Pediatr Transplantation 2014: 18: 783–785
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12379
Editorial
Finding the optimal therapeutic window for tacrolimus Tacrolimus is the most widely used calcineurin inhibitor in pediatric renal transplantation (1). In a head-to-head trial against microemulsified ciclosporin with concomitant azathioprine and steroids in 196 (103 tacrolimus and 93 ciclosporin) pediatric renal transplant recipients, the tacrolimus group exhibited a lower incidence of rejection within the first six months (2) and a significant graft survival advantage after four yr (3, 4). Tacrolimus is a critical dose drug, meaning that it demonstrates a high inter- and intra-individual variability. Therapeutic drug monitoring is therefore mandatory (5). The manufacturer only provides very broad therapeutic windows, namely 10–20 ng/mL from Day 0 to Day 30 and 5–10 ng/mL from Day 30 onward (2). In the above mentioned randomized and controlled clinical trial, the mean tacrolimus trough level was 13.0 8.7 ng/mL early after transplant and 8.9 2.8 ng/mL during months 4-6 post-transplant. Although most of the sponsor-driven studies were short term, a four-yr investigator-driven follow-up to the above study demonstrated a further decline in the tacrolimus levels. The patients’ trough levels decreased from 7.1 2.8 ng/mL (mean 1 standard deviation) at one yr to 6.7 2.8 ng/mL at two yr and 6.2 2.3 ng/mL at three yr (Fig. 1, unpublished data). Most pediatric renal transplant centers follow a similar approach and often accept lower longterm tacrolimus targets based on the individual’s risk for rejection. There is, however, a paucity of long-term prospective data on tacrolimus therapy in pediatric renal transplant recipients. The data from the FG506-0203 trial (2) do not apply as most centers are now using a tacrolimus and mycophenolate mofetil (MMF)-based immunosuppressive protocol (1). We are therefore delighted that Larkins and Matsell from the University of British Columbia completed a thorough retrospective study, analyzing 48 renal transplant recipients being treated with a tacroli-
Fig. 1. All available tacrolimus trough levels from (4), including patients who were converted from ciclosporin to tacrolimus. While the regression line demonstrates a slow decline over time beyond one yr, one-way ANOVA was actually not significant (p = 0.1132). This analysis also demonstrates a wide variation of targeted trough levels. These data have not previously been published. At three yr post transplantation, there was no correlation between the tacrolimus trough level and serum creatinine or the Schwartz eGFR (data not shown).
mus and MMF-based protocol (6). Patients were followed up to five yr after transplantation. The most important finding was a mean tacrolimus level of over 10 ng/mL in the first three months, which is higher than what the manufacturer recommends after 30 days post-transplant (2). The authors suggest that higher tacrolimus levels, especially during the first three months, may lead to better long-term graft function. Retrospective cohort studies inherently possess limitations, several of which were thoroughly addressed in the discussion. For example, the authors suggest an association between higher tacrolimus levels at three months and better graft outcomes, but this does not infer causality. It is useful to discuss some of the elements that may have contributed to these somewhat unexpected findings. There are many factors that affect long-term graft survival. Chronic allograft dysfunction (CAD) is poorly understood but remains a major 783
Editorial
cause of late graft failure. Donor factors also play a major role. Non-immunological elements include donor factors such as cause of brain death in the donor, increasing donor age, ischemia–reperfusion injury, and nephron endowment of the transplanted kidney (7). There is some evidence to support calcineurin inhibitor-induced vasoconstriction, which may lead to increased serum creatinine (8) and improves if the patient’s tacrolimus exposure is lowered. The serum creatinine of patients with a higher functional reserve and higher nephron endowment in the renal allograft may not rise as quickly as in those with a lower nephron endowment, and they may tolerate higher tacrolimus levels. Since creatinine does not increase until the patient’s GFR has dropped considerably, monitoring the renal allografts using cystatin C may have revealed similar tacrolimus-induced vasoconstriction in the creatinine-blind range (9). As such, these grafts may have tolerated higher tacrolimus levels without an increase in serum creatinine, but their superior GFR may simply be due to a higher nephron endowment. We previously reported superior outcomes for en bloc infant kidney transplant recipients who received twice the nephron endowment of single kidney transplants (10). There are also limitations in using GFR as a surrogate when predicting graft survival (11). Recipient factors include calcineurin inhibitor nephrotoxicity, hypertension, diabetes mellitus, hyperlipidemia and other cardiovascular risk factors, chronic obstruction, and chronic viral infections (7, 12). De novo donor-specific antibodies seem to correlate with inferior outcomes (13). Notably, pharmacokinetic monitoring of mycophenolic acid (MPA), the active compound of MMF, was not mentioned, and long-term graft function may depend on both the exposure to MPA and the calcineurin inhibitor. There is growing evidence for the need to monitor MPA exposure (14, 15), but unfortunately, exposure can only be accurately assessed using limited sampling methods (16) rather than the trough level alone (which suffices for tacrolimus) (17). Regardless, the study by Larkins and Matsell (6) has merit and addresses an important issue that has not yet been addressed despite the use of tacrolimus-based immunosuppression as the main calcineurin inhibitor following renal transplantation, in both adults and children. This is one of the first studies that aims to find evidence for more refined therapeutic windows at different time intervals following pediatric renal transplantation. In conclusion, we would like to congratulate the authors of the recent manuscript published 784
in Pediatric Transplantation for their important work. Prospective studies that correlate histological, immunological, and renal function parameters with a given therapeutic window are needed to define optimal therapeutic windows for drug trough levels at various time points after renal transplantation. This is important for both tacrolimus and for MMF, which also shows substantial inter- and intrapatient variability. Conflicts of interest None.
