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PHYSICIAN PERSPECTIVE - Viewpoint based on presentations from the 15th Congress of the European Society for Organ Transplantation

Glasgow, UK / September 4-7, 2011

Reviewed and edited by:

Jeffrey S. Zaltzman, MD, FRCPC

Director, Renal Transplant, St. Michael’s Hospital, Associate Professor of Medicine, Division of Nephrology, University of Toronto, Toronto, Ontario

Causes of Graft Failure

About 3% of kidney transplant patients progress to graft failure annually. The causes are emerging through observational studies, particularly those focused on biopsies for clinical indications. Here at ESOT, Dr. Philip Halloran, Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, explained that the major cause of late kidney graft failure is antibody-mediated rejection (ABMR) or mixed rejection.

Dr. Halloran presented data from the most recently available update of the Genome Canada study, which is prospectively following consenting kidney transplant recipients after biopsies for clinical indications to identify causes of late graft loss. The data came from 315 patients who had 403 indication biopsies. Sixty failures have been observed to date, 65% attributed to ABMR, probable ABMR or mixed rejection, and 48% of these recipients were considered by their attending physicians to be nonadherent (Figure 1). Only about half the biopsies of ABMR showed positive C4d staining. This would indicate that C4d alone is not a sensitive test to detect ABMR and that new diagnostic criteria are needed. Glomerulonephritis and polyomavirus nephropathy (PVN) also accounted for some failures and some kidneys failed in the context of a major medical illness. Chronic T-cellmediated rejection, calcineurin inhibitor (CNI) toxicity and unexplained scarring did not play a major role.

Figure 1.

Pathological diagnoses were dependent on the time of presentation for biopsy. Initially the main phenotype was acute kidney injury, followed by T-cell-mediated rejection at 1 to 6 months and some PVN at 6 to 12 months. Beyond 1 year, pathology was dominated by ABMR secondary to de novo antibody responses, mixed rejection and recurrence of primary disease. The patients who present after 1 year predominate in the population in terms of reaching failure end points and they have graft failure within about 3 years of the biopsy. Dr. Halloran noted that the newest data from the Genome Canada study continue to support these findings.

He also stressed that failure of kidney transplants after indication biopsies is seldom due to pure CNI toxicity, although it is a valid concern in renal transplantation. CNIs are known to be capable of causing end-stage renal disease (ESRD), but the lesions are nonspecific with characteristics such as arteriolar hyalinosis, fibrosis and atrophy (nephron loss), and this has led to overestimations of this form of injury. After indication biopsies, kidneys with no diseases tend to remain stable despite atrophy-fibrosis and arteriolar hyalinosis lesions. Arteriolar hyalinosis is common with age and hypertension, even at the time of implantation, he pointed out. It can be induced by CNIs, but should be regarded as an unavoidable CNI “effect” rather than a progressive disease. Dr. Halloran cited a study of kidney allograft loss by researchers at the Mayo Clinic in Rochester, New York, who identified a specific cause(s) in 81% of cases with atrophyfibrosis that was rarely attributable to CNI toxicity alone (El- Zoghby et al. Am J Transplant 2009;9:527-35).

Concerns about CNI nephrotoxicity have been based on assumptions from protocol biopsy studies; however, Dr. Halloran suggested that data from studies of cyclosporine in kidney transplantation have been misinterpreted. He pointed out that protocol biopsies are almost never a random sample of the population and they almost always reflect some bias in selection. The occurrence of chronic renal failure in some nonrenal transplant recipients has been cited in support of the toxicity of CNIs. ESRD in nonrenal transplants is multifactorial and the high incidence may indicate that these nonrenal transplants have not been managed appropriately. Based on the Mayo Clinic study, only 1% of graft failures would be due to pure CNI toxicity, he told ESOT delegates.

According to Dr. Halloran, transplants fail due to diseases, mostly ABMR. Many of these diseases could be treated more successfully with better adjustment of immunosuppression and tighter follow-up of the patients. CNIs remain effective drugs for controlling rejection, and “minimizing” CNIs may put kidneys at risk. There is no evidence for the role of CNIs as accelerators of progression in diseased kidneys and when there is no positive diagnosis of CNI toxicity, it is a default to explain dysfunction when no other explanation is available, he maintained. However, questions remain about how to manage high-risk patients and whether renal damage attributable to CNIs occurs in these patients.

