Long-term management of the successful adult liver transplant: 2012 practice guideline by the -AASLD
Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation†
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|Strength of Recommendation||Criteria|
|1. Strong||Factors influencing the strength of the recommendation include the quality of the evidence, the presumed patient-important outcomes, and the cost.|
|2. Weak||There is variability in the preferences and values or more uncertainty. The recommendation is made with less certainty, or the cost or resource consumption is higher.|
|Quality of Evidence||Criteria|
|A. High||Further research is unlikely to change confidence in the estimate of the clinical effect.|
|B. Moderate||Further research may change confidence in the estimate of the clinical effect.|
|C. Low||Further research is very likely to affect confidence in the estimate of the clinical effect.|
AIH, autoimmune hepatitis; ALD, alcoholic liver disease; BMD, bone mineral density; CKD, chronic kidney disease; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CUC, chronic ulcerative colitis; DM, diabetes mellitus; EBV, Epstein-Barr virus; ESRD, end-stage renal disease; FDA, Food and Drug Administration; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; HAART, highly active antiretroviral therapy; HbA1c, hemoglobin A1c; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; LT, liver transplantation; mTOR, mammalian target of rapamycin; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NODM, new-onset diabetes mellitus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PTLD, posttransplant lymphoproliferative disorder; TB, tuberculosis.
LT AS A TREATMENT FOR END-STAGE LIVER DISEASE
LT is the treatment of choice for patients with decompensated cirrhosis, acute liver failure, small hepatocellular carcinomas (HCCs), or acute liver failure. The success of LT has meant that there is a growing cohort of LT recipients throughout the world. From 1985 through 2011, approximately 100,000 persons in the United States underwent LT. On December 30, 2011, there were 30,000 LT recipients who were alive and had survived at least 5 years, and there were more than 16,000 recipients with 10 or more years' survival. These long-term survivors are at risk of early death and increased morbidity. The purpose of this guideline is to assist in the management of adult recipients of LT, identify the barriers to maintaining their health, and make recommendations on the ways to best prevent or ameliorate these barriers. This guideline focuses on management beyond the first 90 days after transplantation.
MORTALITY AFTER LT
The greatest proportion of deaths or retransplants after LT occur soon after transplantation. The causes of death and graft loss vary according to the interval from transplantation, with infection and intraoperative and perioperative causes accounting for nearly 60% of deaths and graft losses in the first posttransplant year. After the first year, death due to acute infections declines, whereas malignancies and cardiovascular causes account for a greater proportion of deaths. The recurrence of the pretransplant condition, especially hepatitis C virus (HCV) or autoimmune liver disease, is an increasingly important cause of graft loss the longer the patient survives transplantation for these etiologies. Today, death (or a need for retransplantation) attributable to acute or chronic allograft rejection is uncommon throughout the first 10 years after transplantation.
MORBIDITY AFTER LT
The transplanted liver becomes partially tolerant of immune-mediated injury, so the requirement for immunosuppression declines after the first 90 days. Although some LT recipients may eventually achieve operational tolerance (ie, maintenance without immunosuppressant medications), this is rare. Most patients receive immunosuppression throughout the life of the allograft.5 The continued use of immunosuppression carries inevitable consequences: an increased risk of bacterial, viral, and fungal infections, which can be recurrent or newly acquired; metabolic complications such as hypertension, diabetes mellitus (DM), hyperlipidemia, obesity, and gout; and hepatobiliary or extrahepatic de novo cancers [including posttransplant lymphoproliferative disorder (PTLD)]. The combination of the complications of immunosuppression and the recurrence of the underlying liver disease translates into a heavy burden of ill heath for many LT recipients. An analysis of a longitudinal US database of 36,847 LT recipients indicated that the prevalence of kidney failure [defined as a glomerular filtration rate of 29 mL/minute/1.73 m2 of body surface area or less or the development of end-stage renal disease (ESRD)] was 18% at 5 years and 25% at 10 years.6 LT recipients have at-risk cardiovascular profiles with a high prevalence of hypertension requiring antihypertensive medications, recurrent DM and new-onset diabetes mellitus (NODM), and hyperlipidemia requiring lipid-lowering agents.
