947 through improved quality and/or duration of life Absolute contraindications to childhood renal transplantation include florid infections, malignancies, and severe concomitant diseases (e g , cardi[.]
49 Evaluating and Preparing the Pediatric Dialysis Patient for Kidney Transplantation 947 Table 49.1 Key elements of the transplant evaluation Consultant Required Nurse or Advance Practice Provider/Transplant Educator Transplant Nephrologist Transplant Nephrologist Transplant Surgeon Psychologist Social Worker Transplant Pharmacist Transplant Dietician Financial Counselor Urology Recommended Infectious Disease Cardiology Anesthesiology Other considerations Dentist Ophthalmologist Gynecologist Rationale Provide overview of transplantation process Sets expectations Provides education regarding living donation Review medical history in detail to identify any issues which might impact success of transplant Planning of immunosuppressive therapy Review surgical history and anatomy to identify any issues which might impact success of transplant Assess baseline psychosocial factors that may affect treatment adherence and help develop plan for intervention to optimize transplant readiness Assess baseline social support and resources available to support transplant and identify any potential concrete barriers to treatment adherence Explain anticipated treatment regimen, including risk profiles, drug interactions, and side effects Elicits potential adherence barriers related to medication regimen Assess overall nutritional status and discusses anticipated changes to diet and nutritional support post-transplant Assess insurance coverage (if applicable) and explains anticipated financial expectations and burdens after transplant (USA) Required assessment for all children with CAKUT Review vaccine history, assess antibody responses, and recommend any outstanding vaccinations to optimize infectious disease protection prior to transplant Obtain echocardiogram or EKG as indicated Review anesthesia history pre-operatively to assess any required modifications or concerns Identify and treat any dental caries prior to transplant Obtain baseline fundoscopic exam to rule out increased intraocular pressure, cataracts, etc For all menstruating females through improved quality and/or duration of life Absolute contraindications to childhood renal transplantation include florid infections, malignancies, and severe concomitant diseases (e.g., cardiovascular, bronchial/lung, and liver disorders), which may prove life-threatening during transplantation or which could compromise the long-term successful outcome of transplant surgery Physical or intellectual disability is not a contraindication to transplantation [9] Relative contraindications to kidney transplantation include nonadherence and lack of family support or supervision to the extent that these conditions would impair successful transplant maintenance Surgical Considerations In children, the timing of transplantation may be heavily impacted by disease etiology Unlike adults, the most common cause of end-stage renal failure in children is congenital anomalies of the kidney and urinary tract (CAKUT), estimated to account for between 30% and 60% of cases worldwide, as reflected by various national and international registries [10] For children with significant urological impairment in childhood, the involvement of pediatric urology prior to transplant is critical Patients with severe vesicoureteral reflux or frequently recurring urinary tract infections may require single or bilateral 948 ureteronephrectomy to avoid the risk of urosepsis as a result of immunosuppressive therapy administered after transplantation Patients with significant voiding dysfunction will usually require urodynamic studies to ensure adequate bladder drainage to support successful transplantation Both bladder capacity and compliance should be assessed in children with CAKUT pre-transplant whenever feasible [11] Children with high pressure and small capacity bladders that are refractory to catheterization regimens may require urological reconstruction prior to transplantation to ensure reliable urinary drainage and to reduce the risk of urinary tract infection and allograft injury Occasionally, it may be necessary to augment a small bladder prior to transplantation using material taken from the intestine or ureter Nephrotic syndrome, focal segmental glomerulosclerosis (FSGS), and other secondary forms of glomerulonephritis account for 5–30% of pediatric chronic kidney disease [10] and also demand thoughtful surgical planning in advance of transplantation Nephrotic states will pose increased risk for acute thrombosis, and consequently, children with actively nephrotic end- stage renal disease may require nephrectomies with interim dialysis until hypoalbuminemia and proteinuria improve Besides active nephrosis, there are a few other conditions in which nephrectomies are performed either in advance or at the time of transplant Pre- transplant nephrectomy is generally performed in children with genetic predisposition to renal malignancies, i.e., Wilms tumor/Denys-Drash syndrome [11] Nephrectomies are also often necessary for children with autosomal recessive polycystic kidney disease, due to the large renal mass of the native kidneys which may limit the space available for the newly