Pediatric Kidney Transplantation Treatment & Management

As 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.^[17] 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 below.

Immunosuppressive agents used are as follows:

Corticosteroids

• Names - Methylprednisolone, prednisone
• Method of action - Inhibition of production and release of interleukin (IL)-1
• Dosage

  • Varies by center (Some centers administer additional pretransplant steroids to recipients of living donor kidneys.)
  • Methylprednisolone typical dose - 10 mg/kg intravenously (IV) immediately prior to transplant with relatively rapid conversion to prednisone and tapering of dose over 12 weeks to baseline dose of 0.3 mg/kg/d orally (PO)
• Adverse effects - Hirsutism, acne, hypercholesterolemia, hyperlipidemia, avascular necrosis of the hip, glucose intolerance, growth retardation, gastritis, gastric ulcer, obesity, cataracts, impaired wound healing, mood alteration
• Notes

  • In an effort to increase growth of pediatric recipients of kidney transplants and to avoid adverse effects, some centers taper and ultimately discontinue corticosteroids within 1 year of transplantation.^{[18, 19]}
  • This method is generally not used 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

• Names - Mycophenolate mofetil (CellCept), azathioprine (Imuran)
• Method of action - Inhibition of cell proliferation

  • 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.
• Dosage - Varies by transplant center

  • Mycophenolate mofetil, typical dose - 1200 mg/m²/d PO divided in 2 doses
  • Azathioprine, typical dose - 1-2 mg/kg PO once per day
• Adverse effects

  • Mycophenolate mofetil - Nausea, vomiting, increased susceptibility to infections
  • Azathioprine - Leukopenia, thrombocytopenia, alopecia, cholestatic jaundice, squamous cell carcinoma, hepatotoxicity, increased susceptibility to infections
• Notes

  • 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.
  • Also note that mycophenolate is available in 2 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. A newer formulation, mycophenolic acid (MPA, Myfortic), is an enteric-coated product that delivers the active moiety.

Macrolides

• Names - Cyclosporine (Sandimmune, Neoral, Gengraf), tacrolimus (Prograf), sirolimus (Rapamune)
• Method of action - Blocks production of or action of IL-2 or other cytokines
• Dosage - Varies by transplant center and by individual patient

  • Cyclosporine, typical dose - 14 mg/kg/d PO divided twice daily; dose adjusted to maintain 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; therefore, adjust dose individually; very young children and those with rapid metabolism of the drug may require 3 doses per day to maintain adequate trough level
  • Tacrolimus, typical dose - 0.2-0.3 mg/kg/d PO divided twice daily; dose adjusted to maintain trough whole blood level of 10-20 ng/mL in first year following transplantation
  • Sirolimus
    • Typical adult dose for patients with low immunologic risk (coadministered with cyclosporine and corticosteroids): loading dose day 1 posttransplantation is 6 mg PO once; initial maintenance dose beginning day 2 posttransplantation is 2 mg/d PO as single daily dose; obtain trough blood level between days 5 and 7 (target trough level [whole blood] is 10-15 ng/mL).
    • Typical adult dose for patients with low immunologic risk (sirolimus dose following cyclosporine withdrawal): Gradually withdraw cyclosporine 2-4 mo following transplantation, then increase sirolimus dose (about 4-fold higher than when combined with cyclosporine and corticosteroid) to maintain target blood levels (target trough whole blood concentration of 16-24 ng/mL for remaining year after transplantation, then 12-20 ng/mL thereafter).
    • Typical adult dose for patients with high immunologic risk
      • Loading dose day 1 posttransplantation is 15 mg or less PO once.
      • Initial maintenance dose beginning day 2 posttransplantation: Administer 5 mg PO as a single daily dose. Obtain trough blood level between days 5 and 7 (target trough level [whole blood] is 10-15 ng/mL). Use in combination with cyclosporine and corticosteroids for first year following transplantation. After first year, consider adjusting immunosuppressive regimen on basis of patient's clinical status.
    • Typical pediatric dose
      • Younger than 13 years: Dose is not established.
      • Age 13 years or older and weight less than 40 kg: Loading dose is 3 mg/m² PO once. Maintenance dose is 1 mg/m² PO qd.
      • Age 13 years or older and weight 40 kg or more: Administer as in adults.
      • Administer sirolimus 4 hours following cyclosporine.
      • The dose is adjusted to maintain trough whole blood level of 8-15 ng/mL.
      • Simultaneous ingestion of fat may decrease absorption.
      • Patients should take sirolimus consistently either with or without food.
      • It should not be taken with grapefruit juice (impairs absorption).
• Adverse effects

