Incidence and Etiology

The incidence of ESRD in pediatric patients in the USA in 2006 according to the USRDS annual report varies by age group (Table 530-1). There is an adjusted incident rate of 14.4 per million population for ages 0 to 19 yr.

Table 530-1 INCIDENT RATES OF REPORTED ESRD IN THE USA

ESRD, end-stage renal disease.

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* Rates are adjusted for sex and race.

The etiology of ESRD in children varies significantly by age (Table 530-2). Congenital, hereditary, and cystic diseases cause ESRD in more than 52% of children 0 to 4 yr of age, whereas glomerulonephritis and focal segmental glomerulosclerosis (FSGS) account for 38% of cases of ESRD in patients 10 to 19 yr of age. The most common diagnosis in children with transplanted kidneys is structural disease (49%), followed by various forms of glomerulonephritis (14%) and FSGS (12%). Children also often start ESRD therapy with a higher estimated glomerular filtration (eGFR) rate than do adults; in 2001, approximately 50% of patients 0 to 19 yr of age had an eGFR >10 mL/min, compared to approximately 38% in patients 20 yr old.

Table 530-2 COMMON CAUSES OF ESRD IN PEDIATRIC TRANSPLANT RECIPIENTS (N = 9854)

ESRD, end-stage renal disease; MPGN, membranoproliferative glomerulonephritis.

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Indications

Almost all children with ESRD are considered to be candidates for renal transplantation. There are very few absolute contraindications for pediatric kidney transplantation. Relative contraindications include children with preexisting metastatic malignancy or HIV. Patients with remission of malignancy off maintenance treatment for a minimum of 2 yr may be reconsidered on an individual basis for transplantation, with close post-transplantation surveillance. Similarly, patients with autoimmune diseases resulting in ESRD are candidates for transplantation after a period of immunologic quiescence of the primary disease for a period of at least 1 year before transplantation. Another relative contraindication includes severe neurologic dysfunction, but the wishes of the parents and the potential for rehabilitation must be considered.

Renal transplantation is considered for any child when renal replacement therapy is indicated. In children, dialysis may be required for a period before transplantation to optimize nutritional and metabolic conditions, to achieve an appropriate size in small children, or to keep a patient stable until a suitable donor is available. For young infants, a recipient may need to weigh at least 8-10 kg to minimize the risk for vascular thrombosis and to accommodate an adult-sized kidney. This can require a period of dialysis support until the child is at least 12 to 18 mo of age. Transplantation with an adult-sized kidney has been successful in children who weighed <10 kg or were <6 mo of age.

Preemptive transplantation (i.e., transplantation without prior dialysis) continues to account for approximately 25% of all pediatric renal transplants, based mostly on a desire by the child and the family to avoid dialysis. There may be a small benefit in allograft outcome if transplantation occurs without prior dialysis, which might relate to a lower incidence of infections and cardiovascular risk factors. Preemptive renal transplant should be considered when GFR is <10-15 mL/min/1.73 m² and with symptomatic ESRD or rapidly declining GFR and need for dialysis within 6 to 12 mo. The rates of preemptive transplantation differ moderately for different age groups, being 20% for recipients aged ≤2 yr, 24% for 2-5 yr, 28% for 6-12 yr, and 22% for 13-17 yr.

Characteristics of Donors and Recipients

Data from the 2007 Scientific Registry of Transplant Recipients (SRTR) showed that approximately 2/3 of transplants are performed in children 11-17 yr of age, 17% are done in patients 6-12 yr of age, and 17% are in patients 1-5 yr of age.

Almost half of all pediatric kidney transplants come from living donors. From 1998 to 2003, 58% of pediatric transplants had come from living donors. According to the USRDS, for children ranging from 0-19 yr of age, there were 29 live donor transplants and 27 cadaver donor transplants per 100 dialysis patient–years. These figures are more than double the corresponding rates for adults. The highest rates of transplantation are in the 5-9-yr-old group, with 40 live donor transplants and 46 cadaver donor transplants performed per 100 dialysis patient-years.

