Kidney Transplantation in Infants

Abstract

After completing this article, readers should be able to:Kidney transplantation is the preferred mode of treatment for most children who have end-stage renal disease (ESRD). Despite advances in dialysis management, children who undergo this treatment modality experience stunting in growth and development,1 and mortality rates are higher for children on dialysis compared with those who receive transplants for all age groups.2 In the past, results of kidney transplantation in infants had made the procedure prohibitive, and success rates were extremely low. Compared with adults and larger pediatric patients, infants who have ESRD are at the highest risk for early graft loss and consistently have had the highest mortality rates. Recent advances in the medical and surgical management of these infants have led to improved results in survival and long-term renal transplant function. However, survival rates vary among transplant centers, and the infant subgroup remains the most challenging of any age group receiving transplantation.According to analyses of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and the United Network of Organ Sharing (UNOS) data, 15% of living donor grafts and 35% of cadaver grafts in infants are lost in the early posttransplant period due to technical complications, vascular thrombosis, or irreversible acute rejection.33,4 Graft survival at 7 years for infants receiving transplantation from living donors (those in whom the best possible outcome is expected) is approximately 71% nationally,4 although results vary. This long-term graft survival is surprisingly high, considering that graft survival at 1 year was only 80% nationally.In our experience with 45 consecutive kidney transplants performed in patients weighing at least 15 kg during an 8-year period, we have reported 100% graft survival at 1 to 3 years (excluding a transplant-unrelated death) and 85% survival at 8 years for combined living donor and cadaver transplants.5 In this review of the clinical outcome, we also present parallel investigative data supporting our approaches.ESRD describes a state in which “the patient's renal dysfunction has progressed to the point at which homeostasis and ultimately survival cannot be sustained with native renal function, and either dialysis or renal transplantation is required.”6 Early serious renal injury, such as that resulting from birth asphyxia or congenital structural abnormalities, causes nonrecoverable damage because of the inability for severely damaged nephrons to repair or regenerate. Thus, chronic renal insufficiency in infants and young children follows a relentless course that ultimately progresses to ESRD. The goal in these patients is early recognition, aggressive medical and nutritional management, and appropriate institution of renal replacement therapy. All children who have ESRD, with very rare exceptions, are candidates for renal transplantation. Transplantation offers better therapy than chronic dialysis in terms of growth, development, quality of life, and long-term survival.2The incidence of ESRD in the pediatric population (0 to 18 y of age) is 10 per 1 million children and involves a small proportion of infants. Listed in Table 1 are the causes of ESRD in pediatric transplant recipients in our series and in series reported by the NAPRTCS.7 In contrast to the adult population in whom ESRD typically is acquired and often results from long-standing underlying disorders such as diabetes and hypertension, ESRD in the pediatric population most frequently is the result of congenital and structural abnormalities. Therefore, early and appropriate intervention is critical in these patients and should be carried out so as not to hasten the progression of renal failure, increase the number of unneeded procedures, cause undue morbidity to the infant, or preclude the safe performance of future kidney transplantation.Contraindications to kidney transplantation in infants who have ESRD are few and include human immunodeficiency virus infection, malignancy other than nonmetastatic Wilms tumor, and devastating neurologic injury. Within these guidelines, there is a spectrum of scenarios that requires a complete assessment by an experienced team to make the final decision about the individual infant's candidacy for transplantation.Once an infant reaches ESRD, he or she needs to be maintained on an optimal dialysis regimen that allows medical stabilization and optimal nutrition. A significant number of these patients have accompanying urologic and multisystem disorders that also must be addressed. Once infants reach a desired weight (at our center, 10 kg, but 7.5 kg is acceptable), they are prepared for transplantation. Preemptive