Cardiovascular disease and renal failure are the leading nonhepatic causes of morbidity and mortality late after LT (Table 2). The recurrence of the original disease, such as a chronic HCV infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or HCC, can cause ongoing morbidity and mortality. Many of the patients undergoing LT have a past or present history of addictions, especially to alcohol, cigarettes, or both, which may also persist with harmful effects on patients' health, often by interacting with other risk factors already mentioned.
|Cardiovascular risk factor|
|CKD (stage 3-4)†||30%-80%|
|End-stage kidney disease||5%-8%|
An assessment of the quality of life after LT has shown that although quality measures improve in LT patients in most domains in comparison with their status before transplantation, LT recipients continue to have many deficits in comparison with age-matched control populations; these are manifested as worsening physical symptoms, fatigue, and a greater sense of being unwell.7
COMPLICATIONS OF PORTAL HYPERTENSION AFTER LT
Allograft parenchymal damage
|Immune-mediated disease (rejection and de novo AIH)|
|Recurrent disease (HCV, HBV, PBC, PSC, AIH, and others)|
|Drug toxicity (including immunosuppressive drugs)|
|Alcohol and other toxins|
|De novo infection (including de novo HBV and HCV)|
|Space-occupying lesion (recurrent cancer)|
|De novo or recurrent NAFLD|
|Biliary strictures (anastomotic strictures, hepatic artery thrombosis or stenosis, and others)|
|Biliary stones/cast syndrome|
|Hepatic artery thrombosis|
|Portal or hepatic vein thrombosis|
|Metabolic disease in the allograft|
|Nonhepatic disease mimicking liver disease|
|Hemolysis causing raised indirect bilirubin levels|
|Bone disease causing raised alkaline phosphatase levels|
|Nonhepatic disease causing liver abnormalities|
Elevated alkaline phosphatase, total bilirubin, and aminotransferase levels may arise from the late appearance of biliary anastomotic strictures due to thrombosis or stenosis of the hepatic artery or to recurrent PSC or PBC. Appropriate biliary imaging includes endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and/or ultrasound. Biliary cast syndrome refers to a severe form of intrahepatic bile duct ischemic injury unique to post-LT patients,8 and it is associated with hepatic artery thrombosis and the use of a split liver, including partial grafts derived from living donors and, more commonly, from donation after cardiac death donors. Biliary cast syndrome may resolve with repeated clearance of bile duct debris either percutaneously or endoscopically.
- 1The frequency of monitoring with liver tests should be individualized by the transplant center according to the time from LT, the complications from LT, the stability of serial test results, and the underlying cause (grade 1, level A).
- 2Depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, endoscopic retrograde cholangiopancreatography, and sonography may be appropriate (grade 1, level A).
- 3Liver histology should be obtained when parenchymal injury is suspected as the cause of abnormal liver tests (grade 1, level A).
- intrahepatic non-anastomotic strictures and/or sterile or infected fluid collections within the liver, sometimes referred to as bilomas,
- ischemic cholangiopathy or
- biliary cast syndrome.
- 4Bilomas and biliary cast syndrome should be managed in a center with expertise in LT medicine, radiology, and biliary endoscopy (grade 1, level A).
- 5Hepatic artery thrombosis or stenosis is most readily assessed initially by Doppler ultrasound, but angiography is usually required to confirm the diagnosis and plan therapy (grade 1, level B).
- Indication for transplantation: the choice of immunosuppression may affect disease recurrence (eg, HCV, malignancy, or autoimmune disease).
- Drug side effects: calcineurin inhibitors (CNIs) may cause renal impairment.
- Likelihood of pregnancy: mycophenolate and mammalian target of rapamycin (mTOR) inhibitors such as sirolimus are potential teratogens.
- History of severe or recurrent rejection.
- Prior experience with the various immunosuppressive agents.
- History of or risk for cancers.
- History of or risk for infections.
There is no reliable marker for determining the effective level of immunosuppression; therefore, the choice of the agent (or agents) and doses given will be determined by the clinical, laboratory, and histological response. The CNI dose is generally determined by the drug level; the target levels after 3 months are 5 to 10 ng/mL for tacrolimus and 100 to 150 ng/mL for cyclosporine (both are whole blood trough levels). The target whole blood trough level for sirolimus is 5 ng/mL. The need for therapeutic drug monitoring for mycophenolate is uncertain. Table 4 describes drug-drug interactions involving the commonly used immunosuppressant medications. Common side effects of immunosuppressants are presented in Table 5.
|Fluoroquinolones (primarily ofloxacin > ciprofloxacin)||Increased levels|
|Macrolides (erythromycin > clarithromycin > azithromycin)||Markedly increased levels||Markedly increased levels|
|Rifamycins (rifampin > rifabutin)||Markedly decreased levels||Markedly decreased levels|
|Linezolid||Increased myelosuppression||Increased myelosuppression and platelet decrease|
|Triazoles (ketoconazole/ voriconazole/posaconazole > itraconazole/fluconazole)||Increased levels||Increased levels (voriconazole contraindicated)|
|Ganciclovir/valganciclovir||Increased myelosuppression||Increased myelosuppression|
|Side Effect||Corticosteroids||CNIs||mTOR Inhibitors||Mycophenolate Mofetil|
|Kidney injury||−||+++||+ (proteinuria)||−|
|Bone marrow suppression||−||−||−||+|
The majority of LT recipients need lifelong immunosuppression to maintain graft function. A very small number of LT recipients develop operational tolerance to the allograft and do not require long-term immunosuppression.5
- Reduction of immunosuppression (whether iatrogenic or due to noncompliance).
