Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group.

TL;DR: In this article, the authors provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year.

Abstract: Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

Summary

Modifiable Risk Factors for Graft Loss Posttransplantation

• The survival is less than an age-matched cohort from the general population.
• 32-34 In both kidney and liver transplant recipients, modifiable risk factors for graft failure over the longer term include issues related to immunosuppression, such as nonadherence,35 underimmunosuppression,36 toxicity and adverse effects related to immunosuppression,37 and high intrapatient variability (IPV) in immunosuppressive exposure.
• This list of risk factors is not exhaustive.
• Other factors that may have an impact on graft or patient survival include recurrence of initial disease.

Existing Clinical Guidance for Long-Term Management in Transplantation

• There are several national and international guidelines outlining approaches to improve both kidney and liver graft outcomes.
• Implementation of some of the recommendations has been shown to improve outcomes; for example, implementation of the predefined donor management goals defined by the United Network for Organ Sharing (UNOS) has resulted in a significant decrease in the incidence of DGF in those cases where the donor management goals were met.43.
• In addition, cardiovascular prediction models and risk calculators to predict the risk of developing cardiovascular complications posttransplant are being introduced in the clinic and their use may allow introduction of targeted interventions that will reduce morbidity and mortality.
• 44 However, comprehensive, standardized methods to identify, screen and manage potentially reversible risk factors for graft failure and patient death are lacking in many of the current guidelines, as discussed below.
• Furthermore, with the increasing number of surviving allograft recipients, many are being followed in nontransplant centers and by HCPs who may not be as familiar with current best practice as those working in transplant units.

Objectives and Aims of COMMIT

• COMMITwas formed in 2015 to provide expert practical guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks of poor graft and patient survival posttransplant.
• The COMMIT expert group comprises 20 leading kidney and liver transplant specialists from 9 countries across Europe.

Recommendations

• The recommendations are intended to complement, rather than replace, local guidelines.
• To increase the clinical utility and accessibility of the recommendations, the authors have created a checklist (Appendices 2 and 3) that could be used as an aide-memoire for the professionals looking after these patients.
• Specific recommendations have not been provided on immunosuppression regimens or the investigation and management of abnormal graft function.
• These guidelines focus on major modifiable risk factors that improve long-term outcomes after liver and kidney transplantation in adults.
• If the patient becomes unwell, graft function deteriorates, changes medication, then the review should be more frequent.

METHODS

• The COMMIT program featured 2 organ-specific working groups (kidney and liver).
• Eachworking groupwas further divided intoworkstreams to develop the recommendations for each of the modifiable risk factors in parallel.
• Aworkstream lead was appointed to oversee the development of the practical recommendations and to facilitate consensus within the respective workstreams.
• All members of the COMMIT program reviewed and provided feedback on all sections of the guidance report as part of a Delphi study, as described below.

Literature Review

• A literature review was conducted to gain an understanding of current posttransplant clinical practices and to identify the key gaps in the available guidance related to the practical management of modifiable risk factors in posttransplantation care.
• MEDLINE and Google Scholar databases, and resources from international transplant societies were searched for kidney and liver transplantation guidelines using varying search terms including kidney transplant guidelines, liver transplant guidelines, kidney transplant recommendations, liver transplant recommendations.
• The original search was conducted between August 7, 2015, and September 10, 2015, and was restricted to English language articles; the guidelines included were published between 1999 and 2015.
• The search results were filtered according to relevance for kidney or liver transplantation and for guidance posttransplantation.
• A summary document, or “concept paper,” was created based on the results of the literature review to focus and inform initial discussions on the concept and content of the recommendations.

Development of Practical Recommendations Using a Modified Delphi Approach

• A modified Delphi approach was used to reach agreement and validate the practical clinical recommendations.
• A preliminary meeting of all authors was held on December 9, 2015, to discuss the results of the literature review and the Delphi-like online survey.
• In the second survey, COMMIT group members were asked to review the first draft of the guidance report, and to state their level of alignment with the content included.
• The results of the second Delphi-like survey included responses from 18 COMMIT members.
• The evidence supporting each recommendation was evaluated and graded according to the Oxford Centre for Evidence-Based Medicine system .50.

Limitations of Methodology

• The use of any evidence ranking system, such as the OCEBM, for patient management recommendations should be carried out with clinical judgment as forethought.50.
• This method identifies current medical opinion, and is not an alternative to rigorous clinical trials, where evidence is lacking.
• AGENTS AS A MODIFIABLE RISK FACTOR FOR POOR OUTCOMES IN LIVER AND KIDNEY TRANSPLANTATION.

Problem to be Addressed

• DGF is a common early complication associated with higher risk of EAD and biliary strictures (BS), increased hospital stay and/or hospital readmission, inferior graft and patient survival, and increased costs.
• Anastomotic BS can usually be managed endoscopically; this approach is more difficult and less successful in patients with nonanastomotic BS.
• Up to 50% of patients with nonanastomotic BS, and in particular diffuse intrahepatic BS, are not amenable to endoscopic or surgical treatments.
• The incidence of EAD in liver transplant recipients ranges from 21% to 25%377; the incidence of nonanastomotic BS is 0.5% to 10% and these account for 10% to 25%of all strictures complicating liver transplant.

Risk factor Examples

• Sociodemographic factors Adolescence, senior patient age (eg, when cognitively impaired) Lack of social support Non-white race Patient-related factors Previous nonadherence Disturbing side-effects Barriers: busy lifestyle, interruption of daily routine Forgetfulness Inadequate health beliefs History of substance abuse Treatment-related factors 55,60.
• There are several studies on the recipients’ perspectives of medicine-taking.
• Massey et al61 found that in kidney transplant recipients, despite reporting a high degree of perceived necessity and had relatively few concerns about their immunosuppressive regimen, nonadherence increased significantly over a period of 18 months.
• Furthermore, it has been reported that nonadherence may be a contributing factor to graft loss in 36% of kidney transplant recipients.
• Understanding the factors associated with nonadherence contributes to risk assessment, and could aid the development of preventative and remediating interventions.

Multilevel Risk Factors for Nonadherence: Call for Multilevel Adherence Interventions

• Nonadherence is the result of many interacting factors, and can be tackled at different levels of the healthcare system.73 Established multilevel risk factors for nonadherence include sociodemographic factors, treatment- and conditionrelated factors, healthcare teams, and system-related factors.
• Patient-level interventions for nonadherence to immunosuppressive regimens55,82,83,86,93,95.

Patient-level interventions Examples

• Training patients during inpatient recovery on how to take medications .
• Based on this, the authors suggested a shift in focus towards provider-related and system-related factors.

Identification of Nonadherent Transplant Recipients

• Accurate recognition of patients who are nonadherent is often difficult, so effective tools for identifying at-risk patients are very important.
• Some of the available tools/methods for identifying nonadherent patients are shown in Figure 6.

Strategies for Managing Nonadherence

• Identification of patients at risk for nonadherence could be initiated by routinely and systematically assessing medication adherence as the “fifth vital sign” (integrated into the electronic medical record) along the transplant continuum.
• 82,83 Transplant follow-up care based on principles of chronic illness management, in which support for patient self-management for adherence to an immunosuppressive regimen is integrated, resulted in higher levels of adherence and/or improved clinical and healthcare utilization parameters in 2 renal transplant studies.
• There is convincing evidence that a simplified immunosuppressive regimen might benefit all patients, regardless of their susceptibility to nonadherence.
• 95 Nonadherence increases among adolescents, young adults, and with senior patient age, signifying that these patient subgroups may require specific attention.
• In summary, a combination of different interventions may be the most effective strategy in enhancing patient self-management and adherence to medication, and ultimately improving outcomes posttransplant.

