Pediatric Kidney Transplantation

Updated: Jun 30, 2022
Author: Rekha Agrawal, MD; Chief Editor: Stuart M Greenstein, MD 


Practice Essentials

In children and adolescents younger than 18 years, the adjusted incidence of end-stage renal disease (ESRD) in the United States in 2019 was 12 cases per million population. Over the decade from 2009 to 2019, the adjusted ESRD incidence in that age group declined by 14.3%. Treatment options include hemodialysis, peritoneal dialysis, and kidney transplantation. Kidney transplantation has become the primary method of treating ESRD in the pediatric population, with 1-year all-cause mortality rates significantly lower than with either form of dialysis.[1] The reported 1- and 5-year patient survival rates are approximately 98% and 94% respectively, while graft survival at 1 and 5 years are 93-95% from living donors and 77-85% from deceased donors.[2]

Unfortunately, the demand for kidney transplants continues to exceed the supply of donor organs. In 2020, 811 pediatric kidney transplantations were performed, but a lack of donor kidneys saw the pediatric transplant waitlist reach 1695 by the end of the year.[3]

Over the past decade, the age of pediatric candidates on the list has shifted, with an increase in those aged 1–5 years (14.9% to 20.9%) and a decrease in those aged 11–17 years (63.4% to 61.9%). However, teenagers still represent the largest group of pediatric kidney transplant recipients.[4] The leading cause of ESRD changes with age: congenital anomalies of the kidney and urinary tract (CAKUT) are most common in children younger than 6 years of age, while focal segmental glomerulosclerosis and glomerulonephritis are more common in older children.[3] Congenital anomalies of the lower urinary tract that lead to ESRD pose significant difficulty for kidney transplantation; treatment of these urologic disorders may require additional procedures, such as open vesicostomy and bladder augmentation.[2]

Table 1. Demographics of pediatric patients awaiting kidney transplant: United States, 2020 [3] (Open Table in a new window)

Patient Characteristic


Age < 1 y


Age 1-5 y


Age 6-10 y


Age 11-17 y










Other or unknown


Table 2 Primary causes of end-stage renal disease (ESRD) in pediatric patients on the kidney transplant waiting list: United States, 2020 [3] (Open Table in a new window)

Cause of Kidney Failure


Focal segmental glomerulosclerosis




Congenital anomalies


Other or unknown


Of current treatment options, kidney 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 kidney 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 the recipient protected from infection.

For patient education information, see the Kidney Transplant Directory.


Until 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, and elucidation of the pathophysiology of rejection, starting in the mid-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.[5]  That same year, Carrel reported an improved method of suturing vessels together, work that eventually won him a Nobel Prize.[6]  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.[7]  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.[8]  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.[9]  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.[10]  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.[11]

In the early 1960s, Calne found that a derivative of 6-mercaptopurine (azathioprine) increased the success of experimental kidney transplantation in dogs.[12]  Human use of azathioprine followed, and long-term graft survival from non-identical donor kidneys became a possibility. The success of kidney transplantation increased significantly when Goodwin and Starzl added prednisolone to azathioprine.[13, 14]  Encouraged by this success, transplant centers began performing non-identical 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.[15]  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.[16]  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.[17]  Improvement in graft survival followed the routine use of human leukocyte antigen (HLA) tissue matching[18]  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.[19]  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.


Despite 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.[9] 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 dramatically increased over the 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) widely vary 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 below).

Simplified diagram of the immune response to nonid Simplified diagram of the immune response to nonidentical major histocompatability complex (MHC) antigens. Foreign antigens are processed by macrophages or dendritic cells (antigen-presenting cell) and then presented to T-helper lymphocytes. Release of interleukin-1 from macrophages activates T-helper lymphocytes. Thus activated, these T-helper lymphocytes produce cytokines (interleukin-2) that stimulate production of cytotoxic T lymphocytes, antibody-producing B lymphocytes, and natural killer cells. Diagram provided by David A. Hatch, MD, copyright 2001, used with permission.

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, specifically directed 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, typified by a gradual obliteration of the lumen of small arteries in the graft caused by endothelial thickening, along with interstitial fibrosis and tubular atrophy. This response occurs more commonly, but not exclusively, in recipients who have experienced an acute rejection. Therefore, these chronic changes may be a long-term consequence of acute rejection, a low-grade indolent immune reaction, toxicity of immunosuppressive medications, or a combination of those processes.[20] Consequently, the term chronic allograft nephropathy is preferred over chronic rejection to describe these chronic changes.


It is critical to 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 candidates for kidney transplantation. Patients with hepatitis- and HIV-related kidney disease may receive a transplant once they no longer have active disease.

Transplantation is also contraindicated in any child with active anti–glomerular basement membrane (GBM) disease (Goodpasture syndrome) with elevated levels of circulating anti-GBM antibodies or active hemolytic-uremic syndrome because those processes can damage an allograft.

Children with renal failure from primary glomerulonephritis, such as focal segmental glomerulosclerosis (FSGS) or membranoproliferative glomerulonephritis, are at increased risk of recurrence following transplantation. Patients with FSGS can receive a transplant once they are no longer nephrotic. These patients undergo medical or surgical nephrectomy before transplantation and thus are not candidates for a preemptive transplant.