- Pre-LT autoimmune liver disease.
- Concurrent administration of interferon (for HCV treatment).
The differential diagnosis includes infection, recurrent and de novo autoimmune disease, and drug toxicity; it may sometimes be difficult to distinguish cellular rejection from HCV infection, and indeed, the two often coexist.
- Recurrent and unresponsive cellular rejection.
- Transplantation for autoimmune disease.
- Exposure to interferon.
- Loss of a previous graft to ductopenic rejection.
The differential diagnosis includes recurrent disease (PBC or PSC) and drug toxicity.
- 6Immunosuppressive drugs for LT recipients should be prescribed and monitored only by those with knowledge and expertise in that area. The choice of agents will depend on many factors, and no one regimen can be recommended for any patient (grade 2, level A).
- 7Every patient's immunosuppressive regimen should be reviewed at least every 6 months and modified as required with the goal of minimizing long-term toxicities (grade 1, level B).
- 8Rejection can be reliably diagnosed only on the basis of liver histology; a biopsy sample should be taken before treatment initiation and classified according to the Banff criteria (grade 1, level A).
- 9Although the long-term withdrawal of all immunosuppression can be achieved in a small number of patients, this should be undertaken only with select recipients and under close supervision (grade 2, level C).
- 10Frequent handwashing reduces the risk of infection with pathogens acquired by direct contact, including Clostridium difficile, community-acquired viral infections, and pathogens found in soil (grade 1, level A).
- 11Shoes, socks, long-sleeve shirts, and long pants should be worn for activities that will involve soil exposure and tick exposure and also to avoid unnecessary sun exposure (grade 1, level A).
- 12During periods of maximal immunosuppression, LT recipients should avoid crowds to minimize exposures to respiratory illnesses (grade 1, level A).
- 13Work in high-risk areas, such as construction, animal care settings, gardening, landscaping, and farming, should be reviewed with the transplant team to develop appropriate strategies for the prevention of high-risk exposures (grade 2, level A).
- 14LT recipients should avoid the consumption of water from lakes and rivers (grade 1, level A).
- 15LT recipients should avoid unpasteurized milk products and raw and undercooked eggs and meats (particularly uncooked pork, poultry, fish, and seafood; grade 1, level A).
- 16LT recipients should avoid high-risk pets, which include rodents, reptiles, chicks, ducklings, and birds (grade 1, level A).
- 17Travel by LT recipients, especially to developing countries, should be reviewed with the transplant team a minimum of 2 months before departure to determine optimal strategies for the reduction of travel-related risks (grade 1, level A).
- 18LT recipients should take precautions to prevent vector (including mosquito) -borne diseases. These include avoiding going out during peak mosquito feeding times (dawn and dusk) and using N,N-diethyl-meta-toluamide–containing insect repellants (grade 1, level A).
- 19LT recipients should undertake a thorough review of hobbies to assess potential infectious disease risks, particularly those associated with outdoor hobbies (grade 2, level A).
- 20All LT recipients should be educated about the importance of sun avoidance and sun protection through the use of a sun block with a sun protection factor of at least 15 and protective clothing. They should be encouraged to examine their skin on a regular basis and report any suspicious or concerning lesions to their physicians (grade 1, level A).
- 21Because of the strong association of lung, head, and neck cancers with smoking, the sustained cessation of smoking is the most important preventative intervention (grade 1, level A).
- 22For female LT recipients of a child-bearing age, preconception counseling about contraception and the risks and outcomes of pregnancy should start in the pretransplant period and should be reinforced after transplantation (grade 1, level A).
|Assessment of bone pain or fractures|
|Dietary intake of protein and calcium|
|Serum calcium, phosphorus, and parathormone levels|
|25-hydroxyvitamin D level|
|24-hour urinary calcium (200-300 mg/day)*|
|Gonadal status: free testosterone (males) or menopausal status (females)|
|BMD: lumbar spine and hips|
|Spinal radiographs (thoracolumbar)|
In order to diminish factors that promote bone loss, glucocorticoids should be reduced or discontinued as soon as possible after LT. Calcium supplements are recommended for all LT recipients with (or at risk of) osteopenia, and all patients should receive 1000 to 1200 mg of elemental calcium daily to optimize bone remodeling and mineralization. Vitamin D levels should be maintained at a serum level of at least 30 ng/mL, and most LT patients will require supplementation (generally 400-1000 IU/day). The serum levels of 25-hydroxyvitamin D must be checked to assess the adequacy of replacement, even with supplementation, and should be rechecked annually or more frequently if a deficiency is diagnosed. Many issues with regard to bisphosphonate therapy for LT recipients remain to be defined: the optimal duration of therapy, the optimal doses of bisphosphonates, whether oral or intravenous therapy is better, and the LT population most likely to benefit. Despite these caveats, we suggest that bisphosphonate therapy should be considered in the following circumstances:
- T-score less than −2.5 or atraumatic fractures.
