AMERICAN SOCIETY OF TRANSPLANT SURGEONS 15TH ANNUAL STATE OF THE ART WINTER SYMPOSIUM
ABSTRACTS
PRE-MEETING
7.
Pre-Meeting Abstract #PM-1
Surgical Challenges in Liver Transplantation William C. Chapman, MD, FACS, Washington University School of Medicine, St. Louis, MO
Kim, D.J., Clark, P.J., Heimbach, J., Rosen, C., Sanchez, W., Watt, K., and Charlton, M.R. 2014. Recurrence of hepatocellular carcinoma: importance of mRECIST response to chemoembolization and tumor size. Am J Transplant 14:1383-1390.
Abstract #PM-3
Many new challenges face surgeons in the field of liver transplantation. Increasingly complex surgical needs are present, and these impact day-to-day operations for transplantation. These include, but are not limited to, extended criteria donors and increasing use of vascular reconstruction, both in donors and in recipients. Much of fellowship training is devoted to mastering the basic skill set for liver transplantation, yet frequently patients undergoing liver transplantation may have significantly increased complexity. A critical skill for effective liver transplantation involves recognition and anticipation of technical challenges that must be anticipated prior to encountering such difficulties. Surgeons in these potential situations must have colleagues with sufficient skills and willingness to assist. While not regularly common, such situations may arise and lead to a critical need for a well-skilled team of surgeons for effective surgical intervention. The fully trained surgeon must be familiar with special techniques which may often be required, including the use of venovenous bypass, cut down techniques for split liver transplant, unique vascular and biliary reconstruction, and the judgment required for use of other teams, including interventional radiology. Each of these complex areas will be discussed in the course of this presentation.
The Impact of Donor Specific Antibody in Liver Transplantation Julie Heimbach, MD, Timucin Taner, MD. Division of Transplantation Surgery, Mayo Clinic, Rochester, MN
The role of donor-specific antibody (DSA) in liver transplant is currently an area of renewed interest. Based upon early reports suggesting a minimal role for antibody-mediated injury in liver transplantation (LT)1, 2, concern over the role of antibodies waned, and for two decades, the potential of antibody-mediated injury to liver allografts was largely ignored. Unlike other potential transplant recipients, prospective cross-matches are not performed in LT and waitlisted liver transplant patients are generally not screened for DSA. However, perhaps as a result of newer technologies that have allowed for a more precise identification of DSA, a series of more recent reports have implicated antibody-mediated injury as a potentially more significant cause of liver allograft injury than previously thought. This renewed interest is highlighted by the fact that an inaugural consensus conference solely focused on antibody-mediated injury in LT was held in 2013, as well as at the most recent Banff conference also held in 2013, which had a specific focus on clarification of the histologic features of antibody-mediated rejection (AMR) in non-renal transplant recipients including liver. 3, 4 The more recent reports related to the impact of DSA in liver transplant recipients began with a 2005 report published by Muro et al on a series of 268 LT recipients which identified that those with DSA had a 28% 1 year graft survival while recipients without DSA had a 72% 1 year graft survival.5 Following that, Castillo-Rama et al published their experience with 896 patients and noted reduced graft survival (75% vs 83%) at 1 year for patients with DSA.6 Another series published just 1 year later on more than 1100 living donor recipients also noted inferior graft survival for recipients who were identified to have donor-specific antibody (58% vs 85%).7 In addition, O’Leary et al published their observations on a case-matched series of 39 patients with DSA who were paired with 39 matched controls, and they also noted chronic rejection and increased graft loss in those with DSA.8 While these relatively large series are compelling, it is essential to note that the antibody analysis was performed retrospectively, and there is no information about the antibody status of the patients at the time of transplant. It is uncertain whether the expression of DSA noted in patients with increased graft loss is the cause or the consequence of their graft injury. In addition, several other recent large retrospective series demonstrated no difference in patient or graft survival based on DSA at the time of transplant.9-11 A prospective analysis of all adults undergoing primary liver-only transplantation was performed at Mayo Clinic in 2009-2010 (n=90) and measured DSA at time 0, day 7, day 21, 4 months, and 12 months.12 In this series, 20% of patients were positive for DSA (as defined by a mean fluorescence index, or MFI, of 2000), and 18% had a positive cross-match. However, in nearly all the patients, the DSA was undetectable at day 7. The day 7 biopsies noted diffuse staining in patients who had persistent DSA,; however, there were no differences in graft function based on the presence of DSA. In addition, no patient developed de novo antibody during the study period, and there was no difference in outcome during the first year between patients with antibody and those without antibody. Another recent report analyzed the impact of DSA on longer term LT outcomes.13 In this series, starting in 2008 all patients (n=267) who were 6 months or more from LT underwent screening for DSA which was repeated annually through 2012. The report found 13% of patients had DSA at the first screen (using an MFI of >1000 as positive), and an additional 21 (9%) developed new DSA during the study period. While the death and graft loss rates were not different in patients with or without DSA, the fibrosis score was higher in patients with DSA. Examination of outcomes for multi-organ liver transplant recipients (liver-heart or liver-kidney) is also of interest. Leca et al recently reported their results with 56 combined liver-kidney transplant recipients transplanted during 1991-2011 and found no differences in patient survival, renal allograft survival, or renal allograft function when comparing sensitized versus non-sensitized patients, which is contrary to the inferior outcomes which have been well-demonstrated for sensitized kidney-only transplant recipients.14 Similar reports are also becoming available for liver-heart transplant recipients, though multi-organ recipients are still at risk for both cellular and humoral rejection.15, 16 In summary, DSA and antibody-mediated rejection seems to have a lower impact on liver transplant recipients compared to other solid organ transplant recipients, understanding the interaction between the liver and DSA is crucial, and essential questions remain. What is the mechanism of the dramatic decrease in levels of DSA seen in the early post-transplant period for sensitized liver transplant recipients? Why does DSA persist in certain patients? What are the long-term implications