transplanted organ Lastly, surgical evaluation of a pediatric candidate is also focused on ensuring that there is a suitable location for vascular anastomoses that will provide adequate venous outflow Any child with known or suspected thrombosis of the pelvic vessels will require abdominal imaging for surgical planning Inferior vena cava (IVC) thromboses make kidney transplantation extremely challenging [12, 13] Femoral hemo- S Amaral and L Pape dialysis catheters pose a significant risk for IVC thromboses and should be avoided in children with chronic kidney disease as much as possible [13] Similarly, in children on peritoneal dialysis, the complexity of transplant surgery is increased in children who have experienced encapsulating peritoneal sclerosis, and all efforts should be made to follow national and international guidelines and care bundles to reduce the risk of peritoneal infections [14–16] There is some international variation when peritoneal catheters are removed after transplant, but there is a risk of peritonitis and exit site infections when catheters are not removed at the time of transplant [17] Timing of removal of either hemodialysis or peritoneal catheters will depend on the likelihood of delayed graft failure or risk of recurrent disease after transplant and should be discussed as part of advanced surgical planning Medical and Immunological Considerations Whenever possible, living donation is preferred as it is associated with graft and patient survival benefits compared with deceased donation Living donors are most commonly parents and immunologically well-matched, but there have been trends toward more unrelated donors [18] Some centers offer kidney paired exchange programs, in which an incompatible donor for recipient candidate A can donate to recipient candidate B and recipient candidate B’s incompatible donor donates to recipient candidate A. Such exchanges can occur over many more than two recipient–donor pairs and are an excellent option for increasing access to living donation for children and adults, particularly for those patients who are highly sensitized [19, 20] Typically, children are transplanted with ABO compatible organs, although AB0 blood-group incompatibility is no longer considered an absolute immunological contraindication Some pediatric transplant centers have successfully achieved long-term results with ABO- incompatible kidneys similar to the outcomes achieved following 49 Evaluating and Preparing the Pediatric Dialysis Patient for Kidney Transplantation ABO blood group-compatible procedures [22] However, the organ recipient must undergo conditioning treatment prior to transplantation in the form of antigen-specific immunoadsorption to remove blood group antibodies Due to the device-related extracorporeal volume, immune adsorption is less problematic to carry out in older children than in infants In addition, the protocols currently used for living kidney donors who are incompatible with the ABO blood groups advocate more intensive immunosuppressant induction therapy with the B-cell-depleting antibody rituximab, which potentially increases the risk of infection A notable exception to this higher immunologic risk is the transplantation of A2 and A2B kidneys into B and O blood type recipients when there are low (≤4) anti-A IgG isoagglutinin titers In such a situation, immunosuppressive regimens and long-term outcomes are favorable and similar to ABO-compatible transplantation [23] The issue of specific immunological risks should be broached during discussions with the recipient and their family members Previous graft losses due to immunological causes have an adverse effect on subsequent graft survival The presence of pre-formed class I or class II cytotoxic anti-human leukocyte antigen (HLA)-specific antibodies in the blood is also critical, especially if these have originated through a previous transplant or transfusion A complete HLA-typing is needed, and tests for pre-formed, panel-reactive antibodies should be repeated at least quarterly, especially after blood transfusions Children with FSGS are at risk of recurrence of nephrotic syndrome following kidney transplantation Caregivers of children with FSGS should be counseled about this possibility However, children with FSGS associated with an identified mutation(s) are at negligible risk and thus genetic testing may be helpful to better understand the risk of post-transplant recurrence A recent US study of children with steroid-resistant nephrotic syndrome found that overall, 41% recurred in their renal allograft Disease recurrence was much more common among children with latesteroid resistance (78%) vs children with primary steroid resistance (40%) [24] 949 Screening for congenital or acquired thrombophilia is also strongly recommended in order to plan anticoagulation therapy for the transplant procedure (Table 49.1) When children are on dialysis, there are numerous opportunities to promote the long-term success of their transplant through optimal chronic kidney disease management For example, appropriate use of erythropoietin-stimulating agents and iron can reduce the need for pre-transplant blood transfusions which ultimately reduces the risk of human leukocyte antigen (HLA) sensitization Although blood transfusions can be administered as leukocyte-reduced, this procedure does