© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2015: 29: 365–372 DOI: 10.1111/ctr.12525
Clinical Transplantation
Risk factors for postoperative bleeding in ABO-incompatible kidney transplantation Kim MH, Jun KW, Hwang JK, Kim JI, Chung BH, Choi BS, Kim YS, Yang CW, Moon IS. Risk factors for postoperative bleeding in ABO-incompatible kidney transplantation. Abstract: Introduction: The outcome of ABO-incompatible kidney transplantation (ABOi KT) has improved and is now comparable to that of ABO-compatible kidney transplantation (ABOc KT). However, ABOi KT may be associated with a higher risk of postoperative bleeding than ABOc KT. Methods: Seventy patients with ABOi KT were divided into a bleeding group (n = 9) and non-bleeding group (n = 61). General, immunologic, and hematological characteristics were compared to identify the risk factors for postoperative bleeding. Results: Pre-emptive transplantation and a high pre-transplant blood urea nitrogen level were more common in the bleeding group (p = 0.0176 and 0.023, respectively). A high anti-ABO antibody titer after plasmapheresis (median, ≥16; p = 0.0226), a low platelet count of ≤100 000/mm3 after plasmapheresis (p = 0.0289), a prolonged activated partial thromboplastin time (p = 0.0073), and impaired platelet function (p = 0.0274) were associated with an increased risk of bleeding after ABOi KT. Conclusion: Postoperative bleeding after ABOi KT was difficult to control and increased the risk of immediate graft loss (p = 0.015). Our results suggest that changes in coagulability associated with uremia and plasmapheresis may increase the risk of bleeding after ABOi KT.
Mi Hyeong Kima, Kang Woong Juna, Jeong Kye Hwangb, Ji Il Kima, Byung Ha Chungc, Bum Soon Choic, Yong Soo Kimc, Chul Woo Yangc and In Sung Moona a
Division of Vascular and Transplant Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, bDivision of Vascular and Transplant Surgery, Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon and cDivision of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea Key words: blood coagulation factors – blood group incompatibility – kidney transplantation – plasmapheresis – postoperative hemorrhage – uremia Corresponding author: In Sung Moon, MD, PhD, Division of Vascular and Transplant Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 550 Banpo4dong, Seocho-gu, Seoul 137-040, Korea. Tel.: +82 2 2258 6098; fax: +82 2 595 2822; e-mail: [email protected] Conflict of interest: The authors declare no conflict of interests. Accepted for publication 29 January 2015
Great advancements in the antibody depletion technique and efficacy of immunosuppressants have helped to overcome the poor outcomes of ABO-incompatible kidney transplantation (ABOi KT). In the 2000s, ABOi KT became an effective alternative procedure in the face of a shortage of donor kidneys. In Korea, the performance of ABOi KT increased from 14/663 cases of livingdonor KT in 2008 (2.11%) to 118/1015 cases of living-donor KT in 2012 (18.5%) (1). According to Takahashi et al. (2), ABOi KT accounts for 30% of living-donor KTs in Japan.
The survival rates of patients and grafts have improved and are now comparable to those of ABO-compatible KT (ABOc KT). However, postABOi KT complications such as postoperative bleeding, lymphocele formation, and viral infection have been reported at several institutes, including ours (3–10). According to these reports, the incidence of postoperative bleeding after ABOi KT was 8% to 66% (mean, 17.5%) in contrast to 1–6% after ABOc KT (11–13). Postoperative bleeding after ABOi KT is a serious complication that requires multiple transfusions in most cases
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Kim et al.
and which may cause graft loss. However, there are few reports on the factors that increase the risk of postoperative bleeding after ABOi KT. We investigated the risk factors for bleeding after ABOi KT.