Abstract #PM-2
Hepatocellular Carcinoma: Who Not to Transplant, That’s the Question Theodore H. Welling, MD, University of Michigan
The incidence of hepatocellular carcinoma (HCC) is rising, and therapies designed to target early stage HCC which show curative efficacy include hepatic resection, liver transplantation (OLT), radiofrequency ablation, and other developing ablative options such as stereotactic body radiation therapy (SBRT)1. However, the donor liver supply remains flat over time despite the increasing incidence of HCC. It is estimated that the incidence of HCC in the U.S. is rising faster than other solid organ malignancies, greater than 5 cases/100,000 persons2, and is believed to be related to the HCV epidemic and rising burden of NASH. While OLT remains a useful therapy for patients with HCC and a significant burden of liver disease3, the donor organ supply, complication/cost rate, and risk of recurrence in patient subsets limits this modality from being used universally in HCC patients. Indeed, it has recently been brought to attention that OLT may be over-utilized in HCC patients when compared to non-HCC patients receiving OLT4,5. HCC biologic factors such as tumor stage, AFP, and response to therapy remain important criteria affecting overall outcomes following OLT1,6,7. Therefore the question remains: which patients are most likely to benefit from other therapies? Is there evidence supporting OLT versus other therapies? What is the role of “bridging” or “down-staging” therapies with regard to expanding the use of OLT to HCC patients? The best available evidence regarding outcomes for resection, ablation, and the overall best means by which to stratify patients into therapeutic groups in order to maximize efficacy and reduce complications will be reviewed and discussed. These outcomes will be placed into the context of current experience with OLT, utilization of donor livers, and current allocation schema. The goal of this discussion will be to allow participants to have a greater understanding regarding treatment of HCC patients with respect to liver directed therapies. A balanced, multidisciplinary approach, considering oncologic burden, liver disease burden, and identification of where clinical equipoise exists is essential to the care of HCC patients. References 1. Marrero, J.A., and Welling, T. 2009. Modern diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 13:233-247. 2. El-Serag, H.B. 2011. Hepatocellular carcinoma. N Engl J Med 365:1118-1127. 3. Mazzaferro, V., Regalia, E., Doci, R., Andreola, S., Pulvirenti, A., Bozzetti, F., Montalto, F., Ammatuna, M., Morabito, A., and Gennari, L. 1996. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699. 4. Washburn, K., Edwards, E., Harper, A., and Freeman, R. 2010. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant 10:1643-1648. 5. Pomfret, E.A., Washburn, K., Wald, C., Nalesnik, M.A., Douglas, D., Russo, M., Roberts, J., Reich, D.J., Schwartz, M.E., Mieles, L., et al. 2010. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 16:262-278. Hameed, B., Mehta, N., Sapisochin, G., Roberts, J.P., and Yao, F.Y. 2014. 6. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 20:945-951.
41
Pre-Meeting
All authors and co-authors and/or individuals involved with the abstract are required to disclose relevant financial relationships with respect to their abstract. All relevant disclosures are published following each abstract.
PRE-MEETING transplantation is variable and not highly predictable, although in general patients with HRS have a high likelihood of recovery and those with CKD a low likelihood. For those with advanced renal dysfunction and low predicted likelihood of renal recovery, simultaneous liver-kidney (SLK) transplantation is an important option. As the incidence of severe renal dysfunction has increased over the past decade, so have the numbers of SLK transplants. This has engendered controversy within the transplant community because SLK transplants draw deceased donor kidneys from the kidney transplant candidate pool. Because renal recovery after liver transplant alone (LTA) is difficult to predict, indications for SLK are not precisely defined. While dialysis status is a consideration, those with HRS can have renal recovery after as much as 12 weeks on dialysis, while recipients with Stage 4/5 CKD not on dialysis may have immediate or early ESRD after LTA due to perioperative events and CNI exposure. While large retrospective observational analyses generally show slightly improved survival in SLK recipients compared with LTA, inferences that may be drawn from these studies are limited by important selection biases in the current registry data structure. Therefore, a true survival benefit of SLK over LTA in candidates without ESRD is still unproven. Cause of renal dysfunction and dialysis duration are not reported for LTA recipients, and are known to be quite different between LTA and SLK recipients. In general, candidate selection is such that LTA candidates tend to have more renal dysfunction due to severe liver disease such as HRS and AKI, while SLK candidates tend to have less severe liver disease and more CKD or ESRD. However, due to the lack of clarity in indications for SLK, selection practices vary widely. The concept of a safety net in deceased donor kidney allocation, which would entail priority for LTA recipients who develop ESRD after transplantation, has been proposed to help reduce the number of SLK transplants, but has not yet been adopted. The incidence of post-transplant ESRD is also increasing as pre-transplant renal dysfunction has become more commonplace. While many factors present at the time of transplant influence the risk, prevention is aimed at identifying patients at risk, management of complications that may lead to peri- or postoperative AKI, and limiting CNI exposure both immediately after transplantation and in the long-term. Patient survival following kidney transplantation in prior LTA recipients is superior to SLK recipients, but inferior to KTA recipients without a prior liver transplant. References: Davis CL, Feng S, Sung RS, Wong F, Goodrich NP, Melton LB, Reddy KR, 1. Guidinger MK, Wilkinson A, Lake J. Simultaneous liver-kidney transplantation: evaluation to decision making. American Journal of Transplantation 2007; 7: 1702-1709. 2. Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation. American Journal of Transplantation 2008: 8; 2243-2451. 3. Nadim MK, Davis C, Sung RS, Kellum JA, Genyk YS. Simultaneous Liver Kidney Transplantation: A Survey of US Transplant Centers. American Journal of Transplantation 2012; 12; 3119-3127. 4. Nadim MK, Sung RS, Davis CL, et al. Simultaneous Liver- Kidney Transplantation Summit: Current State and Future Directions. American Journal of Transplantation 2012; 12: 2901-2908. 5. Locke JE, Warren DS, Singer AL, Segev DL, Simpkins CE, Maley WR, et al. Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: ineffective usage of renal allografts. Transplantation. 2008;85(7):935-42. 6. Schmitt TM, Kumer SC, Al-Osaimi A, Shah N, Argo CK, Berg C, et al. Combined liver-kidney and liver transplantation in patients with renal failure outcomes in the MELD era. Transpl Int. 2009;22(9):876-83. 7. Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, et al. Impact of etiology of acute kidney injury on outcomes following liver transplantation: Acute tubular necrosis versus hepatorenal syndrome. Liver Transpl. 2012;18(5):539-48. 8. Bahirwani R, Campbell MS, Siropaides T, Markmann J, Olthoff K, Shaked A, et al. Transplantation: impact of pretransplant renal insufficiency. Liver Transpl. 2008;14(5):665-71. 9. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med 2003;349(10):931-40 10. Campbell MS, Kotlyar DS, Brensinger CM, et al. Renal function after orthotopic liver transplantation is predictted by duration of pretransplantation creatinine elevation. Liver Transpl 2005;11(9):1048-55 11. Sharma P, Goodrich NP, Schaubel DE, Guidinger MK, Merion RM. Patient Specific Prediction of End Stage Renal Disease Risk after Liver Transplantation. Journal of American Society of Nephrology, 2013
of having DSA at the time of transplant, or having persistent DSA post LT? These questions apply both to patients undergoing isolated liver transplant, as well as those undergoing multi-organ transplantation. References 1. Andres GA, Ansell ID, Halgrimson CG, Hsu KC, Porter KA, Starzl TE, et al. Immunopathological studies of orthotopic human liver allografts. Lancet 1972;1:275-280. 2. Gordon RD, Fung JJ, Markus B, Fox I, Iwatsuki S, Esquivel CO, et al. The antibody crossmatch in liver transplantation. Surgery 1986;100:705-715. 3. J. G. O’Leary JG, A. J. Demetris AJ, Friedman LS, Gebel HM, Halloran PF, Kirk AD. The Role of Donor-Specific HLA Alloantibodies in Liver Transplantation. Am J Transplant 2014; 14: 779–787. 4. Haas M, Sis B, Racusen LC, Solez K, Glotz D, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014;14:272-83. 5. Muro M, Marin L, Miras M, Moya-Quiles R, Minguela A,Sanchez-Bueno F, et al. Liver recipients harboring anti-donor preformed lymphocytotoxic antibodies exhibit a poor allograft survival at the first year after transplantation: experience of one centre. Transpl Immunol 2005; 14:91-97. 6. Castillo-Rama M, Castro MJ, Bernardo I, et al. Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: Role of human leukocyte antigen compatibility. Liver Transpl 2008; 14: 554–562. 7. Hori T, Uemoto S, Takada Y, Oike F, Ogura Y, et al. Does a positive lymphocyte cross-match contraindicate living-donor liver transplantation? Surgery 2010 ;147:840-4. 7. Kozlowski T, Rubinas T, Nickeleit V, et al. Liver allograft antibody mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 2011; 17: 357–368. 8. Musat AI, Agni RM, Wai PY, Pirsch JD, Lorentzen DF, Powell A, et al. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011;11:500-510. 8. O’Leary JG, Kaneku H, Susskind BM, Jennings LW, Neri MA, Davis GL, et al. High mean fluorescence intensity donor-specific anti-HLA antibodies associated with chronic rejection postliver transplant. Am J Transplant 2011;11:1868-1876. 9. Shin M, Moon HH, Kim JM, Park JB, Kwon CH, Kim SJ, et al. Significance of true-positive and false-positive pretransplantation lymphocytotoxic crossmatch in primary liver allograft outcomes. Transplantation 2013;95:1410-1417. 10. Lunz J, Ruppert KM, Cajaiba MM, Isse K, Bentlejewski CA, Minervini M, et al. Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring? Am J Transplant 2012;12: 171-182. 11. Ruiz R, Tomiyama K, Campsen J, Goldstein RM, Levy MF, McKenna GJ, et al. Implications of a positive crossmatch in liver transplantation: a 20-year review. Liver Transpl 2012;18:455-460. 12. Taner T, Gandhi MJ, Sanderson SO, et al. Prevalence, course and impact of HLA donor-specific antibodies in liver transplantation in the first year. Am J Transplant 2012; 12: 1504–1510. 13. Markiewicz-Kijewska M, Kaliciński P, Kluge P, Piątosa B, Rękawek A. et al. Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients. Am J Transplant. 2014; 14:867-75. 14. Leca N, Warner P,Bakthavatsalam R, Nelson K, Halldorson J, et al. Outcomes of Simultaneous Liver and Kidney Transplantation in Relation to a High Level of Preformed Donor-Specific Antibodies. Transplant 2013;96: 914-918. 15. Daly RC, Topilsky Y, Joyce L, Hasin T, Gandhi M, et al. Combined heart and liver transplantation: protection of the cardiac graft from antibody rejection by initial liver implantation. Transplantation. 2013 Jan 27;95(2):e2-4. 16. Atluri P, Gaffey A, Howard J, Phillips E, Goldstone AB, et al. Combined heart and liver transplantation can be safely performed with excellent short- and long-term results. Ann Thorac Surg. 2014; 98:858-62.
