Renal transplantation: The present and the future
http://www.100md.com
《美国医学杂志》
Division of Pediatric Nephrology, University of Florida College of Medicine, Gainesville FL, USA
Abstract
Children receiving kidney transplants in the modern era in developed countries have excellent overall results. Graft survival and patient survival in children is now virtually equal to that in adult organ recipients. Deceased donor source kidneys are no longer associated with significantly inferior outcomes. These advances are in large part due to development in more potent immunosuppressive agents and newer combinations. These advances have also come at a price in the form of increased post-transplant infections. The transplant community is now moving to minimization protocols to reduce the adverse effects of many of the medications and to reduce the incidence of infections. Newer techniques of diagnosis of acute rejection, degree of immunosuppression and DNA-based viral surveillance are changing the face of clinical practice. Newer technologies such as stem cell transplantation, tissue engineering and xenotransplantation promise even more changes in the future.
Keywords: Transplantation; Kidney; Pediatrics; Immunosuppression; Cyclosporine; Tacrolimus; Sirolimus; Mycophenolate
The first successful kidney transplant was performed by Nobel Laureate Dr. Joseph Murray in 1954.[1] As kidney transplantation became a reality for many adults with renal failure through the 1960s and 1970s, results of kidney transplantation in children lagged behind.[2] This lag was attributed to several reasons such as technical problems with smaller vessels, potentially greater immunoreactivity in children and the lack of knowledge of drug pharmacokinetics in children versus adults.[3] Since pediatric kidney transplants make up less than 10% of total kidney transplants, it was very difficult to analyze these hypotheses at any one center and institute appropriate changes. The development of multi-center collaborative registries such as the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) with large amounts of data facilitated the elucidation of risk factors for worse graft and patient survival in children.[4], [5] This elucidation was followed by appropriate changes in clinical practice and, along with more potent medications, led to marked improvements in patient and graft survival in children.[6], [7]
History of Immunosuppression in Renal Transplantation
The first successful kidney transplant involved a donor and recipient who were identical twins and thus no maintenance immunosuppression was prescribed for the recipient. Prevention of rejection in other recipients who received allogeneic grafts was attempted with two-drug immunosuppression through the 1950s to 1970s, largely a combination of glucocorticoids and azathioprine. These drugs were modestly successful and achieved 1-year and 5-year graft survival rates on 50%-60% after living donation and 30%-50% after deceased donation. Acute rejection rates were greater than 50% in the first year post- transplant. Transplant investigators at the University of Minnesota were experimenting with an anti-lymphocytic globulin during this time.[8] This period may be referred to as the "early era" in renal transplantation.
The first dramatic change in results came with the development of cyclosporine A in the early 1980s.[9] Use of this drug as an additional maintenance immunosuppressive agent in combination with azathioprine and glucocorticoids led to marked drops in acute rejection rates and improvements in 1-year and 5-year graft survival, though not in 10-year results.[10] This advance led to a surge in interest in developing newer transplant immunosuppressive medications among pharmaceutical companies. Through the 1990s, many newer and more potent maintenance immunosuppressive agents were developed and marketed, such as tacrolimus, mycophenolate mofetil and sirolimus. In addition, newer anti-T cell agents were also introduced for initial induction immunosuppression (to prevent early acute rejections) and as rescue therapy for steroid resistant rejections. These agents included OKT3, anti-thymocytic globulins derived from horse or rabbit serum, and the anti-IL2R antibodies daclizumab and basiliximab. The author refers to this period as the "era of rapid progress".
However, these improved results came at a price. Post transplant infections emerged as a significant problem.[11], [12] In particular, viral infections such as CMV, EBV and BKV appeared in successive order with the introduction of newer immunosuppressive agents.[13], [14] Long-term toxicities of the immunosuppressive agents became a more prominent issue with longer graft and patient survival. However, in the last few years, even graft survival improvements have reached a plateau and no more improvements have been evident.[15] The transplant community has therefore now focused on minimization strategies such as steroid withdrawal/avoidance or calcineurin substitution/avoidance.[16] The author refers to this ongoing period as "the era of reflection".
