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Combined Kidney Transplantation and Splenic Fossa Auxiliary Heterotopic Liver Transplantation in a Highly Sensitized Recipient: A Case Report
Combined Kidney Transplantation and Splenic Fossa Auxiliary Heterotopic Liver Transplantation in a Highly Sensitized Recipient: A Case Report G. Zhanga, Y. Zhub, W. Qina, L. Yua, G. Wua, S. Maa, F. Wanga, R. Qina, X. Yanga, K. Taoc, S. Yuec, G. Zhaod, Z. Yangc, J. Yuane, K. Douc, and J. Yuana,* a Department of Urology, Xijing Hospital, Fourth Military Medical University, Shanxi, China; bDepartment of Urology, Hanzhong Central Hospital, Shanxi, China; cDepartment of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Shanxi, China; dXijing Orthopedic Hospital of the Fourth Military Medical University, Shanxi, China; and eDepartment of Biochemistry, University of Washington, Seattle, Washington
ABSTRACT Background. Combined kidney and auxiliary orthotopic liver transplantation from the same donor is used to treat highly sensitized renal transplant recipients. Auxiliary liver can protect the transplanted kidney against hyperacute rejection. Methods. In the current case, combined kidney and splenic fossa auxiliary heterotopic liver transplantation was performed from the same donor for a highly sensitized recipient without preoperative preconditioning. No postoperative hyperacute rejection occurred. Results. Seven days after surgery, preexisting antibody levels rose and decreased after treatment; meanwhile, the function of transplanted kidney returned to normal. During 24 months of follow-up, the grafts showed good blood perfusion and functioned well. The levels of preexisting antibodies, donor-specific antibodies (DSA) and C1q-fixing human leukocyte antigen (C1q-HLA) antibodies, all decreased. Conclusions. Combined kidney and splenic fossa auxiliary heterotopic liver transplantation can be used in renal transplantation for highly sensitized recipients.
D
ONOR-SPECIFIC antibodies (DSA) that preexist in renal transplant recipients cause postoperative hyperacute rejection [1]. However, in liver transplantation or combined liver-kidney transplantation, hyperacute rejection rarely occurs, even when the donor-recipient cross-matching is positive [2,3]. Olausson et al [4] performed combined kidney and auxiliary orthotopic liver transplantation in 23 highly sensitized patients, and 70% of the renal grafts functioned well during follow-up. Nevertheless, auxiliary orthotopic liver transplantation is a complex procedure, with many complications. The present study first reported a case of a highly sensitized renal transplant recipient treated by combined kidney and splenic fossa auxiliary heterotopic liver transplantation. During the 24 months of follow-up, the patient was in good condition. Changes in mean fluorescence intensity (MFI) of the recipient’s preexisting antibodies, DSA, and C1q-fixing human leukocyte antigen antibodies (C1q-HLA) were dynamically examined. The results demonstrated satisfactory post-transplantation outcome. ª 2016 Published by Elsevier Inc. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 3191e3196 (2016)
CASE REPORT The patient was a 31-year-old man weighing 65 kg, who first received cadaveric donor renal transplantation in 2005 and showed graft dysfunction 1 year later. In 2013, he underwent transplant nephrectomy to remove the dysfunctional graft. According to panel reactive antibody detection in 2014, class I and II antibodies were found at 31% and 63%, respectively. In March 2014, the patient underwent combined kidney and splenic fossa auxiliary heterotopic liver transplantation. The operation was performed with a donation after cardiac death organ, with approval from the Medical Ethics Committee of our institution. Written informed consent was obtained from the recipient.
Drs Zhang, Zhu, Qin, Yu, and Wu contributed equally to this work. *Address correspondence to Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shanxi, China. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.09.007
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Table 1. Positive Donor-Specific Anti-HLA and C1q-Fixing Human Leukocyte Antigen Antibodies Before Transplantation (Using Cutoff 1000 MFI) DSA*
MFI
C1q-HLA†
MFI
DR8 (DRB1*08:01) DQ6 (DQA1*01:03, DQB1*06:01)
4452 13841
DQ6 (DQA1*01:03, DQB1*06:01) DQ6 (DQA1*01:03, DQB1*06:03) DQ6 (DQA1*01:02, DQB1*06:09) A23 (A*23:01) A24 (A*24:02) A24 (A*24:03)
7588 10,572 3758 1664 7423 1738
*Tests performed with the use of a Luminex platform (LABScreen, One Lambda Inc, Los Angeles, Calif). † Tests performed with the use of a Luminex platform (C1qScreen, One Lambda Inc, Los Angeles, Calif).
