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Experience with cyclosporine in living-donor lobar lung transplantation
Experience With Cyclosporine in Living-Donor Lobar Lung Transplantation H. Date ABSTRACT Living-donor lobar lung transplantation is an alternative to conventional cadaveric lung transplantation for both pediatric and adult patients. In 16 patients, postoperative immunosuppression included cyclosporine, azathioprine, and corticosteroids. Cyclosporine delivery began during the first few postoperative hours via a nasal feeding tube inserted to the proximal jejunum. The dosage was adjusted to maintain trough levels in the target range of 250 to 350 ng/dL during the first 3 months; however, it was often reduced when renal dysfunction was suspected. We judged acute rejection on the basis of radiographic and clinical findings without lung biopsy. During the first month, 15 of 16 patients experienced at least one episode of acute rejection with an average of 1.7 episodes/patient. Cyclosporine was switched to tacrolimus in four patients (25%) due to repeated episodes of acute rejection. No patients experienced infectious complications during the first months. All 16 patients are currently alive with a follow-up period of 3 to 59 months. Three patients (19%) have developed unilateral bronchiolitis obliterans. Cyclosporine-based immunosuppression can be safely given to the recipients of LDLLT without significant adverse effects but the incidence of acute rejection is relatively high. The optimal long-term immunosuppressive regimen remains to be established.
L
IVING-DONOR lobar lung transplantation (LDLLT) was introduced by Starnes and his colleagues for patients who were thought to be too critical to wait for cadaveric lung transplantation.1 In this relatively new procedure, two healthy donors donate their right or left lower lobe to be implanted as a right and a left lung to the recipient.2 Contrary to conventional cadaveric bilateral lung transplantation, each graft has different antigenicity in LDLLT. We summarize our experience of cyclosporine based immunosuppressive therapy after LDLLT
bilateral LDLLT and a 10-year-old boy received a single LDLLT from his mother.3 Among the 45 living donors, 12 were the mothers of recipients; 11, brothers; 9, fathers; 6, sisters; 4, husbands; 2, daughters; and 1, son. Thirteen patients received an ABO-identical LDLLT and 10 patients received LDLLT with a minor ABO mismatch.
Protocols of Immunosuppression
METHODS AND MATERIALS
Postoperative immunosuppression included cyclosporine (CSA) or tacrolimus (FK), azathioprine (AZA) or mycophenolate mofetil (MMF), and corticosteroids. Induction therapy with monoclonal or polyclonal antibodies was not used. The combination of CSA ⫹ AZA ⫹ steroid was chosen for
Twenty-three patients underwent LDLLT at Okayama University Hospital from October 1998 through June 2003. Diagnoses included various lung diseases: hypertensive (primary pulmonary hypertension, Eisenmenger’s syndrome); obstructive (bronchiolitis obliterans, lymphangioleiomyomatosis); restrictive (idiopathic interstitial pneumonia): and infectious (bronchiectasis, cystic fibrosis) lung diseases. There were 19 females and 4 males with ages ranging from 8 to 53 years (average 28.4 years). Five of the patients were children and 18 were adults. All but one patient received
From the Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. Address reprint requests to Hiroshi Date, MD, Department of Cancer and Thoracic Surgery (Surgery II), Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan. E-mail: [email protected]. okayama-u.ac.jp
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 349S⫺351S (2004)
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.034 349S
350S
DATE Table 1. Cyclosporine-based Immunosuppressive Protocol for Living-Donor Lobar Lung Transplantation
Cyclosporine (Neoral) Pretransplant Posttransplant
None Dosage adjusted to maintain trough level at 3 months posttransplant 250 –350 ng/dL 6 months posttransplant 200 –300 ng/dL 12 months posttransplant 150 –250 ng/dL
Azathioprine (Imuran) Pretransplant Posttransplant Corticosteroids Before reperfusion Posttransplant
2 mg/kg 2 mg/kg per day
3 days posttransplant 6 months posttransplant 12 months posttransplant
patients with infectious lung diseases and pediatric patients; the combination of FK ⫹ MMF ⫹ steroid, for adult patients with noninfectious lung diseases. CSA (100 mg) delivery began during the first few postoperative hours via a nasal feeding tube inserted to the proximal jejunum. The dosage was adjusted to maintain trough levels in the target range listed in Table 1. This drug often induces a significant decrease in urine output, necessitating a reduction in dosage. AZA (2 mg/kg) was given orally before operation and then via the nasal feeding tube posttransplant. We adopted the use of moderate-dose corticosteroids during the early postoperative period. Intravenous administration of methylprednisolone was used before reperfusion and during the first 3 days. Then we initiated prednisone via the nasal feeding tube as summarized in Table 1.
