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While renal transplantation quickly became an accepted and preferred mode of therapy in adults, 60 y ago children were allowed to die of renal failure. This was due to the ethical conundrum of the benefit versus risk of aggressive therapy in children with renal failure. While in some countries this remains a reality, this is no longer the case in many places. In fact, in the United States, children get priority on the waitlist for the best deceased donor kidneys. The field of pediatric kidney transplant continues to evolve and children today have outstanding immunosuppression and antiviral options with transplant outcomes that are often better than adults (1). However, there were tragedies and losses as we learned and grew from experience. This review describes the journey and progress the field of pediatric kidney transplantation has made over the last five decades from clinical practice (with an emphasis on the United States) over the last 50 y.

Surgical and Medical Considerations Before and During Transplant

In 1954, Joseph Murray, a plastic surgeon, performed the first successful kidney transplant on the Herrick brothers, adult identical twins; and the field of transplant surgery was born ( Figure 1 ). In 1959, Gordon Murray, in Toronto, carried out the first successful non-twin sibling transplant. A few years later organ procurement from a brain-dead heart-beating donor was performed (2,3). While some aspects of kidney transplantation were similar for children and adults, the surgical approach varied and technical challenges were great in small children (4,5,6). Prolonged pediatric dialysis was fraught with issues related to dialysis access, nutrition, growth, bone disease, and developmental and neuro-cognitive delays (7,8,9). But transplantation often remained a nonviable option with worse outcomes than dialysis partly due to the intuitive belief that pediatric recipients needed pediatric donors (10). The paucity of pediatric deceased donors; and the near-absence of pediatric living donors disadvantaged children waiting for kidneys. Complicating issues was the observed high rate of graft loss, often due to thrombosis upon matching very young donors to very young recipients (11). Today, size and age matching is generally not required in kidney transplantation and smaller children are transplanted via a mid-line incision into the peritoneal cavity. Depending on the size of the child and the blood vessels, the renal vein was anastomosed to the side of the inferior vena cava or common iliac vein and the arterial anastomosis was performed to the side of the aorta or the common iliac artery with good success (12,13,14) as it still is today. Kidneys from very small pediatric deceased donors are now transplanted en bloc (both kidneys together, attached to a single segment of the aorta and vena cava) into adults with excellent results (15).

Figure 1
figure 1

A timeline of some of the milestones in the history of pediatric kidney transplantation. The journey spans more than six decades and involves several continents, countries and patients.

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Initial reports of very poor outcomes in younger children (16) were followed by studies highlighting the importance of adequate pretransplant preparation and shorter duration on dialysis (7). There was also growing awareness of the importance of improved donor-recipient matching, advantages of living related donors and the critical role of an integrated team of pediatric nephrologists, transplant surgeons, anesthesiologists, dialysis and transplant nurses and coordinators, pediatric infectious disease specialists, social workers, psychologists, dieticians, intensive care unit physicians, etc. In 1982, 12 children all under 9 kg were transplanted an adult kidney with only two reported deaths and two graft losses which was comparable to the adult outcomes at that time (7). Severe growth retardation and psychomotor delay, was initially considered a contra-indication to transplant, but in fact transplant was beneficial in many for catch up growth and development (17,18) and elegant studies were done to optimize growth despite steroid inclusive immunosuppression regimens (19). Today, earlier transplant is actively pursued in children with renal failure and it is more often than not considered unethical to withhold dialysis/transplant from children with renal failure even in the setting of comorbidities.

While specifics of the transplant surgery itself are not explored in this paper, surgical techniques have improved including but not limited to urologic pretransplant bladder preparation, donor nephrectomies which today are frequently done laparoscopically and recipient native nephrectomies which previously universal are now done only if clinically indicated. Even pretransplant preparation has evolved with the availability of growth hormone, epoetin alpha, and various modalities of at-home and in-center dialysis.

Pediatric Immunosuppression: Then and Now

Many of our initial transplant failures were due to inappropriate immunosuppression. New immunosuppression in children was studied most often if there were preliminary safety and efficacy data from adult studies. Smaller numbers of pediatric recipients also reduced the capacity for adequately powered randomized controlled trials and so the field of pediatric kidney transplant has mirrored but remained a step behind that of the adult kidney transplant.

