Biliary Atresia

Children with extrahepatic biliary atresia constitute at least 50% of the pediatric LT population. Successful biliary drainage achieving an anicteric state following the Kasai portoenterostomy is the most important factor affecting preservation of liver function and long-term survival.¹ Primary transplantation without portoenterostomy is not recommended in patients with biliary atresia unless the initial presentation is greater than 120 days of age and the liver biopsy shows advanced cirrhosis.^2,3 We believe that the Kasai portoenterostomy should be the primary surgical intervention for all other infants with extrahepatic biliary atresia. Patients with progressive disease following a Kasai procedure should be offered early orthotopic liver transplantation (OLT). The sequential use of these two procedures optimizes overall survival and organ use.³

Patients with extrahepatic biliary atresia who are seen for transplantation form several cohorts. Infants with a failed Kasai have recurrent cholangitis, ascites, rapidly progressive portal hypertension, malnutrition, and progressive hepatic synthetic failure, and often require OLT within the first two years of life. Children with the successful establishment of biliary drainage have an improved prognosis, but this alone does not preclude the development of cirrhosis and portal hypertension leading to hypersplenism, variceal hemorrhage, ascites, and occasionally hepatopulmonary syndrome. These patients may require LT later in childhood. Patients with mild hepatocellular enzyme and bilirubin elevation, and mild portal hypertension can be observed with ongoing medical therapy. Approximately 20% of all patients with biliary atresia will not require OLT at some point in their life.4,5

Alagille Syndrome

Alagille syndrome (angiohepatic dysplasia) is an autosomal dominant genetic disorder that manifests as bile duct paucity which leads to progressive cholestasis and pruritus, xanthomas, malnutrition, and growth failure. Liver failure occurs late, if at all. Specific criteria for LT are difficult to quantify. Preoperative evaluation must include assessment for congenital cardiac disease and renal insufficiency, both of which are associated with this syndrome. Hepatocellular carcinoma (HCC) has also been seen in occasional patients.6,7

Experience using external biliary diversion or internal ileal bypass accompanied by ursodeoxycholic acid therapy has demonstrated a significant decrease in both pruritus and complications of hypercholesterolemia.⁸ Both of these procedures may ameliorate or decrease the rate of ongoing parenchymal destruction and cirrhosis, obviating the need for LT. Quality of life issues such as intractable pruritus, hypercholesterolemia, severe growth retardation, and intractable bone disease are criteria for consideration for LT.^9–11

Metabolic Disease

An important indication for hepatic transplantation in older children is hepatic-based metabolic disease. In these patients, LT is not only lifesaving but also accomplishes phenotypic and functional cure. A review of these diseases and their mode of presentation are given in Box 45-1 and Table 45-2.

Hepatic replacement to correct the metabolic defect should be considered before other organ systems are affected, and before complications develop that would preclude transplantation, such as in patients with tyrosinemia, in whom there is a high risk of HCC.¹² Although results of transplantation are excellent in the metabolic disease subgroup, replacement of the entire liver in order to correct single enzyme deficiencies is an inefficient, but presently necessary procedure. Current research centers around hepatocyte transplantation and gene therapy.^13–17 These efforts may better serve this patient population in the future. Patients with primarily extrahepatic manifestations of their disease, such as cystic fibrosis, are occasionally helped by LT, although their prognosis is most often determined by their primary illness.¹⁸

Fulminant Hepatic Failure

Patients with fulminant hepatic failure without recognized antecedent liver disease present diagnostic and prognostic difficulties. Rapid clinical deterioration frequently makes establishment of a definitive diagnosis impossible before there is an urgent need for transplantation. Acute viral hepatitis of undefined etiology makes up the largest group, followed by drug toxicity and toxin exposure. Previously unrecognized metabolic disease must also be considered. Recently, an immune-based defect has been recognized as a cause of fulminant liver failure.¹⁹ This population needs to be identified as these children may require a combination of bone marrow and LT to achieve long-term survival. When acceptable clinical and metabolic stability make liver biopsy safe, diagnostic information allowing directed treatment of the primary liver disease is helpful. The presence of ongoing coagulopathy often dictates the need for an open approach to biopsy.

The prognosis of patients with fulminant liver failure is difficult to predict, and neurologic outcome is potentially suboptimal.16,20,21 Use of intracranial pressure (ICP) monitoring in patients with progressive encephalopathy has allowed early recognition and treatment for increased ICP. Monitoring should be instituted for patients with advancing grade III encephalopathy, and in all patients with grade IV encephalopathy. Intracranial monitoring is continued intraoperatively and for 24 to 48 hours after OLT, because significant increases in ICP can develop postoperatively. Failure to maintain a cerebral perfusion pressure greater than 50 mmHg and an ICP less than 20 mmHg has been associated with very poor neurologic outcomes.²¹ Also, survival following LT is significantly decreased in patients who reach grade IV encephalopathy. Efforts to identify and perform LT in children before this deterioration occurs are of utmost importance. When candidates are identified before they develop irreversible neurologic abnormalities, the results of transplantation are dramatically improved.

Liver Tumors

Transplantation for hepatoblastoma is recommended for individuals who, after the administration of several cycles of chemotherapy, have a neoplasm confined to the liver that is unresectable.22,23 Children who had prior isolated metastasis that disappeared while undergoing preoperative chemotherapy can be considered in select instances.²⁴ A favorable response to pretransplant chemotherapy suggests a more favorable long-term outcome.²⁵ In the current Children’s Oncology Group (COG) trial AHEP 0731, early referral for transplant evaluation is being evaluated for children who present with large lesions that appear unresectable.

Transplantation for HCC is complicated by less successful chemotherapy options and frequent extrahepatic involvement. The reported two-year survival rates are only 20–30%.²⁶ Most deaths are due to recurrent HCC within the allograft or to extrahepatic tumor involvement. When primary HCC is discovered incidentally within the cirrhotic native liver at the time of hepatectomy, the overall prognosis is unaffected by the tumor.²⁷

Vascular tumors represent a group of patients with diffuse pathology who can benefit from transplantation. Children with progressive, intractable congestive heart failure, even when caused by non-neoplastic arteriovenous malformations or diffuse hemangiomas, offer a unique opportunity for complete removal of the vascular malformation and correction of congestive heart failure. Transplantation in these instances in our experience offers significantly better long-term survival compared to embolization or hepatic artery occlusion which can precipitate sudden and widespread hepatic necrosis. Pretransplant biopsy is essential in large or complex lesions to exclude angiosarcoma.