Generally, younger children are transplanted once they reach a weight of 10 kg.


Graft survival

The 2018 annual report of the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) demonstrates that graft survival was highest for living-donor recipients younger than 11 years (93.1% at 5 years) and lowest for deceased-donor recipients aged 11–17 years (77.2% at 5 years). The incidence of acute rejection in the first year was 11.4% overall—highest, at 12.5%, for ages younger than 6 years and lowest, at 7.9% for ages 6-10 years.[3]

A study that analyzed North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) data and found that pediatric recipients of young donors (< 5 years) had equivalent patient and graft survival with that of pediatric recipients of ideal donors (6-35 years) and older donors (36-55 years). Estimated glomerular filtration rate of functioning grafts in young donors was comparable to that of ideal donors but better than that of older donors, though primary graft non-function was higher in young donors. The analysis concluded that young donors may be a good option for kidney transplantation in pediatric patients.[21]

Using data from the United Network for Organ Sharing (UNOS) database, one study evaluated the impact of age at transfer to adult-oriented care on renal allograft failure rates. The data noted that graft failures were 58% higher among those who had transferred early (aged < 21 y) compared with those who were transferred late (aged ≥21 y).[22]

Patient survival

The most common causes of death reported for children (0 - 21 y) with ESRD are cardiac arrest cause unknown, withdrawal from dialysis, and sepsis. Cardiovascular disease accounts for a mortality rate of 36% among all pediatric patients with ESRD, 34% in those undergoing dialysis and 11% after transplantation.[23] The youngest children have reported causes similar to those in older children and adolescents.[1]

Managing chronic kidney disease and related cardiovascular morbidity should be an essential component to the care of pediatric transplant patients. Timely identification of any irregularities, such as albuminuria and hypertension, aid in the early detection of renal damage and increase the probability of restoring lost kidney function.[24]

Analysis of NAPRTCS data from 1988 to 2010 on pediatric patients with post-transplant lymphoproliferative disorder (PTLD) showed that in the most recent cases, patient survival was 87.4% at 5 years post-PTLD, compared with 48% cross-sectional survival reported in the 1990s. Recent graft survival post-PTLD was 81.8% at 1 year and 65% at 5 years. Interventions for PTLD included reduction of immunosuppression; use of anti-CD20 antibody, interferon alpha, or antiviral therapy; and surgical reduction.[25]

In a study of 18,911 patients who received a first transplant before age 21 years, mortality was highest in the first year post transplantation. After the first year of the first transplant, mortality rates and age-, sex-, and race-standardized mortality ratios decreased slightly. The age-adjusted all-cause mortality rate decreased by 1% and the cardiovascular mortality rate by 16% for every year after the first post transplantation year; the infection-related mortality rate did not change. Those results suggest that exposure to the "transplantation milieu" does not negatively affect long-term cardiovascular health.[26, 27]



Laboratory Studies

The following studies are indicated in kidney transplantation candidates:

  • Complete blood cell count (CBC)
  • Comprehensive metabolic panel, plus serum phosphorus and magnesium
  • Parathyroid hormone
  • Liver function tests
  • Coagulation studies - These should include prothrombin time with International Normalized Ratio (INR) and activated partial thromboplastin time
  • Human leukocyte antigen (HLA) and panel reactive antibody (PRA) testing
  • Viral titers

In PRA testing, recipient serum is incubated with white blood cells pooled from a group of blood donors with human leukocyte antigen (HLA) types representative of the community. Cell kill indicates that the recipient has antibodies against the donor cells. The percentage of the donors against which the recipient reacts is used as a predictor of the likelihood of a positive cross-match that would prevent transplantation.

Viral titers include the following:

Children who demonstrate no antibody to CMV, VZV, and EBV are at increased risk of posttransplant primary infection, especially if they receive kidneys from donors who are seropositive for these viruses.

One must therefore closely monitor such recipients following transplantation and provide appropriate antiviral therapy (agents that prevent viral proliferation or antibodies directed against a specific virus). One should ensure that all children receive routine childhood immunizations, including pneumococcal 13-valent conjugate vaccine and hepatitis B vaccine. In addition, children age 2 years and older should also receive the 23-valent pneumococcal vaccine, given at least 8 weeks after the child has received the final dose of the 13-valent vaccine. All live vaccines should be given at least 2 months prior to transplantation. See Pediatric Hepatitis B for complete information on this topic.

Imaging Studies

Imaging studies include chest radiography and abdominal ultrasonography. Additional studies depend on the child's urologic pattern, as revealed by a thorough medical history. A history of congenital urologic anomaly, recurrent urine infections, and/or voiding abnormalities (eg, incontinence, frequency, urgency) identifies children who should undergo further urologic imaging or evaluation, including voiding cystourethrography and possible urodynamic studies and cystoscopy.

