Small children represent a minority of all pediatric patients with end-stage renal disease (ESRD) in need of kidney transplantation (KT). The incidence of children undergoing renal replacement therapy before 2 years of age is about 7–8 per million age-related population.1 Recipients younger than 1-year-old sum <5% of kidney transplanted children in the NAPRTCS transplant registry.2 This subgroup is predominantly composed of males with congenital abnormalities of the urinary tract as the leading cause of ESRD3-5 and usually need surgical correction of urinary tract before KT. More than one-third of these patients have comorbidities, such as syndromic diagnosis diagnosis, cerebral palsy, heart disease, and developmental delay.6
Kidney transplant in small children is considered a challenge because there are some added risks as thrombosis and surgical complications due to the small size of vessels and size discrepancy between the graft and the recipient. Excellent intraoperative fluid management and blood pressure maintenance to ensure adequate perfusion of the allograft are particularly essential goals. Besides that, awareness and prompt treatment of viral infections and malignancies in these patients are also crucial to ensure the success of the transplant, considering that a significant proportion of them have negative serology for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and other viruses.3
Despite the exposed difficulties, there has been a marked improvement in the overall outcome of KT in children ≤15 kg, with an excellent long-term patient and graft survival that is comparable with older children and adults in specialized centers.7-19 Additionally, KT outcomes are superior to dialysis in terms of survival rates,20 growth,2 neurocognitive development,21 quality of life,22 and are also a more cost-effective therapy.23
Summing up, KT is the treatment of choice for children with ESRD and should be performed as early as possible.3,20 The appropriate timing for KT in small children is not precise, but studies have shown that children ≥6–7 kg can be safely transplanted in specialized centers.10-12,14 However, when compared with other pediatric age groups, small children have lesser access to KT, both in Brazil and other countries.4,24-26 Several factors are cited as barriers to referral and transplantation of small children as a shortage of specialized centers in pediatric KT, emphasizing the particular need for pediatric urologists.27
This study describes a strategy performed in Brazil to enable and accelerate KT in children ≤15 kg based on the establishment of one specialized KT center focused on small children working in network with distant pediatric centers throughout the country. In this article, we also present the number and outcomes of KT performed in small children as a result of this strategy. We believe that the implemented model can be useful to other locations.
MATERIALS AND METHODS
Description of the Strategy Adopted
The approach was the establishment of one specialized pediatric center focused on providing KT for small children throughout the country. Since its inception, this center has acted simultaneously on 3 fronts: (a) providing excellent medical assistance, to enable and accelerate KT in children ≤15 kg; (b) coordinating educational activities to disseminate expertise and to establish professional network in the care of children with ESKD around the country; and (c) fostering research to contribute to the promotion of scientific knowledge in the area.
The center started in 2008 with a partnership between the National Transplant System (Brazilian Ministry of Health) and a nonprofit hospital (Hospital Samaritano de São Paulo). The hospital structure and human resources necessary to the operation of the center and practical actions are described in Figure 1. The Ministry of Health financed all the activities. Projects and plans of action were elaborated by the specialized center team for repeated periods of 3 years. They were consecutively submitted for analysis and approval by the government in each triennium.
Children from different states of the country needing KT could be referred by local pediatric teams to the specialized center, regardless of public or private funding. The partnership engaged between the center and the “Support Houses,” which are temporary housing for patients and companions from other locations during the treatment period in São Paulo, was invaluable to enable the program. Therefore, low-resource families were able to use these dwellings for the entire period necessary to the workup for KT and subsequently up to an average of 3 months after the surgery. After the first 3 months post KT, follow-up was performed alternating consultations in the dedicated center and the origin hospital.
As for education, a program was designed to qualify professionals to take care of small kidney transplanted children close to their localities, sharing the posttransplant follow-up with staff from the transplant center. A hands-on course, with 3 months duration at the specialized center, was offered annually for 4 sets, each composed by a nephrologist, a nurse, and a surgeon. The Ministry of Health screened and selected the professionals to participate in this program, favoring professionals from the regions in the most significant need for the training. Additionally, a weekly teleconference was conducted involving professionals from the specialized and local team to exchange clinical opinions about shared follow-up patients ensuring the sustained training of selected professionals and the quality of assistance.