transplantation (ie, transplantation prior to a course of dialysis) is becoming more prevalent and has been reported in 24% of pediatric transplants8 and in 22% of the infants transplanted at our center.5 Clear guidelines for the use of preemptive transplantation are lacking, but this approach has been instituted in infants who have evidence of growth retardation and significant renal insufficiency.Until the infant who has ESRD has reached adequate size and both the medical issues resulting from renal failure and the medical and surgical issues stemming from accompanying disorders are stabilized, the infant must be maintained on dialysis. There are advantages to both forms of dialysis, and results of comparisons between peritoneal dialysis (PD) and hemodialysis (HD) have been equivocal.9 The majority of infants who have ESRD now are managed with PD, and in our own series, 62% were maintained on PD prior to transplantation.5 When the onset of ESRD occurs in the neonatal period or early in infancy, patients often are too small for safe HD because their small blood volumes make them less tolerant of sudden fluid and metabolite shifts. Further, establishment of PD is technically easier, and it can be provided at home with proper training and avoids complications of vascular thrombosis and line sepsis.Given the negative effect that dialysis has on growth, aggressive nutrition management is essential during the pretransplant period. Many patients receive supplemental feedings via nasogastric or gastrostomy feeding tubes. In our center, the goals for caloric and protein intake are 150 kcal/kg per day and 3 g/kg per day, respectively. The dialysis regimen is optimized to tolerate this load. Renal osteodystrophy is managed with 1,25-dihydroxyvitamin D3 andnonaluminum-containing phosphate binders to suppress parathyroid hormone. Aggressive iron repletion and erythropoeitin therapy have allowed avoidance of blood transfusion, thereby minimizing the risk of sensitizing the infant who eventually will undergo transplantation. Some groups have reported improvement in growth with administration of recombinant human growth hormone.10The incidence of prenatal renal anomalies or hydronephrosis has been shown to be 0.28% to 1.4% in large prospective studies.6 In fact, more than three times as many cases of hydronephrosis were diagnosed prenatally as postnatally. The underlying conditions resulting in bilateral hydronephrosis include posterior uretheral valves, high-grade reflux, prune belly syndrome, ureteropelvic junction obstruction, distal ureteral obstruction, and duplex anomalies with upper pole hydronephrosis. Prenatal studies may identify abnormal urinary tract anatomy, but they often are unable to define the physiologic significance of the hydronephrosis or the underlying anatomic abnormalities. Furthermore, milder degrees of renal pelvic dilatation have been reported to resolve in utero in 23% of cases.11 Postnatal studies, therefore, are critical for diagnostic confirmation and appropriate intervention in neonates in whom urinary obstruction is suspected. At times, the diagnosis of a congenital urologic disorder may not be made readily postnatally; the diagnosis is more obvious in the infant who has prenatal studies that are confirmed postnatally or in those who exhibit apparent clinical findings. The failure to void within the first 48 hours of life should lead to an aggressive diagnostic evaluation, as should specific findings on examination, such as a palpable abdominal mass in the infant who has polycystic kidney disease or overt dysmorphic features such as those seen with prune belly syndrome.In patients who have congenital urologic abnormalities, often several anomalies must be addressed (Fig. 1 ). Once the diagnosis is made, the treatment approach should be guided by relief of any obstruction, clearance of any complicating infection, and appropriate correction, if possible, of anatomic defects. The primary goal, however, is to accomplish these ends without hastening renal deterioration. Unfortunately, when the insult is sufficient to cause chronic renal insufficiency, affected infants inevitably develop ESRD, and many do so at an early stage, despite intervention. Thus, undertaking extensive urologic renconstruction may be inappropriate and may accelerate the progression of renal insufficiency. Urologic management also must take into account plans for future transplantation.Accordingly, we advocate the following treatment approaches: For posterior urethral valves with associated renal insufficiency, we avoid early valve ablation because the small neonate or infant is predisposed to urethral scarring and recurrent obstruction. Instead, we perform a vesicostomy for urinary tract decompression, promote