Urodynamic Evaluation

Urodynamic evaluation should be performed in children with a history of voiding dysfunction (eg, incontinence) or major reconstruction of the lower urinary tract. A urodynamic study is a functional evaluation of the bladder that measures the following:

  • Bladder capacity
  • Bladder storage pressures
  • Voiding function and pressure
  • Coordination of the components of the lower urinary tract

If low bladder capacity, high storage pressure, incomplete emptying, or high voiding pressure is found on urodynamic testing, instituting intervention prior to transplantation to prevent urine infection, urinary obstruction, or incontinence may be appropriate.



Medical Therapy

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. Currently used immunosuppressive agents are generally classified into 4 groups: corticosteroids, antimetabolites, macrolides, and antibodies. Most commonly used is a combination of tacrolimus, mycophenolate, and prednisone. The sites of action along the cascade of immunologic stimulation of each class of immunosuppressive medication are depicted below.

Simplified diagram illustrating the points of acti Simplified diagram illustrating the points of action of immunosuppressive drugs. Corticosteroids inhibit production of interleukin-1. Macrolides (ie, cyclosporine, tacrolimus, sirolimus) inhibit production of or use of interleukin-2, thus inhibiting stimulation of a clone of cytotoxic T lymphocytes directed against specific human lymphocyte antigen types. Antimetabolites (ie, mycophenolate mofetil, azathioprine) inhibit purine production, thus impairing cell proliferation. Antibodies impair normal function of cell surface markers, thus inhibiting stimulation of T-lymphocyte clones directed against foreign antigens. Diagram provided by David A. Hatch, MD, copyright 2001, used with permission.


Corticosteroids used in transplant recipients include methylprednisolone and prednisone. These agents work by inhibiting the production and release of interleukin (IL)-1.

Dosage varies by center. Some centers administer additional pretransplant steroids to recipients of living-donor kidneys. Methylprednisolone is typically given in a dose of 10 mg/kg intravenously (IV) immediately prior to transplantation, with relatively rapid conversion to prednisone and tapering of the dose over 12 weeks to a baseline dose of 0.3 mg/kg/d orally (PO).

Long-term corticosteroid therapy has a substantial number of adverse effects. These include hirsutism, acne, hypercholesterolemia, hyperlipidemia, avascular necrosis of the hip, glucose intolerance, growth retardation, gastritis, gastric ulcer, obesity, cataracts, impaired wound healing, and mood alteration.

In an effort to increase the growth of pediatric recipients of kidney transplants and to avoid adverse effects, some centers taper and ultimately discontinue corticosteroids within 1 year of transplantation.[28, 29] This method is generally not used, however, because of the possibility of acute rejection and graft loss. Centers that ultimately eliminate corticosteroids generally use higher doses of other immunosuppressive agents (ie, tacrolimus).


Antimetabolites include mycophenolate mofetil (CellCept) and azathioprine (Imuran). Mycophenolate mofetil blocks inosine monophosphate dehydrogenase, an enzyme necessary for purine synthesis specifically in lymphocytes. This provides more specific immunosuppression for transplantation than azathioprine. Azathioprine impedes purine synthesis, thus impairing cell division and proliferation in all replicating cells. 

Because of the increased specificity of mycophenolate mofetil, azathioprine is rarely used in current transplant immunosuppression regimens. However, many long-term recipients who received transplants in childhood remain on azathioprine.

Dosage varies by transplant center. Mycophenolate mofetil is typically given in a dosage of 1200 mg/m2/d PO divided in two doses. Azathioprine is typically given in a dosage of 1-2 mg/kg PO once per day

Adverse effects of mycophenolate mofetil are as follows:

  • Nausea
  • Vomiting
  • Increased susceptibility to infections

Adverse effects of azathioprine are as follows:

  • Leukopenia
  • Thrombocytopenia
  • Alopecia
  • Cholestatic jaundice
  • Squamous cell carcinoma
  • Hepatotoxicity
  • Increased susceptibility to infections

Mycophenolate is available in two formulations that are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that, once hydrolyzed in vivo, releases the active moiety, mycophenolic acid. The oral suspension, tablets, and capsules are approved by the FDA for pediatric kidney transplant recipients aged 3 months and older in combination with other immunosuppressants. A newer formulation, mycophenolic acid (MPA, Myfortic), is an enteric-coated product that delivers the active moiety. Mycophenolic acid is approved for children aged 5 years and older. 

Calcineurin inhibitors

Calcineurin inhibitors used in transplant recipients include cyclosporine and tacrolimus. These agents block the production of or action of IL-2 or other cytokines. Dosages vary by transplant center and by the individual patient.

Cyclosporine dosage

The typical dose of cyclosporine is 14 mg/kg/d PO divided twice daily. The dose is adjusted to maintain a trough whole blood level of 325-400 ng/mL or a 2-hour peak level of 1,000-1,200 ng/mL. Absorption and metabolism vary considerably, so the dose should be adjusted individually; very young children and those with rapid metabolism of the drug may require three doses a day to maintain an adequate trough level.

Tacrolimus dosage

The typical dose of tacrolimus is 0.2-0.3 mg/kg/d PO divided twice daily. The dose is adjusted to maintain a trough whole blood level of 10-20 ng/mL in first year following transplantation.