Recommendations for Managing Nonadherence in Kidney Transplantation

• (Level 3) ◯ Assess the patient’s previous ability to adhere to therapeutic regimens ▪Tools include the Immunosuppressant TherapyAdherence Scale (ITAS), simplified medication adherence questionnaire (SMAQ), Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) (https://www.uea.ac. uk/pharmacy/research/imab-q/quest), Basel Assessment of Adherence to Immunosuppressive Medication Scale questionnaire (available on request from the developers), or other validated self-report questionnaires ◯.
• Trough levels of relevant immunosuppressive drugs should be regularly monitored (at least every 3 months when the patient is stable) to assess for medication nonadherence; in particular, unexplained high IPV and unexpected fluctuations in immunosuppressant trough levels, despite a fixed dose, should prompt a discussion with the patient about the importance of drug adherence.
• Use specific assays (eg, single-antibody bead assay) to monitor the development of de novo DSAs (also refer to recommendations in DSA section of this document) ▪.
• Discuss any suspicion of nonadherence openly and nonjudgmentally with the patient.
• Together with the patient, identify his/her current barriers to adherence and develop a personalized action plan with specific solutions, for example, pill boxes, reminder systems, education and psychological behavioral support.

Recommendations for Managing Nonadherence in Liver Transplantation

• (Level 3) ◯ Assess the patient's previous ability to adhere to therapeutic regimens ▪Tools include the Immunosuppressant TherapyAdherence Scale (ITAS), simplified medication adherence questionnaire (SMAQ), Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) (https://www.uea.ac.uk/ pharmacy/research/imab-q/quest), Basel Assessment of Adherence to Immunosuppressive Medication Scale questionnaire (available on request from the developers), or other validated self-report questionnaires 2.
• Trough levels of relevant immunosuppressive drugs should be regularly monitored (at least every 3 months when the patient is stable) to assess for medication nonadherence; in particular, unexplained high IPV and unexpected fluctuations in immunosuppressant trough levels, despite a fixed dose, should prompt a discussion with the patient about the importance of drug adherence.
• (Level 3) ◯Assess the patient’s social support network and emotional and mental status (eg, using available questionnaires) ◯ (Level 2) ◯ Discuss nonadherence with patients, and on indication, ask patients to complete a questionnaire 6.
• Together with the patient, identify his/her current barriers to adherence and develop a personalized action plan with specific solutions, for example, pill boxes, reminder systems, education and psychological behavioral support.

Slightly Modifiable Contributors to

• They are classified according to their detectability and the ease with which they can be modified by clinicians and/or patients.
• Nonmodifiable factors will not be discussed here because they are hard to detect and/or impossible to control in daily practice.
• In kidney transplantation, the impact is likely to be limited given the intrinsic pharmacokinetics of tacrolimus (ie, liver metabolism and bile excretion), although supporting literature is lacking.
• Hypoalbuminemia and anemia may alter the distribution of tacrolimus by increasing its circulating free fraction, leading to significant variability and increased exposure.

Highly Modifiable Contributors to Variability

• Diet content and interactions with other drugs (or some herbal products) may be the focus of patient education.
• Drugs that interfere with CYPmetabolism are able tomodify tacrolimus exposure when used simultaneously, and sometimes have a clinically significant impact.

Determinants of IPV of tacrolimus103,120,121,123,124

• Any clinical situation motivating liver graft dysfunction 145,146 However, the first-generation protease inhibitors, telaprevir and boceprevir, and the combination ombitasvir/paritaprevir/ritonavir+/−dasabuvir, have a major impact on tacrolimus metabolism, increasing tacrolimus trough concentrations exponentially; therefore, these drugs should be avoided whenever possible.
• There appears to be insufficient evidence to provide reassurance that, in transplanted patients, generics are therapeutically equivalent to innovator immunosuppressants.
• The conversion from twice-daily to prolonged-release tacrolimus , both in kidney and liver transplant recipients, leads to lower blood trough concentrations and a reduced IPVof tacrolimus.

Recommendations for Managing IPV in Kidney Transplantation

• Regular assessment of the serum trough concentrations of the immunosuppressivemedication ismandatory (every3months or when there is an unexplained change in graft function), even in patients who are stable in the long term and are taking a constant dosage.
• Potential problems with drug adherence should be discussed with patients in whom tacrolimus trough concentrations fluctuate more than expected, despite a stable dose.
• Generic substitution should only be carried out if subsequent substitutions from one generic to another generic will not be attempted.
• Low tacrolimus trough levels will increase the risk of TCMR, even in the presence of CNI-associated renal impairment.
• Therefore, low levels of tacrolimus/underexposure should be avoided.

Recommendations for Managing IPV in Liver Transplantation

• (Level 1) 2. CNI trough levels should be assessed once every 2 or 3 days within the first 15 days after liver transplant, weekly from week 2 to week 4, monthly until the sixth month after liver transplant, and every 3 months thereafter.
• Avoiding significant variability, particularly large fluctuations in tacrolimus trough concentration early after liver transplant, is strongly recommended, as these are associated with inferior outcomes.
• Drug–drug interactions should be anticipated and/or avoided.
• Any treatment modification should motivate checking for potential interactions and more frequent assessment of trough levels.

The Basis for CNI-Sparing Regimens

• Over the last 10 years, there has been a strong move in the renal transplant community to minimize CNI-based immunosuppressive regimens, largely based on reports of longterm nephrotoxicity.
• The risk of chronic renal failure associated with the use of a CNI increased with a cyclosporine regimen compared with tacrolimus therapy (overall relative risk 1.24 [1.17-1.30]).
• In clinical practice, whole blood trough levels have generally been in the range of 5-20 ng/mL in liver transplant recipients and 10-20 ng/mL in kidney transplant patients in the early posttransplant period.

Evidence for CNI-Minimization Strategies

• In kidney transplantation, studies have failed to show long-term benefits for transplant recipients on CNI-free regimens.
• At the 3-year follow-up, these differences had reduced over time and were often not significant.
• In the first year after liver transplant, underimmunosuppression (tacrolimus levels <3 ng/mLa or cyclosporine levels <75 ng/mL) is associated with an increase in de novo DSA formation.

Large meta-analysis of

• DIAMOND study (multicenter, 24-week, randomized study) 857 liver transplant recipients Patients were treated with: – Prolonged-release tacrolimus (initial dose 0.2 mg/kg/day) +.
• In clinical practice, whole blood trough levels have generally been in the range of 5-20 ng/mL in liver transplant recipients and 10-20 ng/mL in kidney transplant patients in the early posttransplant period.
• Complete immunosuppression withdrawal has shown to be feasible in approximately 20% of carefully selected liver transplant recipients.

Strategies for Prevention of Underimmunosuppression

• Higher risk patients include those who188: Are sensitized from previous blood transfusions or previous transplant .
• Had successive pregnancies Present with HLA-DR mismatch Panel reactive antibody (PRA) above 0%, and preformedDSAs Younger age at time of transplant Recipients of black ethnicity A standardCNI protocol is generally advisable in these patients,188 with target trough levels of tacrolimus between 5 and 10 ng/mL and concomitant use of azathioprine, mycophenolate or corticosteroids.
• In liver transplantation, although it is easier to reverse the effect of underimmunosuppression compared with the adverse effects of overimmunosuppression, defining and adhering to the appropriate target levels for immunosuppressive regimens should remain a priority.
• There is also a strong unmet need for pharmacodynamic biomarkers that reflect the biological effect of the immunosuppressive regimen to guide dosing in individual patients.
• It is important to take into account that the “how low can you go” immunosuppression considerations of the past 10 years,160 have now shifted toward the need to maintain immunosuppression at a certain minimum level.