The kidney and liver were from the same donor who had the same blood type as the recipient. Luminex (One Lambda Inc, Los Angeles, Calif) detection showed positive preexisting DSA and C1q-HLA for the recipient (Table 1). Taking into account the immuno-protective effect of liver graft, no desensitization pretreatment was performed before transplantation. Surgical procedures were as follows. (1) The left lateral lobar segments II and III of the donor’s liver were split in vitro, and two thirds of the right liver was transplanted into another recipient. (2) The patient’s spleen was removed while retaining splenic artery and vein. (3) The left lateral lobar segments II and III of donor’s liver were implanted upside-down into the recipient’s splenic fossa. (4) The left renal vein was de-vascularized and ligated at the distal end. (5) The transplanted hepatic and splenic arteries were anastomosed, as well as the portal and splenic veins; splenic arterial branches were endto-side anastomosed to the splenic vein. The splenic vein was arterialized. Meanwhile, the transplanted hepatic vein was anastomosed to the proximal renal vein, and Roux-en-Y anastomosis was performed between the bile duct and the jejunum. (6) Blood perfusion was restored to the transplanted liver, and kidney transplantation was performed after of observation of biliary secretion. Cold ischemia times were 8 hours and 14 hours for the transplanted liver and kidney, respectively, for warm ischemia times of 35 minutes and 30 minutes, respectively. The operation lasted 8 hours, 25 minutes, in all. During the operation, 1 g of methylprednisolone sodium succinate, 75 mg of rabbit anti-human thymocyte globulin (ATG), and 10 g of intravenous immunoglobulin (IVIG) were intravenously injected into the patient. The 24-hour postoperative urine volume was 4060 mL, and thereafter, the patient had a daily urine volume of 1700 to 2500 mL. The patient was given 50 mg of ATG and 10 g of IVIG on a daily basis, which were discontinued at 6 days after surgery. The patient was also administered oral tacrolimus at an initial dose of 0.8 mg/kg, whose plasma concentration was maintained at 4 to 8 ng/mL; 0.75 g of oral mycophenolate mofetil (MMF) was given as well, twice daily. At 6 days after surgery, serum creatinine fell to 141 mmol/L. At 7 days after surgery, creatinine levels increased to 202 mmol/L, and the 24-hour urine volume fell to 1100 mL. B-scan ultrasound showed a slightly increased volume of the transplanted kidney, parenchymal echo enhancement, augmented artery resistance index to 0.8, and good blood perfusion of the transplanted liver. No needle biopsy was carried out. On the same day, the patient was administered a single dose of 375 mg/m3 rituximab, as well as IVIG at 10 g/d for 5 days. At 8 days after surgery, the patient was administered intravenous ATG at 50 mg/d for 5 days and oral 48 mg/d methylprednisolone, whose dose was reduced by 4 mg/d until 16 mg/d maintained for 1 week, then reduced 4 mg/week until 4 mg/d maintained for 4 weeks, and thereafter reduced to 2 mg/d. At 9 days after surgery, repeated
plasmapheresis was performed for a total of 6 times. No dialysis was given during the treatment period. Serum creatinine amounts began to decline from postoperative day 9 and fell to 131 mmol/L on postoperative day 60; besides, urine volume was 2000 mL/d. After discharge, the following immunosuppressive regimen was maintained: tacrolimus capsules, 3 mg p.o. twice daily; MMF, 0.75 g p.o. twice daily; and methylprednisolone, 2 mg p.o. once daily. When the patient had been followed up for 24 months, the transplanted liver and kidney were well perfused and baseline serum creatinine remained at 130 mmol/L. Preexisting antibodies were assessed in serum samples from the recipient before operation, before kidney reperfusion, and at 3 hours after surgery. The results showed that most of the preexisting antibodies had a high MFI before surgery (Fig 1). In addition, MFI values for class I declined before kidney reperfusion and at 3 hours after surgery (Fig 1AeC); at 3 hours after surgery, antibodies