  • Cyclosporine - Hypertension, nephrotoxicity, hirsutism, gingival hyperplasia, neuropathy, increased susceptibility to infections, increased risk of malignancy
  • Tacrolimus - Nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, increased susceptibility to infections, increased risk of malignancy
  • Sirolimus - Hypercholesterolemia, hyperlipemia, hypertension, rash, increased susceptibility to infections, increased risk of malignancy, interstitial pneumonitis
• Interactions

  • 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.
• Notes

  • 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.
  • One study analyzed linear growth in children who received sirolimus therapy after renal transplantation versus those who were maintained on tacrolimus, and whether sirolimus had an adverse effect on growth. Using data from 25 children aged 1-15 years, height z-scores at baseline were compared with those at 24 months. The results noted that height z-scores did not change significantly over 24 months in the sirolimus group; height z-scores in both groups were no different at baseline and after 24 months. These results suggest that linear growth was similar in both groups and sirolimus did not show an adverse effect on growth.^[20]

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.

• Names - Antithymocyte globulin (eg, Thymoglobulin, Atgam), muromonab-CD3 (Orthoclone OKT3), daclizumab (Zenapax), basiliximab (Simulect)
• Method of action - In general, antibodies used in immunosuppression interfere with the function of T lymphocytes; lysis of lymphocytes with a resulting lymphopenia caused by some agents; some antibodies cover or impair 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
• Dose - Varies according to center and use

  • Antithymocyte globulin (Atgam), typical dose - 10-15 mg/kg/d IV administered once daily for 5-14 days; many centers vary the duration, discontinuing the antibody when cyclosporine or tacrolimus levels are consistently within therapeutic range
  • Muromonab-CD3, typical dose - 1 mg (< 20 kg), 2 mg (20-40 kg), 5 mg (>40 kg) IV administered with premedication (ie, methylprednisolone, acetaminophen, diphenhydramine) prior to first 1-3 doses; dose is administered once daily for 7-14 days; some centers vary duration, discontinuing the antibody when cyclosporine or tacrolimus levels are consistently within therapeutic range; because of the effectiveness of other antibodies (Daclizumab and Basiliximab) and the lower incidence of significant side effects of these preparations, Muromonag-CD3 is rarely used in immunosuppression induction protocols
  • Daclizumab, typical dose - 1 mg/kg IV on the day of transplant and repeated at weeks 2, 4, 6, and 8 following transplantation; some centers use only 2 doses in adults and older pediatric recipients (teenagers)
  • Basiliximab, typical dose
    • Children aged 2-15 years - 12 mg/m² 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

  • Muromonab-CD3 (OKT3) - 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)
  • Basiliximab and daclizumab - Early experience suggests relatively few adverse effects directly attributable to use of these antibodies;^[21] however, concern remains regarding potential to increase risk of infection and malignancy.

With the establishment of brain death laws and successful immunosuppression protocols, cadaver kidney transplantation became an attractive treatment option for children with end-stage renal disease (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. Over half of kidneys transplanted into children in North America came from living donors, most from a parent.

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.

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

• Twenty-four–hour urine collection for creatinine clearance
• CBC count
• 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])

Imaging evaluation

• Chest radiography
• Imaging of the kidneys and renal vessels

  • In the past, this included intravenous pyelography and angiography.
  • However, current radiologic techniques provide suitable imaging of the entire urinary tract with 3-dimensional CT (3D CT) scanning or magnetic resonance angiography (MRA) using gadolinium to demonstrate the vascular anatomy (see below). 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 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 one 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.^[22] Because removal of the kidney requires an abdominal incision, some 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.^[23] Laparoscopic surgery takes longer than open nephrectomy but provides a more rapid recovery for the donor. The vast majority of living donor nephrectomies are now performed laparoscopically, with donors discharged from the hospital about 48 hours following the surgery.

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.

Operative history

Early experimental human kidney transplants consisted of anastomosing the vessels of the renal allograft to thigh or arm vessels.^[3] 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. 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 A in the image below).

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

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 below).^{[24, 25]}

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 B in the image below).

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.

One study evaluated the difference in outcomes between the intraperitoneal and extraperitoneal approach in renal transplantation in small children. The study 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 days 2 and 14 postoperatively; however, this difference did not differ significantly over time. The results conclude that extraperitoneal kidney transplantation in small children is a safe and feasible alternative to the intraperitoneal approach, with similar outcomes.^[26]

A new protocol has been designed to enable safe ABO-incompatible kidney transplantation. This protocol, introduced by Tydén et al, 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 has been achieved in 60 patients, with 10 being children. No differences in success rate, renal function, or adverse events were found when compared with ABO-compatible transplantation.^[27]

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 with allograft survival comparable to that in children with normal bladders.