- T-score between −1.5 and −2.5 and other risk factors.
Oral alendronate at 70 mg weekly is an appropriate starting point, although other oral agents may, however, be equally efficacious. If oral therapy is not tolerated, intravenous zolendronic acid or ibandronate can be used. The optimal duration of therapy is unknown, although oral alendronate has been given with good effect for 10 years for postmenopausal osteoporosis. Hormone replacement therapy is an alternative in postmenopausal women.
- 23In the first 5 years after transplantation, screening by BMD should be done yearly for osteopenic patients and every 2 to 3 years for patients with normal BMD; thereafter, screening depends on the progression of BMD and on risk factors (grade 2, level B).
- 24If osteopenic bone disease is confirmed or if atraumatic fractures are present, then patients should be assessed for risk factors for bone loss; in particular, this should include an assessment of calcium intake and 25-hydroxyvitamin D levels, an evaluation of gonadal and thyroid function, a full medication history, and thoracolumbar radiography (grade 1, level A).
- 25The osteopenic LT recipient should perform regular weight-bearing exercise and receive calcium and vitamin D supplements (grade 1, level A).
- 26Bisphosphonate therapy should be considered in LT recipients with osteoporosis or recent fractures (grade 1, level A).
- 27Monitoring of renal function in LT recipients for the detection and management of CKD should use an estimating equation to evaluate the glomerular filtration rate (grade 1, level B).
- 28Urinary protein quantification using the concentration ratio of protein to creatinine in a spot urine specimen should be evaluated at least once yearly (grade 1, level B).
- 29The reduction or withdrawal of CNI-associated immunosuppression is an appropriate response to the development of CKD in LT recipients (grade 1, level A).
- 30Kidney transplantation from deceased or living donors is beneficial in improving survival and should be considered the optimal therapy for LT recipients who develop ESRD (grade 1, level A).
The spectrum of hyperglycemia after LT includes preexisting DM and NODM, some of which is transient in the perioperative period. Insulin-requiring DM that is present at the time of transplantation virtually always persists after LT, and many patients on oral hypoglycemic agents need a conversion to insulin early after LT. In LT recipients followed beyond 1 year, estimates of the prevalence of NODM vary from 5% to 26%. Diabetogenic factors after LT include corticosteroids, CNIs (tacrolimus more than cyclosporine), HCV infection, and metabolic syndrome.28-33 NODM tends to remit over time, especially as corticosteroids are withdrawn and the tacrolimus dosage is reduced, and patients may go from insulin therapy to oral hypoglycemic agents to diet control only over the years.
|Diagnosis||Fasting plasma glucose||Every 3 months in the first year and then annually|
|Monitoring||Self-monitoring of blood glucose||Review every 3 months|
|HbA1c||Every 3 months (intervention at ≥7.0%*)|
|Diabetic complications||Annual screening (retinopathy)|
|Tailoring of immunosuppression (especially if there is poor control): discontinuation of steroids and change from tacrolimus to cyclosporine|
|Lipid levels||Annual evaluation|
|Treatment||For all patients|
|Dietary and lifestyle modification: exercise and weight loss (if the patient is obese)|
|Control of hypertension and dyslipidemia|
|Depending on glycemic control|
|Oral agent or agents|
|Insulin ± oral agent (if there is poor control)|
- 31The treatment of DM after LT should aim for an HBA1c target goal of <7.0% with a combination of lifestyle modifications and pharmacological agents as appropriate (grade 1, level B).
- 32When high-dose corticosteroids are administered, insulin therapy is the most effective and safest agent with which to control hyperglycemia; however, as the interval from LT extends, patients with NODM may experience a decline in insulin requirements, and oral hypoglycemic agents may be appropriate if allograft function is normal (grade 1, level C).
- 33Metformin or sulfonylureas may be used in LT recipients with normal renal function, whereas sulfonylureas such as glipizide and glimepiride are preferable if there is any deterioration of renal function (grade 1, level C).
- 34Consideration can be given to the conversion of immunosuppression from tacrolimus to cyclosporine in LT recipients with poor glycemic control (grade 2, level B).
Hypertension in LT recipients increases the risk of fatal and nonfatal cardiovascular disease events and CKD.15 Although there are no clinical trials of antihypertensive therapy in LT recipients, it is prudent to target a blood pressure treatment goal of 130/80 mm Hg in LT recipients with systemic hypertension.34
- 35The treatment of hypertension should aim for a target goal of 130/80 mm Hg with a combination of lifestyle modifications and pharmacological agents as appropriate (grade 1, level A).