such as B13:01 and Cw17 were negative (MFI <1000). In contrast, before kidney reperfusion, the change in MFI was more significant. Meanwhile, class II showed a similar trend of change (Fig 1DeF). During hospitalization and follow-up, preexisting antibodies of classes I and II showed unknown trends, mostly fluctuating within 2 postoperative months. The highest values were obtained at slightly different time points, from 7 days to 2 months after surgery. However, after 2 months, MFI values began to decrease and further declined to become negative (MFI <1000) at 1 year after surgery (Fig 2). Serotyping of the donor’s HLA showed A11, A11, B62, B60, Cw9, Cw4, DR4, DR8, DQ4, and DQ6; A2, A26, B60, B54, Cw1, Cw7, DR4, DR4, DQ4, and DQ4 were found in the recipient. Preexisting antibodies against DR8 and DQ6 were DSA in the recipient, with MFI values of 4452 and 13,841, respectively. In the following 3 months, DR8 amounts showed a fluctuating trend, with the highest value of 18,377; in the following 2 months, DQ6 levels showed a fluctuating trend, with the highest value of 8700. However, after 3 and 2 months, respectively, MFI values for DR8 and DQ6 showed a significant declining trend and were 271 and 1143, respectively, at 1 year after surgery (Fig 3). Preexisting positive C1q-HLA antibodies in the recipient before operation were determined as A23 (A*23:01), A24 (A*24:02), A24 (A*24:03), DQ6 (DQA1*01:03, DQB1*06:01), DQ6 (DQA1*01:03 DQB1*06:03), and DQ6 (DQA1*01:02 DQB1*06:09). DQ6 belonged to preexisting DSA, and highest MFI value was DQ6 (DQA1*01:03 DQB1*06:03) (MFI ¼ 10,572); the lowest was A23 (A*23:01) (MFI ¼ 1664). A value above 1000 was defined as positive. MFI values of all preexisting positive C1q-HLA antibodies started to increase at 7 days after surgery, with most peaking at 1 month after surgery. Afterward, several antibodies fluctuated but generally followed a gradual decreasing trend (Fig 4). At 1 year after surgery, A23 (A*23:01) (MFI ¼ 2156) had the highest MFI
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Fig 1. MFI values of single preexisting antibodies during surgery (AeF). All preexisting antibodies showed declined BKR (before kidney reperfusion) and at 3 hours after surgery. To distinguish between serotypes, the genotypes are provided in parentheses. values; the lowest was found for DQ6 (DQA1*01:03 DQB1*06:01) (MFI ¼ 32). Interestingly, MFI values of all preexisting positive C1q-HLA antibodies were 0 before kidney reperfusion (Fig 5).
DISCUSSION
No hyperacute rejection reaction was observed in the combined liver and kidney transplantation, which had positive cross-match before surgery [5,6]. This could be attributed to the immune-protective effect of the grafted liver on other allografts from the same donor [4]. In highly sensitized recipients, it is hard to find a donor kidney with negative cross-match [7]; even if a suitable donor is found and the transplantation successful, the risk for postoperative
antibody-mediated injury and the odds of the grafted kidney losing its function remain high [8]. The method of removing or reducing preexisting antibodies before operation has been demonstrated in the literature [9,10], but the long-term outcome of transplantation is controversial. However, auxiliary liver transplantation before renal transplantation could not only prevent postoperative hyperacute rejection effectively in highly sensitized recipients but also improve the long-term survival rate of the grafted kidney [11]. Olausson et al [12] treated highly sensitized recipients with renal transplantation combined with auxiliary partial orthotopic liver transplantation, effectively avoiding the occurrence of hyperacute rejection. In comparison, the present strategy of implanting transplanted liver into spleen
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Fig 2. MFI values of single preexisting antibodies during follow-up (AeF). The trend of decline was distinct, with most becoming negative (MFI <1000) at 1 year after surgery. To distinguish between serotypes, the genotypes are provided in parentheses.