Guido Filler1,2,3 Department of Pediatrics, Schulich School of Medicine & Dentistry, London, ON, Canada, N6A 5W9 2 Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada, N5A 5A5 3 Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada, N5A 5A5 E-mail: guido.fi[email protected]
1
References 1. SMITH JM, MARTZ K, BLYDT-HANSEN TD. Pediatric kidney transplant practice patterns and outcome benchmarks, 1987–2010: A report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant 2013: 17: 149–157. 2. TROMPETER R, FILLER G, WEBB NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002: 17: 141–149. 3. FILLER G, TROMPETER R, WEBB N, et al. One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: A randomized trial of tacrolimus vs cyclosporine microemulsion. Transplant Proc 2002: 34: 1935– 1938. 4. FILLER G, WEBB NJ, MILFORD DV, et al. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 2005: 9: 498–503. 5. FILLER G. Calcineurin inhibitors in pediatric renal transplant recipients. Paediatr Drugs 2007: 9: 165–174. 6. LARKINS N, MATSELL D. Tacrolimus therapeutic drug monitoring and pediatric renal transplant graft outcomes. Pediatr Transplant 2014: 18: 803–809. 7. FADILI W, HABIB ALLAH M, LAOUAD I. Chronic renal allograft dysfunction: Risk factors, immunology and prevention. Arab J Nephrol Transplant 2013: 6: 45–50. 8. NIELSEN FT, LEYSSAC PP, KEMP E, STARKLINT H, DIEPERINK H. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995: 10: 334– 340. € 9. FILLER G, BOKENKAMP A, HOFMANN W, Le BRICON T, MARTINEZ-BRU C, GRUBB A. Cystatin C as a marker of GFR–history, indications, and future research. Clin Biochem 2005: 38: 1–8.
Editorial 10. FILLER G, LINDEKE A, BOHME K, DEVAUX S, SCHONBERGER B, EHRICH JH. Renal transplantation from donors aged < 6 years into children yields equal graft survival when compared to older donors. Pediatr Transplant 1997: 1: 119–123. 11. FILLER G, BROWNE R, SEIKALY MG. Glomerular filtration rate as a putative ‘surrogate end-point’ for renal transplant clinical trials in children. Pediatr Transplant 2003: 7: 18–24. 12. FILLER G. Challenges in pediatric transplantation: The impact of chronic kidney disease and cardiovascular risk factors on long-term outcomes and recommended management strategies. Pediatr Transplant 2011: 15: 25–31. 13. LIONAKI S, PANAGIOTELLIS K, INIOTAKI A, BOLETIS JN. Incidence and clinical significance of de novo donor specific antibodies after kidney transplantation. Clin Dev Immunol 2013: 2013: 849835.
14. TONSHOFF B, DAVID-NETO E, ETTENGER R, et al. Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando) 2011: 25: 78–89. 15. KUYPERS DR, LE MEUR Y, CANTAROVICH M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 2010: 5: 341–358. 16. FILLER G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int 2004: 17: 120–125. 17. FILLER G, GRYGAS R, MAI I, et al. Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants. Nephrol Dial Transplant 1997: 12: 1668–1671.
