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Challenging immunosuppression treatment in lung transplant recipients with kidney failure
Transplant Immunology 35 (2016) 18–22
Contents lists available at ScienceDirect
Transplant Immunology journal homepage: www.elsevier.com/locate/trim
Brief communication
Challenging immunosuppression treatment in lung transplant recipients with kidney failure Benjamin A. Högerle a,1, Neeraj Kohli a,1, Kirsty Habibi-Parker a, Haifa Lyster a, Anna Reed a, Martin Carby a, Mohamed Zeriouh b, Alexander Weymann b, André R. Simon b, Anton Sabashnikov b,⁎, Aron-Frederik Popov b, Simona Soresi a a
Department of Respiratory and Transplant Medicine, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom
b
a r t i c l e
i n f o
Article history: Received 15 December 2015 Received in revised form 11 February 2016 Accepted 12 February 2016 Available online 15 February 2016 Keywords: Basiliximab Lung transplantation Kidney failure
a b s t r a c t Kidney failure after lung transplantation is a risk factor for chronic kidney disease. Calcineurin inhibitors are immunosuppressants which play a major role in terms of postoperative kidney failure after lung transplantation. We report our preliminary experience with the anti-interleukin-2 monoclonal antibody Basiliximab utilized as a “calcineurin inhibitor-free window” in the setting of early postoperative kidney failure after lung transplantation. Between 2012 and 2015 nine lung transplant patients who developed kidney failure for more than 14 days were included. Basiliximab was administrated in three doses (Day 0, 4, and 20) whilst Tacrolimus was discontinued or reduced to maintain a serum level between 2 and 4 ng/mL. Baseline glomerular filtration rate pre transplant was normal for all patients. Seven patients completely recovered from kidney failure (67%, mean eGFR pre and post Basiliximab: 42.3 mL/min/1.73 m2 and 69 mL/min/1.73 m2) and were switched back on Tacrolimus. Only one of these patients still needs ongoing renal replacement therapy. Two patients showed no recovery from kidney failure and did not survive. Basiliximab might be a safe and feasible therapeutical option in patients which are affected by calcineurin inhibitor-related kidney failure in the early post lung transplant period. Further studies are necessary to confirm our preliminary results. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Lung transplantation (LTX) is the treatment of choice of end stage lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung disease (ILD), or idiopathic pulmonary arterial hypertension (IPAH) [1–3]. However, the outcome is limited by the recipients' rejection of the donor organ (50% of the patients at 5-year postprocedure) defined as pathological obliterative bronchiolitis (OB) [4]. The rejection rate has been significantly decreased by the Abbreviations: AF, Arterial fibrillation; ALG, Anti-lymphocyte globulin; ATG, Antithymocyte globulin; BAX, Basiliximab; BSSLTX, Bilateral sequential single lung transplantation; CMV, Cytomegalovirus; CVVH, Continuous veno-venous hemofiltration; DBD, Donation after brain death; DCD, Donation after circulatory death; OB, Obliterative bronchiolitis; CF, Cystic fibrosis; CNI, Calcineurin inhibitor; COPD, Chronic obstructive pulmonary disease; ECMO, Extracorporeal membrane oxygenation; eGFR, estimated Glomerular filtration rate; GI, Gastrointestinal; IL2, Interleukin 2; ILD, Interstitial lung disease; IPAH, Idiopathic pulmonary arterial hypertension; LTX, Lung transplantation; TLC, Total lung capacity. ⁎ Corresponding author at: Department of Cardiothoracic Transplantation and Mechanical Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB9 6JH, United Kingdom. E-mail address: [email protected] (A. Sabashnikov). 1 Both authors contributed equally to this work.
http://dx.doi.org/10.1016/j.trim.2016.02.002 0966-3274/© 2016 Elsevier B.V. All rights reserved.
introduction of the first calcineurin inhibitor (CNI) Cyclosporin in 1983. A further rejection reduction was made by the CNI Tacrolimus in 1994. Today CNIs are widely used as induction and maintenance immunosuppressant drugs [5,6]. Nevertheless, CNIs promote, for example, the genesis of inflammation and tumors as well as kidney failure (up to 83%) [7,8]. Due to their narrow therapeutic range and their administration mostly in combination with prophylactic antimicrobial drugs CNIs play a major role in terms of possible kidney failure after LTX especially in the early postoperative course [9]. However, CNIs remain the best treatment option for immunosuppression after LTX as Sirolimus is well known to affect the on-going surgical healing process. Additionally, it has impact on polyclonal anti-lymphocyte globulins (ALGs) or antithymocyte globulins (ATGs) which may lead to an increased risk for infection and sepsis [10–12]. Since 1998 the antibody-based drug Basiliximab is increasingly used for induction therapy in LTX patients with good overall survival and rejection outcomes in comparison to non antibody-based drugs like CNIs. Basiliximab is an interleukin 2 (IL2) receptor antagonist which inhibits T lymphocyte proliferation and differentiation and only minimal side effects were observed [11,13–15]. In the setting of applying CNIs as induction therapy after LTX and successive early postoperative kidney failure with the need of renal
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22
19
replacement therapy the treatment options are limited and only rare data is available in the literature. Due to the promising performance of Basiliximab we report our preliminary clinical experience with Basiliximab utilized in a “CNI-free window” to gain recovery from early postoperative kidney failure.
recipient at the time of transplantation (Table 1). The overall one-, three-, and six-year survival rates after LTX in our center are 90.5, 79.0, and 57.4%, respectively. All survivors were converted back to tacrolimus once they were weaned off CVVH and basiliximab (after day 20) whereas the therapeutic range was set between 5 and 10 ng/mL.