Donor Options

The single factor limiting the availability of LT is the supply of donor organs. The number of patients awaiting LT has increased by eleven fold since 1991.28,29 Available donor resources have not kept pace. As a consequence, the waiting time to transplant for all pediatric age groups has increased significantly, with young children and infants most affected (Figs 45-1 and 45-2). This severely limited supply of available donor organs has driven the advancement of many innovative liver transplant surgical procedures. The development of reduced-size LT allowed significant expansion of the donor pool for infants and small children. This not only improved the availability of donor organs but also allowed access to donors with improved stability and organ function. Evolution of these operative techniques has resulted in the development of both split-LT and live donor (LD) transplantation.

In the hands of experienced transplant teams, these procedures all have similar success to whole organ transplantation. Furthermore, access to these donor options has reduced the waiting list mortality rate to less than 5%.

Organ Allocation

In 1998, the ‘final rule’ established by the Health Resources and Service Administration (HRSA) mandated the formation of a system for candidate stratification based on a continuous severity score reflecting 90 day waiting list mortality, i.e., outcome.³⁰ The system for pediatric patients, the Pediatric End-Stage Liver Disease (PELD) score, was created using an analysis of the prospective registry of children listed for transplantation by the consortium Studies of Pediatric Liver Transplantation (SPLIT).³¹ The parameters selected included total bilirubin, international normalized ratio (INR), albumin, age <1 year, and evidence of failure to thrive (Box 45-2). The primary function of PELD is the stratification of candidates for LT by risk of 90 day waiting list mortality, allowing optimal use of donor organs. When death rates for all children listed were analyzed, PELD was an accurate predictor of mortality risk and demonstrated progressive risk until high scores were reached (>35) (Fig. 45-3).³²

Donor Selection

Assessment of donor organ suitability is undertaken by evaluating clinical information, static biochemical tests, and dynamic tests of hepatocellular function. Static biochemical tests identify preexisting functional abnormalities or organ trauma, but do not serve as good benchmarks to differentiate among acceptable and poor donor allografts. Donor liver biopsy is helpful in questionable cases to identify preexisting liver disease or donor liver steatosis. The shortage of donor organs has led to expanded efforts to use individuals of advanced age and marginal stability, termed ‘extended criteria donors’ (ECD).³³ The evolving donor risk index (DRI) is used as a guide that quantifies relative risk of graft failure.³⁴ In the future, organ allocation may be based on maximal life years gained, an approach being utilized in kidney allocation.³⁵

Anatomic replacement of the native liver in the orthotopic position requires selection or surgical preparation of the donor liver to fill, but not exceed available space in the recipient. When using full-sized allografts, a donor weight range from 50–125% of the recipient weight is usually appropriate, taking into consideration body habitus and factors that would increase the abdominal size in the recipient such as ascites and hepatosplenomegaly. The right lobe graft, using segments 5 to 8, and the right trisegmentectomy graft using segments 4 to 8 can be accommodated when the weight difference is no greater than 2 : 1 between the donor-to-recipient (D:R). The thickness of the right lobe makes this allograft of limited usefulness in small recipients. Right lobe grafts from LDs have become widely used in adults. The left lobe, using segments 1 to 4, is applicable with a D:R disparity from 2.5 : 1 to 5 : 1, and a left lateral segment (segments 2 and 3) can be used with up to a 10 : 1 D:R weight difference.

Although whole organ allografts are preferred, technical variant grafts are commonly employed. Preoperative preparation of variant liver allografts is based on the anatomy of the hepatic vasculature and bile ducts. In the past, reduced-size grafts were common, but because of the donor shortage, split-liver transplantation has become widespread using either ex situ or an in situ approach. The result is two transplantable grafts. The ex situ split procedure divides the right lobe allograft (segments 5 to 8) from the left lateral segment allograft (segments 2 and 3) after the whole donor organ has been procured. As this division is undertaken under hypothermic conditions without hepatic perfusion, the vascular integrity of segment 4 is difficult to assess and is frequently discarded. Conventional techniques for implanting the respective allografts are then used.

The successful experience with in situ division of the living donor left lateral segment is a basis for the in situ split procedure. Two variations of the procedure are utilized depending on the needs of the recipients, a right–left lobe split or a right trisegmentectomy–left lateral segment split. For the right trisegmentectomy–left lateral segment split, the left lateral segment is prepared similar to a living related donor graft. The viability of segment 4 can be examined at the time of the division and is usually incorporated with the right lobe graft to increase the cellular mass of the allograft. For a left-right lobe graft, the parenchymal resection follows the anatomic lobar plane through the gallbladder fossa to the vena cava.36,37 A crush and tie technique is preferred to achieve good closure of the vascular and biliary structures. The bile duct, portal vein, and hepatic artery are divided at the right or left confluence. The vena cava is left incorporated with the allograft in both right and left lobe preparation. Vena caval reduction by posterior caval wall resection and closure is occasionally necessary. Resection of the inferior protruding portion of the caudate lobe is necessary during left lobe preparation to reduce the likelihood of arterial angulation, which can result in arterial thrombosis. This also facilitates shortening of the inferior vena cava to fit in a small recipient.³⁸ When using left lateral segment (LLS) allografts, the parenchymal dissection follows the right margin of the falciform ligament with preservation of the left hilar structures. Direct implantation of the left hepatic vein into the combined orifice of the right and middle/left hepatic veins in the recipient vena cava is preferred; the donor vena cava is not retained with this segmental allograft. Further reduction of the LLS graft to a monosegmental graft may be necessary in very small recipients. Resection of the distal LLS is technically easier than an anatomic segment II/III division. Because this procedure adds considerably to the donor procurement time, and the necessary skill of the donor team, it is more demanding and occasionally difficult to successfully orchestrate. This technique is, however, despite these considerations, the preferred method for split-liver donor preparation.^39,40

The benefits of split-liver transplantation are best achieved when ideal donors are selected. Strict restrictions on age, vasopressor administration, pre-donation hepatic function, and limited donor hospitalization have been used to select optimal donor candidates. When these donors are selected, the results from both in situ and ex-situ techniques are similar, with both techniques now having patient survival for both allografts of 90–93% and graft survival rates of 86–89%.⁴¹

