Recent Progress in Cell Therapy in Solid Organ Transplantation.

There has been ample of preclinical and animal studies showing efficacy and safety of using various cells, such as stem cells or T regulatory cells, after transplantation for tissue repair, immunosuppression or tolerance induction. However, there has been a significant progress recently using cell therapy in solid organ transplantation in small clinical trials. Recent results have been promising and using cell therapy in solid organ transplantation seems feasible and safe. However, there are more hurdles to overcome such as dose and timing of the infusions. Current studies mainly focused on live donor kidney transplantation. Expansion of current regimes to other organs and deceased donor transplantation would be crucial.

Outcomes of Full-Right-Full-Left Split Liver Transplantation in Adults in the USA: A Propensity-Score Matched Analysis.

BACKGROUND: Splitting a liver for utilization in adult/pediatric recipients has been shown to decrease mortality on the wait list without increasing the overall risk of long-term graft failure compared to a whole graft. However, splitting a single donor organ for two adult recipients, full-right-full-left split liver transplantation (FRFLSLT), to overcome organ shortage is still considered controversial. OBJECTIVE: This study assessed the outcome of FRFLSLT comparing full-right (FR) and full-left (FL) with whole liver (WL) allografts in adults (1998-2010) using UNOS standard transplant analysis and research (STAR) file. Methods: Unadjusted allograft and patient survival were estimated using Kaplan-Meier survival curves. Adjusted analyses of survival were conducted controlling for propensity for WL allograft. RESULTS: There were 83,313 cases of WL, 651 FR and 117 FL. Significant differences were evident in the unadjusted cohort between recipients who received FR and FL including donor, cold ischemic time, and days on transplant waiting list. Use of FL allograft resulted in a trend toward lower graft and patient survival compared to WL and FR, which was not statistically significant (p=0.07). In the matched cohort, FL hemiliver allograft had no detrimental effect on the allograft or patient survival after split liver transplantation when compared to FR and WL. CONCLUSION: After adjusting for donor and recipient characteristics, there was no difference in allograft or patient survival with the use of FL, FR, or WL after liver transplantation in adults. FRFLSLT is a valuable and safe option to expand the donor pool.

Competitive Market Analysis of Transplant Centers and Discrepancy of Wait-Listing of Recipients for Kidney Transplantation.

BACKGROUND: There are over 250 kidney transplant programs in the USA. OBJECTIVE: To determine if highly competitive regions, defined as regions with a higher number of transplant centers, will approve and wait-list more end-stage renal disease (ESRD) candidates for transplant despite consistent incidence and prevalence of ESRD nationwide. METHODS: ESRD Network and OPTN data completed in 2011 were obtained from all transplant centers including listing data, market saturation, market share, organs transplanted, and ESRD prevalence. Herfindahl-Hirschman Index (HHI) was used to measure the size of firms in relation to the industry to determine the amount of competition. RESULTS: States were separated into 3 groups (HHI<1000 considered competitive; HHI 1000-1800 considered moderate competition; and HHI>1800 considered highly concentrated). The percentage of ESRD patients listed in competitive, moderate, and highly concentrated regions were 19.73%, 17.02%, and 13.75%, respectively. The ESRD listing difference between competitive versus highly concentrated was significant (p<0.05). CONCLUSION: When there is strong competition without a dominant center as defined by the HHI, the entire state tends to list more patients for transplant to drive up their own center's market share. Our analysis of the available national data suggests a discrepancy in access for ESRD patient to transplantation due to transplant center competition.

Mesenchymal Stem Cells and Co-stimulation Blockade Enhance Bone Marrow Engraftment and Induce Immunological Tolerance.

BACKGROUND: Organ transplantation currently requires long-term immunosuppression. This is associated with multiple complications including infection, malignancy and other toxicities. Immunologic tolerance is considered the optimal solution to these limitations. OBJECTIVE: To develop a simple and non-toxic regimen to induce mixed chimerism and tolerance using mesenchymal stem cell (MSC) in a murine model. METHODS: Wild type C57BL6 (H2D(k)) and Bal/C (H2D(d)) mice were used as donors and recipients, respectively. We studied to achieve tolerance to skin grafts (SG) through mixed chimerism (MC) by simultaneous skin graft and non-myeloablative donor bone marrow transplantation (DBMT) +/- MSC. All recipients received rapamycin and CTLA-4 Ig without radiation. RESULTS: DBMT+MSC combined with co-stimulation blockage and rapamycin led to stable mixed chimerism, expansion of Tregs population and donor-specific skin graft tolerance. The flow cytometry analysis revealed that recipient mice developed 15%-85% chimerism. The skin allografts survived for a long time. Elimination of MSC failed to induce mixed chimerism and tolerance. CONCLUSION: Our results demonstrate that donor-specific immune tolerance can be effectively induced by non-myeloablative DBMT-MSC combination without any additional cytoreductive treatment. This approach provides a promising and non-toxic allograft tolerance strategy.