2. Materials and methods
3.1. Case 1
We hereby present an observational single-center case series of nine patients. All patients were treated between August 2012 and January 2015 at Harefield Hospital, Royal Brompton & Harefield NHS Foundation Trust, UK. This study was approved by the Ethics Committee of the Royal Brompton & Harefield NHS Foundation Trust. A written informed consent is available for all patients. The group of patients included all recipients of bilateral sequential single lung transplantation (BSSLTX) presenting with acute peri-operative kidney failure. Kidney dysfunction was defined as the need for continuous veno-venous hemofiltration (CVVH). Usually, patients requiring CVVH had anuria and eGFR (estimated glomerular filtration rate) of 29 mL/min or less. As long as the kidney failure persisted a renal replacement therapy with continuous veno-venous hemofiltration (CVVH) was performed. The kidney failure had to last for more than 14 days post LTX and was defined as impossibility to wean the patients from CVVH because of anuria and/or metabolic acidosis with high urea/potassium levels. This decision was made considering that for the first 10 to 14 days after transplantation our recipients received antibiotics, antifungal and antiviral treatment as regular prophylactic regime. The combination of these drugs with CNI can cause acute kidney injury that is normally reversible once the regime is reduced to immunosuppression alone. Our protocol used 20 mg Basiliximab on day 1, 4, and 20. During this time Tacrolimus was discontinued or the dose was reduced to maintain at least a serum level between 2 and 4 ng/mL (Fig. 1). eGFRs were calculated at the time of LTX registration, on day before the Basiliximab treatment has begun, 30 days, and 60 days after the Basiliximab administration. Furthermore, Tacrolimus serum levels were recorded on the days 1, 4, and 20 of the Basiliximab treatment as well as 30 days and 60 days after the Basiliximab administration. Also nephrotoxic concomitant medications (e.g. antibiotics) were also recorded.
A 55-year old female recipient underwent uneventful BSSLTX due to COPD. Postoperatively, she needed a cecostomy due to bowel obstruction. The recipient developed CVVH requiring kidney failure on day 1 after LTX. Basiliximab treatment was initiated on day 14 after LTX. CVVH has been no longer necessary since day 2 of the Basiliximab administration and the recipient was discharged in full renal recovery and is well after three years of follow-up.
3. Results The patient population of this study contains seven female and two male patients with end stage lung diseases (3× COPD, 2× bronchiectasis, 2 × CF, 1 × ILD, and 1 × IPAH) between 20 and 67 years (mean: 44.4 years). The mean time on the waiting list was 531 days. One patient received an organ donated after circulatory death (DCD); eight patients received an organ donated after brain death (DBD). The lungs were matched to the recipients according to blood group, height, total lung capacity (TLC), time on the waiting list, and clinical status of the
3.2. Case 2 A 28-year old female recipient underwent uneventful BSSLTX due to CF. In the postoperative course the recipient needed antibiotic treatment because of aspiration pneumonia in consequence of gastroparesis and subsequent episodes of vomiting. The recipient developed kidney failure and required CVVH on day 11 after LTX. The Basiliximab treatment was started on day 60 after LTX. CVVH has been obsolete since day 9 of the Basiliximab administration and the recipient. However, the recipient died on day 124 after LTX due to sepsis. 3.3. Case 3 This 32-year old female recipient preoperatively needed extracorporeal membrane oxygenation (ECMO) and Novalung® implantation as bridge to transplantation due to IPAH. She underwent uneventful BSSLTX and developed an acute cellular rejection postoperatively which was treated with high-dose steroids. Pneumonia was treated with antibiotics. Additionally, the recipient developed CVVH requiring kidney failure on day 1 after LTX. Administration of Basiliximab was started on day 14 after LTX. CVVH has been no longer necessary since day 13 of the Basiliximab administration. The recipient could be discharged in full renal recovery and is well after three years of follow-up. 3.4. Case 4 This 30-year old female recipient underwent difficult lobular transplantation due to bronchiectasis. An episode of acute cellular rejection occurred within the first 20 days post LTX and was treated with high dose of steroids. She subsequently developed a bowel perforation which required surgery, followed by a peritonitis. The patient required prolonged treatment with systemic antibiotics (Meropenem,
Fig. 1. Time line of the Basiliximab treatment.