not entirely eliminate the risk of sensitization Vascular access should be preserved to the extent possible, ideally avoiding the pelvic vessels as previously noted Optimizing growth through the use of recombinant growth hormone and nutritional supplements with or without feeding tubes can help a child reach the minimal bodyweight for transplant eligibility and also provide longterm benefits in terms of growth and nutritional status Pre-transplant growth failure has been associated with faster time to reduced kidney function after transplant [25] The leading causes of mortality in transplant recipients are cardiovascular and infectious complications Achieving optimal blood pressure control and fluid management can reduce long-term cardiovascular risks [26] Generally, children under transplant evaluation are required to receive all age-appropriate vaccinations, particularly vaccinations with live vaccines, to reduce the risk of vaccine-preventable infections Of note, pediatric transplant recipients have been shown to have impaired vaccine responses compared with healthy children, children with chronic kidney disease, and children on dialysis Whether additional vaccine doses or altered dosing schedules are needed is not clear based on current evidence and should be discussed on a case-by-case basis [26, 27] In turn, cautious infection prophylaxis is crucial prior to elective transplantation Potential infectious foci (urinary tract, skin, teeth, and paranasal sinuses) must be cleansed Furthermore, family members and medical staff coming into close contact with the 950 patient should have an up-to-date vaccination schedule to promote herd immunity Pediatric transplant candidates should also meet with a renal dietician for assessment of their baseline growth and nutritional needs and discussion of anticipated changes post-transplant As suggested above, many younger patients may require g-tube placement prior to transplant to promote growth and nutrition and reach minimum bodyweight for surgery Although many children will experience increased appetite after transplant, particularly if they are on steroid- based immunosuppressive regimens, some children will have ongoing problems with speech and feeding disorders and may require long-term g-tubes and enteral support to meet nutritional needs and fluid goals Attention to pre-transplant nutritional status is critical, both to identify underweight and growth failure conditions, as well as obesity and overweight conditions Aberrant weight and growth in children pre- transplant are associated with poorer transplant outcomes across numerous studies [25, 29–31] In a US study of 18,261 pediatric kidney transplant recipients, obesity was associated with greater odds of delayed graft function (OR 1.3; 95% CI: 1.13–1.49), acute rejection ((OR 1.23; 95% CI: 1.06–1.43), graft failure (HR 1.08; 95% CI: 1.05–1.22), and mortality (HR 1.19; 95% CI: 1.05–1.35) [29] Obesity post-transplant has also been associated with a higher cardiometabolic risk [31] Transplant pharmacists also play a key role in the pediatric transplant evaluation The transplant pharmacist reviews the anticipated post-transplant medications and common adverse effects with patients and families and identifies any potential allergies or drug interactions Further, the transplant pharmacist can identify potential barriers to children receiving their medications as directed For example, a pharmacist may identify that a child has difficulty swallowing pills or an oral aversion which can alert the transplant team of the need to create plans for liquid formulations of required medications or g-tube administration Pharmacists may also be the first to recognize that a child or parent has difficulty understanding directions and can help the team determine how S Amaral and L Pape to promote adherence in the setting of poor health literacy [32] Pharmacists will discuss and reinforce the importance of timing and consistency in medication administration They also help identify ways to reduce treatment complexity, such as reducing the number of different pharmacies from which a patient receives medication or setting up mail-order pharmacy services Establishing a relationship between transplant pharmacy and the pre-transplant candidate may also prove beneficial in the post-transplant setting The participation of transplant pharmacists in the interdisciplinary kidney transplant team has been associated with improved medication management, discharge planning, and patient education for transplant recipients [32] Psychosocial Considerations Although transplantation is the preferred treatment modality for end-stage renal disease over dialysis, transplant still incurs substantial demands on the patient and family and requires rigorous adherence to a complex treatment regimen Assessment of any psychosocial barriers that might impair a patient or family’s ability to obtain daily immunosuppressive medications or required laboratory studies and clinic visits is essential prior to moving forward with transplantation A psychosocial assessment is generally mandated by regulatory and government agencies to be part of the transplant evaluation; however, how the psychosocial assessment is attained may vary In many transplant centers, the assessment is performed by a pediatric clinical psychologist and a social