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International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients

Charlton, Michael MD1; Levitsky, Josh MD2; Aqel, Bashar MD3; O'Grady, John MD4; Hemibach, Julie MD5; Rinella, Mary MD2; Fung, John MD1; Ghabril, Marwan MD6; Thomason, Ray MD7; Burra, Patrizia MD8; Little, Ester Coelho MD9; Berenguer, Marina MD10; Shaked, Abraham MD11; Trotter, James MD12; Roberts, John MD13; Rodriguez-Davalos, Manuel MD14; Rela, Mohamed MBBS4; Pomfret, Elizabeth MD15; Heyrend, Caroline PharmD14; Gallegos-Orozco, Juan MD7; Saliba, Faouzi MD16

Author Information
doi: 10.1097/TP.0000000000002147


In the May 2018 issue of Transplantation , in the article by Charlton et al, the affiliation and funding statement for Dr. Marina Berenguer was incomplete. Affiliation number 10 should have appeared as:

Hepatology and Liver Transplantation Unit, La Fe University Hospital, Instituto de Investigación Sanitaria and Ciberehd, Valencia, Spain.

Ciberehd is partially funded by the Instituto de Salud Carlos III.

Transplantation. 103(1):e37, January 2019.

The steady improvement in patient and graft survival rates after liver transplantation (LT) has been related to many factors, including improved efficacy of immunosuppression (IS). Effective IS management is central to achieving optimal outcomes in liver transplant recipients. The advent of more specific, potent IS agents has, while greatly reducing graft losses through acute and chronic rejection, been associated with an increasing burden of toxicities. Although dosing guidelines are available for individual IS agents, the overall approach to IS varies widely between transplant centers. The ILTS convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to develop guidelines on key aspects of IS management. Summaries of the evidence were presented to the entire group of panelists. Six broad areas of IS were addressed by the consensus panel. These topics were addressed through a critical review of the literature, followed by working group proposals and subsequent consensus, which was reviewed by the whole group. As for other ILTS guidelines, the Grading of Recommendations Assessment Development and Evaluation approach was used to determine the grade of the evidence and the strength of the recommednations.1 Quality of evidence, benefits to risk ratio, resource use, and cost-effectiveness were all considered in developing guidelines. Recommendations were rated according to quality of the evidence (rated as very low, low, moderate, or high) and strength (rated as strong or conditional [weak]) and reflect perceived probability of benefit likely to be gained by adherence to guidance.

The consensus findings and recommendations of the International Liver Transplant Society Consensus guidelines on IS in liver transplant recipients are presented in this document. The guidance, which will be updated to reflect new evidence as it becomes available, is intended for healthcare providers caring for patients before and after LT. This guidance is also intended to assist third parties in decision making regarding access to IS regimens.

General Aspects of Liver Transplant IS

Immunosuppression after LT can be divided into the induction and maintenance phases, as well as general resumption of these phases in managing a rejection episode. Induction therapy usually consists of intravenous corticosteroids immediately posttransplant for several days until oral corticosteroids can be initiated. Use of other induction agents, such as IL-2 receptor antibodies or more lymphodepleting therapy (antithymocyte globulin), is increasing because these are often used to delay the introduction of calcineurin inhibitor (CNI) therapy in patients with kidney dysfunction. Other uses of induction therapy are for those at higher immunological risk (retransplantation for rejection, immune-mediated liver disease, simultaneous liver-kidney; highly sensitized) compared with essentially all other recipients who are considered lower immunological risk. The mainstay of maintenance IS therapy are the CNIs, with tacrolimus (TAC) being preferred over cyclosporine for initial therapy. Antiproliferative agents, such as mycophenolic acid and azathioprine, and mTORis can be used to lower the toxicity of CNI therapy or for those at higher risk of rejection, usually in combination with lower-dose CNI therapy. The specific nuances of induction and maintenance therapy decision making are further discussed in the sections below, after the initial review of liver transplant rejection.

Acute and Chronic T Cell-mediated and Antibody-mediated Rejections

Hepatic allograft rejection remains an important cause of morbidity and can lead to graft loss in patients undergoing LT. Major advances in immunosuppressive therapy have significantly lowered the incidence of rejection, and for the most part, the IS required to treat rejection is often more impactful on outcomes than the rejection itself, with the exception being late acute or chronic rejection.2-5 Liver biopsy is mandatory for all types of rejection discussed below and may need to be repeated if biochemical responses are not achieved or other etiologies implicated. Based on the Banff Working Group, T cell–mediated rejection (TCMR) should replace the older terminology of acute cellular rejection, and antibody-mediated rejection (AMR) should replace the older terminology of humoral rejection.6


T cell–mediated rejection is characterized by T-cell infiltrates with fewer populations of other inflammatory cells. Tacrolimus-based IS is more effective at reducing the incidence and severity of TCMR compared with cyclosporine-based therapy and remains the mainstay for initial and maintenance IS therapy. T cell–mediated rejection severity is based on the following1: inflammation intensity and distribution,2 tissue damage extent, and3 direct or indirect signs of vascular/ischemic injury.6,7 Histological grading should be standardized based on the Banff working group on liver allograft pathology6-8: global assessment of the overall rejection grade and a semiquantitative assessment of the 3 main histological characters: portal inflammation, bile duct inflammation/damage, and venous endothelial inflammation. The individual scores are added to produce the overall rejection activity index (RAI): mild (RAI, < 4), moderate (RAI, 4-6), and severe (RAI, > 7-9).