−
Yes Yes
Deceased Yes Yes
4.7 143 −
66.3
12.3
− − 200 126
− − 531 − −
455 523 (245 of OCS) 503 DBD DCD 0+ A+ 523 97
57 67 59
20 52
44.4
Recipient 5 Recipient 6 Recipient 7
Recipient 8 Recipient 9
Mean
Female Male
55 28 32 30
DBD DBD DBD A+ A+ A+ 34 204 287
ILD COPD COPD/ Emphysema CF Bronchiectasis Male Female Female
On On Off
On On
27.0 55.0
12.3 13.9
4.5 4.6 4.4 112 75 265 75.0 71.0 17.0
15.0 7.4 10.1
4.6 4.6 4.7 5.4 184 200 93 30 On On On On
This is a 57-year old male recipient with previous exposure to Cyclophosphamide therapy, high dose of steroids, Azathioprine, and Mycophenolate mofetil due to ILD and progressive fibrosis being his primary diagnosis. He underwent uneventful BSSLTX with the use of pre-operative ECMO support (for 52 days prior to the surgery). Postoperatively, he needed recurrent blood transfusions, developed gastrointestinal (GI) bleedings, and a liver dysfunction. A degree of kidney failure was pre-existing to the transplant and secondary to the ECMO implantation and he therefore was on CVVH therapy at the time of his LTX. We started the Basiliximab treatment as a single dose application (only day 1) on day 30 after LTX. Unfortunately, the recipient died on day 120 after LTX due to multiple organ failure.
3.6. Case 6 A 67-year old female recipient underwent uneventful BSSLTX due to COPD. However, the recipient developed a kidney failure and required CVVH since day 10 after LTX. We started the Basiliximab treatment on day 14 after LTX. CVVH has been obsolete since day 6 of the Basiliximab administration. The recipient was discharged in full renal recovery and is well after six months of follow-up; her immunosuppressant regime was later on (3 months post surgery) swapped from Tacrolimus to Sirolimus, once the healing process (sternal wound and bronchial anastomosis) was achieved.
3.7. Case 7 This 59-year old female recipient underwent uneventful BSSLTX diagnosed by COPD. Postoperatively, she developed episodes of arterial fibrillation (AF) which were treated with antiarrhythmic drugs, a pulmonary artery stenosis at her vascular anastomosis which required redo-surgery, and an acute cellular rejection which was treated with high-dose steroids (day 33 post LTX). The recipient also developed kidney failure and needed CVVH on day 1 after LTX. The Basiliximab treatment was started on day 14 after LTX. CVVH has been no longer necessary since day 19 of the Basiliximab administration. The recipient was discharged in full renal recovery and is well after six months of follow-up.
3.8. Case 8
Recipient 1 Recipient 2 Recipient 3 Recipient 4
Female Female Female Female
B+ A+ 0+ A235 745 2289 369 COPD CF IPAH Bronchiectasis
DBD DBD DBD DBD
449 317 369 530 (380 of OCS) 774 580 530
29.0 33.0 64.0 226.6
19.3 15.9 8.4 8.2
Potassium (μmol/L, day 1/BAX start) Urea (mmol/L, day 1/BAX start) Creatinine (μmol/L, day 1/BAX start) eGFR (mL/min/1.73 m2, day 1/BAX start) On pump/off pump Total ischemic time (in minutes) DCD or DBD donor Days on the waiting list
Blood group
Metronidazole, Ceftazidime, and Colomycin). In this context, the recipient developed kidney failure and needed CVVH since day 2 after LTX. Basiliximab treatment was commenced on day 38 after LTX and was uncomplicated, however, the recipient died on day 87 after LTX due to sepsis.
3.5. Case 5
Diagnosis Sex Age (years, LTX registration)
Table 1 Demographic characteristics of the patient population.
Yes Yes Yes Deceased
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22 Recovery from kidney failure?
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A 20-year old female recipient underwent uneventful BSSLTX due to CF. The recipient had postoperatively two cardiac arrests. Additionally pneumonia and kidney failure were observed in the early postoperative period (within the first 20 days post LTX). The CVVH requiring kidney failure was developed on day 1 after LTX. We started the Basiliximab treatment as a double dose application (only day 1 and 20) and reduced the CNI dose to achieve Tacrolimus blood levels between 2 and 4 ng/mL. CVVH has been no longer necessary since day 2 of the Basiliximab administration. The recipient gained full renal recovery. Unfortunately, the recipient died on day 120 after LTX due to cytomegalovirus (CMV)-pneumonitis following treatment with immunoabsorption due to further development of acute antibody mediated rejection.
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22
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3.9. Case 9 This 52-year old female recipient underwent difficult BSSLTX due to bronchiectasis. The surgical procedure was performed with cardiopulmonary bypass. Perioperatively, the recipient had a cardiogenic shock because of ongoing hemorrhage. The primary graft failure was treated with central ECMO implantation. The postoperative course was complicated by a right-side-endocarditis which was treated in a conservative way. The recipient developed a kidney failure and needed CVVH on day 1 after LTX. The Basiliximab treatment was started on day 70 after LTX. The recipient was recently discharged but still needs ongoing renal replacement therapy.