Abstract #PM-4
The Kidney in Liver Transplantation Randall S. Sung, MD. University of Michigan
Renal function can be compromised in all phases of liver transplant care: pre-transplant due to the natural history of advanced liver disease, in the peri-operative period due to intraoperative events and surgical complications, and post-transplant due to long-term CNI exposure. As the organ shortage intensifies, the percentage of liver transplant candidates with renal dysfunction has increased, and pre-transplant renal dysfunction is the most significant predictor of post-transplant renal insufficiency. Pre-transplant renal insufficiency can be broken down into three different types: hepatorenal syndrome, acute kidney injury, and chronic kidney disease. These are conceptually distinguishable both by etiology and predicted reversibility after liver transplantation. Evaluation of pretransplant renal insufficiency is primarily clinical: considerations include the history and trajectory of dysfunction, severity of liver disease, and other chronic and acute comorbid conditions. Radiographic assessments such as ultrasound may show indications of CKD. Biopsy can help distinguish in some circumstances between reversible and irreversible causes of renal dysfunction, but carries significant risks and is not commonly utilized. Traditional measures of renal function such as creatinine clearance are not validated in end stage liver disease and are considered less reliable in this setting. Treatment is primarily supportive and aimed at optimizing both renal function and volume status. Renal recovery after liver
Abstract #PM-5
BMI+MELD>SBP - Selecting Good Candidates Shimul A. Shah, MD, MHCM. University of Cincinnati College of Medicine
In the evolving pay for performance era, appropriate risk-stratification models are necessary to compare care delivered across different centers and regions for disparate sets of patients. In no other specialty is this more striking than in liver transplantation, where a scarce resource is used to serve thousands of waitlisted patients with high mortality and high cost before and after transplantation. The need for appropriate and effective risk-stratification methodology to allow for enhanced allograft allocation is paramount. The total number of patients with end-stage liver disease (ESLD) in 2030 is expected to be more than four-fold the current number
42
PRE-MEETING
Abstract #PM-7
Techniques in Pediatric Liver Transplantation to Achieve Optimal Outcomes George V. Mazariegos, MD. Children’s Hospital of Pittsburgh at UPMC
Exceptional outcomes in pediatric liver transplantation require a coordinated effort among multiple medical and surgical specialists that begins in the evaluation phase and spans a lifetime. Current evolution in the medical care of children with liver disease has led to an increasing complexity of liver disease presenting for consideration for liver transplantation. Among the challenges facing the management of these children are understanding cardiac manifestations of liver disease, hepato-pulmonary interactions, the increasing proportion of children with metabolic disease, as well as the challenges of infants with acute liver failure1. Elimination of wait list mortality and optimal transplant outcomes require expertise in all applicable transplant options, including technical variant and living related transplantation. Reducing technical complications is critical to improving short term outcomes2 and requires understanding of optimizing portal3 and hepatic venous flow as well as arterial and biliary techniques utilizing best practice4. These babies often present with abnormal vascular inflow due to their underlying disease or congenital anomaly and also require proper management of the abdominal closure to avoid compartment syndrome. Post-transplant management requires both a high level of awareness of technical complications5 as well as optimal management of immunosuppression, since longterm survival and outcomes are primarily influenced by these factors6,7. 1. Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, and Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Journal of pediatric gastroenterology and nutrition. 2014;59(1):112-31. 2. McDiarmid SV, Anand R, Martz K, Millis MJ, and Mazariegos G. A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation. Annals of surgery. 2011;254(1):145-54. 3. de Magnee C, Bourdeaux C, De Dobbeleer F, Janssen M, Menten R, Clapuyt P, and Reding R. Impact of pre-transplant liver hemodynamics and portal reconstruction techniques on post-transplant portal vein complications in pediatric liver transplantation: a retrospective analysis in 197 recipients. Annals of surgery. 2011;254(1):55-61. 4. Englesbe MJ, Kelly B, Goss J, Fecteau A, Mitchell J, Andrews W, Krapohl G, Magee JC, Mazariegos G, Horslen S, et al. Reducing pediatric liver transplant complications: a potential roadmap for transplant quality improvement initiatives within North America. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012;12(9):2301-6. 5. Feier FH, Chapchap P, Pugliese R, da Fonseca EA, Carnevale FC, Moreira AM, Zurstrassen C, Santos AC, Miura IK, Baggio V, et al. Diagnosis and management of biliary complications in pediatric living donor liver transplant recipients. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2014;20(8):88292. 6. Ng VL, Alonso EM, Bucuvalas JC, Cohen G, Limbers CA, Varni JW, Mazariegos G, Magee J, McDiarmid SV, Anand R, et al. Health status of children alive 10 years after pediatric liver transplantation performed in the US and Canada: report of the studies of pediatric liver transplantation experience. The Journal of pediatrics. 2012;160(5):820-6 e3. 7. Soltys KA, Mazariegos GV, Squires RH, Sindhi RK, Anand R, and Group SR. Late graft loss or death in pediatric liver transplantation: an analysis of the SPLIT database. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007;7(9):2165-71.
Abstract #PM-6
Long-Term Living Donor Outcomes: When To Say No Dorry Segev, MD, PhD. Johns Hopkins University
“The only remaining problem was the ethical decision concerning the removal of a healthy organ from a normal person for the benefit of someone else. For the first time in medical history a normal healthy person was to be subjected to a major surgical operation not for his own benefit.” Joseph Murray, Nobel Lecture December 8, 1990 There are both surgical and medical risks that healthy individuals face when trying to help a loved one or even a stranger by donating a kidney. It is critically important to understand these risks, to keep studying these risks, and to refine methods for responsibly communicating these risks to individuals considering donation. The risks of donation are real. And serious. And attributable to donating. In other words, there are things that might happen to an individual if he donates that would not happen to that individual had he not donated. The risk of peri-operative death is 3 in 10,000. There are also risks of other peri-operative complications associated with an abdominal operation. Medically, the greatest concern is development of ESRD in someone who has lost half of their renal mass. Estimated risk of ESRD at 15 years after donation is 30.8 per 10,000 (95% CI, 24.3-38.5) in kidney donors and 3.9 per 10,000 (95% CI, 0.8-8.9) in their matched healthy nondonor counterparts (P B6), from B6 into inducible HDAC2 floxed mice (B6->HDAC2), or B6 into B6 mice (B6->B6). Native nephrectomy was performed 14 days after transplantation, and mice were subsequently treated with tamoxifen to induce HDAC2 deletion. Two weeks later, mice underwent standardized 25-minute IRI with microvascular clamping of the transplanted renal pedicle under tight temperature control. Results: HDAC2->B6 mice (n =10) demonstrated significantly lower daily BUN levels over the 4 days following injury compared to B6->HDAC2 mice (n=5, p=0.0001) or B6->B6 mice (n=5, p=0.0003) (Figure 1). Computerized scoring of renal fibrosis by Sirius Red staining at 28-days after IRI demonstrated significantly reduced fibrosis in the HDAC2->B6 group compared to both other groups (p
ABSTRACTS
PRE-MEETING
7.