Early TCMR is typically within 90 days of transplant and characterized by inflammatory bile duct damage and pleomorphic portal inflammation, with paucity of interface activity. Incidence is between 10% and 30%, and most studies reveal little impact on graft and patient survival, depending on the era analyzed.2,5 Mild TCMR should be treated by an increase in CNIs with or without addition of other agents (antimetabolites or mTORi); pulse steroid therapy may not be required. Moderate and moderate to severe TCMR should be treated with pulse steroid therapy (typically 500-1000 mg given daily or every other day for 3 doses) with an increase in maintenance CNI and/or other agents if appropriate. Patients who fail to respond, generally on repeat biopsy, or select patients with severe cholestatic TCMR should be treated with lymphodepletional antibody therapy (eg, antithymocyte globulin). T-cell and B-cell subset monitoring can be considered when using thymoglobulin and dose can be increased in absence of adequate response. IL-2 receptor blockers have no role in treatment and there is limited evidence to support the use of alemtuzumab. On balance, most would advocate for resuming opportunistic infection prophylaxis (antiviral, antifungal, pneumocystis carinii pneumonia) for a period similar to after the transplant procedure - 3 to 6 months - in patients given lymphodepleting antibodies or several courses of pulse steroids.

Early TCMR

Recommendation 1.1

Diagnosis of TCMR (early and late) should be based on histological findings. Repeat liver biopsy after treatment is not required in patients with appropriate biochemical response. However, repeat liver biopsy should be considered in patients with suboptimal biochemical response to guide further treatment escalation.

Recommendation 1.2

Treatment of TCMR should be determined by degree of liver injury and histological activity.

Mild TCMR should be treated by an increase in CNI and may not require steroid therapy.

Moderate and moderate-severe TCMR should be treated by an increase in CNI with pulse intravenous steroid therapy followed by a slow oral steroid taper. In selected patients with severe TCMR associated with significant graft injury and cholestasis, antibody-depleting therapy can be considered as a first-line therapy.

Steroid-resistant TCMR should be treated with antibody depleting therapy (anti-thymocyte globulin).

Quality/Certainty of Evidence: High

Strength of Recommendation: Strong

Late TCMR occurs greater than 90 days in 7.5%-23% of liver recipients.2,4 Several studies showed that late TCMR is associated with reduced graft survival.2-4,9 Risk factors include younger age, female gender, autoimmune etiology of liver disease, nonbiologically related donor, prior episode of early TCMR, and noncompliance. Histology can be different than classic TCMR, for example, interface hepatitis, plasma cell infiltrates, and perivenulitis.10,11 Although there may be a correlation between plasma cell hepatitis and the development of alloantibodies, it is unclear if hepatic injury is inflammation or antibody-mediated. Treatment is generally based on the same algorithm used to treat early TCMR (see above). Steroid resistance can be seen in a small percentage, with up to 25% progressing to chronic rejection.2-4,9

Chronic rejection usually evolves from severe or persistent acute rejection and results in potentially irreversible bile duct and/or vascular injury.8 The incidence of chronic rejection is approximately 1% to 5% in adults, but as high as 16% in the pediatric population.12 Risk factors include autoimmune etiology of liver disease, donor/recipient sex mismatch, cyclosporine-based IS, noncompliance, number and severity of TCMR episodes, and retransplantation for rejection.13,14 The minimal diagnostic criteria include: 1. Bile duct loss affecting greater than 50% of the portal tracts or 2. Bile duct atrophy/pyknosis affecting the majority of the bile ducts with or without duct loss or 3. Foam cell obliterative arteriopathy.8 Although there is limited evidence to support a specific immunosuppressive regimen for chronic rejection, a cyclosporine-based regimen should be switched to a TAC-based one.13

Chronic TCMR

Recommendation 1.3

Diagnosis of Chronic TCMR should be suspected in patients with prior history of TCMR, who develop progressive cholestasis that is unresponsive to modifications in the IS regimen. Diagnosis should always be confirmed by liver biopsy.

Treatment of chronic TCMR is difficult. Patients with chronic TCMR who are receiving cyclosporine should be switched to TAC.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong


Although donor-specific antibodies may be seen in nearly 25% of liver transplant candidates and recipients, biopsy-proven AMR is rare (<1% of all and <5% of sensitized patients).15-20 In patients with TCMR not responding to the standard therapy, AMR should be considered.

Utilizing the Banff criteria, a diagnosis of acute AMR requires classic histologic features, C4d (+) vascular staining, circulating DSA, exclusion of other causes and classified as definite, suspicious, or indeterminate.6 Mild acute AMR likely responds to steroid boluses or lymphodepletion therapy used to treat moderate to severe TCMR, which can be coexisting. Moderate to severe AMR should be treated with DSA-depleting strategies, despite a lack of evidence and consensus. The only available data are based on case reports or inferred from the strategies used in nonhepatic transplants, such as plasmapheresis, intravenous immunoglobulin, and anti-B cell or plasma cell agents (ie, rituximab, bortezomib).21-23 Treatment, such as eculizumab aimed at blocking complement, has been described in kidney AMR.24-26

The diagnosis of chronic AMR requires mild-moderate inflammation with low-grade interface activity and fibrosis, (+) C4d staining (may be negative, and this is “possible” chronic AMR), and circulating DSA present in last 3 months.6 However, there is a lack of certainty regarding the diagnosis of chronic AMR given that many of the findings have been noted in biopsies of stable patients with normal liver tests. Evidence on incidence is limited, and there is currently no defined treatment strategy.


Recommendation 1.4

Diagnosis of AMR requires a liver biopsy demonstrating classic histology, C4d (+), circulating DSA, and exclusion of other causes.

Initial treatment of mild, acute AMR should be with steroid boluses.

Treatment of moderate to severe AMR can include plasmapheresis and IVIG with or without anti-B cell agents, such as rituximab, bortezemib, or eculizumab

Chronic AMR has no defined treatment strategy.

Quality/Certainty of Evidence: Moderate

Strength of Recommendation: Conditional

IS in Patients With Metabolic Syndrome

The metabolic syndrome (MetS), widely defined by the modified National Cholesterol Education Program Adult Treatment Panel III,27 is characterized by the presence of central obesity, hyperlipidemia, insulin resistance and hypertension. Metabolic syndrome can worsen or develop de novo after LT. The International Diabetes Federation definition should be considered in Asian patients.28 The risk of developing de novo MetS after LT has been reported to be 33%, 27%, and 40% at 3, 6, and 12 months, respectively.29

The Impact of IS on Metabolic Syndrome

Choice of IS can influence the development of various aspects of the MetS (Table1). Calcineurin inhibitors are associated with hyperlipidemia, hypertension, and diabetes mellitus, steroids are associated with these conditions as well as obesity and mTORis are associated with hyperlipidemia (strong evidence).

