You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation Kidney TransplantationArticle Last Updated: Feb 12, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: David Hatch, MD, Chief, Section of Pediatric Urology, Professor of Urology & Pediatrics, Departments of Urology and Pediatrics, Foster G McGaw Hospital and Loyola University of Chicago David Hatch is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Society of Transplant Surgeons, and American Urological Association Coauthor(s): Rekha Agrawal, MD, Director, Division of Pediatric Nephrology, Professor, Department of Pediatrics, Loyola University Medical Center Editors: Casimir F Firlit, MD, PhD, Consulting Staff, Department of Urology, Cardinal Glennon Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Brian F Gilchrist, MD, Chief, Division of Pediatric Surgery, Tufts-New England Medical Center; Associate Professor, Department of Surgery, Tufts University School of Medicine; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Riccardo A Superina, MD, Professor of Surgery, Northwestern University School of Medicine; Consulting Surgeon, Director of Transplant Surgery, Department of Surgery, Children's Memorial Hospital of Chicago Author and Editor Disclosure Synonyms and related keywords: kidney transplantation, transplant, kidney transplant, end-stage renal disease, ESRD, renal transplant, renal transplantation, kidney donation, dialysis, hemodialysis, glomerulonephritis, histocompatibility antigens, HLAs, kidney rejection, nephrectomy INTRODUCTIONSection 2 of 11
  Approximately 1 in 65,000 children develops end-stage renal disease (ESRD) each year. Before the 1950s, this condition was essentially untreatable. However, because of advances in surgical techniques and suppression of the immune system, the mortality rate of children with chronic renal failure has declined dramatically. Kidney transplantation has become the primary method of treating ESRD in the pediatric population. For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Kidney Transplant. History of the ProcedureUntil the 1950s, ESRD from any cause was uniformly lethal. Hope for treating renal failure grew with the development of surgical techniques that allowed the anastomosis of blood vessels in the early 20th century. In 1902, Ullman demonstrated the successful autotransplant of a canine kidney to the dog's neck. Following anastomosis of the artery and vein, the kidney made urine (Ullman, 1902). That same year, Carrel reported an improved method of suturing vessels together, work that eventually won him a Nobel Prize (Carrel, 1902). In 1906, Jaboulay, in whose laboratory Carrel had worked, performed the first human kidney transplant, a xenograft between a pig and human. This kidney made urine for only a short time (Jaboulay, 1906). In 1909, Ernst Unger transplanted an ape's kidney to a young girl with renal failure. The failure of this attempt convinced Unger that a nonsurgical barrier to transplantation existed (Unger, 1909). Other early attempts at the transplantation of kidneys were unsuccessful. Within hours or days, transplanted kidneys became swollen, ceased urine production, became ischemic, and, in some cases, ruptured. In a series of experiments, Medawar and colleagues demonstrated that skin grafts from nonidentical rabbits were rejected and sloughed by a reaction involving leukocyte invasion of the graft (Medawar, 1944). This reaction increased in severity and rapidity when the recipient received a previous transplant from the same donor. Researchers began to look for ways to prevent this response. Ionizing radiation, known to suppress bone marrow production of leukocytes, was used in an attempt to prevent the immune reaction to allografting. Armed with new information about the immune response to allografting, researchers revived interest in renal transplantation. In 1954, a kidney transplant was performed between identical twins, thus skirting the problems of immune compatibility (Hume, 1955). Several transplants between twins followed. However, the possibility of kidney transplantation for patients with renal failure who did not have a twin donor remained unrealized (Murray, 1958). In the early 1960s, Calne found that a derivative of 6-mercaptopurine (azathioprine) increased the success of experimental kidney transplantation in dogs (Calne, 1962). Human use of azathioprine followed, and long-term graft survival from nonidentical donor kidneys became a possibility. The success of kidney transplantation increased significantly when Goodwin and Starzl added prednisolone to azathioprine (Goodwin, 1962; Starzl, 1963). Encouraged by this success, transplant centers began performing nonidentical living donor kidney transplantation. Simultaneously, dialysis became available as a pretransplant therapy for patients with ESRD and as a life-preserving measure for recipients of transplants whose kidneys failed. This increased the number of individuals who were candidates for kidney transplantation. Terasaki reported a marked decrease in early allograft failure from hyperacute rejection when a crossmatch between donor lymphocytes and recipient serum was performed (Terasaki, 1965). A negative crossmatch (no reaction against donor lymphocytes when incubated with recipient serum) indicated that no antibody was present in the recipient, directed against the donor's organ. In 1968, the Harvard Committee on Irreversible Coma described the features of brain death and made the important observation that patients who had lost basic brainstem function were dead despite the persistence of a heartbeat sustained by artificial ventilator support (Cranford, 1991). In 1970, Kansas became the first state to enact legislation defining brain death. Within several years, such statutes were widely established. This provided a legal framework for families to donate the organs of deceased loved ones for use in transplantation. The number of kidney transplants dramatically increased because of the combination of this legislation and the contemporary advances in immunosuppression. Concurrently, in 1973 the Medicare program in the United States was expanded to provide insurance coverage for patients with ESRD, meaning that individuals were provided renal transplantation or dialysis regardless of their health insurance coverage