fossa not only showed a protective effect on the grafted liver but also reduced operational difficulty. Splenectomy can effectively reduce the incidence and intensity of rejection reaction after transplantation, prolonging the survival time of grafts [13]. Some studies suggested that the immunoprotective effect of the grafted liver can only ease the pretransplant cross-match and may increase the incidence of graft rejection [14]. However, in most reported cases, this rejection can be reversed [15]. It should be mentioned that the liver does not always confer full protective alloimmunity; indeed, kidney rejection was observed in about 20% of patients simultaneously receiving liver and kidney transplants [16]. In the current case, with multiple anti-HLA antibodies and no preoperative pretreatment, the grafted liver first implanted would consume large amounts of preexisting antibodies, creating an environment of absence/limited
amounts of antibodies for the subsequent kidney transplantation from the same donor. The unique anatomic structure and physiological function of the grafted liver lead to spontaneous immune tolerance [17e19]. Therefore, at 7 days after surgery, the high levels of antibodies would decrease with no rebound after treatment with plasma exchange and other clinical interventions. At 1 year after surgery, the DR8 and DQ6 levels obtained indicated a very low rejection risk for the recipient. The Luminex technology detecting C1q-HLA antibodies can be used to predict rejection occurrence, with 100% sensitivity and specificity for positive and negative prediction values of rejection within 1 month after surgery [20]. Furthermore, biopsy was shown to be always negative in the absence of C1q antibodies (positive and negative prediction values of 100%), with C1q-HLA antibodies always occurring before the humoral rejection reaction [20]. In the current case,
COMBINED KIDNEY AND LIVER TRANSPLANTATION
Fig 3. Preexisting DSA of DR8 and DQ6 showed a fluctuating trend in the short term after surgery. However, after 3 and 2 months, respectively, both DR8 and DQ6 showed a significantly declining trend.
preexisting C1q-HLA antibody levels were reduced to 0 before kidney reperfusion. The findings indicated good immune-protective effects of the grafted liver. During follow-up, C1q-HLA antibody amounts gradually decreased, also predicting a better long-term outcome. However, Lowe et al [21] suggested that early re-synthesis of DSA does not always result in antibody-mediated rejection in a sensitized recipient, and antibody assessment in terms of antigen specificity could yield erroneous conclusions. With the aforementioned method, no tissue biopsy was obtained. Although renal transplantation combined with auxiliary liver transplantation has been reported, theoretical data regarding this method must be updated. The observations of the present study were as follow: (1) Through renal transplantation combined with auxiliary liver transplantation, highly sensitized recipients without preoperative pretreatment could accept transplantation successfully with no postoperative hyperacute rejection. (2) Although the risk
Fig 4. MFI values of preexisting positive C1q-HLA antibodies showed a gradual declining trend. To distinguish between serotypes, the genotypes are provided in parentheses.
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Fig 5. MFI values of all preexisting positive C1q-HLA antibodies. Each antibody is represented by a symbol. All of them were 0 before kidney reperfusion.
of acute rejection in a short time after operation exists, it could be reversed by the clinical intervention. (3) After transplantation, normal blood perfusion and liver function should be maintained, which is important for the postoperative outcome. In conclusion, this study used renal transplantation combined with splenic fossa heterotopic auxiliary liver transplantation for the treatment of highly sensitized patients in the first attempt. The findings provide a basis for further theoretical studies.
REFERENCES [1] Dilioglou S, Cruse JM, Lewis RE. High panel reactive antibody against cross-reactive group antigens as a contraindication to renal allotransplantation. Exp Mol Pathol 2001;71:73e8. [2] Neumann UP, Lang M, Moldenhauer A, et al. Significance of a T-lymphocytotoxic crossmatch in liver and combined liver-kidney transplantation. Transplantation 2001;71:1163e8. [3] Mjornstedt L, Friman S, Backman L, et al. Combined liver and kidney transplantation against a positive cross match in a patient with multispecific HLA-antibodies. Transplant Proc 1997;29:3164e5. [4] Ingelsten M, Karlsson-Parra A, Granqvist AB, et al. Postischemic inflammatory response in an auxiliary liver graft predicts renal graft outcome in sensitized patients. Transplantation 2011;91: 888e94. [5] Gutierrez A, Crespo M, Mila J, et al. Outcome of simultaneous liver-kidney transplantation in highly sensitized, crossmatchpositive patients. Transplant Proc 2003;35:1861e2. [6] Morrissey PE, Gordon F, Shaffer D, et al. Combined liverkidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation. Liver Transpl Surg 1998;4:363e9. [7] Morath C, Schmidt J, Opelz G, et al. Kidney transplantation in highly sensitized patients: are there options to overcome a positive crossmatch? Langenbecks Arch Surg 2011;396:467e74. [8] Susal C, Dohler B, Opelz G. Presensitized kidney graft recipients with HLA class I and II antibodies are at increased risk for graft failure: a Collaborative Transplant Study report. Hum Immunol 2009;70:569e73. [9] Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med 2008;359:242e51.