4. Discussion Lung transplantation is the surgical strategy to manage patients with end stage pulmonary disease not responding to conventional medical treatment. However, complication as kidney failure with necessity of renal replacement treatment after LTX is still very common. The current estimated rates for kidney failure among lung transplant recipients can vary widely from 10 to 83% [7–9]. The nephrotoxic side effects of the immunosuppressive agents, particularly CNIs, is in fact well known. However, treatment options early post surgery are very limited and only rare data are available about the management of these patients at this stage post lung transplantation. Basiliximab is a well established drug used mostly as induction therapy after LTX. So, the administration of IL2 receptor antagonists such as Basiliximab nearly doubled from 2000 to 2010 (20 versus 37%). Of all IL2 receptor antagonists Basiliximab is applied up to 62% with satisfying overall survival rates [16,17]. In terms of postoperative kidney failure after organ transplantation there is initial promising experience using Basiliximab as induction immunosuppressant drug after heart and liver transplantation to prevent kidney failure by postponing the use of CNIs until the fourth postoperative day, a time point at which patients seem to stabilize hemodynamically and may be less prone to kidney failure [9,18–20]. Furthermore, Basiliximab can bridge the application of CNIs after heart transplantation until freedom of dialysis is restored with good overall results [18,19]. We hereby present our single-center experience of nine LTX patients who were initially treated with CNIs and then developed kidney failure (mean eGFR pre and post Basiliximab 66.3 mL/min/1.73 m2 and 68.2 mL/min/1.73 m2) for more than 14 days utilizing Basiliximab in a “CNI-free window” to gain recovery from early postoperative kidney failure. Seven patients (67%) of the so treated patients recovered
Fig. 3. Overall duration of CVVH after starting the Basiliximab administration and eGFR in LTX patients with early postoperative kidney failure.
completely from kidney failure in this study (mean eGFR pre and post Basiliximab 42.3 mL/min/1.73 m2 and 69 mL/min/1.73 m2) and were switched back on Tacrolimus without complications (Fig. 2). Two patients did not survive and showed also no recovery from kidney failure (1× lobar transplant and 1× transplanted from long term ECMO). Out of seven patients who showed a sufficient response to the treatment, six were discharge home, whilst the remaining one is still with on-going rehabilitation (Fig. 3). Long-terms outcome of our patient cohort after restarting tacrolimus was good in terms of freedom from relapse of kidney dysfunction. This fact supports our hypothesis that the CNI nephrotoxic effect early after transplantation might be exacerbated by the antibiotic, antiviral and antifungal prophylactic regime use as per protocol. Once the drug regime is deescalated, CNI might be safely used, however strictly controlling serum levels to minimize kidney toxicity. The literature provides only rare data on Basiliximab as immunosuppressant in LTX patients with subsequent postoperative kidney failure. However, Basiliximab was hereby administered as induction therapy. In a single case Matsuda et al. used Basiliximab as preoperative induction therapy followed by once-daily Cyclosporine administration as maintenance therapy. In this context the blood concentration of cyclosporine could be lowered by Basiliximab for protection of renal function [21]. Borro et al. compared 15 LTX patients with impaired renal function receiving Basiliximab as induction therapy to a control group. Basiliximab has a trend to reduce the rate of acute and chronic rejection in lung transplant recipients with no increased incidence of infections or malignancies [22]. However, the influence of Basiliximab used in a “CNI-free window” after CNI induction has not been reported so far. In conclusion, CNI-related kidney failure after LTX is a common complication after LTX. However, the therapeutical options are still limited. This study demonstrates the general feasibility to utilize Basiliximab as a “CNI-free window” in patients which are affected by CNI-related kidney failure in the immediate post lung transplant period. In this context, we believe that Basiliximab is a promising and safe treatment method. We therefore plan further studies with a prospective study design, a larger number of patients, and a control group to confirm our preliminary experience.
Disclosure Fig. 2. Tacrolimus serum levels and eGFR in LTX patients with early postoperative kidney failure.
The authors of this manuscript have no conflicts of interest to disclose.
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References [1] A.F. Popov, D. García Sáez, A. Sabashnikov, Utilization of the organ care system — a game-changer in combating donor organ shortage, Med. Sci. Monit. Basic Res. 21 (2015) 29–32. [2] A.F. Popov, A. Sabashnikov, N.P. Patil, Ex vivo lung perfusion — state of the art in lung donor pool expansion, Med. Sci. Monit. Basic Res. 21 (2015) 9–14. [3] S. Soresi, A. Sabashnikov, A. Weymann, M. Zeriouh, A.R. Simon, A.F. Popov, When the battle is lost and won: delayed chest closure after bilateral lung transplantation, Med. Sci. Monit. Basic Res. 21 (2015) 222–225. [4] G.M. Verleden, R. Vos, B. Vanaudenaerde, et al., Current views on chronic rejection after lung transplantation, Transpl. Int. 28 (2015) 1131–1139. [5] L.H. Lund, L.B. Edwards, A.Y. Kucheryavaya, et al., The registry of the international society for heart and lung transplantation: thirty-first official adult heart transplant report–2014; focus theme: retransplantation, J. Heart Lung Transplant. 33 (2014) 996–1008. [6] J.L. Scheffert, K. Raza, Immunosuppression in lung transplantation, J. Thorac. Dis. 6 (2014) 1039–1053. [7] C. Magee, M. Pascual, The growing problem of chronic renal failure after transplantation of a nonrenal organ, N. Engl. J. Med. 349 (2003) 994–996. [8] A.O. Ojo, P.J. Held, F.K. Port, et al., Chronic renal failure after transplantation of a nonrenal organ, N. Engl. J. Med. 349 (2003) 931–940. [9] P.B. Rosenberg, A.E. Vriesendorp, M.H. Drazner, et al., Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation, J. Heart Lung Transplant. 24 (2005) 1327–1331. [10] M.G. Hartwig, L.D. Snyder, J.Z. Appel, E. Cantu, S.S. Lin, S.M. Palmer, R.D. Davis, Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation, J. Heart Lung Transplant. 27 (2008) 547–553. [11] S.C. Sweet, Induction therapy in lung transplantation, Transpl. Int. 26 (2013) 696–703.
