|Year : 2006 | Volume
| Issue : 4 | Page : 549-558
|Pre-emptive Pediatric Renal Transplantation
Edward Sacca, Issa Hazza
Pediatric Nephrology, King Hussein Medical Center, Amman, Jordan
Click here for correspondence address and email
|How to cite this article:|
Sacca E, Hazza I. Pre-emptive Pediatric Renal Transplantation. Saudi J Kidney Dis Transpl 2006;17:549-58
| Introduction|| |
Kidney transplantation is the treatment of choice for children with end-stage renal disease (ESRD).  In the year 2000, more than 27,000 kidney transplants were performed worldwide,  of which approximately 1500 (5%) were in the pediatric age group.  According to the USRDS data, the number of primary pediatric transplants performed in the United States in 1995 was 373 cadaver and 392 living related transplants. 
Transplantation is becoming more popular because it is associated with longer survival  and a better quality of life than what can be achieved by any modality of long-term dialysis.  Moreover, children and adolescents with ESRD have unique features that are different from the adult population, including the need to achieve normal growth and normal cognitive development, as well as the development of secondary sexual characteristics at puberty. These features are currently the main concerns of every pediatric nephrologist. Accordingly, transplantation provides the most appropriate and physiologic way of renal replacement therapy that fulfills the pre-requisites for normal growth and development in children.
Pre-emptive transplantation (PET), which denotes transplantation prior to the initiation of dialysis, has recently been growing in popularity, as it is postulated that transplanting children before they develop symptoms of severe uremia avoids many of the associated long-term complications of ESRD and dialysis.
| Graft and Patient Survival|| |
During the past decade, there has been significant improvement in graft and patient survival in the pediatric age group, mostly attributed to better immunosuppressive drugs, improvements in surgical techniques and post-operative care, as well as early diagnosis and treatment of acute rejection and infection episodes. Currently, patient and graft survival in children is equivalent to or better than that achieved in the adult population. 
In the most recent report of the North American Pediatric Report Transplant Cooperative study (NAPRTCS), the one- and five-year patient survival rates for all children were 97% and 93%, respectively. There was no significant difference in patient survival according to donor source except in infants 0-1 year of age, where patient survival rate for cadaver donor (CD) transplants was 79.1% compared to 90% for living related donor (LRD) transplants, while the one and five year graft survival rates were 83% and 65% for CD transplants, and 91% and 80% for LRD transplants, respectively. 
According to age, NAPRTCS data show that for CD transplants, the graft survival rate was 67% in the 0-2 year-old age group, 80% in the 2-5 year-old age group, and 86% in children over 5 year-old age group at the time of transplantation, whereas the graft survival rate according to age for LRD transplants was 80% for the 0-2 year-old age group, 88% in the 2-5 year-old age group, and 95% in the > 5 year-old age group.  The main reason for the observation of the worst graft survival in younger children is the increased risk of graft thrombosis, which is exacerbated by widening of the difference between the donor and recipient ages.
| Incidence and Age of Onset of ESRD|| |
ESRD is an uncommon condition in children.  In the 1991 report of the European Renal Association (ERA), the incidence of new patients less than 15 years of age accepted for renal replacement therapy was 4-6 children per million-childhood population per year. The proportion of different age groups was 13% under 2 years of age, 20% between 2 and 5 years of age, 25% between 6 and 9 years of age, and 42% between 10 and 15 years of age. 
The incidence of pediatric ESRD in the United States is somewhat higher than that reported in Europe. During 1995, the adjusted ESRD incidence in the United States was 13 per million population per year for ages 0-19 years. A higher ESRD incidence rate was seen in the 15-19 year age group within the pediatric cohort, with incidence rates more than twice as high as the 10-14 yearold age group and more than three times higher than the 5-9 year-old age group. There was also a large variation in the incidence of ESRD by race, with the highest incidence of 19 per million population per year for black children, and 10 for white children. 
| Etiology of ESRD in Children|| |
The etiology of the primary disease leading to ESRD in children differs substantially from that in the adult population; structural renal diseases predominate, especially in younger children.  Data from the NAPRTCS between 1987 and 1993 indicates that four entities account for half of the primary renal disease of transplant recipients. These include aplastic, hypoplastic, and dysplastic kidneys (17%), obstructive uropathy (16.8 %), focal segmental glomerulosclerosis (11.5 %), and reflux nephropathy (5.7%). 