Recommendations for Managing Underimmunosuppression in Kidney Transplantation

• Determine pretransplant risk factors and immunological risk status for each patient before transplantation.
• (Level 1) Pretransplant risk factors, including patients with a “higher risk” immunological risk status188 Sensitized from previous blood transfusion(s), previous transplant, or pregnancies HLA mismatch (particularly HLA-DR mismatch) PRA >0% (HLA antibodies) Preformed HLA-DSA Younger age at time of transplant Consider the following: (Level 2 or Level 3) ◯.
• For higher risk patients, consider induction therapy (Level 1) ◯.

Recommendations for Managing Underimmunosuppression in Liver Transplantation

• Take into account both the risks and the benefits to each individual patient when determining their immunosuppressive regimen and optimal trough levels.
• Original liver disease, overall status (age, nutritional status, tumor history, infection status, etc.) and transplant history (other organ transplantation, causes of graft loss), also known as Consider the following.
• For combination therapy where tolerability/toxicity is an issue, lower tacrolimus trough levels are acceptable.
• Maintenance steroids are generally unnecessary for the avoidance of TCMR in liver transplantation.

Overimmunosuppression and Infection

• Invasive fungal infection is associated with high morbidity and mortality in liver transplant recipients,229,230 with candidiasis, aspergillosis and cryptococcosis respectively being the most common fungal infections.
• It is important to S22 Transplantation ■ April 2017 ■ Volume 101 ■ Number 4 www.transplantjournal.com screen liver transplant candidates, if admitted to the intensive care unit (ICU) pretransplant, for fungal colonization, to determine whether targeted pretransplant or posttransplant antifungal prophylaxis is required.

Overimmunosuppression and Cancer

• De novo neoplasms are one of the most common causes of late mortality in liver transplant patients (cumulative incidence of 34.7% at over 15 years postliver transplant versus 8.9% in the nontransplanted population), and typically associated with male sex and patients aged >34 years.
• The most common malignancies directly related to immunosuppression are nonmelanoma skin cancers and PTLD (Table 6).239 TABLE 6.
• Risk factors associated with common malignancies postliver tra.

Cancer type

• Head and neck or lung cancers Colorectal carcinomas Table based on data from Chak and Saab, 2010.239 Patientswith a history of alcohol abuse and smoking have a high risk of upper gastrointestinal, oropharyngeal-laryngeal and lung cancers.
• In liver transplantation, accepted tumor surveillance options include yearly colonoscopies in patients with PSC and IBD, as well as annual skin examinations in all patients.
• There is some evidence that a link exists between the use of CNIs and renal impairment postliver transplant.
• Induction therapy with reduced or delayed initiation of prolonged-release tacrolimus capsules combined with MMF and basiliximab 2.

Metabolic Syndrome

• Metabolic syndrome is highly prevalent after liver transplantation, with an incidence of 50% to 60% in liver transplant recipients.
• Conversion from CNIs to mTORi increases the incidence of diabetes mellitus and arterial hypertension postliver transplant.
• In patients with persistent BK viremia and increasing proteinuria and/or deterioration of renal function, a renal biopsy is indicated to confirm pathology.
• Prevention and screening for cancer should follow the same recommendations as for the general population (eg, gynecological, breast, prostate or colon cancer screening).
• (Level 4) Recommendations for theManagement andPrevention of Adverse Effects Related to Immunosuppression in Liver Transplantation 1.

Slightly Modifiable or Nonmodifiable Contributors to DSA Occurrence

• The age of the recipient (younger, usually <50 years) has been identified as a risk factor for de novo DSAs— potentially attributable to nonadherence.
• Early TCMR has been linked with the risk of development of de novo DSAs.

Cause of de novo DSA Study

• Reduction or discontinuation of CNI therapy Registry studies published by Opelz et al report that dose reduction or discontinuation of cyclosporine, tacrolimus, or MPA were associated with reduced graft survival compared with full-dose regimens CNI-free mTORi-based immunosuppression.
• Figure 11 highlights the slightly/ nonmodifiable contributors to DSA formation.

Highly Modifiable Contributors to DSA Occurrence

• Reduction or discontinuation of CNI therapy, CNI-free mTORi-based immunosuppression, and nonadherence to treatment are well-established risk factors for the occurrence of de novo DSAs (Table 7).20,270 Nonadherence to immunosuppression is a major risk factor for the formation of DSAs.20.
• There are many reasons for nonadherence, including side effects and the complexity of treatment (pill numbers, frequency of dosing).
• 11 More effective educational programs, better engagement of younger recipients, and use of long-acting parenteral immunosuppressive therapies and once-daily drugs can be used to reduce the complexity of immunosuppressive regimens and improve adherence.
• The long-term use of belatacept significantly reduces the risk of de novo DSAs compared with cyclosporine A–based immunosuppression.
• Conversion from twice-daily tacrolimus to once-daily prolonged-release tacrolimus capsules intake has significantly improved adherence to therapy, as assessed by electronic monitoring of drug intake.95.

DSA assessment postkidney transplantation

• Risk level Risk factor High-risk patients Recipients with preexisting DSAs Intermediate-risk patients Patients who have history of DSAs but are negative for DSAs at transplantation Low-risk patients Nonsensitized patients receiving a first kidney trans Table based on data from Tait 2013.274 tacrolimus.
• The authors are not aware of any prospective comparison of belatacept and tacrolimus regimens on the development of DSAs.
• To achieve these goals,minimization strategies and complex immunosuppressive regimens should be avoided.

Detection of DSAs

• DSA assessment should be done using solid-phase immunoassay technology.
• The reactivity of DSA should be determined, and strength of reactivity expressed as mean fluorescence intensity (MFI).
• In low-risk patients with stable kidney function, although there are no robust data to support systematic screening for DSAs, it is done in some centers at least once in the first 3 to 12 months after transplantation.
• At least moderate portal/periportal, sinusoidal and/or perivenular fibrosis 2.

AMR Postliver Transplant: Histopathological Definitions

• Histopathological evidence of diffuse microvascular endothe- lial cell injury and microvasculitis 3.
• Strong and diffuse C4d positivity in allograft tissue (if available) 4.
• Reasonable exclusion of other causes of injury that might re- sult in similar histological findings A recent report from the Banff group also proposes the following criteria (Table 9) for diagnosis of active chronic AMR in the liver allografts.

Prevalence and Impact of Preformed DSAs on Graft Function and Patient Survival

• Pretransplant DSA positivity with potential clinical significance has been tentatively defined as MFI ≥5000, but standardization is still needed.
• Recent data suggest that activation of complement is observed more frequently with DSA MFIs greater than 10000.278 Data from 3 studies have shown an increased risk of early acute rejection in patients with pretransplant DSAs,277,279,280 including in patients with a very lowMFI.

Prevalence and Impact of De Novo DSAs on Graft Function and Patient Survival

• De novo DSAs had a negative impact on both graft and patient survival, reducing 5-year survival rates by 6% to 7%.
• Predictors of de novo DSA development included cyclosporine-based immunosuppression (versus tacrolimus) and lowCNI trough levels.
• In an update, presence of IgG3 antibodies, antibody-fixing complement (C1q) and de novo DSAs with MFI greater than 5000 were found to be associated with an increased risk of mortality.
• Another area in which DSAs can impact on graft function is liver fibrosis posttransplant.