The use of LDs has increased as the safety and success of this approach has been demonstrated (Fig. 45-4).^42–44 One of the critical elements of LD transplantation is the proper selection of a donor, usually a parent or relative. This procedure is performed on the assumption that donor safety can be assured and that the donor’s liver function is normal. Careful attention to proper living donor consent is important. Parental concerns to help their ill child make true informed consent are a challenge. A dedicated ‘donor advocate’ not directly associated with the transplant team should assist with this process. Independent medical assessment of the donor is essential. United Network Organ Sharing (UNOS) has recently established clear criteria for this process.⁴⁵ After a satisfactory medical and psychological examination by a physician not directly involved with the transplant program, computed tomography (CT) scanning is used to measure the volume of the potential donor segment to assure that it will meet the metabolic needs, but not exceed the space available in the recipient. If acceptable, CT angiography or arteriography is undertaken to assess the hepatic arterial anatomy, thereby excluding potential donors with multiple arteries to segments 2 and 3, and facilitating minimal hilar vascular dissection at the time of LT. Experience has shown that, when donors were deemed unacceptable, 90% of patients were excluded on the basis of history, examination, laboratory screening, and ABO type. Donor safety has been excellent in all pediatric LD series.^46–48

In most pediatric cases, the LLS donated from an adult is used as the graft. In situ dissection of the LLS, preserving the donor vascular integrity until the parenchymal division is completed, is undertaken. At the time of harvest, the left hepatic vein is divided from the vena cava, and the left branch of the portal vein and hepatic artery are removed with the allograft.⁴⁶ Vascular continuity of the hepatic arterial branches to segment 4 is maintained, if possible. Increased experience has been gained using the right lobe as an LD allograft for larger recipients such as adolescents and adults.^42,49,50 This more extensive operation has proven to be a challenge to the donor and recipient alike, with complication and mortality rates significantly exceeding that of left lateral segmentectomy. The number of right lobe LD recipients now greatly exceeds the number of children receiving LD grafts;⁵¹ however, several publicized donor deaths and increased interest in ‘split-liver’ cadaveric procurement have slowed the enthusiasm and growth of right lobe donation.

The selection of a donor segment with an appropriate parenchymal mass for adequate function is critical to success. However, the minimal mass necessary for recovery is not yet established. Any calculation must take into account loss of function following preservation damage, acute rejection, and technical problems. When the D:R weight range falls within the normal 8 : 1 to 10 : 1 ratio, risk is minimal. Estimates of donor graft to recipient body weight ratio (GRWR) may prove to be a more accurate predictor of adequate graft volume. When the GRWR is less than 0.7%, overall allograft and patient survival suffered. In extreme cases in which small-for-size grafts are used, excessive portal flow can lead to hemorrhagic necrosis of the graft. Large-for-size allografts (GRWR >5.0%) have a less deleterious effect.⁵² A review of these donor anatomic options is shown in Figure 45-5.

Primary Nonfunction

Primary nonfunction (PNF) of the hepatic allograft implies the absence of metabolic and synthetic activity following LT. Complete nonfunction requires immediate retransplantation before irreversible coagulopathy and cerebral edema occur. Lesser degrees of allograft dysfunction occur more frequently, and are associated with several donor, recipient, and operative factors (Box 45-3). The status of the donor liver contributes significantly to the potential for PNF. Ischemic injury secondary to anemia, hypotension, hypoxia, or trauma is often difficult to ascertain in the history of multiple trauma victims. Donor liver steatosis has also been recognized as a factor contributing to severe dysfunction or nonfunction in the donor liver.^53,54 Macrovesicular steatosis on donor liver biopsy is somewhat more common in adult than pediatric donors and, when severe, is recognized grossly by the enlarged yellow, greasy consistency of the donor liver. The risk of PNF increases as the degree of fatty infiltration increases.⁵⁴ Histologic findings are classified as mild if less than 30% of the hepatocytes have fatty infiltration, moderate if 30 to 60% are involved, and severe if more than 60% of the hepatocytes have fatty infiltration. Livers with severe fatty infiltration should be discarded, and donors with moderate involvement are used with some concern, with the degree of steatosis and the condition of the recipient determining use of the allograft.

The use of ABO-incompatible donors has been controversial. Allograft and patient survival rates in adult recipients have not been comparable to those achieved using ABO-identical or compatible donors.55,56 However, pediatric recipients of ABO-incompatible allografts have achieved survival rates equivalent to those using ABO-compatible and ABO-identical donors with either cadaveric donors (CDs) or LDs.^57–59

Vascular Thrombosis

Hepatic artery thrombosis (HAT) occurs in children three to four times more frequently than in adult transplant series, occurring most often within the first 30 days following transplantation.60,61 Factors influencing the development of HAT are listed in Box 45-4. HAT presents with a variable clinical picture that may include: (1) fulminant allograft failure; (2) biliary disruption or obstruction; or (3) systemic sepsis. Doppler ultrasound (US) imaging has been accurate in identifying arterial thrombosis, and is used as the primary screening modality to assess vascular flow following transplantation or whenever complications arise. Acute HAT with allograft failure most often requires immediate retransplantation. Successful thrombectomy and allograft salvage is possible if reconstruction is undertaken before allograft necrosis.⁶² Biliary complications are particularly common following HAT. Ischemic injury to the biliary tree or anastomosis can result in intraparenchymal biloma formation or cholestasis. The development of septicemia or multifocal abscesses in sites of ischemic necrosis secondary to gram-negative enteric bacteria, Enterococcus, anaerobic bacteria, or fungi can also occur. Antibiotic therapy directed toward these organisms, along with operative or percutaneous drainage, is indicated when specific abscesses are identified. Drainage and biliary stenting may control bile leakage and infection until retransplantation is undertaken.

Late HAT can be asymptomatic or present with slowly progressive bile duct stenosis. Rarely, allograft necrosis occurs. Arterial collaterals from the Roux-en-Y limb can provide a source of revascularization through hilar collaterals. These collateral channels develop during the first postoperative months, often making late thrombosis a clinically silent event. Conversely, disruption of this collateral supply during operative reconstruction of the central bile ducts in patients who later develop HAT can precipitate hepatic ischemia and parenchymal necrosis. When HAT is asymptomatic, careful observation alone is indicated.