Immunosuppressive Agents, Classification and Combinations
The principle of multiple agents for post-transplant immunosuppression was derived from the oncology literature that showed greater benefit and reduced side- effects from using multiple medications that blocked different steps in the alloantigen-directed immune activation process. Figure1 lists the different immunosuppressive agents available or under development, stratified by class and mechanism. Figure2 depicts the different steps of alloantigen-directed immune activation that these agents block. It is worth noting that very few of these agents were actually tested in children prior to regulatory approval. Thus, pediatric transplant physicians have usually had to extrapolate from adult pharmacokinetic data for initial use. In some cases, such as with sirolimus and cyclosporine A (Neoral formulation), drug pharmacokinetics in children have been found to be very different than in adults.[17], [18] In other cases, the pediatric community has found some paradoxical results, for example, mycophenolate mofetil toxicities are more pronounced when steroids are not administered concomitantly.[19], [20] table1 lists some of the more common adverse effects of immunosuppressive medications.
With the availability of so many drugs, the number of possible combinations is very large. It is theoretically possible to construct more than 100 possible combinations, though some combinations are scientifically unsound, such as the calcineurin inhibitors cyclosporine and tacrolimus together or the DNA synthesis inhibitors MMF and azathioprine together. In general, renal transplantation through the late 1980s and early 1990s was characterized by the use of three maintenance drug combinations, such as 1) a calcineurin inhibitor plus 2) a DNA synthesis inhibitor and 3) glucocorticoids. In higher risk cases, some centers also included induction antibody treatment (referred to as quadruple immunosuppression). In more recent times, there have been attempts to reduce maintenance immunosuppression to 2 drugs or less. Monotherapy is still rare in pediatric kidney transplantation but is much more common in pediatric liver transplantation.
Current Directions in Pediatric Renal Transplantation
A majority of centers in the USA and Europe currently use three drug maintenance immunosuppression, comprising a calcineurin inhibitor, glucorticoids and either an antimetabolite or sirolimus.[21], [22] Use of anti-T cell agents is also frequent but the type of agent is highly variable, with rabbit-ATG or an IL-2R antibody being the most frequent. The use of azathioprine and OKT3 has declined dramatically in recent years. Sirolimus use in the early period post transplant has been associated with surgical complications such as lymphoceles or poor wound healing.[23], [24] but it is still an attractive agent for later use due to lack of nephrotoxicity.[25] Since childhood growth and adherence to medications are a priority for pediatric practitioners, steroid avoidance has been tried with great initial single center success.[19], [20] A multi-centered trial is currently underway in the USA to confirm these early results.
Newer Agents Recently Approved or in the Pipeline
The transplant community must constantly keep up to date with the fast pace of newer immunosuppressive agents being developed by the pharmaceutical community. Campath-1H (alemtuzumab; anti-CD52) is a newer anti-T cell agent developed at Cambridge University, which shows prolonged and potent lymphocyte depletion and has promising early results after renal transplantation.[26] FTY720 is a unique agent that traffics lymphocytes to the periphery.[27] Leflunomide is an interesting immunosuppressant that also has anti-viral activity, particularly against BK virus.[28] Myfortic is a newer enteric coated formulation of mycophenolate mofetil that was intended to have less gastrointestinal side effects but appears to have a similar adverse effect profile while maintaining equivalent efficacy.[29]
The Future of Solid Organ Transplantation
Many newer technologies are likely to change the face of solid organ transplantation in the not too distant future. Many experiments are proceeding with xenotransplantation, i.e., tissues from different species other than humans, particularly with tissues derived from swine.[30] Overcoming the hyperactive rejection due to the alpha-Gal epitope, prevention of human transmission of animal infections and ethical concerns are major obstacles at this time. Tissue engineering strategies to reduce the antigenicity of allografts are also being investigated.[31], [32] Stem cells show great promise in the regeneration of organs, particularly if the issue of teratoma development can be overcome.[33] Therapeutic cloning could become a reality very soon, but ethical concerns are a major issue. Some of these strategies are not mutually exclusive and may be combined.[34] It is possible that, in 50 years time, transplantation of allogeneic human solid organs will cease completely as these newer technologies become a reality.
Acknowledgements
The author presented parts of this review at the annual meeting of the Indian Pediatric Nephrology Group in New Delhi, India on November 26, 2004.
References
1. Murray JE. The first successful organ transplants in man. J Am Coll Surg 2005; 200(1): 5-9.
2. Fine RN, Malekzadeh MH, Pennisi AJ, Ettenger RB, Uittenbogaart CH, Negrete VF et al. Long-term results of renal transplantation in children. Pediatrics 1978; 61(4): 641-650.
3. Ettenger RB. Children are different: the challenges of pediatric renal transplantation. Am J Kidney Dis 1992; 20(6): 668-672.