Clinical transplantation and tolerance: are we there yet?

Organ transplantation is not only considered as the last resort therapy but also as the treatment of choice for many patients with end-stage organ damage. Recipient-mediated acute or chronic immune response is the main challenge after transplant surgery. Nonspecific suppression of host immune system is currently the only method used to prevent organ rejection. Lifelong immunosuppression will cause significant side effects such as infections, malignancies, chronic kidney disease, hypertension and diabetes. This is more relevant in children who have a longer life expectancy so may receive longer period of immunosuppressive medications. Efforts to minimize or complete withdrawal of immunosuppression would improve the quality of life and long-term outcome of pediatric transplant recipients.

Challenges of organ shortage for transplantation: solutions and opportunities.

Organ shortage is the greatest challenge facing the field of organ transplantation today. A variety of approaches have been implemented to expand the organ donor pool including live donation, a national effort to expand deceased donor donation, split organ donation, paired donor exchange, national sharing models and greater utilization of expanded criteria donors. Increased public awareness, improved efficiency of the donation process, greater expectations for transplantation, expansion of the living donor pool and the development of standardized donor management protocols have led to unprecedented rates of organ procurement and transplantation. Although live donors and donation after brain death account for the majority of organ donors, in the recent years there has been a growing interest in donors who have severe and irreversible brain injuries but do not meet the criteria for brain death. If the physician and family agree that the patient has no chance of recovery to a meaningful life, life support can be discontinued and the patient can be allowed to progress to circulatory arrest and then still donate organs (donation after circulatory death). Increasing utilization of marginal organs has been advocated to address the organ shortage.

Outcomes of patients with portal vein thrombosis undergoing live donor liver transplantation.

BACKGROUND: Live donor liver transplantation (LDLT) for patients with portal vein thrombosis (PVT) creates several technical challenges due to severe pre-operative condition and extensive collaterals. Although deceased donor liver transplantation in patients with PVT is now routinely performed at most centers, the impact of PVT on LDLT outcomes is still controversial. OBJECTIVE: To determine the outcome of patients with PVT who underwent LDLT. METHODS: We reviewed the outcome of adult patients with PVT who underwent LDLT in the USA from 1998 to 2009. RESULTS: 68 (2.9%) of 2402 patients who underwent LDLT had PVT. Comparing patients with and without PVT who underwent LDLT, those with PVT were older (53 vs 50 yrs), more likely to be male, had longer length of stay (25 vs 18 days) and higher retransplantation rate (19% vs 10.7%). The allograft and patient survival was lower in patients with PVT. In Cox regression analysis, PVT was associated with worse allograft survival (HR=1.7, 95% CI: 1.1-2.5, p<0.001) and patient survival (HR=1.6, 95% CI: 1.2-2.4, p<0.001) than patients without PVT. CONCLUSIONS: Patients with PVT who underwent LDLT had a worse prognosis than those without PVT.

Improving Outcomes of Liver Transplantation for Polycystic Disease in MELD Era.

BACKGROUND: Liver transplantation (LT) for polycystic liver disease (PLD) has evolved to be an option for treating these patients. Patients with PLD suffer from incapacitating symptoms because of very large liver volumes but liver function is preserved until a late stage. OBJECTIVE/METHODS: Herein, we reviewed the outcome of adult patients with PLD who underwent LT in the US comparing pre-MELD (1990-2001) to MELD era (2002-2009). RESULTS: During this period, only 309 patients underwent LT for PLD. The number of LT for PLD is very low comparing the two eras. The percentage of patients who had combined liver and kidney transplantation (CLKT) for this disease has not changed during MELD era (42.8% vs 38.6%). The waiting time for LT (337 vs 272 days) and CLKT (289 vs 220) has increased in MELD era (p<0.001). In MELD era, 53.4% of LT and 31.2% of CLKT were done as MELD exceptional cases. The allograft and patent survival have significantly improved in MELD era. CONCLUSION: Patients with PLD had marked improvement of their outcomes after LT in MELD era.