Recommendations for Managing DSAs in Kidney Transplantation

• Routine screening for DSAs is neither universally available nor implemented in all centers.
• Low immunosuppression and protocols aimed at minimizing CNI-based immunosuppression (eg, low-dose CNI or CNIfree therapies) are high-risk factors for the development of de novo DSAs; the risk of these regimens should be balanced with the potential benefit to the patient.
• Refer to nonadherence section of this document.
• Solid-phase immunoassay technologies, such as the singleantigen bead assay, are able to identify DSAs not readily detected using other methods, and are, therefore, favored over other DSA detection methods.
• In intermediate-risk patients (such as those who have a history of DSAs but are negative for DSAs at transplantation), DSAs should be monitored within the first month ◯.

Recommendations for Managing DSAs in Liver Transplantation

• Routine screening for DSAs is neither universally available nor implemented in all centers.
• Firm conclusions with regard to the effect on outcomes cannot be drawn in the absence of any proven therapy.
• Screening for DSAs is encouraged before any attempt to strongly minimize immunosuppression.
• Corticosteroids in cases where the histological pattern is suggestive of de novo autoimmune hepatitis with positive DSAs ▪.
• In patients whose liver function tests are normal over the long term, screening for DSAs at 1, 5 and 10 years postliver transplant is proposed.

CVD in Kidney and Liver Transplant Recipients

• Registry data show that CVD accounts for 18% to 30% of premature deaths among kidney transplant recipients,292 and almost 40% of kidney transplant recipients experience a S28 Transplantation ■ April 2017 ■ Volume 101 ■ Number 4 www.transplantjournal.com CVE in the first 3 years posttransplant.
• In a UK registry study, cardiovascular and cerebrovascular events, combined, were the leading cause of death (22.9%) in the first year postkidney transplantation, accounting for more deaths than infection (21.6%).302 Data from observational studies suggest particularly high frequencies of CVEs during the first few months after kidney transplantation.
• When a wider composite cardiovascular end point was assessed (including atrial fibrillation [AF], HF, and pulmonary embolism) the event rate was 8% and 11% at 30 and 90 days after liver transplantation, respectively.

Risk Factors for CVEs in Kidney and Liver Transplant Recipients

• In general, risk factors for CVEs, for both kidney and liver transplant recipients, can be present before transplantation and posttransplantation.
• Incidence of metabolic disorders in liver and kidney transplant re Metabolic disorder % of liver transplant recip.

Metabolic syndrome 44-58%

• Diabetes 2.5-25% 40-60% (HCV-infected liver transpla Dyslipidemia 45-69% Hypertension Up to 70% for CVEs include conventional demographic (and nonmodifiable) factors, such as age (young age in kidney transplantation and older age in liver transplantation), sex, race, preexisting conditions, such as diabetes, ischemic heart disease, duration of dialysis for kidney transplant recipients, smoking and general patient health .289,292,313,314.
• Posttransplant risk factors for CVEs include NODAT, hypertension, impaired glucose tolerance,288,289,292,315 impaired kidney function295,316 and posttransplant hyperglycemia .317,318 289.
• Other nonclassic CVE risk factors (anemia, proteinuria, number of episodes of graft rejection, reduction in allograft function) have also been identified in kidney transplant recipients.
• Anemia has been shown to be an independent risk factor for de novo congestive heart failure, and for allcause and cardiovascular mortality.
• In liver transplantation, diabetes has also been linked with long-term CVD,307 with duration of diabetes, but not hypertension or hyperlipidemia, shown to be an independent predictor of long-termmortality due to the combination of CVE, recurrent HCV, and infection.

Managing Cardiovascular Risk After Transplantation

• In general, modifiable risk factors for CVE after transplantation should be targeted and proactively managed to improve patient outcomes.
• Routine monitoring for CVE risk TABLE 11.
• Factors in kidney and liver transplant recipients should be performed every 3 months in the first year of transplantation and then annually after the first year.
• Transplant recipients at risk of developing cardiovascular complications should be managed according to established guidelines.

Diabetes

• Frequent monitoring of plasma glucose levels is recom- mended, particularly soon after transplantation and in patients receiving high-dose steroid treatment for acute rejection.
• This should be done at least every day during the first postoperative week, during treatment with highdose steroids and at least 3-monthly during the first year.
• A study by Choi and Kwon338 demonstrated the incidence of NODAT is higher in patients receiving tacrolimus (25%) compared to patients receiving cyclosporine (9.5%) (P < 0.001).
• Glucose-lowering agents used in kidney transplant patients with.

Class Drug

• New-onset diabetes *Potential increase in the levels of cyclosporine, tacrolimus and mTORi.
• CYP, cytochrome P450; DDP-4, dipeptidyl peptidase-4. should mirror that of the general population, and follow these guidelines.
• The management of NODAT should also include modification of immunosuppression in kidney transplant patients; specifically, the minimization and possible withdrawal of corticosteroids, with the option to switch from tacrolimus to cyclosporine.

Hypertension

• Analyses of patients from the CTS database suggest that control of systolic blood pressure (BP) may be associated with improved graft, patient, and CVD-free survival.
• The KDIGO guidelines recommend a target of 130/80 mm Hg301; however, the evidence for specific BP targets is still lacking.
• The changes in immunosuppressive drugs include CNI minimization, conversion from cyclosporine to tacrolimus, the use of CNI-free immunosuppressive regimens and avoiding steroids.

Lifestyle Changes

• Educating patients in lifestyle changes, such as including exercise into their daily/weekly routine, cessation of smoking and alcohol consumption, is important to minimize the risk of cardiovascular complications posttransplant.
• The benefit of exercise should be emphasized as this can lead to improvements in activity levels, overall health and the ability to perform daily tasks.

Liver Transplantation

• In 2013, the American Association for the Study of Liver Diseases published a practice guideline for the long-term management of recipients after a liver transplant; key points from this guidance are included in the TABLE 13.
• These recommendations were based on relevant published information with the aim of improving the long-term outcomes in adult liver transplant recipients.

Recommendations for Managing CVD Complications in Kidney Transplantation

• Ensure that patients undergo regular monitoring for risk factors for CVE after transplantation (eg, BP, lipids [at 2-3 months after transplantation and at least annually thereafter], plasma glucose levels, HbA1c every 6 months after the first postoperative year).
• Insulin therapy is the best choice during high-dose steroids administration (eg, antirejection therapy); however, recipients with new-onset diabetes mellitus should be preferably treated with oral hypoglycemic agents before insulin-based maintenance therapy is considered ▪.
• Metformin or sulfonylureas may be used in kidney transplant recipients with normal renal function ▪.
• Educate patients on the benefits of lifestyle modification and provide support in achieving these goals (such as dedicated nurse practitioners).

Recommendations for Managing CVD Complications in Liver Transplantation

• Screen high-risk patients (chronic smokers, older than 50 years, or a clinical or family history of CAD or diabetes) preoperatively to establish risk factors for CVE (dobutamine stress echocardiography, followed by cardiac catheterization in case of abnormal findings).
• The combination of diuretics with other classes of antihypertensive medication may be effective in some liver transplant patients ◯Hyperlipidemia: the target LDL cholesterol level is dependent on the patient’s cardiac risk level; the target of 3.4 mmol/L (130 mg/dL) should be reduced to 2.6 mmol/L (100 mg/dL) or 1.8 mmol/L (70 mg/dL) for those with increasing risk ▪.
• In cases of refractory hyperlipidemia: consider changes in immunosuppression – Conversion from cyclosporine to tacrolimus – CNI reduction (eg, substitute with mycophenolate) – Replacing sirolimus with other agents 5.
• Educate patients on the benefits of other lifestyle changes, such as cessation of smoking and alcohol consumption.
• (Level 5) EARLY ISCHEMIC INJURYAND DGF IN KIDNEY.