The impact of IS on metabolic syndrome

Posttransplant MetS andIS

Recommendation 2.1

Corticosteroids carry significant risk for all components of MetS and should be minimized where possible.

Calcineurin inhibitors, in addition to independently causing renal insufficiency, contribute to post-LT hypertension and dyslipidemia.

Antiproliferatives, (azathioprine and mycophenolate) and antibody-based therapies (basiliximab and thymoglobulin) are neutral with regard to impact on features of post-LT MetS.

Mammalian target of rapamycin inhibitors (mTORi) (eg, everolimus [EVL]) are associated with diminished weight gain, a lower frequency of cardiac events but also with dyslipidemia post-LT. They are neutral with regard to diabetes mellitus (DM) and hypertension (HTN).

Quality/certainly of evidence: Limited-Moderate

Strength of recommendation: Conditional

Considerations in the Management of Obesity

Liver transplant recipients gain 10% to 20% of their weight in the first 6 to 12 months post,30,31 and pre-LT obesity predicts post-LT diabetes mellitus.32 There are limited data on the efficacy of general diet and exercise recommendations or weight loss medications on the prevalence or outcomes of MetS post-LT.33 Sleeve gastrectomy during or after LT, and gastric bypass post-LT appear to be effective in selected patients.34-38 Among bariatric surgery techniques, sleeve gastrectomy has the comparative advantage of not altering IS absorption.

The impact of steroid avoidance or minimization on weight gain post-LT is likely favorable, though evidence has been mixed.39-42 The use of mTORi for CNI minimization or elimination is associated with less weight gain post-LT than standard-dose CNI regimens.43,44


Recommendation 2.2

Exercise and nutritional modifications are cornerstones of managing weight gain after LT.

Specific medical or surgical interventions for post-LT obesity can be considered on an individual basis. Weight loss surgery can be considered in patients with medically complicated obesity resistant to behavioral modification.

Minimizing exposure CNIs and corticosteroids is recommended to mitigate posttransplant weight gain.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong

Considerations in Management of Hyperlipidemia

Dyslipidemia is present in 40% to 66% of post-LT patients. Immunosuppressants (CNI, mTORi, and corticosteroids) can contribute to post-LT hyperlipidemia.45-47 Therefore, yearly fasting lipid panel is recommended in LT recipients. It is important to consider the interaction between HMGCoA reductase inhibitors (statin) and CNIs, as both are metabolized by cytochrome P450-3A4, resulting in increased statin concentrations that may increase the risk of rhabdomyolysis. Statins should be started at a lower dose and gradually titrated. Hydrophilic statins such as fluvastatin and pravastatin are preferred as they are not metabolized by cytochrome P450-3A4 (Table 2).

Important DDI between IS and common medications to treat metabolic conditions

The American Cardiology Association/American Heart Association atherosclerotic cardiovascular disease (ASCVD) risk calculator is recommended to assess risk of ASCVD48 ( followed by selection of appropriate therapy according to risk category.49 Recommendations for managing dyslipidemia post-LT are summarized in Figure 1.45

A stepwise approach to the treatment of dyslipidemia post liver transplantation.


Recommendation 2.3

Screening: Fasting lipid panel should be obtained at 3-6 months, 1 year and annually thereafter post LT. Recommended target LDL-C is <100 mg/dL. Recommended triglyceride levels <250 mg/dL.

Management: All patients with post-LT dyslipidemia should attempt dietary/lifestyle measures. If no improvement within six months, a statin should be added.

Pravastatin is preferred for initial statin therapy due to less interactions with calcineurin inhibitors. Other statins should be started at 50% of recommended dose in patients on CNI and avoided in conjunction with cyclosporine A.

If dyslipidemia develops on cyclosporine A, consider switching to tacrolimus due to decreased severity of drug-drug interactions with statins.

If dyslipidemia develops while receiving mTORi, initially treat with lipid lowering agent. If unable to reach triglyceride goal, then consider mTORi dose-reduction or switching to alternative immunosuppressive agent.

Quality/certainly of evidence: Limited-Moderate

Strength of recommendation: Conditional

Considerations in Management of Diabetes Mellitus

The prevalence of DM pre-LT is approximately 33% 1 year post-LT, with the prevalence of new-onset DM after transplant occurring in up to 26% of patients.50,51 Diabetes mellitus is a major predictor of adverse events, including hepatic artery thrombosis, rejection and mortality.46,52

Pretransplant DM almost always persists and may become more severe after LT. Contributing factors include IS, weight gain and denervation of the liver at transplantation.51 The goals of post-LT DM management are similar to the nontransplant setting, with the exception of HgbA1c target goal of less than 7.0%.51 Lifestyle modifications, such as American Diabetes Association Diet and exercise, are cornerstones of managing DM post-LT.

Tacrolimus and cyclosporine impair insulin synthesis and secretion by beta cells. Corticosteroids can promote insulin resistance via an increase in gluconeogenesis, decreased beta-cell insulin production and peripheral glucose utilization. mTORi can decrease beta-cell proliferation and increase glucose transporter-4 signaling. Early posttransplant hyperglycemia can often be improved by addressing modifiable factors, such as minimization of maintenance IS agents (corticosteroids and CNI). Transplant specific and general facets of medical therapy of DM are presented in Table 3. When high-dose corticosteroids are administered, insulin therapy is the safest and most effective agent for hyperglycemia control. As TAC is more diabetogenic than cyclosporine, conversion might improve glucose control.

