Pediatric Renal-Replacement Therapy — Coming of Age
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《新英格兰医药杂志》
Before the middle of the 20th century, the prospect that a child with end-stage renal disease (ESRD) would reach adulthood was essentially nil. Once dialysis and transplantation became available, that death sentence was lifted, as increasing numbers of children with ESRD were offered renal-replacement therapy. Now, most can expect to live for many years. The time course of this improvement in prognosis is reflected in the data from the Australia and New Zealand Dialysis and Transplant Registry presented by McDonald and Craig in this issue of the Journal (pages 2654–2662). These authors examined the long-term survival of children and adolescents who were less than 20 years of age when renal-replacement therapy was provided, and their report chronicles the marked improvement in expected survival during the past four decades. Similar improvement in prognosis has been evident throughout the developed world.
Renal failure during childhood has profound effects. Abnormalities of skeletal development, with associated growth retardation, affect most patients. Abnormal neurocognitive development, pubertal delay, and disordered psychosocial maturation also occur. Renal-replacement therapy in the form of dialysis provides only a small fraction of normal renal clearance. Dialysis alleviates — but does not eliminate — uremic symptoms such as fatigue and anorexia and does not address the nearly universal abnormalities of growth and development.
In contrast, renal transplantation can provide renal function that is 40 to 80 percent of the normal level. A successful transplantation is followed by improved linear growth, particularly in younger children; improved cognitive performance, as reflected by standardized neurocognitive testing and school attendance; enhanced psychosocial development; and an improved quality of life for the child and his or her family. Hospitalization rates are reduced and patient survival is significantly better among children who receive transplants than among those who undergo dialysis. Accordingly, renal transplantation is preferred to dialysis for the management of end-stage renal failure and should be undertaken as soon as possible after advanced renal failure becomes evident. Some would argue that transplantation is the only acceptable form of long-term treatment for patients in this age group.
Outcomes of transplantation have improved steadily since the 1960s, when transplantation was first made available to children. According to the 2003 report of the North American Pediatric Renal Transplant Cooperative Study,1 the three-year rate of patient survival was 96.6 percent among children in the study who received a kidney from a living donor and 94.8 percent among those who received a cadaveric kidney. Among children who underwent transplantation between 1995 and 2001, three-year allograft survival was 90 percent among those who received a kidney from a living donor and 82 percent among those who received a cadaveric kidney.1
The average duration of hospitalization for transplantation is shorter, and postoperative recovery more rapid, than in the past. The rate of acute rejection has been reduced with the use of newer, more effective immunosuppressive medications, and an array of antimicrobial, antihypertensive, and lipid-lowering agents has reduced morbidity. Immunosuppressive protocols that do not include corticosteroids are currently under investigation at a number of transplantation centers, with encouraging preliminary results. Kidneys from living donors, the use of which leads to better outcomes than the use of cadaveric organs, are now available for a greater proportion of patients because of the acceptance of the use of unrelated living donors, laparoscopic nephrectomy techniques for organ procurement, and promising early trials of transplantation across selected cross-match and blood-type boundaries. In the United States, thanks to the success of transplantation, the number of children and adolescents with functioning kidney allografts doubled between 1993 and 2002.2
Challenges remain. Most children who receive a renal transplant require long-term corticosteroid therapy and are subject to all the attendant complications, including the inhibition of linear growth. The avoidance or discontinuation of the use of corticosteroids, if proved safe in clinical trials, will alleviate this problem. Opportunistic infections are an increasing cause of concern as ever-more-effective immunosuppressive medications become available. Cancer is another consequence of immunosuppression, affecting 2.6 percent of children who have received kidney transplants1; children younger than 10 years of age are at greatest risk.3 Most of these cancers are due to post-transplantation lymphoproliferative disease associated with the Epstein–Barr virus.
The longevity of an allograft is particularly important for the pediatric transplant recipient, because renal-replacement therapy is necessarily a lifelong undertaking. Calcineurin inhibitors, taken by more than 90 percent of the children who have received transplants since 1995,1 lead to renal interstitial fibrosis and loss of renal allograft function over time. Declining allograft function also occurs in association with polyomavirus infection, chronic rejection, allograft nephropathy, and recurrence of the primary renal disease. Allograft-survival rates are lower among adolescents who receive a kidney transplant than among younger recipients (see Figure). Inconsistent adherence to medication regimens among adolescents has been implicated as one explanation for this observation.
