Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

American Transplant Congress 2007

San Francisco, California / May 5-9, 2007

Presently, the median expected graft survival following deceased donor renal transplantation is approximately 10 years. With the advent of potent immunosuppressive regimens, short-term graft survival is almost uniformly excellent at well over 90%. Nevertheless, long-term success rates are not as promising, as graft losses tend to accumulate over time. The contribution of calcineurin inhibitors (CNIs) to chronic allograft nephropathy has fuelled the current drive towards CNI-sparing regimens or complete CNI avoidance.

As well, chronic exposure to steroids is known to increase cardiovascular disease (CVD) and diabetes risk; thus, as an overall strategy to increase quality of life and survival, steroid-sparing or avoidance has consequently become standard of care in many transplant centres.

Improving Renal Function

At this year’s American Transplant Congress, Dr. Matthew Weir, Head of Nephrology, University of Maryland, Baltimore, presented an interim analysis from the STN (Spare-the-Nephron) trial in which renal transplant patients maintained on mycophenolate mofetil (MMF) plus sirolimus (SRL) following CNI withdrawal were evaluated.

At one year, while rates of biopsy-proven acute rejection (BPAR) and graft loss were low and comparable in both arms, patients converted to MMF/SRL 30 to 180 days post-transplantation had almost a 30% mean increase in glomerular filtration rate (GFR) from baseline vs. 8% for those who continued on MMF/CNI, suggesting that kidney function may be better preserved with a switch to MMF/SRL.

Chronic renal failure also occurs in recipients of other donor organs and for this reason, the investigators analyzed the effect of switching liver transplant recipients to the MMF/SRL regimen. Six month interim analysis presented by Dr. Anthony Sebastian, Henry Ford Hospital, Detroit, Michigan, showed an improvement in renal function from baseline in favour of the MMF/SRL regimen vs. the MMF/CNI regimen. Treatment failures and rates of BPAR were, however, numerically higher with the MMF/SRL regimen.

The Importance of Trough Concentrations

Even though CNI avoidance in the early posttransplant period may increase acute rejection rates, this strategy was put to the test in a large group of de novo renal allograft recipients. In the ORION trial, all patients received two doses of daclizumab. Group 1 patients were treated with SLR plus corticosteroids and a gradually decreasing dose of tacrolimus (TAC) whereas Group 2 patients received MMF/SRL and corticosteroids. Both groups were compared to Group 3 patients treated with MMF/TAC and corticosteroids.

As reported by Dr. Stuart Flechner, Professor of Surgery, Cleveland Clinic Learner College of Medicine, Ohio, patient and graft survival in all groups was excellent and comparable at over 90% at 18 months. While a BPAR rate of approximately 30% was observed in the MMF/SRL group, compared with about 11% for MMF/TAC and about 17% for the TAC elimination arm, subtherapeutic SRL trough concentrations were reported in 43% of patients who experienced acute rejection in the MMF/SRL group, an observation that could explain the high rates of BPAR in this arm.

Early CNI Withdrawal and Proteinuria

Proteinuria has been reported to occur when transplant recipients are converted to SRL from CNI regimens and its development may lead to worse outcomes. Because clinical trials involving SRL typically have not included de novo use of SRL, Dr. Juan Carlos Ruiz, Hospital Universitario Marqués de Valdecilla, Santander, Spain, and colleagues documented proteinuria from three to 60 months posttransplantation in renal transplant patients who received either de novo SRL/steroids and cyclosporine (CsA) which was stopped at three months, or SRL/steroids plus CsA. In the latter group, CsA was withdrawn 5 years post-transplant.

Median protein excretion was approximately 0.3 g/day in both groups until 48 months. Between months 48 and 60, after late discontinuation of CsA, proteinuria rose to almost 0.8 g/day. When CsA was eliminated three months post-transplantation, proteinuria levels remained consistently low.

The investigators suggested that the rise in proteinuria observed after late CsA withdrawal was the result of the hemodynamic effects of CsA elimination on the renal vasculature in a chronically damaged kidney.

Steroid-free Regimens

As some investigators have reported, conversion to SRL from a CNI-based regimen in the absence of steroids may be associated with a higher rejection rate. To that end, Dr. Darshika Chhabra, Senior Resident, Northwestern University, Chicago, Illinois, and colleagues compared outcomes in a small number of patients who were not treated with steroids and converted from TAC to SRL one year post-transplant to those who continued on TAC.