Detection and Management of Acute Rejection In cadaveric lung transplantation, transbronchial lung biopsy, as a safe and accurate means, has emerged as the procedure of choice for the diagnosis of acute rejection.4 However, the risk of pneumothorax and bleeding by transbronchial lung biopsy may be greater in LDLLT because the small grafts are receiving high blood flow. Thus we judge acute rejection on the basis of radiographic and clinical findings. Early acute rejection episodes are characterized by dyspnea, low grade fever, leukocytosis, hypoxemia, and diffuse interstitial infiltrates on chest radiographs. Because two lobes are donated by different donors, acute rejection is usually seen unilaterally. After administration of a trial bolus dose of methylprednisolone (500 mg), various clinical signs are carefully observed. If acute rejection seems to be the problem, two additional daily bolus doses of methylprednisolone were delivered. If acute rejection was encountered more than three times, CSA ⫹ AZA was switched to FK ⫹ MMF. When all these treatments failed, OKT3 was used.
RESULTS
The combination of CSA ⫹ AZA ⫹ steroid was chosen for 16 patients. During the first month, 15 of 16 patients treated
Methylprednisolone (IV) Methylprednisolone (IV) Prednisone (oral) Prednisone (oral)
1000 mg 125 mg per day 0.4 mg/kg per day 0.2 mg/kg per 2 days
with CSA-based immunosuppressive regimens experienced at least one episode of acute rejection with an average of 1.7 episodes per patient. CSA ⫹ AZA was switched to FK ⫹ MMF in four patients (25%) due to repeated episodes of acute rejection. No patient experienced infectious complications during the first months. Urine output was often reduced a few hours after CSA administration. The actual mean CSA trough level was kept below the target range and serum creatinine level remained normal (Table 2). All 16 patients are currently alive with a follow-up of 3 to 59 months. After receiving LDLLT, three patients (19%) developed unilateral bronchiolitis obliterans (10, 12, and 42 months). Their immunosuppressive regimens were changed from CSA ⫹ AZA to FK ⫹ MMF; their FEV1 reached a plateau within 6 months. DISCUSSION
LDLLT is a new and evolving option for patients with end-stage lung diseases. There are several important notions in the management of LDLLT recipients. Two grafts are donated from two donors; therefore, each graft has different antigenicity. Lung edema is often seen in small grafts receiving the entire cardiac output.5 The risk of pneumothorax and bleeding after transbronchial lung biopsy may be higher among LDLLT because the small grafts are receiving high blood flow. The main causes of early mortality after lung transplantation are known to be infection and acute graft failure. Acute rejection is often encountered but is usually manageable by bolus injection of steroids. Our approach to LDLLT recipients focuses on avoiding excessive immunosuppression to decrease the risk of infection, to protect renal function are thereby to decrease the risk of lung edema. We believe the risk of infection is lower with CSA- than
Table 2. Cyclosporine Trough Level and Serum Creatinine Level
Cyclosporine (ng/dL) Creatinine (mg/dL)
1 day
3 days
7 days
3 weeks
3 months
6 months
1 year
100 ⫾ 20 0.50 ⫾ 0.04
243 ⫾ 27 0.59 ⫾ 0.06
219 ⫾ 21 0.49 ⫾ 0.04
277 ⫾ 23 0.67 ⫾ 0.09
242 ⫾ 16 0.78 ⫾ 0.07
239 ⫾ 14 0.83 ⫾ 0.07
208 ⫾ 11 0.71 ⫾ 0.06
CYCLOSPORINE IN LIVING-DONOR LUNG TRANSPLANT
FK-based immunosuppressive regimens. Of note, no early infection was encountered among the 16 recipients treated with CSA-based immunosuppression. However, the incidence of acute rejection appeared to be higher among CSA(1.7 episodes/patient) than FK-treated patients (1.0 episode/patient). The high incidence of acute rejection among CSA-treated patients may be related to the intentionally relatively low trough levels maintained to protect renal function. We avoided intravenous administration of CSA using a feeding tube inserted into the proximal jejunum. Enteral administration of CSA appeared to be less toxic to renal function. The feeding tube was also useful for nutritional support in the early postoperative period. Starnes et al reported that pediatric patients receiving LDLLT experienced less chronic rejection than those receiving conventional cadaveric lung transplantation.6 The incidence of chronic rejection in our experience (3/16, 19%) was also relatively low. Chronic rejection was seen only on
351S
one side due to the different antigenicity between two LDLLT grafts. In summary, CSA-based immunosuppression can be safely administered to recipients of LDLLT without significant adverse effects, but the incidence of acute rejection is relatively high. The optimal long-term immunosuppressive regimen remains to be established. REFERENCES 1. Starnes VA, Barr ML, Cohen RG, et al: J Thorac Cardiovasc Surg 112:1284, 1996 2. Cohen RG, Barr ML, Schenkel FA, et al: Ann Thorac Surg 57:1423, 1994 3. Date H, Sano Y, Aoe M, et al: J Thorac Cardiovasc Surg 123:1211, 2002 4. Trulock EP, Ettinger NA, Brunt EM, et al: Chest 102:1049, 1992 5. Date H, Aoe M, Nagahiro I, et al: J Thorac Cardiovasc Surg 126:476, 2003 6. Starnes VA, Woo MS, MacLaughlin EF, et al: Ann Thorac Surg 68:2279, 1999