or their ability to pay. From a relatively rare procedure performed in research centers, kidney transplantation became available in most major cities. During the 1970s, a 1-year allograft survival rate of 75% was typical for kidneys donated by living relatives; a rate of 50% was typical for organs from cadavers (Banowski, 1983). Improvement in graft survival followed the routine use of human leukocyte antigen (HLA) tissue matching (Ting, 1978) and the use of antilymphocyte antibodies as a temporary adjunct to immunosuppression regimens. In 1978, Calne reported improvement in allograft survival with the use of a new immunosuppressive agent, cyclosporine (Calne, 1978). Widespread use of cyclosporine led to a dramatic improvement in allograft survival. New protocols incorporating cyclosporine and other drugs have increased the specificity of immunosuppression and decreased the prevalence of infection complications in transplant recipients. FrequencyApproximately 1200 children (aged 0-19 y) in the United States develop ESRD each year (United States Renal Data System, 2001). This represents approximately 16 cases per 1 million children. EtiologyThe most common cause of renal failure in children (£19 y) is glomerulonephritis (see Image 2). Other etiologies are demonstrated in all children in Image 1 and by age group in Image 2. Treatment options include hemodialysis, peritoneal dialysis, and renal transplantation. Approximately two thirds of children with ESRD receive a kidney transplant (see Image 3). PathophysiologyDespite numerous attempts and prolific experimentation, kidney transplantation between nonidentical twins was not successful until the 1960s. Early experimenters understood the outcome of the unmodified response to allografting (ie, a rapid or gradual decrease in urine output and ultimate demise of the transplanted kidney) but not its mechanism. In the 1940s, through a series of elegant animal experiments, Medawar demonstrated that skin grafts between nonidentical rabbits were ultimately sloughed (Medawar, 1944). He found that this reaction occurred much more rapidly in animals that had previously been grafted from the same donor and that the process involved a leukocytic infiltration in the allograft. Medawar reasoned that exposure to foreign tissue resulted in an activation of the immune system and that it induced specific memory that allowed rapid reaction to subsequent exposure to similar grafts. Modulation of that response became the goal of transplant investigators in the subsequent decades. Although understanding of the immune response to allografts has increased dramatically during the past 50 years since Medawar's experiments, it remains incomplete. The description that follows is a simplified schema intended primarily to assist in the reader's understanding of currently used immunosuppressive agents. Histocompatibility antigens are glycoproteins found on the cell membrane of all nucleated cells. These antigens (ie, HLAs) are highly variable between individuals and are coded by genes located on the short arm of chromosome 6. Following allografting, the recipient is exposed to foreign HLAs from the graft. Macrophages or dendritic cells process these foreign antigens and present them to T-helper lymphocytes. Thus activated, the T-helper lymphocytes produce lymphokines that stimulate maturation of other reactive cells. Interleukin (IL)–2 stimulates production of cytotoxic T lymphocytes. IL-4 induces transformation of B lymphocytes into plasma cells that produce antibody directed specifically against foreign HLAs. In addition, T-helper lymphocytes can be stimulated directly by the secretion of IL-1 from macrophages (see Image 4). Once stimulated, the immune response results in a rapid or gradual attack on the vascular endothelium of the allograft, resulting in rejection. If an individual is exposed to an organ expressing antigens against which the recipient already has developed antibodies, the rejection occurs rapidly. This is called hyperacute rejection, and it can cause swelling, rupture, and loss of the allograft within minutes or hours. Currently used pretransplant cross-matching techniques (between recipient serum and donor lymphocytes) have dramatically reduced the occurrence of this type of rejection. Stimulated cytotoxic T lymphocytes, directed specifically against the mismatched tissue, and natural killer cells attack target cells, causing acute rejection. This response can vary in severity from mild allograft dysfunction to a dramatic rise in serum creatinine with loss of urine output. Some recipients of transplants experience a gradual reduction in allograft function, called chronic rejection, typified by a gradual obliteration of the lumen of small arteries in the graft caused by endothelial thickening. This response occurs more commonly, but not exclusively, in recipients who have experienced an acute rejection. Therefore, chronic rejection may be a long-term consequence of acute rejection, a low-grade indolent immune reaction, or a combination of both processes. RELEVANT ANATOMYSection 3 of 11
See Pathophysiology. CONTRAINDICATIONSSection 4 of 11
Obtain a thorough history from all potential pediatric recipients of kidney transplants. Children with acute or chronic active infection and those with malignancy are not generally candidates for kidney transplantation. Most centers consider transplantation in a child who has been disease free for 2 years following treatment of cancer. Transplantation is also contraindicated in any child or family with a history or high likelihood of noncompliance with a prescribed medication regimen. Active systemic lupus erythematosus and Goodpasture disease are also contraindications to transplantation because these processes can damage an allograft. Children with renal failure from focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, systemic lupus erythematosus, hemolytic-uremic syndrome, and Henoch-Schönlein purpura are at increased risk of recurrence following transplantation. Although this increased risk does not necessarily contraindicate transplantation, it can have a significant impact on organ survival and function. Counsel families accordingly. The success rate of renal transplantation in very young children, especially those younger than 1 year, is significantly less than that in older children. Therefore, carefully evaluate all alternatives for treatment of ESRD. Generally, continuous ambulatory peritoneal dialysis (CAPD) is the preferred method of treatment of children younger than 1 year. However, CAPD may not be possible because of peritoneal scarring. Hemodialysis is difficult in very small children. In such persons, transplantation may be the best option. WORKUPSection 5 of 11