At the same time, a pediatric KT Medical Residency Program was started at the specialized center for pediatric nephrologist physicians with a 1-year duration for 2 annual openings.
Research activities were initially aimed at understanding the epidemiology of ESKD in children in Brazil or to report new aspects of clinical care of children with ESKD. Residents and doctors of the service were encouraged to develop research in these areas. Master’s and postdoctoral theses were developed in partnership with one University.
KT Outcomes During the Strategy Period
To evaluate the clinical efficacy of the program, we compared outcomes of KT performed in “small children” (≤15 kg) to the outcomes of KT in children >15 kg performed in the same specialized center. We also compared patient and graft survival of KT in small children with data from the literature.
Data from all pediatric KT (<18 y) performed at Hospital Samaritano de São Paulo in the studied period (2009–2017) were evaluated. Children were categorized into 2 groups according to their body weight at the time of KT: (a) those with weight ≤15 kg (group 1, “small children” group) and (b) weighing >15 kg (group 2, “heavier children” group) to compare the outcomes between the 2 groups.
The primary clinical outcomes adopted were (a) the patient survival at 1, 3, and 5 years; (b) the death-censored graft survival at 1, 3, and 5 years; and (c) graft function, represented by estimated glomerular filtration rate at 3 years. Major complications as the need for reoperation before hospital delivery, vascular thrombosis, and posttransplant lymphoproliferative disease (PTLD) were secondary outcomes.
The following data regarding patients and kidney transplants were obtained from medical records: age, weight, and height at KT, gender, cause of ESRD, renal replacement treatment immediately before KT, and necessity of >1 renal replacement treatment modality, number of blood transfusions, CMV and EBV serology, donor type, donor age, retransplants, patients transplanted in waitlist priority, panel-reactive antibody, cold ischemia time (CIT) for deceased donors, number of HLA mismatches between recipient and donor, induction therapy, initial immunosuppressive therapy, length of stay at hospital after KT, and complications after KT (incidence of reoperation before discharge from hospital after KT, vascular thrombosis, PTLD, graft loss and death).
Estimating the Number of Pediatric KT Throughout the Country During the Strategy Period
The number of KT performed in children aged <5 years around the country was collected from the database of the CoBrazPed registry (Brazilian Registry of Pediatric Kidney Transplant). CoBrazPed is an active and voluntary registry that represents KT centers in the country since 2004. We used these data to test a likely increase in KT in small children throughout the country and to infer the impact of the activity of the specialized pediatric KT center in the result. Age range (0–5 y) was used, because there is no data on children’s weight in the CoBrazPed registry.28,29 The ratio of KT in children 0–5 years registered before (2004–2008) and during the strategy period (2009–2017) was compared.
A comparison of proportions between groups was made using the chi-square test or Fisher’s exact test, whereas the quantitative variables were compared with the Student t tests for independent samples or the Mann-Whitney U test. We used the Kaplan-Meier method to estimate the patient’s survival, the death-censored graft survival, and comparisons between groups were through the log-rank test.
All tests were 2-tailed, and a 5% limit (α < 0.05) was adopted for the null hypothesis rejection. We used Stata software (College Station, TX) version 15.1 in all statistical analyses.
The study was conducted in compliance with the Declaration of Helsinki and the Declaration of Istanbul and approved by the institutional review board ethical committee.
In this article, we report the results of the strategy from January 2009 to December 2017 (3 triennial periods).
Three hundred forty-six pediatric KTs were performed in the specialized center during this period, being 130 in children ≤15 kg (38%, being 41 children ≤10 kg) and 216 in >15 kg (62%). The mean (SD) weight and age in the “small children” group were 11.6 kg (2.1) and 3.8 years (1.8), whereas, in the “heavier children” group, these values were 29.2 kg (12.3) and 11.6 years (4.0), respectively. The patient with minimum weight at KT had 6.7 kg. Congenital abnormalities of the urinary tract was the most common cause of ESRD in both groups, being responsible for 66% of cases in the “small children” group and 43% in the “heavier children” group. Forty-three percent of the transplanted patients came from the state of São Paulo, the most populated state in the country, and where the center of excellence is located. In contrast, the remaining 57% came from 14 of 26 different states of the country.