Adverse effects

Cyclosporine adverse effects are as follows:

  • Hypertension
  • Nephrotoxicity
  • Hirsutism
  • Gingival hyperplasia
  • Neuropathy
  • Increased risk of malignancy

Tacrolimus adverse effects are as follows:

  • Nephrotoxicity
  • Neurotoxicity
  • Hyperglycemia
  • Hyperkalemia
  • Increased susceptibility to infections
  • Increased risk of malignancy


Cyclosporine, tacrolimus, and sirolimus are metabolized by the hepatic cytochrome P-450 system. Drugs similarly metabolized by this system compete, thus delaying metabolism and increasing the serum level of the macrolide (eg, diltiazem, nicardipine, verapamil, ketoconazole, fluconazole, itraconazole, danazol, bromocriptine, metoclopramide, erythromycin).

Drugs that stimulate the hepatic cytochrome P-450 system increase the rate of metabolism of macrolides, thus decreasing serum levels (eg, rifampin, phenytoin, phenobarbital, carbamazepine). Some herbal preparations (eg, St. John's Wort) may also stimulate elimination and decrease serum concentration.

Cyclosporine and, to a lesser degree, tacrolimus are potentially nephrotoxic. Use other nephrotoxic drugs (eg, aminoglycosides) with extreme caution in patients receiving cyclosporine.


Tacrolimus is 100 times more potent than cyclosporine. Some centers using tacrolimus wean transplant recipients off corticosteroids. Sirolimus interferes with the immune cascade at a point beyond IL-2 production; therefore, it has been used to advantage in combination with cyclosporine.

A microemulsion form of cyclosporine (Neoral) was developed to provide more predictable and consistent absorption. Although the microemulsion increases intestinal absorption, some patients ultimately have higher peak blood levels and/or lower trough levels on this form of cyclosporine. Some transplant physicians believe that the trough level is most important, whereas others emphasize peak cyclosporine level.


Sirolimus dosage

The dosage for sirolimus is determined on the basis of patient age and weight and degree of immunologic risk. For patients younger than 13 years, the dose has not been established. For patients age 13 years or older and weight less than 40 kg, the loading dose is 3 mg/m2 PO once, and the maintenance dose is 1 mg/m2 PO qd; the dose is adjusted to maintain trough whole blood levels of 8-15 ng/mL. For patients age 13 years or older with weight 40 kg or more, sirolimus is administered as in adults.

For patients at low immunologic risk, the typical adult regimen for sirolimus (coadministered with cyclosporine and corticosteroids) is as follows:

  • Loading dose, day 1 posttransplantation: 6 mg PO once

  • Initial maintenance dose, beginning day 2 posttransplantation: 2 mg/d PO as single daily dose Subsequent maintenance dose: Obtain trough blood level between days 5 and 7; target trough level (whole blood) is 10-15 ng/mL

For sirolimus adult dosage following cyclosporine withdrawal, in patients at low immunologic risk, the regimen is to gradually withdraw cyclosporine 2-4 mo following transplantation. Then increase the sirolimus dose to maintain a trough whole blood concentration of 16-24 ng/mL for the remaining year after transplantation (typically, this requires a dose about four-fold higher than when sirolimus is combined with cyclosporine and corticosteroid). Thereafter, the target trough blood level is 12-20 ng/mL.

For patients at high immunologic risk, the typical adult regimen is as follows:

  • Loading dose, day 1 posttransplantation: 15 mg or less PO once

  • Initial maintenance dose, beginning day 2 posttransplantation: 5 mg PO as a single daily dose

  • Subsequent maintenance dose: Obtain trough blood level between days 5 and 7; target trough level (whole blood) is 10-15 ng/mL

  • Use sirolimus in combination with cyclosporine and corticosteroids for first year following transplantation; after the first year, consider adjusting immunosuppressive regimen on basis of patient's clinical status.

Considerations with sirolimus use are as follows:

  • Administer sirolimus 4 hours following cyclosporine
  • Simultaneous ingestion of fat may decrease absorption
  • Patients should take sirolimus consistently either with or without food
  • Sirolimus should not be taken with grapefruit juice (impairs absorption)

Sirolimus adverse effects are as follows:

  • Hypercholesterolemia
  • Hyperlipemia
  • Hypertension
  • Rash
  • Increased susceptibility to infections
  • Increased risk of malignancy
  • Interstitial pneumonitis

In animal studies, sirolimus has been shown to inhibit skeletal and muscle growth, but a study that compared linear growth in children who received sirolimus therapy after renal transplantation versus those who were maintained on tacrolimus found no difference in growth between the two groups, and no adverse effect on growth with sirolimus. Height z-scores at baseline in 25 children 1-15 years of age who were treated with sirolimus did not change significantly over 24 months, and were no different from height z-scores at baseline and after 24 months in patients .[30]


Antilymphocyte antibodies used in transplantation include the following:

These antibodies are used for induction (temporary use immediately following transplantation, while other immunosuppressive agents are adjusted) and for treatment of acute rejection. In general, these antibodies interfere with the function of T lymphocytes. Some cause lysis of lymphocytes with a resulting lymphopenia; some cover or impair the function of cell surface markers necessary for recognition and processing of foreign antigens in the cascade of the immune response; others may result in an increase of suppressor T lymphocytes.