3196 [10] Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011;365:318e26. [11] Ingelsten M, Gustafsson K, Oltean M, et al. Is indoleamine 2,3-dioxygenase important for graft acceptance in highly sensitized patients after combined auxiliary liver-kidney transplantation? Transplantation 2009;88:911e9. [12] Olausson M, Mjornstedt L, Norden G, et al. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients. Am J Transplant 2007;7:130e6. [13] Sutherland DE, Fryd DS, So SK, et al. Long-term effect of splenectomy versus no splenectomy in renal transplant patients: reanalysis of a randomized prospective study. Transplantation 1984;38:619e24. [14] Parasuraman RK, Venkat KK, Abouljoud M, et al. Renal allograft outcome in recipients of positive-crossmatch combined liver-kidney transplantation. Transplant Proc 2013;45:3269e72. [15] Reichman TW, Marino SR, Milner J, et al. Acute humoral rejection in an ABO compatible combined liver-kidney transplant:
ZHANG, ZHU, QIN ET AL the kidney is not always protected. Am J Transplant 2009;9: 1957e60. [16] Nilles KM, Krupp J, Lapin BJ, et al. Incidence and impact of rejection following simultaneous liver-kidneytransplantation. J Hepatol 2015;62:340e5. [17] Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev 2000;174:21e34. [18] Benseler V, Schlitt HJ. The liver as an immunological organ. Z Gastroenterol 2011;49:54e62. [19] Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006;43:S54e62. [20] Chin C, Chen G, Sequeria F, et al. Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant 2011;30:158e63. [21] Lowe D, Shabir S, Buckels J, et al. HLA incompatible combined liver-kidneytransplantation: dynamics of antibody modulation revealed by a novel approach to HLA antibody characterisation. Transpl Immunol 2014;30:30e3.
ABSTRACT Background. Combined kidney and auxiliary orthotopic liver transplantation from the same donor is used to treat highly sensitized renal transplant recipients. Auxiliary liver can protect the transplanted kidney against hyperacute rejection. Methods. In the current case, combined kidney and splenic fossa auxiliary heterotopic liver transplantation was performed from the same donor for a highly sensitized recipient without preoperative preconditioning. No postoperative hyperacute rejection occurred. Results. Seven days after surgery, preexisting antibody levels rose and decreased after treatment; meanwhile, the function of transplanted kidney returned to normal. During 24 months of follow-up, the grafts showed good blood perfusion and functioned well. The levels of preexisting antibodies, donor-specific antibodies (DSA) and C1q-fixing human leukocyte antigen (C1q-HLA) antibodies, all decreased. Conclusions. Combined kidney and splenic fossa auxiliary heterotopic liver transplantation can be used in renal transplantation for highly sensitized recipients.
D
ONOR-SPECIFIC antibodies (DSA) that preexist in renal transplant recipients cause postoperative hyperacute rejection [1]. However, in liver transplantation or combined liver-kidney transplantation, hyperacute rejection rarely occurs, even when the donor-recipient cross-matching is positive [2,3]. Olausson et al [4] performed combined kidney and auxiliary orthotopic liver transplantation in 23 highly sensitized patients, and 70% of the renal grafts functioned well during follow-up. Nevertheless, auxiliary orthotopic liver transplantation is a complex procedure, with many complications. The present study first reported a case of a highly sensitized renal transplant recipient treated by combined kidney and splenic fossa auxiliary heterotopic liver transplantation. During the 24 months of follow-up, the patient was in good condition. Changes in mean fluorescence intensity (MFI) of the recipient’s preexisting antibodies, DSA, and C1q-fixing human leukocyte antigen antibodies (C1q-HLA) were dynamically examined. The results demonstrated satisfactory post-transplantation outcome. ª 2016 Published by Elsevier Inc. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 48, 3191e3196 (2016)
CASE REPORT The patient was a 31-year-old man weighing 65 kg, who first received cadaveric donor renal transplantation in 2005 and showed graft dysfunction 1 year later. In 2013, he underwent transplant nephrectomy to remove the dysfunctional graft. According to panel reactive antibody detection in 2014, class I and II antibodies were found at 31% and 63%, respectively. In March 2014, the patient underwent combined kidney and splenic fossa auxiliary heterotopic liver transplantation. The operation was performed with a donation after cardiac death organ, with approval from the Medical Ethics Committee of our institution. Written informed consent was obtained from the recipient.
