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JOURNAL CLUB - Transplantation

June 2010

Based on The KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients.

Am J Transplant 2009;9(suppl 3):S1-S155.

IMMUNOSUPPRESSION FOR KIDNEY TRANSPLANT RECIPIENTS: EVIDENCE-BASED KDIGO PRACTICE GUIDELINES

Editorial Overview:

Bryce A. Kiberd, MD, FRCPC

Medical Lead, Multi-Organ Transplant Program, Queen Elizabeth II Health Sciences Centre, Professor of Medicine, Dalhousie University, Halifax, Nova Scotia

The two most comprehensive clinical practice guidelines on the care of kidney transplant recipients (KTR) were published in the year 2000 by the American Society of Transplantation and the European Best Practices Guidelines Expert Group. While these guidelines were primarily based on expert opinion, new guidelines recently published by the Kidney Disease: Improving Global Outcomes (KDIGO) consortium used an evidence-based approach. Arriving by consensus at recommendations based on systematic reviews of relevant clinical trials, the new clinical practice guidelines were published late in 2009 (Am J Transplant 2009;9(suppl 3):S1-S155)

The KDIGO recommendations were graded “Level 1,” i.e. the benefits outweigh the risks for most patients and the recommended course of action should be taken, and “Level 2,” i.e. different choices may be appropriate for different patients and the guidelines suggest a course of action. Quality of evidence was also graded from high to very low based on evidence (or lack thereof) from randomized controlled trials. Both level and grade of evidence are included in the guidelines. In addition, the rationale and supporting evidence are included to allow specialists themselves to judge the statements. The new guidelines are intended for the management of KTR alone and are not intended to be a standard of care for all patients. The recommendations do not specifically take into account costs but rather focus on improving outcomes. The document suggests areas for future research and will need to be updated as more high-quality evidence becomes available.

Induction and Maintenance Immunosuppressive Regimens

The KDIGO guidelines recommend induction therapy with a combination of immunosuppressive agents before or at the time of transplantation and the inclusion of a biologic agent as part of the initial immunosuppressive regimen. For initial maintenance, a regimen combining a calcineurin inhibitor (CNI) and an antiproliferative agent, with or without corticosteroids, is recommended. Mycophenolate mofetil (MMF) is the suggested first-line antiproliferative agent and tacrolimus the first-line CNI, started either before or at the time of transplantation rather than delayed until the onset of graft function. The recommendation of tacrolimus was based on a meta-analysis of randomized controlled trials (RCTs) in which a reduced risk of acute rejection and improved graft survival was repor ted with tacrolimus compared to cyclosporine (CsA).

While there have been concerns that early use of CNIs may increase the incidence and severity of delayed graft function, analysis of a series of RCTs that compared early vs. delayed CNI initiation found that there is no reason to delay the initiation of CsA. No similar studies have been carried out with tacrolimus but evidence suggests that the risk for early CNI nephrotoxicity is minimized and acute rejection is optimally prevented by using a regimen including induction and reduced-dose tacrolimus.

It is suggested that discontinuation of corticosteroids be considered during the first week after transplantation in patients at low immunological risk, and guidelines recommend that if a mammalian target of rapamycin inhibitor (mTORi) is used, it should not be initiated until graft function is established and surgical wounds are healed.

For most patients, an interleukin 2-receptor antagonist (IL2-RA) is recommended as firstline therapy but for those at higher risk of acute rejection and graft failure, a lymphocytedepleting agent is suggested.

Factors that contribute to a high immunologic risk include the number of human leukocyte antigen (HLA) mismatches; younger recipient age; older donor age; panel-reactive antibody >0%; and the presence of donorspecific antibody (Table 1). Because induction therapy with lymphocyte-depleting antibodies increases the risk of serious adverse events such as infection, it is suggested that the use of these agents be limited in order to achieve a favourable balance between benefit and harm.