Immunosuppressive Therapies

Acute rejection is still the most important predictor of longterm graft survival, so treatment strategies should focus on preventing acute rejection and preserving graft function and survival in the long term. Prof. Henrik Ekberg, Lund University Hospital, Malmö, Sweden, noted that graft function has improved in recent years due to increased skill in selection, risk stratification and medical management, including the emergence of new immunosuppressive regimens. He defined the optimal immunosuppressive regimen as one that is efficacious, low-toxicity, CNI-sparing, steroid-sparing, graft-protecting and non-nephrotoxic; it should prevent acute and chronic rejection; and it should not be a risk factor for cardiovascular (CV) disease, infection or malignancy. Although this would be impossible to achieve currently, a regimen that comes close to this definition is low-dose tacrolimus plus mycophenolate mofetil (MMF), corticosteroids and induction.

Based on the results of the SYMPHONY study, low-dose tacrolimus should be the comparator to emerging alternatives, Prof. Ekberg indicated. SYMPHONY showed that after 12 months, a low-dose tacrolimus regimen resulted in superior graft function and survival to regimens comprising low-dose cyclosporine or low-dose sirolimus, all including MMF, daclizumab induction and corticosteroids, or standarddose cyclosporine plus MMF and corticosteroids (Ekberg et al. N Engl J Med 2007;357:2562-75). This effect was seen in young and old patients, recipients of suboptimal kidneys, recipients of kidneys from living or deceased donors, rejectors and nonrejectors, intention-to-treat and per-protocol populations, and in all participating countries.

Prof. Ekberg presented data from his own clinical practice in Malmö for 2004-2010. At Lund University Hospital, graft survival was 94% at 5 years with low-dose tacrolimus plus MMF, prednisone and induction with a monoclonal antiinterleukin- 2 receptor (IL-2R) antibody. This compared with 84% with standard-dose tacrolimus plus MMF, 78% cyclosporine plus MMF, 72% with cyclosporine plus azathioprine and 47% with azathioprine plus prednisolone. These data confirmed the results of the SYMPHONY study, but also demonstrated that it is possible to do better in clinical practice, according to Prof. Ekberg.

Emerging alternative immunosuppressants have often been associated with better graft function but more acute rejection, which has negative implications for the long term, Prof. Ekberg noted. However, these new treatments may be alternatives to CNI used in the short term. The mammalian target of rapamycin (mTOR) inhibitor sirolimus was studied in the ORION (Optimizing Renal Transplant Immunosuppression to Overcome Nephrotoxicity) trial, but sirolimus-based regimens were not associated with improved outcomes compared with tacrolimus-based regimens (Flechner et al. Am J Transplant 2011;11:1633-44). Sotrastaurin, a selective protein kinase C inhibitor, administered together with mycophenolic acid (MPA), was associated with better graft function than tacrolimus/MPA (Friman et al. Am J Transplant 2011;11:1444-55). However, the acute rejection rate was higher with sotrastaurin, leading to early termination of the trial.

In BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial), the co-stimulation blocker was associated with superior renal function and similar patient/graft survival vs. cyclosporine, but a higher rate of early acute rejection at 1 year post-transplant (Vincenti et al. Am J Transplant 2010;10:535-46). Data presented here at ESOT revealed acute rejection at 3 years of 24% and 17% with more and less intensive regimens, respectively, vs. 10% with cyclosporine. More importantly, the BENEFIT-EXT study showed post-transplant lymphoproliferative disorder (PTLD) present in 8.8% of EBV(-) patients treated with belatacept vs. 1.75% with cyclosporine (Durrbach et al. Am J Transplant 2010; 10:547-57).

Prof. Ekberg reminded delegates that the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for care of the kidney transplant recipients recommend an immunosuppressive regimen tailored to the patient’s risk profile and maintenance with a combination of immunosuppressive medications, including a CNI and an antiproliferative agent with or without corticosteroids (Am J Transplant 2009;3[suppl 9]:S1-S155). The guidelines suggest using tacrolimus as the first-line CNI. To date, it is the only agent proven to be effective in controlling immunologic injury to the allograft and improving graft function and graft survival. The recommendation of low-dose tacrolimus as best option is based on current data in the absence of a study of low-dose tacrolimus vs. belatacept, Prof. Ekberg concluded, adding that such a study should be carried out before any conclusions can be drawn about the future of these 2 regimens.

