- Email: [email protected]
Cyclosporine in pediatric kidney transplantation
Cyclosporine in Pediatric Kidney Transplantation L. Pape, J.H.H. Ehrich, and G. Offner ABSTRACT Before the era of cyclosporine (CsA), immunosuppression with azathioprine and steroids resulted in high rejection rates and severe growth retardation in pediatric renal transplant recipients. In the early 1980s, immunosuppression with CsA was introduced for children. Because of differences in metabolism rates and relation of weight and body surface area, special pediatric dosing regimens and monitoring strategies had to be developed. Use of CsA led to a decreased number of acute rejections and, consequently, to a marked increase in graft survival rates. The growth rates of transplanted children were significantly higher under CsA-based immunosuppression than with classical regimens. This was due to a decreased need of steroid co-administration. Main side effects of CsA in children were nephrotoxicity and hirsutism. The introduction of CsA mircroemulsion in the 1990s led to more reliable absorption profiles and to a lower interindividual variability of CsA area-under-the-curve concentrations and thus to another improvement in rejection rates. New monitoring strategies, based on CsA levels taken 2 hours’ postdose, seem promising. In pediatric transplantation, CsA is often successfully combined with an antibodyinduction therapy in order to reduce the number of early acute rejections. Combination with mycophenolate mofetil reduces the appearance of chronic rejection. Additional therapy with ToR inhibitors might enforce a reduction of CsA doses and therefore lead to a reduction of CsA toxic effects.
I
N THE LATE 1960s, the first programs for renal transplantation in children were initiated. A first report of long-term results of children transplanted in Los Angeles who received prednisolone and azathioprine as immunosuppression was published in 1978.1 The 5-year survival rate of grafts from living related donors (LRD) was 73%, and that of cadaveric donors (CAD) 39%. The main reasons for graft failure were hyperacute rejections, acute rejections, and chronic rejections. Most of these children experienced severe growth retardation.1 The main causes were longterm, high-dose steroid therapy, and fused distal femoral and proximal tibial epiphyses at the time of transplantation.2,3
INTRODUCTION OF CSA IN CHILDREN
As a result of these problems, new immunosuppressive strategies had to be developed. A new substance, the fungus metabolite of CsA, was used in children for the first time in 1979. A study of 34 patients (few children) with CsA immunosuppression after solid-organ transplantation was published. The study revealed fewer numbers of infections, reduced CsA toxicity, and better graft function than in © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 203S⫺207S (2004)
smaller studies in adults that had been performed before.4 – 6 The first multicenter trial comparing azathioprine with CsA, which included a small number of children, showed a significantly higher 1-year survival rate when CsA was used. The number of infections was similar in both groups.7,8 In those early years, knowledge about CsA pharmacodynamics and pharmacokinetics improved greatly. Better strategies concerning co-administration of other immunosuppressive drugs were invented, which led to a reduction of the number of graft losses. In those first studies, only small numbers of children were included; thus, until 1982 almost no data existed on how to administer CsA in pediatric transplant recipients. The first good pediatric experiences with CsA were published between 1983 and 1984.9 –11 A larger study from 1985 showed good results without any graft losses due to CsA toxicity and From the Department of Pediatric Nephrology, Medical School of Hannover, Hannover, Germany. Address reprint requests to Dr Lars Pape, Department of Pediatric Nephrology, Medical School of Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.053 203S
204S
an incidence of acute rejection of 39% 16 months after transplantation.12 In addition to the positive effects of CsA, negative effects were also observed: a study comparing 32 children with CsA immunosuppression to conventional therapy showed a significantly lower renal function in the CsA group based on early loss of the glomerular filtration rate with a comparable decline of transplant function in both groups later.13 These results were confirmed in larger studies in the following years.14 –16 A main advantage of CsA in pediatric transplantation that was observed at a very early stage was the improvement in growth. Combined with low-dose prednisolone, CsA treatment yielded excellent results and allowed normal growth rates after pediatric kidney transplantation.17,18 Even catch-up growth in these children was observed.19 Thus, the growth rates achieved with CsA immunosuppression were much better than growth rates under immunosuppression with azathioprine in the decade previous.20 The main side effects of CsA therapy in youngsters were nephrotoxicity and hirsutism.18 In 1985 it was shown that the described effects of higher creatinine levels under CsA therapy compared to azathioprine were largely reversible after dose reduction.21 However, it also became evident that over the long run, CsA therapy may lead to interstitial fibrosis and therefore deterioration of graft function.22 Thus, it is important to find the