Indian J Gastroenterol DOI 10.1007/s12664-013-0379-1 ORIGINAL ARTICLE Use of marginal grafts in deceased donor liver transplant: Assessment of early outcomes Rajesh Godara & C. Sudeep Naidu & Pankaj P. Rao & Sanjay Sharma & Jayant K. Banerjee & Anupam Saha & Kapileshwer Vijay Received: 1 May 2013 / Accepted: 30 July 2013 # Indian Society of Gastroenterology 2013 Abstract Introduction Orthotopic liver transplantation has become a routinely applied therapy for an expanding group of patients with end-stage liver disease. Shortage of organs has led centers to expand their criteria for the acceptance of marginal donors. There is current debate about the regulation and results of liver transplantation using marginal grafts. Methods The study included data of all patients who received deceased donor liver grafts between March 2007 to December 2011. Patients with acute liver failure, living donor transplantation, split liver transplantation, and retransplantation were excluded. Early allograft dysfunction, primary nonfunction, patient survival, and incidence of surgical complications were measured. Results A total of 33 patients were enrolled in this study. There were 20 marginal and 13 nonmarginal grafts. The two groups were well matched regarding age, sex and indication of liver transplantation, model for end-stage liver disease score, technique of transplant, requirement of vascular reconstruction, warm ischemia time, blood loss, mean operative time, etc. In our study, posttransplant peak level of liver enzymes, international normalization ratio, and bilirubin were not statistically significant in the marginal and nonmarginal group. Wound infection occurred in 10 % of marginal compared with 7.7 % of nonmarginal graft recipients (p>0.05). In the marginal group, the incidences of vascular complications, hepatic artery thrombosis (four), and portal vein thrombosis (one) were not statistically significant compared to the nonmarginal group. Acute rejection was observed in a total of seven patients (21.2 %)—five (25 %) in the marginal group and two (15.4 %) in the nonmarginal graft recipients. Primary nonfunction occurred in three (9.1 %) patients—two (10 %) in the marginal and one (7.7 %) in the nonmarginal group. Average patient survival for the whole group was 91 % at 1 week, 87.8 % at 3 months, and 84.8 % at 6 months. Conclusion Because organ scarcity persists, additional pressure will build to use a greater proportion of the existing donor pool. The study, although small, clearly indicates that marginal livers can assure a normal early functional recovery after transplantation. Keywords Donor pool expansion . Graft dysfunction . Orthotopic liver transplantation Introduction The use of marginal grafts is an option used worldwide to increase the organ supply for transplantation. The guidelines for using marginal grafts vary from center to center. The pretransplantation liver disease status of the recipient appears to be an important criterion for allocating these organs. Nevertheless, there is ongoing disagreement regarding this issue. Some authors have selected marginal grafts for healthier patients who can tolerate retransplantation, whereas others have advocated their unrestricted use to meet the needs of transplantation lists. Thus, there is a current debate about the regulation and results of liver transplantation using marginal grafts. Herein, we report the outcome of a series of patients receiving marginal grafts. Methods R. Godara (*) : C. S. Naidu : P. P. Rao : S. Sharma : J. K. Banerjee : A. Saha : K. Vijay Department of Gastrointestinal Surgery and Liver Transplantation, Army Hospital (Research & Referral), Delhi 110 010, India e-mail: drrajeshgodara@yahoo.co.uk The study included data of all patients who received deceased donor liver grafts between March 2007 and December 2011 at the Liver Transplant Center, Army Hospital (Research & Referral), Delhi. Patients with acute liver failure, living donor Indian J Gastroenterol transplantation, split liver transplantation, and retransplantation were excluded. As per our institutional policy, we rejected grafts from patients with history of malignancy, grossly fatty liver on inspection, cirrhotic liver, serum sodium >170 mEq/L, and not showing decreasing trend with sodium-free fluid, liver enzyme level >200 U/L, and serum bilirubin >3 mg %. Visual inspection of graft was made regarding fat status; frozen section biopsy was done whenever indicated. The scale of allograft fatty infiltration was defined as follows: absent or mild (<30 %) and significant (>30 %) macrovesicular steatosis. The donor management, retrieval, recipient evaluation, transplantation, and management were as per the protocol followed by this center. was defined as nonlife-sustaining function of the liver requiring retransplantation or leading to death