[12] J.L. Taylor, S.M. Palmer, Critical care perspective on immunotherapy in lung transplantation, J. Intensive Care Med. 21 (2006) 327–344. [13] K.D. Lake, Immunosuppressive drugs and novel strategies to prevent acute and chronic allograft rejection, Semin. Respir. Crit. Care Med. 22 (2001) 559–580. [14] S.V. Onrust, L.R. Wiseman, Basiliximab, Drugs 57 (1999) 207–213. [15] L.R. Wiseman, D. Faulds, Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients, Drugs 58 (1999) 1029–1042. [16] M. de la Torre, E. Pena, M. Calvin, et al., Basiliximab in lung transplantation: preliminary experience, Transplant. Proc. 37 (2005) 1534–1536. [17] B.A. Whitson, A. Lehman, A. Wehr, et al., To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival, Clin. Transpl. 28 (2014) 450–461. [18] J. Cai, P.I. Terasaki, Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of united network for organ sharing registry data, Transplantation 90 (2010) 1511–1515. [19] M. Dandel, H.B. Lehmkuhl, C. Knosalla, R. Hetzer, Impact of different long-term maintenance immunosuppressive therapy strategies on patients' outcome after heart transplantation, Transpl. Immunol. 23 (2010) 93–103. [20] A.A. Schnitzbauer, J. Sothmann, L. Baier, T. Bein, E.K. Geissler, M.N. Scherer, H.J. Schlitt, Calcineurin inhibitor free de novo immunosuppression in liver transplant recipients with pretransplant renal impairment: results of a pilot study (PATRON07), Transplantation (2015), http://dx.doi.org/10.1097/TP.0000000000000779. [21] Y. Matsuda, F. Chen, H. Miyata, H. Date, Once-daily oral administration of cyclosporine in a lung transplant patient with a history of renal toxicity of calcineurin inhibitors, Interact. Cardiovasc. Thorac. Surg. 19 (2014) 171–173. [22] J.M. Borro, M. de la Torre, C. Miguelez, R. Fernandez, D. Gonzalez, C. Lemos, Comparative study of basiliximab treatment in lung transplantation, Transplant. Proc. 37 (2005) 3996–3998.
Contents lists available at ScienceDirect
Transplant Immunology journal homepage: www.elsevier.com/locate/trim
Brief communication
Challenging immunosuppression treatment in lung transplant recipients with kidney failure Benjamin A. Högerle a,1, Neeraj Kohli a,1, Kirsty Habibi-Parker a, Haifa Lyster a, Anna Reed a, Martin Carby a, Mohamed Zeriouh b, Alexander Weymann b, André R. Simon b, Anton Sabashnikov b,⁎, Aron-Frederik Popov b, Simona Soresi a a
Department of Respiratory and Transplant Medicine, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton and Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom
b
a r t i c l e
i n f o
Article history: Received 15 December 2015 Received in revised form 11 February 2016 Accepted 12 February 2016 Available online 15 February 2016 Keywords: Basiliximab Lung transplantation Kidney failure
a b s t r a c t Kidney failure after lung transplantation is a risk factor for chronic kidney disease. Calcineurin inhibitors are immunosuppressants which play a major role in terms of postoperative kidney failure after lung transplantation. We report our preliminary experience with the anti-interleukin-2 monoclonal antibody Basiliximab utilized as a “calcineurin inhibitor-free window” in the setting of early postoperative kidney failure after lung transplantation. Between 2012 and 2015 nine lung transplant patients who developed kidney failure for more than 14 days were included. Basiliximab was administrated in three doses (Day 0, 4, and 20) whilst Tacrolimus was discontinued or reduced to maintain a serum level between 2 and 4 ng/mL. Baseline glomerular filtration rate pre transplant was normal for all patients. Seven patients completely recovered from kidney failure (67%, mean eGFR pre and post Basiliximab: 42.3 mL/min/1.73 m2 and 69 mL/min/1.73 m2) and were switched back on Tacrolimus. Only one of these patients still needs ongoing renal replacement therapy. Two patients showed no recovery from kidney failure and did not survive. Basiliximab might be a safe and feasible therapeutical option in patients which are affected by calcineurin inhibitor-related kidney failure in the early post lung transplant period. Further studies are necessary to confirm our preliminary results. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Lung transplantation (LTX) is the treatment of choice of end stage lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), interstitial lung disease (ILD), or idiopathic pulmonary arterial hypertension (IPAH) [1–3]. However, the outcome is limited by the recipients' rejection of the donor organ (50% of the patients at 5-year postprocedure) defined as pathological obliterative bronchiolitis (OB) [4]. The rejection rate has been significantly decreased by the Abbreviations: AF, Arterial fibrillation; ALG, Anti-lymphocyte globulin; ATG, Antithymocyte globulin; BAX, Basiliximab; BSSLTX, Bilateral sequential single lung transplantation; CMV, Cytomegalovirus; CVVH, Continuous veno-venous hemofiltration; DBD, Donation after brain death; DCD, Donation after circulatory death; OB, Obliterative bronchiolitis; CF, Cystic fibrosis; CNI, Calcineurin inhibitor; COPD, Chronic obstructive pulmonary disease; ECMO, Extracorporeal membrane oxygenation; eGFR, estimated Glomerular filtration rate; GI, Gastrointestinal; IL2, Interleukin 2; ILD, Interstitial lung disease; IPAH, Idiopathic pulmonary arterial hypertension; LTX, Lung transplantation; TLC, Total lung capacity. ⁎ Corresponding author at: Department of Cardiothoracic Transplantation and Mechanical Support, Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB9 6JH, United Kingdom. E-mail address: [email protected] (A. Sabashnikov). 1 Both authors contributed equally to this work.