Pre-Meeting Abstract #PM-1
Surgical Challenges in Liver Transplantation William C. Chapman, MD, FACS, Washington University School of Medicine, St. Louis, MO
Kim, D.J., Clark, P.J., Heimbach, J., Rosen, C., Sanchez, W., Watt, K., and Charlton, M.R. 2014. Recurrence of hepatocellular carcinoma: importance of mRECIST response to chemoembolization and tumor size. Am J Transplant 14:1383-1390.
Abstract #PM-3
Many new challenges face surgeons in the field of liver transplantation. Increasingly complex surgical needs are present, and these impact day-to-day operations for transplantation. These include, but are not limited to, extended criteria donors and increasing use of vascular reconstruction, both in donors and in recipients. Much of fellowship training is devoted to mastering the basic skill set for liver transplantation, yet frequently patients undergoing liver transplantation may have significantly increased complexity. A critical skill for effective liver transplantation involves recognition and anticipation of technical challenges that must be anticipated prior to encountering such difficulties. Surgeons in these potential situations must have colleagues with sufficient skills and willingness to assist. While not regularly common, such situations may arise and lead to a critical need for a well-skilled team of surgeons for effective surgical intervention. The fully trained surgeon must be familiar with special techniques which may often be required, including the use of venovenous bypass, cut down techniques for split liver transplant, unique vascular and biliary reconstruction, and the judgment required for use of other teams, including interventional radiology. Each of these complex areas will be discussed in the course of this presentation.
The Impact of Donor Specific Antibody in Liver Transplantation Julie Heimbach, MD, Timucin Taner, MD. Division of Transplantation Surgery, Mayo Clinic, Rochester, MN
The role of donor-specific antibody (DSA) in liver transplant is currently an area of renewed interest. Based upon early reports suggesting a minimal role for antibody-mediated injury in liver transplantation (LT)1, 2, concern over the role of antibodies waned, and for two decades, the potential of antibody-mediated injury to liver allografts was largely ignored. Unlike other potential transplant recipients, prospective cross-matches are not performed in LT and waitlisted liver transplant patients are generally not screened for DSA. However, perhaps as a result of newer technologies that have allowed for a more precise identification of DSA, a series of more recent reports have implicated antibody-mediated injury as a potentially more significant cause of liver allograft injury than previously thought. This renewed interest is highlighted by the fact that an inaugural consensus conference solely focused on antibody-mediated injury in LT was held in 2013, as well as at the most recent Banff conference also held in 2013, which had a specific focus on clarification of the histologic features of antibody-mediated rejection (AMR) in non-renal transplant recipients including liver. 3, 4 The more recent reports related to the impact of DSA in liver transplant recipients began with a 2005 report published by Muro et al on a series of 268 LT recipients which identified that those with DSA had a 28% 1 year graft survival while recipients without DSA had a 72% 1 year graft survival.5 Following that, Castillo-Rama et al published their experience with 896 patients and noted reduced graft survival (75% vs 83%) at 1 year for patients with DSA.6 Another series published just 1 year later on more than 1100 living donor recipients also noted inferior graft survival for recipients who were identified to have donor-specific antibody (58% vs 85%).7 In addition, O’Leary et al published their observations on a case-matched series of 39 patients with DSA who were paired with 39 matched controls, and they also noted chronic rejection and increased graft loss in those with DSA.8 While these relatively large series are compelling, it is essential to note that the antibody analysis was performed retrospectively, and there is no information about the antibody status of the patients at the time of transplant. It is uncertain whether the expression of DSA noted in patients with increased graft loss is the cause or the consequence of their graft injury. In addition, several other recent large retrospective series demonstrated no difference in patient or graft survival based on DSA at the time of transplant.9-11 A prospective analysis of all adults undergoing primary liver-only transplantation was performed at Mayo Clinic in 2009-2010 (n=90) and measured DSA at time 0, day 7, day 21, 4 months, and 12 months.12 In this series, 20% of patients were positive for DSA (as defined by a mean fluorescence index, or MFI, of 2000), and 18% had a positive cross-match. However, in nearly all the patients, the DSA was undetectable at day 7. The day 7 biopsies noted diffuse staining in patients who had persistent DSA,; however, there were no differences in graft function based on the presence of DSA. In addition, no patient developed de novo antibody during the study period, and there was no difference in outcome during the first year between patients with antibody and those without antibody. Another recent report analyzed the impact of DSA on longer term LT outcomes.13 In this series, starting in 2008 all patients (n=267) who were 6 months or more from LT underwent screening for DSA which was repeated annually through 2012. The report found 13% of patients had DSA at the first screen (using an MFI of >1000 as positive), and an additional 21 (9%) developed new DSA during the study period. While the death and graft loss rates were not different in patients with or without DSA, the fibrosis score was higher in patients with DSA. Examination of outcomes for multi-organ liver transplant recipients (liver-heart or liver-kidney) is also of interest. Leca et al recently reported their results with 56 combined liver-kidney transplant recipients transplanted during 1991-2011 and found no differences in patient survival, renal allograft survival, or renal allograft function when comparing sensitized versus non-sensitized patients, which is contrary to the inferior outcomes which have been well-demonstrated for sensitized kidney-only transplant recipients.14 Similar reports are also becoming available for liver-heart transplant recipients, though multi-organ recipients are still at risk for both cellular and humoral rejection.15, 16 In summary, DSA and antibody-mediated rejection seems to have a lower impact on liver transplant recipients compared to other solid organ transplant recipients, understanding the interaction between the liver and DSA is crucial, and essential questions remain. What is the mechanism of the dramatic decrease in levels of DSA seen in the early post-transplant period for sensitized liver transplant recipients? Why does DSA persist in certain patients? What are the long-term implications