Drs Zhang, Zhu, Qin, Yu, and Wu contributed equally to this work. *Address correspondence to Jianlin Yuan, Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shanxi, China. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.09.007
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Table 1. Positive Donor-Specific Anti-HLA and C1q-Fixing Human Leukocyte Antigen Antibodies Before Transplantation (Using Cutoff 1000 MFI) DSA*
MFI
C1q-HLA†
MFI
DR8 (DRB1*08:01) DQ6 (DQA1*01:03, DQB1*06:01)
4452 13841
DQ6 (DQA1*01:03, DQB1*06:01) DQ6 (DQA1*01:03, DQB1*06:03) DQ6 (DQA1*01:02, DQB1*06:09) A23 (A*23:01) A24 (A*24:02) A24 (A*24:03)
7588 10,572 3758 1664 7423 1738
*Tests performed with the use of a Luminex platform (LABScreen, One Lambda Inc, Los Angeles, Calif). † Tests performed with the use of a Luminex platform (C1qScreen, One Lambda Inc, Los Angeles, Calif).
The kidney and liver were from the same donor who had the same blood type as the recipient. Luminex (One Lambda Inc, Los Angeles, Calif) detection showed positive preexisting DSA and C1q-HLA for the recipient (Table 1). Taking into account the immuno-protective effect of liver graft, no desensitization pretreatment was performed before transplantation. Surgical procedures were as follows. (1) The left lateral lobar segments II and III of the donor’s liver were split in vitro, and two thirds of the right liver was transplanted into another recipient. (2) The patient’s spleen was removed while retaining splenic artery and vein. (3) The left lateral lobar segments II and III of donor’s liver were implanted upside-down into the recipient’s splenic fossa. (4) The left renal vein was de-vascularized and ligated at the distal end. (5) The transplanted hepatic and splenic arteries were anastomosed, as well as the portal and splenic veins; splenic arterial branches were endto-side anastomosed to the splenic vein. The splenic vein was arterialized. Meanwhile, the transplanted hepatic vein was anastomosed to the proximal renal vein, and Roux-en-Y anastomosis was performed between the bile duct and the jejunum. (6) Blood perfusion was restored to the transplanted liver, and kidney transplantation was performed after of observation of biliary secretion. Cold ischemia times were 8 hours and 14 hours for the transplanted liver and kidney, respectively, for warm ischemia times of 35 minutes and 30 minutes, respectively. The operation lasted 8 hours, 25 minutes, in all. During the operation, 1 g of methylprednisolone sodium succinate, 75 mg of rabbit anti-human thymocyte globulin (ATG), and 10 g of intravenous immunoglobulin (IVIG) were intravenously injected into the patient. The 24-hour postoperative urine volume was 4060 mL, and thereafter, the patient had a daily urine volume of 1700 to 2500 mL. The patient was given 50 mg of ATG and 10 g of IVIG on a daily basis, which were discontinued at 6 days after surgery. The patient was also administered oral tacrolimus at an initial dose of 0.8 mg/kg, whose plasma concentration was maintained at 4 to 8 ng/mL; 0.75 g of oral mycophenolate mofetil (MMF) was given as well, twice daily. At 6 days after surgery, serum creatinine fell to 141 mmol/L. At 7 days after surgery, creatinine levels increased to 202 mmol/L, and the 24-hour urine volume fell to 1100 mL. B-scan ultrasound showed a slightly increased volume of the transplanted kidney, parenchymal echo enhancement, augmented artery resistance index to 0.8, and good blood perfusion of the transplanted liver. No needle biopsy was carried out. On the same day, the patient was administered a single dose of 375 mg/m3 rituximab, as well as IVIG at 10 g/d for 5 days. At 8 days after surgery, the patient was administered intravenous ATG at 50 mg/d for 5 days and oral 48 mg/d methylprednisolone, whose dose was reduced by 4 mg/d until 16 mg/d maintained for 1 week, then reduced 4 mg/week until 4 mg/d maintained for 4 weeks, and thereafter reduced to 2 mg/d. At 9 days after surgery, repeated
