End-stage renal disease (ESRD) is characterized by kidney failure that requires either chronic dialysis or kidney transplant. According to the US Renal Data System (USRDS) 2016 Annual Report, at the end of December 2014, 9721 children were receiving care for management of ESRD; of these, 1398 children represented incident cases of ESRD. Etiologies of pediatric ESRD can be divided into 4 main categories: congenital abnormalities of the kidney and urinary tract (CAKUT), primary glomerular diseases, secondary glomerular diseases, and hereditary/cystic kidney disease (Table 474-1). The degree of renal failure is characterized along a continuum and defined by chronic kidney disease (CKD) staging. The Kidney Disease Outcomes Quality Initiative (KDOQI) provides recommendations for follow-up and management based on CKD staging.
TABLE 474-1COMMON ETIOLOGIES OF PEDIATRIC END-STAGE RENAL DISEASE ||Download (.pdf) TABLE 474-1COMMON ETIOLOGIES OF PEDIATRIC END-STAGE RENAL DISEASE
|Glomerular diseases || |
Focal segmental glomerulosclerosis
Immunoglobulin A (IgA) nephropathy
|CAKUT || |
Congenital obstructive uropathies
Posterior urethral valves
Ureteropelvic junction obstruction
Ureterovesical junction obstruction
Prune belly syndrome
|Secondary glomerulonephritis || |
Systemic lupus erythematosus (SLE) nephritis
|Cystic/hereditary disorders || |
Autosomal recessive polycystic kidney disease
Congenital nephrotic syndrome
Renal transplantation is recognized as the better form of treatment for pediatric ESRD when compared to chronic dialysis as it offers the possibility of restoring normal kidney function, eliminating morbidity associated with renal impairment, and allowing for maximal cognitive, psychomotor, and physical development. However, preemptive transplantation is not always an option, and dialytic therapy often needs to be initiated. Timing of initiation of chronic dialysis therapy typically involves integration of laboratory data, clinical parameters, and psychosocial issues. There is no defined blood urea nitrogen (BUN) or creatinine value that serves as an absolute indication for the initiation of dialysis. Dialysis should be considered in children who are CKD stage 5 (glomerular filtration rate [GFR] < 15 mL/min/1.73 m2) and should be initiated in children who have uncontrolled hypertension, volume overload, metabolic derangements (hyperkalemia, acidosis, or hyperphosphatemia), malnutrition or poor growth, or uremic symptoms despite medical therapy with appropriate medication management and dietary modifications. There are 2 main modalities available in a dialysis program for infants, children, and adolescents: peritoneal dialysis (PD) and hemodialysis (HD). Selection of the appropriate modality is individualized to the needs of each patient and family. Patient size, age, lifestyle choices, parental preferences, and psychosocial assessments all play key roles in evaluating the choice of modality for chronic renal replacement therapy. Hence, the need for dialysis care should be anticipated as CKD progresses to allow for proper education of the patient and family, selection of modality, and planning for access.
PD is the preferred modality for smaller patients and infants with ESRD. It is the most common initial modality for children younger than 9 years of age and weighing less than 20 kg, as the treatment is provided without an extracorporeal blood circuit or need for large-bore venous access. For school-age children, it offers the advantage of greater flexibility in the timing of treatment, allowing for less frequent interruptions in school schedules. It can be successfully performed in patients with cutaneous ureterostomies, vescicostomies, prune belly syndrome, posterior urethral valves, and polycystic kidney diseases. There are, however, several absolute contraindications to PD, which include extensive peritoneal adhesions that obstruct the flow of dialysate, mechanical defects (eg, omphalocele, gastroschisis, diaphragmatic hernia, bladder exstrophy), peritoneal-membrane failure, and psychosocial issues such as the lack of a care provider. Relative contraindications to PD include the presence of ventricular peritoneal shunts, peritoneal leaks, body size (severe malnutrition or obesity), and inflammatory or ischemic bowel disease. As a home-based therapy, PD requires a structured program to prepare the caregivers with an adequate knowledge base to understand and participate in PD care while providing support to reduce anxiety and stress associated with providing a life-sustaining therapy at home.
PD is performed via a process of repeated instillation and drainage of dialysate into, and out of, the peritoneal space through a PD catheter. It is implemented without an extracorporeal blood circuit and works via a complex physiology based on the capillary permeability of the peritoneal membrane lining the surface of the abdominal wall reflecting over the visceral organs. The dialysate solutions contain electrolytes additives, except for potassium and phosphorus, in physiologic concentrations to facilitate correction of electrolyte abnormalities and acid–base abnormalities. The dialysate solutions have different glucose contents ranging from 1.5% to 4.25%. This glucose concentration creates an osmotic gradient that facilitates net movement of water into the peritoneal cavity, which is referred to as ultrafiltration. In PD, solute clearance occurs via a process of diffusion, whereby solutes move from a compartment of higher concentration to a compartment of lower concentration across the peritoneal membrane, and by convection, whereby solutes move via solvent drag with the movement of fluid between the blood and dialysate compartments. As fluid is also reabsorbed by the lymphatic system, the net fluid removal achieved by PD is a reflection of differences between ultrafiltration and lymphatic resorption.