Figure. Survival of Kidney Allografts from Living Donors among Patients 1 to 17 Years of Age.
Adapted from the 2003 annual report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients.2
Other long-term medical complications of transplantation require attention. Corticosteroids and tacrolimus, both of which are widely used for post-transplantation immunosuppression, are associated with the development of diabetes mellitus. Hyperlipidemia is common after transplantation. Vascular changes, including premature coronary-artery and other vascular calcification, are increasingly recognized in pediatric kidney-transplant recipients once they have entered their third or fourth decade of life.
An understanding of the factors that influence the survival of patients and of renal allografts requires longitudinal outcome studies involving large numbers of patients. The annual incidence of renal failure among persons 0 to 19 years of age in the United States is 15 cases per 1 million population — much lower than the incidence of 625 per 1 million among adults 45 to 64 years of age.3 Only 812 pediatric patients (0 to 17 years of age) underwent renal transplantation in 2003, as compared with 14,317 adults.2 With more than 140 centers in this country providing care for children and adolescents with ESRD, the number of patients per center is small. As children mature into young adults, they often move away from their primary dialysis and transplantation centers, and continuity of care and follow-up information are frequently lost in the process. Thus, long-term results have been difficult to obtain. The work of McDonald and Craig provides valuable information on long-term outcomes in a sizable and stable pediatric population.
Despite impressive improvement during the past four decades, morbidity and mortality among children with ESRD remain high. There is much work to be done as pediatric renal replacement comes of age. Barriers to transplantation in children with ESRD must be overcome, and greater longevity of allografts must be attained at an acceptable biologic cost.
Source Information
From the Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minn.
References
North American Pediatric Renal Transplant Cooperative Study. 2003 Annual report. (Accessed June 3, 2004, at http://spitfire.emmes.com/study/ped/resources/annlrept.pdf.)
U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. 2003 Annual report. (Accessed June 3, 2004, at http://www.optn.org/AR2003/Chapter_V_AR_CD.htm?cp=6.)
U.S. Renal Data System. 2003 Annual data report: atlas of end stage renal disease in the United States. (Accessed June 3, 2004, at http://www.usrds.org/2003/pdf/08_pediatrics_03.pdf.)(Dawn S. Milliner, M.D.)
Renal failure during childhood has profound effects. Abnormalities of skeletal development, with associated growth retardation, affect most patients. Abnormal neurocognitive development, pubertal delay, and disordered psychosocial maturation also occur. Renal-replacement therapy in the form of dialysis provides only a small fraction of normal renal clearance. Dialysis alleviates — but does not eliminate — uremic symptoms such as fatigue and anorexia and does not address the nearly universal abnormalities of growth and development.
In contrast, renal transplantation can provide renal function that is 40 to 80 percent of the normal level. A successful transplantation is followed by improved linear growth, particularly in younger children; improved cognitive performance, as reflected by standardized neurocognitive testing and school attendance; enhanced psychosocial development; and an improved quality of life for the child and his or her family. Hospitalization rates are reduced and patient survival is significantly better among children who receive transplants than among those who undergo dialysis. Accordingly, renal transplantation is preferred to dialysis for the management of end-stage renal failure and should be undertaken as soon as possible after advanced renal failure becomes evident. Some would argue that transplantation is the only acceptable form of long-term treatment for patients in this age group.