nutrition and growth of the child, and ablate the valve and close the vesicostomy when the child weighs approximately 7 to 8 kg, preferably within several months prior to transplantation. When performing ureteral procedures, one must assess the appropriateness of the contemplated procedure because the intervention may not improve renal function and, in some cases, may hasten development of ESRD. When the sterilization of an infected urinary tract is not possible, nephroureterectomy may be necessary prior to transplant. Otherwise, this procedure is best done at the time of transplantation so as to avoid scarring around the aorta and inferior vena cava, the sites of future vascular anastomoses at transplantation (Fig. 2 ). Appropriate urethral reconstruction and bladder repair should be undertaken, but we avoid bladder augmentation because with immunosuppression, this predisposes to recurrent infection and possible irreversible consequences to the kidney graft.12 In cases involving patients who have ESRD and have been referred with augmented bladders, we have taken the augments down prior to transplantation to avoid potential septic complications with immunosuppression. As will be discussed in the next section, we preferentially use the native bladder for ureteral implantation at transplant as long as we have ruled out or corrected any obstruction and ruled out a neurogenic component. Even the small-capacity, defunctionalized bladder recovers and functions normally after urinary flow is re-established following a successful renal transplant.13 For the neurogenic bladder, we prefer an intermittent catherization regimen that relies on strict compliance and sterile technique and drainage via a constructed ileal loop conduit.The incidence of ARPKD is 1 in 10,000 to 1 in 40,000, and the locus has been mapped to chromosome 6p21. Prenatal ultrasonography may reveal enlarged kidneys, oligohydramnios, and absence of urine in the bladder, findings that may not be apparent until 30' weeks' gestation. Increased maternal alpha-fetoprotein (AFP) may be detected, but it is not specific for this disorder. This disease has been categorized based on age of presentation and the relative degrees of renal and hepatic involvement. Most patients present in infancy.14 The kidneys are not as large with the milder presentation as with the severe form, and patients experience a slow decrease in glomerular filtration rate (GFR), ultimately reaching ESRD in childhood or early adolescence. Affected patients may have a concentrating defect that results in polydipsia and polyuria and one must be wary of dehydration in these cases. Those who have the most severe form of ARPKD present at birth with huge abdominal and flank masses that often complicate delivery and may be accompanied by oligohydramnios, hypertension, and pulmonary hypoplasia. Infants who have true pulmonary hypoplasia frequently die soon after birth.Mortality associated with the infantile presentation of ARPKD has been high, but aggressive surgical and dialysis intervention can salvage many of these newborns for later transplantation. For those who have the severe form of disease, early bilateral nephrectomy usually is necessary to decompress the abdomen, relieve functional bowel obstruction, and improve the pulmonary status. Figure 3 is a photo of an infant who had ARPKD and suffered from malnutrition due to the sheer mechanical limitations imposed by the massive kidneys. We performed bilateral nephrectomy on this child at 9 months of age at which time a PD catheter was placed. With aggressive PD, adequate nutrition could be delivered and when he reached 13 months of age and 9.5 kg, he received a kidney transplant from his mother. This patient is doing well 24 months posttransplant, with a serum creatinine of 44.2 mcmol/L (0.5 mg/dL).Congenital nephrotic syndrome is an inherited autosomal recessive trait, the gene of which has been localized to chromosome 19q13.1 and has been named NPHS1.15 This disease is characterized by massive loss of protein in the urine that begins in utero. Affected infants frequently are born preterm with a birthweight that falls below the 5th percentile in one third of cases. They often exhibit edema and abdominal distension at birth.6 Prenatal diagnosis is suspected in the presence of a high maternal serum AFP accompanied by amniotic AFP levels tenfold above normal at 16 to 20 weeks' gestation with normal ultrasonographic findings and cholinesterase levels. Analysis of the NPHS1 gene is now the diagnostic method of choice.16 Postnatal findings include massive proteinuria, microscopic hematuria, and leukocyturia with a low serum albumin concentration and hypertriglyceridemia. Ultrasonography findings can vary from early findings