All patients were induced with alemtuzumab and were initially maintained on a steroid-free regimen with MMF/TAC. At one year, 37 patients were converted from TAC to SLR. Patient and graft survival were excellent and similar at 100% vs. 95% and 97% vs. 91% in the SRL and TAC groups, respectively, at a median follow-up of 1.7 years. No significant differences in acute rejection episodes were seen at 16% for SRL and 10% for TAC. At two years, the mean GFR was 69.1 mL/min in the SRL group and 59.3 mL/min in the TAC group, suggesting that renal function is better preserved with a non-CNI-containing regimen.

Contrary to earlier reports indicating that SRL should not be combined with CsA, results presented by Dr. Ronald Ferguson, Professor of Surgery and Director, Comprehensive Transplant Center, Ohio State University Medical Center, Columbus, suggested that combination SRL/reduced-dose CsA in the absence of steroids is a very effective maintenance regimen for mismatched living donor renal transplant recipients. At three years, patient and graft survival was approximately 95% and 91%, respectively. Importantly, over 90% of patients remained free of steroids while almost 59% remained on combination SRL/CsA at three years. Renal function remained reasonably stable over the three-year follow-up, with little evidence of functional deterioration. Tolerability of this combination regimen was variable, the most common causes for discontinuation of SRL being joint pain, skin lesions, and elevated lipids, while nephrotoxicity was the most common reason for CsA discontinuation.

As is widely reported, African Americans (AAs) are potentially at higher risk for rejection following renal transplantation and physicians are often reluctant to use a steroid-sparing regimen for fear of precipitating a rejection episode. Thus, findings presented by Dr. Mysore Anil Kumar, Professor of Surgery, Drexel University, Philadelphia, Pennsylvania, comparing outcomes in non-AA kidney transplant recipients to those in their AA counterparts were noteworthy. They showed that early steroid withdrawal following transplantation appeared to be equally safe for AA recipients as for non-AA recipients on the same maintenance immunosuppression.

In this study, BPAR rates in the first year were comparable at 16% for AAs vs. 14% for non-AAs, although the incidence of subclinical acute rejection was higher during the first month in the AA cohort. Nevertheless, at five years, patient survival at 81% and 88% and graft survival rates at 71% and 73% for AAs and non-AAs, respectively, were comparable. These results are important, as they suggest that higher-risk AA transplant recipients can take advantage of a steroid-free maintenance regimen as long as they are monitored with protocol biopsies.

Some of the concern surrounding long-term use of steroids in immunosuppressive regimens stems from their association with post-transplant diabetes. Therefore, it is felt that steroid-sparing regimens or at least very early withdrawal of steroids should be associated with a lower risk of post-transplantation diabetes.

A meta-analysis of trials evaluating the incidence of post-transplantation diabetes showed that the risk was reduced by 42% at a hazard ratio of 0.58 in the steroid avoidance group compared with conventional immunosuppressive regimens. However, Dr. Julio Pascual, Department of Nephrology, Hospital Ramon y Cajal, Madrid, Spain, noted a higher incidence of treated acute rejections in trials where steroids were avoided or withdrawn very early. Nevertheless, he concluded that in low- to medium-risk kidney transplant recipients, avoidance or early withdrawal of steroids following an induction protocol using an IL-2 receptor blocker or thymoglobulin plus either CsA or TAC is associated with improved metabolic outcomes, including a lower risk of new-onset diabetes.

An analysis of an Australian kidney transplant population followed out to 20 years confirmed that long-term exposure to CsA is associated with higher rates of graft loss than either short-term CsA followed by azathioprine and prednisolone (CyAP) or azathioprine and prednisolone (AP) alone.

As presented by Dr. Martin Gallagher, Senior Research Fellow, The George Institute for International Health, and Staff Specialist Nephrologist, Concord Repatriation General Hospital, Sydney, Australia, graft survival at 20 years was 55% with the CyAP regimen vs. approximately 35% for the other two regimens. This analysis suggests that short-term CsA exposure followed by AP is associated with the best long term graft survival in this cohort of first renal transplant patients randomized to three treatment groups between 1983 and 1986. -