Considerations in treatment of diabetes mellitus post-LT

Diabetes Mellitus (DM)

Recommendation 2.4

Screening and Monitoring: Glucose intolerance is very common post-LT. All LT recipients should undergo fasting glucose and HgbA1c measurement, at a minimum, at 3 to 6 months, 1 year and annually thereafter. HgbA1c target goal should be <7.0%, Screening for retinopathy and proteinuria should be performed annually.

Management: A combination of lifestyle modifications and IS minimization, especially corticosteroids, aligned with program protocols is the most important modifiable factors in limiting the impact of post-LT DM. Medical therapy of post-LT DM should be according to standard guidelines (eg, American Diabetes Association guidelines).

Conversion from TAC to cyclosporine-based IS may improve control of diabetes and glucose intolerance.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong

Considerations in Management of Hypertension

Hypertension increases cardiovascular disease, chronic kidney disease (CKD), and the risk of overall death more than 1-year post-LT.46 The prevalence of post-LT hypertension approaches 70%, with blood pressure being particularly abile in the early posttransplant period46,53-55 primarily related to the effects of the CNI through renal vasoconstriction.

The ILTS recommendations on the management of HTN are guided primarily by the presumed mechanism, concomitant diseases, and the recommendations from national joint taskforces for the general population. Table 4 displays the considerations of anti-hypertensive agents in the liver transplant population.

Considerations in the pharmacologic management of hypertension in liver transplant recipient


Recommendation 2.5

Screening and Monitoring: Hypertension is common post-LT. All LT recipients should undergo measurement of resting blood pressure at a minimum, daily for the first month, at 3 to 6 months, 1 year and annually thereafter. The blood pressure goal after LT (not adjusting for age) is less than 130/80 mm Hg.

Quality/certainly of evidence: High

Strength of recommendation: Strong

Management: A combination of lifestyle modifications and IS minimization, especially corticosteroids and CNIs, are the important modifiable factors in limiting the impact of post-LT HTN. Lifestyle measures should include sodium restriction, weight loss and exercise. Medical therapy (see Table 4) is often initiated in conjunction with lifestyle and IS modifications.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong

IS Minimization

Long-term IS management should be aimed at identifying the appropriate drug type(s) and dose that suppresses alloimmune responses while minimizing adverse consequences of IS. The identification of the ideal IS regimen for each individual patient begins at the time of transplantation and is based primarily on the clinical presentation at the time of transplant and the etiology of liver failure. Personalizing IS can be viewed as adjustment of IS protocols that take into consideration recipient characteristics, etiology of primary liver disease and magnitude of alloimmune activation. Immunosuppression minimization strategies are safest when initiated after the first third postoperative month and should, in general, be considered in the context of liver chemistry tests that have been stable for at least 4 weeks preceding the protocol initiation. There is no need for a liver biopsy before starting the IS minimization protocol. If liver chemistry tests become elevated during the protocol, the first step is to return to the previous dose of/or regimen of IS. If the liver chemistry tests remain elevated, liver biopsy is performed to evaluate for late rejection.2,4,56 Overall, clinically guided minimization is possible and safe, whereas the development of biomarkers of immune activation is still in its early stages.

Eligibility forISMinimization

Recommendation 3.1

Patients may be considered for IS minimization protocols, except:

  • (1) those with biopsy proven steroid-resistant rejection,
  • (2) those who are transplanted for immune mediated diseases (initial or re-transplant) and
  • (3) those who had a definitive episode of AMR

Quality/certainly of evidence: Moderate

Strength of recommendation: Conditional

Steroid Discontinuation

By 3 months after liver transplant, most patients should be off corticosteroids. The recommendation is to decrease the dose of corticosteroids slowly with a goal of discontinuation. As mentioned above, in patients at higher immunological risk (eg, immune-mediated diseases), consideration should be given to either maintaining low dose steroids long term or adding AZA, mycophenolate mofetil (MMF) or MPA to facilitate steroid weaning.57

CNI Monotherapy

Patients who had an uneventful first 3 months posttransplant and remain stable are candidates for CNI monotherapy after 3 months.58 In countries where sustained release TAC formulation is not available, compressing the standard dose of TAC and administering the equivalent dose once a day can be considered with the goal of improving compliance. For transplant centers that favor the IS with TAC, the trough TAC level at 3 months should be 6 to 10 ng/mL.59 If cyclosporine is the CNI of choice, the expected level at 3 months is between 150 and 200 ng/mL. From months 3 to 12, the dose of CNI can be decreased slowly while monitoring levels. At the end of the first year, TAC trough levels should be no higher than 5 ng/mL and cyclosporine trough levels no higher than 100 ng/mL. From year 1 onward, the TAC trough levels can be dropped to 3 ng/mL. After year 5, drug levels are less important, and if there is good graft function as evidenced by stable and normal liver chemistry tests, trough levels of TAC just above the lower limit of detection are acceptable. However, complete IS withdrawal should be limited to clinical trials. In patients with posttransplant lymphoproliferative disorder and those with other malignancies postliver transplant, the rate of IS minimization can be accelerated with a goal of using very low doses of IS (see malignancy section below).

Dual to Monotherapy Conversion

A patient on dual therapy should be evaluated for possible switch to monotherapy at any time point post-LT (usually >1 year), assuming low immunological risk and likelihood of benefit from monotherapy. Monotherapy can be with TAC, with a trough level around 5 ng/mL; EVL with a trough level between 3 and 8 ng/mL60; MMF at a dose of 1 g every 12 hours.61,62 The switch to EVL monotherapy, for example, for renal sparing effect, may be done earlier than at 1 to 2 years, keeping in mind the substantial risk of rejection seen in EVL monotherapy conversion studies. It may be preferable to utilize a second maintenance agent, for example, MMF or low dose corticosteroids. In such cases, close monitoring for rejection is recommended. The ILTS recognizes that some centers use sirolimus (SRL) in posttransplant patients. Nevertheless, the consensus group did not make any recommendations for SRL use, given that it is not FDA-approved, and there are other alternatives (EVL) available.