Liver transplantation from a donor with multiple biliary hamartomata.

Biliary hamartomata are rare benign lesions. Herein, we report on a 48-year-old man with a history of end-stage liver disease secondary to alcoholic liver disease. The patient received an orthotropic liver transplant from a brain-death woman. At the time of recovery, there were multiple lesions in the transplanted liver measuring 7-10 mm. Pathology revealed multiple biliary hamartomata. The postoperative course of the recipient was uncomplicated and he was discharged home 10 days after the transplantation.

Living Donor Liver Transplantation for Hepatocellular Carcinoma: It Is All about Donors?

BACKGROUND: Live-donor liver transplantation (LDLT) is a valuable option for patients with hepatocellular carcinoma (HCC) as compared with deceased-donor liver transplantation (DDLT); the tumor could be eradicated early. METHODS: Herein, we reviewed the outcome of adult patients with HCC who underwent LDLT from 1990 to 2009 in the USA, as reported to United Network for Organ Sharing. RESULTS: Compared to DDLT (n=5858), patients who underwent LDLT for HCC (n=170) were more likely to be female (43.8% vs 23.8%), younger (mean age 48.6 vs 54.9 years) and have more tumors outside Milan criteria (30.7% vs 13.6%). However, the recipients of LDLT for HCC had a significantly shorter mean wait time before transplantation (173 vs 219 days; p=0.04). The overall allograft and patient survival were not different, though more patients in LDLT group were outside Milan criteria. Since implementation of the MELD exception for HCC, DDLT for HCC has increased form 337 (2.3%) cases in 2002 to 1142 (18.7%) in 2009 (p<0.001). However, LDLT for HCC has remained stable from 16 (5.7%) in 2002 to 14 (9.2%) in 2009 (p=0.1). Regions 1, 5 and 9 had the highest rate of LDLT for HCC compared to other regions. CONCLUSIONS: LDLT can achieve the same long-term outcomes compared to DDLT in patients with HCC. The current MELD prioritization for HCC reduces the necessity of LDLT for HCC except in areas with severe organ shortage.

Liver transplantation from hepatitis B surface antigen-positive donors.

One possibility to increase the organ pool is to use grafts from hepatitis B virus (HBV) surface antigen (HBsAg)-positive donors, but few data are currently available in this setting. Herein, we reviewed the outcome of 92 liver transplantations using allografts from HBsAg-positive donors in the United States (1990-2009). They had experienced HBV-related (n = 68) or HBV-unrelated disease (n = 24). There was no difference between patients who received HBsAg-positive versus HBsAg-negative allografts based on age, Model for End-stage Liver Disease (MELD) score, length of stay, wait time, and donor risk index. HBsAg-positive allografts were more likely to be imported and used in MELD exceptional cases. Allograft and patient survival were comparable between the two groups. HBsAg-positive allografts deserve consideration when no other organ is available in a suitable waiting time in the present era of highly effective antiviral therapy.

Current status of pancreas and islet cell transplantation.

Pancreas transplantation has emerged as an effective treatment for patients with diabetes mellitus, especially those with established end-stage renal disease. Surgical and immunosuppressive advances have significantly improved allograft survival. The procedure reduces mortality compared with diabetic kidney transplant recipients and wait listed patients. Improvements in diabetic nephropathy and retinopathy have also been demonstrated. Pancreas transplantation can improve cardiovascular risk profiles, improve cardiac function and decrease cardiovascular events. Lastly, improvements in diabetic neuropathy and quality of life can result from pancreas transplantation. Pancreas transplantation remains the most effective method to establish durable euglycemia for patients with diabetes mellitus.

Liver Transplantation in Patients with Portal Vein Thrombosis: Comparing Pre-MELD and MELD era.