Prevention of HAT requires meticulous arterial reconstruction at the time of transplantation. Anatomic reconstruction is preferred in whole organ allografts; direct implantation of the celiac axis into the infrarenal aorta is recommended for all reduced-size liver allografts. All complex vascular reconstructions of the donor hepatic artery should be undertaken ex vivo whenever possible using microsurgical techniques before transplantation. When vascular grafts are required, they should also be implanted onto the infrarenal aorta.⁶³ No systemic anticoagulation is routinely used by our group, but aspirin (20–40 mg/day) is administered to all children for 100 days.

Portal vein thrombosis (PVT) is uncommon in whole organ allografts unless prior portosystemic shunting has altered the flow within the splanchnic vascular bed or unless severe portal vein stenosis in the recipient has impaired flow to the allograft. Preexisting PVT in the recipient can be overcome by thrombectomy, portal vein replacement, or extra anatomic venous bypass. In biliary atresia recipients, portal vein hypoplasia is best corrected by anastomosis of the portal vein to the confluence of the splenic and superior mesenteric veins in the recipient. When there is inadequate portal vein length on the donor organ, iliac vein interposition grafts are used. Early thrombosis following LT requires immediate anastomotic revision and thrombectomy. Discrepancies in venous size imposed by reduced-size allografts can be modified to allow anastomotic construction.64,65 Deficiencies of anticoagulant proteins, such as protein C and S, and antithrombin III deficiency in the recipient must also be excluded as a contributing cause for vascular thrombosis.⁶⁶ Failure to recognize PVT can lead to either allograft demise or, on a more chronic basis, to significant portal hypertension with hemorrhagic sequelae or intractable ascites.

Biliary Complications

Complications related to biliary tract reconstruction occur in approximately 10% of pediatric liver transplant recipients. Their spectrum and treatment is determined by the status of the hepatic artery and the type of allograft used. Although whole and reduced-size allografts have an equivalent risk of biliary tract complications, the spectrum of complications differs.67,68

Primary bile duct reconstruction is the preferred biliary tract reconstruction in adults, but it is less commonly used in children. It has the advantage of preserving the sphincter of Oddi, decreasing the incidence of enteric reflux and subsequent cholangitis, and not requiring an intestinal anastomosis. Experience using primary choledocho-choledochostomy without a T-tube has been favorable.⁶⁹ Late complications following any type of primary ductal reconstruction include anastomotic stricture, biliary sludge formation, and recurrent cholangitis. Endoscopic dilation and internal stenting of anastomotic strictures has been successful in early postoperative cases. Roux-en-Y choledochojejunostomy is the preferred treatment for recurrent stenosis or postoperative leak.

Roux-en-Y choledochojejunostomy is the reconstruction of choice in small children and is required in all patients with biliary atresia. Recurrent cholangitis, a theoretical risk, suggests anastomotic narrowing or an intrahepatic biliary stricture or small bowel obstruction within the Roux limb or distal to the Roux-en-Y anastomosis. In the absence of these complications, cholangitis is uncommon.

Reconstruction of the bile ducts in patients with reduced-size allografts is more challenging. Division of the bile duct in close proximity to the cut-surface margin of the allograft, with careful preservation of the biliary duct collateral circulation, decreases but does not eliminate a ductal stricture secondary to ischemia. In our early experience, in 14% of patients with left lobe reduced-size allografts, a short segmental stricture developed requiring anastomotic revision (Fig. 45-8). Operative revision of the biliary anastomosis and reimplantation of the bile ducts into the Roux-en-Y is necessary. Percutaneous transhepatic cholangiography is essential to define the intrahepatic ductal anatomy before operative revision, and temporary catheter decompression of the obstructed bile ducts promotes treatment of cholangitis and allows elective reconstruction. Operative reconstruction is accompanied by transhepatic passage of exteriorized multifenestrated biliary ductal stents, which remain in place until reconstructive success is documented. Late stenosis is unlikely. Dissection away from the vasobiliary sheath in the donor has significantly decreased the incidence of this complication.

Biliary complications have been seen with an increased frequency following LD in children. The LLS 2 and 3 bile ducts are frequently separate at the plane of parenchymal division. The need for individual drainage of these small biliary ducts makes the development of late anastomotic stenosis more frequent. Individual segmental strictures may not lead to jaundice in the recipient, but rather are identified by elevated gamma glutamyl transferase (GGT) or through ultrasound surveillance. Reoperation after ductal dilatation from the stricture allows for easier reconstruction due to the increased caliber of the segmental bile duct.

Acute Cellular Rejection

Allograft rejection is characterized by the histologic triad of endothelialitis, portal triad lymphocyte infiltration with bile duct injury, and hepatic parenchymal cell damage.⁷⁰ Allograft biopsy is essential to establish the diagnosis before treatment. The rapidity of the rejection process and its response to therapy dictates the intensity and duration of antirejection treatment.

Acute rejection occurs in approximately two-thirds of patients following LT.⁷¹ The primary treatment is a short course of high-dose steroids. Bolus doses administered over several days with a rapid taper to baseline therapy is successful in 80% of cases.⁷² When refractory or recurrent rejection occurs, antilymphocyte therapy using the monoclonal antibody OKT-3^® or thymoglobulin^® is successful in 90% of cases.³⁸

Chronic Rejection

Uniform diagnosis and management of chronic rejection is complicated by the lack of a consistent definition or clinical course. Chronic rejection occurs in 5–10% of transplanted patients. Its incidence appears to be decreasing in all transplant groups, perhaps related to better overall immunosuppressive strategies. There is some suggestion that the use of tacrolimus based immunosuppression is a key element in this apparent decrease.73,74 Risk factors for its development are many, and no factor predicts the outcome of treatment. The chronic rejection rate is significantly lower in recipients of LD grafts compared with cadaveric grafts.⁷⁵ In that study, African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients. In addition, the number of acute rejection episodes, transplantation for autoimmune disease, occurrence of post-transplant lymphoproliferative disease (PTLD), and cytomegalovirus (CMV) infection were also significant risk factors for chronic rejection. The primary clinical manifestation is a progressive increase in biliary ductal enzymes (alkaline phosphatase, GGT) and progressive cholestasis. Chronic rejection can be initially asymptomatic or may follow unsuccessful treatment for acute rejection. It can occur within weeks of transplantation or later in the postoperative course.

Chronic rejection usually follows one of two clinical forms.⁷⁶ In the first, the injury is primarily to the biliary epithelium and the clinical course is slowly progressive with preservation of synthetic function. Histologically, either interlobular bile duct destruction in the absence of ischemic injury or hepatocellular necrosis is seen. In full expression, this form is characterized as acute vanishing bile duct syndrome when severe ductopenia is seen in at least 20 portal tracts.^77,78 The eventual spontaneous resolution in up to one-half of affected patients with tacrolimus therapy has led to the development of enhanced immunosuppression protocols for this patient subgroup.⁷⁶ Retransplantation is occasionally necessary, but it is rarely needed emergently.