4. Alexander SR, Arbus GS, Butt KM, Conley S, Fine RN, Greifer I et al. The 1989 report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1990; 4(5): 542-553.
5. McEnery PT, Stablein DM, Arbus G, Tejani A. Renal transplantation in children. A report of the North American Pediatric Renal Transplant Cooperative Study. N Engl J Med 1992; 326(26): 1727-1732.
6. Tejani A, Stablein DM, Donaldson L, Harmon WE, Alexander SR, Kohaut E et al. Steady improvement in short-term graft survival of pediatric renal transplants: the NAPRTCS experience. Clin Transpl 1999:95-110.
7. McDonald R, Ho PL, Stablein DM, Tejani A. Rejection profile of recent pediatric renal transplant recipients compared with historical controls: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2001; 1(1): 55-60.
8. Najarian JS, Simmons RL. The clinical use of antilymphocyte globulin. N Engl J Med 1971; 285(3): 158-166.
9. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; 2(8104-5): 1323-1327.
10. Calne R. Cyclosporine as a milestone in immunosuppression. Transplant Proc 2004; 36(2 Suppl): 13S-15S.
11. Dharnidharka VR, Harmon WE. Management of pediatric postrenal transplantation infections. Semin Nephrol 2001; 21(5): 521-531.
12. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant 2004; 4(3): 384-389.
13. Vats A. BK virus-associated transplant nephropathy: need for increased awareness in children. Pediatr Transplant 2004; 8(5): 421-425.
14. Dharnidharka VR, Tejani AH, Ho PL, Harmon WE. Post-transplant lymphoproliferative disorder in the United States: young Caucasian males are at highest risk. Am J Transplant 2002; 2(10): 993-998.
15. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4(3): 378-383.
16. Gourishankar S, Turner P, Halloran P. New developments in immunosuppressive therapy in renal transplantation. Expert Opin Biol Ther 2002; 2(5): 483-501.
17. Schachter AD, Meyers KE, Spaneas LD, Palmer JA, Salmanullah M, Baluarte J et al. Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 2004; 8(2): 171-177.
18. Bunchman TE, Parekh RS, Flynn JT, Smoyer WE, Kershaw DB, Valentini RP et al. Neoral induction in pediatric renal transplantation. Pediatr Nephrol 1998; 12(1): 2-5.
19. Sarwal MM, Yorgin PD, Alexander S, Millan MT, Belson A, Belanger N et al. Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation. Transplantation 2001; 72(1): 13-21.
20. Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O, Jr. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 2003; 76(9): 1331-1339.
21. Smith JM, Nemeth TL, McDonald RA. Current immunosuppressive agents in pediatric renal transplantation: efficacy, side-effects and utilization. Pediatr Transplant 2004; 8(5): 445-453.
22. Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: evolution in practice and trends, 1993-2003. Am J Transplant 2005; 5(4 Pt 2): 874-886.
23. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002; 74(6): 804-808.
24. Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 2002; 36(9): 1391-1395.
25. Morales JM, Wramner L, Kreis H, Durand D, Campistol JM, Andres A et al. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant 2002; 2(5): 436-442.
26. Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR et al. Alemtuzumab (CAMPATH 1H) Induction Therapy in Cadaveric Kidney Transplantation-Efficacy and Safety at Five Years. Am J Transplant 2005; 5(6): 1347-1353.
27. Kunzendorf U, Ziegler E, Kabelitz D. FTY720-the first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant 2004; 19(7): 1677-1681.
28. Fischereder M, Kretzler M. New immunosuppressive strategies in renal transplant recipients. J Nephrol 2004; 17(1): 9-18.
29. Budde K, Glander P, Diekmann F, Waiser J, Fritsche L, Dragun D et al. Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother 2004; 5(6): 1333-1345.
30. Calne R. Xenografting-the future of transplantation, and always will be Xenotransplantation 2005; 12(1):5-6.
31. Briscoe DM, Dharnidharka VR, Isaacs C, Downing G, Prosky S, Shaw P et al. The allogeneic response to cultured human skin equivalent in the hu-PBL- SCID mouse model of skin rejection. Transplantation 1999; 67(12): 1590-1599.
32. Hammerman MR, Cortesini R. Organogenesis and tissue engineering. Transpl Immunol 2004; 12(3-4): 191-192.
33. Peck AB, Ramiya V. In vitro-generation of surrogate islets from adult stem cells. Transpl Immunol 2004; 12(3-4): 259-272.