Lab Studies
Imaging Studies
Other Tests
TREATMENTSection 6 of 11
Medical therapyAs the early experience with transplantation dramatically illustrated (see History of the Procedure), modulation of the normal immune response mechanisms is a vital prerequisite to successful organ transplantation. The cascade of immunologic events triggered by the presence of foreign antigens can be interrupted or diminished at several key points. In the 1960s and 1970s, relatively nonspecific immunosuppressive medications and ionizing radiation were used to blunt the body's immune reactivity. Use of these modalities was accompanied by high rates of complications including infection, impaired wound healing, and malignancy. Currently used immunosuppressive agents are generally much more specific in their mechanism of action. These drugs can be classified into 4 groups: corticosteroids, antimetabolites, macrolides, and antibodies. The sites of action along the cascade of immunologic stimulation of each class of immunosuppressive medication are depicted in Image 5. Immunosuppressive agents used are as follows: Corticosteroids
Antimetabolites
Macrolides
Antibodies Many antilymphocyte antibodies have been used in transplantation. Polyclonal antibodies provide a relatively less specific impairment of lymphocyte activity. Monoclonal antibodies (ie, muromonab-CD3, daclizumab, basiliximab) provide more specific inhibition of lymphocyte function. Antibodies are used for induction (temporary use immediately following transplantation, while other immunosuppressive agents are adjusted) and for treatment of acute rejection.
Preoperative detailsOrgan sourceWith the establishment of brain death laws and successful immunosuppression protocols, cadaver kidney transplantation became an attractive treatment option for children with ESRD. However, kidneys obtained from cadavers remain in limited supply. Since the advent of successful kidney transplantation in the early 1950s, transplantation of kidneys from living donors has continued to play an important role. Advantages of kidneys obtained from living donors include the availability of organs, the quality of renal function, and an increase in allograft survival. With improvement in immunosuppressive protocols, the gap in allograft survival between living donors and cadaver donors has narrowed. Still, many centers have found that living kidney donors provide a significant and increasing proportion of the organs available for transplantation. Evaluation of potential living donorsThe ideal organ donor for kidney transplantation is a living identical twin or a sibling with identical HLA. However, taking an organ from a minor who cannot give informed consent is not ethical. Hence, few such transplants are performed in children. Parents, adult siblings, or other blood relatives serve as the most common donors for children. With improvement in immunosuppression, even donation from HLA-mismatched individuals can be successful. Carefully interview potential living donors to assess their motivation and their understanding of the ramifications of donor nephrectomy. Obtain a thorough medical history and perform a physical examination, including a careful evaluation of the donor's potential for renal disease, diabetes mellitus, chronic infection, and other factors that contraindicate organ donation. Laboratory evaluation
Imaging evaluation
Kidney selection In general, the left kidney is preferred for living donor nephrectomy because the renal vein is longer on the left. However, when multiple renal arteries are present only on 1 side, the kidney with a single renal artery is usually preferred. Living donor nephrectomy can be performed either through a flank incision or by laparoscopic techniques (Kim, 2000). Because removal of the kidney requires an abdominal incision, many centers prefer to perform nephrectomy using a hand-assisted laparoscopic procedure in which a sealed glove allows insertion of a hand into the abdomen to assist in the dissection (Slakey, 1999). Laparoscopic surgery takes longer than open nephrectomy, but it provides a more rapid recovery for the donor. Most living donor nephrectomies are now performed laparoscopically, with donors discharged from the hospital about 48 hours following the surgery. Cadaver kidneysWaiting times for cadaver kidney transplants vary by region from a few months to more than 2 years. Because the number of potential recipients is much higher than the number of cadaver kidneys available, a point system was developed to provide a fair allocation of organs. Points are accumulated for time spent on the waiting list and immune sensitivity. Because ESRD stunts growth and delays development, additional points are usually given to young children. When a cadaver kidney becomes available, a list of serologically compatible recipients is generated. First priority is given to offering the kidney to a recipient with identical HLAs. If no such recipient is available, then the organ is offered to the potential recipient with the highest point accumulation. In 1998, 45% of the 746 US pediatric transplant patients received a cadaver kidney (United States Renal Data System, 2001). Potential cadaver organ donors All persons with brain death from trauma, intracerebral hemorrhage, or other nonmalignant causes should be considered for organ donation. Many families find that the potential of organ donation to save the life of someone with organ failure is comforting in a time of acute sorrow. When a potential organ donor is identified, notify the local organ bank, whose professionals are trained to be sensitive and are expert in the delicate approach to grieving families. Intraoperative detailsOperative history Early experimental human kidney transplants consisted of anastomosing the vessels of the renal allograft to thigh or arm vessels (Hamilton, 1994; Jaboulay, 1906). This technique