The PD catheter is made of a silicone rubber or polyurethane and is either straight or curled in configuration, with 1 or 2 Dacron cuffs to prevent dislocation, fluid leak, and bacterial migration. It is placed surgically with the intra-abdominal portion positioned in the pelvis slightly lateral to midline and tunneling of the catheter up through the skin to form the exit site (Fig. 474-1). One cuff is placed between the anterior and posterior fascia of the rectus sheath and the other 1.5 to 2 cm from the exit site to prevent cuff extrusion and infection. The exit site is positioned away from vesicostomies, gastrostomies, and ureterostomies in a lateral or down-facing orientation in order to reduce risk of development of infection. Ideally, use of the PD catheter is delayed for 2 weeks to allow for healing.
Appropriate peritoneal dialysis catheter placement in an infant.
PD usually is performed daily and thus achieves more steady biochemical and blood pressure control with fewer dietary and fluid restrictions than occur with HD. PD is delivered continuously either manually (continuous ambulatory PD [CAPD]) or with an automated machine via continuous cycling PD (CCPD). CAPD is performed as 3 to 4 exchanges during the day and 1 longer exchange overnight. In comparison, CCPD usually is performed nightly by the patient or caregiver as 5 to 10 exchanges over a 10- to 12-hour period overnight with a long dwell during the day. This technique is performed for the majority of pediatric patients in the Unites States. The PD prescription subsequently is tailored to the child’s age, body size, metabolic control, peritoneal membrane transporter characteristics, and residual renal function to achieve goals as outline by the evidence-based clinical practice guidelines defined by KDOQI.
COMPLICATIONS OF PERITONEAL DIALYSIS
The most common complications of PD are infection-related: peritonitis and catheter-related exit-site or tunnel infections. Peritonitis occurs more frequently in younger children. A diagnosis of peritonitis needs to be considered in the setting of abdominal pain and cloudy PD effluent. The diagnosis is based on an effluent white blood cell count > 100/μL with at least 50% neutrophils. Gram-positive peritonitis, followed by culture-negative and then gram-negative peritonitis, are the more common causes of peritonitis. Fungal peritonitis occurs infrequently but is difficult to treat and often requires catheter removal. Peritonitis is a cause of significant morbidity and hospitalizations which can lead to the development of intra-abdominal adhesions and, ultimately, peritoneal membrane failure. PD catheter exit-site and tunnel infections are important risk factors for peritonitis and can require removal of the catheter if persistent or recurrent. Hence, regular monitoring of the exit site and prompt diagnosis of infection are important aspects of PD care. The diagnosis of a catheter exit-site or tunnel infection is made by the presence of purulent drainage, pericatheter swelling, redness, and/or tenderness. Routine care of the exit site followed by application of topical antibiotics (mupirocin or gentamicin) to the exit site reduces the incidence of exit-site infections and peritonitis.
Some of the noninfectious complications of PD include the development of dialysate leak, abdominal hernias, hydrothorax, and hemoperitoneum. Dialysate leaks more often occur in the postoperative period following placement of the catheter, with early manipulation of the catheter. Immobilizing the catheter after placement with healing for at least 2 weeks prior to use allows the exit site to seal and is critical to obtaining a functional catheter. Leakage that occurs later, after the PD catheter maturation, occurs in the abdominal wall and often is due to anatomical defects. The incidence of abdominal hernias is higher in young children and is inversely related to age. Hernias can be incisional, at the site of catheter placement, or midline, umbilical, or inguinal in origin. Inguinal hernias are more common in boys and are frequently bilateral in newborns because 80% to 90% have a patent processus vaginalis, which in the setting of PD can progress to a hernia. Hernias can interfere with ability to perform adequate PD by limiting exchange volume due to increasing hernia size. Because untreated hernias increase risk for bowel entrapment and/or strangulation, evaluation for the presence of hernias with placement of a PD catheter is now considered standard of care. Hydrothorax (Fig. 474-2) is a leakage of dialysate into the pleural space and occurs in approximately 3% of children on PD. Pleural effusions usually are unilateral and occur more commonly on the right side. A hydrothorax can develop after initiating PD, several months after initiation, or after surgery; the diagnosis is confirmed with an elevated pleural fluid-to-serum glucose concentration gradient of > 50 mg/dL. Management involves stopping PD temporarily; however, if fluid accumulation recurs, it may force transition to HD. Hemoperitoneum is observed primarily in adolescent females, usually 2 to 3 days prior to onset of menses or midcycle at time of ovulation. Hemoperitoneum can also be seen in the setting of abdominal or catheter trauma or, more rarely, in the setting of pancreatitis. Frequently, it can be managed conservatively with observation and instillation of intraperitoneal heparin to prevent obstruction of the catheter.
