Year : 1994 | Volume
: 5 | Issue : 3 | Page : 336--346
Pediatric renal transplantation: A review of data from north American pediatric renal transplant cooperative study (NAPRTCS)
Paul T McEnery
Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA
Paul T McEnery
Children«SQ»s Hospital Medical Center, Cincinnati, Ohio 45229-3039
|How to cite this article:|
McEnery PT. Pediatric renal transplantation: A review of data from north American pediatric renal transplant cooperative study (NAPRTCS).Saudi J Kidney Dis Transpl 1994;5:336-346
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McEnery PT. Pediatric renal transplantation: A review of data from north American pediatric renal transplant cooperative study (NAPRTCS). Saudi J Kidney Dis Transpl [serial online] 1994 [cited 2020 Dec 1 ];5:336-346
Available from: https://www.sjkdt.org/text.asp?1994/5/3/336/41168
Nephrologists and renal transplant physicians, health care providers and society are beginning to accept the idea that end-stage renal disease (ESRD) care is a highly technical procedure that should also be offered to children to maintain their health and wellness. This question of need and initiation of dialysis and renal transplant care is occurring more frequently due to the success of such therapy in children of all ages. To continue this success physicians and medical centers providing renal transplant care must review their outcomes, analyze their successes and failures, and establish standards of care that build on past experience and ensure continued and improved short and long-term care of children with renal problems.
There are many problems in the provision of ESRD care to children, the primary problem being one of their small size. When compared to adults, children also have major medical differences in their response and tolerance to medication and the procedures involved in transplantation. In addition to the problem of being small is the problem of low number of pediatric renal transplant centers and the low number of patients. In the United States, most centers for children perform approximately 10 transplants annually.
Our pediatric ESRD center in Cincinnati, Ohio, performed the first renal transplant in Cincinnati in 1965. Over the initial four years, all transplants were from living donors but with time cadaveric donor transplants became more commonly performed. Over the past 28 years, we have performed 100 living donor and 155 cadaver donor transplants in 190 children. Our long-term outcome of grafts in children with their first or index transplant is diagramed in [Figure 1]. This is a small number of patients and transplants and our ability to develop statistically significant data is obviously limited by our small numbers of children.
Most of us involved in pediatric renal transplantation are very aware of our small numbers where children aged 0 to 18 years make up only four percent of patients who receive transplants in the United States each year. Several years ago, those of us interested in pediatric renal transplantation joined together to share our data and better analyze the unique problems of pediatric patients receiving kidney transplants. Since 1987, through the voluntary participation of pediatric nephrologists, renal transplant surgeons, transplant coordinators and others, the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has studied renal transplantation in children and adolescents in the United States and Canada. This report is a review of observations accumulated and cited with the 1993 annual report of NAPRTCS.
Some 82 participating centers have registered 3223 children who have eventually received 2,819 transplants during the period of January 1987 through January 1993. The data collection and follow-up on all patients is on-going and has been analyzed to examine trends in transplantation practices over the six years of the study and to identify factors that have affected the outcome of renal transplantation in these pediatric patients.
The NAPRTCS is made up of a clinical coordinating center, a data coordinating center and 82 medical centers treating children with ESRD in the United States and Canada. The data for this report compiled in February 1993, includes renal transplants reported during the six preceding years. Since January 1987, each renal allograft received at participating centers by a child or adolescent 17 years of age or less has been reported to the data coordinating center along with information on graft function and therapy one month after transplantation and every six months thereafter ,, .
Standard univariate, multivariate statistical methods including product-limit estimates of survival distribution were used to analyze the data. Proportion-hazard survival models were constructed that equated an individual patient's hazard to an underlying hazard multiplied by an estimated exponentiated linear combination of risk factors. Multivariate models were scaled so that risk increased with larger values of the covariates; the relative risk for a single dichotomous risk factor was the exponentiated parameter.