Polyclonal antibodies provide a relatively less specific impairment of lymphocyte activity. Monoclonal antibodies (ie, muromonab-CD3, basiliximab) provide more specific inhibition of lymphocyte function. Because basiliximab is more effective than muromonag-CD3 and has a lower incidence of significant side effects, muromonag-CD3 is rarely used in immunosuppression induction protocols.

Daclizumab (Zenapax) was withdrawn from the United States market because of diminished use and emergence of other effective therapies.


Antithymocyte globulin is typically given in a dosage of 10-15 mg/kg/d IV administered once daily for 5-14 days. Many centers individualize the duration, discontinuing the antibody when cyclosporine or tacrolimus levels are consistently within therapeutic range.

Muromonab-CD3 dose varies by weight: typical doses are 1 mg for patients < 20 kg, 2 mg for those 20-40 kg, and 5 mg for those >40 kg. Premedication (ie, methylprednisolone, acetaminophen, diphenhydramine) is given prior to the first one to three doses. The dose is administered IV, once daily for 7-14 days; some centers individualize the duration, discontinuing the antibody when cyclosporine or tacrolimus levels are consistently within therapeutic range.

Basiliximab is typically given in the following dosages:

  • Children aged 2-15 years: 12 mg/m 2 IV administered within 2 hours prior to transplantation and repeated 4 days following transplantation
  • Patients older than 15 years: 20 mg IV administered within 2 hours prior to transplantation and repeated 4 days following transplantation

Adverse effects

Adverse effects of muromonab-CD3 (OKT3) include the following:

  • Fever
  • Myalgias
  • Lymphopenia
  • Thrombocytopenia
  • Increased susceptibility to viral infections or reactivation of latent viral infections
  • Increased susceptibility to posttransplant lymphoproliferative disorder (varies in severity from a premalignant lymphoproliferation to a frankly malignant lymphoma)

With basiliximab, early experience suggests relatively few adverse effects directly attributable to use of this antibody.[31] Concern remains, however, regarding potential to increase the risk of infection and malignancy.

Organ Source

With the establishment of brain death laws and successful immunosuppression protocols, transplantation with brain-death donor (DBD) cadaver kidneys became an attractive treatment option for children with end-stage renal disease (ESRD). However, kidneys obtained from cadavers remain in limited supply. In response to the shortage of donor kidneys, there has been an increase in the use of donation-after–circulatory death (DCD) kidneys. 

Analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, both short- and long-term transplant outcomes are similar in recipients of DCD and DBD kidneys.[32]  Nevertheless, DCD kidneys are three times more likely to be declined for transplantation due to concerns over their quality.[33]

With improvement in immunosuppressive protocols, the gap in allograft survival between living donors and cadaver donors has narrowed. Still, the decline in the proportion of living donor kidney transplants in pediatric recipients is of concern. In 2016, only 34.2% of pediatric transplants were from living donors, compared with 47.2% in 2005.[3]

In an effort to increase the availability of living-donor transplants, a process of kidney paired donation (KPD) has been employed. In its simplest form, two living donors who are incompatible with their chosen recipients agree to an exchange and their donated organs go to each other’s compatible recipient. More complex exchanges involving three or more recipient-donor pairs have also occurred. Altruistic, undirected donors have also initiated complex chains. The counts of KPD transplants in the Unitied States have increased sharply from 27 in 2005 to 642 in 2016, though they appear to have plateaued and now represent about 10% of all living-donor transplantations.[1, 3]

Evaluation of Potential Living Donors

The ideal organ donor for kidney transplantation is a living identical twin or a sibling with identical human leukocyte antigen (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.

Potential living donors should be carefully interviewed to assess their motivation and their understanding of the ramifications of donor nephrectomy. It is important to determine if a potential donor is being coerced to donate a kidney, in which case donation should be declined. A thorough medical history should be obtained and a physical examination performed, including a careful evaluation of the donor's potential for kidney disease, diabetes mellitus, chronic infection, and other factors that contraindicate organ donation.

Laboratory evaluation

Tests include the following:

  • 24-hour urine collection for creatinine clearance and urinalysis
  • Complete blood cell count (CBC)
  • Complete metabolic panel
  • Coagulation evaluation (international normalized ratio [INR], prothrombin time [PT] and partial thromboplastin time [PTT])
  • Viral titers (hepatitis B virus [HBV], hepatitis C virus [HCV], HIV, Epstein-Barr virus [EBV], herpes simplex virus [HSV])
  • Cardiac evaluation

Imaging evaluation

The imaging evaluation includes chest radiography. Imaging of the kidneys and renal vessels was previously done with intravenous pyelography and angiography; however, current radiologic techniques provide suitable imaging of the entire urinary tract with three-dimensional computed tomography (3D CT) scanning or magnetic resonance angiography (MRA) using gadolinium to demonstrate the vascular anatomy (see the image below).

Comparison of imaging techniques for a living kidn Comparison of imaging techniques for a living kidney donor. (A) Digital subtraction angiogram showing lower pole artery. (B) Three-dimensional CT scan depicting 2 left renal arteries. Images provided by David A. Hatch, MD, copyright 1999, used with permission.