Hydrothorax in a patient on peritoneal dialysis.
HD is the predominant initial dialysis modality in children older than age 10 years. According to the USRDS 2016 Annual Report, approximately 50% of incident pediatric ESRD patients initiate HD once renal replacement therapy is needed, and 18% of prevalent children with ESRD are maintained on HD. According to data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), it is not uncommon for children on PD to transition to HD as a result of recurrent infections, peritoneal membrane failure, family choice, or dialysis-access failure. The rationale for selection of HD as an initial modality includes psychosocial concerns, patient/family freedom from dialysis treatment responsibility, and overall shorter treatment times. Capability to provide HD is dependent on ability to place and maintain vascular access. In younger children, HD is more challenging due to the patient’s size, high rates of vascular-access failure, and need for expertise in pediatric dialysis.
HD mimics the function of the normal kidney by removing the waste products, solutes, and excess fluid via diffusion, convection, and ultrafiltration. Diffusion refers to the transmembrane solute movement across a semipermeable membrane in response to a concentration gradient. Convection, on the other hand, is transmembrane solute movement in association with plasma water and is determined by the ultrafiltration rate and membrane pore sizes. Ultrafiltration describes the movement of water across the membrane by convective flow down a pressure or osmotic gradient. In HD, there are 2 separate circuits, the blood circuit and the dialysate circuit, which run in opposite directions. The dialyzer provides the interface between the 2 circuits. The dialyzer has a hollow fiber configuration, which increases its surface area. During HD, the blood leaves the patient through the blood lines, passes through a dialyzer in an extracorporeal circuit as dialysate fluid runs countercurrent, and returns to the patient. The countercurrent flow maintains the gradient between the 2 compartments, thereby facilitating diffusion-based clearance. The clearance of different solutes is determined by the specific properties of dialyzer and the solute sizes. Fluid removal is regulated by the pressure gradient across the membrane (transmembrane pressure) and the permeability of the membrane to water (ultrafiltration coefficient of the dialyzer). Dialyzer selection is based on dialyzer properties and patient size. The dialysate fluid contains electrolytes in physiologic concentrations to normalize electrolyte and acid–base abnormalities. Potassium content is adjusted based on serum potassium concentrations. Bicarbonate is used as a buffer.
Pediatric dialysis programs in the United States offer conventional HD typically 3 times per week for 3 to 4 hours. A few centers in the United States offer more frequent HD, either as 4 days per week or as home HD 5 to 6 times per week for 2 to 3 hours. More intensified regimens with increases in session length and/or frequency have been developed in pediatric dialysis centers in Canada, France, the United Kingdom, and Germany. An intensified dialysis regimen can be delivered as an overnight treatment ranging from 6 to 8 hours, 3 to 7 times per week, or as shorter more frequent HD for 2 to 3 hours, 5 to 7 times per week, in a center or at home. Conventional HD can easily provide adequate dialysis as defined by KDOQI guidelines; however, there is increasing evidence that a more intensified regimen results in better blood pressure and phosphate control with decreased medication burden and improved appetite and growth.
Vascular access is the backbone of HD. For children with ESRD, focus should be on vein preservation. Good vascular access is needed to accommodate the necessary blood flow to provide adequate clearance during the HD treatment. There are several options for HD access. Arteriovenous fistulas (AVFs) are considered the best option even in pediatric patients. AVFs have superior access survival rates with less rates of infection compared to catheters. KDOQI guidelines recommend creation of AVF in children greater than 20 kg for whom transplant is not imminent. AVFs are created surgically by anastomosis of an artery to a vein. They can be created at the wrist using the radial artery and cephalic vein or radial artery and basilic vein, or at the elbow using the brachial artery and cephalic vein or brachial artery and basilic vein. Ideally AVF should be created at least 6 weeks prior to the expected need for dialysis in order to allow time for maturation of the fistula and to avoid the need for urgent catheter placement. Prior to AVF creation, vein mapping is recommended to identify acceptable access sites and areas of venous occlusion, stenosis, or outflow obstruction. However, AVFs are not always possible. In younger children, children in whom transplant is anticipated within 1 year, or children with poor anatomy for an AVF, a catheter may be necessary. Catheters should be placed in the internal jugular vein with the distal tip in the proximal atrium (Fig. 474-3). Placement in the subclavian vein should be avoided due to risk of developing subclavian stenosis, which could preclude placement of an AVF in the future. Arteriovenous grafts (AVGs) are another option for vascular access. AVGs may be an option for children who have poor anatomy for an AVF. With an AVG, an artificial conduit using a synthetic material is looped between the artery and vein. AVGs are used less frequently in children and are at higher risk than AVFs for infection due to the presence of synthetic material.