The second subtype is characterized by the early development of progressive ischemic injury to both bile ducts and hepatocytes, leading to ductopenia and ischemic necrosis with fibrosis. The clinical picture of cholestasis is accompanied by significant synthetic dysfunction with superimposed vascular thrombosis or biliary stricture formation. The vascular endothelial injury responsible for the progressive ischemic changes is characterized by the development of subintimal foam cells or fibrointimal hypertrophy. The clinical course is relentlessly progressive, and nearly always requires retransplantation. Unfortunately, recurrence of chronic rejection in the retransplanted allograft is common.⁷⁷

Recent studies have focused on donor specific antibody mediated abnormalities that may be the pathophysiologic basis for chronic rejection.⁷⁹ The immunologic nature of this process is emphasized by the primary target role of the biliary and vascular endothelium, the only tissues in the liver that express class II antigen. Other interdependent cofactors such as CMV infection, human leukocyte antigen (HLA) mismatching, positive B-cell crossmatching, and differing racial demographics of the donor to recipient have all failed to show consistent correlation with the development of chronic rejection.76,77

Renal Insufficiency

The long-term success of LT has been related to the effective immunosuppression with calcineurin inhibitors (CNI), such as cyclosporine and tacrolimus. However, nephrotoxicity associated with their long-term use has become a major problem which can affect up to 70% of all nonrenal transplant recipients. Renal insufficiency can present in many ways following CNI administration and LT. When this occurs during the initial post-transplant weeks, it is most often related to transient excessive blood levels, and is reversible with appropriate dose correction. Impaired glomerular filtration rate (GFR) seen in pediatric recipients with stable graft function represents a more serious problem. Up to 20% may have a drop in their GFR to below 50 mL/min/1.73m², and 5% may progress to end-stage renal disease (ESRD). Adult studies have shown a progressive increase in chronic renal failure from 0.9% at year 1 to 8.6% at year 13 post OLTx.⁸⁰ Similarly, ESRD rose from 1.6% at year 1 to 9.5% at year 13 after LT, yielding a total incidence of renal dysfunction of 18%. The presence of an elevated serum creatinine pre-LT, at one-year post-transplant, and the presence of hepato-renal syndrome prior to transplant were all identified risk factors.^80,81 Cyclosporine and tacrolimus both appear to be similar in risk.

In a review from our program, in children who were more than three years post-LT, we found that 32% had a GFR <70 mL/minute/1.73 m².⁸² The factors primarily related to lower GFR were the presence of an elevated creatinine at one year after LT and the length of time following transplantation. Our data supported the concept of a continued decline in renal function following LT.^83,84 Considering the expected long survival for children undergoing LT, the possibility of progressive asymptomatic renal insufficiency leading to severe kidney disease poses a significant challenge.

Efforts to reverse ongoing renal insufficiency using protocols that include instituting non-nephrotoxic agents, such as mycophenolate mofetil (MMF) while decreasing the CNI dose, have shown limited success in improving GFR while protecting against the risks of acute rejection at the time of immunosuppressive drug conversion.⁸⁵ Efforts have also been undertaken to use the new class of monoclonal anti-CD25 antibodies for induction therapy coupled with MMF and steroids in an effort to avoid administration of CNI during the first post-transplant week. These agents appear to afford sufficient protection against rejection to successfully allow the late administration of CNI. Whether these efforts will prevent the later development of renal insufficiency is yet unproven.⁸⁶ Efforts to completely eliminate CNI use have been complicated by acute or ductopenic rejection. Current efforts suggest that earlier staged reduction of CNI prior to the development of severe GFR reduction will decrease, but not eliminate this complication. Once established, chronic renal failure does not appear to resolve with CNI dose adjustment. Although CNI toxicity is now well appreciated, the association of both hepatic and renal disease in many metabolic diseases of childhood may also contribute to the GFR abnormalities seen after LT.

Infection

Infectious complications have become the most common source of morbidity and mortality following LT. Multiple organism infection is common as are concurrent infections by different agents.

Bacterial infections occur in the immediate post-transplant period and are most often caused by Gram-negative enteric organisms, Enterococcus, or Staphylococcus species. Intra-abdominal abscesses or infected collections of serum along the cut surface of the reduced-size allograft are best addressed with extraperitoneal, abdominal, or percutaneous drainage. Intrahepatic abscesses suggest hepatic artery stenosis or thrombosis, and treatment is directed toward the vascular status of the allograft and associated bile duct abnormalities. Sepsis originating at sites of invasive monitoring lines can be minimized by replacing or removing all intraoperative lines soon after transplantation. Antibacterial prophylaxis are discontinued as soon as possible to prevent the development of resistant organisms.

Fungal sepsis represents a significant potential problem in the early post-transplant period. Aggressive protocols for pretransplant prophylaxis are based on the concept that fungal infections originate from organisms colonizing the receipient’s gastrointestinal (GI) tract. In two studies, selective bowel decontamination was successful in eliminating pathogenic Gram-negative bacteria from the GI tract in 87% of adult patients.87,88 Also, in all cases, Candida was eliminated. However, these protocols have not been practical in pediatric recipients because there is a long waiting time for pediatric organs and the taste of the antibiotics is not well accepted. However, these regimens are commonly used in the preoperative preparation for combined liver/small intestinal transplantation. Fungal infection most often occurs in patients requiring multiple operative procedures and those who have had multiple antibiotic courses. Development of fungemia or urosepsis requires retinal, cardiac, and renal investigation, and antifungal therapy should be promptly initiated. Severe fungal infection has a mortality rate greater than 80%, making early treatment essential. All patients undergoing LT should receive antifungal prophylaxis with fluconazole.

The majority of early and severe viral infections are caused by viruses of the Herpesviridae family, including Epstein–Barr virus (EBV), CMV, and herpes simplex virus (HSV). CMV transmission dynamics are well studied and serve as a prototype for herpesvirus transmission in the transplant population. The likelihood that CMV infection will develop is influenced by the preoperative CMV status of the donor and recipient.89,90 Seronegative recipients receiving seropositive donor organs are at greatest risk, with seropositive donor-to-recipient combinations at the next greatest risk. Use of various immune-based prophylactic protocols including IV IgG or hyper immune anti-CMV IgG, coupled with acyclovir or ganciclovir/valganciclovir, have all achieved success in decreasing the incidence of symptomatic CMV infection, although seroconversion in seronegative recipients from seropositive donor organs inevitably occurs.