Kidney procurement

The left kidney is preferred for living-donor nephrectomy because the renal vein is longer on the left. However, when vascular, urological or other abnormalities are present, the right kidney may be procured.[34]

Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines recommend “mini-open” laparoscopy, hand-assisted laparoscopy, or robotic-assisted surgery by trained surgeons as the optimal approaches for living-donor nephrectomy. In select circumstances, such as donors with extensive previous surgery or adhesions, and at centers where laparoscopy is not routinely performed, open nephrectomy (flank or laparotomy) may be acceptable.[34]

Robotic and laparoscopic surgery often take longer than open nephrectomy but provide a more rapid recovery for the donor. The vast majority of living-donor nephrectomies are now performed robotically or laparoscopically, with donors discharged from the hospital about 48 hours following the surgery.

Follow-up care

A personalized postdonation care plan should be provided prior to donation with follow-up care recommendations, including monitoring for chronic kidney disease (CKD). Annual post-donation monitoring should also include the following[34] :

  • Blood pressure measurement
  • Body mass index (BMI) measurement
  • Serum creatinine measurement with calculation of estimated glomerular filtration rate (eGFR)
  • Albuminuria measurement
  • Review and promotion of a healthy lifestyle, including regular exercise, healthy diet, and abstinence from tobacco
  • Review and support of psychosocial health and well-being

Cadaver Kidneys

Waiting times for cadaver kidney transplants vary by region from a few months to more than 4 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.

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 Details

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 A in the image below).

Incisions used for kidney transplantation. (A) Gib Incisions used for kidney transplantation. (A) Gibson incision used for large children and adults. (B) Midline abdominal incision used for small children.

The renal artery is anastomosed either to the external iliac or the internal iliac artery, as shown below.

Vascular anastomoses used in a kidney transplantat Vascular anastomoses used in a kidney transplantation in a 5-year-old patient, renal artery to common iliac artery and renal vein to common iliac vein. Image provided by David A. Hatch, MD, copyright 2001, used with permission.

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, kidney transplants are most often 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 below).[35, 36]

Anastomosis of kidney transplant ureter to bladder Anastomosis of kidney transplant ureter to bladder.

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 children receive an adult-sized kidney transplant. Through a midline incision, the peritoneal cavity is entered and the great vessels are exposed (see B in the image below).

Incisions used for kidney transplantation. (A) Gib Incisions used for kidney transplantation. (A) Gibson incision used for large children and adults. (B) Midline abdominal incision used for small children.

In recent years, the ability to perform renal transplantation using robotic assisted technology has been proven to be effective in adults and in children, (1) when performing the transplant itself[37] or (2) in the management of urologic complications secondary to pediatric renal transplantation, like ureteral stenosis.[38] To date, most studies have suggested that although robotic-assisted procedures take longer and may be more expensive, physiologic outcomes are similar and more rapid recovery of the patients typically occurs.

In small children, theThe renal vessels are then anastomosed to the abdominal aorta and inferior vena cava. The common iliac artery and vein may also be used, depending on the size of the kidney and the recipient. The ureter is anastomosed to the bladder as described above.

A study by Heap et al concluded that extraperitoneal kidney transplantation in small children is a safe and feasible alternative to the intraperitoneal approach, with similar outcomes. These researchers examined the medical notes of 30 transplant recipients younger than 6 years; the intraperitoneal approach was used in 18 patients and the extraperitoneal approach was used in 12 patients. No significant difference was observed in the number of complications or length of stay. A significant difference was found in absolute plasma creatinine between the 2 surgical groups between postoperative days 2 and 14, but not in the trend of change in mean plasma creatinine values over time.[39]

In 2011, Tydén et al introduced new protocol designed to enable safe ABO-incompatible kidney transplantation. The protocol uses antigen-specific immunoadsorption instead of nonspecific plasma exchange to remove existing anti-A/B antibodies. In addition, it uses rituximab rather than splenectomy to prevent rebound of antibodies. Successful transplantation with this protocol was achieved in 60 patients, 10 of them children. No differences in success rate, renal function, or adverse events were found when compared with ABO-compatible transplantation.[40]

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 A below), an incontinent urinary conduit (see B below), or a continent urinary reservoir. Allograft survival in these cases is comparable to that in children with normal bladders.

Anastomosis of kidney transplantation. Ureter to ( Anastomosis of kidney transplantation. Ureter to (A) bladder augmented with a patch of bowel and (B) urinary conduit constructed from a segment of ileum.

Such recipients are at increased risk of urine infections and therefore require close monitoring. When necessary, clean intermittent catheterization has been successfully used in these patients to drain the urine.[41]


Laboratory studies

Tests include the following:

  • Complete blood cell count (CBC)
  • Serum electrolytes and liver enzyme tests
  • Macrolide trough levels

Perform a CBC to detect leukopenia (a potential adverse effect of some immunosuppressive agents), leukocytosis (evidence of infection), and anemia. Measure serum electrolytes to monitor potassium and phosphorus levels (hypophosphatemia is common following successful kidney transplantation). Measure liver enzymes to detect hepatotoxicity from immunosuppressive medications.