Appropriate placement of right internal jugular hemodialysis catheter.
COMPLICATIONS OF HEMODIALYSIS
Access-related complications are associated with significant morbidity for children maintained on HD. Access dysfunction occurs in children with AVFs, AVGs, or catheters. Venous stenosis occurs not infrequently. Severe venous stenosis in children with an AVF or AVG is associated with increased risk for thrombosis. Monitoring with noninvasive ultrasound dilution flow can identify stenosis early, allowing for timely intervention with angioplasty or surgical revision. Catheter dysfunction can be due to thrombosis or a fibrin sheath. Thrombosis can be treated with thrombin plasminogen activator, but persistent dysfunction may require catheter replacement.
HD catheter infections may develop at the exit site, along the subcutaneous catheter, or in the catheter. Line sepsis typically presents with fever and/or chills while on HD. The presence of an exit site or tunnel infection increases the risk of catheter-associated sepsis. If signs of infection develop, the site should be cultured and broad-spectrum antibiotics initiated while awaiting culture results. If an exit site or tunnel infection is not improving, there are recurrent positive blood cultures, or septic shock occurs despite appropriate antibiotics, catheter removal may be needed with line replacement in 24 to 48 hours if possible. Infection rates are significantly lower in AVFs. If there is persistent bacteremia in a patient with an AVG, surgical revision may be required due to a nidus of infection within the synthetic component of the AVG.
The most common complication of HD is hypotension. Intradialytic hypotension is usually multifactorial in etiology, associated with fluid shifts from the extracellular to intracellular space, impaired sympathetic activity, and vasodilation in response to warmed dialysate. Hypotension can also be associated with excessive ultrafiltration requirements due to high interdialytic fluid gains. During hypotensive episodes, children can experience nausea, vomiting, cramping, dizziness, and headaches. There is also increasing evidence that children experience HD-associated reversible myocardial dysfunction or myocardial stunning in the setting of intradialytic blood pressure changes. Frequent reassessment of fluid goals, use of noninvasive monitoring of hematocrit changes, ultrafiltration modeling, and frequent reevaluation of dry weight help guide ultrafiltration goals, decrease symptoms of hypovolemia, and improve blood pressure profiles. If persistent hypotension prohibits ultrafiltration, an adrenergic agonist such as midodrine and dialysate cooling may be necessary in order to meet treatment ultrafiltration goals.
PEDIATRIC ESRD INTERDISCIPLINARY TEAM
Irrespective of the dialysis modality used, ESRD care requires an interdisciplinary team approach, which includes participation of not only the pediatric nephrologists but also the dialysis nurses, dietitian, social worker, child life specialist, school teachers, child psychologist, other subspecialty services (pediatric surgeons, vascular surgeons, interventional radiologists, and urologists), and family. The dietitian, for example, assists with manipulation of different formulas and nutritional supplements to enhance caloric density and protein content while balancing nutritional requirements with volume restrictions to promote growth. The social worker provides knowledge of available local, regional, state, and national resources and helps to assess the impact of ESRD on the family unit. Children with ESRD have lower health-related quality of life scores compared to healthy children; these scores are associated with frequent hospitalizations, procedures, and medical visits; school absences; disruption to home life; and restrictions on activities. The quality of life team, in conjunction with the child life specialist, school teachers, psychologist, and social worker, helps with this adjustment and assists with the development of coping strategies to address the stressors associated with need for renal replacement therapy. Together, each participant of the interdisciplinary team helps to address specific areas of care required to promote growth and development, provides psychosocial support, and addresses health-related quality of life with the goal to successfully nurture the child with ESRD and bridge the child to renal transplantation.
Because all renal allografts eventually lose function, transplantation must be considered a treatment and not a cure for ESRD. By providing good renal function, a transplant not only improves physical and cognitive development in the affected child but also enhances the quality of life experienced by children and families dealing with pediatric ESRD. In comparison to renal replacement therapy with chronic dialysis, transplantation also increases life expectancy by decades and is a more cost-effective therapy. As such, the optimal treatment for the vast majority of children with ESRD is transplantation.
EPIDEMIOLOGY AND OUTCOMES
Because pediatric ESRD is rare, transplantation involving a child accounts for fewer than 5% of the kidney transplants done in the United States, averaging approximately 800 procedures annually. During the last several decades, just over a third of transplants in children have come from living donors, with parents serving as the most frequent source.
Outcomes have shown consistent improvement in long-term graft survival, with these better statistics arising as a result of disparate advances including more centers acquiring longitudinal experience with pediatric transplantation, a better understanding of technical surgical issues with renal transplantation in small children, enhanced approaches to prophylaxis or treating transplant-associated infections, and a better understanding of the pharmacokinetics of immunosuppressant medications in pediatric patients.