http://dx.doi.org/10.1016/j.trim.2016.02.002 0966-3274/© 2016 Elsevier B.V. All rights reserved.
introduction of the first calcineurin inhibitor (CNI) Cyclosporin in 1983. A further rejection reduction was made by the CNI Tacrolimus in 1994. Today CNIs are widely used as induction and maintenance immunosuppressant drugs [5,6]. Nevertheless, CNIs promote, for example, the genesis of inflammation and tumors as well as kidney failure (up to 83%) [7,8]. Due to their narrow therapeutic range and their administration mostly in combination with prophylactic antimicrobial drugs CNIs play a major role in terms of possible kidney failure after LTX especially in the early postoperative course [9]. However, CNIs remain the best treatment option for immunosuppression after LTX as Sirolimus is well known to affect the on-going surgical healing process. Additionally, it has impact on polyclonal anti-lymphocyte globulins (ALGs) or antithymocyte globulins (ATGs) which may lead to an increased risk for infection and sepsis [10–12]. Since 1998 the antibody-based drug Basiliximab is increasingly used for induction therapy in LTX patients with good overall survival and rejection outcomes in comparison to non antibody-based drugs like CNIs. Basiliximab is an interleukin 2 (IL2) receptor antagonist which inhibits T lymphocyte proliferation and differentiation and only minimal side effects were observed [11,13–15]. In the setting of applying CNIs as induction therapy after LTX and successive early postoperative kidney failure with the need of renal
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22
19
replacement therapy the treatment options are limited and only rare data is available in the literature. Due to the promising performance of Basiliximab we report our preliminary clinical experience with Basiliximab utilized in a “CNI-free window” to gain recovery from early postoperative kidney failure.
recipient at the time of transplantation (Table 1). The overall one-, three-, and six-year survival rates after LTX in our center are 90.5, 79.0, and 57.4%, respectively. All survivors were converted back to tacrolimus once they were weaned off CVVH and basiliximab (after day 20) whereas the therapeutic range was set between 5 and 10 ng/mL.
2. Materials and methods
3.1. Case 1
We hereby present an observational single-center case series of nine patients. All patients were treated between August 2012 and January 2015 at Harefield Hospital, Royal Brompton & Harefield NHS Foundation Trust, UK. This study was approved by the Ethics Committee of the Royal Brompton & Harefield NHS Foundation Trust. A written informed consent is available for all patients. The group of patients included all recipients of bilateral sequential single lung transplantation (BSSLTX) presenting with acute peri-operative kidney failure. Kidney dysfunction was defined as the need for continuous veno-venous hemofiltration (CVVH). Usually, patients requiring CVVH had anuria and eGFR (estimated glomerular filtration rate) of 29 mL/min or less. As long as the kidney failure persisted a renal replacement therapy with continuous veno-venous hemofiltration (CVVH) was performed. The kidney failure had to last for more than 14 days post LTX and was defined as impossibility to wean the patients from CVVH because of anuria and/or metabolic acidosis with high urea/potassium levels. This decision was made considering that for the first 10 to 14 days after transplantation our recipients received antibiotics, antifungal and antiviral treatment as regular prophylactic regime. The combination of these drugs with CNI can cause acute kidney injury that is normally reversible once the regime is reduced to immunosuppression alone. Our protocol used 20 mg Basiliximab on day 1, 4, and 20. During this time Tacrolimus was discontinued or the dose was reduced to maintain at least a serum level between 2 and 4 ng/mL (Fig. 1). eGFRs were calculated at the time of LTX registration, on day before the Basiliximab treatment has begun, 30 days, and 60 days after the Basiliximab administration. Furthermore, Tacrolimus serum levels were recorded on the days 1, 4, and 20 of the Basiliximab treatment as well as 30 days and 60 days after the Basiliximab administration. Also nephrotoxic concomitant medications (e.g. antibiotics) were also recorded.
A 55-year old female recipient underwent uneventful BSSLTX due to COPD. Postoperatively, she needed a cecostomy due to bowel obstruction. The recipient developed CVVH requiring kidney failure on day 1 after LTX. Basiliximab treatment was initiated on day 14 after LTX. CVVH has been no longer necessary since day 2 of the Basiliximab administration and the recipient was discharged in full renal recovery and is well after three years of follow-up.