within 7 days after liver transplantation [3]. The immunosuppression consists of tacrolimus, MMF, and corticosteroids. The patients were weaned off corticosteroids within 3 months, except in cases of transplantation due to autoimmune hepatitis which were treated with corticosteroid continuously. Statistical analysis The Kaplan–Meier test was used to compare recipient survival, Fisher’s exact test was used to assess the incidence of surgical complications, and Student’s t test was used to evaluate the liver enzyme peak. The significance level was 0.05. Graft scoring system Graft quality was assessed using a previously described scoring system—score of 1 for the following characteristics: donor age >60 years, ICU stay >4 days, cold ischemia time >13 h, hepatic macrosteatosis ≥30 %, bilirubin >2.0 mg/dL, alanine aminotransferase (ALT) >170 U/L, and aspartate aminotransferase (AST) >140 U/L, and score of 2 for the following: use of vasopressor drugs (dopamine >10 μg/kg/min or use of ≥ two vasopressors) and serum sodium >155 mEq/L. The graft was considered as marginal when the score reached ≥3 [1]. Parameters of assessment Outcome parameters were assessed daily—serum peaks of ALT and AST, serum bilirubin, INR, hepatic encephalopathy, biliovascular complications, and patient survival—1 week, 1 month, and 6 months after transplantation. Early allograft dysfunction was defined as presence of at least one of the following—serum bilirubin >10 mg/dL on postoperative day 7, INR ≥ 1.6 on postoperative day 7, and ALT or AST >2,000 IU/mL within the first 7 days [2]. Primary nonfunction Results Between March 2007 and December 2011, out of 104 brain deaths, 85 potential donors were counseled for organ donation, and only 38 consented for liver donation. Two cases were rejected during the organ procurement process, one due to micronodular cirrhosis and the other due to massive colonic gangrene. Of 36 patients who underwent multiorgan retrieval, 35 orthotopic whole liver and 2 split liver transplantations were performed. A total of 33 patients were enrolled in this study after excluding two split and one retransplantation case as per study protocol. Donor demographics and biochemical data are shown in Table 1. In our study, out of 20 marginal grafts, five were subjected to frozen section biopsy on visual inspection, and one was found to have significant steatosis but not rejected as graft as it was not grossly fatty. There were 20 (60.6 %) marginal grafts and 13 (39.4 %) nonmarginal grafts. In the marginal graft group, average score was 6.01 (3 to 8). The two groups were well matched regarding age, sex and indication of liver transplantation, model for end-stage liver Table 1 Donor demographics, clinical characteristics, and biochemical data Age (years), mean±SD Gender M/F Cause of death NS not significant, CVA cerebrovascular accident Marginal (20) Nonmarginal (13) p-value Trauma 56.35±16.94 12/8 7 34.76±13.03 8/5 5 0.0005 NS NS CVA Others 11 2 5 3 2.76±0.72 4 102.92±27.45 81.69±34.93 1.1±0.24 140.84±6.53 4.64±0.99 0 0.75 0.072 0.008 NS 0.074 0.31 0.31 0.66 0.03 0.26 ICU stay (days), mean±SD Dopamine >10 μg/kg/min or ≥2 vasopressors SGOT (U/L), mean±SD SGPT (U/L), mean±SD Total bilirubin (mg/dL), mean±SD Serum sodium, mean±SD Cold ischemia time (h), mean±SD Hepatic steatosis >30 % 3.9±1.33 13 134.4±57.03 97.55±48.05 1.23±0.41 142.2±9.91 5.72±1.51 3 Indian J Gastroenterol disease (MELD) score, technique of transplant, requirement of vascular reconstruction, warm ischemia time, blood loss, mean operative time, etc. (Table 2). In our study, posttransplant peak level of liver enzymes (SGOT 887.75 ± 580.95 vs. 562.07± 414.69, p= 0.09, and SGPT 657.25± 575.38 vs. 441.84 ± 441.47, p = 0.47), INR day 7 (1.68 ± 0.6 vs. 1.34±0.21, p=0.059), and bilirubin day 7 (3.91±4.78 vs. 2.37±2.37, p=0.29) were not statistically significant in the marginal and nonmarginal groups. Postoperative complications were broadly categorized as vascular, biliary, wound, and others. Wound infection occurred in 10 % of marginal compared with 7.7 % of nonmarginal graft recipients (p=NS). In the marginal group, the incidences of vascular complications, hepatic artery thrombosis (four), and portal vein thrombosis (one) were not statistically significant compared to the nonmarginal group. Acute rejection was observed in a total of seven patients (21.2 %)—five (25 %) in the marginal group and two (15.4 %) in the nonmarginal graft recipients. Primary nonfunction occurred in three (9.1 %) patients in our study—two (10 %) marginal graft recipients and one (7.7 %) nonmarginal graft recipient. All three patients expired in the first week posttransplant due to nonavailability of a donor organ for transplantation. Both patients of the marginal group with primary nonfunction had a high MELD (>20) score while only patient with primary