The Organ Procurement and Transplantation Network (OPTN) provides preference for children waiting for a deceased donor renal transplant. Owing to improved outcomes in deceased donor pediatric transplantation using donors 5-35 yr of age, OPTN in 2005 implemented a pediatric kidney allocation policy that gave priority for kidneys from deceased donors <35 yr of age. These kidneys were assigned to recipients <18 yr, after 0 mismatch transplants, recipients with a panel reactive antibody (PRA) >80, or candidates receiving a kidney with a nonrenal origin. This policy shortened the wait time for children versus adults and is associated with improved outcomes.

From the 2008 North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) annual report, 48% of transplants in the registry were from deceased donors and 52% from living donors. Data from the OPTN/Scientific Registry of Transplant Recipients (SRTR) 2007 annual report show that in 2004 there were an equal number of living and deceased donor kidney transplants; recipients of living donor kidneys dropped to 47% in 2005 and declined even further to 35% in 2006.

Living donor kidney transplantation graft survival has improved over the years, and from 2003 to 2007 the graft survival rate in living donor renal transplants was 96.1%, unchanged from the 1999-2002 rate of 95.9%. Graft survival rates for deceased donors from 2003-2007 are 94.4%, also improved from 92.7% in 1999-2002.

For children awaiting deceased donor renal transplants the goals are to minimize waiting times, transplanting kidneys into children 0-6 yr of age within 6 mo, children 7-12 yr within 12 mo, and children 12-18 yr within 18 mo.

Evaluation and Preparing for Transplantation

The team approach includes evaluations by a transplant surgeon, nephrologist, nutritionist, social worker, psychologist, financial counselor, pretransplant nurse, and dialysis nurse (if the patient is on dialysis). Patients have a complete evaluation and discussions are undertaken with the patient and family as to what to expect with transplantation and during the post-transplant course.

Primary renal disease can recur in a number of renal diseases, but it is not a contraindication to transplantation. Recurrent disease in the renal graft accounts for graft loss in almost 7% of primary transplantations and 10% in repeat transplantations.

With focal segmental glomerulosclerosis (FSGS) and primary oxalosis, patients are at risk for major renal function impairment with recurrence of disease. The NAPRTCS database has found that grafts in ∼20-30% of patients with the diagnosis of FSGS fail because the disease recurs. In patients with the original disease of FSGS whose grafts fail, the mean time to failure is 17 months. Alport syndrome can recur as an antiglomerular basement membrane (anti-GBM) glomerulonephritis in approximately 3-4% of patients after transplantation and lead to graft loss. Histologic evidence of recurrence of membranoproliferative glomerulonephritis (MPGN) type I varies widely, from 20% to 70%, and graft loss can occur in ≤30% of cases. Histologic recurrence of MPGN type II disease occurs in virtually all cases, with graft loss in ≤50% cases. Histologic recurrence with mesangial IgA deposits is common and occurs in about half of the patients with IgA nephropathy and in about 30% of patients with Henoch-Schönlein purpura. Congenital nephrotic syndrome rarely recurs after transplantation, though patients can develop anti-nephrin antibodies and present with nephrotic syndrome. Some cases (∼25%) of nephrotic syndrome after transplantation are likely de novo. Membranous nephropathy occurs very rarely in children. The recurrence rate after kidney transplantation for patients who have been treated for Wilms tumor is about 13%.

Owing to the high risk of developing Wilms tumor, patients with Denys-Drash syndrome should undergo bilateral nephrectomy before transplantation. Other indications for bilateral native nephrectomies include hyposthenuria with polyuria, significant proteinuria, and severe hypertension resistant to medical management. Nephrectomies are also indicated in cases such as autosomal polycystic kidney disease, where more room may be needed to place the transplanted kidney and to create space in the abdominal cavity to improve feeding tolerability and the infant’s ability to thrive.