right CsA dose that achieves enough immunosuppression in combination with the minimal number of side effects. By consequence, therapeutic drug monitoring of CsA was introduced as a standard method in order to reach this goal. One important problem was the dosage of CsA in pediatric transplant recipients. Children have a higher body surface area in relation to body weight than do adults. When CsA dosage was calculated based on body weight as in adults, the CsA serum levels were too low. A new pediatric dosing regimen based on body surface area helped to find the right amount of CsA needed for the individual patient.23 It was shown that the CsA maintenance dosage based on body weight was higher than that recommended for adults. As in adults, interactions of CsA with other medications (ie, erythromycin, phenobarbital, phenytoin, doxycycline, or others) based on the metabolic pathway, including cytochrome P450, have to be taken into account. These are often responsible for unexpected CsA toxicity or for rejections due to decreasing CsA levels. CYCLOSPORINE MICROEMULSION
Many factors had to be considered to guarantee an effective and safe use of CsA in children. One important aspect was the difference of absorption in the lumen of the upper intestinal tract. For optimal and consistent absorption, CsA as a hydrophobic agent had always to be mixed with the same drink—for instance, apple juice or chocolate milk.23 Another invention was the development of CSA capsules that allowed more exact dosing. However, these capsules
PAPE, EHRICH, AND OFFNER
could not be given to small children. A co-administration of food with CsA resulted in a significant increase in peak and trough blood levels depending on the kind of food eaten.24 It was therefore concluded in pediatric transplantation that CsA should be taken without food and that there should be a fixed interval between CsA administration and the next meal. A new formulation of CSA, the microemulsion, was available from 1993 onwards. The pharmacokinetics of this formulation in adults was much more predictable, and the absorption rate was more consistent. In addition, the effect of food on absorption was much lower than with the standard formulation.25 In patients who were switched from the old formulation to the new microemulsion, absorption rates were significantly higher after the switch;26 this was associated with a decrease in the creatinine clearance as a result of higher blood levels, but not with any other adverse effects.27 The pharmacokinetic values of CsA were less variable and therefore more predictable, with a more consistent concentration-time profile when using the microemulsion.28 These results were confirmed in pediatric transplant recipients. With the use of CsA microemulsion, the drug availability increased up to 300%; concomitantly, signs of CsA toxicity increased.29 Hence, the dose as well as the target trough levels had to be decreased in order to avoid overdosing. Starting in 1995, it was also discussed whether CsA blood levels drawn earlier than 12 hours after administration are needed for dose adjustment.29 Variations in intraindividual CsA trough levels, as well as the variability of full areaunder-the-curve concentrations and CsA levels drawn 2 hours’ postdose, were lower in children when the new formulation was used.30,31 These pharmacokinetic advantages of the CsA microemulsion led to a lower number of acute rejections in children after solid-organ transplantation; thus, CsA microemulsion became the standard immunosuppressive agent in many pediatric transplantation centers. Cyclosporine With Induction Therapy
As a next step in reducing rejection rates, CsA immunosuppression in children was combined with antibody induction therapies. Initially, OKT3, a drug with substantial side effects, was believed to reach this goal successfully32 but failed to reduce acute and chronic rejection in a large, double-blind, randomized pediatric trial.33 The role of thymoglobulin as a polyclonal induction antibody remains unclear; a small study from 2002 showed a low number of acute rejections.34 In recent years, monoclonal antibodies (MAbs) have mainly been used as an induction therapy in addition to CsA. Most data have been published about basiliximab, a monoclonal chimerical human-murine IL-2 (CD25) antibody that has shown a significant decrease in the number of acute rejections in both adults35 and in pediatric patients.36 An interaction between basiliximab and CsA blood levels has been described.37 Data about the use of daclizumab, a humanized CD-25 antibody, in pedi-
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children that C2 levels correlated better with the areaunder-the-curve (AUC) concentration of CsA than with trough levels.49 –51 Equations for AUC estimation in children based on C2 monitoring were established,52 and preliminary target levels for C2 levels in pediatric transplant recipients were defined.53 It still remains unclear whether C2-based adoption of the CsA dose leads to a better graft survival in children.54,55 Studies that might answer this question will be performed in the coming years. Cyclosporine-Sparing Immunosuppressive Regimens With Target of Rapamycin Inhibitors
Fig 1. Graft survival rates under immunosuppression with azathioprine (Aza), cyclosporine (CsA), partly in combination with basiliximab (Bas) or mycophenolate mofetil (MMF) in pediatric renal transplantation in Hannover, Germany.