BACKGROUND: Portal vein thrombosis (PVT) used to be a relative contraindication for liver transplantation (LT). This obstacle has been dealt with following the improvement of LT-related techniques. OBJECTIVE: To compare the outcome of adult patients with PVT who underwent LT before and after adopting MELD. METHODS: We retrospectively searched our database for deceased donor LT recipients who had PVT, were operated between 1990 and 2009, and were 18 years old or more. The outcome of patients operated in pre-MELD era (1990-2001) was then compared with that of those operated in MELD era (2002-2009). RESULTS: The incidence of patients undergoing LT with PVT has increased from 1.2% (491/40,730) in pre-MELD era to 6% (2540/42,601) in MELD era (p<0.01). Patients with PVT in MELD era were older (53.6 vs 50.5), had higher calculated MELD (21.3 vs 18.9), shorter length of hospital stay after LT (25 vs 21.7 days), more likely to develop HCC (14.8% vs 0), and more likely to receive DCD allograft (3.9% vs 0.8%). Donor risk indices were comparable in both groups (1.9 vs 1.9). The median waiting time before transplantation decreased during MELD era (71 vs 99 days). Allograft and patients survival was comparable between the two eras. However, allograft and patients survival rates were lower in patients with PVT compared to those without. In Cox regression analysis, PVT was associated with worse allograft (HR=1.3, 95% CI: 1.2-1.4, p<0.001) and patient survival (HR=1.3, 95% CI: 1.2-1.5, p<0.001) compared to non-PVT patients. CONCLUSIONS: The incidence of patients with PVT has increased in MELD era without improvement in outcomes. Donor and recipients characteristics changed in MELD era. PVT is still associated with poor outcomes compared to patients without PVT.

Changing pattern of organ donation and utilization in the USA.

BACKGROUND: Organ transplantation has proven highly effective in the treatment of various forms of end-stage organ failure. However, organ shortage is still the greatest challenge facing the field of organ transplantation. OBJECTIVE: To assess the pattern of organ donation and utilization during the past decade in the USA. METHODS: We studied OPTN/UNOS database for organ donation between January 2000 and December 2009. The retrieved records were then categorized into two time periods-from January 2000 to December 2004 (era 1), and from January 2005 to December 2009 (era 2). RESULTS: There were 65,802 living and 71,401 deceased donors in the US from 2000 to 2009, including 66,518 (93.2%) brain-dead donors and 4,883 (6.8%) donation after cardiac death. Comparing two periods-from January 2000 to December 2004 (era 1) and from January 2005 to December 2009 (era 2), the number of deceased donors increased by 25% from 31,692 to 39,709 and living donors decreased by 7.6%. Donation after cardiac death increased from 3.5% to 9.3%. The portion of donors older than 64 years increased from 6.9% in era 1 to 11.3% in era 2 (p=0.03). The number of donors with a body mass index of >35 kg/m(2) was also increased from 6.8% to 11.2%. A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was also noted from 38.1% in era 1 to 56.1% in era 2 (p<0.001), as was a corresponding decrease in the incidence of death due to head trauma (34.9% vs. 48.8%). The overall discard rate also increased by 41% from 13,411 in era 1 to 19,516 in era 2. This increase in discards was especially more prominent in donation after cardiac death group which rose by 374% from 440 in era 1 to 2,089 in era 2. The discard rate for livers and kidneys increased by 31% and 68%, respectively, comparing era 1 and era 2. We noted a 78% increase for discarded donation after cardiac death livers and 1,210% for discarded donation after cardiac death kidneys. CONCLUSION: We detected significant changes in the make-up of the donor pool over the past decade in the US. Over time, donor characteristics have changed with increased numbers of elderly donors and donors with comorbidities, especially donors who died of cardiovascular/cerebrovascular disease. The incidence of donation after cardiac death has increased significantly; brain-dead donors have only increased slightly and living donors have decreased. As the result, the discard rates have increased. The transplant community and policy makers should consider every precaution to safeguard the donor pool and prevent the decay of organ quality in favor of quantity.

Induction with Rabbit Antithymocyte Globulin following Orthotopic Liver Transplantation for Hepatitis C.