3. Results The patient population of this study contains seven female and two male patients with end stage lung diseases (3× COPD, 2× bronchiectasis, 2 × CF, 1 × ILD, and 1 × IPAH) between 20 and 67 years (mean: 44.4 years). The mean time on the waiting list was 531 days. One patient received an organ donated after circulatory death (DCD); eight patients received an organ donated after brain death (DBD). The lungs were matched to the recipients according to blood group, height, total lung capacity (TLC), time on the waiting list, and clinical status of the
3.2. Case 2 A 28-year old female recipient underwent uneventful BSSLTX due to CF. In the postoperative course the recipient needed antibiotic treatment because of aspiration pneumonia in consequence of gastroparesis and subsequent episodes of vomiting. The recipient developed kidney failure and required CVVH on day 11 after LTX. The Basiliximab treatment was started on day 60 after LTX. CVVH has been obsolete since day 9 of the Basiliximab administration and the recipient. However, the recipient died on day 124 after LTX due to sepsis. 3.3. Case 3 This 32-year old female recipient preoperatively needed extracorporeal membrane oxygenation (ECMO) and Novalung® implantation as bridge to transplantation due to IPAH. She underwent uneventful BSSLTX and developed an acute cellular rejection postoperatively which was treated with high-dose steroids. Pneumonia was treated with antibiotics. Additionally, the recipient developed CVVH requiring kidney failure on day 1 after LTX. Administration of Basiliximab was started on day 14 after LTX. CVVH has been no longer necessary since day 13 of the Basiliximab administration. The recipient could be discharged in full renal recovery and is well after three years of follow-up. 3.4. Case 4 This 30-year old female recipient underwent difficult lobular transplantation due to bronchiectasis. An episode of acute cellular rejection occurred within the first 20 days post LTX and was treated with high dose of steroids. She subsequently developed a bowel perforation which required surgery, followed by a peritonitis. The patient required prolonged treatment with systemic antibiotics (Meropenem,
Fig. 1. Time line of the Basiliximab treatment.
−
Yes Yes
Deceased Yes Yes
4.7 143 −
66.3
12.3
− − 200 126
− − 531 − −
455 523 (245 of OCS) 503 DBD DCD 0+ A+ 523 97
57 67 59
20 52
44.4
Recipient 5 Recipient 6 Recipient 7
Recipient 8 Recipient 9
Mean
Female Male
55 28 32 30
DBD DBD DBD A+ A+ A+ 34 204 287
ILD COPD COPD/ Emphysema CF Bronchiectasis Male Female Female
On On Off
On On
27.0 55.0
12.3 13.9
4.5 4.6 4.4 112 75 265 75.0 71.0 17.0
15.0 7.4 10.1
4.6 4.6 4.7 5.4 184 200 93 30 On On On On
This is a 57-year old male recipient with previous exposure to Cyclophosphamide therapy, high dose of steroids, Azathioprine, and Mycophenolate mofetil due to ILD and progressive fibrosis being his primary diagnosis. He underwent uneventful BSSLTX with the use of pre-operative ECMO support (for 52 days prior to the surgery). Postoperatively, he needed recurrent blood transfusions, developed gastrointestinal (GI) bleedings, and a liver dysfunction. A degree of kidney failure was pre-existing to the transplant and secondary to the ECMO implantation and he therefore was on CVVH therapy at the time of his LTX. We started the Basiliximab treatment as a single dose application (only day 1) on day 30 after LTX. Unfortunately, the recipient died on day 120 after LTX due to multiple organ failure.
3.6. Case 6 A 67-year old female recipient underwent uneventful BSSLTX due to COPD. However, the recipient developed a kidney failure and required CVVH since day 10 after LTX. We started the Basiliximab treatment on day 14 after LTX. CVVH has been obsolete since day 6 of the Basiliximab administration. The recipient was discharged in full renal recovery and is well after six months of follow-up; her immunosuppressant regime was later on (3 months post surgery) swapped from Tacrolimus to Sirolimus, once the healing process (sternal wound and bronchial anastomosis) was achieved.
3.7. Case 7 This 59-year old female recipient underwent uneventful BSSLTX diagnosed by COPD. Postoperatively, she developed episodes of arterial fibrillation (AF) which were treated with antiarrhythmic drugs, a pulmonary artery stenosis at her vascular anastomosis which required redo-surgery, and an acute cellular rejection which was treated with high-dose steroids (day 33 post LTX). The recipient also developed kidney failure and needed CVVH on day 1 after LTX. The Basiliximab treatment was started on day 14 after LTX. CVVH has been no longer necessary since day 19 of the Basiliximab administration. The recipient was discharged in full renal recovery and is well after six months of follow-up.
3.8. Case 8
Recipient 1 Recipient 2 Recipient 3 Recipient 4
Female Female Female Female
B+ A+ 0+ A235 745 2289 369 COPD CF IPAH Bronchiectasis
DBD DBD DBD DBD
449 317 369 530 (380 of OCS) 774 580 530
29.0 33.0 64.0 226.6
19.3 15.9 8.4 8.2
Potassium (μmol/L, day 1/BAX start) Urea (mmol/L, day 1/BAX start) Creatinine (μmol/L, day 1/BAX start) eGFR (mL/min/1.73 m2, day 1/BAX start) On pump/off pump Total ischemic time (in minutes) DCD or DBD donor Days on the waiting list
Blood group
Metronidazole, Ceftazidime, and Colomycin). In this context, the recipient developed kidney failure and needed CVVH since day 2 after LTX. Basiliximab treatment was commenced on day 38 after LTX and was uncomplicated, however, the recipient died on day 87 after LTX due to sepsis.
3.5. Case 5
Diagnosis Sex Age (years, LTX registration)
Table 1 Demographic characteristics of the patient population.
Yes Yes Yes Deceased
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22 Recovery from kidney failure?