of renal cortex hyperechogenicity to increased kidney size and loss of corticomedullary differentiation to eventual decrease in kidney size and parenchymal hyperechogenicity at later stages. Histologic changes include increased dilatation of proximal tubules and later interstitial fibrosis and glomerular sclerosis.As a result of ongoing protein loss, patients develop ascites, anasarca, failure to thrive, growth retardation, and superimposed infectious complications from poor nutrition and loss of immunoglobulins in the urine. Although the majority of protein lost is albumin, there is significant urinary loss of gammaglobulins and complement, thereby rendering these infants severely debilitated and immunosuppressed.17 Similarly, the loss of antithrombin III predisposes them to a significant risk for vascular thrombosis.1818Corticosteroids and cyclophosphamide therapies have been attempted for affected patients, but they are associated with severe side effects and have failed to control the disease. Currently, renal transplantation is the only definitive mode of therapy for infants who have congenital nephrotic syndrome. However, nationally, these infants have had a higher renal graft failure rate (33%) than those who have other causes of ESRD (23.9%), and these losses are attributable to higher rates of vascular thrombosis and complicating infections.18 Several centers, including our own, now perform bilateral nephrectomy and initiate dialysis at least 6 weeks to 3 months prior to transplantation, an approach that has been associated with a decreased incidence of posttransplant vascular thrombosis19 and improvement in overall outcome for future renal transplantation.20 We encourage early nephrectomy, preferably by 6 months of age, to reduce protein losses and the associated attendant infectious and thrombotic complications and to improve the infant's nutritional status prior to transplantation. All infants managed by this approach at our center have 100% graft survival.Hyperoxaluria type I, a rare autosomal recessive disorder, results from deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase. This deficiency causes increased oxalate production, which deposits in the kidney as its calcium salt. Recurrent nephrolithiasis and nephrocalcinosis leads to renal failure. The kidney is the only effective route of oxalate clearance, and once the GFR falls below 40 to 20 mL/kg per 1.73 m2, there is systemic deposition of calcium oxalate in bones, nerves, blood vessels, retina, and the heart.21 The infantile form, most likely due to a complete enzyme deficiency, is particularly aggressive and associated with early renal failure and systemic oxalosis.The primary medical therapy includes adequate hydration; pyridoxine administration; use of magnesium, citrate, and orthophosphate to inhibit crystallization; and aggressive dialysis. However, even combined PD and HD is not adequate to prevent systemic oxalate deposition. Without transplantation, affected patients have a 30% to 40% survival rate,22 and infants fare particularly poorly. Isolated kidney transplantation for oxalosis has met with disappointing results in all age groups, with a 60% to 80% inevitable graft loss due to recurrent oxalate deposition. Combined liver and kidney transplantation was introduced as therapy for oxalosis in 198423 as a means of replacing the enzyme defect and, thereby, protecting the transplanted kidney. We recently reported 100% long-term (7 y) graft and patient survival in seven infants who had hyperoxaluria type I and received combined liver and kidney transplantation.24 In our series of infants transplanted for oxalosis, the mean age at transplant was 15 months and the mean weight was 11 kg.Infants historically have the worst outcome of any age group receiving kidney transplantation, especially in the first year postsurgery. Results have improved, with graft survival at 1 year reported to be 80% to 90% and at 7 years to be 71% to 76% years, according to the UNOS4 and NAPRTCS25 registries, respectively. In transplanted infants, 15% of living donor renal allografts and 35% of cadaver grafts were lost in the early posttransplant period.3,4 Technical factors accounted for 33.4% of early graft losses,4 and of these, 23.8% were due to graft thrombosis. Additionally, the incidence of acute irreversible rejection is highest in pediatric kidney recipients younger than 6 years of age, and acute rejection is the most important risk factor for chronic rejection, the major cause of graft loss after 1 year.8 It has been pointed out that elimination of technical causes of graft failure conceivably could allow 85% to 90% long-term survival rates.26To achieve optimal results by eliminating graft thrombosis, primary nonfunction, and