BACKGROUND: Hepatitis C (HCV) is the most common indication for liver transplantation in the US. OBJECTIVE: Since steroids are the major stimulus of viral replication, we postulated that steroid-free immunosuppression might be a safer approach. METHODS: From January 1995 to October 2002, we used steroid plus calcineurin inhibitor (CNI) immunosuppression after liver transplantation for HCV (steroid group, n=81). From October 2002 to June 2007, rabbit antithymocyte globulin (RATG) induction, followed by CNI and azathioprine (RATG group, n=73) was utilized. RESULTS: There were no differences in 1- and 3-year patient/allograft survival rates. The incidence of acute rejection rate (19% vs. 28%), of biopsy-proven HCV recurrence (70% vs. 75%), and chronic rejection (6% vs. 9%) were comparable. The mean time to develop recurrent HCV was significantly longer in the RATG group (16.2 vs. 9.2 months, p=0.008). The incidence of severe portal fibrosis appears to be lower in RATG group compared to the steroid group; 14% vs. 4% (p=0.07). CONCLUSIONS: RATG induction is safe and effective after liver transplantation for HCV, but has no impact on the incidence of HCV recurrence and patient/allograft survival. However, a significant delay in time to HCV recurrence and a trend toward less rejection and portal fibrosis was observed.

Treating hepatocellular carcinoma with sorafenib in liver transplant patients: an initial experience.

Sorafenib has been approved for the treatment of advanced hepatocellular carcinoma (HCC). However, there are no data reported on its use in HCC patients with localized disease who have undergone orthotopic liver transplantation (OLT). Herein, we have reviewed our initial experience with 7 HCC patients who were candidates for OLT and were treated with sorafenib. Treating liver transplant patients with sorafenib appeared to be safe based upon our limited experience. There is a strong need for clinical trials to comprehensively study the safety of sorafenib before OLT.

Changing pattern of organ donation at a single center: are potential brain dead donors being lost to donation after cardiac death?

Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation.We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98-12/02), era 2 (01/03-12/05) and era 3 (01/06-11/08), DCD's comprised 14.8,48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p<0.001),as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group.We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.

Donor kidney recovery methods and the incidence of lymphatic complications in kidney transplant recipients.

BACKGROUND: Lymphatic leak and lymphocele are well-known complications after kidney transplantation. OBJECTIVE: To determine the incidence of lymphatic complications in recipients of living donor kidneys. METHODS: Among 642 kidney transplants performed between 1999 and 2007, the incidence of lymphatic complications was retrospectively analyzed in recipients of living donor kidneys procured by laparoscopic nephrectomy (LP, n=218) or by open nephrectomy (OP, n=127) and deceased donor kidneys (DD, n=297). A Jackson-Pratt drain was placed in the retroperitoneal space in all recipients and was maintained until the output became less than 30 mL/day. RESULTS: Although the incidence of symptomatic lymphocele, which required therapeutic intervention, was comparable in all groups, the duration of mean±SD drain placement was significantly longer in the LP group-8.6±2.7 days compared to 5.6±1.2 days in the OP group and 5.4±0.7 days in the DD group (p<0.001). Higher output of lymphatic drainage in recipients of LP kidneys could lead to a higher incidence of lymphocele if wound drainage is not provided. CONCLUSION: More meticulous back table preparation may be required in LP kidneys to decrease lymphatic complications after kidney transplantation. These observations also support the suggestion that the major source of persistent lymphatic drainage following renal transplantation is severed lymphatics of the allograft rather than those of the recipient's iliac space.

Live donor partial hepatectomy for liver transplantation: is there a learning curve?

BACKGROUND: Donor safety is the first priority in living donor liver transplantation (LDLT). OBJECTIVE: To determine the characteristics and outcome of live liver donors who underwent donor hepatectomy from January, 1997 to May, 2007 at Massachusetts General Hospital. METHODS: 30 patients underwent LDLT between January, 1997 and May, 2007 at our institution. RESULTS: The type of graft was the right lobe (segments 5-8) in 14, left lobe (segments 2-4) in 4, and left lateral sector (segments 2 and 3) in 12 patients. The mean donor age was 36 (range: 26-57) years. The mean follow-up was 48 (range: 18-120) months. No deaths occurred. Overall, 8 (26.6%) patients experienced a total of 14 post-operative complications. Donor complications based on graft type were as follows: left lateral sector (16.7%), left lobe (25%), and right lobe (35.7%). The experience was divided into two periods 1997-2001 (n=15) and 2002-2007 (n=15). Overall complications during 2 periods were 40% and 13.3%, respectively (p<0.001). The incidence of grade III complication also significantly decreased; 66.7% vs 33.3% (p<0.01). CONCLUSION: Partial hepatectomy in living donors has a learning curve which appears to be approximately 15 cases. This learning curve is not restricted to the surgeons performing the procedure but involves all aspects of patient care.