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.^[28]

Laboratory studies

• CBC count: Perform CBC count to detect leukopenia (potential adverse effect of some immunosuppressive agents), leukocytosis (evidence of infection), and anemia.
• Serum electrolytes and liver enzyme tests: Perform these tests to monitor K⁺, PO₄ (hypophosphatemia common following successful kidney transplantation), and liver enzymes (hepatotoxicity from immunosuppressive medications).
• Macrolide trough levels: 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 - 10-20 ng/mL
  • Sirolimus - 8-15 ng/mL

Imaging studies

• Ultrasonography: By far the most useful imaging technique following transplantation, ultrasonography allows rapid visualization of the kidney, the collecting system, and the 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. (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.
• Nuclear renography: Although ultrasonography can be useful, it provides no indication of renal function. Nuclear renography provides an accurate representation of perfusion, tubular function, and drainage of the kidney transplant. Two techniques are currently used: mercaptotriglycylglycine (MAG-3), which demonstrates both glomerular filtration and tubular excretion, and the combination of technetium-diethylenetriamine pentaacetic acid (DTPA) and iodine 131 (¹³¹ I)–labeled hippuran (see below). Some centers prefer the latter because of the increased expense of MAG-3. Delayed or decreased perfusion to the kidney may indicate acute rejection or compromise of arterial inflow. Decreased tubular excretion may be due to nephrotoxicity (cyclosporine or other drugs), acute or chronic rejection, or acute tubular necrosis. 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

Lymphocele

• 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 E below).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. 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.^[29] 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 C in the image above). 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, as shown in the image below, is the most sensitive diagnostic test. Digital subtraction angiogram showing renal artery stenosis. Image provided by David A. Hatch, MD, copyright 1998, used with permission.
• 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 Complications

Urologic 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 D in the image below). When the diagnosis is in question, percutaneous antegrade pyelography and a pressure-flow study (Whitaker test) is indicated.^[30] 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. 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 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.
• 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.^[31]

Medical Complications

Immunosuppression

• 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 significantly add 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.^[32] 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%.^{[33, 34]}
• 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. Cytomegalovirus (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 Epstein-Barr virus (EBV), varicella zoster virus (VZV), and herpes simplex virus (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%.^[35] 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%.^[36] 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).^{[37, 38, 39]} 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.^[40]
• 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.^{[41, 42]} 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.^[41] 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.^[43] 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.^{[44, 45]}
• 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.
• The prevalence of fungal infections in adult recipients of transplants varies from 2-14.1%.^[46] 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.^[47] 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.^[48] 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.

Immunizations

All potential pediatric recipients of transplants should receive standard immunizations at least 6 weeks prior to transplantation.^[49]

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.^[50] 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.^[51] 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).^[52]

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.^[41] 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. 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.^[53]

Malignancy

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.^[54]

Rejection

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 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 below). 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.^[55] 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.^[56] 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 B in the image below). 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 acute rejection has been established. Prevention of acute rejection is the best method of avoiding chronic rejection.

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 below.

Actual kidney transplantation survival in North American children. Data from US Renal Data Systems, 2008.

The most recent report from North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) 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 compared with children who receive adult kidneys.^[57]

One study analyzed 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.^[58]

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).^[59]

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. 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 below).

Patient survival

Patient survival for pediatric recipients of kidney transplants reported by the US Renal Data System is illustrated below.^[16]

Patient survival is significantly lower for very young (< 1 y) recipients. Infant recipients of cadaveric kidneys have the highest mortality rate.

Managing chronic kidney disease and related cardiovascular morbidity should be an essential component to the care of post-pediatric transplant patients. Timely identification of any irregularities, such as microalbuminuria and hypertension, aid in the early detection of renal damage and would increase the probability of restoring lost kidney function.^[60]

One study analyzed NAPRTCS data on pediatric patients with PTLD and found that patient survival has improved in recent PTLD cases. The study calculated patient survival was 87.4% at 5 years post-PTLD, which is improved from 48% actual 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, anti-CD20 antibody, alpha-interferon use, antiviral therapy use, and surgical reduction.^[61]

The data from a study of 18,911 patients who received a first transplant before age 21 years noted that 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 1-year after the first post transplantation year; the infection-related mortality rate did not change. These results suggest that exposure to the "transplantation milieu" does not negatively effect long-term cardiovascular health.^[62]

Etiology of patient death

The NAPRTCS report from 2007 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 below.

Currently, of any of the options for treatment, renal transplantation offers children with end-stage renal disease (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.

General

The greatest challenges facing those who treat children with end-stage renal disease (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.