However, recent data from the USRDS 1997 annual report show that there is an increasing frequency of acquired glomerular nephropathy (GN) in the 5-19 year-old age group at the onset of ESRD. In that report, GN was the primary cause of ESRD in 34.1% of all pediatric patients, whereas the primary causes of ESRD in the younger patients of the 0-4year-old age group were cystic, hereditary, and congenital diseases. 
The different causes of ESRD in the pediatric population may have significant implications on the outcome of renal transplantation when compared with the adult population and should always be taken into consideration, as certain congenital conditions may mandate bilateral nephrectomy prior to transplantation.
| Trends in the Pediatric Management of ESRD|| |
Although the treatment modalities available for ESRD patients in the pediatric age group are the same as those available for adults, there are big differences in the way these modalities are applied, as there are special needs and features in children that are non-existent in adults.
The choice of treatment modality in children is governed by age as well as different physical, social, and emotional needs. The limitations imposed on educational and social integration by in-center hemodialysis (HD), as well as the required dietary and fluid restriction, favor peritoneal dialysis (PD) as the preferred option in the pediatric age group. 
Reduced growth rates for children on dialysis contribute to a strong preference for transplantation, whereas the availability of LRD in children, as well as the presumed advantages of PET, makes the latter option the most preferred in children. ,
According to the NAPRTCS data, 75% of children with ESRD underwent some sort of dialysis therapy before primary renal transplantation, whereas up to 25% are currently transplanted pre-emptively.
Among European countries, the frequency of PET is highly variable. Recent analysis of the ERA registry data shows that in Sweden, 70% of the pediatric transplants are performed pre-emptively, whereas pre-emptive transplants are almost non-existent in other countries like Germany and Austria.  Although it is difficult to estimate the frequency of PETs in the United Kingdom, data from the UK Transplant (UKT) indicate that around 20% of children with ESRD undergo PET, with a high degree of variation from one center to another. 
| Advantages of PET|| |
PET Avoids Dialysis and All of its Hazards
Dialysis is nowadays perceived by most pediatric nephrologists as a temporary measure pending future transplantation rather than a long-term therapeutic option, and it is regarded by most patients and parents as an inconvenient experience requiring frequent hospital visits for HD and frequent dialysate exchanges for PD.
However, most children experience one form of dialysis before transplantation. Data from the NARPTCS shows that approximately two thirds of the dialysis population in the United States is maintained on automated PD (APD), being the preferred modality over HD. 
APD is performed at home. This gives the child greater flexibility to continue with a normal daily routine and school attendance, when compared to HD. However, it is by no means an optimal solution. The risk of peritonitis in the same report was one episode for every 13 patient months, and school attendance was 77% vs. 45% for those on HD. Peritonitis is a serious event, and its recurrence may lead to loss of peritoneal membrane in the future.  Furthermore, there have been some reports associating long-term peritoneal dialysis (> 1 year) with an increased risk of post transplantation graft thrombosis , and hypertension. 
HD is sometimes required,  although with all of its morbidity, including vascular access difficulties and complications, along with the inconvenience of frequent hospital visits which interrupt daily routine and school attendance, it not the preferred method in children, , HD in the young age group is also known to be associated with elevated rates of morbidity and mortality. 
Dialysis in general has been shown to be associated with deceleration in growth velocity  as well as difficulties in nutritional care, which is often hard to maintain without nutritional supplementation through a nasogastric tube or a gastrostomy button.  Other metabolic problems that need to be addressed during dialysis include disturbance of calcium and phosphorous hemostasis, with the resultant renal osteodystrophy with all of its comorbidity.  Recently, there have been reports demonstrating that children submitted to PET achieved normal parathyroid hormone (PTH) levels sooner than dialysis children; this suggests a state of inappropriate PTH secretion in the dialysis group. 
On the other hand, PET spares children and parents this inconvenient experience, with all of its associated complications, morbidity, and mortality. It also circumvents dependence on dialysis machines. Data from the NAPRTCS indicate that the most common reason for selecting PET in the United States was basically to avoid dialysis by both parents and children in addition to the nephrologists' recommendation.
PET Has a Favorable Effect on Growth and Cognitive Development
The need for adequate growth is one of the concerns when caring for children with ESRD as compared with adults. Pediatric nephrologists are currently very aggressive in accomplishing this task, especially as children with ESRD are now surviving into adulthood; therefore, short stature is becoming one of the most significant long-term sequelae of childhood chronic renal failure (CRF). ,
Growth retardation in children with CRF was described nearly two centuries ago,  and since then it has been one of the most typical and persistent manifestations of CRF in childhood. 