34. Ogle B, Cascalho M, Platt JL. Fusion of approaches to the treatment of organ failure. Am J Transplant 2004; 4 Suppl 6:74-77.(Dharnidharka Vikas R)
Abstract
Children receiving kidney transplants in the modern era in developed countries have excellent overall results. Graft survival and patient survival in children is now virtually equal to that in adult organ recipients. Deceased donor source kidneys are no longer associated with significantly inferior outcomes. These advances are in large part due to development in more potent immunosuppressive agents and newer combinations. These advances have also come at a price in the form of increased post-transplant infections. The transplant community is now moving to minimization protocols to reduce the adverse effects of many of the medications and to reduce the incidence of infections. Newer techniques of diagnosis of acute rejection, degree of immunosuppression and DNA-based viral surveillance are changing the face of clinical practice. Newer technologies such as stem cell transplantation, tissue engineering and xenotransplantation promise even more changes in the future.
Keywords: Transplantation; Kidney; Pediatrics; Immunosuppression; Cyclosporine; Tacrolimus; Sirolimus; Mycophenolate
The first successful kidney transplant was performed by Nobel Laureate Dr. Joseph Murray in 1954.[1] As kidney transplantation became a reality for many adults with renal failure through the 1960s and 1970s, results of kidney transplantation in children lagged behind.[2] This lag was attributed to several reasons such as technical problems with smaller vessels, potentially greater immunoreactivity in children and the lack of knowledge of drug pharmacokinetics in children versus adults.[3] Since pediatric kidney transplants make up less than 10% of total kidney transplants, it was very difficult to analyze these hypotheses at any one center and institute appropriate changes. The development of multi-center collaborative registries such as the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) with large amounts of data facilitated the elucidation of risk factors for worse graft and patient survival in children.[4], [5] This elucidation was followed by appropriate changes in clinical practice and, along with more potent medications, led to marked improvements in patient and graft survival in children.[6], [7]
History of Immunosuppression in Renal Transplantation
The first successful kidney transplant involved a donor and recipient who were identical twins and thus no maintenance immunosuppression was prescribed for the recipient. Prevention of rejection in other recipients who received allogeneic grafts was attempted with two-drug immunosuppression through the 1950s to 1970s, largely a combination of glucocorticoids and azathioprine. These drugs were modestly successful and achieved 1-year and 5-year graft survival rates on 50%-60% after living donation and 30%-50% after deceased donation. Acute rejection rates were greater than 50% in the first year post- transplant. Transplant investigators at the University of Minnesota were experimenting with an anti-lymphocytic globulin during this time.[8] This period may be referred to as the "early era" in renal transplantation.
The first dramatic change in results came with the development of cyclosporine A in the early 1980s.[9] Use of this drug as an additional maintenance immunosuppressive agent in combination with azathioprine and glucocorticoids led to marked drops in acute rejection rates and improvements in 1-year and 5-year graft survival, though not in 10-year results.[10] This advance led to a surge in interest in developing newer transplant immunosuppressive medications among pharmaceutical companies. Through the 1990s, many newer and more potent maintenance immunosuppressive agents were developed and marketed, such as tacrolimus, mycophenolate mofetil and sirolimus. In addition, newer anti-T cell agents were also introduced for initial induction immunosuppression (to prevent early acute rejections) and as rescue therapy for steroid resistant rejections. These agents included OKT3, anti-thymocytic globulins derived from horse or rabbit serum, and the anti-IL2R antibodies daclizumab and basiliximab. The author refers to this period as the "era of rapid progress".
However, these improved results came at a price. Post transplant infections emerged as a significant problem.[11], [12] In particular, viral infections such as CMV, EBV and BKV appeared in successive order with the introduction of newer immunosuppressive agents.[13], [14] Long-term toxicities of the immunosuppressive agents became a more prominent issue with longer graft and patient survival. However, in the last few years, even graft survival improvements have reached a plateau and no more improvements have been evident.[15] The transplant community has therefore now focused on minimization strategies such as steroid withdrawal/avoidance or calcineurin substitution/avoidance.[16] The author refers to this ongoing period as "the era of reflection".