Strategies for Minimization of IS

Recommendation 3.2

Corticosteroids: By 3 months after liver transplant most patients should be tapered off of corticosteroids; those at higher immunological risk (eg, immune-mediated diseases, history of steroid-resistant rejection) should be considered for long-term low-dose steroids or replacement with antiproliferative agents.

Calcineurin Inhibitor monotherapy: All patients who are eligible for minimization of IS are potential candidates for CNI monotherapy after 3 months.

Dual to monotherapy conversion: Patients who are intolerant of CNI monotherapy or at higher immunological risk should be considered for dual therapy with a combination of 2 of the following: CNI, MMF, or EVL. Generally after 1 year, non-CNI monotherapy may be considered in patients at low immunological risk.

Quality/certainly of evidence: Moderate

Strength of recommendation: Conditional

Malignancy and IS

Malignancy is one of the most important complications in liver transplant recipients. The most common cancers are nonmelanoma skin cancer and recurrent hepatocellular carcinoma (HCC), followed by non-Hodgkins lymphoma, lung and renal cell cancer (RCC).63 Patients transplanted for alcoholic liver disease and primary sclerosing cholangitis are particularly at risk.64 There are convincing data in animal and human studies that IS promotes malignancy.65-67 Modulation of IS may alter the development of specific malignancies and the most widely recognized immunosuppressive agents in this category are mTORis which have anti-neoplastic effects.68 In fact, mTOR inhibitors are approved for the treatment of several malignancies including neuroendocrine tumor (NET), advanced RCC, astrocytoma, pancreatic cancer and certain breast cancers. Because of their recognized anti-neoplastic effects, mTOR inhibitors have been extensively studied in the prevention of malignancies common in transplant recipients, namely skin cancer and HCC.

IS and HCC

There is some evidence suggesting that high levels of IS may be associated with higher rates of HCC recurrence. Longer courses of corticosteroids and higher levels of CNIs are associated with an increased risk of recurrence.69,70 Results from retrospective studies suggest that mTOR inhibitors, primarily SRL, reduce HCC recurrence by approximately 50%71-75 and several meta-analyses reiterate these findings.76-78 However, these studies may have been biased by the selection of historical controls whose rate of recurrence was up to twofold higher. Based on these initial promising findings, a randomized controlled trial (RCT) was undertaken to study the effect of SRL on HCC recurrence.79 Five hundred twenty-five liver transplant recipients with HCC were randomized at 4 to 8 weeks after transplant to SRL or non-SRL containing immunosuppressive regimens. Although there was no difference in recurrence-free or overall survival with SRL at study end (year 8), patients within Milan criteria at transplant (lower risk) had higher recurrence-free and overall survival at five years. Whether the same findings would be observed with EVL, which is approved in LT as opposed to SRL, is unknown. Currently, there is an ongoing RCT evaluating the effect of EVR on HCC recurrence in patients whose disease is over Milan criteria on explant.44

IS and Skin Cancer

Early observations reported significantly less squamous cell skin cancer in kidney transplant recipients on SRL. These observations led to 4 RCTs which reported an approximately 50 % reduction in the recurrence of nonmelanoma skin cancer in patients with previous skin lesions, mostly prior SCCa.80-83 These results have been confirmed in meta-analyses.84,85

IS and Other Malignancies

Because posttransplant malignances are so problematic, pretransplant candidates are actively screened for malignancies and affected patients are often disqualified from transplantation. As a result, studies measuring the impact of IS on these other cancers require large cohorts of patients primarily drawn from registry analyses and meta-analyses of large registration trials.63,84,86 These reports have shown no overall benefit of mTOR inhibitors in preventing other malignancies. Although there is a higher rate of prostate cancer in recipients on mTOR inhibitors, the clinical significance and explanation for this observation are not clear. Because EVR has demonstrated efficacy against NET and RCC, recipients with either of these tumors may benefit from EVR-based IS.87,88

IS and Malignancies

Recommendation 4.1

HCC: Beyond generally minimizing overall IS, the optimal IS strategy for minimizing the frequency and severity of recurrence of HCC, including the use of mTOR inhibitors, has not been determined

Skin cancers (SCCa): There is evidence that SRL reduces the risk of nonmelanoma skin cancer recurrence in kidney transplant patients. Whether the same effects occur with EVL, which is approved in LT, is not known but seems likely.

Non-HCC, non-SCCa malignancies: There is no direct evidence that mTOR inhibitors prevent other (nonskin, non-HCC) malignancies in liver transplant recipients, although patients with NET or RCC may benefit from EVL-based IS.

Quality/certainly of evidence: Moderate

Strength of recommendation: Conditional

IS in Pediatric Liver Transplant Recipients

Management of IS in the pediatric liver transplant (PLT) population presents several unique challenges compared to adults due to variations in growth and development, disease states, adherence, and risks of long-term exposure to IS. Differences in pediatric pharmacokinetics, route of administration, medication formulation, and sensitivity to medication toxicities further complicate management. Despite the lack of robust studies, consensus guidelines on the management of IS are needed for this population.89,90

Initial IS in PLT Recipients

Review of the centers enrolled in the Studies for Pediatric Liver Transplantation revealed that more than 90% use TAC, a CNI, as primary IS.91 Tacrolimus is generally preferred over cyclosporine as the latter has increased nephrotoxicity, can cause hirsutism and gingival hyperplasia and may have less bioavailability related to the bilio-enteric anastomosis commonly used in children.92,93 Most high-volume pediatric LT programs will start TAC on postoperative days 0 to 1 in combination with intravenous steroids. A third of international centers utilize induction therapy with either IL-2 receptor antagonists or antithymocyte globulin.94 With induction therapy, TAC administration can be delayed until postoperative days 3 to 5, particularly if renal sparing is required due to perioperative renal dysfunction.95 The use of induction has also been shown in small randomized European studies to reduce exposure to corticosteroids, which are associated with growth retardation, osteoporosis, hypertension, and diabetes.96,97