As a result, children younger than 10 years of age, who once represented the group with the worst long-term renal allograft survival, now hold the best allograft outcomes across all ages. With current approaches to pediatric kidney transplant across all pediatric patients with ESRD in North America, 50% of deceased donor transplants are still functioning after 12.5 years and 50% of living donor kidney transplants are still functioning approaching 20 years after transplant.
Only 20% of pediatric kidney transplantations are done in children 5 years of age or younger, and expertise in transplantation for very small children is more limited than in older and larger children. In preadolescent children who require transplantation, congenital anomalies of the kidneys and urinary tract such as dysplasia, hypoplasia, and urologic anomalies are the most common ESRD etiologies. By adolescence, an increasing number of transplanted children have reached ESRD because of acquired kidney disease such as focal segmental glomerulosclerosis (FSGS). Among African-American children, FSGS represents the most frequent reason for ESRD (Table 474-2).
TABLE 474-2PEDIATRIC KIDNEY TRANSPLANT DEMOGRAPHICS ||Download (.pdf) TABLE 474-2PEDIATRIC KIDNEY TRANSPLANT DEMOGRAPHICS
| ||Age Range at Transplant |
| ||0–5 Years ||6–12 Years ||13–18 Years |
| Boy ||70% ||60% ||55% |
| Girl ||30% ||40% ||45% |
| White ||70% ||60% ||55% |
| African American ||10% ||15% ||20% |
| Hispanic ||15% ||20% ||20% |
|End-stage renal disease diagnosis |
| Dysplasia/hypoplasia ||30% ||15% ||10% |
| Urologic abnormalities ||20% ||15% ||15% |
| Focal glomerulosclerosis ||5% ||12.5% ||15% |
CONTRAINDICATIONS TO TRANSPLANTATION
Almost all children with ESRD will be considered transplant candidates. There are relatively few absolute contraindications, but they include active malignancy or uncontrolled infection. Data from children with Wilms tumor suggest that those treated can undergo successful transplantation after being in remission and off treatment for 2 years, and, as a result, most pediatric transplant centers will wait 1 to 2 years before transplanting children who have overcome other malignancies.
Neurodevelopmental disability may be considered in the broad discussion of factors that may have an impact on a child’s candidacy for receiving a transplant, but there is general consensus in the transplant community that cognitive impairment or intellectual disability should not be a factor that automatically excludes transplant candidacy. In fact, data from the United Network for Organ Sharing (UNOS) show that approximately 15% of recent first renal transplantations in the United States have been performed in children with intellectual disabilities.
FACTORS DELAYING TRANSPLANTATION
Some temporary conditions may delay transplantation once ESRD has been reached. In infants, there is a significantly increased risk of graft thrombosis if small kidneys are transplanted, and babies generally need to grow to a weight between 6.5 and 10 kg and a length exceeding 65 cm before centers with expertise transplanting infants will go forward. Children of any age may have associated congenital anomalies that need to be medically or surgically addressed to optimize transplant outcomes as well, especially as it pertains to the need for urinary tract repair or reconstruction in children with urologic etiologies of ESRD. Proceeding to transplantation without such urologic repairs having been done places the allograft at risk for dysfunction related to infection or obstruction. In children with aggressive glomerulonephritis related to autoimmune or systemic immunologic factors, the renal disease generally must be quiescent without active systemic disease that could negatively impact the transplanted kidney or the posttransplant course. Finally, given chronic immunosuppression and the risk for infection after transplantation, it is crucial for transplant recipients to be adequately immunized prior to undergoing the procedure.
Certain conditions may mandate native nephrectomies prior to or at the time of transplantation to prevent posttransplant complications or potential risk to the transplanted allograft. They include transplantation in children smaller than 20 kg in whom blood flow to native kidneys may represent a vascular steal from the transplanted allograft. Children with recurrently infected native kidneys will benefit from nephrectomy to reduce the likelihood of a posttransplant episode of bacteremia or urosepsis from a pyelonephritis. Children with uncontrolled renal hypertension may need nephrectomies, given the potential for additional posttransplant hypertension related to medications such as calcineurin inhibitors. Children with urinary concentrating defects and pretransplant daily urine volumes exceeding 1 L/m2 of body surface area may also benefit from a native nephrectomy to prevent the need for posttransplant daily hydration at volumes that may be problematic to maintain or that induce satiety and complicate long-term nutrition. Similarly, in children with ongoing nephrotic syndrome and heavy proteinuria despite ESRD, native nephrectomy will reduce the risk of nephrosis-related loss of proteins that place these children at higher risk for infection, thrombosis, and nutritional deficiency.