technical losses, we advocate the following principles. Adult-size kidneys are better grafts than pediatric kidneys,27 especially if acute tubular necrosis (ATN) is avoided. In the absence of ATN, infants receiving adult-size kidneys have the best long-term graft survival rates of any transplantable organ and of any recipient age group. Projected graft half-lives after the first year are at least equivalent to those of the gold-standard human leukocyte antigen-identical sibling recipients ages 19 to 45.28 Thus, donor quality should be optimal, and live donor transplantation should be performed if at all possible. Results with living donor transplantation are consistently better than with cadaver donors,25 with an approximately 10% graft survival advantage at any time point from 1 to 5 years after transplantation. Attention to intraoperative and perioperative fluid management is critical. When maximum intravascular volume is provided, adult-size kidneys transplanted into infants receive only two thirds of the blood flow they received prior to removal from the donor.29 There is, therefore, very little latitude before a “low blood flow state” results that predisposes to graft thrombosis, ATN, or permanent graft nonfunction. Thus, hypotension and hypovolemia in infant recipients of adult-size kidneys must be avoided at all costs.26Avoidance of delayed graft function and ATN has been associated, in our experience, with significant long-term survival advantage5 by preventing both immunologic and nonimmunologic injury.30 To minimize the chance of vascular complications and technical graft loss, transplants should be performed by experienced pediatric transplant surgeons who have specific training and expertise as well as consistent technical results. We advocate the use of an antireflux procedure during ureteral implantation in all infants, such as either the Politano-Ledbetter technique, or the recently described “trough” technique in small defunctionalized bladders in which a formal antireflux procedure is not possible.13Immunosuppressive management to prevent acute and chronic rejection is paramount to successful kidney transplantation. The incidence of graft loss from irreversible acute rejection is more prominent in younger recipients and is the cause of graft loss in 28.6% of infants receiving living related transplants.3 Improved graft survival has been associated with the use of antibody induction and increased daily maintenance levels of the calcineurin inhibitor cyclosporine.31 With ongoing modifications in protocols, most centers (80% to 85%) employ triple immunosuppressive therapy composed of prednisone, azathioprine, and cyclosporine.31 The incidence of acute rejection by the first year posttransplant in pediatric kidney transplant recipients has been reported as 49% in living donor recipients and 63% in cadaver renal transplant recipients.31 We report a 15.5% overall rejection rate in infant kidney transplant recipients,5 which we attribute to avoidance of ATN, the predominant use of living-related donors, and an extremely tight immunosuppressive protocol that includes close monitoring of renal function and drug levels.32Fever in the transplant recipient is caused by an infectious etiology in 74% to 78% of cases, and its presence should lead to a systematic, thorough search for common and uncommon infections. The propensity of infections to occur within the first few months after transplantation is directly related to high doses of immunosuppressive agents and the frequent use of monoclonal or polyclonal antilymphocyte preparations to prevent or treat rejection. Clostridium difficile colitis is one of the most common bacterial infections encountered in the first 2 weeks posttransplant, and most patients respond to oral metronidazole or vancomycin. Urinary tract infection (UTI) is the second most common bacterial infection, followed by bacteremia and line sepsis. Compared with the nonimmunosuppressed host, these infections more frequently are associated with pyelonephritis and bacteremia, and there is a high rate of relapse when treated with a conventional course of antibiotics. Pediatric kidney transplant recipients who have prune-belly syndrome, Eagle-Barrett syndrome (who frequently have other urologic anomalies), or ileal conduits or who require intermittent bladder catheterization for neurogenic bladder have a higher incidence of UTI than other pediatric kidney transplant recipients. Therefore, we use the native bladder whenever possible and perform an antireflux ureteral implantation in all cases. Many groups, including our own, place these patients on low-dose antibiotic prophylaxis (trimethoprim-sulfamethoxazole) for the first few months after transplantation, an approach that has