Because absorption and metabolism of cyclosporine and, to a lesser degree, tacrolimus can widely vary, periodically measuring trough drug levels is important. Typical target trough levels for the first year following transplantation are as follows:

  • Cyclosporine: 325-375 ng/mL
  • Tacrolimus: 10-15 ng/mL
  • Sirolimus: 8-15 ng/mL

Imaging studies

Ultrasonography is by far the most useful imaging technique following transplantation, allowing rapid visualization of the kidney, the collecting system, and the renal vessels. Color Doppler ultrasonography detects abnormalities of blood flow, including kinking of the artery or vein and thrombosis (see image below). Ultrasonography also aids in the detection of obstruction (hydronephrosis), lymphocele, urine or blood leakage (perinephric fluid collection), and kidney stones (rare).

Kidney transplantation ultrasonograms. (A) Normal Kidney transplantation ultrasonograms. (A) Normal kidney. (B) Color Doppler ultrasonogram documenting normal perfusion to the kidney. (C) Color Doppler ultrasonogram showing absence of perfusion in a patient with thrombosis. (D) Hydronephrosis. (E) Lymphocele. (F) Stone in a kidney transplant. Images provided by David A. Hatch, MD, copyright 1998, used with permission.

A disadvantage of ultrasonography is that it provides no indication of renal function. Nuclear renography provides an accurate representation of perfusion, tubular function, and drainage of the kidney transplant.

Currently, the preferred nuclear medicine imaging agent used to determine renal tubular function is mercaptotriglycylglycine (MAG-3), which demonstrates both glomerular filtration and tubular excretion. If determination of the degree of cortical scarring is critical, a cortical imaging agent such as glucoheptonate is usually preferred.

On nuclear renography, delayed or decreased perfusion of the kidney may indicate acute rejection or compromise of arterial inflow. Decreased tubular excretion may be due to nephrotoxicity (from cyclosporine or other drugs), acute or chronic rejection, or acute tubular necrosis. (See the image below.)

Nuclear renograms of kidney transplantations. (A) Nuclear renograms of kidney transplantations. (A) Normal perfusion. Note that the isotope is observed in the aorta, iliac vessels, and the kidney in the first image (0-5 s). (B) Normal tubular function and drainage. Note that the isotope is rapidly excreted and drained. The highest concentration of isotope (darkest image) is observed in the first image (0-3 min). (C) Delayed perfusion in a patient with acute rejection. Note that the isotope is observed in the aorta and iliac vessels in the first frame (0-5 s), but the kidney first shows uptake of the isotope in the second frame (6-10 s). (D) Decreased tubular function in a cadaver kidney transplant with acute tubular necrosis. Image provided by David A. Hatch, MD, copyright 2001, used with permission.


Surgical complications

Surgical complications include the following:

  • Lymphocele
  • Wound infection
  • Thrombosis
  • Renal artery stenosis


A lymphocele is an accumulation of lymphatic fluid around the kidney. The lymphatic fluid originates either from the lymphatics of the allograft or from 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 the image below.)

Kidney transplantation ultrasonograms. (A) Normal Kidney transplantation ultrasonograms. (A) Normal kidney. (B) Color Doppler ultrasonogram documenting normal perfusion to the kidney. (C) Color Doppler ultrasonogram showing absence of perfusion in a patient with thrombosis. (D) Hydronephrosis. (E) Lymphocele. (F) Stone in a kidney transplant. Images provided by David A. Hatch, MD, copyright 1998, used with permission.

A lymphocele appears as a fluid collection adjacent to the kidney transplant. If the diagnosis is in question, the fluid collection can be aspirated under sterile conditions using ultrasonographic guidance. Analysis of the aspirated fluid can be used to distinguish lymphocele from urine leak, as follows:

  • Creatinine level: High in urine leak, low in lymphocele
  • Lipid levels: High in lymphocele, low in urine leak
  • Cell count: High lymphocyte count in lymphocele, low cell count in urine leak

Treatment options include surgical 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.[42] 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. Surgical drainage and administration of parenteral antibiotics should be undertaken immediately.


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 elevating serum creatinine level.

Thrombosis is readily diagnosed with the assistance of color Doppler ultrasonography (see C in the image above). If a prompt diagnosis is made, emergency treatment can be attempted 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 may result from a technical error or a hypercoagulable condition in the recipient. Once should 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. Patients with hypertension that is difficult to control should be evaluated 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, one should 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, as shown in the image below, is the most sensitive diagnostic test. Three-dimensional CT scanning has also been used in making the diagnosis. 

Digital subtraction angiogram showing renal artery Digital subtraction angiogram showing renal artery stenosis. Image provided by David A. Hatch, MD, copyright 1998, used with permission.

Treatment options include balloon angioplasty or open surgical revascularization. Balloon angioplasty has the highest success rate with the lowest risk of complications.

Urologic Complications

Obstruction of urine drainage and urine leak are the most common surgical complications following pediatric kidney transplantation.