In pediatric patients who have been previously transfused or transplanted or who have received tissue allografts or in adolescents who have previously been pregnant, there is the additional risk of immune sensitization to human leukocyte antigen (HLA) or non-HLA antigens that mediates an immune response by the recipient against an allograft. This sensitization reduces the potential to find a compatible kidney transplant and may require desensitization to proceed to transplantation. The desensitization process generally involves combination therapy that may include intravenous immunoglobulin, rituximab, apheresis, and systemic immunosuppression.
Living donor transplantation is the preferred transplant modality. With living transplantation, there is increased likelihood of performing a preemptive transplant prior to the need for dialysis. There is also better long-term renal allograft function and survival, related in part to lower rates of delayed graft function after transplantation and fewer acute rejection episodes. Although children with ESRD are more likely to receive a living donor transplant than are adults, only approximately 35% of pediatric patients currently receive a living donor, and efforts to expand living donation remain a focus of the pediatric transplant community. Donor exchange or donor “swap” is a strategy that has also been used by some pediatric kidney transplant programs. In these programs, living donor/recipient pairs who have been found to be incompatible with each other are matched with other incompatible pairs to find new pairs who may then be compatible.
The precept underlying living donation is that the donor cannot be put at any physical or psychological risk through the act of donation. The donor evaluation is focused on assessing the prospective donor for overall medical and emotional fitness for the process and is overseen by a donor team that is independent of the patient’s transplant team. In addition to having no chronic medical problems that may be exacerbated by surgery or the loss of renal reserve that comes with a nephrectomy, to be considered as a successful donor for a pediatric patient, the candidate must have a compatible blood type (the Rh factor is of no concern) and no immunologic contraindications based on histocompatibility testing and cross-matching. Moreover, the donor must be at least 18 years of age to be able to give legal consent and, for most pediatric transplant recipients, be no older than approximately 60 years to allow for good nephron mass in the donated kidney. Because all nephrons have an element of natural obsolescence, even the healthiest adult loses a significant number of nephrons over time, resulting in a kidney from the average donor of 60 years or more possessing fewer nephrons than a kidney from a younger adult, which places the transplanted kidney at risk for a shorter duration of effective function.
The costs of a donor evaluation and the hospitalization and immediate outpatient surgical follow-up care for donation are covered by the recipient’s insurance. Despite the widespread application of laparoscopic techniques to perform the donor nephrectomy, the donor’s surgical procedure is more complex than is the recipient’s and often results in a more uncomfortable recovery. Most donors require at least a month of recovery prior to returning to work, with some individuals who perform more physically challenging employment requiring even longer periods of recovery. In the United States, a small number of employers, most notably certain government and military agencies and some healthcare facilities, provide paid leave for organ donation, but to date, there is no widespread mandated paid leave, and many donors face financial constraints to become a donor. Following donation, it is recommended that donors have ready access to medical care for acute problems and that they seek ongoing maintenance and preventative care to be monitored for the evolution of any unexpected renal sequelae of their organ donation such as proteinuria, hypertension, or progressive loss of GFR.
DECEASED DONOR TRANSPLANTS
If there is no living donor, then most children requiring kidney transplant will get listed for a deceased donor kidney. With deceased donor transplants in children, there is generally less HLA matching than seen with living donation in children. Although improved immunosuppression renders such matching less important than at one point in time, more matched allografts do tend to function longer. Nonetheless, the benefits of receiving a functioning renal allograft regardless of matching far outweigh the health disadvantages of remaining on dialysis awaiting a better-matched allograft.
Given the effect that transplantation has on improving growth, development, and quality of life in pediatric patients with ESRD, deceased donor kidney allocation schemes have been constructed to give advantage to those listed prior to 18 years of age so that they receive a kidney sooner than the average adult listed for a transplant. Children on the list are also preferentially allotted kidneys from younger donors to minimize the effects of natural nephron obsolescence with aging.
The actual surgical procedure varies depending on the size of the recipient. For most younger and smaller children weighing less than 20 kg, a midline transperitoneal approach is considered, with the allograft placed intra-abdominally and anastomosed to the aorta and the inferior vena cava. For children weighing more than 20 kg, a retroperitoneal approach is used with the allograft placed in the iliac fossa and vascular anastomoses to the common or external iliac vessels.
During the surgical procedure, there is ongoing attention given to the child’s effective volume and adequacy of perfusion of the kidney once transplanted. Ischemic injury to the transplant can occur after the kidney is removed from the donor and placed on ice prior to its placement in the donor. This so-called “cold ischemia” is generally more of a concern with deceased donor kidneys and places the donated graft at risk for acute kidney injury immediately after transplant, but cold ischemia times up to a day are used by many pediatric kidney transplant programs to allow for placement of deceased donor organs over large distances. Warm ischemia time refers to the period the organ is at body temperature but not being adequately perfused. It is largely a factor of the length of time it required for the kidney to be placed and vessels re-anastomosed into the recipient after the kidney is removed from the ice.