atric transplantation have not yet been published. These induction antibodies will become more important in the coming years in both steroid-sparing and calcineurin-inhibitor-sparing immunosuppressive regimens. Cyclosporine and Mycophenolate Mofetil
In many pediatric centers, mycophenolate mofetil (MMF), a substance that selectively blocks the proliferation of Tand B-lymphocytes has been added to CsA. MMF inhibits the inosine monophosphate-dehydrogenase. It has been shown that CsA alters MMF metabolism.38 In children with chronic allograft nephropathy, MMF is capable of reversing glomerular filtration loss.39 Therefore, the combination of CsA and MMF has become a standard immunosuppressive regimen in many pediatric renal transplant centers worldwide. Figure 1 shows the improvement in graft survival rates in association with changes in the immunosuppressive regimen.
In recent years, efforts have been made to minimize CsA side effects like nephrotoxicity or the formation of malignomas by dose reductions of CsA in pediatric transplantation. New immunosuppressive agents with antiproliferative effects that belong to the group of TOR (target of rapamycin) inhibitors initiated small studies at first. It was speculated that, for example, rapamycin (sirolimus) might enable this step and therefore decrease the amount of chronic rejection in pediatric renal transplant recipients.56 First data of CsA/everolimus combination therapy represent another potential drug combination that might help to reach that goal without an increase in infections.57 Future long-term results studies have to be awaited before it can be concluded whether a routine combination of CsA with a TOR inhibitor will prolong graft function and reduce side effects in children. CONCLUSION
The introduction of CsA in pediatric transplant recipients prolonged long-term graft survival, reduced the number of early and late rejections, and allowed nearly normal body growth rates. The steps in improving graft function included the switch from classical CSA to CsA microemulsion as well as new drug monitoring strategies and innovative combinations of CsA with other immunosuppressive drugs. In summary, the invention of CsA was the most important step in making renal transplantation the gold standard for renal replacement therapy in children.