Long-term Maintenance Immunosuppression

With the potential long-term complications of CNI exposure, most importantly chronic al lograft injury (CAI ), withdrawing the CNI component of maintenance immunosuppression after three months when the peak period for immunologicallymediated complications is over is an attractive option. However, RCTs in which the CNI has been completely withdrawn indicate that the risk of acute rejection increases significantly with no clear benefit for improved graft survival. While exposure to CNIs is not the only potential cause of CAI, the guidelines do suggest that the risk can be minimized by using lower CNI doses. Thus, if low doses of a CNI are not used at the time of transplantation, the dose should be reduced two to four months after transplantation to reduce nephrotoxicity while preventing acute rejection.

Table 1.

Balancing Acute Rejection and NODAT

The KDIGO guidelines note that for every 100 patients treated in the first year with tacrolimus rather than CsA, acute rejection would be prevented in 12 patients and graft failure would be prevented in two patients. However, five patients on tacrolimus would develop new-onset diabetes after transplantation (NODAT) compared to those on CsA. Not all studies have found significantly elevated rates of NODAT with tacrolimus compared with CsA.

Steroids unequivocally prevent acute rejection and immunologically-mediated graft loss. Arguments for early steroid withdrawal are supported by the systemic effects of steroids with long-term use; these include hypertension, dyslipidemia, NODAT, osteoporosis and consequent fractures. Practitioners need to decide whether to withdraw or substitute any one of the drugs within a combination regimen based on individual risk factors: if patients have impaired glucose tolerance or NODAT, reducing the dose of steroids or withdrawing them altogether may be beneficial; if they remain hypertensive despite adequate antihypertensive therapy, steroid reduction or withdrawal may be helpful; if they develop osteopenia or osteoporosis, steroid reduction or withdrawal may also be helpful. KDIGO recommends continuing prednisone in patients who are on steroids beyond the early post-transplant period, as RCTs indicate that steroid withdrawal beyond this time point increases
ection.

Table 2.

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Optimal Dosage

CsA has a narrow therapeutic window and variable absorption characteristics even with the microemulsion formulation. Consequently, the dose of CsA must be individualized, although standard-dose CsA may be defined as that dose achieving a trough (C₀) of of 200 (150-300) ng/mL or a 2-hour post-dose concentration of 1400- 1800 ng/mL early, and 800 to 1200 ng/mL later after transplantation.

The standard tacrolimus target is a 12-hour C₀ level of 10 (5-15) ng/mL. However, the SYMPHONY study demonstrated that a low-dose tacrolimus target was the best overall immunosuppressive regimen in lower immunologic risk KTRs for maintainance of graft function, prevention of acute rejection and superior graft survival at 12 months compared with either low-dose CsA, standarddose CsA or low-dose sirolimus.

There are no RCTs that examine optimal CNI monitoring frequency. Nonetheless, the guidelines provide some guidance and suggest CNI blood levels be measured at least every other day during the immediate post-operative period until target levels are achieved; whenever there is a change in medication or patient status that could affect blood levels; or when there is a decline in kidney function suggestive of nephrotoxicity or rejection. The immediate release (b.i.d.) tacrolimus should be monitored using 12-hour C₀ measurement and the extended-release formulation (once-daily) should be monitored using 24-hour trough measurement. Target levels should reflect the patient’s overall immunosuppressive regimen and risk for rejection, with higher targets early after transplantation and lower targets later.

Addressing Adherence

The issue of non-adherence has not been graded as there are insufficient data to establish clear guidelines. It is nevertheless worthwhile to address this question as non-adherence is associated with a high risk of acute rejection and allograft loss. According to one study, the risk of graft loss increases sevenfold in non-adherent compared to adherent individuals (Butler et al. Transplantation 2004;77:769-76).

The guidelines state that risk factors for non-adherence include long duration of treatment (with decline in rates of adherence over time), poor communication and lack of social support. The number of prescribed medications and dosing frequency also has an effect on adherence rates. The highest rate of non-adherence among KTRs involved immunosuppressive medications (35.6 cases per 100 people per year)

Simplification of drug therapy— including both immunosuppressive and non-immunosuppressive medications (e.g. antihypertensives)—remains among the main strategies to increase adherence. Therefore, wherever possible, medications should be given either once or, at most, twice daily.