Prevention of Early Ischemic Injury and DGF in Kidney Transplantation

• With the marked negative impact of DGF on graft and patient survival, UNOS has released recommendations to optimize the hemodynamic stability of a transplanted graft using a variety of predefined donormanagement goals (Table 14).43,365.
• The implementation of these strategies in clinical practice reduces the risk of DGF by approximately 50%.43.
• UNOS region 5, donor management goals in kidney transplantation.

Parameter Goal

• Central venous pressure 4-10 mm Hg Ejection fraction >50% Vasopressors ≤1 and low dose*.
• Blood glucose <150 mg/dL Urine output 0.5-3 mL/kg per hour over 4 h Mean arterial pressure 60-100 mm Hg Recommended donor management goals to raise organ yield per donor.
• A first single case report in humans performed by Hosgood et al in 2011 and a larger case series in 2013 demonstrated the feasibility of normothermic machine perfusion for the preservation of the kidney graft before transplantation.
• Other areas of research include findings from a retrospective analysis that suggest combined hormonal resuscitation (methylprednisolone, vasopressin, and triiodothyronine/Lthyroxine) increases the yield of recovered organs.
• These assessments of risk for DGF may be useful tools in clinical practice in order to select those patients who may benefit most from new techniques and pharmaceutical interventions.

Considerations Potential interventions

• Cold ischemia time (the period between cold flush in the donor and graft implantation in the recipient) should be kept as short as possible, particularly for higher risk livers (DCD, steatosis) .
• Whether this strategy (‘relax and repair’ instead of ‘rush and retrieve')383 is also valid in liver transplantation is still to be confirmed.
• 32 A recent meta-analysis has also confirmed that the University of Wisconsin and Celsior preservation solutions result in similar outcomes, including rates of EAD.392.
• In a study of hypothermic machine perfusion in 31 adults receiving livers from donors with a high KDPI, EAD was lower in this group (19%) compared to the static cold storage control group (30%), with significantly less biliary complications (4 vs 13; P = 0.016).397.
• With advances in the understanding of the etiology of nonanastomotic BS, machine perfusion may be best placed to provide a better protective effect during donor liver preservation.

Potential Risk Factors Associated With EAD and Nonanastomotic BS After Liver Transplantation

• Liver transplantation studies have highlighted the risk factors for EAD and nonanastomotic BS (Table 16).
• Modifying these risk factors and preventing organ damagemay improve results in liver transplantation and widen its application by increasing the pool of organs suitable for transplantation.

Recommendations for Managing EAD and Nonanastomotic BS in Liver Transplantation

• EAD and nonanastomotic BS should be prevented by targeting all the factors related to all stages of liver transplantation, from preretrieval of the organ, through to procurement, preservation of the organ, and posttransplantation.
• Donor pretreatment with corticosteroids should be standard.
• Cold ischemia time (the period between cold flush in the donor and graft implantation in the recipient) should be kept as short as possible, particularly for higher-risk livers (DCD, steatosis, etc).
• Bile duct should be abundantly and properly flushed during and at the end of the procurement.
• Multi-interventional strategies (simultaneously targetingmul- tiple pathways) will have to be tested for the prevention of IRI.

CONCLUSION AND CALLTO ACTION

• Patient and graft outcomes continue to improve in the short-term postkidney or postliver transplant, with survival rates now at over 80% at the 1-year mark.
• Improving the maintenance of grafts and health of patients would not only improve quality of life, but would also reduce the need for retransplantation and thus increase the number of organs available for transplant.
• Modifiable risk factors influencing the longer-term maintenance of the graft and patient include nonadherence, IPV, underimmunosuppression, adverse effects due to immunosuppression, DSAs, and cardiovascular and metabolic complications.
• Some strategies to manage risk are already available, and should be part of the standard of care for patients, and some are still in development.
• It will also lead to improved use of immunosuppression, which will promote tolerance and reduce or even abolish the need for long-term treatment with immunosuppressive agents, and so reduce associated adverse effects.

Figures

FIGURE 4. Causes of late allograft loss in liver transplant recipients. Diabetes, hypertension, hyperlipidemia, high variability and nonadherence to immunosuppressive agents are modifiable risk factors. Figure based on data from Hübscher 2011, Bekker 2009, O’Leary 2014, Supelana 2014, Charlton 2013 and Kamar 2008.26-31

TABLE 7. Highly modifiable risk factors for de novo DSAs20,270,273

TABLE 8. DSA assessment postkidney transplantation

FIGURE 9. Infections in solid organ transplant recipients. The timeline of infections after organ transplantation. The risk for infection after organ transplantation follows a standard pattern with routine immunosuppression and infectious exposures. The potential pathogens for which the risk is modified by prophylaxis, including vaccinations and antimicrobial agents, are indicated (*). Individual risk is modified by events such as surgery, treatment of graft rejection, or malignancy. Note that graft rejection and drug reactions may be among noninfectious causes of fever in transplant recipients. JC virus, John Cunningham virus; HSV, herpes simplex virus. Modified with permission from the author; reprinted with permission from Fishman JA. Opportunistic infections – coming to the limits of immunosuppression? Cold Spring Harb Perspect Med. 2013;3:1–14; original source of data: Fishman J. Infection in solid-organ transplant recipients.N Engl J Med. 2007;357:2601–2614. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.195,205

FIGURE 12. Risk factors for CVE after kidney transplantation. Pretransplant and posttransplant factors conferring increased cardiovascular risk after kidney transplantation. CHF, congestive heart failure; CV, cardiovascular; LVH, left ventricular hypertrophy; PTDM, posttransplantation diabetes mellitus. Reprinted with permission from Stoumpos S, Jardine AG, Mark PB. Cardiovascular morbidity and mortality after kidney transplantation. Transpl Int. 2015;28:10–21.292

FIGURE 10. Screening and management of kidney transplant recipients for BKV replication and PVAN. BKV, BK virus; EM, electron microscopy; IVIG, intravenous immunoglobulin. Reprinted with permission from Hirsch HH, Randhawa P. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013;13(Supp. 4):179–188.211

FIGURE 6. Identification of risk factors in nonadherent transplant recipients. Grey boxes represent methods of measurement/assessment of nonadherence, and white boxes are warning signs for the nonadherent patient. Figure based on data from Prendergast 2010, Pabst 2015, Denhaerynck 2005 and Dobbels 2010.55,77-79

TABLE 4. Determinants of IPV of tacrolimus103,120,121,123,124

TABLE 15. Considerations for managing early ischemic injury and DGF in kidney transplantation43,365,369,373

TABLE 5. Results of studies investigating CNI-free/minimization regimens161,176-178

FIGURE 5. Modified Delphi approach.

FIGURE 8. DIAMOND study design. *0 to 1000mg IV bolus corticosteroid (preoperatively, intraoperatively, or postoperatively) on day 0. Arm 2 only: if the patient had not received treatment for an acute rejection episode and the last recorded trough level recorded was ≥5 ng/mL at day 43, then the dose was reduced by 20% to 25%. IV, intravenous. Reprinted with permission from Trunecka P, Klempnauer J, Bechstein WO, et al. Renal function in de novo liver transplant recipients receiving different prolonged-release tacrolimus regimens—the DIAMOND study. Am J Transplant. 2015;15:1843–1854.178

FIGURE 1. 1- to 10-year graft and patient survival rates after kidney transplantation.*1-year and cumulative 5- and 10-year age-adjusted kidney graft survival rates calculated for 2005 to 2008 by period analysis; †Survival probabilities were adjusted for age, sex and cause of end-stage renal disease (data shown in figure for period 2004-2008); ‡Data from 2007 to 2011 period not shown in figure. Figure based on data from Gondos 2013 and Kramer 2016.3,5

FIGURE 2. 1- to 10-year graft and patient survival rates in liver transpla Registry: www.eltr.org/Evolution-of-LTs-in-Europe.html4 (Accessed July