Results and Discussion
A total of 2,604 patients from 82 centers have been registered between January 1987 and January 1993. The data were compiled on 2,819 transplant procedures of which 215 represent additional transplants in the same patient since the studies started. Due to late reporting from each of the annual studies, it is anticipated that the total number of transplants for 1992 will increase in next year's report. As is shown in [Table 1], for each year, approximately 435 transplants are performed on children annually. Males consistently received approximately 60% of registered transplants and the proportion of white recipients is 68%. Living donors provide 46% of transplanted kidneys over the six years of study, but for the last two years, living donors were the source in some 54% of reported transplants. One of the goals of the NAPRTCS was to report data on 80% of the pediatric transplants performed annually in North America and from the best estimate comparing NAPRTCS numbers with the Canadian and United States Renal Data System reports from the Federal Government, and we are close to that number.
The age distribution of recipients of index transplants (a transplant performed at the time of study enrollment) is shown in [Table 2]. Using age groups defined as 0-1, 2-5, 6-12 and 13-17 years of age at the time of transplantation, since 1987, only minor changes in age distribution have been seen among the groupings. In a similar manner, the proportion of male and white patients have also been fairly constant over the six years of reporting. Of interest is a decline in the number of transplants performed in recipients  .
The three most common primary renal disease diagnoses in transplanted children were hypoplastic, dysplastic kidney, obstructive uropathy and focal segmental glomerulosclerosis. Renal dysplasia and obstructive malformations are responsible for adding an average of 170 new patients annually and among children five years of age or less, congenital lesions accounted for about 50% of the causes of ESRD while acquired forms of glomerulonephritis made up more than 50% of the causes among older age groups. The next three most common causes for ESRD were reflux nephropathy, systemic immunologic disease and chronic glomerulonephritis. The six most frequent causes total 54% of the cases while the remaining 20 diagnoses are each present in no more than 4%.
Transplantation without prior dialysis ("preemptive" transplantation) was used as initial renal replacement therapy in 23% of patients  . The rate of pre-emptive transplantation differs for recipients of living (33%) and cadaver (13%) source organs, for males (26%) and females (18%), across age groups with rates of 19%, 26%, 26% and 19% in the 0-1, 2-5, 6-12 and 13-17 age groups respectively and across races with whites, blacks, Hispanics and others respectively having pre-emptive transplantation rates of 26%, 14%, 17% and 19%. The primary reason for pre-emptive transplantation in most cases was the desire to avoid dialysis by 66% of the cases so treated. At the time of transplant surgery some 26% of the NAPRTCS patients were not on dialysis, 28% were on hemodialysis only and 41% were exclusively on peritoneal dialysis immediately prior to their transplant. The median waiting time for transplantation for patients who were on dialysis immediately prior to their index transplant was 11 months and the mean time is 16 months.
There was a higher frequency of aplastic, hypoplastic dysplastic kidneys (62%) and obstructive uropathy (88%) in the male population. As noted in [Table 2], the relative incidence of these diagnoses decreased with age. An important difference in the distribution by sex is that obstructive uropathy was a diagnosis in 25% of the males and only 5% of the females. Systemic immunologic disease occurred predominantly in females (72% vs 28%) and focal segmental glomerulosclerosis was prevalent in the non-white population.
Donor History and Antigen Match
As shown in [Table 3], 46% of transplanted organs have come from living donors, ^his includes 88 siblings with 61 of the siblings ranging from the age 18-20 years. Five donors were 17 years of age or less. Three of the transplants were between identical twins, the youngest pair being 13 years old. During the initial four years of this study, the percent of cadaver donors older than 10 years of age ranged from 59-68% but in the last two years, the use of small donors has become less frequent with some 80% of the donors now older than 10 years of age. In the cadaver source transplant, the cold ischemia times were generally less than 24 hours with only 1% having cold ischemia time greater .than 48 hours. The percent age of patients receiving donor specific transfusions has decreased considerably and the percent of patients without prior random transfusions has increased 17% in 1987 to 33% in 1992. In the living donor transplant procedures, 87% had at least a single haplotype match and known matches for all six HLA-A, -B, and - DR alleles occurred in 4% of living donor source transplants and 2.4% of the cadaver source transplants.