Despite the recent advances in medical management, including the use of growth hormone, vigorous nutritional support offered for children with CRF, and the recent improvement in dialysis technique and delivery, the outcome of poor growth and indeed short stature is still one of the most significant problems in children with ESRD. 
NAPRTCS data indicate that dialysis adversely affected growth velocity. The height deficit for ESRD children on dialysis continued; even those who started with less of a growth deficit at baseline experienced a doubling of that deficit by 24 months of dialysis. 
On the other hand, transplantation generally has a favorable effect on growth when compared with dialysis. , Data from the NAPRTCS show that at the time of transplantation, the mean height deficit for all patients in 1996 was less than 2 standard deviations (SDs) below the appropriate age and sex adjusted height levels.  Catch-up growth was seen in 47% of 0-1 year-old recipients, 40% of 2-5 year-old recipients, 17% of 6-12 yearold recipients, and only 12% of 13-17 yearold recipient. Older children of 6-12 years of age showed, however, a linear growth post transplantation that was comparable to that of the normal population, despite lacking catch-up growth or improvement in growth deficit. 
The lack of satisfactory catch-up growth in most transplanted children, in addition to the adverse clinical outcome associated with short stature at dialysis initiation,  emphasizes the importance of transplanting CRF children before they reach a stage of severe uremia and require dialysis.  PET provides a better option for the prevention of short stature with all of its co-morbidity and psychosocial implications.
In a recently published study, growth retardation in PET in children less than 15 years of age was significantly less apparent at the time of transplantation and after 3 years of follow-up compared with children who were transplanted after initiation of dialysis. 
ESRD and dialysis have a well-known effect on cognitive development, resulting in neuropsychological deficits in children, especially infants . ,
The effect of dialysis and transplantation on cognitive development has been evaluated in several studies, with most studies showing a better outcome with transplantation.  In 1984, Fennel RS et al reported improvement in intelligence quotient (IQ) and full scale IQ one month after successful kidney transplantation.  In 1994, Lawry KW et al reported that although overall IQ and subsets score did not differ between the dialysis and transplanted groups, the transplant patients did significantly better on achievement tests of written language and in school performance compared with the dialysis group. 
As most of the effects on cognitive development are related to uremia, it is postulated that PET will have further favorable effect over post dialysis transplantation.
Chronic renal disease, like any other chronic disease, results in severe psychological and social stress for both the child and the family, and the effect of stress is even greater when the child is maintained on any form of chronic dialysis. 
In 1988 Reynolds JM et al, reported that the child's illness caused disruption in family life in 77% of those in the dialysis group compared with 31% in the non-dialysis group (p=0.0002).  Up to a certain extent, a successful transplant attenuates this psychosocial disruption. In 1991, a study compared children treated by hospital HD to children who received transplants. The latter had more favorable parental views of behavioral and emotional adjustment, better parental psychiatric adjustment, and indications of superior child rated mood, self esteem, and social conduct. 
Brownbridge et al also reported that children with transplants suffered less functional impairment and fewer practical difficulties associated with treatment than children undergoing dialysis  Moreover, PET offers intervention before development of symptoms of uremia and therefore a self image as a sick child with ESRD. It also avoids any change in parenting and maintains an optimistic orientation towards future goals and aspirations. 
Data regarding the expected psychosocial benefits of PET in children are lacking. However, Stardoms R et al compared adult patients and family adjustment to kidney transplantation with and without an interim period of dialysis. They concluded that PET resulted in significantly less physical and psychological impact for both the patients and their spouses. 
PET is Cost Effective
Dialysis is expensive. It is estimated that the cost to peritoneally dialyze a child would reach approximately £20,000 / year, whereas the cost of a renal transplant is around £20,000 in the first year, and £5,000 / year for immunosuppressive therapy thereafter. 
In the United States, it is estimated that Medicare expenditures for children with ESRD range from $14,000 for transplant recipients to $43,000 for dialysis patients per year.  Therefore, decreasing the period in which patients are on dialysis or even omitting dialysis altogether whenever appropriate has a significant effect on the cost of care of ESRD children.
| Concerns of PET|| |
Uremic patients are well known to have depressed mixed lymphocyte stimulation, prolonged survival of skin homografts, and reduced skin test antigen reactivity; ,, as such they are immunosupressed. The concern was that PET reduces this uremia-associated immunosuppression and may therefore result in worse outcomes. However, most of the recent studies performed to date confirmed that this fear was unjustified. On the contrary, PET was associated with either similar out comes to PDT ,,, or better graft survival. ,
A recent analysis of the NAPRTCS registry data for the outcome of PET in pediatric patients showed an improvement in graft survival that persisted even after adjustment for multiple variables by proportional hazards analysis. ,
In a recent study among adult patients, Kevin C et al reported that PET from a living donor was associated with a 52% reduction in the risk of allograft failure during the first year after transplantation, an 82% reduction during the second year, and an 86% reduction during subsequent years. 
