Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation—A single center matched cohort study
Christoph Leiskau
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorJeremy Rajanayagam
Department of Gastroenterology and Nutrition, Royal Children′s Hospital, Melbourne, Australia
Search for more papers by this authorEva-Doreen Pfister
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorImeke Goldschmidt
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorNorman Junge
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorAndré Karch
Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorChristian Lerch
Division of Pediatric Nephrology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorNicolas Richter
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Search for more papers by this authorFrank Lehner
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Search for more papers by this authorHarald Schrem
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorCorresponding Author
Ulrich Baumann
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Birmingham Children´s Hospital, Liver Unit and University of Birmingham, Institute of Immunology and Immunotherapy, UK
Correspondence
Ulrich Baumann, Division of Pediatric Gastroenterology and Hepatology, Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Email: [email protected]
Search for more papers by this authorChristoph Leiskau
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorJeremy Rajanayagam
Department of Gastroenterology and Nutrition, Royal Children′s Hospital, Melbourne, Australia
Search for more papers by this authorEva-Doreen Pfister
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorImeke Goldschmidt
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorNorman Junge
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Search for more papers by this authorAndré Karch
Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Search for more papers by this authorChristian Lerch
Division of Pediatric Nephrology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorNicolas Richter
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Search for more papers by this authorFrank Lehner
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Search for more papers by this authorHarald Schrem
General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
Search for more papers by this authorCorresponding Author
Ulrich Baumann
Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
Birmingham Children´s Hospital, Liver Unit and University of Birmingham, Institute of Immunology and Immunotherapy, UK
Correspondence
Ulrich Baumann, Division of Pediatric Gastroenterology and Hepatology, Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Email: [email protected]
Search for more papers by this authorAbstract
Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L).
Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5).
GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.
Supporting Information
| Filename | Description |
|---|---|
| petr13207-sup-0001-FigureS1.jpgimage/jpg, 157.8 KB | |
| petr13207-sup-0002-TableS1.docxWord document, 12.4 KB | |
| petr13207-sup-0003-TableS2.docxWord document, 12.9 KB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schroter GP. Liver transplantation with use of cyclosporin a and prednisone. N Engl J Med. 1981; 305: 266-269.
- 2Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989; 2: 1000-1004.
- 3Miloh T, Barton A, Wheeler J, et al. Immunosuppression in pediatric liver transplant recipients: unique aspects. Liver Transpl. 2017; 23: 244-256.
- 4Rao V, Haywood S, Abecassis M, Levitsky J. A non-induction renal sparing approach after liver transplantation: high dose mycophenolate mofetil with delayed, low-dose tacrolimus. Transplant Proc. 2013; 45: 320-322.
- 5Boudjema K, Camus C, Saliba F, et al. Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transplant. 2011; 11: 965-976.
- 6Creput C, Blandin F, Deroure B, et al. Long-term effects of calcineurin inhibitor conversion to mycophenolate mofetil on renal function after liver transplantation. Liver Transpl. 2007; 13: 1004-1010.
- 7Haywood S, Abecassis M, Levitsky J. The renal benefit of mycophenolate mofetil after liver transplantation. Clin Transplant. 2011; 25: E88-E95.
- 8Tannuri U, Gibelli NE, Maksoud-Filho JG, et al. Mycophenolate mofetil promotes prolonged improvement of renal dysfunction after pediatric liver transplantation: experience of a single center. Pediatr Transplant. 2007; 11: 82-86.
- 9Ferraris JR, Duca P, Prigoshin N, et al. Mycophenolate mofetil and reduced doses of cyclosporine in pediatric liver transplantation with chronic renal dysfunction: changes in the immune responses. Pediatr Transplant. 2004; 8: 454-459.
- 10Evans HM, McKiernan PJ, Kelly DA. Mycophenolate mofetil for renal dysfunction after pediatric liver transplantation. Transplantation. 2005; 79: 1575-1580.
- 11Raimondo ML, Dagher L, Papatheodoridis GV, et al. Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Transplantation. 2003; 75: 186-190.
- 12Ponton C, Vizcaino L, Tome S, et al. Improvement of renal function after conversion to mycophenolate mofetil combined with low-level calcineurin inhibitor in liver transplant recipients with chronic renal dysfunction. Transplant Proc. 2010; 42: 656-659.