“Small children” group had a higher percentage of boys and negative serology for both CMV (52% versus 22%) and EBV (65% versus 24%) before KT and a statistically significant need for a switch in dialysis therapy and blood transfusions. Demographics and clinical data are described in Table 1.
Regarding KT, the groups were similar for donor type (around 80% deceased donor), donor age, CIT, number of HLA mismatches, delayed graft function, and prioritized patients in the waitlist. However, the length of hospital stay after KT was longer in the small children, and retransplant was more frequent in the “heavier children” group. The immunosuppression scheme preferred for both groups was the induction therapy with Basiliximab and maintenance with calcineurin inhibitor (CNI) associated with steroids and antiproliferative drugs. As for the CNI, tacrolimus was preferred in the “heavier children” group, whereas cyclosporine was more frequently used in children from the “small children” group. Azathioprine was the most used antiproliferative drug in both groups.
Patient and graft survival after 1, 3, and 5 years of KT were similar in both groups. The patient survival was 97%, 97%, and 95% in the “small children” group, while 99%, 97%, and 96% in the “heavier children” group. Regarding the graft survival, we observed in the “small children” group 91%, 88%, and 87%, whereas in the “heavier children” group, the results were 94%, 90%, and 87%, respectively. The results are depicted in Figure 2. The groups were similar in the incidence of reoperation after KT surgery, vascular thrombosis and PTLD, and estimated GFR (Table 2). Moreover, survival data from our sample were comparable to similar data from the literature8-19,30-37 (Table S1, SDC, https://links.lww.com/TP/B939).
The workup for transplantation was predominantly done at the specialized center and is detailed elsewhere.27 In brief, pediatric urologists’ interventions, psychological preparation, and other needs for KT preparation were shared with local colleagues, when available. The transplant surgeries were performed at Hospital Samaritano. Patients from distant states of the country were repatriated 3 months after transplantation or later as soon as clinically stable to continue the shared posttransplant follow-up. There was no loss of follow-up. When needed, patients requiring graft biopsy or surgical interventions were referred to the specialized center, as very few local services can perform these procedures.
Data from CoBrazPed Registry show 242 KT performed in children aged <5 years throughout the country during the period 2009–2017, being 112 KT (46%) performed at Hospital Samaritano.
Proper care of young children in need of KT requires a large number of skilled professionals and a complex and expensive hospital structure. The relatively small number of these children makes it difficult to attract and train professionals to work in this area. For all these reasons, it is not justified that these transplants be performed in many centers, especially in less-populated areas. However, studies show that young children have restricted access to KT both in Brazil and in other countries4,24-26 although KT is their treatment of choice.20
In this scenario, the strategy adopted in Brazil made it possible to perform a large number of KT in young children from various regions of the country and with excellent results.
Pediatric KT centers generally report 15%–25% of their pediatric transplants in children <15 kg.10,17 We performed 130 KT in children weighing ≤15 kg (38% of total transplanted children) in 9 years of operation. To the best of our knowledge, this is the largest small children KT series described in a single-center, considering the period evaluated as represented in the Table S1, SDC, https://links.lww.com/TP/B939.
A large number of referrals of young children from various regions of the country reflect the rapid acceptance of the program by Brazilian pediatric nephrologist groups. We consider that the shortage of specialized services for referral of these patients, in conjunction with the initiatives carried out in the educational/networking and research fields, were critical factors in this result.
The presence of professionals from pediatric centers of different locations involved in the hands-on course, and the weekly teleconferences with professionals from referring centers, has prompted well-established partnerships. These actions were fundamental to ensure uniformity of clinical care in the follow-up of KT children in their localities and also to reduce the need for families to travel to the specialized center, improving quality of life and decreasing costs for treatment. Besides, it encouraged pediatric nephrologists from other transplant centers to reduce the minimum weight required for the transplant recipient at their localities.