was simpler than placing the graft in the abdomen; however, it was not suitable for long-term kidney transplant function. In the early 1950s, while working independently, Simonsen in Denmark, Dempster in London, and Kuss in Paris placed allografts in the pelvis, anastomosing the renal vessels to the iliac vessels (Hamilton, 1994). This has become the standard technique for human transplantation. Operative procedures In larger children, as in adults, the renal allograft is placed in the iliac fossa outside of the peritoneal cavity. A curved lower abdominal (Gibson) incision is made in either lower quadrant, and the iliac vessels are exposed (see Image 7A). The renal artery is anastomosed either to the external iliac or the internal iliac artery (see Image 8). In past decades when allograft survival rates were significantly lower, use of the internal iliac artery for a first kidney transplant was more common because this left the external iliac artery available for subsequent grafting. Currently, most kidney transplants are performed using the external iliac artery for blood supply. The renal vein is anastomosed to the external iliac vein. With the kidney perfused, the ureter is anastomosed to the bladder, using an extravesical technique that avoids opening of the bladder (see Image 9) (Barry, 1983; Lich, 1961). Infants and small children require modification of the standard surgical approach because of their size. Although transplantation of a small kidney into a young child can be performed using the approach and technique described above, most such children receive an adult-sized kidney transplant. Through a midline incision, the peritoneal cavity is entered and the great vessels are exposed (see Image 7B). The renal vessels are then anastomosed to the abdominal aorta and inferior vena cava. The common iliac artery and vein can also be used, depending on the size of the kidney and the recipient. The ureter is anastomosed to the bladder as described above. Special considerations Approximately 1 in 4 children presenting for transplantation have ESRD from urologic abnormalities. A small but significant proportion of these children have abnormal urine storage function due to a neurogenic bladder, lower urinary tract obstruction, reflux, or a congenital anomaly of the bladder or urethra (eg, exstrophy, posterior urethral valves). In addition, some children may have lost their bladders as a consequence of malignancy, radiation, or scarring from chronic infection. Despite these challenges, kidney transplantation can be successful in these patients. Several reports describe drainage of a kidney transplant ureter to an augmented bladder (see Image 10A), an incontinent urinary conduit (see Image 10B), or a continent urinary reservoir with allograft survival comparable to that in children with normal bladders (Hatch, 1993). Such recipients are at increased risk of urine infections; therefore, closely monitor them. When necessary, clean intermittent catheterization has been successfully used in these patients to drain the urine (Gill, 1992). Follow-upLaboratory studies
Imaging studies
COMPLICATIONSSection 7 of 11
Surgical complicationsLymphocele A lymphocele is an accumulation of lymphatic fluid around the kidney. The lymphatic fluid originates either from the lymphatics of the allograft or from the lymphatics cut during the dissection of large blood vessels in the recipient. Some transplant surgeons prefer to place kidney transplants within the peritoneal cavity to allow lymph fluid to be reabsorbed by the peritoneum. Lymphoceles occur in 1-10% of pediatric recipients of transplants. They manifest as fullness over the allograft, pain, or decreasing renal function. Large lymphoceles can compress the pelvis and ureter of the kidney transplant and cause urinary obstruction. They can also cause venous obstruction. Ultrasonography is the optimal means of imaging a lymphocele (see Image 11E). A lymphocele appears as a fluid collection adjacent to the kidney transplant. If a question exists regarding the diagnosis, the fluid collection can be aspirated under sterile conditions using ultrasonographic guidance. Analyze fluid thus removed for creatinine level (high in urine leak, low in lymphocele), lipids (high in lymphocele, low in urine leak), and cell count (high lymphocyte count in lymphocele, low cell count in urine leak) to establish the diagnosis. Treatment options include laparoscopic drainage with creation of a peritoneal window (communicating tract between the perinephric fluid collection and the peritoneum) and open creation of a peritoneal window. Laparoscopic surgery is currently the preferred method of treatment. Wound infection With the use of lower doses and more rapid tapering of steroid therapy in kidney transplantation, the risk of wound infection is decreasing. Most transplant surgeons administer perioperative antibiotics to decrease the risk of infection. Children with augmented bladders or complete diversion of the urine (eg, ileal conduit) are at increased risk of wound infection following transplantation (Hatch, 2001). Wound infections manifest as swelling, erythema, or purulent drainage from the incision, usually within days of transplantation. Obtaining imaging studies is usually unnecessary in making the diagnosis. However, a febrile patient with wound tenderness or erythema should undergo ultrasonography or CT scanning of the pelvis or abdomen to detect potentially infected perinephric fluid. Prompt surgical drainage and administration of parenteral antibiotics should be undertaken immediately. Thrombosis One of the most devastating complications of transplantation, thrombosis (either of the renal artery or the renal vein) occurs in 1-3% of kidney transplants. In patients who were anuric before transplantation, thrombosis manifests as a sudden cessation of urine production. In children whose native kidneys made urine before transplantation, thrombosis may manifest as a persistently elevated serum creatinine level. Thrombosis is readily diagnosed with the assistance of color Doppler ultrasonography (see Image 11C). If a prompt diagnosis is made, attempt emergency exploration by removing the thrombus, flushing the kidney, and reconstructing the affected vascular anastomosis. However, once the clotting cascade is initiated