Kidney transplantation (KTX) is the treatment of choice for children and adolescents with end stage renal disease (ESRD) as hemodialysis (HD) and peritoneal dialysis (PD) are only replacement therapies for a limited time. Besides technical difficulties (shunt obstruction and peritonitis), HD and PD have a strong negative impact on the social (e.g., school attendance) and family life of the child and his or her parents. Pediatric KTX recipients have 1- and 3-year graft and recipient survival rates of 95 and 90%, respectively, even though congenital and structural pathologies have a better outcome than ESRD due to glomerulonephritis (FSGS), hemolytic uremic syndrome (HUS) or neuropathies with concomitant voiding disorders. Offering KTX as early as possible to children is crucial, as ESRD-affected children (prevalence of 4–6 per million children) suffer not only from effects of the underlying disease itself, but also from nutritional deficits, cardiovascular problems, osteoporosis and a lack of growth and development. Almost all countries have special programs for ESRD children and adolescents that serve to expedite KTX and keep waiting time short. Nevertheless, there is still a missing unity in pediatric KTX. For example, the term ‘pediatric’ is defined differently in different countries: while the threshold is below 18 years in the UK, Ireland and USA, it is below 16 years in France and the Eurotransplant community, and below 15 years in Italy and Spain.
Furthermore, nephrologic care for children differs widely. Of the 170,000 pediatricians in the 42 European countries, only approximately 850 are specialized pediatric nephrologists. For the respective country there is a wide variation in the number of pediatric nephrologists available with 1.1 per 1 million children in Denmark and 8.8 in Germany. Specific knowledge in this subset of patients is necessary as the underlying disease for ESRD in children differs from adults. Approximately 40% of children suffer from congenital conditions such as aplasia and dysplasia of the kidneys, obstructive uropathy or cystic kidney disease. Glomerular disorders in pediatric ESRD cause approximately 25% of cases with FSGS accounting for half of them. HUS is a rare cause of ESRD in childhood and adolescence currently (∼3%), with incompletely understood disease-specific implications for KTX.
Kidney transplantation in pediatric recipients is performed by more than half of the European pediatric centers, but differences are large – while 87% of the centers in countries of the EU perform pediatric KTX, this is only carried out by approximately 30% in non-EU countries. Owing to the great share of congenital anomalies, pediatric urologists, pediatric surgeons and pediatric nephrologists must team up early to constitute optimal conditions for a transplantation, often requiring reconstructive surgery prior to or at the time of transplantation. Indispensable prerequisites for pediatric KTX are the existence of a low-pressure reservoir and the elimination of obstructive pathologies such as posterior urethral valves. Some children (bladder exstrophy and prune belly) require extensive pre-KTX operations. There is no minimum age for pediatric kidney recipients but mostly transplantation is not performed before the age of 2 years or below a weight of 15–20 kg. The preferred graft site is extraperitoneal with vessel anastomosis performed with absorbable monofil material (polydioxanone) in order to promote growth of the anastomoses and prevent stenosis. Irrespective of the ureteral implantation technique – most authors prefer the extravesical approach – ureteral stenting under antibiotic prophylaxis must be seen as the standard. Surgical complications of the urinary system after pediatric KTX are urinary obstruction (1–30%), urinary leakage (0.3–9%) and urolithiasis (1–11%). Lymphoceles may develop in 1–7% of patients and should be operated on laparoscopically. Vascular complications occur especially when the donor kidney is very small. Daily monitoring including Doppler ultrasound and serological parameters should be performed in the early phase after pediatric KTX.
Immunosuppression has consistently improved. Boundaries are currently being pushed by specific immunosuppressive agents, however, as in adults, absolute contraindications for pediatric KTX are ‘active’ malignancies and patients with a Wilms tumor must be disease-free for at least 2 years. A current contraindication is a positive cross-match with a current donor, in addition, HIV disease is still considered a contraindication by most investigators. The aim of immunosuppression is a tailored regimen to reduce side effects and improve compliance; current studies on individual enzyme constellations are promising. Pediatric KTX is most often performed via an induction therapy with IL-2 receptor antibodies. Aazathioprine has proven to be inferior to mycophenolate mofetil. Both calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (Tac), are used in pediatric KTX. In the USA, Tac has almost replaced CsA even though some authors found an increased number of lympho-proliferative disorders when Tac was used in Epstein–Barr virus-negative recipients of Epstein–Barr virus-positive donor kidneys. Steroids are still routinely used and side effects may negatively affect longitudinal growth in children. Overall, protocols reducing or avoiding steroids and calcineurin inhibitors are increasingly applied. Rejection therapy is usually performed as in adults, with short steroid boost and switch of the calcineurin inhibitors as initial medication. For antibody-mediated rejection, several concepts exist and new agents are tested with promising potential for the future.
Pediatric kidney recipients are at high risk for viral (re)infections. The therapeutic strategy, besides administration of antiviral agents in some cases, is to reduce immunosuppression in order to reconstitute the recipient‘s immune response. Viruses of the herpes group represent the largest reservoir. In addition, polyomavirus (BK and JC) infection is becoming more common, possibly owing to intensified immunosuppressive strategies. Alarmingly, the share of pediatric recipients developing a malignant disease has increased more than threefold over the past 20 years, with post-transplant lymphoproliferative disorder as the most frequent malignancy after pediatric KTX (75–80%). The reason for this development may be the intensified immunosuppressive strategies.
Most importantly for graft loss in pediatric recipients is the non-adherence to medical protocols with the beginning of adolescence. This accounts for graft loss of 5–50% in pediatric KTX and must always be taken into consideration when graft function deteriorates. Improving adherence necessitates intense counselling of the child and the parents prior to, during and after KTX, and some countries have started with specific programs for children to increase adherence. This is definitely one of the most important fields for the future in pediatric KTX and a team counselling a transplanted child should always include a pediatric psychologist.
Expanding the donor pool for pediatric KTX is crucial. Age-matching programs should be installed as they can improve graft survival. A gross size mismatch may cause hypoperfusion of an adult donor kidney in a pediatric recipient and approximately 25% of the functional renal mass may be lost within 6 months. No publications on crossover KTX in pediatric recipients exist and only three case reports have been published on pediatric KTX of organs from nonheart-beating pediatric donors. ABO-incompatible pediatric KTX from living donors has been performed, mainly in Japan, and results are encouraging. With the expanding numbers of ABO-incompatible KTX in adults this may encourage pediatric KTX also. For organ explantation techniques, laparoscopic donor kidney retrieval was found to have a higher share of delayed graft function compared with open donation techniques. The reasons remain unclear but the learning curve is essential.
Overall, KTX is the best therapy for pediatric ESRD. All efforts must be made to reduce waiting time for ESRD-children. Close cooperation of pediatric nephrologists, pediatric urologists, pediatric surgeons and pediatric psychologists prior to, during and after KTX, is crucial as optimal results can only be achieved if the specific requirements of KTX in children are taken into account rather than treating children and adolescents as ‘small adults’. International guidelines for pediatric KTX should include a uniform definition of a ‘pediatric’ recipient and common allocation schemes of donor organs, including crossover KTX. As only a small number of children require KTX in each country, multinational studies should be initiated to optimize the outcome of KTX in children and adolescents.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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