Finally, a combination of educational, behavioural and social support interventions may provide the best results. Patients should know that non-adherence, even when their transplant is functioning well, can lead to chronic rejection that is insidious in onset, hard to diagnose in its early stages and often not reversible once established. Patients should feel comfortable discussing any perceived adverse effects of their
r health care team before making changes themselves.

Table 3.

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questions and answers

Panel

Philip F. Halloran, MD, PhD, FRCPC, OC, FRSC

Editor-in-Chief, American Journal of Transplantation, Director, Alberta Transplant Applied Genomics Centre, Canada Research Chair in Medicine (Transplant Immunology), Professor of Medicine, University of Alberta, Edmonton, Alberta

Marcelo Cantarovich, MD

Medical Director, Kidney and Pancreas Transplant Program, Associate Director, Multi-Organ Transplant Program, MUHC-Royal Victoria Hospital, Professor of Medicine, McGill University, Montreal, Quebec, Toronto, Ontario

Bryce A. Kiberd, MD, FRCPC

Medical Lead, Multi-Organ Transplant Program, Queen Elizabeth II Health Sciences Centre, Professor of Medicine, Dalhousie University, Halifax, Nova Scotia

What are the main advantages of using a lymphocyte-depleting agent during induction therapy?

Dr. Kiberd: A meta-analysis examined IL2-RA induction therapy and found good evidence that these agents reduce acute rejection, as there is a trend for better graft survival. There may well be a subgroup of patients who will benefit from a lymphocyte-depleting agent. High-risk patients will have less acute rejection with lymphocyte-depleting agents but may suffer from an increased risk of infection and cancer. Therefore the balance between benefit and risk is uncertain in any individual patient.

Dr. Halloran: The use of lymphocytedepleting therapy induces a state of fairly intense immunosuppression which can be advantageous in stabilizing the patient at high immunologic risk. That said, the evidence of benefits in high-risk patients is not as clear as we would like it to be. Nevertheless, it is standard practice in most centres to use lymphocyte-depleting therapy. We would particularly like more evidence that lymphocyte-depleting therapy has an advantage in people at risk for antibodymediated rejection, which is the big problem in sensitized patients.

Dr. Cantarovich: There is moderate quality of evidence (2B) supporting the use of lymphocyte-depleting agents compared to anti-IL-2 receptor monoclonal antibodies as induction therapy for kidney transplant recipients at high risk for acute rejection or delayed graft function. Although lymphocytedepleting agents decrease the risk of acute rejection, there is no evidence that these agents improve graft survival, and there is an increased risk of infections (especially CMV) and post-transplant lymphoproliferative disorder. Therefore, risks and benefits need to be assessed.

The new guidelines suggest that tacrolimus be considered first-line CNI in the maintenance immunosuppressive regimen. Why do you think KDIGO made that recommendation?

Dr. Kiberd: The evidence supporting tacrolimus comes from the ELITE-SYMPHONY study which showed that lower exposure levels of tacrolimus were associated with better kidney function and lower rejection rates than comparator regimens in the short term. In addition, tacrolimus has no important effects on cholesterol and blood pressure and less cosmetic effects (gum hyperplasia and hirsutism) than CsA, but the trade-off has been higher rates of new-onset diabetes and possibly polyomavirus nephropathy. As the guidelines suggest, you have to make treatment decisions based on the patient at hand.

Dr. Halloran: As first-line immunosuppressive therapy, tacrolimus has been shown to induce a more favourable balance between any risks and benefits in a number of studies, including the SYMPHONY study. Although it causes a higher incidence of diabetes and neurotoxicity, overall, the incidence of rejection (T-cell-mediated rejection) and decrease in renal function have been higher in studies of CsA, as studies of tacrolimus vs. CsA have shown. Nevertheless, in patients at risk for tacrolimus complications, particularly post-transplant diabetes, CsA is a successful strategy. Long-term survival rates with CsA and tacrolimus are equivalent.

Dr. Cantarovich: There is high quality of evidence (2A) supporting the first-line use of tacrolimus. It decreases the risk of acute rejection and improves graft survival during the first year of transplantation compared with cyclosporine. Based on a meta-analysis of randomized controlled trials, it is estimated that for every 100 renal transplant patients treated for the first year with tacrolimus rather than with cyclosporine, 12 would be prevented from having acute rejection and two graft failures would be prevented, but five more patients on tacrolimus would develop new-onset diabetes mellitus compared with cyclosporine. There also appears to be less subclinical rejection with tacrolimus but the implications of this remain to be determined by long-term analysis.