worker The clinical psychologist’s focus is generally two-fold: (1) to assess the child’s psychosocial abilities and co-morbidities and (2) to assess the family structure [33] An understanding of the child’s neurocognitive abilities with respect to their potential for independent healthcare self-management is critical to formulate realistic expectations regarding how much assistance a child will need to adhere to their treatment regimen as they transition into adolescent and young adulthood Adolescence is a high-risk period for allograft 49 Evaluating and Preparing the Pediatric Dialysis Patient for Kidney Transplantation loss and risk factors for nonadherence may be identified pre-transplant to help alert the transplant team about patients who may need additional post-transplant support [33] Screening for psychiatric co-morbidities, such as depression, should also be performed as these disorders may also pose a risk for difficulties in adhering to treatment regimens [34] The psychologist also assesses family dynamics to understand the child’s emotional support structure Abnormal family dynamics, including parental distress and a lack of family cohesion, are well-recognized risk factors for poor transplant outcomes in children [35] The psychologist must also evaluate the child and family coping abilities, identifying any fears and anxieties surrounding transplantation The evaluation conducted by the social worker generally focuses on assessment of concrete resources, such as travel logistics for attending appointments and obtaining laboratory studies and anticipated insurance and out-ofpocket costs Social workers may also help liaise with a child’s school and caregiver’s employer to create plans for supporting a child’s education and a family’s financial stability during the posttransplant period 951 Deceased Donation Although children generally receive priority for deceased donor kidney transplantation, waiting times for deceased donation vary from months to years, depending on national allocation schemes, deceased donor organ supply and demand issues, and individual-level factors such as blood type and sensitization As examples, the allocation systems of Eurotransplant and of the United Network for Organ Sharing (UNOS) in the United States are described In the case of many European centers, listing is managed by the Eurotransplant Foundation in Leiden (the Netherlands), which is the central European distribution center for donor organs In Eurotransplant, kidneys are initially allocated for transplantation according to histocompatibility criteria and secondly based on the level of immunization and patient waiting times This allocation procedure is widely accepted in Europe as extensive data corroborate the important role of histocompatibility in confirming early and late graft survival Children under 16 years of age are given preferential treatment for organ donation The aim of carrying out early transplantation of a deceased donor kidney during childhood is often impossible today due to the Evaluation to Transplant high number of dialysis patients, the declining willingness of the population to donate organs, Once a child has completed the required com- and the inevitable increase in waiting times for ponents of the transplant evaluation, the multi- transplantation The average waiting time for disciplinary transplant selection committee meets children under 16 is currently 1.5–2 years in to determine eligibility In most cases, a child Eurotransplant countries, depending on blood is approved to either be placed on a deceased group In contrast to children, adolescents aged donor waiting list or scheduled to receive a living 16 and over have closed growth plates and are donor transplant In the United States (but not in viewed as adults by the Eurotransplant organ Eurotransplant countries), a child may be listed location center – hence the average waiting time inactive status (a condition in which the child can for this age group is currently 3.6–9 years The accrue waiting time but not receive organ offers) Eurotransplant allocation guidelines for pediatuntil certain criteria, such as demonstration of ric renal transplants were consequently changed consistent adherence or completion of vaccines, from 1.12.2010 to ensure that adolescents aged are met The actual time between reaching end- 16 and over, who still have the potential to grow, stage renal disease, completing transplant evalu- i.e., with open epiphyseal plates, receive the same ation, and receiving transplantation depends on benefits as younger children The waiting time numerous factors Access to living donation vs was reduced by adding extra pediatric points and deceased donation kidneys varies internationally, allocating the kidneys of donors under 16 years by country and cultural values of age to pediatric recipients [4] S Amaral and L Pape 952 In the United States, the United Network for Organ Sharing (UNOS) manages the national organ allocation, and organs are generally distributed locally, then regionally and nationally Similar to the Eurotransplant system, organs are allocated first based on blood type compatibility and then by sensitization and waiting times Pediatric priority is provided to children who are waitlisted at 50 years of age is linked to poor graft survival – hence only a kidney from a deceased donor