Monitoring by 2-Hour Levels
Management of transplanted adults by CsA monitoring (microemulsion) according to drug levels at 2-hour postdose improved clinical outcome when compared to conventional trough-level monitoring in adult liver40 and heart transplantation.41 Several clinical trials performed in kidney transplantation show an effect of C2 monitoring as an additional tool to C0 monitoring,42,43 but no data have been published in renal transplantation comparing C2 to C0 monitoring. Clinical validation studies for C2 monitoring with the goal of establishing target levels were performed,44 – 46 and guidelines for the use of C2 monitoring in adults were implemented.47,48 As already described above, the pharmacokinetics of CsA in children differs from those in adults. It was also shown in
REFERENCES 1. Fine RN, Malekzadeh MH, Pennisi AJ, et al: Long-term results of renal transplantation in children. Pediatrics 61:641, 1978 2. Grushkin CM, Fine RN: Growth in children following renal transplantation. Am J Dis Child 125:514, 1973 3. Gradus D, Ettenger RB: Renal transplantation in children. Pediatr Clin North Am 29:1013, 1982 4. Borel JF, Feurer C, Magnee C, et al: Effects of the new anti-lymphocytic peptide ciclosporine A in animals. Immunology 32:1017, 1977 5. Calne RY, White DJG, Thiru S, et al: Ciclosporine A in patients receiving renal allografts from cadaver donors. Lancet 2:1323, 1978 6. Calne RY, Rolles K, White DJG, et al: Ciclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs; 32 kidneys, 2 pancreases and 2 livers. Lancet 2:1033, 1979
206S 7. The European Ciclosporin Study Group: Ciclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 2:986, 1983 8. The European Ciclosporin Study Group: Ciclosporin as a sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Preliminary results of a European multicentre trial. Lancet 2:57, 1982 9. Starzl TE, Iwatsuki S, Malatack JJ, et al: Liver and kidney transplantation in children receiving ciclosporine A and steroids. J Pediatr 100:681, 1982 10. Conley SB, Brewer ED, Flechner SM, et al: Renal transplantation using ciclosporine in pediatric patients 3 to 17 years old. Transplant Proc 15:2528, 1983 11. Klare B, von Walter J, Hahn H, et al: Ciclosporine in renal transplantation in children. Lancet 2:692, 1984 12. Conley SB, Flechner SM, Rose G, et al: Use of ciclosporine in pediatric renal transplant recipients. J Pediatr 106:45, 1985 13. Hoyer PF, Krohn HP, Offner G, et al: Renal function after kidney transplantation in children: a comparison of conventional immunosuppression with ciclosporine A. Transplantation 43:489, 1987 14. Tejani A, Butt KMH, Khawar MR, et al: Ciclosporine experience in renal transplantation in children. Kidney Int Suppl 19:38, 1986 15. Conley SB, Portman RJ, Lemire JM, et al: Five years’ experience with ciclosporine in children. Transplant Proc 20:280, 1988 16. Offner G, Hoyer PF, Brodehl J, et al: Ciclosporine A in paediatric kidney transplantation. Pediatr Nephrol 1:125, 1987 17. Brodehl J, Offner G, Hoyer PF, et al: Ciclosporin A in pediatric kidney transplantation and its effect on posttransplantation growth. Nephron 44:26, 1986 18. Flechner SM, Conley SB, Van Buren CT, et al: Impact of ciclosporine on renal function and growth in pediatric renal transplant recipients. Transplant Proc 17:1284, 1985 19. Knight JF, Roy LP, Sheil AGR: Catch-up growth in children with successful renal transplants immunosuppressed with ciclosporin alone. Lancet 1:159, 1985 20. Pennisi AJ, Costin G, Phillips LS, et al: Linear growth in long-term renal allograft recipients. Clin Nephrol 8:412, 1977 21. Chapman JR, Giffiths D, Harding NGL, et al: Reversibility of ciclosporin nephrotoxicity after three months’ treatment. Lancet 1:128, 1985 22. Klintmalm G, Bohman SO, Sundelin B, et al: Interstitial fibrosis in renal allografts after 12 to 46 months of ciclosporine treatment: beneficial effects of low doses in early post-transplantation period. Lancet 2:950, 1984 23. Hoyer PF, Offner G, Wonigeit K, et al: Dosage of ciclosporine A in children with renal transplants. Clin Nephrol 22:68, 1984 24. Hoyer PF, Brodehl J, Ehrich JHH, et al: Practical aspects in the use of ciclosporin in pediatric nephrology. Pediatr Nephrol 5:630, 1991 25. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, et al: The effect of food on ciclosporine absorption. Transplantation 40:174, 1985 26. Holt DW, Mueller EA, Kovarik JM, et al: The pharmacokinetics of Sandimmun Neoral: a new oral formulation of ciclosporine. Transplant Proc 26:2935, 1994 27. Kovarik JM, Mueller EA, van Bree JB, et al: Ciclosporine pharmacokinetics and variability from a microemulsion formulation—a multicenter investigation in kidney transplant patients. Transplantation 58:658, 1994 28. Kovarik JM, Mueller EA, van Bree JB, et al: Reduced interand intraindividual variability in ciclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 83:444, 1994 29. Bo ¨kenkamp A, Offner G, Hoyer PF, et al: Improved absorption of ciclosporin A from a new microemulsion formulation:
PAPE, EHRICH, AND OFFNER implications for dosage and monitoring. Pediatr Nephrol 9:196, 1995 30. Bo ¨kenkamp A, Offner G, Hoyer PF, et al: Excessive ciclosporine trough level variation with classic ciclosporine can be reduced with the new oral microemulsion formulation of ciclosporine. Transplant Proc 28:2273, 1996 31. Portman RJ, Meier-Kriesche HU, Swinford R, et al: Reduced variability of Neoral pharmacokinetic studies in pediatric renal transplantation. Pediatr Nephrol 15:2, 2000 32. Soulillou JP: Relevant targets for therapy with monoclonal antibodies in allograft transplantation. Kidney Int 46:857, 1994 33. Tejani A, Harmon W, Benfield M, et al: A randomized, prospective multicentre trial of T-cell antibody induction therapy in pediatric renal transplantation. Transplantation 69:S111, 2000 34. Ault BH, Honaker MR, Osama Gaber A, et al: Short-term outcomes of thymoglobulin induction in pediatric renal transplant recipients. Pediatr Nephrol 17:815, 2002 35. Nashan B, Moore R, Amlot P, et al: Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 350:1193, 1997 36. Pape L, Strehlau J, Henne T, et al: Single-centre experience with basiliximab in paediatric renal transplantation. Nephrol Dial Transplant 17:276, 2002 37. Strehlau J, Pape L, Offner G, et al: Interleukin-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients. Lancet 356:1327, 2000 38. Pape L, Froede K, Stehlau J, et al: Alterations of ciclosporin A metabolism induced by mycophenolate mofetil. Pediatr Transplant 7:302, 2003 39. Henne T, Latta K, Stehlau J, et al: Mycophenolate mofetil induced reversal of glomerular filtration loss in children with chronic allograft nephropathy. Transplantation 76:1236, 2003 40. Levy G, Burra P, Cavallari A, et al: Improved clinical outcome for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2). Transplantation 73:953, 2002 41. Cantarovich M, Elstein E, der Varennes B, et al: Clinical benefit of Neoral dose monitoring with ciclosporine 2h post-dose levels compared with trough levels in stable heart transplant patients. Transplantation 68:1839, 1999 42. Keshavamurthy M, Al Ahmadi I, Mohammed RS: Singlecenter study utilizing C2 level as monitoring tool in de novo renal transplant recipients treated with Neoral. Transplant Proc 33:3098, 2001 43. Maham N, Cardella C, Cole E: Optimization of ciclosporine exposure utilizing C2-level monitoring in de novo renal transplant recipients. Transplant Proc 33:2098, 2001 44. Canadian Neoral Renal Transplantation Study Group: Absorption profile of ciclosporine microemulsion (Neoral) during the first two weeks after renal transplantation. Transplantation 72: 1024, 2001 45. Nashan B, Cole E, Levy G, et al: Clinical validation studies of Neoral C2 monitoring: a review. Transplantation 73:S3, 2002 46. Mahalati K, Belitsky P, West K, et al: Approaching the therapeutic window for ciclosporine in kidney transplantation: a prospective study. J Am Soc Nephrol 12:823, 2001 47. Cole E, Midtvedt K, Johnston A, et al: Recommendations for the implementation of Neoral C2 monitoring in clinical practice. Transplantation 73:S19, 2002 48. Levy G, Thervet E, Lake J, et al: Patient management by Neoral C2 monitoring: an international consensus statement. Transplantation 73:S12, 2002 49. Dello Strolongo L, Campagnano P, Federici G, et al: Ciclosporine A monitoring in children: abbreviated area under curve formulas and C2 level. Pediatr Nephrol 13:95, 1999 50. Mahalati K, Belitsky P, Sketris I, et al: Neoral monitoring by simplified sparse sampling area under the concentration-timecurve: its relationship to acute rejection and ciclosporine nephro-