During the transplant surgery, the ureter from the transplanted kidney is implanted into the recipient’s bladder. An anti-refluxing anastomosis is optimal because it will prevent vesicoureteral reflux into the renal transplant and reduce the risk of infection from urinary stasis. Some transplant programs routinely leave a ureteral stent in place for several weeks to prevent any ureteral obstruction while the anastomosis heals.
IMMEDIATE TRANSPLANT OUTCOMES
Immediate outcomes after transplantation tend to be good in most children. With advances in histocompatibility testing and cross-matching, hyperacute antibody-mediated rejection rarely is encountered. Primary graft dysfunction with ongoing absence of any renal function whatsoever for other reasons occurs in fewer than 3% of pediatric kidney transplants. Although varying degrees of acute kidney injury are seen frequently, actual delayed graft function requiring dialysis while awaiting better allograft function occurs in only 5% of pediatric living donor and 15% of pediatric deceased donor kidney transplants. Such delayed graft function is a risk factor for poorer long-term transplant function.
Most transplanted children require some degree of initial and ongoing immunosuppression to allow long-term function of the allograft (Table 474-3). During the last 3 decades, approaches to immunosuppression in children receiving kidney transplants have evolved with the introduction of new immunosuppressive agents and a focus on trying to reduce overall immunosuppression burden but maintain highly efficacious results. Many pediatric transplant programs now use induction therapy just prior to the transplantation with an agent such as thymoglobulin, alemtuzumab, or basiliximab that depletes lymphocytes or reduces their ability to activate, replicate, or recruit other immune cells. The rationale behind induction therapy is to provide intense initial immunosuppression to minimize the likelihood for early acute rejection of the transplant. After induction, most children are then maintained on chronic immunosuppression with a calcineurin inhibitor such as tacrolimus and an antiproliferative agent such as mycophenolate mofetil. Although many children receive oral steroids as the third leg of chronic immunosuppression, there is increasing adoption of steroid-free regimens with good graft survival outcomes in children considered at lower immunologic risk for rejection. There is also pediatric experience with the mammalian target of rapamycin (mTOR) inhibitor sirolimus as a way to provide effective immunosuppression while reducing exposure to calcineurin inhibitors given their nephrotoxicity. Some pediatric programs transition from a calcineurin inhibitor to sirolimus within a few months after transplantation, whereas others will use it once there is concern for calcineurin nephrotoxicity.
TABLE 474-3COMMON IMMUNOSUPPRESSION IN PEDIATRIC KIDNEY TRANSPLANTS ||Download (.pdf) TABLE 474-3COMMON IMMUNOSUPPRESSION IN PEDIATRIC KIDNEY TRANSPLANTS
|Class ||Transplant Drug(s) ||Mechanism of Action ||Phase(s) of Transplant Used |
|Polyclonal antibody || |
|Depletes T-cells ||Induction |
|Monoclonal antibody ||Basiliximab ||Inhibits lymphocyte proliferation ||Induction |
|Humanized monoclonal antibody ||Alemtuzumab ||Depletes T-cells ||Induction |
|Glucocorticoid || |
|Directly lymphocytic; also alters lymphocyte proliferation; inhibits cytokine production ||Induction and maintenance |
|Purine antagonist || |
|Blocks nucleotide synthesis; inhibits T- and B-cell replication and proliferation ||Maintenance |
|Calcineurin inhibitor || |
|Inhibits calcineurin, c-Jun N-terminal kinase (JNK), and p38 pathways; induces expression of transforming growth factor-β1 ||Maintenance |
|mTOR inhibitor || |
|Inhibits immune cell proliferation via cell cycle arrest; antiproliferative ||Maintenance |
COMPLICATIONS OF IMMUNOSUPPRESSION
With chronic immunosuppression comes concern for infection, especially in the initial 6 to 12 months after the procedure, when immunosuppression may be more intense. This is particularly true in younger children who may not yet have acquired native immunity to certain opportunistic viral infections such as cytomegalovirus (CMV), Ebstein-Barr virus (EBV), or the BK polyomavirus and who then encounter these viruses through direct infection from the transplanted organ or from exposure in the community. Most transplant programs will prescribe some period of valganciclovir prophylaxis to reduce the risk of acquiring CMV disease, especially in patients who have negative CMV serologies going into transplant and receive a kidney from a CMV-positive donor. Trimethoprim-sulfamethoxazole or atovaquone often is used for prophylaxis against Pneumocystis carinii pneumonia during the first year. In many transplant programs, there is often interval laboratory surveillance for evidence of viral infection with CMV, EBV, or BK virus using polymerase chain reaction (PCR). Infection is often considered an indication of excess ongoing immunosuppression in the transplanted patient, and maintenance immunosuppressive medications may be reduced to allow for a native immune response to be mounted, although a concern is reducing the immunosuppression excessively and putting the allograft at risk of rejection.