plasmapheresis was performed for a total of 6 times. No dialysis was given during the treatment period. Serum creatinine amounts began to decline from postoperative day 9 and fell to 131 mmol/L on postoperative day 60; besides, urine volume was 2000 mL/d. After discharge, the following immunosuppressive regimen was maintained: tacrolimus capsules, 3 mg p.o. twice daily; MMF, 0.75 g p.o. twice daily; and methylprednisolone, 2 mg p.o. once daily. When the patient had been followed up for 24 months, the transplanted liver and kidney were well perfused and baseline serum creatinine remained at 130 mmol/L. Preexisting antibodies were assessed in serum samples from the recipient before operation, before kidney reperfusion, and at 3 hours after surgery. The results showed that most of the preexisting antibodies had a high MFI before surgery (Fig 1). In addition, MFI values for class I declined before kidney reperfusion and at 3 hours after surgery (Fig 1AeC); at 3 hours after surgery, antibodies such as B13:01 and Cw17 were negative (MFI <1000). In contrast, before kidney reperfusion, the change in MFI was more significant. Meanwhile, class II showed a similar trend of change (Fig 1DeF). During hospitalization and follow-up, preexisting antibodies of classes I and II showed unknown trends, mostly fluctuating within 2 postoperative months. The highest values were obtained at slightly different time points, from 7 days to 2 months after surgery. However, after 2 months, MFI values began to decrease and further declined to become negative (MFI <1000) at 1 year after surgery (Fig 2). Serotyping of the donor’s HLA showed A11, A11, B62, B60, Cw9, Cw4, DR4, DR8, DQ4, and DQ6; A2, A26, B60, B54, Cw1, Cw7, DR4, DR4, DQ4, and DQ4 were found in the recipient. Preexisting antibodies against DR8 and DQ6 were DSA in the recipient, with MFI values of 4452 and 13,841, respectively. In the following 3 months, DR8 amounts showed a fluctuating trend, with the highest value of 18,377; in the following 2 months, DQ6 levels showed a fluctuating trend, with the highest value of 8700. However, after 3 and 2 months, respectively, MFI values for DR8 and DQ6 showed a significant declining trend and were 271 and 1143, respectively, at 1 year after surgery (Fig 3). Preexisting positive C1q-HLA antibodies in the recipient before operation were determined as A23 (A*23:01), A24 (A*24:02), A24 (A*24:03), DQ6 (DQA1*01:03, DQB1*06:01), DQ6 (DQA1*01:03 DQB1*06:03), and DQ6 (DQA1*01:02 DQB1*06:09). DQ6 belonged to preexisting DSA, and highest MFI value was DQ6 (DQA1*01:03 DQB1*06:03) (MFI ¼ 10,572); the lowest was A23 (A*23:01) (MFI ¼ 1664). A value above 1000 was defined as positive. MFI values of all preexisting positive C1q-HLA antibodies started to increase at 7 days after surgery, with most peaking at 1 month after surgery. Afterward, several antibodies fluctuated but generally followed a gradual decreasing trend (Fig 4). At 1 year after surgery, A23 (A*23:01) (MFI ¼ 2156) had the highest MFI
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Fig 1. MFI values of single preexisting antibodies during surgery (AeF). All preexisting antibodies showed declined BKR (before kidney reperfusion) and at 3 hours after surgery. To distinguish between serotypes, the genotypes are provided in parentheses. values; the lowest was found for DQ6 (DQA1*01:03 DQB1*06:01) (MFI ¼ 32). Interestingly, MFI values of all preexisting positive C1q-HLA antibodies were 0 before kidney reperfusion (Fig 5).