L
IVING-DONOR lobar lung transplantation (LDLLT) was introduced by Starnes and his colleagues for patients who were thought to be too critical to wait for cadaveric lung transplantation.1 In this relatively new procedure, two healthy donors donate their right or left lower lobe to be implanted as a right and a left lung to the recipient.2 Contrary to conventional cadaveric bilateral lung transplantation, each graft has different antigenicity in LDLLT. We summarize our experience of cyclosporine based immunosuppressive therapy after LDLLT
bilateral LDLLT and a 10-year-old boy received a single LDLLT from his mother.3 Among the 45 living donors, 12 were the mothers of recipients; 11, brothers; 9, fathers; 6, sisters; 4, husbands; 2, daughters; and 1, son. Thirteen patients received an ABO-identical LDLLT and 10 patients received LDLLT with a minor ABO mismatch.
Protocols of Immunosuppression
METHODS AND MATERIALS
Postoperative immunosuppression included cyclosporine (CSA) or tacrolimus (FK), azathioprine (AZA) or mycophenolate mofetil (MMF), and corticosteroids. Induction therapy with monoclonal or polyclonal antibodies was not used. The combination of CSA ⫹ AZA ⫹ steroid was chosen for
Twenty-three patients underwent LDLLT at Okayama University Hospital from October 1998 through June 2003. Diagnoses included various lung diseases: hypertensive (primary pulmonary hypertension, Eisenmenger’s syndrome); obstructive (bronchiolitis obliterans, lymphangioleiomyomatosis); restrictive (idiopathic interstitial pneumonia): and infectious (bronchiectasis, cystic fibrosis) lung diseases. There were 19 females and 4 males with ages ranging from 8 to 53 years (average 28.4 years). Five of the patients were children and 18 were adults. All but one patient received
From the Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. Address reprint requests to Hiroshi Date, MD, Department of Cancer and Thoracic Surgery (Surgery II), Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan. E-mail: [email protected]. okayama-u.ac.jp
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 349S⫺351S (2004)
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.034 349S
350S
DATE Table 1. Cyclosporine-based Immunosuppressive Protocol for Living-Donor Lobar Lung Transplantation
Cyclosporine (Neoral) Pretransplant Posttransplant
None Dosage adjusted to maintain trough level at 3 months posttransplant 250 –350 ng/dL 6 months posttransplant 200 –300 ng/dL 12 months posttransplant 150 –250 ng/dL
Azathioprine (Imuran) Pretransplant Posttransplant Corticosteroids Before reperfusion Posttransplant
2 mg/kg 2 mg/kg per day
3 days posttransplant 6 months posttransplant 12 months posttransplant
patients with infectious lung diseases and pediatric patients; the combination of FK ⫹ MMF ⫹ steroid, for adult patients with noninfectious lung diseases. CSA (100 mg) delivery began during the first few postoperative hours via a nasal feeding tube inserted to the proximal jejunum. The dosage was adjusted to maintain trough levels in the target range listed in Table 1. This drug often induces a significant decrease in urine output, necessitating a reduction in dosage. AZA (2 mg/kg) was given orally before operation and then via the nasal feeding tube posttransplant. We adopted the use of moderate-dose corticosteroids during the early postoperative period. Intravenous administration of methylprednisolone was used before reperfusion and during the first 3 days. Then we initiated prednisone via the nasal feeding tube as summarized in Table 1.
Detection and Management of Acute Rejection In cadaveric lung transplantation, transbronchial lung biopsy, as a safe and accurate means, has emerged as the procedure of choice for the diagnosis of acute rejection.4 However, the risk of pneumothorax and bleeding by transbronchial lung biopsy may be greater in LDLLT because the small grafts are receiving high blood flow. Thus we judge acute rejection on the basis of radiographic and clinical findings. Early acute rejection episodes are characterized by dyspnea, low grade fever, leukocytosis, hypoxemia, and diffuse interstitial infiltrates on chest radiographs. Because two lobes are donated by different donors, acute rejection is usually seen unilaterally. After administration of a trial bolus dose of methylprednisolone (500 mg), various clinical signs are carefully observed. If acute rejection seems to be the problem, two additional daily bolus doses of methylprednisolone were delivered. If acute rejection was encountered more than three times, CSA ⫹ AZA was switched to FK ⫹ MMF. When all these treatments failed, OKT3 was used.