CyA IN PEDIATRIC KIDNEY TRANSPLANT toxicity early after kidney transplantation. Transplantation 68:55, 1999 51. Filler G, Mai I, Filler S, et al: Abbreviated ciclosporine AUCs on Neoral—the search continues. Pediatr Nephrol 13:98, 1999 52. Meier-Kriesche HU, Bonilla-Felix MA, Ferris ME, et al: A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients. Pediatr Nephrol 13:742, 1999 53. Pape L, Lehnhardt A, Latta K, et al: Ciclosporin A monitoring by 2h-levels: preliminary target levels in stable pediatric kidney transplant recipients. Clin Transplant 17:1, 2003 54. Hoyer P: Therapeutic drug monitoring of ciclosporine A:
207S should we use the area under the concentration time-curve and forget trough levels? Pediatr Transplant 4:2, 2000 55. Oellerich M, Armstrong VW: Two-hour ciclosporine concentration determination: an appropriate tool to monitor Neoral therapy? Ther Drug Monit 24:40, 2002 56. Kahan BD: The potential role of rapamycin in pediatric transplantation as observed from adult studies. Pediatr Transplant 3:175, 1999 57. Vester U, Kranz B, Wehr S, et al: Everolimus (Certican) in combination with Neoral in pediatric renal transplant recipients: interim analysis after 3 months. Transplant Proc 34:2209, 2002
I
N THE LATE 1960s, the first programs for renal transplantation in children were initiated. A first report of long-term results of children transplanted in Los Angeles who received prednisolone and azathioprine as immunosuppression was published in 1978.1 The 5-year survival rate of grafts from living related donors (LRD) was 73%, and that of cadaveric donors (CAD) 39%. The main reasons for graft failure were hyperacute rejections, acute rejections, and chronic rejections. Most of these children experienced severe growth retardation.1 The main causes were longterm, high-dose steroid therapy, and fused distal femoral and proximal tibial epiphyses at the time of transplantation.2,3
INTRODUCTION OF CSA IN CHILDREN
As a result of these problems, new immunosuppressive strategies had to be developed. A new substance, the fungus metabolite of CsA, was used in children for the first time in 1979. A study of 34 patients (few children) with CsA immunosuppression after solid-organ transplantation was published. The study revealed fewer numbers of infections, reduced CsA toxicity, and better graft function than in © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 203S⫺207S (2004)
smaller studies in adults that had been performed before.4 – 6 The first multicenter trial comparing azathioprine with CsA, which included a small number of children, showed a significantly higher 1-year survival rate when CsA was used. The number of infections was similar in both groups.7,8 In those early years, knowledge about CsA pharmacodynamics and pharmacokinetics improved greatly. Better strategies concerning co-administration of other immunosuppressive drugs were invented, which led to a reduction of the number of graft losses. In those first studies, only small numbers of children were included; thus, until 1982 almost no data existed on how to administer CsA in pediatric transplant recipients. The first good pediatric experiences with CsA were published between 1983 and 1984.9 –11 A larger study from 1985 showed good results without any graft losses due to CsA toxicity and From the Department of Pediatric Nephrology, Medical School of Hannover, Hannover, Germany. Address reprint requests to Dr Lars Pape, Department of Pediatric Nephrology, Medical School of Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2003.12.053 203S
204S
an incidence of acute rejection of 39% 16 months after transplantation.12 In addition to the positive effects of CsA, negative effects were also observed: a study comparing 32 children with CsA immunosuppression to conventional therapy showed a significantly lower renal function in the CsA group based on early loss of the glomerular filtration rate with a comparable decline of transplant function in both groups later.13 These results were confirmed in larger studies in the following years.14 –16 A main advantage of CsA in pediatric transplantation that was observed at a very early stage was the improvement in growth. Combined with low-dose prednisolone, CsA treatment yielded excellent results and allowed normal growth rates after pediatric kidney transplantation.17,18 Even catch-up growth in these children was observed.19 Thus, the growth rates achieved with CsA immunosuppression were much better than growth rates under immunosuppression with azathioprine in the decade previous.20 The main side effects of CsA therapy in youngsters were nephrotoxicity and hirsutism.18 In 1985 it was shown that the described effects of higher creatinine