The clinical diagnosis of CMV infection is suggested by the development of fever, leukopenia, maculopapular rash, hepatocellular abnormalities, respiratory insufficiency, or GI hemorrhage. Hepatic biopsy or endoscopic biopsy of colonic or gastroduodenal sites allows early diagnosis with immunohistochemical evaluation. Rapid blood and urine assays for CMV can also expedite the diagnosis. In suspected cases, treatment should be instituted while awaiting culture or biopsy results owing to the potential rapidity and severity of this infection in a previously seronegative child. The treatment of CMV has been greatly improved by the development of ganciclovir. Early treatment with IV IgG and ganciclovir is successful in most cases.

EBV infection occurring in the perioperative period represents a significant risk to the pediatric recipient.⁹¹ It has a varying presentation including a mononucleosis-like syndrome, hepatitis-simulating rejection, extranodal lymphoproliferative infiltration with bowel perforation, peritonsillar or lymph node enlargement, and encephalopathy. In small children, its primary portal of entry is often the tonsils, making asymptomatic tonsillar hypertrophy a common initial presentation.⁹² EBV infection can occur as a primary infection or following reactivation of a past infection. When serologic evidence of active infection exists, an acute reduction in immunosuppression is indicated. It has become clear that continuous surveillance is necessary as the presentation is often nonspecific and the prognosis is related to early diagnosis. Screening using quantitative PCR testing to determine the EBV blood viral load appears to be the best current predictor of risk. However, viral loads have been identified in asymptomatic patients and patients recovering from PTLD, limiting the specificity of this approach. The balance between viral load measured by quantitative PCR and specific cellular immune response, perhaps mediated by CD8 T-cells specific to EBV, may explain this lack of specificity to viral load alone.^93–95

Many pediatric transplant centers now use serially measured quantitative EBV DNA PCR as an indication for primary immunosuppression modulation. We recommend monthly EBV DNA PCR counts to monitor increased genomic expression. Increasing viral load levels warrant more frequent monitoring on a weekly or every two week schedule. In the EBV seronegative pretransplant patients, >40 genomes/10⁵ peripheral blood leukocytes (PBL), and >200 genomes/10⁵ PBL identify patients needing reduction in primary immunosuppression by 25 to 100%. Institution of antiviral therapy with ganciclovir and CMV IgG is also used in most cases, although only nonrandomized observational studies support their use. Both agents are active in vitro against linear replicating forms of the EBV, but have no activity against the circular episome in immortalized B-cells. Treatment should be continued until symptoms of lymphadenopathy have resolved and viral EBV DNA PCR has returned to baseline.91,96 It should however be cautioned that PTLD can develop and progress without increases in EBV-PCR viral load.⁹⁷

PTLD, a potentially fatal abnormal proliferation of B-lymphocytes, can occur in any situation in which immunosuppression is used. The importance of PTLD in pediatric LT is a result of the intensity of the immunosuppression required, its lifetime duration, and the absence of prior exposure to EBV infection in 60–80% of pediatric recipients. PTLD is the most common tumor in children following transplantation representing 50% of all tumors compared to 15% in adults. About 80% of cases occur within the first two years following transplantation.⁹⁴ Multiple studies analyzing immunosuppressive therapy and the development of PTLD have shown a progressive increase in its incidence with (1) the increase in total immunosuppressive load; (2) EBV naïve recipients; and (3) the intensity of active viral load.⁹⁸ No single immunosuppressive agent has been directly related to PTLD, although high-dose cyclosporine, tacrolimus, polyclonal antilymphocyte sera (MALG, ALG), and monoclonal antibodies (OKT-3) have all been implicated. Prolonged treatment with anti–T-cell agents and the increased duration, intensity, and total immunosuppressive load are the origin of the immunity that creates the background for neoplasia.

The second pathogenic feature influencing PTLD appears to be EBV infection. Primary or reactivation infections usually precede the recognition of PTLD. Active EBV infection, whether primary or reactivation, involves B-cell proliferation. A simultaneous increase in cytotoxic T-cell activity is the normal host’s mechanism for preventing EBV dissemination. Loss of this natural protection as a result of the administration of T-cell inhibitory immunotherapy allows polyclonal B-cell proliferation to progress following EBV viral replication and release. These EBV proliferating cells express specific viral antigens which represent possible targets for the immune system, thereby explaining the well described regression of PTLD after immunosuppressive tapering. With time, transformation of a small population of cells results in a malignant monoclonal aggressive B-cell lymphoma.93,99–101

Most tumors seen in children are large cell lymphomas, 80% being of B-cell origin. Extranodal involvement, uncommon in primary lymphomas, is seen in 70% of PTLD cases. Extranodal sites include central nervous system, 27%; liver, 23%; lung, 22%; kidney, 21%; intestine, 20%; and spleen, 13%. Allograft involvement is common and can mimic rejection. T-cell and B-cell immunohistochemical markers of the infiltrating lymphocyte population define the B-cell infiltrate and assist in establishing an early diagnosis.

Treatment of PTLD is stratified according to the immunologic cell typing and clinical presentation.¹⁰² Documented PTLD requires an immediate decrease or discontinuation of immunosuppression and institution of anti-EBV therapy. We prefer to use IV ganciclovir for initial antiviral therapy owing to the high incidence of concurrent CMV infection. Acyclovir is used for long-term treatment. The development of newer antiviral alternatives such as valganciclovir may offer better long-term options in the future.¹⁰³ Patients with polyclonal B-cell proliferation frequently show regression with this treatment.^91,96 If tumor cells express B-cell marker CD 20 on histology, the anti-CD 20 monoclonal antibody Rituximab can be administered weekly. Although associated in many cases with significant reduction in tumor mass, patients have frequently experienced reversible neutropenia requiring granulocyte colony stimulating factor (GCSF) and hypogammaglobulinemia requiring supplementation.¹⁰⁴ Acute liver rejection has frequently been seen during Rituximab treatment. Patients with aggressive monoclonal malignancies have poor survival even with immunosuppressive reduction, acyclovir, and conventional chemotherapy or radiation therapy. These additional treatment modalities often precipitate the development of fatal systemic infection. Efforts to reconstitute the EBV specific cellular immunity using partially HLA matched EBV specific cytotoxic T-cells may offer improved treatment outcome for advanced cases. The future development of anti-EBV vaccine may decrease the present significant risks of this unique complication of pediatric transplantation.¹⁰⁵ When treatment is successful, careful follow-up to identify recurrent disease or delayed central nervous system involvement is essential.