TABLE 17. Considerations for managing EAD and nonanastomotic BS in liver transplantation32,384,387,388,392,395,397-402

FIGURE 3. Causes of late graft loss in kidney transplant recipients. Figur Lefaucheur 2010, Koenig 2016, Valenzuela 2013, Siedlecki 2011 and P

Full text

University of Birmingham
Practical Recommendations for Long-term
Management of Modifiable Risks in Kidney and
Liver Transplant Recipients
Neuberger, James; Bechstein, Wolf O; Kuypers, Dirk R J; Burra, Patrizia; Citterio, Franco; De
Geest, Sabina; Duvoux, Christophe; Jardine, Alan G; Kamar, Nassim; Krämer, Bernhard K;
Metselaar, Herold J; Nevens, Frederik; Pirenne, Jacques; Rodríguez-Perálvarez, Manuel L;
Samuel, Didier; Schneeberger, Stefan; Serón, Daniel; Truneka, Pavel; Tisone, Giuseppe; van
Gelder, Teun
DOI:
10.1097/TP.0000000000001651
License:
Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)
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Publisher's PDF, also known as Version of record
Citation for published version (Harvard):
Neuberger, J, Bechstein, WO, Kuypers, DRJ, Burra, P, Citterio, F, De Geest, S, Duvoux, C, Jardine, AG, Kamar,
N, Krämer, BK, Metselaar, HJ, Nevens, F, Pirenne, J, Rodríguez-Perálvarez, ML, Samuel, D, Schneeberger, S,
Serón, D, Truneka, P, Tisone, G & van Gelder, T 2017, 'Practical Recommendations for Long-term Management
of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the
Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group', Transplantation, vol. 101, no.
4S, pp. S1-S56. https://doi.org/10.1097/TP.0000000000001651
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Practical Recommendations for Long-term
Management of Modifiable Risks in Kidney
and Liver Transplant Recipients: A Guidance
Report and Clinical Checklist by the Consensus
on Managing Modifiable Risk in Transplantation
(COMMIT) Group
James M. Neuberger, MD, FRCP,
1
Wolf O. Bechstein, MD, PhD,
2
Dirk R.J. Kuypers, MD, PhD,
3
Patrizia Burra, MD, PhD,
4
Franco Citterio, MD, FEBS,
5
Sabina De Geest, PhD, RN,
6,7
Christophe Duvoux, MD, PhD,
8
Alan G. Jardine, MD, FRCP,
9
Nassim Kamar, MD, PhD,
10
Bernhard K. Krämer, MD,
11
Herold J. Metselaar, MD, PhD,
12
Frederik Nevens, MD, PhD,
13
Jacques Pirenne, MD, MSc, PhD,
14
Manuel L. Rodríguez-Perálvarez, MD, PhD,
15
Didier Samuel, MD, PhD,
16
Stefan Schneeberger, MD,
17
Daniel Serón, MD, PhD,
18
Pavel Trunečka, MD, PhD,
19
Giuseppe Tisone, MD,
20
and Teun van Gelder, MD, PhD
21
Abstract: Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival
rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of re-
cipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase
the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient mod-
ifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.
COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across
Europe. The group’s remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with
the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.
The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and
best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first post-
operative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by
offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
(Transplantation 2017;101: S1–S56)
Received 14 October 2016. Revision received 21 December 2016.
Accepted 6 January 2017.
1
Liver Unit, Queen Elizabeth Hospital Birmingham, United Kingdom.
2
Department of General and Visceral Surgery, Frankfurt University Hospital and
Clinics, Germany.
3
Department of Nephrology and Renal Transplantation, University Hospitals
Leuven, Campus Gasthuisberg, Belgium.
4
Department of Surgery, Oncology, and Gastroenterology, Padova University
Hospital, Padova, Italy.
5
Renal Transplantation Unit, Department of Surgical Science, Università Cattolica
Sacro Cuore, Rome, Italy.
6
Department of Public Health, Faculty of Medicine, Institute of Nursing Sci-
ence, University of Basel, Switzerland.
7
Department of Public Health, Faculty of Medicine, Centre for Health Services and
Nursing Research, KU Leuven, Belgium.
8
Department of Hepatology and Liver Transplant Unit, Henri Mondor Hospital
(AP-HP), Paris-Est University (UPEC), France.
9
Department of Nephrology, University of Glasgow, United Kingdom.
10
Department of Nephrology and Organ Transplantation, CHU Rangueil, Université
Paul Sabatier, Toulouse, France.
11
Vth Department of Medicine & Renal Transplant Program, University Hospital
Mannheim, University of Heidelberg, Mannheim, Germany.
12
Department of Gastroenterology and Hepatology, Erasmus MC, University
Hospital Rotterdam, the Netherlands.
13
Department of Gastroenterology and Hepatology, University Hospitals KU
Leuven, Belgium.
14
Abdominal Transplant Surgery, Microbiology and Immunology Department,
University Hospitals KU Leuven, Belgium.
15
Department of Hepatology and Liver Transplantation, Reina Sofía University
Hospital, IMIBIC, CIBERehd, Spain.
16
Hepatobiliary Centre, Hospital Paul-Brousse (AP-HP), Paris-Sud University,
Université Paris-Saclay, Villejuif, France.
17
Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical
University, Austria.
Supplement
Transplantation
■
April 2017
■
Volume 101
■
Number 4 www.transplantjournal.com S1