levels under CsA therapy compared to azathioprine were largely reversible after dose reduction.21 However, it also became evident that over the long run, CsA therapy may lead to interstitial fibrosis and therefore deterioration of graft function.22 Thus, it is important to find the right CsA dose that achieves enough immunosuppression in combination with the minimal number of side effects. By consequence, therapeutic drug monitoring of CsA was introduced as a standard method in order to reach this goal. One important problem was the dosage of CsA in pediatric transplant recipients. Children have a higher body surface area in relation to body weight than do adults. When CsA dosage was calculated based on body weight as in adults, the CsA serum levels were too low. A new pediatric dosing regimen based on body surface area helped to find the right amount of CsA needed for the individual patient.23 It was shown that the CsA maintenance dosage based on body weight was higher than that recommended for adults. As in adults, interactions of CsA with other medications (ie, erythromycin, phenobarbital, phenytoin, doxycycline, or others) based on the metabolic pathway, including cytochrome P450, have to be taken into account. These are often responsible for unexpected CsA toxicity or for rejections due to decreasing CsA levels. CYCLOSPORINE MICROEMULSION
Many factors had to be considered to guarantee an effective and safe use of CsA in children. One important aspect was the difference of absorption in the lumen of the upper intestinal tract. For optimal and consistent absorption, CsA as a hydrophobic agent had always to be mixed with the same drink—for instance, apple juice or chocolate milk.23 Another invention was the development of CSA capsules that allowed more exact dosing. However, these capsules
PAPE, EHRICH, AND OFFNER
could not be given to small children. A co-administration of food with CsA resulted in a significant increase in peak and trough blood levels depending on the kind of food eaten.24 It was therefore concluded in pediatric transplantation that CsA should be taken without food and that there should be a fixed interval between CsA administration and the next meal. A new formulation of CSA, the microemulsion, was available from 1993 onwards. The pharmacokinetics of this formulation in adults was much more predictable, and the absorption rate was more consistent. In addition, the effect of food on absorption was much lower than with the standard formulation.25 In patients who were switched from the old formulation to the new microemulsion, absorption rates were significantly higher after the switch;26 this was associated with a decrease in the creatinine clearance as a result of higher blood levels, but not with any other adverse effects.27 The pharmacokinetic values of CsA were less variable and therefore more predictable, with a more consistent concentration-time profile when using the microemulsion.28 These results were confirmed in pediatric transplant recipients. With the use of CsA microemulsion, the drug availability increased up to 300%; concomitantly, signs of CsA toxicity increased.29 Hence, the dose as well as the target trough levels had to be decreased in order to avoid overdosing. Starting in 1995, it was also discussed whether CsA blood levels drawn earlier than 12 hours after administration are needed for dose adjustment.29 Variations in intraindividual CsA trough levels, as well as the variability of full areaunder-the-curve concentrations and CsA levels drawn 2 hours’ postdose, were lower in children when the new formulation was used.30,31 These pharmacokinetic advantages of the CsA microemulsion led to a lower number of acute rejections in children after solid-organ transplantation; thus, CsA microemulsion became the standard immunosuppressive agent in many pediatric transplantation centers. Cyclosporine With Induction Therapy
As a next step in reducing rejection rates, CsA immunosuppression in children was combined with antibody induction therapies. Initially, OKT3, a drug with substantial side effects, was believed to reach this goal successfully32 but failed to reduce acute and chronic rejection in a large, double-blind, randomized pediatric trial.33 The role of thymoglobulin as a polyclonal induction antibody remains unclear; a small study from 2002 showed a low number of acute rejections.34 In recent years, monoclonal antibodies (MAbs) have mainly been used as an induction therapy in addition to CsA. Most data have been published about basiliximab, a monoclonal chimerical human-murine IL-2 (CD25) antibody that has shown a significant decrease in the number of acute rejections in both adults35 and in pediatric patients.36 An interaction between basiliximab and CsA blood levels has been described.37 Data about the use of daclizumab, a humanized CD-25 antibody, in pedi-
