%, 89%, and 90%, respectively. Survival, initial length of stay, and maintenance immunosuppression (including early steroid elimination) were similar between alemtuzumab and rATG groups, but biopsy-proven acute rejection (BPAR) episodes occurred in 16 (14%) alemtuzumab patients compared with 28 (26%) rATG patients (P=0.02). Late BPAR (>12 months after transplant) occurred in 1 (8%) alemtuzumab patient and 3 (11%) rATG patients (P=NS). Infections and malignancy were similar between the two induction arms. Conclusion. Alemtuzumab and rATG induction therapies were equally safe, but alemtuzumab was associated with less BPAR.

Increased Kidney Transplantation Utilizing Expanded Criteria Deceased Organ Donors with Results Comparable to Standard Criteria Donor Transplant

Objective:To compare outcomes in recipients of expanded criteria donor (ECD) versus standard criteria donor (SCD) kidneys at a single center using a standardized approach with similar immunosuppression. Summary Background Data:Expanded criteria deceased organ donors (ECD) are a source of kidneys that permit more patients to benefit from transplantation. ECD is defined as all deceased donors older than 60 years and donors older than 50 years with 2 of the following: hypertension, stroke as the cause of death, or preretrieval serum creatinine (SCr) greater than 1.5 mg/dl. Methods:We retrospectively studied 90 recipients of adult deceased donor kidneys transplanted from October 1, 2001 to February 17, 2003, including 37 (41%) from ECDs and 53 (59%) from SCDs. ECD kidneys were used by matching estimated renal functional mass to recipient need, including the use of dual kidney transplants (n = 7). ECD kidney recipients were further selected on the basis of older age, HLA-matching, low allosensitization, and low body mass index. All patients received a similar immunosuppressive regimen. Minimum follow up was 9 months. Results:There were significant differences in donor and recipient characteristics between ECD and SCD transplants. Patient (99%) and kidney graft survival (88%) rates and morbidity were similar between the 2 groups, with a mean follow-up of 16 months. Initial graft function and the mean 1-week and 1-, 3-, 6-, 12-, and 18-month SCr levels were similar among groups. Conclusions:The use of ECD kidneys at our center effectively doubled our transplant volume within 1 year. A systematic approach to ECD kidneys based on nephron mass matching and nephron sparing measures may provide optimal utilization with short-term outcomes and renal function comparable to SCD kidneys.

Diffuse biliary tract injury after orthotopic liver transplantation

An unusual type of diffuse biliary tract injury after liver transplantation that is characterized by multiple intrahepatic biliary strictures, ductal dilatations, fluid collections, or intrahepatic abscesses has been identified. Over a 5-year period, a total of 10 patients (2%) developed diffuse intrahepatic biliary injury with established vascular patency and no obvious source for their biliary tract pathology. All patients received livers preserved in University of Wisconsin solution with a mean preservation time of 16 hours. This biliary tract injury was associated with the presence of severe preservation injury and Roux limb biliary reconstruction. Of the 10 patients, 5 were treated nonoperatively with multiple stricture dilations and stent placements, 3 underwent retransplantation, 1 was treated operatively with hepaticojejunostomy, and 1 died of sepsis. This study suggests that this complication appears to be related to preservation injury and that the etiology may be ischemic in origin.

Experience with simultaneous pancreas-kidney transplantation.

With refinements in surgical techniques and increased clinical experience, there has been a resurgence of interest in vascularized pancreas transplantation. From December 1986 to April 1988, 30 whole-organ vascularized pancreas transplants with pancreatico duodenocystostomy were performed simultaneously with renal transplantation. The recipient population consisted of 20 men and ten women, with a mean age of 34.7 years (range of 25–53 years). The mean duration of insulin-dependent diabetes mellitus (IDDM) was 22.6 years (range of 10–37 years). The mean pancreas preservation time was 8.7 hours (range 3–19 years). AH patients were immediately insulin-independent. Simultaneous pancreas-kidney engraftment was performed to both iliac fossae via a lower midline incision (n = 28) or through a bilateral lower abdominal incision (n = 2). The mean operating time was 5.9 hours, and packed cell transfusion requirement was 1.3 units. The mean length of hospital stay was 27.4 days. Recipients averaged 2.3 admissions (1–7), with ten patients (34.4%) requiring only one hospital admission. Postoperative immunosuppression consisted of cyclosporine, prednisone, azathioprine, and Minnesota antilymphoblast globulin (MALG). A total of 49 episodes of rejection occurred in 26 patients. Actuarial patient survival rate at two years is 96.3%. The kidney and pancreas survival rates for the same time interval is 94.0% and 84.0%, respectively. Mean serum creatinine at present is 1.75 mg/dl. In conclusion, renal transplantation in concert with pancreas transplantation has a dramatic positive impact on pancreas allograft survival. Combined engraftment does not appear to jeopardize renal allograft functional survival. In view of these results, simultaneous pancreas-kidney transplantation appears to be the treatment of choice for Type I diabetic patients.

Intermediate-Term Outcomes With Expanded Criteria Deceased Donors in Kidney Transplantation: A Spectrum or Specter of Quality?

Objective:To compare intermediate-term outcomes in adult recipients of expanded criteria (ECD) versus concurrent standard criteria (SCD) deceased donor kidney transplants at a single center using a standardized approach. Summary Background Data:Expanded criteria donors (ECDs) are a source of kidneys that increase the donor organ pool, but the value of transplanting these kidneys has been questioned because of concerns regarding diminished survival and predicted poorer intermediate-term outcomes. Methods:Over a 47-month period, we performed 244 deceased donor kidney transplants into adult recipients, including 143 from SCDs and 101 from ECDs. Management algorithms were implemented to preserve nephron function, and recipient selection for an ECD kidney transplant was based on low immunologic risk. All patients received depleting antibody induction in combination with tacrolimus and mycophenolate mofetil. A total of 188 patients (77%) had at least a 1-year follow-up. Results:ECDs were older, had a higher BMI, had an increased incidence of cerebrovascular brain death and preexisting donor hypertension, and had a lower estimated creatinine clearance (CrCl, all P < 0.01) compared with SCDs. Cold ischemic times were similar between groups, but more ECD kidneys were preserved with pulsatile perfusion (P < 0.01). ECD kidney recipients were older, less sensitized, had a lower BMI, had fewer 0-antigen mismatches, and had a shorter waiting time (all P < 0.01) compared with SCD kidney recipients. Actual patient (93%) and kidney graft (83%) survival rates were similar between groups with a mean follow-up of 24 months. The rates of delayed graft function (DGF), acute rejection, readmissions, operative complications, major infections, and resource utilization were comparable between groups. Renal function followed longitudinally was consistently better in SCD patients (P < 0.05). Black recipients had higher rates of DGF, acute rejection, and graft loss (P < 0.05), but the effects were less pronounced in the ECD group. Conclusions:By appropriate donor and recipient profiling and the use of management algorithms to project and protect renal function, excellent intermediate-term outcomes can be achieved with ECD kidney transplants that are comparable to SCD kidney transplants.