in a kidney transplant, the probability of salvage by surgery is low. Success has been reported in such kidneys when intra-arterial instillation of thrombolytic medications has followed surgery. Thrombosis results from a technical error or a hypercoagulable condition in the recipient. Perform a thorough coagulation evaluation prior to repeat transplantation in patients who have experienced thrombosis of an allograft. Renal artery stenosis Obstruction of arterial inflow to a kidney transplant occurs in 1-5% of kidney transplants. Evaluate patients with hypertension that is difficult to control for the presence of renal artery stenosis. Cyclosporine causes an increase in tone of the smooth muscles of the efferent arteriole of the kidney. This commonly results in hypertension following transplantation. However, when multiple antihypertensive medications are required to control blood pressure or when controlling hypertension is impossible, perform an evaluation for renal artery stenosis. Renal artery stenosis can result from a surgical technical error causing constriction at the point of anastomosis, from kinking of the renal artery, or from segmental hypertrophy of the intima of the renal artery or a branch thereof. Although ultrasonography may demonstrate a narrowing in the renal artery or increased velocity of arterial flow, it is not sufficiently sensitive to confirm the diagnosis. Digital subtraction angiography is the most sensitive diagnostic test (see Image 13). Three dimensional CT scanning has also been used in making the diagnosis. Treatment options include balloon angioplasty (highest success rate with the lowest risk of complications) or open surgical revascularization. Urologic complicationsUrologic problems are the most common surgical complications following pediatric kidney transplantation. Obstruction Obstruction of urine drainage occurs in 2-4% of recipients of kidney transplants. Obstruction may be caused by faulty surgical technique or ischemia of the distal ureter. It most often occurs at the point where the ureter is anastomosed to the bladder. Kidneys from young donors (<6 y) are at increased risk of ureteric ischemia because of the more tenuous blood supply. Suspect obstruction in a recipient with hydronephrosis on posttransplantation ultrasonography, decreasing urine output, or a failure of expected drop in serum creatinine. Ultrasonography is the best method of diagnosing obstruction (see Image 11D). When the diagnosis is in question, percutaneous antegrade pyelography and a pressure-flow study (Whitaker test) is indicated (Whitaker, 1978). Treatment options include balloon dilatation or open surgical revision of the ureterovesical anastomosis. When obstruction is found in the recipient of a kidney from a pediatric donor, proceeding with open surgical revision may be preferable. Occasionally, in such cases, complete loss of the ureter may be observed. When this occurs, anastomosis of the native ureter to the transplant kidney pelvis may be possible. Urine leak A breakdown in the anastomosis of the ureter to the bladder results in leakage of urine into the perinephric space. This can result from a technical failure or from ischemia of the distal ureter. Ischemic necrosis is more common in recipients of kidneys from pediatric (<6 y) donors. A urine leak may manifest as a leakage of fluid from the incision, a perinephric fluid collection observed on ultrasonography, or a failure of the serum to decrease as expected following transplantation. When significant drainage from the incision follows kidney transplantation, send a sample of the fluid for creatinine measurement. A high creatinine level (2 times the serum creatinine) differentiates urine leakage from other causes of perinephric fluid collections such as lymphocele or hematoma. If the volume of leakage is small, temporary diversion of urine with a nephrostomy tube and Foley catheter may be successful. Treat high-volume leakage and persisting leakage with open surgical repair. Medical complicationsImmunosuppression For specific adverse effects of individual immunosuppressive agents, see Medical therapy. Infection Infection is one of the most important and common complications of renal transplantation. It can occur at any time after the transplant and can vary considerably in severity. Infections add significantly to the morbidity and mortality of transplantation. The incidence and severity of posttransplant infection has decreased as a result of more judicious use of immunosuppressive medications and the availability of better therapeutic options (Renoult, 2005). In the early era of kidney transplantation, infection occurred in as many as 70% of transplant recipients. More recently, the incidence of infection has decreased to 15-44.1%. Mortality rates from infection have decreased from 11-40% in the 1960s to less than 5% (Silkensen, 2000; Sia, 1998). Posttransplant infections can be caused by bacteria, viruses, fungi, mycobacteria, and other opportunistic microbes. Infections are most common in the first 6 months after transplantation when immunosuppression is relatively high; however, infections can occur at any time. Urinary tract infection (UTI) remains the most common posttransplant infection, especially in children, occurring in as many as 30% of patients. Children at increased risk for UTI include those with congenital anomalies or bladder dysfunction, including children with prune belly syndrome, spina bifida with neurogenic bladder, vesicoureteric reflux, and posterior urethral valves. Children with high-volume urinary reservoirs (eg, hydronephrosis of the native kidneys, hydroureter, large bladder) are at increased risk of urine infection. For this reason, many centers perform nephroureterectomy in such patients before transplantation if the child is on dialysis or at the time of transplantation if the child is not yet on dialysis. Appropriate treatment of urine infection in pediatric transplant recipients depends on the severity of the infection. Children with UTI and fever, nausea, myalgias, or other constitutional symptoms should receive broad-spectrum parenteral antibiotics. Afebrile children with UTI can be treated at home with oral antibiotics. Gram-negative organisms are the most common bacteria causing posttransplant urine