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205S
children that C2 levels correlated better with the areaunder-the-curve (AUC) concentration of CsA than with trough levels.49 –51 Equations for AUC estimation in children based on C2 monitoring were established,52 and preliminary target levels for C2 levels in pediatric transplant recipients were defined.53 It still remains unclear whether C2-based adoption of the CsA dose leads to a better graft survival in children.54,55 Studies that might answer this question will be performed in the coming years. Cyclosporine-Sparing Immunosuppressive Regimens With Target of Rapamycin Inhibitors
Fig 1. Graft survival rates under immunosuppression with azathioprine (Aza), cyclosporine (CsA), partly in combination with basiliximab (Bas) or mycophenolate mofetil (MMF) in pediatric renal transplantation in Hannover, Germany.
atric transplantation have not yet been published. These induction antibodies will become more important in the coming years in both steroid-sparing and calcineurin-inhibitor-sparing immunosuppressive regimens. Cyclosporine and Mycophenolate Mofetil
In many pediatric centers, mycophenolate mofetil (MMF), a substance that selectively blocks the proliferation of Tand B-lymphocytes has been added to CsA. MMF inhibits the inosine monophosphate-dehydrogenase. It has been shown that CsA alters MMF metabolism.38 In children with chronic allograft nephropathy, MMF is capable of reversing glomerular filtration loss.39 Therefore, the combination of CsA and MMF has become a standard immunosuppressive regimen in many pediatric renal transplant centers worldwide. Figure 1 shows the improvement in graft survival rates in association with changes in the immunosuppressive regimen.
In recent years, efforts have been made to minimize CsA side effects like nephrotoxicity or the formation of malignomas by dose reductions of CsA in pediatric transplantation. New immunosuppressive agents with antiproliferative effects that belong to the group of TOR (target of rapamycin) inhibitors initiated small studies at first. It was speculated that, for example, rapamycin (sirolimus) might enable this step and therefore decrease the amount of chronic rejection in pediatric renal transplant recipients.56 First data of CsA/everolimus combination therapy represent another potential drug combination that might help to reach that goal without an increase in infections.57 Future long-term results studies have to be awaited before it can be concluded whether a routine combination of CsA with a TOR inhibitor will prolong graft function and reduce side effects in children. CONCLUSION
The introduction of CsA in pediatric transplant recipients prolonged long-term graft survival, reduced the number of early and late rejections, and allowed nearly normal body growth rates. The steps in improving graft function included the switch from classical CSA to CsA microemulsion as well as new drug monitoring strategies and innovative combinations of CsA with other immunosuppressive drugs. In summary, the invention of CsA was the most important step in making renal transplantation the gold standard for renal replacement therapy in children.
Monitoring by 2-Hour Levels
Management of transplanted adults by CsA monitoring (microemulsion) according to drug levels at 2-hour postdose improved clinical outcome when compared to conventional trough-level monitoring in adult liver40 and heart transplantation.41 Several clinical trials performed in kidney transplantation show an effect of C2 monitoring as an additional tool to C0 monitoring,42,43 but no data have been published in renal transplantation comparing C2 to C0 monitoring. Clinical validation studies for C2 monitoring with the goal of establishing target levels were performed,44 – 46 and guidelines for the use of C2 monitoring in adults were implemented.47,48 As already described above, the pharmacokinetics of CsA in children differs from those in adults. It was also shown in
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