- 36Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and direct renin inhibitors should be used as first-line antihypertensive therapy in LT recipients with DM, CKD, and/or significant proteinuria (grade 1, level A).
|Elevated low-density lipoprotein cholesterol level > 100 mg/dL (with or without elevated triglycerides)|
|1. Therapeutic lifestyle and dietary changes|
|3. Addition of ezetimibe|
|Hypertriglyceridemia with normal cholesterol|
|1. Fish oil at 1000 mg twice daily to 4 g daily if tolerated|
|2. Fibric acid derivatives|
|Refractory hyperlipidemia: consider changes in immunosuppression|
|1. Conversion of cyclosporine to tacrolimus|
|2. CNI reduction (eg, add mycophenolate mofetil)|
|3. Discontinuation of sirolimus|
- 37The measurement of blood lipids after a 14-hour fast is recommended annually for healthy LT recipients. An elevated low-density lipoprotein cholesterol level > 100 mg/dL, with or without hypertriglyceridemia, requires therapy. If therapeutic lifestyle and dietary changes are not enough, statin therapy should be introduced. Suboptimal control with statins can be improved by the addition of ezetimibe (grade 2, level B).
- 38Isolated hypertriglyceridemia is first treated with omega-3 fatty acids (up to 4 g daily if tolerated). If this is not sufficient for control, gemfibrozil or fenofibrate can be added, although patients must be followed carefully for side effects, especially with the concomitant use of statins and CNIs (grade 2, level C).
- 39All LT patients require ongoing dietary counseling to avoid obesity (grade 1, level C).
- 40Among LT recipients who become severely or morbidly obese and fail behavioral weight-loss programs, bariatric surgery may be considered, although the optimal procedure and its timing with respect to transplantation remain to be defined (grade 1, level C).
De Novo Cancer
|Squamous and basal cell carcinoma||20%-70%|
|Oropharyngeal cancer, including esophageal cancer||3%-14% (as high as 25% if the prior diagnosis was alcoholic cirrhosis)|
|Colorectal cancer||25%-30% if ulcerative colitis is present|
- 41All LT recipients should see a dermatologist after transplantation to assess cutaneous lesions, with at least an annual evaluation by a dermatologist 5 years or more after transplantation (grade 1, level A).
- 42Patients with PSC and inflammatory bowel disease or other established risk factors for colorectal cancer should undergo an annual screening colonoscopy with biopsies. Colectomy, including continence-preserving pouch operations, should be considered when colonic biopsy reveals moderate or severe dysplasia (grade 1, level B).
- 43For patients without prior HCC who develop recurrent cirrhosis of the allograft, surveillance for de novo HCC should be undertaken with abdominal imaging every 6 to 12 months (grade 1, level A).
- 44An immunosuppressant regimen that includes sirolimus (started several weeks after transplantation) should be considered for patients undergoing transplantation for HCC (grade 2, level B).
- 45Resection or ablation is usually the treatment of choice for a solitary extrahepatic metastasis or an intrahepatic recurrence of HCC (grade 1, level B).
- At least 1 year after LT.
- Allograft function is stable.
- Medical comorbidities such as diabetes and hypertension are well controlled.
- Immunosuppression is at a low maintenance level.
The choice of immunosuppression should be made before conception. All immunosuppressive drugs cross the placenta and enter the fetal circulation with resulting concerns about teratogenicity and fetal loss. Table 11 shows the Food and Drug Administration (FDA) safety categories for drugs in pregnancy. Generally, CNIs (class C drugs), prednisone (class B), and azathioprine (class D) appear to be safe.54 The newer agents should be avoided if possible; in the National Transplant Pregnancy Registry,51 more structural abnormalities have been seen in babies born to mothers on mTOR inhibitors or mycophenolic acid, especially when they are used in early pregnancy.55, 56 European guidelines for renal recipients advise discontinuing mTOR inhibitors at least 6 weeks before conception.58
|A. Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of risk in later trimesters), and the possibility of fetal harm appears remote.|
|B. Animal reproduction studies have not demonstrated fetal risk, but there are no controlled studies in pregnant women, OR animal studies have shown an adverse effect that has not been confirmed in controlled studies in women in the first trimester.|
|C. Animal studies have revealed adverse effects on the fetus, and there are no controlled studies in women, OR studies in women and animals are not available. Give the drug only if the potential benefit justifies the risk.|
|D. There is positive evidence of human fetal risk, but benefits from use in pregnant women may be acceptable despite the risk.|
|X. A definitive fetal risk exists, and the drug is contraindicated in women who are or may become pregnant.|
- 46Pregnancy in an LT recipient should be managed by a high-risk obstetrician in coordination with the transplant hepatologist (grade 1, level C).
- 47Pregnancy should be delayed for 1 year after LT and occur at a time with good, stable allograft function, with maintenance immunosuppression, and with good control of any medical complications such as hypertension and diabetes (grade 1, level B).