Abstract #PM-2
Hepatocellular Carcinoma: Who Not to Transplant, That’s the Question Theodore H. Welling, MD, University of Michigan
The incidence of hepatocellular carcinoma (HCC) is rising, and therapies designed to target early stage HCC which show curative efficacy include hepatic resection, liver transplantation (OLT), radiofrequency ablation, and other developing ablative options such as stereotactic body radiation therapy (SBRT)1. However, the donor liver supply remains flat over time despite the increasing incidence of HCC. It is estimated that the incidence of HCC in the U.S. is rising faster than other solid organ malignancies, greater than 5 cases/100,000 persons2, and is believed to be related to the HCV epidemic and rising burden of NASH. While OLT remains a useful therapy for patients with HCC and a significant burden of liver disease3, the donor organ supply, complication/cost rate, and risk of recurrence in patient subsets limits this modality from being used universally in HCC patients. Indeed, it has recently been brought to attention that OLT may be over-utilized in HCC patients when compared to non-HCC patients receiving OLT4,5. HCC biologic factors such as tumor stage, AFP, and response to therapy remain important criteria affecting overall outcomes following OLT1,6,7. Therefore the question remains: which patients are most likely to benefit from other therapies? Is there evidence supporting OLT versus other therapies? What is the role of “bridging” or “down-staging” therapies with regard to expanding the use of OLT to HCC patients? The best available evidence regarding outcomes for resection, ablation, and the overall best means by which to stratify patients into therapeutic groups in order to maximize efficacy and reduce complications will be reviewed and discussed. These outcomes will be placed into the context of current experience with OLT, utilization of donor livers, and current allocation schema. The goal of this discussion will be to allow participants to have a greater understanding regarding treatment of HCC patients with respect to liver directed therapies. A balanced, multidisciplinary approach, considering oncologic burden, liver disease burden, and identification of where clinical equipoise exists is essential to the care of HCC patients. References 1. Marrero, J.A., and Welling, T. 2009. Modern diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 13:233-247. 2. El-Serag, H.B. 2011. Hepatocellular carcinoma. N Engl J Med 365:1118-1127. 3. Mazzaferro, V., Regalia, E., Doci, R., Andreola, S., Pulvirenti, A., Bozzetti, F., Montalto, F., Ammatuna, M., Morabito, A., and Gennari, L. 1996. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699. 4. Washburn, K., Edwards, E., Harper, A., and Freeman, R. 2010. Hepatocellular carcinoma patients are advantaged in the current liver transplant allocation system. Am J Transplant 10:1643-1648. 5. Pomfret, E.A., Washburn, K., Wald, C., Nalesnik, M.A., Douglas, D., Russo, M., Roberts, J., Reich, D.J., Schwartz, M.E., Mieles, L., et al. 2010. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 16:262-278. Hameed, B., Mehta, N., Sapisochin, G., Roberts, J.P., and Yao, F.Y. 2014. 6. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 20:945-951.
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All authors and co-authors and/or individuals involved with the abstract are required to disclose relevant financial relationships with respect to their abstract. All relevant disclosures are published following each abstract.
PRE-MEETING transplantation is variable and not highly predictable, although in general patients with HRS have a high likelihood of recovery and those with CKD a low likelihood. For those with advanced renal dysfunction and low predicted likelihood of renal recovery, simultaneous liver-kidney (SLK) transplantation is an important option. As the incidence of severe renal dysfunction has increased over the past decade, so have the numbers of SLK transplants. This has engendered controversy within the transplant community because SLK transplants draw deceased donor kidneys from the kidney transplant candidate pool. Because renal recovery after liver transplant alone (LTA) is difficult to predict, indications for SLK are not precisely defined. While dialysis status is a consideration, those with HRS can have renal recovery after as much as 12 weeks on dialysis, while recipients with Stage 4/5 CKD not on dialysis may have immediate or early ESRD after LTA due to perioperative events and CNI exposure. While large retrospective observational analyses generally show slightly improved survival in SLK recipients compared with LTA, inferences that may be drawn from these studies are limited by important selection biases in the current registry data structure. Therefore, a true survival benefit of SLK over LTA in candidates without ESRD is still unproven. Cause of renal dysfunction and dialysis duration are not reported for LTA recipients, and are known to be quite different between LTA and SLK recipients. In general, candidate selection is such that LTA candidates tend to have more renal dysfunction due to severe liver disease such as HRS and AKI, while SLK candidates tend to have less severe liver disease and more CKD or ESRD. However, due to the lack of clarity in indications for SLK, selection practices vary widely. The concept of a safety net in deceased donor kidney allocation, which would entail priority for LTA recipients who develop ESRD after transplantation, has been proposed to help reduce the number of SLK transplants, but has not yet been adopted. The incidence of post-transplant ESRD is also increasing as pre-transplant renal dysfunction has become more commonplace. While many factors present at the time of transplant influence the risk, prevention is aimed at identifying patients at risk, management of complications that may lead to peri- or postoperative AKI, and limiting CNI exposure both immediately after transplantation and in the long-term. Patient survival following kidney transplantation in prior LTA recipients is superior to SLK recipients, but inferior to KTA recipients without a prior liver transplant. References: Davis CL, Feng S, Sung RS, Wong F, Goodrich NP, Melton LB, Reddy KR, 1. Guidinger MK, Wilkinson A, Lake J. Simultaneous liver-kidney transplantation: evaluation to decision making. American Journal of Transplantation 2007; 7: 1702-1709. 