As opposed to tacrolimus, cyclosporine attenuates the mycophenolic acid enterohepatic recirculation, resulting in lower mycophenolic acid exposure. As therapeutic drug monitoring of mycophenolic acid is not routinely performed, this may contribute to the difference in acute rejection observed in randomized controlled trials comparing cyclosporine to tacrolimus. It is interesting to point out that MMF dose adjustment based on an abbreviated AUC, resulted in a low rejection rate (similar to the tacrolimus arm of the SYMPHONY trial) in renal transplant recipients receiving standarddose cyclosporine, an anti-IL-2 receptor monoclonal antibody and corticosteroids. This observation suggests that assessment of mycophenolic acid exposure may be important.

The guidelines recommend avoiding maintenance corticosteroids beyond the first week. In those patients who must be maintained on steroids, what regimen do you use to minimize adverse effects?

Dr. Kiberd: If a low-risk patient requests a “no steroid” regimen and they are aware of the risks, then we either completely avoid or limit therapy to the first week. Normally, we reduce prednisone to 5 mg daily by month 3 and maintain the patient on this dose indefinitely. In the occasional patient sensitive to prednisone, we will taper to lower doses and occasionally stop with full disclosure to the patient of the potential risks. If the patient develops problems, we reinstitute promptly. About 20% of our patients are not on steroids. Almost all HLA-identical recipients will be off steroids.

Dr. Halloran: The issue of steroid use and avoidance has still not been fully resolved. Although many patients are successfully managed in the absence of steroids, most clinicians will be ready to restart steroids in anyone who is showing signs of instability. The particular issue relates again to antibody facts and to the safety of withdrawal at different times. The alternatives include no steroids, steroids within the first week, or an unlimited number of other protocols. The issue of the risk of donor-specific antibody formation and late graft loss on steroid-free regimens vs. steroid regimens is not satisfactorily resolved. While many physicians feel that in the absence of clearcut evidence that the benefits of avoidance or withdrawal of steroids outweigh the risks, it would be useful to develop more first-class evidence on this point.

Dr. Cantarovich: There is moderate quality of evidence (2B) supporting avoidance of maintenance corticosteroids beyond the first week post-kidney transplantation. At our centre, the majority of the patients are maintained on low-dose steroids (5 mg/day), though there are centres that advocate steroid-free regimens. At the moment, we aim for early discontinuation of steroids on an individual basis but we are planning on using an early withdrawal strategy in the near future.

Under what circumstances would you initiate CNI withdrawal and what strategies do you recommend for reducing the increased risk of acute rejection on CNI withdrawal?

Dr. Kiberd: The most obvious situation for CNI withdrawal is post-transplant lymphoproliferative disease (PTLD) and more recently we have been cautiously withdrawing the CNI in HLA-identical patients after month 3 post-transplantation. I would rather lower the dose in most other situations. I make sure they receive adequate exposure to other immunosuppressive agents such as MMF before tapering.

Dr. Cantarovich: Based on the recent literature (see following question), we are more reluctant to discontinue CNI in renal transplant recipients. We would rather optimize the MMF dose and reduce the CNI dose.

The guidelines also indicate the quality of evidence evaluating the effects of replacing the CNI in patients when CAI is low, and that the resulting benefit-harm trade-off is uncertain. Are there any situations where you would still consider replacing a CNI in patients with CAI despite this uncertain evidence?

Dr. Kiberd: There are several RCTs with fiveyear follow-up examining conversion from CsA to tacrolimus in patients with CAI. There are no benefits based on hard end points (graft survival) to support conversion. One of the biggest concerns is that conversion occurred at the time of advanced irreversible injury. The CONVERT trial (examining substitution of a CNI with an mTOR inhibitor) was published just prior to the publication of the guidelines. As discussed in the rationale, the patients with reduced graft function (and presumably CAI) in this study did not benefit from conversion.