785
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12379
Editorial
Finding the optimal therapeutic window for tacrolimus Tacrolimus is the most widely used calcineurin inhibitor in pediatric renal transplantation (1). In a head-to-head trial against microemulsified ciclosporin with concomitant azathioprine and steroids in 196 (103 tacrolimus and 93 ciclosporin) pediatric renal transplant recipients, the tacrolimus group exhibited a lower incidence of rejection within the first six months (2) and a significant graft survival advantage after four yr (3, 4). Tacrolimus is a critical dose drug, meaning that it demonstrates a high inter- and intra-individual variability. Therapeutic drug monitoring is therefore mandatory (5). The manufacturer only provides very broad therapeutic windows, namely 10–20 ng/mL from Day 0 to Day 30 and 5–10 ng/mL from Day 30 onward (2). In the above mentioned randomized and controlled clinical trial, the mean tacrolimus trough level was 13.0 8.7 ng/mL early after transplant and 8.9 2.8 ng/mL during months 4-6 post-transplant. Although most of the sponsor-driven studies were short term, a four-yr investigator-driven follow-up to the above study demonstrated a further decline in the tacrolimus levels. The patients’ trough levels decreased from 7.1 2.8 ng/mL (mean 1 standard deviation) at one yr to 6.7 2.8 ng/mL at two yr and 6.2 2.3 ng/mL at three yr (Fig. 1, unpublished data). Most pediatric renal transplant centers follow a similar approach and often accept lower longterm tacrolimus targets based on the individual’s risk for rejection. There is, however, a paucity of long-term prospective data on tacrolimus therapy in pediatric renal transplant recipients. The data from the FG506-0203 trial (2) do not apply as most centers are now using a tacrolimus and mycophenolate mofetil (MMF)-based immunosuppressive protocol (1). We are therefore delighted that Larkins and Matsell from the University of British Columbia completed a thorough retrospective study, analyzing 48 renal transplant recipients being treated with a tacroli-
Fig. 1. All available tacrolimus trough levels from (4), including patients who were converted from ciclosporin to tacrolimus. While the regression line demonstrates a slow decline over time beyond one yr, one-way ANOVA was actually not significant (p = 0.1132). This analysis also demonstrates a wide variation of targeted trough levels. These data have not previously been published. At three yr post transplantation, there was no correlation between the tacrolimus trough level and serum creatinine or the Schwartz eGFR (data not shown).
mus and MMF-based protocol (6). Patients were followed up to five yr after transplantation. The most important finding was a mean tacrolimus level of over 10 ng/mL in the first three months, which is higher than what the manufacturer recommends after 30 days post-transplant (2). The authors suggest that higher tacrolimus levels, especially during the first three months, may lead to better long-term graft function. Retrospective cohort studies inherently possess limitations, several of which were thoroughly addressed in the discussion. For example, the authors suggest an association between higher tacrolimus levels at three months and better graft outcomes, but this does not infer causality. It is useful to discuss some of the elements that may have contributed to these somewhat unexpected findings. There are many factors that affect long-term graft survival. Chronic allograft dysfunction (CAD) is poorly understood but remains a major 783
Editorial
cause of late graft failure. Donor factors also play a major role. Non-immunological elements include donor factors such as cause of brain death in the donor, increasing donor age, ischemia–reperfusion injury, and nephron endowment of the transplanted kidney (7). There is some evidence to support calcineurin inhibitor-induced vasoconstriction, which may lead to increased serum creatinine (8) and improves if the patient’s tacrolimus exposure is lowered. The serum creatinine of patients with a higher functional reserve and higher nephron endowment in the renal allograft may not rise as quickly as in those with a lower nephron endowment, and they may tolerate higher tacrolimus levels. Since creatinine does not increase until the patient’s GFR has dropped considerably, monitoring the renal allografts using cystatin C may have revealed similar tacrolimus-induced vasoconstriction in the creatinine-blind range (9). As such, these grafts may have tolerated higher tacrolimus levels without an increase in serum creatinine, but their superior GFR may simply be due to a higher nephron endowment. We previously reported superior outcomes for en bloc infant kidney transplant recipients who received twice the nephron endowment of single kidney transplants (10). There are also limitations in using GFR as a surrogate when predicting graft survival (11). Recipient factors include calcineurin inhibitor nephrotoxicity, hypertension, diabetes mellitus, hyperlipidemia and other cardiovascular risk factors, chronic obstruction, and chronic viral infections (7, 12). De novo donor-specific antibodies seem to correlate with inferior outcomes (13). Notably, pharmacokinetic monitoring of mycophenolic acid (MPA), the active compound of MMF, was not mentioned, and long-term graft function may depend on both the exposure to MPA and the calcineurin inhibitor. There is growing evidence for the need to monitor MPA exposure (14, 15), but unfortunately, exposure can only be accurately assessed using limited sampling methods (16) rather than the trough level alone (which suffices for tacrolimus) (17). Regardless, the study by Larkins and Matsell (6) has merit and addresses an important issue that has not yet been addressed despite the use of tacrolimus-based immunosuppression as the main calcineurin inhibitor following renal transplantation, in both adults and children. This is one of the first studies that aims to find evidence for more refined therapeutic windows at different time intervals following pediatric renal transplantation. In conclusion, we would like to congratulate the authors of the recent manuscript published 784
in Pediatric Transplantation for their important work. Prospective studies that correlate histological, immunological, and renal function parameters with a given therapeutic window are needed to define optimal therapeutic windows for drug trough levels at various time points after renal transplantation. This is important for both tacrolimus and for MMF, which also shows substantial inter- and intrapatient variability. Conflicts of interest None.