2. Eason JD, Gonwa TA, Davis CL, Sung RS, Gerber D, Bloom RD. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation. American Journal of Transplantation 2008: 8; 2243-2451. 3. Nadim MK, Davis C, Sung RS, Kellum JA, Genyk YS. Simultaneous Liver Kidney Transplantation: A Survey of US Transplant Centers. American Journal of Transplantation 2012; 12; 3119-3127. 4. Nadim MK, Sung RS, Davis CL, et al. Simultaneous Liver- Kidney Transplantation Summit: Current State and Future Directions. American Journal of Transplantation 2012; 12: 2901-2908. 5. Locke JE, Warren DS, Singer AL, Segev DL, Simpkins CE, Maley WR, et al. Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: ineffective usage of renal allografts. Transplantation. 2008;85(7):935-42. 6. Schmitt TM, Kumer SC, Al-Osaimi A, Shah N, Argo CK, Berg C, et al. Combined liver-kidney and liver transplantation in patients with renal failure outcomes in the MELD era. Transpl Int. 2009;22(9):876-83. 7. Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, et al. Impact of etiology of acute kidney injury on outcomes following liver transplantation: Acute tubular necrosis versus hepatorenal syndrome. Liver Transpl. 2012;18(5):539-48. 8. Bahirwani R, Campbell MS, Siropaides T, Markmann J, Olthoff K, Shaked A, et al. Transplantation: impact of pretransplant renal insufficiency. Liver Transpl. 2008;14(5):665-71. 9. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med 2003;349(10):931-40 10. Campbell MS, Kotlyar DS, Brensinger CM, et al. Renal function after orthotopic liver transplantation is predictted by duration of pretransplantation creatinine elevation. Liver Transpl 2005;11(9):1048-55 11. Sharma P, Goodrich NP, Schaubel DE, Guidinger MK, Merion RM. Patient Specific Prediction of End Stage Renal Disease Risk after Liver Transplantation. Journal of American Society of Nephrology, 2013
of having DSA at the time of transplant, or having persistent DSA post LT? These questions apply both to patients undergoing isolated liver transplant, as well as those undergoing multi-organ transplantation. References 1. Andres GA, Ansell ID, Halgrimson CG, Hsu KC, Porter KA, Starzl TE, et al. Immunopathological studies of orthotopic human liver allografts. Lancet 1972;1:275-280. 2. Gordon RD, Fung JJ, Markus B, Fox I, Iwatsuki S, Esquivel CO, et al. The antibody crossmatch in liver transplantation. Surgery 1986;100:705-715. 3. J. G. O’Leary JG, A. J. Demetris AJ, Friedman LS, Gebel HM, Halloran PF, Kirk AD. The Role of Donor-Specific HLA Alloantibodies in Liver Transplantation. Am J Transplant 2014; 14: 779–787. 4. Haas M, Sis B, Racusen LC, Solez K, Glotz D, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014;14:272-83. 5. Muro M, Marin L, Miras M, Moya-Quiles R, Minguela A,Sanchez-Bueno F, et al. Liver recipients harboring anti-donor preformed lymphocytotoxic antibodies exhibit a poor allograft survival at the first year after transplantation: experience of one centre. Transpl Immunol 2005; 14:91-97. 6. Castillo-Rama M, Castro MJ, Bernardo I, et al. Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: Role of human leukocyte antigen compatibility. Liver Transpl 2008; 14: 554–562. 7. Hori T, Uemoto S, Takada Y, Oike F, Ogura Y, et al. Does a positive lymphocyte cross-match contraindicate living-donor liver transplantation? Surgery 2010 ;147:840-4. 7. Kozlowski T, Rubinas T, Nickeleit V, et al. Liver allograft antibody mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver Transpl 2011; 17: 357–368. 8. Musat AI, Agni RM, Wai PY, Pirsch JD, Lorentzen DF, Powell A, et al. The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation. Am J Transplant 2011;11:500-510. 8. O’Leary JG, Kaneku H, Susskind BM, Jennings LW, Neri MA, Davis GL, et al. High mean fluorescence intensity donor-specific anti-HLA antibodies associated with chronic rejection postliver transplant. Am J Transplant 2011;11:1868-1876. 9. Shin M, Moon HH, Kim JM, Park JB, Kwon CH, Kim SJ, et al. Significance of true-positive and false-positive pretransplantation lymphocytotoxic crossmatch in primary liver allograft outcomes. Transplantation 2013;95:1410-1417. 10. Lunz J, Ruppert KM, Cajaiba MM, Isse K, Bentlejewski CA, Minervini M, et al. Re-examination of the lymphocytotoxic crossmatch in liver transplantation: can C4d stains help in monitoring? Am J Transplant 2012;12: 171-182. 11. Ruiz R, Tomiyama K, Campsen J, Goldstein RM, Levy MF, McKenna GJ, et al. Implications of a positive crossmatch in liver transplantation: a 20-year review. Liver Transpl 2012;18:455-460. 12. Taner T, Gandhi MJ, Sanderson SO, et al. Prevalence, course and impact of HLA donor-specific antibodies in liver transplantation in the first year. Am J Transplant 2012; 12: 1504–1510. 13. Markiewicz-Kijewska M, Kaliciński P, Kluge P, Piątosa B, Rękawek A. et al. Prevalence, incidence and risk factors for donor-specific anti-HLA antibodies in maintenance liver transplant patients. Am J Transplant. 2014; 14:867-75. 14. Leca N, Warner P,Bakthavatsalam R, Nelson K, Halldorson J, et al. Outcomes of Simultaneous Liver and Kidney Transplantation in Relation to a High Level of Preformed Donor-Specific Antibodies. Transplant 2013;96: 914-918. 15. Daly RC, Topilsky Y, Joyce L, Hasin T, Gandhi M, et al. Combined heart and liver transplantation: protection of the cardiac graft from antibody rejection by initial liver implantation. Transplantation. 2013 Jan 27;95(2):e2-4. 16. Atluri P, Gaffey A, Howard J, Phillips E, Goldstone AB, et al. Combined heart and liver transplantation can be safely performed with excellent short- and long-term results. Ann Thorac Surg. 2014; 98:858-62.