S
olid organ transplantation has evolved from an experi-
mental procedure to an established treatment option
for many types of end-stage organ failure. Both patient and
graft outcomes are continuing to improve, and 1-year patient
and graft survival currently exceed 80%.
1,2
However, sur-
vival rates gradually decline over the long term. In kidney
transplant, 5- and 10-year graft survival rates in Europe are
77% and 56%, and for liver transplant, 64% and 54%
(Figures 1 and 2).
3,4
Although most European countries have seen an increase
in both living and deceased donation, transplantation is not
available to all who would benefit from the procedure, and
there is considerable morbidity and mortality for those
listed for transplant.
6
Therefore, maximizing long-term
graft survival and reducing the need for retransplantation
is paramount, not only in improv ing outcomes for the re-
cipients but also for those awaiting a graft. The improve-
ment in outcomes is predominantly due to reduction in
18
Nephrology Department, Hospital Vall d’Hebrón, Autonomous University of
Barcelona, Spain.
19
Transplant Center, Institute for Clinical and Experimental Medicine (IKEM), Prague,
Czech Republic.
20
Department of Experimental Medicine and Surgery, University of Rome Tor
Vergata, Italy.
21
Department of Hospital Pharmacy and Internal Medicine, Erasmus MC, the
Netherlands.
Disclosure and contributions: The concept of the Consensus On Managing
Modifiable risk In Transplantation (COMMIT) program arose from feedback
following the Astellas Pharmaceutical Europe Ltd-sponsored meeting ‘Advancing
Transplantation: New questions, New possibilities’ held at the Karolinska Institute
in Sweden in January 2015 (Transplantation. 2017;101:S1–S41). The authors
were approached by Astellas to discuss the practical implementation of evidence
and discussion from the meeting related to managing modifiable risk factors in
posttransplantation care.
COMMIT is an expert-led program. The authors formed a “consensus group” which
met at various times over a period of approximately 1 year to discuss the
development of a practical guidance document. Led by chairs, James Neuberger,
Wolf Bechstein and Dirk Kuypers, the group developed their own content for their
meetings, with editorial support from iS Health. Astellas had input into the
selection of the program members and the appointment of iS Health to support
the program. Astellas Pharma Europe Ltd has provided support in the form of
funding for the meeting expenses, secretariat services by iS Health, and
placement of the supplement (guidance report and checklist) in the journal
selected by the authors.
Expert comments and guidance provided in this supplement are based on the
clinical experience and independent opinion of the authors, and reference
published clinical trial data. Previously unpublished data that could not be
included, due to existing embargo policies or to protect intellectual property, have
been excluded from this guidance document. The unpublished data in this
document were included at the discretion of the authors as personal
communications. All authors had final editorial authority over the content and
approved the final version of this supplement before submission. Astellas has had
no influence or input into the content development of the document.
Astellas Pharma and associated companies developed, manufacture and supply
tacrolimus (tacrolimus hard capsules (Prograf™), tacrolimus prolonged-release
hard capsules (Advagraf™)). Prescribing information can be found on page S54.
Advagraf is not licenced for patients receiving allogeneic liver transplants in the
United States. Discussions of tacrolimus dosing protocols unsupported by the
Advagraf license recommendations are included based on the clinical opinion of
the authors and referenced to published data.
J.M.N. reports nonfinancial support from Astellas during the development of this
supplement; nonfinancial support and personal fees from Astellas, Novartis,
Intercept, Roche, outside of the submitted work. D.R.J.K. reports nonfinancial
support from Astellas during the development of this supplement; nonfinancial
support and personal fees from Astellas, Novartis, Roche, Pfizer, BMS, Chiesi,
Polyphor, Alexion, Opsona Therapeutics; grants from Astellas, Novartis and
Roche, outside of the submitted work. W.O.B. reports nonfinancial support from
Astellas during the development of this supplement; nonfinancial support and
personal fees from Amgen, Astellas, Celgene, Dansac, Integra, Johnson and
Johnson, LifeCell, Medupdate GmbH, Merck Serono, Novartis, Pharmacept,
Roche; grants from Astellas, Baxter, Novartis, Pfizer, outside of the submitted
work. P.B. reports nonfinancial support from Astellas during the development of
this supplement; nonfinancial support and personal fees from Astellas, Novartis,
Kedrion, Grifols, Biotest, Gilead, Alfa Wassermann, outside of the submitted work.
F.C. reports nonfinancial support from Astellas during the development of this
supplement; nonfinancial support and personal fees from Astellas, Novartis, BMS,
outside of the submitted work. S.D.G. reports nonfinancial support from Astellas
during the development of this supplement; grant support from Astellas, Novartis,
Roche and Sanofi, outside of the submitted work. C.D. reports nonfinancial support
from Astellas during the development of this supplement; nonfinancial support and
personal fees from Astellas, Novartis, Chiesi; grants from Astellas, Novartis and
Roche, outside of the submitted work. A.G.J. reports nonfinancial support from
Astellas during the development of this supplement; nonfinancial support and per-
sonal fees from Astellas, Amgen, Novartis, Genzyme, Relypsa, AstraZeneca,
Boehringer Ingelheim, Bayer, Opsona Therapeutics; grants from Novartis, outside
of the submitted work. N.K. reports nonfinancial support from Astellas during the de-
velopment of this supplement; nonfinancial support and personal fees from Astellas,
Amgen, Novartis, Roche, Neovii, Sanofi; grants from Astellas, Novartis, outside of
the submitted work. B.K.K. reports nonfinancial support from Astellas during the de-
velopment of this supplement; nonfinancial support and personal fees from Amgen,
Astellas, Bayer, BMS, Chiesi, Hexal, Opsona Therapeutics, Pfizer, outside of the
submitted work. H.J.M. reports nonfinancial support from Astellas during the devel-
opment of this supplement; nonfinancial support and personal fees from Astellas,
Novartis, Intercept, Biotest; grants from Astellas, Biotest, Gilead, outside of the sub-
mitted work. F.N. reports nonfinancial support from Astellas during the development
of this supplement; nonfinancial support and personal fees from Centrale Afdeling
Fractionering (CAF), Intercept, Gore, BMS, Abbvie, Novartis, MSD, Janssen-Cilag,
Promethera Biosciences, Ono Pharma, Durect, Gilead; grants from Roche, Astellas,
Ferring, Novartis, Janssen-Cilag, Abbvie, outside of the submitted work. J.P. reports
nonfinancial support from Astellas during the development of this supplement;
nonfinancial support and personal fees from Astellas; grants from Astellas, Roche,
Centrale Afdeling Fractionering (CAF), Institut Georges Lopez (IGL), outside of the
submitted work. M.L.R.-P. reports nonfinancial support from Astellas during the de-
velopment of this supplement; nonfinancial support and personal fees from Astellas,
Novartis; grants from Astellas, outside of the submitted work. D.S. reports
nonfinancial support from Astellas during the development of this supplement;
nonfinancial support and personal fees from Astellas, Novartis, Biotest, Abbvie, Gil-
ead, Intercept, MSD, LFB; grants from Astellas, Novartis, Gilead, outside of the sub-
mitted work. S.S. reports nonfinancial support from Astellas during the development
of this supplement; outside of the submitted work: fees for Expert Groups/Advisory
Boards from Astellas, Novartis, Teva, Sandoz; fees for Steering Committees:
Astellas; unrestricted grants from Koehler Chemie, Novartis, Roche, Sandoz; travel
support: Astellas, Novartis, Roche, BMS. D.S. reports nonfinancial support from
Astellas during the development of this supplement; nonfinancial support and per-
sonal fees from Astellas, Novartis, Teva; grants from Astellas, Novartis, Teva,
Diaverum, outside of the submitted work. P.T. reports nonfinancial support from
Astellas during the development of this supplement; nonfinancial support and per-
sonal fees from Astellas, Novartis, Pfizer, outside of the submitted work. G.T. re-
ports nonfinancial support from Astellas during the development of this
supplement. T.vG. reports nonfinancial support from Astellas during the develop-
ment of this supplement; nonfinancial support and personal fees from Astellas,
Chiesi, Novartis, Teva; grants from Astellas, Chiesi, outside of the submitted work.
Correspondence: James M. Neuberger, MD, FRCP, Liver Unit, Queen Elizabeth
Hospital Birmingham, United Kingdom. (jamesneuberger@hotmail.co.uk).
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. All rights
reserved. This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided it is prop-
erly cited. The work cannot be changed in any way or used commercially without
permission from the journal.
ISSN: 0041-1337/17/10104-01
DOI: 10.1097/TP.0000000000001651
TX/16/0018/APEL March 2017.
S2 Transplantation
■
April 2017
■
Volume 101
■
Number 4 www.transplantjournal.com

early graft loss and patient death, better surgical and anes-
thetic skills, technological innovations, improved donor
and recipient management, and the advent of newer and
more effective immunosuppressive agents.
7
Despite the im-
provement in survival rates, attention is now becoming
more focused on improving longer-term outcomes beyond
the first year posttransplant.
Posttransplantation care requires involvement from multi-
disciplinary healthcare professionals (HCPs) who must work
collaboratively with the patient, their family , and the healthcare
FIGURE 1. 1- to 10-year graft and patient survival rates after kidney transplantation.
*
1-year and cumulative 5- and 10-year age-adjusted kid-
ney graft survival rates calculated for 2005 to 2008 by period analysis;
†
Survival probabilities were adjusted for age, sex and cause of end-stage
renal disease (data shown in figure for period 2004-2008);
‡
Data from 2007 to 2011 period not shown in figure. Figure based on data from
Gondos 2013 and Kramer 2016.
3,5
FIGURE 2. 1- to 10-year graft and patient survival rates in liver transplantation. Reprinted with permission of the European Liver Transplant
Registry: www.eltr.org/Evolution-of-LTs-in-Europe.html
4
(Accessed July 2016).
© 2017 Wolters Kluwer Neuberger et al S3