Guido Filler1,2,3 Department of Pediatrics, Schulich School of Medicine & Dentistry, London, ON, Canada, N6A 5W9 2 Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada, N5A 5A5 3 Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada, N5A 5A5 E-mail: guido.fi[email protected]
1
References 1. SMITH JM, MARTZ K, BLYDT-HANSEN TD. Pediatric kidney transplant practice patterns and outcome benchmarks, 1987–2010: A report of the North American Pediatric Renal Trials and Collaborative Studies. Pediatr Transplant 2013: 17: 149–157. 2. TROMPETER R, FILLER G, WEBB NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol 2002: 17: 141–149. 3. FILLER G, TROMPETER R, WEBB N, et al. One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: A randomized trial of tacrolimus vs cyclosporine microemulsion. Transplant Proc 2002: 34: 1935– 1938. 4. FILLER G, WEBB NJ, MILFORD DV, et al. Four-year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion. Pediatr Transplant 2005: 9: 498–503. 5. FILLER G. Calcineurin inhibitors in pediatric renal transplant recipients. Paediatr Drugs 2007: 9: 165–174. 6. LARKINS N, MATSELL D. Tacrolimus therapeutic drug monitoring and pediatric renal transplant graft outcomes. Pediatr Transplant 2014: 18: 803–809. 7. FADILI W, HABIB ALLAH M, LAOUAD I. Chronic renal allograft dysfunction: Risk factors, immunology and prevention. Arab J Nephrol Transplant 2013: 6: 45–50. 8. NIELSEN FT, LEYSSAC PP, KEMP E, STARKLINT H, DIEPERINK H. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995: 10: 334– 340. € 9. FILLER G, BOKENKAMP A, HOFMANN W, Le BRICON T, MARTINEZ-BRU C, GRUBB A. Cystatin C as a marker of GFR–history, indications, and future research. Clin Biochem 2005: 38: 1–8.
Editorial 10. FILLER G, LINDEKE A, BOHME K, DEVAUX S, SCHONBERGER B, EHRICH JH. Renal transplantation from donors aged < 6 years into children yields equal graft survival when compared to older donors. Pediatr Transplant 1997: 1: 119–123. 11. FILLER G, BROWNE R, SEIKALY MG. Glomerular filtration rate as a putative ‘surrogate end-point’ for renal transplant clinical trials in children. Pediatr Transplant 2003: 7: 18–24. 12. FILLER G. Challenges in pediatric transplantation: The impact of chronic kidney disease and cardiovascular risk factors on long-term outcomes and recommended management strategies. Pediatr Transplant 2011: 15: 25–31. 13. LIONAKI S, PANAGIOTELLIS K, INIOTAKI A, BOLETIS JN. Incidence and clinical significance of de novo donor specific antibodies after kidney transplantation. Clin Dev Immunol 2013: 2013: 849835.
14. TONSHOFF B, DAVID-NETO E, ETTENGER R, et al. Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando) 2011: 25: 78–89. 15. KUYPERS DR, LE MEUR Y, CANTAROVICH M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol 2010: 5: 341–358. 16. FILLER G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int 2004: 17: 120–125. 17. FILLER G, GRYGAS R, MAI I, et al. Pharmacokinetics of tacrolimus (FK 506) in children and adolescents with renal transplants. Nephrol Dial Transplant 1997: 12: 1668–1671.
785
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
