Since transplantation first started in the 1960s and began in earnest in children in the 1980s, the field of pediatric renal transplantation has seen significant changes that have improved the quality of patient care in both the short and long term.
However, as outcomes have improved, the patient population has become increasingly complex, including more children who have multiple congenital anomalies or who are recipients of nonrenal solid organ or stem cell transplants.
The disease processes that cause end-stage renal disease (ESRD) are different in children compared with adults, and factors such as metabolic consequences and growth, emotional and sexual maturity, and education make the child with ESRD distinct.
While pediatric transplantation accounts for a very small proportion of the total number of transplants in North America—approximately 5%—it demands careful attention to the special considerations in these young patients.
In the last decade, the major push for adults with Stage 4 chronic kidney disease (CKD) and greater has been the concept of fistula first, which aims to improve care by increasing arteriovenous fistula placement and use in suitable hemodialysis patients. This approach helps avoid the complications of acute or cuffed catheters and of poorly matured fistulas for chronic hemodialysis.
Whereas fistula first may work very effectively in adults, the concept is not valid in children. In the pediatric population, fistulas should be second, and consideration for preemptive transplantation should be first.
Between 2007 and 2009, 29.4% of pediatric transplants were preemptive, dodging dialysis and vascular insults from dialysis catheters and, potentially, sending a much healthier child to the operative suite at the time of transplantation.
For years, there has been a concern that preemptive transplantation may jeopardize compliance, driven by the thought that time on dialysis may improve adherence. Data to date, however, has yet to show that dialysis changes the behavior of a child at risk for nonadherence after transplantation.
Since criteria for preemptive transplantation include the availability of a donor, most children transplanted before dialysis initiation have a living donor.
In addition, the disease physiology must imply the absence of risk factors for perioperative complications. Such risk factors include active nephrotic syndrome, reflux nephropathy, and malignant hypertension. Data from the 1960s showed that patients who undergo transplantation at the time of active nephrotic syndrome have a greater chance of clotting their new allograft.
Children who have renal dysplasia as a component of progressive kidney function loss are candidates to undergo transplantation preemptively. In contrast to the clinical features of adult glomerular-based renal disease, renal dysplasia is associated with polyuria and polydipsia in the pediatric population. A major concern is to make sure that these patients are not volume depleted during the perioperative period, as volume depletion means a higher incidence of clotting.
The presence of a chronic infection is considered a contraindication to a preemptive transplant because of increased risk in the future immunosuppressed patient.
In addition to the clinical benefits of preemptive transplantation, data in adults show that after 2.7 years, it is cheaper to have been transplanted than to be on dialysis. While there is no pediatric-specific data in this area, logic would suggest the same situation.
Therefore, the push in children should be for preemptive transplantation unless there is a contraindication. If preemptive transplantation is not an option, then a reasonable short-term solution would be peritoneal dialysis or hemodialysis with a cuffed catheter for up to one year.
If hemodialysis is pursued after a period of time, then perhaps a change from a cuffed catheter to a fistula or a switch from hemodialysis to peritoneal dialysis would be in order.
Nonadherence in Adolescence
There is great concern about nonadherence to medical therapy as children reach the stage of adolescence.
Adolescence is an age of independence and often a time of acting out. These children have a high risk of believing they are invincible and that medical intervention may not be necessary. It is very important at this time that children be monitored and walked through the process of becoming independent while adhering to medication therapy.
A decade and a half ago, a medical adherence meeting was held with transplant recipients, medical systems, and industry to discuss how to balance maximum benefit of medication and avoid complications and nonadherence. Many families and patients would suggest that medical systems are too protocol driven and that many medications are used because of historical protocols.
The new generation of immunosuppressive agents allows for the use of fewer medications overall, but the agents have a higher potency and pose potential risks to the patient.
An honest and open discussion needs to occur between the transplant pediatric nephrologist and the adolescent about managing the priority of medications and staying on schedule in order to promote adherence and avoid complications.
High PRA Patients
In patients who have lost their allograft or have been exposed to a number of blood products, high panel-reactive antibodies (PRA) may be found. Like adults, these pediatric patients are at a high risk of not receiving another transplant.
Antibody-reduction protocols common to adults and children are used in many institutions. These protocols include the use of B-cell monoclonal antibodies (rituximab) in combination with plasma infusions, with or without plasmapheresis.
There has yet to be a controlled demonstration in children that antibodies in all high-titer patients can be reduced. Many programs will attempt to reduce antibodies seen in a historically crossmatch-positive patient in the hopes of enabling transplantation, especially if there is a living donor.
Because of an anamnestic response, antibody production can occur at the time of transplantation. Therefore, not only standard immunosuppressive agents but also historically used antibody-reduction protocols may be in order to prevent acute and chronic rejection.
After transplantation, these patients not only need routine monitoring but surveillance for the presence of donor-specific antibodies, which may trigger the use of an antibody-reduction protocol prior to overt rejection.
Transplantation in Small Children
The size and age of children poses another special issue in pediatric transplantation. The peak ages of transplantation in this patient group are 5 and 15, which correspond to times of rapid growth.
One can make the case that the 15-year-old has physiology and anatomy similar to that of a small adult and, therefore, becomes less problematic. One would agree, though, that the small child, especially the child younger than 5, has unique issues from the physiologic, anatomic, and metabolic points of view.
In terms of anatomy, children between 8 and 15 kg often undergo an anastomosis of the allograft to their aorta and inferior vena cava. This approach addresses the coordination of the size of the donor kidney vessels with the size of the recipient's vessels and may require aortic cross-clamping intraoperatively.
The use of an adult kidney in smaller children affects the ratio of the surface area of the kidney to the surface area of the child. Data from more than 20 years ago identified serum creatinine as a poor indicator of allograft dysfunction in this setting and showed that fevers or changes in blood pressure may identify allograft dysfunction weeks before changes in creatinine occur.
The metabolism of medications is quite different in smaller children than in adults. While calcineurin inhibitors are usually given every 12 hours in older individuals, they may require dosing once every eight hours in the smaller child because of their high cytochrome P450 activity and the rapid metabolism of these medications.
Case reports indicate that even a medication such as rapamycin, which is given once a day in adults, may require twice-daily dosing in children. The purpose of more frequent dosing is to avoid very high peak levels and area under the plasma concentration-time curve, which may cause complications. Drug monitoring, if available, would be important in order to target proper levels of these agents.
While pediatric renal transplantation has improved over the last three decades, the care of this unique patient population comes with complications. Attention to detail in treating these young patients will lead to better outcomes—not only for the child's health, but in overall impact upon the family and society.