Methods Patient selection and methods
We retrospectively analyzed the medical records of patients who underwent ABOi KT at Seoul St. Mary’s Hospital from May 2009 to October 2013. We divided the patients into two groups according to the presence of postoperative bleeding: the bleeding group (BG) and non-bleeding group (NBG). The BG included patients who required revision surgery to control their bleeding or had definite evidence of bleeding: bloody drainage from the perigraft area, a continuous decrease in the serum hemoglobin level requiring repeated transfusions of red blood cell (RBC) components, and a definite hematoma diagnosed by imaging studies (magnetic resonance angiography, computed tomography without enhancement, or ultrasonography). Patients who required transfusions or exhibited a low hemoglobin level without any abnormalities on imaging studies were not included in the BG. In both groups, data were collected on general characteristics (age, sex, body mass index, relationship between recipient and donor, cause of endstage renal disease [ESRD], type of renal replacement therapy [RRT], pre-transplant levels of blood urea nitrogen [BUN] and creatinine and comorbidities), immunologic characteristics (blood type of donor and recipient, human leukocyte antigen mismatch number, panel-reactive antibody positivity, anti-ABO antibody titer before plasmapheresis [initial anti-ABO antibody titer], anti-ABO antibody titer after plasmapheresis [post-PP anti-ABO antibody titer], number of plasmapheresis sessions, type of substitution fluid used during plasmapheresis and dose of rituximab), and hematological characteristics (platelet count before plasmapheresis [initial platelet count], platelet count after plasmapheresis [post-PP platelet count], prothrombin time as represented by the international normalized ratio [PT INR], activated partial thromboplastin time [aPTT], and platelet function test results using a Platelet Function Analyzer-100 [PFA-100]). Initial platelet count was checked at admission day (before plasmapheresis), PFA-100 was tested the day before transplantation, and post-PP platelet count, hemoglobin, hematocrit, PT INR, and aPTT were evaluated at the morning of transplantation. The pre-transplant BUN level was the mean value of the maximal and minimal
366
levels during the week before transplantation. The type of RRT was divided into two categories: patients who underwent KT before initiating dialysis (pre-emptive KT recipients) and patients on hemodialysis or peritoneal dialysis. The term “immediate graft loss” indicated graft loss that occurred during the same hospitalization period of the transplantation. This study was approved by the institutional review board of Seoul St. Mary’s Hospital. (KC13RISI0341). Antibody depletion and monitoring technique
The ABOi KT protocol of our institute has been previously described (14). Briefly, we used a single dose of rituximab one month before the anticipated date of transplantation and one of two rituximab doses (either 100 or 375 mg/m2) was given according to the immunologic risk of each patient. The number of plasmapheresis sessions before transplantation was determined based on the initial anti-ABO antibody titer with reference to a widely accepted guideline (15), and plasmapheresis was performed using a COBE Spectra (Gambro BCT, Lakewood, CO, USA). Plasmapheresis was performed every other day and immediately followed by intravenous administration of immunoglobulin at a dose of 100 mg/kg. In each plasmapheresis session, one plasma volume was discarded and substituted at 100% volume with 5% albumin or fresh-frozen plasma (FFP). The substitution fluid used during plasmapheresis changed over time. From May 2009 to December 2010, albumin was used as the substitution fluid in every plasmapheresis session excluding the last session before transplantation; in the last session, we used a mixture of albumin and FFP (Method 1, n = 16). From January 2011 to July 2012, 100% FFP was used in the last session (Method 2, n = 33). From August 2012 to October 2013, albumin was used in two consecutive sessions and FFP was used in every third session as well as the last session (Method 3, n = 21). The last session of plasmapheresis was performed the day before transplantation. Acid citrate dextrose-A (ADC-A) was used as the anticoagulant in a 1:20 ratio to whole blood. No other anticoagulant was used before or after transplantation. During the operation, 5000 U unfractionated heparin was mixed with 1 L saline to irrigate the vessel lumen. This solution was not injected into the bloodstream. The acceptance criterion for transplantation was an anti-ABO antibody titer of ≤32, and additional plasmapheresis was performed for patients with higher titers. Post-transplantation plasmapheresis
Incompatible renal transplant bleeding was performed in patients with an anti-ABO antibody titer of >32 and concomitant signs of graft function impairment (with the exception of the first case). The substitution fluid for post-transplantation plasmapheresis was used 5% albumin or FFP according to the patient condition: 5% albumin was preferred, but if a patient had a bleeding tendency, we chose FFP. The anti-ABO antibody titer was measured using standard serologic techniques (14). Immunosuppression therapy