nonfunction in the nonmarginal group had a low MELD score (<20). The phenomenon of posttransplant diabetes mellitus which is of multiple etiology was observed in four patients (21 %) of marginal graft recipients and five (38.4 %) of nonmarginal graft recipients (Table 3). Discussion The use of marginal grafts has now become commonplace, mandated by the need to keep up with the growing demand for donor grafts. However, there is a lack of consensus about the Table 2 General characteristics and liver disease diagnosis of marginal and nonmarginal graft recipients Gender Male Female Age (years) Etiology HBV hepatitis B virus, HCV hepatitis C virus, BCS Budd-Chiari syndrome HBV HCV Alcoholic Cryptogenic BCS Autoimmune MELD score, mean±SD Child–Turcot–Pugh, mean±SD Warm ischemia (min), mean±SD definition of a marginal graft and the factors that should exclude a graft from use because of increased risk to the recipient. The decision to use a specific organ therefore depends on the center protocol, judgment of the transplant surgeon, and specific needs of the recipient. Numerous single-center reports have identified predictors of potentially poor graft function, and in regions of particular scarcity, utilization of these organs with overall satisfactory results has become commonplace, leading to emphasis on expanding donor criteria. “Graft malfunction,” which is multifactorial in etiology, has varying degrees; the severest is the irreversible state of primary nonfunction, with less severe forms exhibiting reversible graft dysfunction termed initial poor function. Primary nonfunction is the most serious end result of initial poor allograft function and may occur in 1.4 % to 8.5 % of cases after orthotopic liver transplantation and requires urgent retransplantation to avoid patient mortality [3–7]. The conditions of the donor, recipient, and surgery influence early function of the transplanted liver. This study focused on the identification of the effect of marginal donor on liver graft function, morbidity, and survival after transplantation. Use of marginal donors, especially aged donors, has become more frequent recently. In Europe, donors over 60 years have increased from less than 5 % in the early 1990s to approximately 20 % in the 2002 European Liver Transplantation Registry [8]. Not accepting a donor liver from a marginal donor may result in the death of a patient requiring an urgent transplantation as another donor liver may not become available immediately. Marginal grafts should be transplanted in recipients with low risk, ie. a low model for MELD score and fewer comorbidities. These grafts perform better in patients who can tolerate a bigger insult immediately following transplantation when compared with high-risk recipients [9–11]. Patient and graft survival have been found to be significantly lower when marginal grafts were used in high-risk recipients. Nonmarginal Marginal p-value 11 2 37.76±12.85 17 3 37.35±10.30 1 1 0.919 6 1 1 4 0 1 15.85±3.79 9.69±1.79 62.38±20.89 9 1 1 6 1 2 17.12±4.81 9.45±1.31 57.45±9.44 1 1 1 1 1 1 0.428 0.659 0.361 Indian J Gastroenterol Table 3 Incidence of postoperative complications in either group Marginal n (%) Nonmarginal n (%) Acute rejection Wound infection Septicemia Pneumonitis Pleural effusion 5 (25) 2 (10) 3 (15) 2 (10) 3 (15) 2 (15.4) 1 (7.7) 1 (7.7) 3 (23.1) 3 (23.1) Hepatic artery thrombosis Portal vein thrombosis Biliary stricture Intraabdominal collection Encephalopathy Primary nonfunction Early allograft dysfunction Survival 1 week 1 month 3 months 6 months 4 (20) 1 (5) 5 (25) 3 (15) 1 (5) 2 (10) 8 (40) 18/20 (90) 17/20 (85) 17/20 (85) 17/20 (85) 0 0 2 (15.4) 0 2 (15.4) 1 (7.7) 2 (15.4) 12/13 (92.3) 12/13 (92.3) 12/13 (92.3) 11/13 (84.61) Mechanism of injury to donor organs and correlation with clinical outcome whenever there is a broadening of donor or recipient criteria are not definitive or objective. The clinical definition of early allograft dysfunction is not firmly established in the current MELD era, however. There have been previous definitions using differing criteria, and the characterization has varied among studies [6, 12, 13]. The operational definition of early allograft dysfunction has significant impact on analyses of clinical studies. As the transplant community continues to stretch the borders of utilization of a wide range of donors, it is important to have an accepted current definition of early allograft dysfunction that correlates with future graft and patient outcome in order to have a clinical endpoint to suggest changes in practice. We chose the definition of early allograft dysfunction which is applicable in the MELD era and is one of the most recent wellvalidated definitions that incorporates well-described clinical variables reflecting overall graft function (injury, cholestasis, coagulopathy) within