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A 20-year old female recipient underwent uneventful BSSLTX due to CF. The recipient had postoperatively two cardiac arrests. Additionally pneumonia and kidney failure were observed in the early postoperative period (within the first 20 days post LTX). The CVVH requiring kidney failure was developed on day 1 after LTX. We started the Basiliximab treatment as a double dose application (only day 1 and 20) and reduced the CNI dose to achieve Tacrolimus blood levels between 2 and 4 ng/mL. CVVH has been no longer necessary since day 2 of the Basiliximab administration. The recipient gained full renal recovery. Unfortunately, the recipient died on day 120 after LTX due to cytomegalovirus (CMV)-pneumonitis following treatment with immunoabsorption due to further development of acute antibody mediated rejection.
B.A. Högerle et al. / Transplant Immunology 35 (2016) 18–22
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3.9. Case 9 This 52-year old female recipient underwent difficult BSSLTX due to bronchiectasis. The surgical procedure was performed with cardiopulmonary bypass. Perioperatively, the recipient had a cardiogenic shock because of ongoing hemorrhage. The primary graft failure was treated with central ECMO implantation. The postoperative course was complicated by a right-side-endocarditis which was treated in a conservative way. The recipient developed a kidney failure and needed CVVH on day 1 after LTX. The Basiliximab treatment was started on day 70 after LTX. The recipient was recently discharged but still needs ongoing renal replacement therapy.
4. Discussion Lung transplantation is the surgical strategy to manage patients with end stage pulmonary disease not responding to conventional medical treatment. However, complication as kidney failure with necessity of renal replacement treatment after LTX is still very common. The current estimated rates for kidney failure among lung transplant recipients can vary widely from 10 to 83% [7–9]. The nephrotoxic side effects of the immunosuppressive agents, particularly CNIs, is in fact well known. However, treatment options early post surgery are very limited and only rare data are available about the management of these patients at this stage post lung transplantation. Basiliximab is a well established drug used mostly as induction therapy after LTX. So, the administration of IL2 receptor antagonists such as Basiliximab nearly doubled from 2000 to 2010 (20 versus 37%). Of all IL2 receptor antagonists Basiliximab is applied up to 62% with satisfying overall survival rates [16,17]. In terms of postoperative kidney failure after organ transplantation there is initial promising experience using Basiliximab as induction immunosuppressant drug after heart and liver transplantation to prevent kidney failure by postponing the use of CNIs until the fourth postoperative day, a time point at which patients seem to stabilize hemodynamically and may be less prone to kidney failure [9,18–20]. Furthermore, Basiliximab can bridge the application of CNIs after heart transplantation until freedom of dialysis is restored with good overall results [18,19]. We hereby present our single-center experience of nine LTX patients who were initially treated with CNIs and then developed kidney failure (mean eGFR pre and post Basiliximab 66.3 mL/min/1.73 m2 and 68.2 mL/min/1.73 m2) for more than 14 days utilizing Basiliximab in a “CNI-free window” to gain recovery from early postoperative kidney failure. Seven patients (67%) of the so treated patients recovered
Fig. 3. Overall duration of CVVH after starting the Basiliximab administration and eGFR in LTX patients with early postoperative kidney failure.
completely from kidney failure in this study (mean eGFR pre and post Basiliximab 42.3 mL/min/1.73 m2 and 69 mL/min/1.73 m2) and were switched back on Tacrolimus without complications (Fig. 2). Two patients did not survive and showed also no recovery from kidney failure (1× lobar transplant and 1× transplanted from long term ECMO). Out of seven patients who showed a sufficient response to the treatment, six were discharge home, whilst the remaining one is still with on-going rehabilitation (Fig. 3). Long-terms outcome of our patient cohort after restarting tacrolimus was good in terms of freedom from relapse of kidney dysfunction. This fact supports our hypothesis that the CNI nephrotoxic effect early after transplantation might be exacerbated by the antibiotic, antiviral and antifungal prophylactic regime use as per protocol. Once the drug regime is deescalated, CNI might be safely used, however strictly controlling serum levels to minimize kidney toxicity. The literature provides only rare data on Basiliximab as immunosuppressant in LTX patients with subsequent postoperative kidney failure. However, Basiliximab was hereby administered as induction therapy. In a single case Matsuda et al. used Basiliximab as preoperative induction therapy followed by once-daily Cyclosporine administration as maintenance therapy. In this context the blood concentration of cyclosporine could be lowered by Basiliximab for protection of renal function [21]. Borro et al. compared 15 LTX patients with impaired renal function receiving Basiliximab as induction therapy to a control group. Basiliximab has a trend to reduce the rate of acute and chronic rejection in lung transplant recipients with no increased incidence of infections or malignancies [22]. However, the influence of Basiliximab used in a “CNI-free window” after CNI induction has not been reported so far. In conclusion, CNI-related kidney failure after LTX is a common complication after LTX. However, the therapeutical options are still limited. This study demonstrates the general feasibility to utilize Basiliximab as a “CNI-free window” in patients which are affected by CNI-related kidney failure in the immediate post lung transplant period. In this context, we believe that Basiliximab is a promising and safe treatment method. We therefore plan further studies with a prospective study design, a larger number of patients, and a control group to confirm our preliminary experience.
Disclosure Fig. 2. Tacrolimus serum levels and eGFR in LTX patients with early postoperative kidney failure.
The authors of this manuscript have no conflicts of interest to disclose.
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