The use of pre-operative immunotherapy has decreased over the years in live donor transplants but is still employed in 64% on one or more days prior to transplantation. Methylprednisolorie and azathioprine are initiated usually on the day of surgery. Median doses of prednisone in both living donor and cadaver source grafts decrease to approximately one-third of the initial amount (1.8 mg/kg/day to 0.6 mg/kg/day) while the median doses of cyclosporine had a slight increase of 8.2 to 9.1 mg/kg/day and azathioprine remained constant at 2 mg/kg/ day. The use of cyclosporine was almost equal for living donor (85%) and cadaver donor (89%) recipients.
The median daily prednisone dose decreased from 2.7 mg/kg/day at six months to 1.5 mg/ kg/day at three years after transplantation [Figure 2]. The percentage of transplanted patients receiving alternate day prednisone therapy increased from 12% at month six to 19%, 25% and 27% at months 12, 24 and 36 respectively. There was little change in the proportion of patients receiving prednisone, cyclosporine, and azathioprine at each time point. The median dose of azathioprine was relatively constant (1.7 mg/kg/day) at each follow-up time although the dose was slightly higher when used in dual therapy with prednisone versus the lower dose when used with cyclosporine. Through the last three years, over 70% of the patients received combination immunosuppressives with prednisone, cyclosporine and azathioprine. As noted in [Figure 2], there have not been substantial dose reductions in the components of the combination over the 48 months of data.
Patients receiving dual therapy prednisone and azathioprine had a greater incidence of rejection prior to 30 days, a higher proportion of hospitalizations for rejection, hypertension, and greater loss of their allograft in the first six months as compared to patients receiving prednisone and cyclosporine or patients receiving prednisone, cyclosporine and azathioprine during the initial six months of follow-up , . This was true for both cadaver and live-related recipients. In addition to immunosuppressive agents, a substantial number of children received anti-hypertensives and antibiotics throughout the follow-up period. Although the percentage of individuals receiving anti-hypertensive therapy decreased during the initial few years of follow-up, over half of the children are receiving antihypertensives throughout the period of observation. Prophylactic antibiotics were used in 37% of patients at one year with minimal decreases thereafter. An anticonvulsant medication was given to about 10% of the transplant recipients with a greater frequency observed among recipients of cadaver organs. Patients with ESRD due to congenital renal lesions were more likely to be on prophylactic antibiotic medication than those with acquired causes for ESRD.
The decision to initiate specific anti-rejection therapy has been used as the definition of a rejection episode with a total of 3,160 incidents being reported from 1,673 transplants. Two or more rejections have occurred in recipients of 780 transplants with a maximum of 11 treated rejections for any one transplant. [Figure 3] displays the cumulative distribution of times to first rejection by allograft source. At days 5, 30 and 45, the proportions of live donor transplant recipients who have experienced a rejection are 0.24, 0.32 and 0.38 versus 0.24, 0.43 and 0.54 for cadaver source transplants. By the end of the second year, 57% of live donor organ recipients and 73% of cadaver source recipients had experienced a rejection episode. For recipients with living donors, time to first rejection was shorter for older patients (six years or older), when there is at least one HLA-DR mismatch and when early prophylaxis with monoclonal or polyclonal antisera are not used. Live donor recipients had similar times to first rejection irrespective of whether or not they received pre-operative immunotherapy. Similar patterns were not observed for recipients of cadaver donor organs except for the early use of polyclonal or monoclonal prophylactic immunotherapy. Overall, 52% of rejection episodes were completely reversed, 41% were partially reversed and 6% ended in graft failure or death. Rejection in which a renal transplant biopsy was not performed had higher reversal rates suggesting an association between the severity of rejection episode and the decision to biopsy. Looking at individuals who were receiving cyclosporine and were rejection-free for at least the first year post-transplantation, but subsequently developed a rejection revealed that the median one year maintenance of cyclosporine in those exhibiting rejection was 4.7 mg/ kg compared to those without a rejection whose median dose was 5.1 mg/kg/day. A regression analysis revealed that the possibility of developing a late rejection was increased for patients over six years of age, was increased for non-white patients and decreased by a factor of 0.9 for each mg per kg increase in maintenance cyclosporine dosage. This suggested that older age and minority status, factors that are important in compliance with medication regimen, and lower doses of cyclosporine-A at one year are somewhat predictive of rejections upon further years of follow-up.