Multivisceral Allograft

Multivisceral transplantation consists of transplantation of the stomach, pancreaticoduodenal complex, and intestine, either with (multivisceral allograft) or without (modified multivisceral allograft) the liver. In the pediatric population, the primary indications for multivisceral transplantation are the intestinal dysmotility syndromes. On occasion, a giant desmoid tumor of the mesentery that extensively infiltrates the mesentery may require this form of transplantation. Exenteration of the native intra-abdominal viscera is followed by transplantation of the multivisceral graft using arterial inflow through the donor celiac and superior mesenteric artery (SMA). Venous outflow for the multivisceral allograft occurs via the transplanted liver placed in the standard orthotopic position. For the modified multivisceral allograft, portal venous return is via an anastomosis with the recipient’s native portal vein. Gastrointestinal continuity is completed via a gastrogastric anastomosis proximally and an ileocolic anastomosis distal to the ileostomy.

Liver–Small Bowel Composite Allograft

A liver–small bowel composite allograft is a modification of the multivisceral allograft in which the stomach is removed during procurement. This form of transplantation is indicated in patients with intestinal failure and impending or overt TPN-induced liver failure, and is the most common type of intestinal transplant currently utilized in children (Fig. 45-10). The recipient’s liver and residual small intestine are removed, while the native stomach, duodenum, pancreas, and spleen are left intact. A portocaval shunt from the native portal vein to the inferior vena cava is necessary to provide venous outflow from the recipient’s foregut organs (Fig. 45-11). As in the multivisceral allograft, the donor celiac artery and SMA are the source of arterial inflow to the transplanted organs. The donor portal vein and biliary tree remain intact, having not undergone dissection during procurement. As a result, no portal vein or bile duct reconstruction is needed. The pancreas is also left intact to protect the peri-biliary ductal vessels and to prevent the possibility of pancreatic leak from a divided surface. Venous outflow from the transplanted organs is once again provided by the donor liver placed in a standard orthotopic position. If the liver is too large, an ex vivo hepatic lobectomy can be performed, usually removing the right lobe of the liver (Fig. 45-12). Gastrointestinal continuity from the patient’s native stomach and duodenum to the newly transplanted small bowel is achieved by anastomosis of the native duodenum to the donor jejunum. If the recipient has any colon remaining, a donor ileum to recipient colon anastomosis is created distal to the ileostomy.

Isolated Small Bowel Allograft

Transplantation of the small intestine alone entails procurement of only the jejunum and ileum. During procurement, the SMA and vein are divided just below the third portion of the duodenum at the root of the mesentery, generating an allograft of jejunum and ileum (Fig. 45-13). This type of transplant is indicated in patients with intestinal failure, but without liver dysfunction. Arterial inflow is provided by anastomosis of the SMA to the recipient’s aorta. Venous drainage of the transplanted intestines is either into the inferior vena cava or to the native superior mesenteric vein. Initially it was believed that venous drainage into the native portal circulation was beneficial to the liver, but recent studies suggest minimal benefit.¹⁴⁷ Therefore, currently, the most common approach to venous reconstruction is an end-to-side anastomosis of the donor superior mesenteric vein to the native inferior vena cava. Gastrointestinal continuity is restored by anastomosis of the recipient’s native proximal bowel to the transplanted jejunum. Once again, if residual colon is present, a donor ileum to native colon anastomosis is created downstream from the ileostomy.

Immunosuppression and Allograft Rejection

The most significant recent advances in the management of intestinal transplant recipients have occurred in the development of immunosuppression regimens. Rejection remains the most common complication after intestinal transplantation, and acute rejection occurs in approximately 60% of pediatric recipients within the first three months after transplantation.¹³⁴ Overwhelming rejection was one of the most frequent causes of allograft loss during the early transplant experience due, in part, to the limited number of immunosuppressive agents available. Prior to the development of tacrolimus as a maintenance immunosuppression approach, high-dose immunosuppression was necessary to prevent rejection. Infections, PTLD, and adverse effects related to high-dose immunosuppression were frequent causes of a poor outcome. The goal of current immunosuppressive regimens is to use just enough immunosuppression to prevent rejection, but not so much that infections and PTLD occur. In an effort to achieve tolerance, many centers utilize a lymphocyte-depleting strategy, such as thymoglobulin or alemtuzumab, to induce early elimination of graft-specific T-lymphocytes. The management of immunosuppression in patients who undergo intestinal transplantation remains the most challenging aspect of the postoperative care.

Surveillance endoscopy and biopsy is initiated within five days of transplantation to evaluate for acute rejection, and is performed twice per week for the first month. Significant progress in the definition of the histologic characteristics of acute small bowel rejection has been achieved.¹⁴⁸ If acute rejection is diagnosed, a short course of high-dose corticosteroids is administered. If rejection is severe or persists despite high-dose corticosteroid administration, antilymphocyte antibody agents (thymoglobulin or alemtuzumab) are required. Chronic rejection remains the most common cause of late allograft dysfunction and failure.

Infection

Owing in large part to the high level of immunosuppression needed after intestinal transplantation, bacterial and fungal infections are common. Patients with intestinal failure are frequently colonized with antibiotic-resistant bacteria due to recurrent infections while on TPN. As mentioned previously, because intestinal perforation is common, peritonitis is a frequent complication often requiring repeat abdominal explorations to completely clear foci of infection.

CMV, EBV, adenovirus, and calicivirus are the most frequent viral pathogens found in the postoperative period, and many can masquerade as acute rejection. PTLD remains a significant problem because most infants are EBV-negative at the time of transplantation. Surveillance for CMV and EBV using PCR, followed by aggressive treatment when detected, has diminished the impact of these dangerous pathogens on patient outcome. All patients are maintained on prophylactic antiviral agents after intestinal transplantation.