Initial immunosuppression involved total body irradiation and splenectomy leading to unacceptably high death rates from overwhelming infection and sepsis (20) followed by an era of unacceptably high rejection rates with steroids alone. The 1960s heralded the development of 6-mercaptopurine, followed by azathioprine; the development of a polyclonal antilymphocyte globulin; and the ability to do histocompatibility and preformed cytotoxic antibody testing to better match donors and recipients (21,22). After the first initially successful series of transplantations performed between 1962 and 1964, azathioprine and steroids became the primary immunosuppressive regimen for the next two decades. In 1967, the first polyclonal antilymphocyte globulin was utilized which spawned the development of other polyclonal and monoclonal antibodies including Minnesota Anti-Lymphocyte Globulin, Thymoglobulin and OKT3. Newer induction agents include but are not limited to Basiliximab and Campath. In children, data today remain limited on the optimal induction therapy.

As knowledge of the immune system has evolved, therapy targeted to specific immune-regulatory sites has become possible. Cyclosporine, introduced in the 1980s, a calcineurin inhibitor, was used in combination with azathioprine and steroids and was credited with a dramatic improvement in graft survival (23,24). In 1994, mycophenolate mofetil (25,26,27) was introduced and over the past two decades has almost universally replaced azathioprine. After tacrolimus (another calcineurin inhibitor) became available in 1994, debate followed regarding which calcineurin inhibitor was superior; and it has gradually supplanted cyclosporine in many pediatric centers. To expand the armamentarium further, sirolimus (Rapamune), a macrolide antibiotic, was developed and released. Today, there are many other immunosuppressive agents available on the market including belatacept targeting the costimulatory pathway and tocilizumab a humanized monoclonal antibody that binds the IL-6 receptor. Nevertheless, many of these newer agents are yet to be used with confidence in children.

While the purpose of this review is not to dwell on the details of any one immunosuppression, mention of the evolving role of steroids is important. Once a cornerstone of transplant immunosuppression, parental and patient aversion to steroids has driven our field to steroid avoidance regimens. Prospective multi-center trial groups summarized in a recent review (28) have shown glucocorticoid avoidance is not immunologically detrimental, but is associated with chronic histologic damage (29). In addition, high doses of immunosuppressive drugs used to compensate for glucocorticoid withdrawal have an unacceptably high rate of post-transplant lymphoproliferative disorder (30). Similarly tacrolimus, almost universally used for pediatric kidney transplant immunosuppression is now losing favor and studies are considering their necessity (31,32).

Assessing newer immunosuppressive agents in children is challenging since pediatrics represents a very small percentage of the total kidney transplants. Retrospective data registries such as the North American Pediatric Renal Trials and Collaborative Studies, combined adult and pediatric registries such as the United Network for Organ Sharing, the United States Renal Data System, the Collaborative Transplant Study, the Australia and New Zealand Dialysis and Transplant Registry, and the newly formed Cooperative European Pediatric Renal Transplant Initiative Registry in Europe have improved prevalence data. But they are all limited, retrospective and have inherent issues related to data collection methods.

Pediatric metabolism cause different drug processing capacity and dosing of immunosuppression. Therefore, despite outstanding adult transplant studies, meticulous pediatric pharmacokinetic studies have been invaluable in accurately dosing immunosuppression in children (24,25,33,34). In addition, unique features of the pediatric immune system have been studied in numerous mechanistic studies (35,36,37).

The pendulum continues to swing between over and under-immunosuppression and as researchers and clinicians attempt to find the balance, novel research continues. Immune cell function assays to measure patient cell-mediate immunity on an individual basis have not been successful (38) and the establishment of antigen-specific tolerance to the kidney transplant is not yet a reality in pediatrics (39).