Failure to maintain adequate perfusion of the adult-sized kidney, secondary to a “perfusion steal” by the native kidneys, results in a histologic picture of “chronic” acute tubular necrosis and a negative impact on graft function.

Urologic problems such as vesicoureteral reflux, posterior urethral valves, abnormal urinary bladders, and/or neurogenic bladders should be addressed before surgery. Malformations and voiding abnormalities (e.g., neurogenic bladder, bladder dyssynergia, remnant posterior urethral valves, and urethral strictures) should be identified and repaired if possible. Children with urologic disease and renal dysplasia often require multiple operations to optimize urinary tract anatomy and function. Such procedures include ureteric reimplantation to correct vesicoureteral reflux, bladder augmentation or reconstruction, creation of a vesicocutaneous fistula by using the appendix to provide a simple, continent, and cosmetically acceptable way for intermittent catheterization (Mitrofanoff procedure), and excision of duplicated systems or ectopic ureteroceles that could cause recurrent infections. There are reports of excellent outcomes often being achieved in posterior urethral valve bladders by following a staged procedure of initial valve resection to limit any injury to the posterior urethra, and bladder rehabilitation, without the requirement of augmentation, by a process of regimented double voiding.

A comprehensive nutritional assessment needs to be done to ensure that optimal nutritional status is achieved before transplant. Many children with ESRD and especially those on dialysis require nutritional supplements to provide them with sufficient protein and calories. Infants and young children on dialysis often require nasogastric or gastric tube feedings to overcome decreased oral intake from nausea and anorexia due to uremia. Optimal outcomes result from transplanting adult-sized kidneys from living donors when the child weighs ≥10 kg.

Even with careful management of nutrition and bone health in children with kidney disease, most of these children have poor linear growth and are candidates for growth hormone therapy. Aggressive nutritional support is essential. Early gastrostomy or nasogastric tube feeding is often employed to improve caloric intake and promote growth, especially in children started on dialysis therapy at a young age. Linear growth tends to improve after transplantation in children with growth potential. Eighty-one percent of children receiving transplants grow better because they are no longer uremic. For children who continue to have poor growth velocity after transplantation, growth hormone can be restarted after the first post-transplant year due to potential risk for rejection if used early after transplant. Steroid-free immunosuppressant protocols show promise for normalization of linear growth after transplantation. Bone disease needs to be evaluated for and treated before transplantation. Secondary hyperparathyroidism needs to be treated before transplant to avoid post-transplant urinary phosphate wasting and hypercalcemia. High calcium phosphorus product before transplantation leads to vascular stiffness and calcifications, increasing the patient’s risk for cardiovascular disease.

Even in pediatric patients, cardiovascular disease is the leading cause of death in most ESRD mortality statistics. In the USA, >25% of the mortality in children on maintenance dialysis is due to cardiovascular disease. Cardiac death is the leading cause of death in young patients after transplant in childhood. Therefore, evaluation of cardiac function is required before proceeding with a kidney transplant in a pediatric patient to be sure that patient has sufficient cardiac function to tolerate the large fluid load that accompanies kidney transplantation. All patients being evaluated for kidney transplant have at least an echocardiogram and electrocardiogram. Hypertension is common and can result from fluid overload and/or intrinsic native renal disease. Blood pressure needs to be under optimal control before transplant. If blood pressure cannot be controlled with medical management, bilateral nephrectomy may need to be performed before transplant to control the hyper-reninemic response from the failing kidneys.

Anemia needs to be treated before transplantation. Most patients are on erythropoietin, folate, and iron to maintain goals for hemoglobin levels between 11 and 12 g/dL. Blood transfusions should be avoided owing to concerns for sensitizing the patient to HLA antigens before transplant. If a blood transfusion is required, patients should receive cytomegalovirus (CMV)-negative, leuko-reduced red blood cells. Blood should not be irradiated owing to concerns for trauma to the cells and potential for increased antigen exposure.

Evaluation for venous thrombosis and hypercoagulable states