Graft-versus-Host Disease (GVHD)

GVHD occurs in approximately 5–10% of intestinal transplant recipients, most commonly in the youngest pediatric recipients. Its high incidence is related to the large burden of donor lymphocytes that are cotransplanted with the allograft. Acute GVHD characteristically affects the skin, native liver, and native gastrointestinal tract, and carries a high mortality. Monitoring of donor-derived T-cell chimerism is being utilized to identify patients at risk for GVHD. Management strategies for GVHD after intestinal transplantation include high-dose corticosteroids and lymphocyte depletion with alemtuzumab.¹⁴⁹

Dialysis

Dialysis is indicated when complications of ESRD occur despite optimal medical management, specifically hyperkalemia, volume overload, acidosis, intractable hypertension, and uremic symptoms such as vomiting and fatigue. In older children, lethargy and poor school performance can signal the need for more aggressive treatment. In addition, dialysis may be necessary to facilitate the administration of adequate protein as part of an extensive nutritional resuscitation plan.

When dialysis is undertaken, the use of peritoneal dialysis is preferred for the following reasons: (1) it avoids the multiple blood transfusions associated with hemodialysis; (2) it allows a gradual correction of electrolyte abnormalities, preventing cerebral disequilibrium syndrome in small infants; (3) it allows for easier control of osteodystrophy; (4) it optimizes nutrition; and (5) it is easy to perform.

Hemodialysis can be used when there is an unsuitable peritoneal cavity due to prior surgery or multiple peritoneal infections. However, the construction and maintenance of adequate long-term vascular access sites in small infants and children is difficult. Use of central venous catheters rather than arteriovenous fistulas is our preferred mode for temporary hemodialysis access in infants and small children, although infection and vascular thromboses complicate this therapy. Access via the internal jugular veins is preferred over subclavian routes to avoid obstruction of the venous outflow from the upper extremity, which compromises future arteriovenous fistula sites. Although dialysis and its complications, such as infection, have a great influence on the complexity of care, they do not affect the ultimate results of renal transplantation.¹⁵⁴

Nutritional Support

The need for vigorous nutritional support of the infant with uremia is well demonstrated by the growth retardation seen in infants and children with ESRD. The etiology of this growth disturbance is multifactorial, including anorexia that leads to protein and calorie insufficiency, renal osteodystrophy, aluminum toxicity, uremic acidosis, impaired somatomedin activity, and growth hormone and insulin resistance.¹⁵⁵ Because the most intense period of a child’s growth occurs during the first 2 years of life, careful nutritional support during that time is essential.

The mean weight at the time of renal transplantation has improved from 2.2 SD to 1.6 SD below the appropriate age-adjusted and gender-adjusted mean for normal children in a recent North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). This growth deficit was greater (2.8 SD) in children younger than 5 years of age. Transplantation afforded a 0.8 SD increase in growth over the first post-transplant year. However, this growth then reached a stable plateau. After 2 to 3 years, the mean weight values were comparable to those of normal children.¹⁵² Children 6 years of age and older showed no improvement in their height deficit 5 years after transplantation.^156,157 These limitations to ‘catch-up’ growth emphasize the need for early transplantation in young ESRD patients. If epiphyseal closure has occurred (bone age >12 years), additional bone growth is often not achieved.^151,158,159 Normalization of growth rarely occurs with hemodialysis or peritoneal dialysis.

The importance of efforts to normalize nutritional parameters is emphasized by the adverse impact of uremia on the infant’s developing nervous system. The significance of this problem was emphasized in a study in which progressive encephalopathy, developmental delay, microcephaly, hypotonia, seizures, and dyskinesia developed in 20 of 23 children with ESRD before 1 year of age.¹⁶⁰ All of these patients had significant growth impairment. Monitoring of the head circumference has been suggested to identify the infant at risk, with the intent to initiate dialysis, nutritional support, or transplantation if this parameter deviates from the normal curve.¹⁵¹

Hypertension

Hypertension following renal transplantation is common. One month after transplantation, 72% of all patients require treatment, although this percentage decreases to 53% at 30 months.¹⁶⁸ Careful attention to the pretransplant control of hypertension and dietary management improves the post-transplant management. Hypertension presents a significant risk to renal function when using small allografts. Hypertension in the early postoperative period is most often due to fluid overload or acute rejection, but it can also originate in the native kidneys.

Preexisting hypertension is augmented by the immunosuppressive drugs cyclosporine, tacrolimus, and prednisone. The development of hypertension more than three months after transplantation suggests possible renal artery stenosis and warrants ultrasound Doppler flow studies for initial evaluation. Arteriography may be needed in unclear cases. Transluminal angioplasty has been successful in alleviating the majority of these stenosis. Operative correction is reserved for angioplasty failures and vessels with complex arterial anastomoses.

Infection

Much like liver and intestinal transplantation, the highest risks for infectious complications arise within the first 6 months post-transplant. During this time, immunosuppression is intense and susceptibility to life-threatening infection is increased. In infants and children who are seronegative, use of organs from donors who have had prior exposure to CMV and EBV enhances the risk of these specific infections. Expanded use of antiviral prophylaxis using ganciclovir and acyclovir has decreased the intensity of these infections and their associated morbidity or mortality.

Immunosuppression

Many immunosuppressive regimens are available and all share similar strategy. Most regimens include corticosteroids, cyclosporine or tacrolimus, and azathioprine or MMF. Polyclonal or monoclonal antilymphocyte antibodies are used when ATN is anticipated or for retransplantation in highly pre-sensitized patients. Significant efforts to decrease or discontinue steroids have been attempted to enhance growth and development. At four years after transplantation, 31% of LD and 23% of DD recipients were receiving alternate-day prednisone.¹⁵²

Overall, there has been a decrease in the frequency of acute rejection with 12 month probabilities in LD of 32% and DD of 36%. The risk of rejection is similar for LD and DD recipients in the first few post-transplant weeks. Factors that increase the likelihood of rejection or long-term graft loss include receiving a graft from a DD rather than a related LD, receiving a graft from a donor younger than 5 years of age, having the graft in cold storage for more than 24 hours, being an African-American recipient, and delayed graft function from ATN.¹⁵² The ability to treat rejection has also improved with complete reversal of acute rejection in 65% of episodes. The rate of success in treating rejection declines with each successive rejection episode, increased recipient age, and late rejection episodes.¹⁵² Most rejection episodes can be treated with steroid administration alone (78%); monoclonal anti–T-cell agents such as orthoclone OKT-3 are needed in 32%. In patients who remain rejection free for the 1st post-transplant year, the risk of rejection in the following year is 20%.¹⁵⁴