infection. Therefore, institute appropriate gram-negative antibiotic therapy pending results of a urine culture. Some children with lower urinary tract dysfunction require clean intermittent catheterization. This results in colonization of the bladder or urinary reservoir. Routine urine culture of an asymptomatic child using clean intermittent catheterization often exhibits bacterial growth. Treatment with a full course of antibiotics in such persons may, in fact, be deleterious because the continued use of the catheter recolonizes the bladder with resistant organisms. In such children, treating only symptomatic episodes (eg, fever, pain, purulent urine) is better. Other bacterial infections that may occur, especially in the first 6 months after transplant, include listeriosis, legionellosis, nocardiosis, and pneumococcal infections. Tuberculosis and atypical mycobacterial infection can occur at any time as a primary infection or a reinfection. Many may develop disseminated disease. Viral infections are a source of significant morbidity as well as mortality in children. CMV is the most common viral infection in pediatric recipients of transplants. Other important viral infections in these children also belong to the herpes group, including EBV, VZV, and HSV. CMV occurs in as many as 90% of pediatric recipients in the first 3-6 months following transplantation. Infected patients may have no symptoms or they may have low-grade fevers, pneumonitis, diarrhea, or hepatitis. Severe infections can be fatal. CMV infection has been associated with acute rejection and organ dysfunction. In a report of the North American Pediatric Renal Transplant Cooperative Study (NAPTRCS), the incidence of CMV infection–related hospitalization in children was 5.6% (Block, 1997). Some of these children had received ganciclovir for CMV prophylaxis. In a report from a single center, in children who did not receive CMV prophylaxis, the prevalence of symptomatic CMV disease was 10.5% (Granger, 1994). The prevalence of infection is highest in children who are CMV seronegative and who receive a kidney from a donor who is CMV positive (CMV D+/R-). However, even children who are CMV positive may develop clinical CMV infection. The NAPRTCS study suggests that CMV prophylaxis may be most effective when an antiviral agent is combined with an enriched anti-CMV immunoglobulin product (CytoGam). EBV infection can cause a varied spectrum of disease. Recipients of transplants contract EBV infection either through contact with infected carriers or from the allograft. Active infection can manifest as an uncomplicated mononucleosis syndrome with fever, leukopenia, and atypical lymphocytosis. It can also cause a potentially fatal posttransplantation lymphoproliferative disease (PTLD) (Cox, 1995; Newell, 1995; Green, 1999). The severity of PTLD varies from a relatively benign polyclonal lymphocytic proliferation to a malignant monoclonal disease with a high mortality rate. Children are at a higher risk of PTLD because of a higher prevalence of primary infection in the posttransplant period (Ho, 1988). The risk factors for malignancy include EBV-negative recipient and positive donor (EBV D+/R-), CMV D+/R- status, high levels of immunosuppression, use of antilymphocyte antibody preparation (especially OKT3), or use of excessive immunosuppression. When EBV infection is suspected, perform biopsy of any enlarged lymph node to detect the virus. Some centers routinely monitor EBV viral load using a polymerase chain reaction (PCR) assay. Alternately, EBV titers can be monitored, although they are not as useful as EBV PCR. Initially treat patients with active EBV infection by decreasing their immunosuppression (typically cyclosporine or tacrolimus by 50%). Initially reduce prednisone and hold any third agents (eg, mycophenolate mofetil [MMF], sirolimus). When the disease is detected early, this modification of immunosuppression is frequently successful. Children with severe infections and those who do not respond to immunosuppression reduction are treated with ganciclovir, cessation of all immunosuppression, administration of anti–CD-20 monoclonal antibody, or even chemotherapy. VZV infections are also an important cause of morbidity in children (Broyer, 1997; Furth, 1997). Varicella is highly communicable and is transmitted to 90% of household contacts. It can be disseminated and fatal in children who are immunosuppressed, especially those who have a primary infection while immunocompromised. Clearly, natural immunity from contracting clinical varicella (chickenpox) is the best protection against posttransplant varicella infection. However, a significant proportion of pediatric candidates for renal transplants have no antibody against varicella. All such children should be immunized with VZV vaccine well before transplantation. Broyer et al reported a seroconversion rate of 87% of children receiving the vaccine (Broyer, 1997). However, VZV immunity was not as durable in these children as in those with natural immunity. Of the vaccinated children, VZV antibody was measurable in 62% at 1 year and only 42% at 10 years following immunization. In children with a history of varicella infection prior to transplantation, measurable VZV antibody was present in 99.6% at 1 year, 97.2% at 2 years, and 95.5% at 4 years following transplantation. After transplantation, severe varicella infection was observed only in children who did not develop the antibodies or in those who reverted to a seronegative state. Clinical varicella infection was almost 4 times more common in vaccinated children who were seropositive than in those who did not convert. In a previous study, Broyer reported that herpes zoster was observed in 13% of 415 of children who had varicella prior to transplantation, 7% in the vaccinees, and 38% in patients without immunity (Broyer, 1985). Thus, all children without natural immunity should receive the chickenpox vaccine prior to transplantation. Currently, vaccinating children with transplants with the live-attenuated varicella vaccine is not recommended; however, Hardy et al and Zamora et al, respectively, reported the use of this vaccine in children with leukemia and in recipients of renal transplants (Hardy, 1991; Zamora, 1994). Varicella infection in immunosuppressed children can be severe or