- 48The ideal immunosuppression for pregnancy is tacrolimus monotherapy, which should be maintained at therapeutic levels throughout pregnancy; cyclosporine, azathioprine, and prednisone may also be used if they are necessary (grade 1, level B).
- 49Allograft function and CNI serum levels are monitored every 4 weeks until 32 weeks, then every 2 weeks, and then weekly until delivery (grade 1, level B).
- 50Contraception should begin before the resumption of sexual activity, although no particular form of contraception can be recommended over another (grade 2, level B).
|Donor-positive/ recipient-negative||Valganciclovir (900 mg/day) or intravenous ganciclovir (5 mg/kg/day)||3-6 months||Valganciclovir is not FDA-approved for LT. Prolonged-duration regimens are effective in kidney transplantation.|
|Recipient-positive||Valganciclovir (900 mg/day), intravenous ganciclovir, or weekly CMV viral load monitoring and antiviral initiation when viremia is identified||3 months||Valganciclovir is not FDA-approved for LT.|
|Fungi||Fluconazole (100-400 mg daily), itraconazole (200 mg twice daily), caspofungin (50 mg daily), or liposomal amphotericin (1 mg/kg/day)||4-6 weeks? (optimal duration unknown)||Reserve for high-risk individuals (pretransplant fungal colonization, renal replacement therapy, massive transfusion, choledochojejunostomy, reoperation, retransplantation, or hepatic iron overload).|
|P. jirovecii (P. carinii)||Trimethoprim sulfamethoxazole (single strength daily or double strength 3 times per week), dapsone (100 mg daily), or atovaquone (1500 mg daily)||6-12 months (optimal duration unknown)||A longer duration of therapy should be considered for patients on augmented immunosuppression. Lifelong therapy should be considered for HIV-infected recipients.|
|TB (latent infection)||Isoniazid (300 mg daily)||9 months||Monitor for hepatotoxicity.|
- 51An assessment for infections following LT should take into account the intensity of immunosuppression, the timing of the presentation, the environmental and donor exposures, the recipient's history of both symptomatic and latent infections, and the utilization of prophylactic antimicrobials and immunizations (grade 1, level A).
- 52Attention should be paid to potential drug interactions when new antimicrobial therapies are initiated (grade 1, level A).
- CMV-seropositive donor organ (especially in the absence of prior immunity, ie, a CMV-seronegative recipient).
- Augmented immunosuppression (especially with the use of anti-lymphocyte antibodies or high-dose mycophenolate).
- Allograft rejection.
- Coinfection with other immunomodulating viruses (eg, human herpesviruses 6 and 7), bacteria, or fungi.
The diagnosis of CMV includes the detection of the virus in conjunction with the recognition of an associated clinical syndrome.61, 62 Patients who are not receiving prophylactic antivirals and are at increased risk for CMV (because of a CMV-seropositive donor and/or treatment for rejection) may be monitored for evidence of infection with nucleic acid testing (polymerase chain reaction). Typically, CMV occurs in the first 3 months in the absence of prophylaxis. However, because of current standard prophylactic strategies, it now presents later after the cessation of prophylaxis, frequently in the first year or after the augmentation of immunosuppression. Currently, routine screening for CMV is not recommended while patients are receiving prophylaxis. After the completion of prophylaxis, some centers have adopted a hybrid approach using nucleic acid testing to screen for infections in the highest risk patients. However, there is no clear evidence to support the screening of asymptomatic patients at this time. The detection of viremia by either nucleic acid testing (polymerase chain reaction) or the pp65 antigenemia assay is recommended for the diagnosis of an active CMV infection.61, 62 Typically, the viral load correlates with the severity of disease and can be a marker of the response to therapy. Some individuals, especially those with hepatitis or gastrointestinal disease, may exhibit low-level or no viremia despite a symptomatic infection and require tissue biopsy for the diagnosis of CMV disease to be made. Finally, some LT recipients exhibit low-level viremia without symptomatic disease.
- 53High-risk recipients (CMV-seronegative recipients of CMV-seropositive donor organs) should receive prophylaxis with ganciclovir or valganciclovir for a minimum of 3 months after transplantation (grade 1, level B).
- 54The treatment of LT recipients with CMV should be maintained until viremia and all symptoms have resolved (grade 2, level B).
- 55Prophylaxis against CMV should be resumed whenever LT recipients receive anti-lymphocyte therapy for the treatment of rejection and should be continued for 1 to 3 months after the treatment of rejection (grade 2, level B).
- 56The treatment of a CMV infection should consist of the following:
- aConsideration of immunosuppression reduction.
- bHigh-dose intravenous ganciclovir or oral valganciclovir in individuals with mild to moderate disease without gastrointestinal involvement or a reduced capacity for absorption.