Maintenance IS in PLT Recipients

Calcineurin inhibitors provide highly effective maintenance IS after LT. Optimal TAC trough concentrations, based on international centers surveyed, are 10 to 12 ng/mL at 0 to 3 months, 6 to 8 ng/mL at 3 to 6 months, and approximately 5 ng/mL after 6 months.98,99 Corticosteroids should be weaned within the first 12 months if appropriate.97,100 Studies have shown that bone density is not always affected by the use of low doses.101 Data on low-dose chronic prednisone for prevention of graft fibrosis is controversial. The goal of most centers is to reach TAC monotherapy at 1 year after pediatric LT.58 Most centers surveyed have set strict goals and monitoring if IS is even more aggressively minimized.97,102

Therapeutic Drug Monitoring in Pediatric LT

Multiple factors affect trough concentrations in children including age, route of administration, medication formulation, graft function, medication interactions, and intestinal motility.103 The current standard of care for therapeutic drug monitoring (TDM) of CNI therapy is to obtain trough concentrations at steady state (approximately 3-4 doses or 2-3 days). mTOR inhibitor TDM should also include trough concentrations at steady state, 5 to 7 days for SRL and 2 to 3 days for EVL. Weight-based doses of mycophenolate without TDM have produced excellent safety and efficacy. When TDM of MPA is performed, MPA-AUC is much more reliable than MPA troughs although difficult to perform in clinical practice.98 Research in pharmacogenomics and immune assays will likely play an important role in the future of pediatric drug dosing and monitoring.97

Modification of IS Based on Primary Disease

More aggressive induction regimens after transplant may be warranted for patients at higher immunological risk, for example, ABO-incompatible organs, retransplantation for rejection, or positive crossmatch if even performed. In contrast, centers often avoid aggressive induction for patients who currently or previously had malignancy or those in acute liver failure.104,105 Antiproliferative agents, such as mycophenolate or azathioprine in combination with a CNI, are used in some centers for patients with autoimmune liver disease or multi-visceral organ transplants. These agents may also facilitate more aggressive steroid or CNI reduction.106 The use of mTOR inhibitors as putative antineoplastic agents has been described for patients with posttransplant lymphoproliferative disorders and other malignancies, such as hepatoblastoma.107,108

Optimization of Adherence

Adherence to IS regimens is always an issue of central importance in pediatric transplantation, requiring the child's and caregiver's cooperation and commitment.109 Deliberate or unintentional nonadherence to medications can include errors in frequency, dose, or timing required. Adherence can be assessed by patient/family report, refill and pill count assessment, and the medication level variability index, an assessment of deviation from standard trough levels. Depression, posttraumatic stress disorder, child abuse, impulsivity and inattention, poor family functioning, and lack of social support may contribute to nonadherence and are best addressed by mental health and social service professionals.110 Mode of delivery, palatability, cost, frequency, and timing of medication administration, male sex, nonwhite race/ethnicity, and the adolescent period can also play a role in nonadherence.111,112

Adherence should be continuously addressed with open communication encouraged. Physicians should ask patients in a nonjudgmental way about how often they miss doses, whether they experience side effects, and whether they understand the benefits of taking the medications. Awareness of modifiable psychosocial and financial risk factors might guide earlier interventions.113-115 Instructions to maximize adherence should be coherent and practical. Simple dosing and cues to remind patients to refill and take medications can improve adherence. Other interventions including a token reinforcement system, incentives, teacher or nurse reminders, organized pillboxes, the use of Disease Management Assistance System, and personalized cell phone alarms/text messages has been shown to improve medication adherence and the incidence of rejection.116,117

IS in Pediatric Recipients

Recommendation 5.1

TAC is the CNI of choice for initial and maintenance IS after pediatric LT.

Antibody induction therapy: If antibody induction therapy is used immediately after LT, initiation of CNI therapy can be delayed, typically for up to 5 days. Antibody induction therapy followed by immediate CNI and antiproliferative agents may be warranted for patients at high immunological risk.

mTOR inhibitors may have a role in patients with a history of prior or current malignancy.

Maintenance IS should, when possible, be with TAC monotherapy without corticosteroids after the first year, weighing the risk of rejection.

Adherence to immunosuppressant therapy should be discussed openly at all points of contact with the patient and caregivers, and the use of technology to provide reminders should be considered in clinical practice.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong

IS in Patients With Renal Insufficiency

Definition and Assessment of Kidney Function in Liver Transplant Candidates and Recipients

Diagnosis and staging of acute kidney injury (AKI) in patients with liver disease should be guided by Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine (Scr) criteria.118-120 Chronic kidney disease is defined as abnormalities of kidney structure (albuminuria, abnormal urine sediment, renal histology and/or renal ultrasonography) or decreased glomerular filtration rate (GFR) present for ≥ 3 months.121 CKD should be classified by severity according to the Kidney Disease Outcomes Quality Initiatives (K/DOQI) (Table 5). While SCr values are used for initial evaluation of kidney function, they should be interpreted with caution in patients with transplant patients due to their tendency to overestimate GFR, especially in patients with malnutrition and fluid overload. Future research is needed to develop estimated GFR (eGFR) equations and biomarkers of renal injury in pre- and post-LT patients.

From KDIGO clinical practice guideline for the evaluation and management of CKD4

Assessing Renal Function

Recommendation 6.1

Before transplantation the MDRD-6 equation should be used to derive an eGFR.

After the third postoperative month MDRD-4, 6 or CKD-EPI equation should be used to derive an eGFR.

GFR-derived equations should be used cautiously for assessment of kidney function in this patient population, since they tend to overestimate GFR. Additional tests, such as measured GFR, should be considered when eGFR equations based on Scr are less accurate.