Pediatric Kidney Transplant Outcomes

Patient Survival and Post-Transplant Infection Burden

Following unacceptably high mortality in the initial transplant recipients due to overwhelming infections, caution and weaker immunosuppression lead to unacceptable high rejection rates that have reduced with modern immunosuppression ( Figure 2 ). In 1971, the results of 58 infant and pediatric kidney recipients, the youngest being 2 mo of age (7) were reported. Prior to 1968, during the era of total body irradiation, mortality rates were staggering particularly for deceased donor kidney recipients (DDKT) (8 of 11 DDKT patients died within the 3-y follow-up period of sepsis and other infectious complications). The introduction of Minnesota Anti-Lymphocyte Globulin and cessation of total body irradiation, improved patient survival dramatically with 3-y death rates of 29% in DDKT although in living donor recipients it was as low as 4% (7). These results were similar to other pioneer centers doing kidney transplantation in children at that time (18).

Figure 2
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Patient and graft survival in the early days of transplant compared to the modern era for living and deceased donor kidney recipients. Of note, graft and patient survival remain the same since the 1970s with same surgical techniques as during the pioneering period. Therefore, despite the improvement in outcomes following initial transplantation, nonsurgical components of kidney transplantation remain imperfect over the last five decades; and indefinite functioning of kidney transplants without immunosuppression remains a target for the next 50 years. *TBI Total Body Irradiation. **Post-TBI Era.

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Today infection is now the dominant cause of pediatric hospitalizations and death after transplant (40) and many infectious agents are oncogenic; dramatically increasing the lifetime risk of cancer for pediatric transplant recipients. “Transplant lung” was a febrile pulmonary symptom seen in many early kidney transplant recipients. Although initially considered as immunologic, it was soon realized to be an infectious process due to cytomegalovirus (CMV). In early kidney transplants, more than 50% of deaths were attributed to CMV (41,42) making the discovery of valganciclovir, an anti-CMV drug, one of the most critical and pivotal advances in the field of kidney transplantation. Valganciclovir has particularly galvanized pediatric kidney transplant since pediatric patients are at higher risk for post-transplant CMV due to the higher prevalence of CMV antibody negativity in children. Today valganciclovir is used for therapy and universal prophylaxis against CMV. The marrow suppressive side effects of valganciclovir have prompted studies to find alternative antiviral drugs and preventive measures (43) and currently a randomized controlled trial comparing valacyclovir and valganciclovir is in progress at the University of Minnesota. Other deleterious viruses in transplant include the Epstein-Barr virus, known for its potential to cause a premalignant post-transplant lymphoproliferative disorder and BK virus, a papova virus, which can cause BK nephropathy leading to graft loss (44,45).

Unique issues related to growth, development, and neurocognitive maturation, the increased risk for primary infections, and complications related to congenital/inherited disorders (the most common cause of renal failure in children) are now recognized in children. Awareness has caused more judicious use of immunosuppression aided by advances in antiviral therapy and research is underway to develop immunosuppressants with antiviral and antioncologic properties (46,47). The advent of modern vaccinations, a new genre of anti-infectives, and the results of several novel studies to identify the role of the donor in post-transplant recipient infections and to reduce donor transmission of these viruses (48,49,50) continue to shape the field of pediatric kidney transplantation. Not surprisingly patient survival has markedly improved, with pediatric patient survival at 3 y > 95% in deceased and living donor recipients of all ages (51,52,53).

Graft Survival and Rejection Rates

Graft survival has also improved with surgical experience, better pretransplant recipient preparation, adult kidney to pediatric recipient transplants, improved induction and maintenance immunosuppression and better donor-recipient matching; with a consequent reduction in technical failures and hyper-acute rejection ( Figure 2 ). In one of the largest pediatric transplant centers at the time, the reported graft survival was 71 and 36% at 3 y of transplant for living and deceased donor recipients respectively prior to the utilization of Minnesota Anti-Lymphocyte Globulin induction therapy. This has improved to 96 and 86% of living donor and DDKT at 3 y following the advent of induction immunosuppression and maintenance with azathioprine and steroids (7). Similar pediatric kidney graft outcomes were reported by others during this era (10,18). Since then short-term graft survival has shown consistent improvement (53). Long-term graft outcomes have plateaued for reasons that are not well-defined.

While modern immunosuppression has bridged the outcome gap between deceased and living donor kidney transplants, living donor graft outcomes remain superior. Recurrence of primary glomerular diseases such as focal segmental glomerulosclerosis and nonadherence remains highly problematic adversely affecting graft outcomes. However, there remains no reliable solution to either problem at this time.