been shown to decrease the incidence of UTIs.33Opportunistic viral infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are most common between 1 and 6 months posttransplant and are related to the individual's net state of immunosuppression. Especially before the era of CMV prophylaxis, the incidence of CMV infection in adult kidney transplant recipients was reported to be as high as 75%. In the pediatric kidney transplant population, the incidence is lower, with a national rate of 5.6%, according to the NAPRTCS registry, although some centers report a rate of more than 20%.34 The risk for CMV infection clearly is increased with a seropositive donor organ and has been correlated with the degree of immunosuppression. Diagnosis is made by serology; polymerase chain reaction (PCR); pathologic evaluations of tissue specimens for the presence of inclusion bodies; immunohistochemical stain; and shell-vial direct culture of buffy coat, bronchoalveolar fluid, blood, urine, or tissue.35 Treatment of active CMV disease consists of judicious reduction of immunosuppression and a 14-day course of intravenous ganciclovir at a dose of 5 mg/kg administered twice daily. In cases of resistant infection, severe CMV hepatitis, or CMV pneumonitis, the addition of CMV hyperimmune globulin or intravenous pooled gammaglobulin may improve the response to ganciclovir. Although the best prophylactic regimen in pediatric renal transplant patients has yet to be defined, some form of CMV prophylaxis is warranted in all recipients or at least in those receiving CMV seropositive allografts or antibody preparations and those who have prolonged intensive care unit and hospital courses. A proposed CMV prophylaxis protocol is outlined in Table 2 . In the past, the incidence of EBV-associated posttransplant lymphoproliferative disease (PTLD) in the pediatric kidney transplant patient was 1.2%. In a center experience of 84 pediatric patients receiving renal transplants from 1986 to 1998, a 7% incidence was reported in patients who received quadruple immunosuppression with antilymphocyte preparation, methylprednisolone, cyclosporine, and azathioprine or mycophenolate mofetil.36 Based on recommendations from this group, we have used PCR to detect EBV viral load and predict the risk for development of PTLD. Intravenous ganciclovir, CMV hyperimmune globulin, or both are instituted in conjunction with a modest reduction of immunosuppression in those who have a significant viral load or clinical manifestations of disease. In contrast to the experience with CMV, antiviral prophylaxis has not been clearly demonstrated to reduce the incidence of EBV and associated PTLD.36,37 However, an aggressive diagnostic approach should be applied, especially in high-risk (positive donor/negative recipient) patients who present with even the most subtle symptomotology. A proposed treatment algorithm is outlined (Fig. 4 ).Beyond 6 months postransplant, varicella zoster virus tends to occur more frequently in younger children and can present with severe manifestations. Treatment of varicella in the transplant recipient consists of immediate admission to the hospital for intravenous acyclovir therapy (10 mg/kg of ideal body weight given every 8 h for 7 to 10 d) and observation for evidence of cutaneous and visceral dissemination. Azathioprine and mycophenolate mofetil should be withheld at least until all lesions have crusted and there are no new vesicles. Calcineurin inhibitors (tacrolimus and cyclosporine) and steroids should be continued to protect against graft rejection. It is important to diagnose and treat these infections aggressively because mortality rates of as high as 25% have been reported in pediatric transplant recipients who developed varicella infections.38Given the progress in management of infants who have ESRD, we can expect excellent long-term survival with kidney transplantation. To achieve optimal results, the following principles must be emphasized: Newborns who have apparently irreversible renal failure must be considered potential transplant candidates. The underlying disease process for ESRD should be addressed, and unnecessary procedures that may hasten progression to ESRD should be avoided. Peritoneal dialysis with optimal nutritional and medical management is absolutely critical in preparing affected infants for eventual renal transplantation. Appropriate antimicrobial prophylaxis after transplantation should be instituted to decrease the risk for opportunistic infection. Results with kidney transplantation in infants can surpass those obtained with older age groups if an experienced pediatric transplant team adheres to strict principles to minimize vascular complications, ATN, delayed graft function, and acute rejection.