fatal. Parents and/or caregivers must be warned about the danger of VZV exposure in susceptible pediatric recipients of transplants. When a child is exposed to VZV following transplantation, current VZV antibody titer should be measured. Seronegative children should be administered varicella-zoster immunoglobulin (VZIG) and observed closely. Those who develop clinical disease should receive acyclovir. In children who are immunosuppressed, varicella can cause a wide range of clinical disease, including the typical skin lesions of chickenpox, fever, and more serious complications, such as pneumonitis, encephalitis, or meningitis. Even apparently mild varicella infections should be treated aggressively to prevent progression. The prevalence of fungal infections in adult recipients of transplants varies from 2-14.1% (Chugh, 1993). No such data are available for children. Candidiasis (especially from Candida albicans) is the most common fungal infection in both children and adults. Candidiasis is usually manifested by mucocutaneous lesions. It can also cause UTI, fungal balls in the urinary tract, or disseminated disease. Cryptococcal infections can cause influenzalike syndrome and asymptomatic pulmonary modules, with an incidence of 2.5-3.6% in adults (Chugh, 1992). It has a predilection for the central nervous system and can cause subacute-to-chronic meningitis with headaches. Many centers use prophylactic oral nystatin for the first 3 months following transplantation to prevent fungal infection. Pneumocystis is another important infection in hosts who are immunocompromised. Pneumonia caused by Pneumocystis carinii has been reported in 5-10% of renal transplant recipients who did not take prophylaxis (Tolkhoff, 1992). It is associated with increased immunosuppression, which can occur with CMV infection and during treatment of acute rejection episodes. Low-dose trimethoprim-sulfamethoxazole is commonly employed prophylactically for the first 6-12 months following transplantation. ImmunizationsAll potential pediatric recipients of transplants should receive standard immunizations at least 6 weeks prior to transplantation (Neu, 1998). Give special attention to the live-attenuated vaccines, including varicella and measles-mumps-rubella (MMR), because the risk of active disease following vaccination is increased in children who are immunocompromised. Similarly, inactivated polio vaccine (IPV) is indicated, rather than oral polio vaccine (OPV). Family and household contacts also should receive MMR and varicella vaccine as indicated. Measure viral titers prior to transplantation to ensure the adequacy of vaccination. Routinely administer diphtheria-tetanus-pertussis vaccine (DTP) to all children. Administer booster immunization with tetanus and diphtheria (Td) posttransplant every 10 years (Bu, 1997). The protective antibody against diphtheria may decline more rapidly, thus monitor titers more frequently with revaccination if needed. Although the HBV vaccine is routinely administered to all children now, nonimmunized children still must be immunized with this vaccine. The recommended dose schedule is at 0, 1, 2, and 6 months. Periodically monitor the antibody level after transplantation and administer a booster to those with low titers ( <10 mIU/mL) (Am Acad Ped, 1997). Routinely measure varicella titers 4-6 weeks after immunization, and if inadequate seroconversion is present, perform repeat vaccination. Of children receiving VZV vaccine prior to transplantation, only 62% have adequate antibodies at 1 year, and only 42% have antibodies 10 years following transplantation (Broyer, 1997). Therefore, periodic VZV antibody monitoring is essential to identify children at risk of active varicella disease. Routinely provide an annual influenza vaccine to children with transplants and their family and/or household contacts. MalignancyImmunosuppression increases the risk of malignancy in children as well as adults. The most common malignancies reported in pediatric transplant recipients are lymphoma, cutaneous cancers, carcinoma of the vulva and/or perineum, liver tumors, and sarcomas (Penn, 1993). RejectionImmunologic reactions against kidney transplants are becoming less common as more specific immunosuppressive agents are used. However, rejection remains the most common cause of allograft loss in children and adults. Rejection can be classified into 2 types. Acute rejection Acute rejection is an immunologic reaction against an allograft resulting in a rapid decline in renal function. Acute rejection typically manifests as a rapid rise in serum creatinine without other signs or symptoms. Severe acute rejection episodes can cause fever, myalgias, pain over the allograft, or a decrease in urine output. Evaluate all children with a rise in serum creatinine for acute rejection. Include ultrasonography to exclude hydronephrosis and an evaluation of trough levels of macrolide (cyclosporine, tacrolimus) to exclude nephrotoxicity. Nuclear renography may demonstrate a delay in perfusion to the allograft and a decrease in tubular excretion. Differentiation among the various causes of allograft dysfunction may be difficult. A percutaneous needle biopsy of the kidney transplant is the most reliable diagnostic test (see Image 14A). Mild acute rejections can be treated with a short-term pulse of corticosteroids (5 mg/kg/d IV for 3 d followed by tapering back to baseline steroid dose over 7-10 d). Acute rejection unresponsive to steroid pulse and severe acute rejections can be treated by an antilymphocyte antibody (see Medical therapy). Acute rejection represents a failure of immunosuppression; thus, a search for the cause of the failure must be undertaken. Include an evaluation of the adequacy of the immunosuppression dose (particularly the macrolide) and the patient's compliance with the regimen. Adolescents are at increased risk of allograft loss from noncompliance. Variability in macrolide trough levels may indicate periodic noncompliance. Advise counseling for children suspected of noncompliance. Mongeau et al found a significant relationship between psychosocial factors and allograft survival (Mongeau, 1997). Some centers alter the immunosuppressive regimen following successful treatment of rejection. For example, if a child experienced an acute rejection on