DISCUSSION
No hyperacute rejection reaction was observed in the combined liver and kidney transplantation, which had positive cross-match before surgery [5,6]. This could be attributed to the immune-protective effect of the grafted liver on other allografts from the same donor [4]. In highly sensitized recipients, it is hard to find a donor kidney with negative cross-match [7]; even if a suitable donor is found and the transplantation successful, the risk for postoperative
antibody-mediated injury and the odds of the grafted kidney losing its function remain high [8]. The method of removing or reducing preexisting antibodies before operation has been demonstrated in the literature [9,10], but the long-term outcome of transplantation is controversial. However, auxiliary liver transplantation before renal transplantation could not only prevent postoperative hyperacute rejection effectively in highly sensitized recipients but also improve the long-term survival rate of the grafted kidney [11]. Olausson et al [12] treated highly sensitized recipients with renal transplantation combined with auxiliary partial orthotopic liver transplantation, effectively avoiding the occurrence of hyperacute rejection. In comparison, the present strategy of implanting transplanted liver into spleen
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Fig 2. MFI values of single preexisting antibodies during follow-up (AeF). The trend of decline was distinct, with most becoming negative (MFI <1000) at 1 year after surgery. To distinguish between serotypes, the genotypes are provided in parentheses.
fossa not only showed a protective effect on the grafted liver but also reduced operational difficulty. Splenectomy can effectively reduce the incidence and intensity of rejection reaction after transplantation, prolonging the survival time of grafts [13]. Some studies suggested that the immunoprotective effect of the grafted liver can only ease the pretransplant cross-match and may increase the incidence of graft rejection [14]. However, in most reported cases, this rejection can be reversed [15]. It should be mentioned that the liver does not always confer full protective alloimmunity; indeed, kidney rejection was observed in about 20% of patients simultaneously receiving liver and kidney transplants [16]. In the current case, with multiple anti-HLA antibodies and no preoperative pretreatment, the grafted liver first implanted would consume large amounts of preexisting antibodies, creating an environment of absence/limited
amounts of antibodies for the subsequent kidney transplantation from the same donor. The unique anatomic structure and physiological function of the grafted liver lead to spontaneous immune tolerance [17e19]. Therefore, at 7 days after surgery, the high levels of antibodies would decrease with no rebound after treatment with plasma exchange and other clinical interventions. At 1 year after surgery, the DR8 and DQ6 levels obtained indicated a very low rejection risk for the recipient. The Luminex technology detecting C1q-HLA antibodies can be used to predict rejection occurrence, with 100% sensitivity and specificity for positive and negative prediction values of rejection within 1 month after surgery [20]. Furthermore, biopsy was shown to be always negative in the absence of C1q antibodies (positive and negative prediction values of 100%), with C1q-HLA antibodies always occurring before the humoral rejection reaction [20]. In the current case,
COMBINED KIDNEY AND LIVER TRANSPLANTATION
Fig 3. Preexisting DSA of DR8 and DQ6 showed a fluctuating trend in the short term after surgery. However, after 3 and 2 months, respectively, both DR8 and DQ6 showed a significantly declining trend.
preexisting C1q-HLA antibody levels were reduced to 0 before kidney reperfusion. The findings indicated good immune-protective effects of the grafted liver. During follow-up, C1q-HLA antibody amounts gradually decreased, also predicting a better long-term outcome. However, Lowe et al [21] suggested that early re-synthesis of DSA does not always result in antibody-mediated rejection in a sensitized recipient, and antibody assessment in terms of antigen specificity could yield erroneous conclusions. With the aforementioned method, no tissue biopsy was obtained. Although renal transplantation combined with auxiliary liver transplantation has been reported, theoretical data regarding this method must be updated. The observations of the present study were as follow: (1) Through renal transplantation combined with auxiliary liver transplantation, highly sensitized recipients without preoperative pretreatment could accept transplantation successfully with no postoperative hyperacute rejection. (2) Although the risk
Fig 4. MFI values of preexisting positive C1q-HLA antibodies showed a gradual declining trend. To distinguish between serotypes, the genotypes are provided in parentheses.
3195
Fig 5. MFI values of all preexisting positive C1q-HLA antibodies. Each antibody is represented by a symbol. All of them were 0 before kidney reperfusion.
of acute rejection in a short time after operation exists, it could be reversed by the clinical intervention. (3) After transplantation, normal blood perfusion and liver function should be maintained, which is important for the postoperative outcome. In conclusion, this study used renal transplantation combined with splenic fossa heterotopic auxiliary liver transplantation for the treatment of highly sensitized patients in the first attempt. The findings provide a basis for further theoretical studies.
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