The lack of data on receptor weight in the Cobrazped registry prevented us from directly assessing the increase in KT number in small children, considering the same criteria of our study (≤15 kg). However, we detected a significant input of Hospital Samaritano in the number of KT in children under 5 years after the inception of our center. We believe that this result is evidence of the efficacy of the approach described in this article.
The strategy presented here should not be uniquely responsible for accelerating KT in young children. Other factors may have contributed to this result, such as improved surgical technique and immunosuppressive drugs in KT over the years. Also, KTs performed at other transplant centers in the country, and the encouragement of physicians to indicate KT earlier may have contributed.
Patient and renal graft survival rates at 1 and 5 years in our cohort were similar in both groups and comparable to those described in the literature (Table S1, SDC, https://links.lww.com/TP/B939). Moreover, the estimated glomerular function at 3 years follow-up was not different. These findings are in line with international reports showing that KT in small children has similar results to those of older children and corroborates the indication for early transplantation in these children.
There is no consensual designation of what criterion defines a “small children” concerning KT. We considered the group of children ≤15 kg as small for the following reasons: (a) from a surgical point of view, weight is more important than age for KT, since children with ESRD are often malnourished and (b) many centers use 15 kg to define small children and cutoffs to accept a patient for KT.8,13,15,17-19,37 In our study, we observed a considerable variation of age (9 mo to 11 y) in the “small children” group, who weighed ≤15 kg, reinforcing the idea that weight should reflect better than age, the size of the child, and the difficulty in his or her management.
In the “small children” group, most of the children were in hemodialysis at the moment of KT. This number differs from most studies in the subject, which describe peritoneal dialysis as therapy of choice for small children.5 Compared with the “heavier children” group, these children had significantly more dialysis therapy exchange and more blood transfusions and also were more often prioritized for lack of dialysis access. We understand that these differences are because Hospital Samaritano is one of the few services that perform hemodialysis in young children in Brazil. Therefore, it is also a reference for infants with loss of peritoneum function.
One of the negative consequences of having a specialized transplant center in a country of continental dimensions like Brazil can be verified by the prolonged CIT verified in both groups. Traveling recipients from remote cities to one specialized transplant center takes time. However, the DGF rate is quite reasonable and perhaps was minimized by the quality of the organs from pediatric donors typically offered to children. The organ allocation system preferentially provides donor kidneys <18 years to recipients younger than 18 years in our country.
The pediatric immunosuppression protocol used in the service is the same for all children. However, thymoglobulin is used in induction when panel >50% and was used more frequently in “heavier children” group children because of the higher number of re-KT in that group. We used more Cyclosporine than Tacrolimus in children in the “small children” group just because of the ease of swallowing this drug by younger children, as Cyclosporine is the only CNI available as a solution in the country. The difference in immunosuppression therapy between groups can represent a limitation of the study.
Despite challenges in the care of ESRD small children mentioned above, the short- and medium-term KT results were similar to the “heavier children” group, as also reported in the literature. Younger children require more vigorous posttransplant hydration to maintain adequate graft perfusion, which may justify significantly longer hospitalization time among children in “small children” group.38
In our study, there was no higher incidence of renal thrombosis in children from the “small children” group, and the incidence of thrombosis is in the average described for this population, which is typically about 0%–12%. Extraperitoneal placement of the graft was the surgical technique in both groups, and the strategy for vascular anastomosis has been previously described by our team.39 The smaller the size of the child, the smaller the diameter of their blood vessels, and, consequently, the more significant technical difficulty for vascular anastomosis during KT and the potential higher risk for renal graft vascular thrombosis. The experience of the group of surgeons operating in a large KT center in young children may have contributed to the reduced number of reoperations and thrombosis. PTLD is one of the most-feared complications in KT of children and is more frequent in younger children with EBV-negative serology before KT, a situation found in children from “small children” group.40-42 Fortunately, there was no higher incidence of PTLD in children from the “small children” group during the study follow-up, and the incidence of PTLD cases was similar to that described in the literature.41
The strategy of creating a center specialized in KT of children ≤15 kg combined with shared patient care, professional training, and stimulating research in the area was very satisfactory, allowing an improvement in the number of KT in young children with excellent results. We believe this experience may be useful in other locations.
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