Another consequence of immunosuppression is a predisposition to the development of posttransplant lymphoproliferative disorder (PTLD). PTLD often is suspected in transplanted children who manifest tonsillar enlargement, lymphadenopathy, or hepatosplenomegaly or who have unexplained persistent fever or the onset of constitutional symptoms such as weight loss. Histologically, PTLD can range from reactive plasmacytic hyperplasia to polymorphic disease of either monoclonal or polyclonal etiology to monomorphic disease that is generally of B-cell origin. In children, a large number of cases are associated with EBV infection, and the increased likelihood for a transplanted child to be immunologically EBV naïve versus a transplanted adult accounts for the increased concern for EBV infection in transplanted children. Depending on its underlying histology, ‘cell markers’ and whether there is an association with an EBV infection, PTLD can be treated by a variety of approaches including reduction in immunosuppression alone, use of the anti–B-cell antibody rituximab, or the use of chemotherapy regimens similar to those employed with aggressive lymphomas. The development of PTLD does increase the likelihood for early graft loss.
Over time, chronic immunosuppression also increases risk of development of non-PTLD malignancy in transplanted children versus the general pediatric population by nearly 7-fold. Renal cell carcinoma, thyroid carcinoma, and skin malignancies such as melanoma are the most frequent cancers seen in children enrolled in the NAPRTCS transplant registry.
With advances in immunosuppression and increased familiarity with its provision in pediatric transplant recipients, rates of acute rejection episodes have fallen. Recent data suggest that the risk for acute rejection is less than 10% in the first year following a living donor kidney transplant and about 15% in a deceased donor transplant, with acute rejection rates falling subsequently over the life of a renal allograft. A rejection episode does tend to reduce long-term graft function, although the overwhelming majority of acute rejection episodes can be acutely reversed by intensification of immunosuppression. Steroids remain the mainstay of antirejection therapy, especially when cellular rejection is diagnosed.
Non-hyperacute antibody-mediated rejection is increasingly being recognized as a cause of allograft dysfunction. There is ongoing focus on the role of donor-specific antibody (DSA) mediating such rejection, especially given that contemporary approaches to cross-matching and histocompatibility testing generally detect problematic antibody that would have existed before transplantation. Optimal strategies as to monitoring for DSA and then reacting to its detection remain unclear in children. Similarly, there is a lack of clarity as to the best treatment for antibody-mediated rejection in children, with most approaches now using a combination of therapies including enhanced immunosuppression, intravenous immunoglobulin G, rituximab, and apheresis.
RECURRENT DISEASE IN THE TRANSPLANTED KIDNEY
Depending on the original etiology of the transplanted child’s ESRD, recurrent disease may complicate the posttransplant course. Historically, this has most frequently been encountered in children with FSGS, atypical hemolytic-uremic syndrome (aHUS), membranoproliferative glomerulonephritis (MPGN), and primary hyperoxaluria (PH). With the advent of eculizumab therapy to block the terminal complement cascade, many cases of recurrent aHUS can be prevented or successfully reversed. With the increased use of liver-kidney transplant in children with PH unresponsive to pyridoxine therapy, the concern for recurrent PH affecting a renal allograft has fallen as well. Recurrent FSGS remains very problematic, however, occurring in as many as 50% of children initially transplanted and upward of 80% of children with prior graft recurrence who are transplanted again. Techniques to reverse recurrence have focused on immunosuppression intensification and apheresis, and although many cases of recurrence are reversed, the renal allograft injury that ensues does place that graft at risk for earlier functional impairment over time. In fact, the usual allograft survival advantage seen with living donation is lost in children with FSGS who suffer a recurrence, with their long-term allograft outcomes similar to those of deceased donor kidneys.
CHRONIC ALLOGRAFT NEPHROPATHY
Eventually, all transplants lose substantial function as result of a process labeled chronic allograft nephropathy. On histologic review, these kidneys demonstrate significant interstitial fibrosis and tubular atrophy of the renal parenchyma with associated glomerulosclerosis. Both immunologic and nonimmune factors are thought to play roles in the development of these chronic changes, and advances in the prevention and management of pertinent factors such as acute cellular and antibody-mediated rejection, recurrent disease, nephrotoxin exposure, and posttransplant infection may allow for successful strategies to stave off these changes and preserve allograft function longer.
For the pediatric patient with ESRD, the advantages of having a functioning kidney transplant throughout childhood and adolescence lie with optimizing normal growth and development, enhancing educational and vocational training opportunities, and maximizing psychosocial health. Hence, increasing transplantation in children with ESRD, minimizing transplant-related medical complications, and improving long-term allograft outcomes remain overarching goals of the pediatric nephrology community and drive most of the research that is ongoing focused on pediatric ESRD.
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