- 13Karie-Guigues S, Janus N, Saliba F, et al. Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study. Liver Transpl. 2009; 15: 1083-1091.
- 14Reich DJ, Clavien PA, Hodge EE, MMF renal dysfunction after liver transplantation working group. Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation. 2005; 80: 18-25.
- 15Zahn A, Mueller F, Hinz U, Schemmer P, Stremmel W, Ganten T. Mycophenolate mofetil combination therapy improves survival after liver transplantation. A single-center retrospective analysis. Ann Transplant. 2013; 18: 525-532.
- 16Wiesner RH, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Lake JR. Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C. Liver Transpl. 2005; 11: 750-759.
- 17Schmeding M, Kiessling A, Neuhaus R, et al. Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation. 2011; 92: 923-929.
- 18McDiarmid SV. Mycophenolate mofetil in liver transplantation. Clin Transplant. 1996; 10: 140-145.
- 19Lopau K, Syamken K, Rubenwolf P, Riedmiller H, Wanner C. Impact of mycophenolate mofetil on wound complications and lymphoceles after kidney transplantation. Kidney Blood Press Res. 2010; 33: 52-59.
- 20Pourfarziani V, Panahi Y, Assari S, Moghani-Lankarani M, Saadat SH. Changing treatment protocol from azathioprine to mycophenolate mofetil: decrease in renal dysfunction, increase in infections. Transplant Proc. 2007; 39: 1237-1240.
- 21Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation. 2003; 76: 984-988.
- 22Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol. 2009; 4: 1832-1843.
- 23Becker T, Foltys D, Bilbao I, et al. Patient outcomes in two steroid-free regimens using tacrolimus monotherapy after daclizumab induction and tacrolimus with mycophenolate mofetil in liver transplantation. Transplantation. 2008; 86: 1689-1694.
- 24Jain A, Mazariegos G, Kashyap R, et al. Comparative long-term evaluation of tacrolimus and cyclosporine in pediatric liver transplantation. Transplantation. 2000; 70: 617-625.
- 25McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant. 2006; 6: 1578-1585.
- 26Ng VL, Fecteau A, Shepherd R, et al. Outcomes of 5-year survivors of pediatric liver transplantation: report on 461 children from a North American multicenter registry. Pediatrics. 2008; 122: e1128-e1135.
- 27Kivela JM, Raisanen-Sokolowski A, Pakarinen MP, et al. Long-term renal function in children after liver transplantation. Transplantation. 2011; 91: 115-120.
- 28Aw MM, Samaroo B, Baker AJ, et al. Calcineurin-inhibitor related nephrotoxicity- reversibility in paediatric liver transplant recipients. Transplantation. 2001; 72: 746-749.
- 29Nobili V, Comparcola D, Sartorelli MR, Diciommo V, Marcellini M. Mycophenolate mofetil in pediatric liver transplant patients with renal dysfunction: preliminary data. Pediatr Transplant. 2003; 7: 454-457.
- 30Loinaz C, Kato T, Nishida S, et al. Bacterial infections after intestine and multivisceral transplantation. The experience of the University of Miami (1994-2001). Hepatogastroenterology 2006; 53: 234-242.
- 31Senft JD, Gotthardt DN, Frischbier L, Bruns H, Schemmer P. A retrospective comparison of mycophenolate mofetil with low-exposure cyclosporine versus standard cyclosporine therapy in de novo liver transplant patients. Ann Transplant. 2015; 20: 539-543.
- 32Cox KL, Lawrence-Miyasaki LS, Garcia-Kennedy R, et al. An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation. Transplantation. 1995; 59: 524-529.
- 33Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation. 2003; 76: 1729-1734.
- 34Younes BS, McDiarmid SV, Martin MG, et al. The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients. Transplantation. 2000; 70: 94-99.
- 35Cao S, Cox KL, Berquist W, et al. Long-term outcomes in pediatric liver recipients: comparison between cyclosporin A and tacrolimus. Pediatr Transplant. 1999; 3: 22-26.
Citing Literature