The causes for graft failure are listed in [Table 4]. A total of 686 graft failures (24%) have occurred among 2,819 transplants. Of them 551 (80%) were returned to dialysis, 28 (4%) were retransplanted at the time of failure, 22% had residual native kidney function, 5% had residual prior graft function, 67 (10%) died with functioning grafts and 11 (1.6%) died with graft failure. With increased length of follow-up of the study cohort, chronic rejection continues to increase in importance as the cause of graft failure. Recurrence of original disease as- a cause of graft failure was observed 54 times (focal segmental glomerulosclerosis 24  , membranoproliferative glomerulonephritis type II 6, oxalosis 6, hemolytic uremic syndrome 4, and in 10 de novo or other glomerular disease). Vascular thrombosis was a major cause of failure in 87 cases. Graft failure attributed to primary non-function, vascular thrombosis or miscellaneous technical causes suggest that immediate problems will occur in about 4.3% of pediatric transplant procedures.
The over-all median follow-up for subjects with functioning graft was 23 months. The estimated graft survival probabilities are exhibited in [Figure 4] with 90%, 85% and 75% graft survival at 1, 2 and 5 years respectively for recipients of living donor organs and 76%, 71%, and 62% for the same years with cadaver source organs. For recipients of living donor grafts, those who are less than two years of age, are of black race or have had greater than five prior transfusions have the worst graft survival rates. The use of monoclonal or polyclonal antisera is not associated with significantly increased living donor graft survival. However, serum creatinine levels among recipients of functioning living donor grafts at six months are significantly lower than those individuals who received monoclonal or polyclonal prophylactic therapy versus non-treated subjects. At one year post-renal transplantation, cadaver allograft survival has increased from 72% in the 1987 cohort to 79% in the 1992 cohort. There has been no change in the graft survival of living donor allografts.
For recipients of cadaver source organs, recipient age, prior transplantation, the use of mono or polyclonal antisera at the initiation of transplantation, donor age of less than six years, prior dialysis, improved annual cohort transplant outcome 1987 versus 1991 and cold storage time more than 24 hours were found to be significant factors affecting graft outcome as is demonstrated in [Table 5]. Race, sex, native nephrectomy, prior transfusions, HLA-A, - B and -DR matches and allograft preservation methods did not significantly contribute to cadaver graft survival when adjustment was made for these variables. When looking at the etiology of ESRD graft survival of patients diagnosed with focal segmental glomerulosclerosis was significantly less than for patients with obstructive uropathy or aplastic, hypoplastic or dysplastic kidneys for both living and cadaver donor kidney recipients. Graft survival beyond the first week was significantly worse in the presence of acute tubular necrosis in both donor source groups. Acute tubular necrosis was defined in this study as the use of dialysis in the transplant week. For living donor transplants, a delay in graft function was reported as 5.6% vs 19.6% in recipients of cadaver organs origin. Delay in graft function has also been observed to decline with the year of transplant with 22.6% of the allografts in 1987 having ATN vs 14.3% of the 1992 transplants. In a fashion similar to graft survival, the measurement of serial serum creatinine values as calculated creatinine clearance for the different age groups demonstrates that over the period of observation, with functioning allografts, there is a trend for a rise in serum creatinine at each point over the first four years post-transplantation. The changes in renal function are equivalent for both living and cadaver donor recipients.