Outcomes of transplantation have improved steadily since the 1960s, when transplantation was first made available to children. According to the 2003 report of the North American Pediatric Renal Transplant Cooperative Study,1 the three-year rate of patient survival was 96.6 percent among children in the study who received a kidney from a living donor and 94.8 percent among those who received a cadaveric kidney. Among children who underwent transplantation between 1995 and 2001, three-year allograft survival was 90 percent among those who received a kidney from a living donor and 82 percent among those who received a cadaveric kidney.1
The average duration of hospitalization for transplantation is shorter, and postoperative recovery more rapid, than in the past. The rate of acute rejection has been reduced with the use of newer, more effective immunosuppressive medications, and an array of antimicrobial, antihypertensive, and lipid-lowering agents has reduced morbidity. Immunosuppressive protocols that do not include corticosteroids are currently under investigation at a number of transplantation centers, with encouraging preliminary results. Kidneys from living donors, the use of which leads to better outcomes than the use of cadaveric organs, are now available for a greater proportion of patients because of the acceptance of the use of unrelated living donors, laparoscopic nephrectomy techniques for organ procurement, and promising early trials of transplantation across selected cross-match and blood-type boundaries. In the United States, thanks to the success of transplantation, the number of children and adolescents with functioning kidney allografts doubled between 1993 and 2002.2
Challenges remain. Most children who receive a renal transplant require long-term corticosteroid therapy and are subject to all the attendant complications, including the inhibition of linear growth. The avoidance or discontinuation of the use of corticosteroids, if proved safe in clinical trials, will alleviate this problem. Opportunistic infections are an increasing cause of concern as ever-more-effective immunosuppressive medications become available. Cancer is another consequence of immunosuppression, affecting 2.6 percent of children who have received kidney transplants1; children younger than 10 years of age are at greatest risk.3 Most of these cancers are due to post-transplantation lymphoproliferative disease associated with the Epstein–Barr virus.
The longevity of an allograft is particularly important for the pediatric transplant recipient, because renal-replacement therapy is necessarily a lifelong undertaking. Calcineurin inhibitors, taken by more than 90 percent of the children who have received transplants since 1995,1 lead to renal interstitial fibrosis and loss of renal allograft function over time. Declining allograft function also occurs in association with polyomavirus infection, chronic rejection, allograft nephropathy, and recurrence of the primary renal disease. Allograft-survival rates are lower among adolescents who receive a kidney transplant than among younger recipients (see Figure). Inconsistent adherence to medication regimens among adolescents has been implicated as one explanation for this observation.
Figure. Survival of Kidney Allografts from Living Donors among Patients 1 to 17 Years of Age.
Adapted from the 2003 annual report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients.2
Other long-term medical complications of transplantation require attention. Corticosteroids and tacrolimus, both of which are widely used for post-transplantation immunosuppression, are associated with the development of diabetes mellitus. Hyperlipidemia is common after transplantation. Vascular changes, including premature coronary-artery and other vascular calcification, are increasingly recognized in pediatric kidney-transplant recipients once they have entered their third or fourth decade of life.
An understanding of the factors that influence the survival of patients and of renal allografts requires longitudinal outcome studies involving large numbers of patients. The annual incidence of renal failure among persons 0 to 19 years of age in the United States is 15 cases per 1 million population — much lower than the incidence of 625 per 1 million among adults 45 to 64 years of age.3 Only 812 pediatric patients (0 to 17 years of age) underwent renal transplantation in 2003, as compared with 14,317 adults.2 With more than 140 centers in this country providing care for children and adolescents with ESRD, the number of patients per center is small. As children mature into young adults, they often move away from their primary dialysis and transplantation centers, and continuity of care and follow-up information are frequently lost in the process. Thus, long-term results have been difficult to obtain. The work of McDonald and Craig provides valuable information on long-term outcomes in a sizable and stable pediatric population.
Despite impressive improvement during the past four decades, morbidity and mortality among children with ESRD remain high. There is much work to be done as pediatric renal replacement comes of age. Barriers to transplantation in children with ESRD must be overcome, and greater longevity of allografts must be attained at an acceptable biologic cost.
Source Information
From the Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minn.
References
North American Pediatric Renal Transplant Cooperative Study. 2003 Annual report. (Accessed June 3, 2004, at http://spitfire.emmes.com/study/ped/resources/annlrept.pdf.)
U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. 2003 Annual report. (Accessed June 3, 2004, at http://www.optn.org/AR2003/Chapter_V_AR_CD.htm?cp=6.)
U.S. Renal Data System. 2003 Annual data report: atlas of end stage renal disease in the United States. (Accessed June 3, 2004, at http://www.usrds.org/2003/pdf/08_pediatrics_03.pdf.)(Dawn S. Milliner, M.D.)