- cA minimum of 2 weeks of treatment. Treatment should be continued to complete the resolution of all symptoms and viremia (grade 1, level A).
- 57Resistant virus should be suspected in patients with a history of prolonged ganciclovir or valganciclovir exposure who have a persistent or progressive infection despite treatment with high-dose intravenous ganciclovir (grade 1, level A). In such instances, genotypic assays should be performed, and consideration should be given to the initiation of foscarnet with or in substitution for ganciclovir (grade 1, level B).
- 58PTLD should be considered in LT recipients (especially high-risk individuals) who present with unexplained fever, lymphadenopathy, or cytopenias (grade 1, level A).
- 59Although EBV may be associated with the development of PTLD, the detection of EBV viremia is not diagnostic for PTLD; a histopathological diagnosis is required (grade 1, level A).
|Candida||Triazoles (fluconazole, Itraconazole, voriconazole, and posaconazole), echinocandins (eg, caspofungin, micafungin, and anidulafungin), or amphotericin B and analogues||Candida glabrata and Candida krusei may be resistant to triazoles (especially fluconazole). Differentiate colonization from infection. The duration of therapy varies with the site of infection.|
|Aspergillus||Triazoles (voriconazole is the drug of choice; itraconazole and posaconazole are also active), caspofungin, or amphotericin B and analogues||The duration of therapy is dependent on the response to therapy.|
|Cryptococcus||Amphotericin B and analogues in combination with 5-flucytosine for 2 weeks followed by fluconazole (400-800 mg/day) for 8 weeks and then fluconazole (200 mg/day) for 6-12 months||Cautiously reduce immunosuppression. Patients with isolated pulmonary disease may not require amphotericin induction. The duration varies with the response.|
|Blastomycosis||Itraconazole (200 mg twice daily) for mild to moderate disease and amphotericin B and analogues for severe disease||The standard duration is 6-12 months.|
|Coccidiomycosis||Fluconazole (400-800 mg daily), itraconazole (200 mg twice daily), or amphotericin B and analogues||Amphotericin should be used for more severe disease and should be considered when there is central nervous system involvement. The standard duration is 6-12 months with chronic suppression thereafter.|
|Histoplasmosis||Itraconazole (200 mg twice daily) or amphotericin B and analogues for 2 weeks of induction followed by fluconazole||The minimum duration is 12 months.|
- 60The diagnosis of fungal infections may require diagnostic biopsy for pathological and microbiological confirmation (grade 1, level A).
- aBlood cultures are most helpful for the diagnosis of Candida bloodstream infections (class 1, level B) and Blastomyces (grade 1, level B).
- bCryptococcal antigen testing of cerebrospinal fluid or blood is most helpful for the diagnosis of Cryptococcus (grade 1, level B).
- cUrinary histoplasmosis and Blastomyces antigens are useful for the diagnosis of disseminated histoplasmosis and blastomycosis, respectively (grade 1, level B).
- 61A cautious reduction of immunosuppression should be initiated to prevent immune reconstitution syndrome, especially for cryptococcal infections (grade 1, level B).
- 62All LT recipients should receive prophylaxis against P. jirovecii with trimethoprim-sulphamethoxazole (single strength daily or double strength 3 times per week) for a minimum of 6 to 12 months after transplantation (grade 1, level A). Atovaquone and dapsone are the preferred alternatives for patients who are intolerant of trimethoprim sulfamethoxazole (grade 1, level B).
- 63Trimethoprim-sulphamethoxazole is the drug of choice for the treatment of P. jirovecii pneumonia. Intravenous pentamidine is the preferred alternative for patients intolerant of trimethoprim-sulphamethoxazole with more severe infections (grade 1, level A).
- 64Patients with clinical signs and symptoms or radiological features suggestive of P. jirovecii pneumonia should undergo sputum sampling or bronchoalveolar lavage with a cytological examination using a silver or Giemsa stain, polymerase chain reaction, or a specific antibody stain to identify the organism (grade 1, level A).
- 65The treatment of active TB should include the initiation of a 4-drug regimen using isoniazid, rifampin, pyrazinamide, and ethambutol (under the assumption of susceptible TB) with adjustments in accordance with subsequent culture results. This may be tapered to 2 drugs (isoniazid and rifampin) after 2 months (under the assumption of no resistance) and continued for a minimum of 4 additional months (grade 1, level B).
- 66Close monitoring for rejection and hepatotoxicity is imperative while LT recipients receive anti-TB therapy (grade 1, level A).
- 67HIV-infected LT recipients receiving HAART require frequent monitoring of CNI levels because of the significant interaction between antiretrovirals and CNIs (grade 1, level A).
- 68HIV-infected LT recipients receiving HAART should be followed with scheduled HIV viral loads and T lymphocyte subset counts (grade 1, level A).