Characterization of growth following renal transplantation has been a major goal of the NAPRTCS study  . Standard Z scores were calculated by subtracting the appropriate population, age and sex specific means and dividing by the standard deviation for the normal population. At transplantation, the mean height deficit (standardized Z score) observed for all patients was -2.19. This means that the average child is more than two standard deviations below the appropriate age and sex adjusted height level. This deficit is slightly greater for males. Overall, mean height scores remain relatively constant over four years of follow-up and are shown in [Figure 5]. Children in the age group of 0-1 years had the maximum deficit and show the maximum improvement in Z score, gaining about one standard deviation (pMorbidity, Malignancy and Mortality
Overall, the median duration of hospitalization at the time of transplant was 16 days [Table 6]. Median initial post-transplant hospital stays were 25, 21, 18 and 17 days for 0-1, 2-5, 6-12 and 13-17 year old recipients respectively. This denotes the high costs, risks, and problems in the younger age recipient. Cadaver donor allografts had a median stay of 19 days which was two days longer than those from living donor sources. The most common reason for hospitalization during the initial six months post-transplant was treatment for rejection. Hospital stays, in both frequency and Length, decreased with the six and subsequent months while the treatment for rejection episodes remained the primary reason for hospitalization. From 1987 through 1992, 27 malignancies have occurred. Fifteen were lymphoproliferative disorders, five were sarcomas and two were carcinomas. In five of the cases the malignancy was observed in patients who had multiple renal allografts. Sixteen of the patients with malignancies have died and in eight the allograft was functioning at the time of death. There have been 143 deaths out of the 2,604 patients with 57 patients dying of infection. With an average of 24 months of follow-up, it can now be seen that the survival of these patients is excellent with a 96% survival of those individuals receiving live donor kidneys and 94% of those with cadaver sources. This success rate is an important factor in pediatric renal transplantation and is, happily, better than that reported from adults centers. If we can go back to the pediatric transplant experience at the Cincinnati Children's Hospitals, [Figure 6] demonstrates the long-term survival of our CHMC patients since we started doing transplants in 1965. This figure demonstrates that the long-term survival up to 25 years is excellent. If we consider that the average patient in our transplant program is approximately 12 years of age at the time of their transplant and if we express this cumulative patient survival in half lives, then, we can expect for the child who has a functioning graft at one year to have a 50% chance of survival for an additional 40 years or a potential life span in excess of 50 years.
In this review of pediatric renal transplant experience, the efforts of the cooperative group of North American pediatric renal transplant physicians have been reviewed [Table 7]. We have tried to gain from our collaborative efforts a better understanding of those features that make the pediatric renal transplant patient unique to that of adults. We have pointed out that the frequency of renal transplantation increases with age. Transplantation without prior dialysis occurs frequently. Congenital obstructive and dysplastic lesions are the cause for ESRD primarily in the younger age patients and males with older children having acquired diseases and that the occurrence of focal and segmental glomerulosclerosis seems to be higher in the black population. In the North American countries living donors account for a very large number of donor sources. In addition, it has been discovered that for pediatric recipients who are less than 24 months of age and those who receive organs from cadaver donors less than six years of age seem to have a worse outcome. Since 1987, the use of pre-operative monoclonal or polyclonal antilymphocyte serum and cyclosporine has increased in frequency and currently most of the living donor and cadaver donor recipients receive triple maintenance immunosuppressive therapy with prednisone, cyclosporine and azathioprine.
Although the median time to the first rejection episode has not been altered through the use of monoclonal or polyclonal antilymphocyte serum, the mean time to first rejection is 38 days for cadaver donors and 261 days for living donors. Over the years of this study, the graft survival has improved with the three years graft survival for cadaver donor recipients now being at 65% and for living donors being at 82%. During the initial months post-transplant surgery rehospitalization is for rejection and infection, with acute and chronic rejection causing the majority of the transplant failures. Unique to pediatric transplantation are the problems of primary non-function and vascular thrombosis when donors less than 6 years of age are used. For cadaver donors factors such as, young donor ages, prolonged cold storage of longer than 24 hours and prior transplantation are associated with decreased probability of graft survival.
One hundred and forty-three deaths have occurred, with 57 attributed to infection and 86 to other causes. The overall two year patients survival is excellent with 95% of the children receiving a cadaver organ and 96% of those receiving living donor organs surviving. Malignancies have occurred in patients.
As pediatricians, we are always interested in growth. A significant number of pediatric patients have a marked deficiency in height at the time of transplantation with their mean height more than two standard deviations below the mean for the population. The use of alternate day prednisone has allowed for improved growth in many of the patients, with the youngest of patients (those less than 6 years of age), who are also at highest risk for graft failure, having the best height increment.
The NAPRTCS project data has been of great assistance in improving the knowledge and analysis of outcomes with children having renal transplants. The study will continue to grow and spawn special projects that will enable us to have a better understanding of problems and better therapy for this unique population of children requiring end-stage renal disease care.
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