Immunosuppressive Agents, Classification and Combinations
The principle of multiple agents for post-transplant immunosuppression was derived from the oncology literature that showed greater benefit and reduced side- effects from using multiple medications that blocked different steps in the alloantigen-directed immune activation process. Figure1 lists the different immunosuppressive agents available or under development, stratified by class and mechanism. Figure2 depicts the different steps of alloantigen-directed immune activation that these agents block. It is worth noting that very few of these agents were actually tested in children prior to regulatory approval. Thus, pediatric transplant physicians have usually had to extrapolate from adult pharmacokinetic data for initial use. In some cases, such as with sirolimus and cyclosporine A (Neoral formulation), drug pharmacokinetics in children have been found to be very different than in adults.[17], [18] In other cases, the pediatric community has found some paradoxical results, for example, mycophenolate mofetil toxicities are more pronounced when steroids are not administered concomitantly.[19], [20] table1 lists some of the more common adverse effects of immunosuppressive medications.
With the availability of so many drugs, the number of possible combinations is very large. It is theoretically possible to construct more than 100 possible combinations, though some combinations are scientifically unsound, such as the calcineurin inhibitors cyclosporine and tacrolimus together or the DNA synthesis inhibitors MMF and azathioprine together. In general, renal transplantation through the late 1980s and early 1990s was characterized by the use of three maintenance drug combinations, such as 1) a calcineurin inhibitor plus 2) a DNA synthesis inhibitor and 3) glucocorticoids. In higher risk cases, some centers also included induction antibody treatment (referred to as quadruple immunosuppression). In more recent times, there have been attempts to reduce maintenance immunosuppression to 2 drugs or less. Monotherapy is still rare in pediatric kidney transplantation but is much more common in pediatric liver transplantation.
Current Directions in Pediatric Renal Transplantation
A majority of centers in the USA and Europe currently use three drug maintenance immunosuppression, comprising a calcineurin inhibitor, glucorticoids and either an antimetabolite or sirolimus.[21], [22] Use of anti-T cell agents is also frequent but the type of agent is highly variable, with rabbit-ATG or an IL-2R antibody being the most frequent. The use of azathioprine and OKT3 has declined dramatically in recent years. Sirolimus use in the early period post transplant has been associated with surgical complications such as lymphoceles or poor wound healing.[23], [24] but it is still an attractive agent for later use due to lack of nephrotoxicity.[25] Since childhood growth and adherence to medications are a priority for pediatric practitioners, steroid avoidance has been tried with great initial single center success.[19], [20] A multi-centered trial is currently underway in the USA to confirm these early results.
Newer Agents Recently Approved or in the Pipeline
The transplant community must constantly keep up to date with the fast pace of newer immunosuppressive agents being developed by the pharmaceutical community. Campath-1H (alemtuzumab; anti-CD52) is a newer anti-T cell agent developed at Cambridge University, which shows prolonged and potent lymphocyte depletion and has promising early results after renal transplantation.[26] FTY720 is a unique agent that traffics lymphocytes to the periphery.[27] Leflunomide is an interesting immunosuppressant that also has anti-viral activity, particularly against BK virus.[28] Myfortic is a newer enteric coated formulation of mycophenolate mofetil that was intended to have less gastrointestinal side effects but appears to have a similar adverse effect profile while maintaining equivalent efficacy.[29]
The Future of Solid Organ Transplantation
Many newer technologies are likely to change the face of solid organ transplantation in the not too distant future. Many experiments are proceeding with xenotransplantation, i.e., tissues from different species other than humans, particularly with tissues derived from swine.[30] Overcoming the hyperactive rejection due to the alpha-Gal epitope, prevention of human transmission of animal infections and ethical concerns are major obstacles at this time. Tissue engineering strategies to reduce the antigenicity of allografts are also being investigated.[31], [32] Stem cells show great promise in the regeneration of organs, particularly if the issue of teratoma development can be overcome.[33] Therapeutic cloning could become a reality very soon, but ethical concerns are a major issue. Some of these strategies are not mutually exclusive and may be combined.[34] It is possible that, in 50 years time, transplantation of allogeneic human solid organs will cease completely as these newer technologies become a reality.
Acknowledgements
The author presented parts of this review at the annual meeting of the Indian Pediatric Nephrology Group in New Delhi, India on November 26, 2004.
References
1. Murray JE. The first successful organ transplants in man. J Am Coll Surg 2005; 200(1): 5-9.
2. Fine RN, Malekzadeh MH, Pennisi AJ, Ettenger RB, Uittenbogaart CH, Negrete VF et al. Long-term results of renal transplantation in children. Pediatrics 1978; 61(4): 641-650.
3. Ettenger RB. Children are different: the challenges of pediatric renal transplantation. Am J Kidney Dis 1992; 20(6): 668-672.
4. Alexander SR, Arbus GS, Butt KM, Conley S, Fine RN, Greifer I et al. The 1989 report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1990; 4(5): 542-553.