Optimizing Immunosuppression

The potential for optimization of immunosuppression lies in the consistency of exposure to the primary immunosuppressant, according to Dr. Frank Lehner, Medizinische Hochschule Hannover, Germany. This is an important consideration, especially in modern approaches, which often target lower levels than in the past. A once-daily dose may improve the absorption profile, reduce withinpatient variability and be more convenient for patients. Absorption of the once-daily formulation of tacrolimus from the gastrointestinal tract is extended to 4 h, with a single lower morning peak concentration and no evening peak. Conversion from twice-daily to a once-daily regimen in kidney and liver transplant recipients results in significantly less intrapatient variability (fourfold reduction in kidney transplant recipients). Variability in tacrolimus exposure has been shown to be a predictor of graft failure. Significantly better graft survival was reported in patients with low variability (mean 9.6%) vs. those with high variability (mean 24.2%) (P=0.003) (Borra et al. Nephrol Dial Transplant 2009;25:2757-63). The same difference was not seen for variability in adjunct MMF exposure. Some sources of this within-patient variability of tacrolimus can be controlled, such as adherence and timing of drug intake, Dr. Lehner told ESOT delegates. Data on the influence of genotype on tacrolimus are contradictory, especially for CYP3A5. Ethnicity, concomitant diet and co-medication, gut transit and blood flow may also affect the pharmacokinetics of the drug.

Adherence is important for long-term transplant success. Subclinically noncompliant transplant recipients show an increased risk of late acute rejection, with greater increases in serum creatinine compared with compliant patients (Vlaminck et al. Am J Transplant 2004;4:1509-13). Dr. Lehner emphasized the importance of patient preference. In the EVOLUTION (Evaluation of Advagraf Conversion and Long-Term Use in Kidney Transplantation) study, a large Spanish conversion trial in kidney transplant recipients, almost all (99.4%) patients expressed a clear preference for once-daily tacrolimus after conversion because of the increased convenience of less frequent administration and because of improved adherence (Guirado et al. Am J Transplant 2011;11:1965-71). In another study, the adherence rate was significantly lower for the evening than the morning dose (P<0.001) (Ichimaru et al. Transplant Proc 2008;40:1362-5).

Early post-transplant levels achieved with oncedaily tacrolimus are high, Dr. Lehner confirmed. In the OSAKA (Optimizing ImmunoSuppression After Kidney Transplantation with Advagraf) trial, data presented at ESOT by Prof. Bernhard Banas, Universitätsklinikum Regensburg, Germany, showed that initiating therapy with tacrolimus 0.2 mg/kg/day q.d. resulted in more patients getting within the range of 5 to 15 ng/mL in the first few days’ post-transplant compared with b.i.d. at the same daily dose (Figure 2). This analysis confirmed the results of a previous double-blind, double-dummy st
etting.

Figure 2.

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Dr. Lehner and colleagues have participated in (among other trials) OSAKA, ADHERE and the DIAMOND liver transplant trial. He confirmed that all of these trials required adjustment to the 24-h pharmacokinetic profile of the tacrolimus once-daily regimen. While conversion to oncedaily dosing results in a lower mean exposure, it does not require a higher dose, but monitoring and frequent dose adjustment, especially around the time of conversion.

Potential renal benefits have been demonstrated in clinical studies with the once-daily tacrolimus formulation. Improved serum creatinine and glomerular filtration rate (GFR) were seen after conversion from the twice-daily regimen that appeared independent of trough levels (Tinti et al. Transplant Proc 2010;42:4047-8), and greater renal blood flow and GFR compared with cyclosporine (Zaltzman et al. Transplantation 2010;90:1185-91). Significant reductions in glycemia and triglycerides seen after conversion to once-daily tacrolimus could be beneficial for CV events (Meçule et al. Transplant Proc 2010;42:1317-9). A significant reduction in steroid use was reported (P<0.001) in the EVOLUTION study (12 months’ post-conversion) and in a conversion study where none of the steroid-free patients required steroid readmission and 60% of the others were withdrawn from steroid administration after the switch (Iaria et al. Transplant Proc 2011;43:1028-9).

Dr. Lehner reminded delegates that the best outcomes are likely to be achieved if efforts are made to ensure that patients receive effective and consistent immunosuppression throughout their lifetime.

Summary

Long-term patient and graft survival are the principal measures of transplant success. Graft survival rates have improved in the short term, despite an increasing proportion of high-risk patients and donors, but long-term graft survival remains suboptimal. Acute rejection remains a major predictor of longterm outcome. Emerging alternative immunosuppressants improve graft function but increase acute rejection risk. Studies are continuing to expand our understanding of late allograft failure. CNIs remain the most effective immunosuppressants to reduce the risk of acute rejection. Consistency of exposure, including by adherence, is important for graft survival. Minimization of immunosuppression is potentially hazardous. The best outcomes are likely to be achieved when patients receive effective and consistent immunosuppression throughout their lifetime.