Although one cannot draw a solid conclusion regarding the favorable outcome of PET on graft survival, given the retrospective nature and small number of patients included in the above-mentioned studies, the results of PET, at worst, can be considered equivalent to post dialysis transplantation.
Another concern in PET was that the child and family who did not experience the inconvenience of dialysis might become less compliant.
Non-compliance has been reported to be a major cause of renal graft loss during the adolescent years. UNOS data, as well as single center reports, have revealed a low late graft survival among adolescents, despite having high graft survival rates initially.  This decreased rate of late graft survival in this subgroup of patients is unexpected and is mostly attributed to non-compliance, especially during transfer from the pediatric to adult clinics.  However, studies to confirm this non-compliance in PET are lacking, and thus far non-compliance should not be regarded as a contraindication for PET. In our opinion, there is usually enough time to encourage active involvement of the child and family in the medical system prior to transplantation, and when combined with a structured educational program, they can acquire a more responsible role regarding future graft care.
| Ethical Considerations|| |
PET raises a serious ethical concern, as renal grafts are withheld from others who have been on dialysis for a considerable period of time; this argument has limited the number of PETs considerably. , This ethical concern only applies to the cadaver kidney donor situation, while the LRD transplantation can be performed pre-emptively whenever feasible, and is currently considered by most to be the preferred approach in the pediatric age group.
In Europe, CD organ allocation is based on two concepts, utility and equity. The concept of utility is easy to apply by giving the kidney to the best HLA match; however the concept of equity is by no means as easy to apply. In the Euro-transplant organ exchange organization, this concept is handled by giving points to the waiting time. However, if waiting time is to be considered from the start of renal replacement therapy, then patients waiting for PET will not receive points for the waiting time factor, making PET only possible when highly matched kidneys are available, or when the mean waiting time is not too long. 
Children have the priority for organ allocation in most European countries, and the mean waiting time is significantly shorter than in adults; for example, in the UK the median waiting time for a CD transplant in the pediatric age group is 182 days versus 652 days in the adult population.  Accordingly, it is postulated that PET from a CD can be performed more frequently in the pediatric age group.
| When to Consider PET|| |
Another important aspect of PET that has not been addressed enough is at which stage of renal disease the procedure should be considered. It is not always possible to accurately predict the progress of chronic kidney disease. In addition, children can often be managed conservatively at low GFR levels for a considerable period of time, and therefore this may result in too early transplantation before renal replacement therapy is really required.
Currently there are no published data regarding this issue; however, according to the UKT guidelines, PET should be considered in two situations: GFR < 10-15 ml/min/ 1.73m 2 and symptomatic ESRD, or rapidly declining GFR and inevitability of the need for dialysis within 6-12 months. Symptomatic ESRD was defined as inadequacy of nutrition or fluid intake, or correction of electrolyte abnormalities and acidosis, need for correction of anemia, treatment with phosphate binders and active vitamin D, and inability to take part in normal childhood activities such as attending school, keep-up with friends, and normal growth. 
| Live Related Donor Program|| |
Due to the shortage of CDs and the increased demand on kidney transplantation, as well as the presumed advantages of PET in children, there is a growing consensus worldwide that LRD programs should be promoted in an attempt to increase the number of PET.
Data from the NAPRTCS and the registry report from Scandinavia demonstrate that 52% and 54% of pediatric transplants were from LRDs in these countries, respectively. ,,
The superiority of LRD graft survival over CD has been well documented, and there is significant improvement in LRD graft survival when transplantation was performed pre-emptively as compared to post dialysis transplantation.  On the other hand, this places the members of the child's family under some pressure to identify an available LRD, which in many instances may have significant disadvantages and social impacts.
| Limitations of PET|| |
PET cannot be done in all patients, as there will always be situations that require dialysis prior to transplantation. These include patients in whom nephrectomy is contemplated as a therapeutic measure before transplantation, such as patients with heavy proteinuria, patients with urosepsis, and indeed patients who present for the first time with ESRD necessitating emergent dialysis.
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Pediatric Nephrology, King Hussein medical Center, PO Box 2387, Amman 11181
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