- 69Standard prophylaxis for CMV is recommended for HIV-infected LT recipients receiving HAART, and lifelong Pneumocystis pneumonia prophylaxis is the norm (grade 1, level A).
- 70Standard HIV-specific prophylaxis for low CD4 counts should be used (grade 1, level A).
|Before Transplantation||After Transplantation|
|Hepatitis A virus†|
|Tetanus/diphtheria/ acellular pertussis‡|
|Human papilloma virus§|
- 71All LT recipients should receive an annual influenza vaccination (grade 1, level B).
- 72All LT recipients should avoid live virus vaccines (grade 1, level A).
- 73Re-immunization is indicated for some vaccines, notably the influenza vaccine (annually) and the pneumococcal vaccine (every 3-5 years; no class or level provided). (grade 1, level A).
Hepatitis B Virus (HBV)
- 74Long-term prophylactic therapy using a combination of antiviral agents and low-dose HBIG on demand or at fixed intervals can effectively prevent HBV recurrence rates in ≥90% of transplant recipients (grade 1, level B).
- 75In patients with low or undetectable HBV DNA levels before transplantation and an absence of high-risk factors for recurrence, HBIG can be discontinued, and long-term treatment with antivirals (single or in combination) can be used as an alternative prophylactic strategy (grade 2, level B).
- 76Lifelong antiviral therapy should be used to treat patients with recurrent HBV infections. Combination antiviral therapy is superior to monotherapy when drugs with a low genetic barrier to resistance are used, whereas the discontinuation of HBIG is generally reserved for patients at low risk for HBV recurrence (grade 1, level B).
- 77Retransplantation for recurrent HBV is appropriate when treatment strategies to prevent or treat recurrent HBV disease are available (grade 1, level C).
- 78Liver biopsy is useful in monitoring disease severity and progression and in distinguishing recurrent HCV disease from other causes of liver enzyme elevations (grade 1, level C).
- 79Prophylactic antiviral therapy has no current role in the management of HCV disease (grade 1, level A).
- 80Moderate acute rejection should be treated with increased maintenance immunosuppression and corticosteroid boluses, whereas lymphocyte-depleting drugs should be avoided (grade 1, level B).
- 81Antiviral therapy is indicated for significant histological disease: grade 3 or higher inflammatory activity and/or stage 2 or higher fibrosis (on a scale of 4) or cholestatic hepatitis. Peginterferon and ribavirin are the current drugs of choice. The risks and benefits of triple therapy with protease inhibitors are to be determined. The goal of antiviral therapy is the achievement of a sustained virological response, and this confers a survival benefit (grade 1, class B).
- 82Retransplantation for recurrent HCV disease should be considered selectively (grade 2, level B).
- 83PBC LT recipients should be routinely monitored for associated autoimmune diseases (eg, thyroid disease) and bone density (grade 2, level B).
- 84For those with histological evidence of recurrent disease, treatment with ursodeoxycholic acid at 10 to 15 mg/kg/day (grade 2, level B) may be considered, and although its use is associated with the improvement of liver tests, no impact on graft survival has been documented (grade 2, level B). There is no indication for offering prophylaxis with ursodeoxycholic acid to patients with normal liver histology (grade 2, level B).
- 85Although there are few data on prevention, it is recommended that those patients grafted for PSC in the presence of CUC have an annual colonoscopy with mucosal biopsy (grade 2, level B).
- 86Although there is no evidence for recommending a particular immunosuppressive regimen in patients undergoing transplantation for AIH, it is prudent to maintain patients on long-term, low-dose corticosteroids in addition to routine immunosuppression (with attention to maintaining bone health; grade 2, level B).
ALCOHOLIC LIVER DISEASE (ALD)
- 87All patients with a prior diagnosis of ALD should be encouraged to remain abstinent from alcohol (grade 1, level B).
- 88Patients should be encouraged to enter therapy or counseling if they relapse into alcohol use (grade 1, level C).
- 89All patients with a prior diagnosis of ALD who are users of tobacco should be encouraged to undertake smoking cessation (grade 1, level B).
- 90Careful attention should be given to the risk of cardiovascular disease and/or new-onset cancers of the aerodigestive tract, especially in cigarette smokers (grade 1, level A).
- 91The confirmation of recurrent or de novo NAFLD, the recognition of fibrosis, and the exclusion of alternate causes of elevated liver chemistry tests require liver biopsy (grade 1, level B).
- 92No specific recommendations regarding the prevention or treatment of NAFLD or NASH in LT recipients can be made other than general recommendations to avoid excessive gains in body weight and control hypertension and diabetes (grade 1, level C).
LATE SURGICAL COMPLICATIONS
- 93LT recipients with an incisional hernia should be instructed to recognize incarcerated hernias and advised to seek immediate medical assistance (grade 1, level B).
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