RESULTS
The combination of CSA ⫹ AZA ⫹ steroid was chosen for 16 patients. During the first month, 15 of 16 patients treated
Methylprednisolone (IV) Methylprednisolone (IV) Prednisone (oral) Prednisone (oral)
1000 mg 125 mg per day 0.4 mg/kg per day 0.2 mg/kg per 2 days
with CSA-based immunosuppressive regimens experienced at least one episode of acute rejection with an average of 1.7 episodes per patient. CSA ⫹ AZA was switched to FK ⫹ MMF in four patients (25%) due to repeated episodes of acute rejection. No patient experienced infectious complications during the first months. Urine output was often reduced a few hours after CSA administration. The actual mean CSA trough level was kept below the target range and serum creatinine level remained normal (Table 2). All 16 patients are currently alive with a follow-up of 3 to 59 months. After receiving LDLLT, three patients (19%) developed unilateral bronchiolitis obliterans (10, 12, and 42 months). Their immunosuppressive regimens were changed from CSA ⫹ AZA to FK ⫹ MMF; their FEV1 reached a plateau within 6 months. DISCUSSION
LDLLT is a new and evolving option for patients with end-stage lung diseases. There are several important notions in the management of LDLLT recipients. Two grafts are donated from two donors; therefore, each graft has different antigenicity. Lung edema is often seen in small grafts receiving the entire cardiac output.5 The risk of pneumothorax and bleeding after transbronchial lung biopsy may be higher among LDLLT because the small grafts are receiving high blood flow. The main causes of early mortality after lung transplantation are known to be infection and acute graft failure. Acute rejection is often encountered but is usually manageable by bolus injection of steroids. Our approach to LDLLT recipients focuses on avoiding excessive immunosuppression to decrease the risk of infection, to protect renal function are thereby to decrease the risk of lung edema. We believe the risk of infection is lower with CSA- than
Table 2. Cyclosporine Trough Level and Serum Creatinine Level
Cyclosporine (ng/dL) Creatinine (mg/dL)
1 day
3 days
7 days
3 weeks
3 months
6 months
1 year
100 ⫾ 20 0.50 ⫾ 0.04
243 ⫾ 27 0.59 ⫾ 0.06
219 ⫾ 21 0.49 ⫾ 0.04
277 ⫾ 23 0.67 ⫾ 0.09
242 ⫾ 16 0.78 ⫾ 0.07
239 ⫾ 14 0.83 ⫾ 0.07
208 ⫾ 11 0.71 ⫾ 0.06
CYCLOSPORINE IN LIVING-DONOR LUNG TRANSPLANT
FK-based immunosuppressive regimens. Of note, no early infection was encountered among the 16 recipients treated with CSA-based immunosuppression. However, the incidence of acute rejection appeared to be higher among CSA(1.7 episodes/patient) than FK-treated patients (1.0 episode/patient). The high incidence of acute rejection among CSA-treated patients may be related to the intentionally relatively low trough levels maintained to protect renal function. We avoided intravenous administration of CSA using a feeding tube inserted into the proximal jejunum. Enteral administration of CSA appeared to be less toxic to renal function. The feeding tube was also useful for nutritional support in the early postoperative period. Starnes et al reported that pediatric patients receiving LDLLT experienced less chronic rejection than those receiving conventional cadaveric lung transplantation.6 The incidence of chronic rejection in our experience (3/16, 19%) was also relatively low. Chronic rejection was seen only on
351S
one side due to the different antigenicity between two LDLLT grafts. In summary, CSA-based immunosuppression can be safely administered to recipients of LDLLT without significant adverse effects, but the incidence of acute rejection is relatively high. The optimal long-term immunosuppressive regimen remains to be established. REFERENCES 1. Starnes VA, Barr ML, Cohen RG, et al: J Thorac Cardiovasc Surg 112:1284, 1996 2. Cohen RG, Barr ML, Schenkel FA, et al: Ann Thorac Surg 57:1423, 1994 3. Date H, Sano Y, Aoe M, et al: J Thorac Cardiovasc Surg 123:1211, 2002 4. Trulock EP, Ettinger NA, Brunt EM, et al: Chest 102:1049, 1992 5. Date H, Aoe M, Nagahiro I, et al: J Thorac Cardiovasc Surg 126:476, 2003 6. Starnes VA, Woo MS, MacLaughlin EF, et al: Ann Thorac Surg 68:2279, 1999