Immunosuppression therapy was initiated seven days before transplantation using tacrolimus (0.1 mg/kg/d), mycophenolate mofetil (1.5 g/d), and prednisolone (30 mg/d). Basiliximab (20 mg) was added on the day of transplantation and postoperative day (POD) 4. The dose of tacrolimus was adjusted to maintain a target trough level of 8–10 mg/mL. All patients received valacyclovir (1.5 g/d), fluconazole (50 mg/d), and trimethoprim/sulfamethoxazole (800 mg/d) starting seven days before transplantation for prophylaxis of opportunistic infection. These medications were continued for three months (valacyclovir and fluconazole) or six months (trimethoprim/sulfamethoxazole) after transplantation. The presence of cytomegalovirus and BK virus infection was checked weekly by real-time polymerase chain reaction, and pre-emptive therapy for cytomegalovirus infection was initiated with intravenous ganciclovir if the viral number increased to >500 copies/mL. Statistical analysis
All data are presented as the mean standard deviation with the exception of the anti-ABO
antibody titer, which is presented as the median value. To evaluate and compare the two groups, categorical data were analyzed using Fisher’s exact test and numerical data were analyzed using the unpaired t-test and Wilcoxon’s rank sum test. A two-sided p value of
Clin Transplant 2015: 29: 365–372 DOI: 10.1111/ctr.12525
Clinical Transplantation
Risk factors for postoperative bleeding in ABO-incompatible kidney transplantation Kim MH, Jun KW, Hwang JK, Kim JI, Chung BH, Choi BS, Kim YS, Yang CW, Moon IS. Risk factors for postoperative bleeding in ABO-incompatible kidney transplantation. Abstract: Introduction: The outcome of ABO-incompatible kidney transplantation (ABOi KT) has improved and is now comparable to that of ABO-compatible kidney transplantation (ABOc KT). However, ABOi KT may be associated with a higher risk of postoperative bleeding than ABOc KT. Methods: Seventy patients with ABOi KT were divided into a bleeding group (n = 9) and non-bleeding group (n = 61). General, immunologic, and hematological characteristics were compared to identify the risk factors for postoperative bleeding. Results: Pre-emptive transplantation and a high pre-transplant blood urea nitrogen level were more common in the bleeding group (p = 0.0176 and 0.023, respectively). A high anti-ABO antibody titer after plasmapheresis (median, ≥16; p = 0.0226), a low platelet count of ≤100 000/mm3 after plasmapheresis (p = 0.0289), a prolonged activated partial thromboplastin time (p = 0.0073), and impaired platelet function (p = 0.0274) were associated with an increased risk of bleeding after ABOi KT. Conclusion: Postoperative bleeding after ABOi KT was difficult to control and increased the risk of immediate graft loss (p = 0.015). Our results suggest that changes in coagulability associated with uremia and plasmapheresis may increase the risk of bleeding after ABOi KT.
Mi Hyeong Kima, Kang Woong Juna, Jeong Kye Hwangb, Ji Il Kima, Byung Ha Chungc, Bum Soon Choic, Yong Soo Kimc, Chul Woo Yangc and In Sung Moona a
Division of Vascular and Transplant Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, bDivision of Vascular and Transplant Surgery, Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon and cDivision of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea Key words: blood coagulation factors – blood group incompatibility – kidney transplantation – plasmapheresis – postoperative hemorrhage – uremia Corresponding author: In Sung Moon, MD, PhD, Division of Vascular and Transplant Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 550 Banpo4dong, Seocho-gu, Seoul 137-040, Korea. Tel.: +82 2 2258 6098; fax: +82 2 595 2822; e-mail: [email protected] Conflict of interest: The authors declare no conflict of interests. Accepted for publication 29 January 2015
Great advancements in the antibody depletion technique and efficacy of immunosuppressants have helped to overcome the poor outcomes of ABO-incompatible kidney transplantation (ABOi KT). In the 2000s, ABOi KT became an effective alternative procedure in the face of a shortage of donor kidneys. In Korea, the performance of ABOi KT increased from 14/663 cases of livingdonor KT in 2008 (2.11%) to 118/1015 cases of living-donor KT in 2012 (18.5%) (1). According to Takahashi et al. (2), ABOi KT accounts for 30% of living-donor KTs in Japan.
The survival rates of patients and grafts have improved and are now comparable to those of ABO-compatible KT (ABOc KT). However, postABOi KT complications such as postoperative bleeding, lymphocele formation, and viral infection have been reported at several institutes, including ours (3–10). According to these reports, the incidence of postoperative bleeding after ABOi KT was 8% to 66% (mean, 17.5%) in contrast to 1–6% after ABOc KT (11–13). Postoperative bleeding after ABOi KT is a serious complication that requires multiple transfusions in most cases
365
Kim et al.
and which may cause graft loss. However, there are few reports on the factors that increase the risk of postoperative bleeding after ABOi KT. We investigated the risk factors for bleeding after ABOi KT.