Dr. Halloran: It is important to begin to actually establish the phenotype of organ transplants that are damaged. There are three main situations: the organ transplant with a disease state; the organ transplant with active injury; and the organ transplant with accumulated burden of injury-scarring and atrophy.

State one is the main concern: if there is evidence of recurrent glomerulonephritis, and in particular of antibody-mediated rejection, than that should be established before any decision is made regarding reducing a CNI. Overall, recent evidence suggests that the implication of CNIs in the deterioration of kidney allografts has been misplaced. Most patients on CNIs should be managed without withdrawal of CNIs unless there is very compelling evidence that they are deteriorating on the CNI in the absence of active disease states (antibody-mediated rejection, recurrent disease). Since the diagnostic criteria for antibody-mediated rejection are changing, this entire body of evidence needs to be revaluated. In summary, the evidence that CNIs are responsible for many deteriorating transplants is probably not sufficient to advocate CNI withdrawal. What the field needs is more detailed phenotyping of trouble transplants, so that physicians will make the appropriate decision for their patient, secure in the knowledge of whether they are dealing with a state which is likely to be improved by reduction of the CNI. I should note that the attribution of kidney deterioration to CNIs is often made on very shaky ground using lesions which are completely non-specific such as arteriolar hyalinosis.

Dr. Cantarovich: There are few RCTs looking into replacing CNI in renal transplantation. These studies showed an improvement in renal function. However, the trials generally included a short-term follow-up and few reported on follow-up biopsies. More importantly, none of the trials included analysis of antibodies. Recent data from the Edmonton group indicated that chronic antibody-mediated rejection is an important cause of graft loss. Therefore, physicians need to rule out antibody-mediated rejection prior to replacing CNI with other immunosuppressive medications in renal transplant recipients. Patients with a GFR <30 mL/min are not candidates for conversion, so while there may be a small window for some patients, this area needs to be revisited.

Do you currently treat borderline acute rejection? What is your rationale for doing so?

Dr. Kiberd: At our centre, we perform a biopsy for cause and treat borderline rejection if detected. We do not perform protocol biopsies and therefore do not treat subclinical rejection. There is no evidence to support protocol biopsies and treatment of subclinical rejection in tacrolimus, MMF and prednisonetreated patients.

Dr. Halloran: We do treat borderline acute rejection with corticosteroids, regardless of renal function in renal transplant recipients on tacrolimus-based immunosuppression. This is based on previous literature on patients who received CsA.

Dr. Cantarovich: We do treat inflammation with steroids regardless of renal function. However, this is based on patients who historically received CsA and the implications of treating subclinical acute rejection in patients treated with tacrolimus still needs to be assessed.

How important an issue is non-adherence in successful immunosuppression? What are the consequences of poor adherence and what strategies do you think could help improve adherence (e.g. once-daily dosing where possible)?

Dr. Kiberd: Non-adherence is difficult to ascertain in any individual patient and therefore its overall impact on outcomes is impossible to quantify. The patients who admit to stopping their medications and present with advanced graft dysfunction are tragic examples but these may be the tip of the iceberg. Lesser degrees of non-adherence may be responsible for some of the insidious deterioration in graft function that we previously attributed to CNI toxicity or now attribute to chronic antibody-mediated rejection. There are no simple answers to reducing non-adherence; it will likely require multiple strategies and this is an important area of research.

Dr. Cantarovich: Non-adherence is a very important issue in the follow-up of transplant recipients. Initially, it was well described in adolescents and young adults but increasingly more reports are documenting non-adherence in adults. However, there is more nonadherence in younger adults than in older adults. With non-adherence there is an increased risk of acute rejection with subsequent increased costs to treat rejection, as well as reinitiating dialysis because of graft loss. Educating patients does help improve adherence. Taking medications with meals may help increase adherence. However, the pharmacokinetics of some medications are influenced by food intake. Consistency with the type of food may overcome variations in the exposure to immunosuppressive medications. We are now using once-a-day tacrolimus to help with adherence as well. Some studies suggest that non-adherence is largely associated with the night time dose, so if tacrolimus is combined with MMF, patients still need to take MMF at night.