Rejection rates initially as high as 80–90% is currently 10% in most pediatrics transplant centers. However, exact comparison of rejection then and now is impossible due to different diagnostic definitions of rejection; the reduction in the incidence of rejection is definite. In addition to advances mentioned above, safer ultrasound guided transplant biopsy techniques, which have increased the yield and number of biopsies per transplant patient with a decrease in morbidity. Surveillance biopsies and the Banff diagnostic pathology guidelines for the diagnosis and staging of rejection have also added greatly to the field; as has the ever-growing range of modern therapies to treat acute cellular and antibody mediated rejection. Research is underway to find noninvasive biomarkers of acute rejection that might replace transplant biopsy (54,55) and shed mechanistic light on rejection allowing for more targeted therapy.

Early studies in patients with a primary graft loss due to rejection showed that retransplantation was associated with poor outcomes (56,57). Nevertheless, with better immunosuppression, this appears to be less of an issue. Prior graft loss to nonadherence is still associated with increased graft loss to nonadherence after retransplant and we appear to be no closer to solving the problem of nonadherence as we were 40 y ago (58,59).

Access to Pediatric Kidney Transplantation

Although children make up only a small fraction of persons awaiting kidney transplantation, today they have been afforded exceptional societal benefits in many countries while in others despite excellent graft outcomes, they remain disadvantaged and neglected due to socio-economic and cultural issues (60). The current kidney allocation scheme in the United States preferentially allocates higher-quality kidneys from deceased donors to children in relatively prompt fashion (61) with an unintended decline in the donation of kidneys from living donors; a greater proportion of poorly HLA-matched kidney transplants from deceased donors in children (1); a reduction in racial disparities in access to pediatric kidney transplantation (62).

The 21st century has also seen a dramatic change in the transition of print media (newspapers, magazines) to electronic media. Since the birth of the internet almost 30 y ago, there has been an information explosion and the imbalance in the need for a kidney transplant and the availability of these organs is now a highly publicized topic as is the minimal morbidity for kidney donors (63,64) and comparable graft and patient outcomes for living donor kidney recipients regardless of whether the donor is related or not (65,68). Therefore media appeals for kidney donors are gaining popularity (67) and living unrelated kidney donation is on the rise. While the ethics of organ donation has always been a sensitive issue, in this modern era of unrelated donors, it is becoming all the more relevant.

While this review focuses on the developed world, in many developing nations, children with kidney failure have limited access to dedicated pediatric nephrology and do not have the option of kidney transplant. Even centers that perform kidney transplant have unacceptably high infection rates and mortality. There remains much to be done.

Summary

In summary, since the first pediatric kidney transplant in the 1960s, the field of pediatric kidney transplantation has come a long way. We have made major advances in immunosuppression, surgical technique, medical management pre-, peri-, and postoperatively, donor–recipient matching, deceased donor kidney allocation, infection prevention and treatment, better recipient and donor selection and preparation with a multi-disciplinary team approach and of course the multi-center randomized controlled trials that have allowed for meaningful outcome analysis.

However, pediatric kidney recipients still die of infections; post-transplant lymphoproliferative disorders and malignancy remain a very real risk; recurrent focal segmental glomerulosclerosis is yet to have a cure; long-term graft attrition remains an issue; tolerance where patients could be weaned off maintenance immunosuppression is currently far from reach; and nonadherence remains a critical and often unsurmountable detriment to graft survival.

No single review article, can truly address all the critical areas that have shaped the field of pediatric kidney transplant. There is much left unsaid in this manuscript on nonadherence, recurrent disease, rare diseases, cardiovascular disease, post-transplant lymphoproliferative disorder, growth and bone disease, quality of life, reasons for the plateau in long-term outcomes, transplant glomerulopathy, and other viral infections than are covered here. In conclusion, the advancement and progress in pediatric kidney transplantation in the developed world is awe-inspiring with still much to be done. Access to pediatric kidney transplantation in developing nations remains suboptimal. As history has shown, careful and methodical prospective multicenter work is critical in advancing our field and while problems remain, the progress made to date promises more advances in the future for pediatric patients requiring kidney transplantation.

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