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 ureteral blood supply. Possible signs of urinary obstruction include the following:

  • Hydronephrosis on posttransplantation ultrasonography
  • Decreasing urine output
  • Failure of the expected drop in serum creatinine

Ultrasonography is the best method of diagnosing obstruction (see D in the image below). When the diagnosis is in question, diuretic renography may be used to confirm obstruction. A percutaneous antegrade pyelography and a pressure-flow study (Whitaker test) may also beis indicated.[43] 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 transplant kidney renal pelvis directly to the bladder or anastomosis of the patient’s native ureter to the transplant kidney pelvis may be possible.

Kidney transplantation ultrasonograms. (A) Normal Kidney transplantation ultrasonograms. (A) Normal kidney. (B) Color Doppler ultrasonogram documenting normal perfusion to the kidney. (C) Color Doppler ultrasonogram showing absence of perfusion in a patient with thrombosis. (D) Hydronephrosis. (E) Lymphocele. (F) Stone in a kidney transplant. Images provided by David A. Hatch, MD, copyright 1998, used with permission.

Urine leak

A breakdown in the anastomosis of the ureter to the bladder leads to 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 creatinine to decrease as expected following transplantation.

When significant drainage from the incision follows kidney transplantation, one should 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. High-volume leakage and persisting leakage most often require surgical repair.

Use of cadaver allografts from infants is associated with an increased risk of ureteric complications (stenosis and leakage) because of the tenuous blood supply of infant ureters. Flechner et al used a novel adaptation to the technique of en-bloc infant kidney transplantation, harvesting the trigone and adjacent tissues intact and transplanting this entire segment, as a patch, onto the recipient bladder.[44]

Medical Complications

Medical complications include immunosuppression and infection. For specific adverse effects of individual immunosuppressive agents, see Medical Therapy.

Infection is one of the most important and common complications of renal transplantation. It can occur at any time after transplantation and can vary considerably in severity. Infections significantly add to the morbidity and mortality of transplantation.

The incidence and severity of posttransplant infection have decreased as a result of more judicious use of immunosuppressive medications and the availability of better therapeutic options.[45] 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%.[46, 47]

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

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 also 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.

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, one should 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

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 patients may develop disseminated disease.

Viral infections

Viral infections are a source of significant morbidity as well as mortality in children. Younger children often get primary infections, as they are naïve to the virus. This includes infection with cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella zoster virus (VZV), and BK polyomavirus.


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%.[48] 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%.[49] 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).

Epstein-Barr virus

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).[50, 51, 52] 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.[53]

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.

Varicella-zoster virus

VZV infections are also an important cause of morbidity in children.[54, 55] 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.[54] 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.[56] 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.[57, 58]

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 closely observed. 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.

Fungal infections

The prevalence of fungal infections in adult recipients of transplants varies from 2-14.1%.[59] 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.[60] 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 jiroveci has been reported in 5-10% of renal transplant recipients who did not take prophylaxis.[61] 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 used prophylactically for the first 6-12 months following transplantation.


All potential pediatric recipients of transplants should receive standard immunizations at least 6 to 8 weeks prior to transplantation.[62]

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.[63] The protective antibody against diphtheria may decline more rapidly, thus monitor titers more frequently with revaccination if needed.

Although the hepatitis B virus (HBV) vaccine is routinely administered to all children now, nonimmunized children still must be immunized with this vaccine.[64] 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).[65]

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.[54]

Children should receive immunization for pneumococcal infection, with the 132-valent vaccine followed by the 23-valent vaccine.

Routinely provide an annual influenza vaccine to children with transplants and their family and/or household contacts. The 2009 pandemic influenza A H1N1 vaccine was found to be safe in renal patients, specifically those who had received kidney transplants or hemodialysis; no adverse events were noted and kidney function was stable. However, a single dose of adjuvant vaccine induced a poor response in these patients.[66]


Immunosuppression 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.[67]

Post-transplant lymphoproliferative disease (PTLD) is a problem in children and is especially associated with primary EBV infection. All children should have EBV titers monitored routinely post transplant, using polymerase chain reaction (PCR) testing.


Immunologic 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 two types, acute and chronic. 

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 the image below).

Histology of percutaneous kidney transplantation b Histology of percutaneous kidney transplantation biopsy. (A) Normal kidney. (B) Acute rejection. Note the infiltration of lymphocytes. Images provided by David A. Hatch, MD, copyright 1999, used with permission.

Mild acute rejections can be treated with a short-term pulse of corticosteroids (5 mg/kg/d intravenously [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.[68] 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 allograft nephropathy (CAN)

CAN is defined as an immunologic reaction against an allograft, resulting in a gradual (but persisting) decline in renal function. It 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.[69] Therefore, some researchers argue that CAN is a subtle persistence of an acute rejection episode.

CAN 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 B in the image below).

Histology of percutaneous kidney transplantation b Histology of percutaneous kidney transplantation biopsy. (A) Normal kidney. (B) Acute rejection. Note the infiltration of lymphocytes. Images provided by David A. Hatch, MD, copyright 1999, used with permission.

No effective therapy for CAN has been established. Prevention of acute rejection is the best method of avoiding CAN.