Methods Patient selection and methods
We retrospectively analyzed the medical records of patients who underwent ABOi KT at Seoul St. Mary’s Hospital from May 2009 to October 2013. We divided the patients into two groups according to the presence of postoperative bleeding: the bleeding group (BG) and non-bleeding group (NBG). The BG included patients who required revision surgery to control their bleeding or had definite evidence of bleeding: bloody drainage from the perigraft area, a continuous decrease in the serum hemoglobin level requiring repeated transfusions of red blood cell (RBC) components, and a definite hematoma diagnosed by imaging studies (magnetic resonance angiography, computed tomography without enhancement, or ultrasonography). Patients who required transfusions or exhibited a low hemoglobin level without any abnormalities on imaging studies were not included in the BG. In both groups, data were collected on general characteristics (age, sex, body mass index, relationship between recipient and donor, cause of endstage renal disease [ESRD], type of renal replacement therapy [RRT], pre-transplant levels of blood urea nitrogen [BUN] and creatinine and comorbidities), immunologic characteristics (blood type of donor and recipient, human leukocyte antigen mismatch number, panel-reactive antibody positivity, anti-ABO antibody titer before plasmapheresis [initial anti-ABO antibody titer], anti-ABO antibody titer after plasmapheresis [post-PP anti-ABO antibody titer], number of plasmapheresis sessions, type of substitution fluid used during plasmapheresis and dose of rituximab), and hematological characteristics (platelet count before plasmapheresis [initial platelet count], platelet count after plasmapheresis [post-PP platelet count], prothrombin time as represented by the international normalized ratio [PT INR], activated partial thromboplastin time [aPTT], and platelet function test results using a Platelet Function Analyzer-100 [PFA-100]). Initial platelet count was checked at admission day (before plasmapheresis), PFA-100 was tested the day before transplantation, and post-PP platelet count, hemoglobin, hematocrit, PT INR, and aPTT were evaluated at the morning of transplantation. The pre-transplant BUN level was the mean value of the maximal and minimal
366
levels during the week before transplantation. The type of RRT was divided into two categories: patients who underwent KT before initiating dialysis (pre-emptive KT recipients) and patients on hemodialysis or peritoneal dialysis. The term “immediate graft loss” indicated graft loss that occurred during the same hospitalization period of the transplantation. This study was approved by the institutional review board of Seoul St. Mary’s Hospital. (KC13RISI0341). Antibody depletion and monitoring technique
The ABOi KT protocol of our institute has been previously described (14). Briefly, we used a single dose of rituximab one month before the anticipated date of transplantation and one of two rituximab doses (either 100 or 375 mg/m2) was given according to the immunologic risk of each patient. The number of plasmapheresis sessions before transplantation was determined based on the initial anti-ABO antibody titer with reference to a widely accepted guideline (15), and plasmapheresis was performed using a COBE Spectra (Gambro BCT, Lakewood, CO, USA). Plasmapheresis was performed every other day and immediately followed by intravenous administration of immunoglobulin at a dose of 100 mg/kg. In each plasmapheresis session, one plasma volume was discarded and substituted at 100% volume with 5% albumin or fresh-frozen plasma (FFP). The substitution fluid used during plasmapheresis changed over time. From May 2009 to December 2010, albumin was used as the substitution fluid in every plasmapheresis session excluding the last session before transplantation; in the last session, we used a mixture of albumin and FFP (Method 1, n = 16). From January 2011 to July 2012, 100% FFP was used in the last session (Method 2, n = 33). From August 2012 to October 2013, albumin was used in two consecutive sessions and FFP was used in every third session as well as the last session (Method 3, n = 21). The last session of plasmapheresis was performed the day before transplantation. Acid citrate dextrose-A (ADC-A) was used as the anticoagulant in a 1:20 ratio to whole blood. No other anticoagulant was used before or after transplantation. During the operation, 5000 U unfractionated heparin was mixed with 1 L saline to irrigate the vessel lumen. This solution was not injected into the bloodstream. The acceptance criterion for transplantation was an anti-ABO antibody titer of ≤32, and additional plasmapheresis was performed for patients with higher titers. Post-transplantation plasmapheresis
Incompatible renal transplant bleeding was performed in patients with an anti-ABO antibody titer of >32 and concomitant signs of graft function impairment (with the exception of the first case). The substitution fluid for post-transplantation plasmapheresis was used 5% albumin or FFP according to the patient condition: 5% albumin was preferred, but if a patient had a bleeding tendency, we chose FFP. The anti-ABO antibody titer was measured using standard serologic techniques (14). Immunosuppression therapy
Immunosuppression therapy was initiated seven days before transplantation using tacrolimus (0.1 mg/kg/d), mycophenolate mofetil (1.5 g/d), and prednisolone (30 mg/d). Basiliximab (20 mg) was added on the day of transplantation and postoperative day (POD) 4. The dose of tacrolimus was adjusted to maintain a target trough level of 8–10 mg/mL. All patients received valacyclovir (1.5 g/d), fluconazole (50 mg/d), and trimethoprim/sulfamethoxazole (800 mg/d) starting seven days before transplantation for prophylaxis of opportunistic infection. These medications were continued for three months (valacyclovir and fluconazole) or six months (trimethoprim/sulfamethoxazole) after transplantation. The presence of cytomegalovirus and BK virus infection was checked weekly by real-time polymerase chain reaction, and pre-emptive therapy for cytomegalovirus infection was initiated with intravenous ganciclovir if the viral number increased to >500 copies/mL. Statistical analysis
All data are presented as the mean standard deviation with the exception of the anti-ABO
antibody titer, which is presented as the median value. To evaluate and compare the two groups, categorical data were analyzed using Fisher’s exact test and numerical data were analyzed using the unpaired t-test and Wilcoxon’s rank sum test. A two-sided p value of