Abstract #PM-4
The Kidney in Liver Transplantation Randall S. Sung, MD. University of Michigan
Renal function can be compromised in all phases of liver transplant care: pre-transplant due to the natural history of advanced liver disease, in the peri-operative period due to intraoperative events and surgical complications, and post-transplant due to long-term CNI exposure. As the organ shortage intensifies, the percentage of liver transplant candidates with renal dysfunction has increased, and pre-transplant renal dysfunction is the most significant predictor of post-transplant renal insufficiency. Pre-transplant renal insufficiency can be broken down into three different types: hepatorenal syndrome, acute kidney injury, and chronic kidney disease. These are conceptually distinguishable both by etiology and predicted reversibility after liver transplantation. Evaluation of pretransplant renal insufficiency is primarily clinical: considerations include the history and trajectory of dysfunction, severity of liver disease, and other chronic and acute comorbid conditions. Radiographic assessments such as ultrasound may show indications of CKD. Biopsy can help distinguish in some circumstances between reversible and irreversible causes of renal dysfunction, but carries significant risks and is not commonly utilized. Traditional measures of renal function such as creatinine clearance are not validated in end stage liver disease and are considered less reliable in this setting. Treatment is primarily supportive and aimed at optimizing both renal function and volume status. Renal recovery after liver
Abstract #PM-5
BMI+MELD>SBP - Selecting Good Candidates Shimul A. Shah, MD, MHCM. University of Cincinnati College of Medicine
In the evolving pay for performance era, appropriate risk-stratification models are necessary to compare care delivered across different centers and regions for disparate sets of patients. In no other specialty is this more striking than in liver transplantation, where a scarce resource is used to serve thousands of waitlisted patients with high mortality and high cost before and after transplantation. The need for appropriate and effective risk-stratification methodology to allow for enhanced allograft allocation is paramount. The total number of patients with end-stage liver disease (ESLD) in 2030 is expected to be more than four-fold the current number
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Abstract #PM-7
Techniques in Pediatric Liver Transplantation to Achieve Optimal Outcomes George V. Mazariegos, MD. Children’s Hospital of Pittsburgh at UPMC
Exceptional outcomes in pediatric liver transplantation require a coordinated effort among multiple medical and surgical specialists that begins in the evaluation phase and spans a lifetime. Current evolution in the medical care of children with liver disease has led to an increasing complexity of liver disease presenting for consideration for liver transplantation. Among the challenges facing the management of these children are understanding cardiac manifestations of liver disease, hepato-pulmonary interactions, the increasing proportion of children with metabolic disease, as well as the challenges of infants with acute liver failure1. Elimination of wait list mortality and optimal transplant outcomes require expertise in all applicable transplant options, including technical variant and living related transplantation. Reducing technical complications is critical to improving short term outcomes2 and requires understanding of optimizing portal3 and hepatic venous flow as well as arterial and biliary techniques utilizing best practice4. These babies often present with abnormal vascular inflow due to their underlying disease or congenital anomaly and also require proper management of the abdominal closure to avoid compartment syndrome. Post-transplant management requires both a high level of awareness of technical complications5 as well as optimal management of immunosuppression, since longterm survival and outcomes are primarily influenced by these factors6,7. 1. Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, and Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Journal of pediatric gastroenterology and nutrition. 2014;59(1):112-31. 2. McDiarmid SV, Anand R, Martz K, Millis MJ, and Mazariegos G. A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation. Annals of surgery. 2011;254(1):145-54. 3. de Magnee C, Bourdeaux C, De Dobbeleer F, Janssen M, Menten R, Clapuyt P, and Reding R. Impact of pre-transplant liver hemodynamics and portal reconstruction techniques on post-transplant portal vein complications in pediatric liver transplantation: a retrospective analysis in 197 recipients. Annals of surgery. 2011;254(1):55-61. 4. Englesbe MJ, Kelly B, Goss J, Fecteau A, Mitchell J, Andrews W, Krapohl G, Magee JC, Mazariegos G, Horslen S, et al. Reducing pediatric liver transplant complications: a potential roadmap for transplant quality improvement initiatives within North America. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012;12(9):2301-6. 5. Feier FH, Chapchap P, Pugliese R, da Fonseca EA, Carnevale FC, Moreira AM, Zurstrassen C, Santos AC, Miura IK, Baggio V, et al. Diagnosis and management of biliary complications in pediatric living donor liver transplant recipients. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2014;20(8):88292. 6. Ng VL, Alonso EM, Bucuvalas JC, Cohen G, Limbers CA, Varni JW, Mazariegos G, Magee J, McDiarmid SV, Anand R, et al. Health status of children alive 10 years after pediatric liver transplantation performed in the US and Canada: report of the studies of pediatric liver transplantation experience. The Journal of pediatrics. 2012;160(5):820-6 e3. 7. Soltys KA, Mazariegos GV, Squires RH, Sindhi RK, Anand R, and Group SR. Late graft loss or death in pediatric liver transplantation: an analysis of the SPLIT database. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007;7(9):2165-71.
Abstract #PM-6
Long-Term Living Donor Outcomes: When To Say No Dorry Segev, MD, PhD. Johns Hopkins University
“The only remaining problem was the ethical decision concerning the removal of a healthy organ from a normal person for the benefit of someone else. For the first time in medical history a normal healthy person was to be subjected to a major surgical operation not for his own benefit.” Joseph Murray, Nobel Lecture December 8, 1990 There are both surgical and medical risks that healthy individuals face when trying to help a loved one or even a stranger by donating a kidney. It is critically important to understand these risks, to keep studying these risks, and to refine methods for responsibly communicating these risks to individuals considering donation. The risks of donation are real. And serious. And attributable to donating. In other words, there are things that might happen to an individual if he donates that would not happen to that individual had he not donated. The risk of peri-operative death is 3 in 10,000. There are also risks of other peri-operative complications associated with an abdominal operation. Medically, the greatest concern is development of ESRD in someone who has lost half of their renal mass. Estimated risk of ESRD at 15 years after donation is 30.8 per 10,000 (95% CI, 24.3-38.5) in kidney donors and 3.9 per 10,000 (95% CI, 0.8-8.9) in their matched healthy nondonor counterparts (P B6), from B6 into inducible HDAC2 floxed mice (B6->HDAC2), or B6 into B6 mice (B6->B6). Native nephrectomy was performed 14 days after transplantation, and mice were subsequently treated with tamoxifen to induce HDAC2 deletion. Two weeks later, mice underwent standardized 25-minute IRI with microvascular clamping of the transplanted renal pedicle under tight temperature control. Results: HDAC2->B6 mice (n =10) demonstrated significantly lower daily BUN levels over the 4 days following injury compared to B6->HDAC2 mice (n=5, p=0.0001) or B6->B6 mice (n=5, p=0.0003) (Figure 1). Computerized scoring of renal fibrosis by Sirius Red staining at 28-days after IRI demonstrated significantly reduced fibrosis in the HDAC2->B6 group compared to both other groups (p