provider . Maintaining a viable graft and healthy patient in-
volves the consideration of many factors and balancing the need
for immunosuppression with the associated risks. In addition to
the direct and indirect consequences of immunosuppression,
a multitude of risk factors influence patient and graft sur-
vival. Some risk factors may be present before transplanta-
tion (such as cardiovascular disease (CVD) seen especially
in kidney transplant recipients), and other factors, such as
donor age, cannot be modified.
8,9
However, some risk fac-
tors have the potential to be modified or mitigated posttrans-
plantation to improve outcomes, including behavioral risk
factors, such as medication adherence.
10-12
The Consensus On Managing Modifiable risk In Trans-
plantation (COMMIT) group was convened to provide
practical recommendations for the identification and man-
agement of modifiable risk factors to maximize the life of
the graft and patient after kidney and liver transplant.
Modifiable Risk Factors for Graft
Loss Posttransplantation
Although solid organ transplantation improves both the
quality and quantity of life of the recipient, the survival is less
than an age-matched cohort from the general population. A
study in the United Kingdom of adult liver allograft recipi-
ents, who had survived the first postoperative year, showed
the average number of life-years lost was 7.7 years; those
who had their transplants at a younger age (17-34 years)
had a far greater loss of life-years than those who had their
transplant later (≥35 years), and women had fewer life-
years lost than men.
13,14
The main causes of death included
cardiac problems, malignancy, and infection, and causes of
graft failure included recurrent disease and chronic rejec-
tion.
15,16
In a retrospective review of 4483 adult primary
liver transplant recipients, major causes of death were malig-
nancy (30.6%), multisystem failure (10%), infection (9.8%),
graft failure (9.8%), and CVD (8.7%).
17
El-Agroudy et al
15
found the main causes of death in kid-
ney allograft recipients were infections (35.6%), CVD
(17.6%), liver disease (11.4%), and malignancy (6.1%). Of
nearly 1600 kidney recipients in Japan, Shimmura et al
16
found the main causes of death with a functioning graft were
infection (24%), stroke (17%), CVD (16%), malignancy
(15%), and liver failure (12%).
Graft loss has been attributed to both immunological and
nonimmunological factors in kidney and liver transplant re-
cipients (Figures 3 and 4).
Preoperative, perioperative, and postoperative factors may
impact long-term outcomes; these include donor and organ
factors as well as logistic factors. For kidney transplantation,
these include early ischemic injury, acute allograft rejection,
and delayed graft function (DGF). For liver transplanta-
tion, early allograft dysfunction (EAD), prolonged cold ische-
mia times and use of steatotic livers and organs from donation
after cardiac death (DCD) donors may contribute to reduced
graft and patient survival.
32-34
In both kidney and liver transplant recipients, modifiable
risk factors for graft failure over the longer term include is-
sues related to immunosuppression, such as nonadherence,
35
underimmunosuppression,
36
toxicity and adverse effects re-
lated to immunosuppression,
37
andhighintrapatientvariabil-
ity (IPV) in immunosuppressive exposure.
38
The development
of de novo donor-specific antibodies (DSAs) is also considered
to be a modifiable risk factor, and has been strongly associated
with nonadherence to immunosuppression in kidney trans-
plant recipients.
20
However, knowledge of the pathological
impact of DSAs is still evolving, particularly with regard to
the impact of DSAs postliver transplantation.
39-41
Furthermore, patient survival can be improved by atten-
tion to modifiable risk factors for CVD and cerebrovascular
disease, some infections and some cancers.
34
The develop-
ment of new-onset diabetes posttransplant (NODAT) is also
associated with reduced patient and graft survival, as well
as an increased risk of infections and CVD.
42
This list of risk
factors is not exhaustive. Other factors that may have an im-
pact on graft or patient survival include recurrence of initial
disease.
34
Although there is little to be done regarding the
nonmodifiable risk factors of graft failure, better screening
and management of modifiable risk factors could improve
long-term survival rates if integrated into routine clinical
practice. Each section in this guidance document includes a
review of the problem to be addressed, a summary of the lit-
erature and current clinical practice.
FIGURE 3. Causes of late graft loss in kidney transplant recipients. Figure based on data from Jevnikar 2008, Pazhayattil 2014, Sellarés 2012,
Lefaucheur 2010, Koenig 2016, Valenzuela 2013, Siedlecki 2011 and Puttarajappa 2012.
18-25
S4 Transplantation
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April 2017
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Volume 101
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Number 4 www.transplantjournal.com

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "University of birmingham practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients" ?

The group ’ s remit is to provide expert guidance for the long-termmanagement of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant. The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for themanagement of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. 

Q2. What have the authors stated for future works in "University of birmingham practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients" ?

Although the future looks promising for the field of transplantation, recipients and HCPs must not lose sight of those factors that can be modified today, so leading to the best possible future outcomes for the recipients, and giving consolation to the donor family. 

Q3. What are the factors that affect the long-term outcomes of a kidney transplant?

perioperative, and postoperative factorsmay impact long-term outcomes; these include donor and organ factors as well as logistic factors. 

Q4. What is the risk factor for poor long-term graft survival?

Ischemia-reperfusion injury (IRI) is considered an unavoidable, but potentially modifiable, risk factor for poor long-term graft survival in solid organ transplantation. 

Q5. What are the main factors that may interfere with the metabolism and elimination of tacrolimus?

In liver transplantation, graft dysfunction and/or biliary complications may interfere with metabolism and elimination of tacrolimus. 

Q6. What is the effect of tacrolimus on trough concentrations?

The conversion from twice-daily to prolonged-release tacrolimus (capsules), both in kidney and liver transplant recipients, leads to lower blood trough concentrations and a reduced IPVof tacrolimus. 

Q7. What are some of the risk factors that can be modified after a transplant?

8,9 However, some risk factors have the potential to be modified or mitigated posttransplantation to improve outcomes, including behavioral risk factors, such as medication adherence. 

Q8. What is the cytolex ImmuKnow Cell Function Assay?

The Cylex ImmuKnow Cell Function Assay measures T-cell function by the release of adenosine triphosphate from CD4-positive lymphocytes in culture after a mitogenic stimulus. 

Q9. What is the role of CNIs and steroids in the development of hypertension in kidney transplant?

CNIs and steroids play a major role in the development of hypertension in kidney transplant patients; therefore, modifications of immunosuppressive regimen may be considered for lowering BP in these patients. 

Q10. What is the importance of maximizing long-term graft survival?

maximizing long-term graft survival and reducing the need for retransplantation is paramount, not only in improving outcomes for the recipients but also for those awaiting a graft. 

Q11. What is the average blood concentration in the liver and kidney transplant recipients?

During subsequent maintenance therapy, blood concentrations have generally been in the range of 5-15 ng/mL in liver and kidney transplant recipients. 

Q12. What is the reason for the large intrapatient and inter-subject exposure variability of tacrol?

the intrinsic pharmacokinetic and pharmacodynamic properties of tacrolimus, including erratic absorption, a variable first-pass effect, and unpredictable metabolism, may be responsible for its large intrapatient and inter-subject exposure variability. 

Q13. What was considered to be the advantages of having a lower burden?

161 For liver transplantation, historically, it was considered that there might be advantages to having a lower immunosuppressive burden. 

Q14. What is the reason for the increase in the use of CNI-based immunosuppressive?

Over the last 10 years, there has been a strong move in the renal transplant community to minimize CNI-based immunosuppressive regimens, largely based on reports of longterm nephrotoxicity. 

Q15. What is the evidence to support the conclusion that generics are safe?

There appears to be insufficient evidence to provide reassurance that, in transplanted patients, generics are therapeutically equivalent to innovator immunosuppressants.