Quality/certainly of evidence: High

Strength of recommendation: Strong

Frequency and Impact of Renal Insufficiency Before and After LT

Kidney dysfunction occurs in 50% of outpatients with decompensated cirrhosis and 20% to 25% of hospitalized patients.122 The incidence of mortality, infections and cirrhosis-specific complications increases with severity of AKI.123 At the time of transplantation, 20% to 25% have eGFR less than 30 mL/min per 1.73 m2.124,125 The incidence of AKI after LT ranges from 17% to 94%.126 Severe AKI and the need for renal replacement therapy have been associated with increased mortality posttransplant.126,127 Causes of AKI are related to perioperative events, such as hemodynamic instability, ischemia-reperfusion syndrome,128 primary dysfunction of the graft, the use of nephrotoxic medications and vena cava clamping.129 After LT, the cumulative incidence of CKD ≥ stage 3 ranges from 36% to 57%129-132 and ≥ stage 4, 5% to 25%.133,134 Subjects with CKD ≥ stage 4 have an increased risk of death parallel to their kidney function.134-136 The cumulative incidence of post-LTx CKD at 5 years in patients with model for end-stage liver disease < 20 and in those with model for end-stage liver disease > 20 at LT was 17% and 37% respectively.136

Immunosuppressive therapy with CNIs has been the major cause of CKD post-LT. Other additional factors related to lesions preexisting before transplant (membranoproliferative glomerulonephritis, diabetes mellitus, IgA nephropathy, acute tubular necrosis) or acquired in the peri-operative period. Kidney biopsies are uncommonly performed after LT and generally show lesions such as focal segmental glomerulosclerosis, thrombotic microangiopathy, or related to diabetes mellitus and the use of CNI therapy and hydroxyethylstarch.137

Initial IS in Patients With Renal Insufficiency

Early Postoperative Period

CNI-based regimens are associated with a decrease of renal function ranging from 13% to 33% according to whether the CNI is administered alone or in combination with antimetabolite or induction therapy.130,138-144 In the 2 largest RCTs (The Respect and the Diamond studies), induction therapy with an anti-interleukine-2 receptor (anti IL-2R) in combination to MMF, with either an initial low dose of prolonged-released TAC or delayed introduction of TAC or prolonged-released TAC until day 5, was associated with significant improvement of renal function at 6 to 12 months.138,145

In the absence of combination therapy with MMF/MPA, the trough levels generally used in RCT during the first month posttransplant range from 8 to 15 ng/mL. In more recent trials using an induction therapy and/or combination with MMF, TAC trough levels during the first month range from 6 to 8 ng/mL with a similar rate of rejection.138,141 In one study, the use of intravenous MMF followed by switch to oral form was associated with a low risk of rejection.146 A meta-analysis of 2 RCTs138,141 for renal impairment (n = 712) showed that reduced TAC trough concentrations (<10 ng/mL) within the first month after LTx were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69] compared with conventional TAC trough levels (>10 ng/mL).99

Early trials with SRL use in the immediate postoperative period were associated with high incidence of hepatic arterial thrombosis, graft loss, and death and this lead to an FDA “black box” warning for its use in de novo LTx recipients.147 Similarly Belatacept, a selective costimulation blocker, has not been approved for liver transplant recipients for similar reasons.142 Despite the use in few centers of low dose mTORis to facilitate TAC reduction during the first week posttransplant, the benefit/risk of a very early initiation of mTORis is still under investigation.

Is in the peri-operative period to optimize renal function

Recommendation 6.2

Induction therapy (interleukin-2 receptor antibodies or short-term of antilymphocyte/thymocyte antibody preparations) combined with cortiosteroids and MMF/MPA and reduced dose or delayed initiation of CNIs is associated with superior renal function and less need for renal replacement therapy than early initiation and standard dosing of CNIs.

mTORis should be avoided in the first postoperative month.

Quality/certainly of evidence: Moderate

Strength of recommendation: Strong

Medium and Long-term Postoperative Periods

There is no strict definition but when taking into consideration immunosuppressive medication changes in trials, the medium-term could be considered between 1 and 6 months posttransplant and the long term, 1 year or longer. No data are available on the impact of modification of immunosuppressive regimens between 6 and 12 months posttransplant. Cautious screening, monitoring and treatment of risk factors that could affect renal function should be taken into account in addition to modification of the immunosuppressive regimen following KDIGO clinical guidelines.121

Randomized controlled trials that have used mTOR inhibitors for CNI sparing are shown in Tables 6 and 7. De novo use of SRL was associated with increased risk of hepatic arterial thrombosis, graft loss and infection without clear benefit on renal function. In the H2304 pivotal trial, a CNI sparing regimen that used EVL (EVL) with target trough levels of 3 to 8 ng/mL, introduced at 28 days posttransplant, and low dose TAC (trough levels below 5 ng/mL) was compared to a TAC arm with standard exposure. EVL plus reduced TAC showed significant improvement of renal function out to 3 years posttransplant, with very low risk of rejection, despite a higher discontinuation rate in the EVL plus reduced TAC arm.148-150 Similar data were shown in the PROTECT multicenter RCT.151,152

Renal function by stage of kidney disease at various timepoints in 1508 liver transplant patients from 15 centers13
Main reported RCTs on the use of mTOR inhibitors after LT according to early or late conversion for EVL and sirolimus respectively

Two main mTOR inhibitor studies with renal function as a primary endpoint tested a CNI-free strategy beyond 1 month and compared SRL + MMF153 and EVL + MPA154 to a control group treated with TAC + MMF/MPA. The use of mTORis plus MMF/MPA groups was associated with a beneficial effect on renal function but a moderate increase risk of rejection rate (10-12%). In the H2304 study, EVL (monotherapy) arm with TAC withdrawal at month 4 was terminated early because of increased risk of rejection (~20%). However, if performed, trough levels of mTOR inhibitors should be 5 ng/mL or higher in CNI-free regimen.149,154,155

Optimizing renal function in the early postoperative period

Recommendation 6.3

Early institution at one month of EVL in combination with low dose TAC (≤5 ng/mL) results in a significantly better renal function than is achieved with standard dosing of TAC. This strategy is particularly beneficial in patients with CKD >/= stage 3 (eGFR <60 mL/min per 1.73 m2).