the first week after transplantation [2]. In our study, the marginal graft comprised 60.6 % of the total deceased donor liver transplants. The overall rates of early allograft dysfunction and primary nonfunction in the present study were 30.3 % and 9.1 %, respectively, using the criteria as set out above. This is similar to most reported studies [12, 14–16]. Ploeg et al. reported that the rate of early allograft dysfunction was 22 %, and that of primary nonfunction was 6 %. Our 1- and 6-month patient and graft survival results of 89.6 % and 86.2 %, respectively, are encouraging and comparable to those of Bachella et al. [17]. We have observed a higher incidence of marginal donors than in most other centers that have reviewed the subject. This may be explained in two ways: differences in graft grading score systems and local deficiencies in donor maintenance. Total p-value 7 3 4 5 6 0.675 1 1 0.360 0.658 4 1 7 3 3 3 10 30 30 30 29 0.135 1 0.675 0.261 0.547 1 0.245 1 1 1 1 There is no consensus regarding a grading system for assessing liver graft quality. Since these grading systems vary from center to center, it is reasonable to assume that some cases were classified in different categories depending on the system adopted. Concerning local deficiencies, it is difficult to compare Indian organ procurement organizations with other centers that have assessed marginal liver transplantation, which have usually been located in developed countries. In India, organ donation and recovery indexes remain poor. Furthermore, many physicians ignore the legislation regarding organ donation and have misunderstandings about the diagnosis of brain death and maintenance of potential donors. The deficiencies in organ procurement and donor assistance in India may influence graft quality, thereby causing a higher incidence of marginal liver use. Similar to our results, previous studies have not found any differences in survival between the recipients of marginal and nonmarginal grafts. Nonetheless, they have demonstrated higher incidence of primary nonfunction and retransplantation among the recipients of marginal grafts. Continuing medical education on organ transplantation and public debates about this topic are important conditions for improving organ donation and the quality of the recovery grafts. Physicians’ training in potential donor management allows application of methods in order to avoid rapid donor deterioration. In this study, we observed that the first month after transplantation was decisive for defining the overall marginal graft outcome and recipient survival. Some authors have accepted any marginal graft and managed any early graft dysfunction by means of aggressive retransplantation [18]. This practice raises ethical issues because retransplantation increases recipient morbidity and mortality. In addition, it is very difficult to Indian J Gastroenterol predict when a suitable graft will become available for urgent retransplantation in India. Thus, using marginal grafts which used to be discarded earlier can compensate for the lacuna of organ shortage. Marginal grafts are now encountered in about 50 % of livers that are available for liver transplantation in the climate of increased requirement for liver grafts coupled with the rising mortality on transplant waiting lists [19]. It has been shown repeatedly that the judicious use of marginal grafts is safe. However, donor and recipient selection is paramount in this setting. The appropriate use of these organs is a challenge we all face, and the emergence of better markers of outcome for graft assessment in the future will no doubt add to the armamentarium the transplant surgeon has at present. Marginal allografts provide an immediate and significant expansion of the existing donor pool. Because organ scarcity persists, additional pressure will build to use a greater proportion of the existing donor pool. Fundamental to further progress in the utilization of marginal allograft is prospective, multicenter data collection to clearly define risk and delineate guidelines for standard and extended criteria donors. Such data would likely broaden the existing deceased donor pool by encouraging the utilization of donors that are currently deemed unsuitable for transplantation. This study, although small, clearly indicates that marginal livers can assure a normal early functional recovery after transplantation, bearing firmly in mind that careful donor evaluation and a short cold ischemia time are needed to avoid additional risk factors for poor outcome. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. References 17. 1. Briceño J, Solórzano G, Pera C. A proposal for scoring marginal liver grafts. Transpl Int. 2000;13:249–52. 2. Olthoff KM, Kulik L, Benjamin S, et al. 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