a regimen of cyclosporine and prednisone, one may add mycophenolate mofetil, change from cyclosporine to tacrolimus, or add sirolimus. Chronic rejection Chronic rejection is defined as an immunologic reaction against an allograft resulting in a gradual (but persisting) decline in renal function. Chronic rejection typically manifests as a gradual rise in serum creatinine. Patients are asymptomatic. The risk of chronic rejection is significantly higher in patients who have experienced an acute rejection (Birk, 1997). Therefore, some researchers argue that chronic rejection is a subtle persistence of an acute rejection episode. Chronic rejection is diagnosed by findings from percutaneous needle biopsy of the kidney transplant. Histologic features include thickening of the intima of arterioles and arteries, sclerosis of glomeruli, and tubular atrophy (see Image 14B). No effective therapy exists for acute rejection. Prevention of acute rejection is the best method of avoiding chronic rejection. OUTCOME AND PROGNOSISSection 8 of 11
Graft survival Kidney transplant survival increased dramatically with the use of cyclosporine A in the late 1980s. Since that time, a steady increase in kidney and patient survival has followed the advent of new immunosuppressive medications and modifications in the way immunosuppressive drugs are used. Actual kidney transplant survival as reported by US Renal Data Systems is illustrated in Image 15. The most recent report from NAPTRCS demonstrates that kidney transplant survival rates in very young children (aged 0-1 y) is approximately 10 percentage points lower than that for older children. This difference is due to graft losses within the first year following transplantation. As in the adult population, black children experience graft loss at a higher rate than people of other races. Children who receive kidney transplants from pediatric donors appear to have more capacity to increase their glomerular filtration rate as they grow comparedtochildren who receive adult kidneys (Pape,2004). Cause of graft loss The most common etiology of allograft loss among children and adolescents is rejection. Acute and chronic rejection caused almost half of the kidney transplant losses reported by members of the NAPRTCS (Benfield, 1999). This was true for both initial and second kidney transplant failures. Other causes in order of decreasing frequency include technical complications including thrombosis, death with a functioning kidney, recurrent or de novo kidney diseases, primary nonfunction, noncompliance with immunosuppression, and others (see Image 16). Patient survival Patient survival for pediatric recipients of kidney transplants reported by the US Renal Data System is illustrated in Image 17. Patient survival is significantly lower for very young ( <1 y) recipients (Benfield, 1999). Infant recipients of cadaveric kidneys have the highest mortality rate. Etiology of patient death The NAPRTCS report from 1997 lists cardiopulmonary event as the most common cause of death among children with kidney transplants. Infection (bacterial more common than viral) was the second most common cause of mortality. Other causes are illustrated in Image 18. Currently, of any of the options for treatment, renal transplantation offers children with ESRD the best opportunity for growth and development. Allograft and patient survival both have demonstrated consistent improvement in the 5 decades during which renal transplantation has been available. This has been the result of improved understanding of the immune response to allografting and the development of increasingly specific strategies to protect a kidney transplant from the body's natural defenses while leaving a recipient protected from infection. FUTURE AND CONTROVERSIESSection 9 of 11
General The greatest challenges facing those who treat children with ESRD are to provide more organs for children waiting for transplant and to prevent acute and chronic rejection without increasing the complications of immunosuppressive drugs. Non–heart-beating cadaver donors In the United States and Europe, most cadaver organs used in transplantation come from heart-beating cadavers. In some countries that have no legal recognition of brain death, transplant surgeons use organs from non–heart-beating cadavers, patients who experienced nonsurvivable injury (but did not meet the criteria for brain death), and those for whom life support systems did not preserve life. Within the last decade, several US and European centers have reported success in this technique. In general, graft survival rates are not as high and renal function is somewhat poorer when kidneys from non–heart-beating cadavers are used. Ongoing research in preservation and harvesting techniques may improve outcomes for transplantation with such organs. Newer immunosuppressive agents In the 1990s, several new immunosuppressive drugs became available. This explosion in transplant pharmacology has left transplant physicians wondering how these new medications should be used. In addition, new techniques in dosing and monitoring of older immunosuppressive regimens have improved graft survival. With the dramatic improvements in graft survival observed in the past decade, proving superiority of newer immunosuppressive agents is more difficult, especially in the short term (1-3 y). Lower rates of chronic rejection are expected as acute rejection rates decrease. Therefore, comparison of long-term graft survival likely is necessary to determine the best combination of immunosuppressive drugs. Xenotransplantation Since the infancy of human kidney transplantation, physicians have sought to use organs from animals. Early experimentation with sheep and primate organs were unsuccessful because of immunologic barriers. More is being learned about such impediments; however, currently xenotransplantation remains an unrealized dream. The two approaches under investigation are (1) immunologic blockade to the antigen-initiated response to interspecies transplantation and (2) genetic engineering to produce animals that lack the antigens against which human recipients mount an immunologic response. For further information, see Mayo Clinic - Kidney Transplant Information. MULTIMEDIASection 10 of 11
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