Quality/certainly of evidence: High

Strength of recommendation: Strong

Long-term IS in Recipients With CKD (>1 year)

Several RCTs and uncontrolled studies that aimed to introduce MMF and either reduce CNI by at least 50% or withdraw CNI completely have been recently summarized.126,137 Introduction of MMF/MPA and reduction of CNI was associated with a modest renal improvement and low risk of rejection rate (3.5%).126,156 Introduction of MMF/MPA and withdrawal of CNI was associated with significant renal improvement (increase of eGFR by a mean of 8.3 mL/mn) but also with an increased risk of acute rejection (3-30%).157 Therefore MMF/MPA monotherapy should be initiated with caution and on a case by case basis.

Outcomes after conversion to mTOR inhibitors beyond 1 year in patients with established CKD have been associated with variable outcomes (Table 6). The 2 main RCTs that compared either SRL beyond 6 months158 or EVL beyond 1 year159 to a CNI regimen failed to demonstrate significant improvement in renal function. Retrospective studies have reported a modest improvement with a low risk of rejection.160,161 Overall, the likelihood of prolonged renal function stabilization or improvement after mTOR conversion has not been demonstrated. Therefore, mTOR inhibitors are not generally recommended after 1 to 2 years.

Optimizing renal function in the late (>1 year) postoperative period

Recommendation 6.4

CNI minimization should attempted in patients with CKD in the late postoperative period.

Late (≥1 yr) conversion to mTORis is of unclear effect on renal function, particularly in patients with CKD ≥ 3.

Quality/certainly of evidence: Moderate

Strength of recommendation: Conditional

Simultaneous Liver and Kidney Transplantation

In patients with simultaneous liver kidney transplantation (SLK), acute cellular rejection and AMR rates are reasonably low.162-164 However, liver allografts may not be fully protective of the renal allograft, especially with preexisting MHC class II DSA.165 In a series of 140 SLK recipients with long-term follow-up, borderline cellular, acute cellular, antibody-mediated, and chronic kidney rejection occurred in 11.4%, 6.4%, 1.4% and 0.7% patients, respectively.162 Acute cellular and chronic liver rejections were diagnosed in 11.4% and 2.9% patients respectively. Taner et al also reported that SLK, when compared to kidney transplantation alone, is associated with reduced chronic cellular (OR : 0.13, 95%CI 0.06-0.27) and antibody-mediated alloimmune injury (OR : 0.11, 95% CI 0.03-0.32) in the kidney allograft.166 In 56 SLK patients, Leca et al167 analyzed positive flow cytometry crossmatches and/or the presence of high levels of donor-specific antibodies and found that sensitization did not have a significant negative impact on the survival.

Analysis of the Scientific Registry of Transplant Recipients database showed that less than 20% of patients undergoing SLK received lymphocyte-depleting agents as induction, even among sensitized recipients.168 In other reports, high-risk recipients with panel-reactive antibody greater than 10% against HLA class I and class II or patients with a positive crossmatch received induction with either an anti IL-2 receptor antagonist or antithymoglobulin. Induction allowed avoidance of steroids and delayed introduction and minimization of CNI therapy.169

In a meta-analysis of RCT, the use of MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation.170 The benefit of MMF in SLK transplantation is not known but likely extrapolated from the kidney alone literature. The use of mTORs to reduce the risk of reduction of cytomegalovirus (CMV) disease and de novo malignancies is common in kidney alone transplantation. No data are available on the use of mTORs in patients with SLK transplantation.171-173

Combined liver and kidney transplant recipients

Recommendation 6.5

Induction therapy, for example, with antithymocyte globulin, can be considered in highly sensitized patients (positive crossmatch, high DSA MFI levels) who undergo SLK to reduce the risk of acute rejection. Induction therapy may also be recommended in patients with delayed renal graft function to delay and/or minimize CNI use.

CNIs, ideally TAC, in combination with corticosteroids and mycophenolate, is recommended for maintenance IS in SLK recipients.

Quality/certainly of evidence: Moderate

Strength of recommendation: Conditional

Future Directions

Unfortunately, several classes of other agents that have had some success and development in non-LT, for example, costimulatory blockade agents, janus-activated kinase inhibitors, protein kinase C inhibitors, have failed to prove both safe and effective in early trials in liver recipients. Thus, the current and near future of IS in liver transplant recipients still relies on better optimization of current therapies that are effective but need to be personalized further, as described in this document. The real future may be in cell therapies, such as regulatory T cells and mesenchymal stem cells, that may allow for minimization or withdrawal of our existing agents, rather than develop and test new ones. This tolerogenic aspect of LT supports the further development of personalized therapies to ensure protection against both immune injury and IS toxicity.


The ILTS also gratefully recognizes the contributions from the following members of the ILTS Consensus Immunosuppression Guidelines workgroups: Mark Boschert, MD, Intermountain Medical Center, Salt Lake City, UT, USA; Ilka Boin, MD, State University of Campinas, Brazil; John Renz, MD, University of Chicago, Chicago, IL, USA; Kelly Birdwell, MD, Vanderbilt University, Nashville, TN, USA; George Therapondos, Ochsner Clinic, New Orleans, LA, USA; Mark Boschert, MD, Intermountain Medical Center, Salt Lake City, UT, USA; Diana Alonso, MD, Intermountain Medical Center, Salt Lake City, UT, USA; Richard Gilroy, MD, Intermountain Medical Center, Salt Lake City, UT, USA; Srinivas Titte, MD, Intermountain Medical Center, Salt Lake City, UT, USA; Hani Wadei, MD, Mayo Clinic Florida, Jacksonville, FL, USA; Mitra Nadim, MD, University of Southern California, Los Angeles, CA, USA; Jain Ashokkumar, MD, Penn State University, Hershey, PA, USA; Amar Mahgoub, MD, University of Minnesota, Minneapolis, MN; and Tamir Miloh, MD, Texas Children’s Hospital, Houston, TX, USA.

The authors would like to acknowledge the contributions of panelists at the ILTS consensus meeting.

The authors appreciate the support of the ILTS Executive Committee and the organizational support of Debbye Todd.


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