5. McEnery PT, Stablein DM, Arbus G, Tejani A. Renal transplantation in children. A report of the North American Pediatric Renal Transplant Cooperative Study. N Engl J Med 1992; 326(26): 1727-1732.
6. Tejani A, Stablein DM, Donaldson L, Harmon WE, Alexander SR, Kohaut E et al. Steady improvement in short-term graft survival of pediatric renal transplants: the NAPRTCS experience. Clin Transpl 1999:95-110.
7. McDonald R, Ho PL, Stablein DM, Tejani A. Rejection profile of recent pediatric renal transplant recipients compared with historical controls: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2001; 1(1): 55-60.
8. Najarian JS, Simmons RL. The clinical use of antilymphocyte globulin. N Engl J Med 1971; 285(3): 158-166.
9. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978; 2(8104-5): 1323-1327.
10. Calne R. Cyclosporine as a milestone in immunosuppression. Transplant Proc 2004; 36(2 Suppl): 13S-15S.
11. Dharnidharka VR, Harmon WE. Management of pediatric postrenal transplantation infections. Semin Nephrol 2001; 21(5): 521-531.
12. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant 2004; 4(3): 384-389.
13. Vats A. BK virus-associated transplant nephropathy: need for increased awareness in children. Pediatr Transplant 2004; 8(5): 421-425.
14. Dharnidharka VR, Tejani AH, Ho PL, Harmon WE. Post-transplant lymphoproliferative disorder in the United States: young Caucasian males are at highest risk. Am J Transplant 2002; 2(10): 993-998.
15. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4(3): 378-383.
16. Gourishankar S, Turner P, Halloran P. New developments in immunosuppressive therapy in renal transplantation. Expert Opin Biol Ther 2002; 2(5): 483-501.
17. Schachter AD, Meyers KE, Spaneas LD, Palmer JA, Salmanullah M, Baluarte J et al. Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 2004; 8(2): 171-177.
18. Bunchman TE, Parekh RS, Flynn JT, Smoyer WE, Kershaw DB, Valentini RP et al. Neoral induction in pediatric renal transplantation. Pediatr Nephrol 1998; 12(1): 2-5.
19. Sarwal MM, Yorgin PD, Alexander S, Millan MT, Belson A, Belanger N et al. Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation. Transplantation 2001; 72(1): 13-21.
20. Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O, Jr. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 2003; 76(9): 1331-1339.
21. Smith JM, Nemeth TL, McDonald RA. Current immunosuppressive agents in pediatric renal transplantation: efficacy, side-effects and utilization. Pediatr Transplant 2004; 8(5): 445-453.
22. Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: evolution in practice and trends, 1993-2003. Am J Transplant 2005; 5(4 Pt 2): 874-886.
23. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002; 74(6): 804-808.
24. Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 2002; 36(9): 1391-1395.
25. Morales JM, Wramner L, Kreis H, Durand D, Campistol JM, Andres A et al. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant 2002; 2(5): 436-442.
26. Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR et al. Alemtuzumab (CAMPATH 1H) Induction Therapy in Cadaveric Kidney Transplantation-Efficacy and Safety at Five Years. Am J Transplant 2005; 5(6): 1347-1353.
27. Kunzendorf U, Ziegler E, Kabelitz D. FTY720-the first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant 2004; 19(7): 1677-1681.
28. Fischereder M, Kretzler M. New immunosuppressive strategies in renal transplant recipients. J Nephrol 2004; 17(1): 9-18.
29. Budde K, Glander P, Diekmann F, Waiser J, Fritsche L, Dragun D et al. Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother 2004; 5(6): 1333-1345.
30. Calne R. Xenografting-the future of transplantation, and always will be Xenotransplantation 2005; 12(1):5-6.
31. Briscoe DM, Dharnidharka VR, Isaacs C, Downing G, Prosky S, Shaw P et al. The allogeneic response to cultured human skin equivalent in the hu-PBL- SCID mouse model of skin rejection. Transplantation 1999; 67(12): 1590-1599.
32. Hammerman MR, Cortesini R. Organogenesis and tissue engineering. Transpl Immunol 2004; 12(3-4): 191-192.
33. Peck AB, Ramiya V. In vitro-generation of surrogate islets from adult stem cells. Transpl Immunol 2004; 12(3-4): 259-272.
34. Ogle B, Cascalho M, Platt JL. Fusion of approaches to the treatment of organ failure. Am J Transplant 2004; 4 Suppl 6:74-77.(Dharnidharka Vikas R)