SPECIAL FEATURE Vol.6 No.4 (June 2001)

What is the Optimal Combination of Immunosuppressive Agents for Renal Transplantation Recipients?

Lecture by JP Van Hooff
Department of Nephrology, Maastricht University, The Netherlands
(Summarized by Dr. Angela Wang, Department of Medicine, Prince of Wales Hospital)

In Maastricht, from 1978 to 1982, azathioprine and prednisolone 30 mg were used as immunosuppressive therapy for renal transplantation. Using this regimen, 15% patients were rejection free but none of them steroid-free. The addition of cyclosporin from 1982 to 1994 has increased the rejection-free rate to about 55% and 35% patients were able to be steroid-free. From 1994 onwards, Tacrolimus was introduced as an alternative immunosuppressive therapy and together with the use of prednisolone 10 mg, 90% of patients were rejection-free but the rate of steroid-free needs further evaluation. The use of anti-rejection therapy was noted to have significant influence on the frequency of developing avascular necrosis of bone. Use of less than 3 times anti-rejection treatment resulted in 10% AVN of bone while more than 3 times anti-rejection treatment resulted in AVN of bone in 53%.

A Phase III International multi-center open-labelled randomized study comparing Tacrolimus (N=303) with Cyclosporin (N=135) in cadaveric renal transplantation observed that the acute allograft rejection (AR) rate (as study endpoint) was 34.2% for Tacrolimus vs 57.2% for Cyclosporin. The incidence of clinical acute rejection was reduced nearly 50% with the use of Tacrolimus. Incidence of biopsy proven rejection and steroid resistant rejection was also reduced by about 50% with the use of Tacrolimus compared to that with Cyclosporin. This difference in acute rejection rate was observed with the use of non-microemulsion form of cyclosporin (Sandimmun).

Subsequent study performed in 50 centers in 7 European countries in 557 renal transplant recipients comparing Tacrolimus (FK506) (N=286) with Cyclosporin microemulsion (CsA-ME) (N=271) and looking at the incidence of acute rejection and time to first acute rejection within the first 6 months post-transplant period noted the following results: acute rejection rate was 19.6% vs 37.3% (FK506 vs CsA-ME), steroid resistant rejection rate was 9.4% vs 21.0% (FK506 vs CsA-ME). Switch of cornerstone immunosuppressive was 0.3% with FK versus 10.0% with CsA-ME. Moreover, the histological grade of rejection was found to be more severe with Cyclosporin. On the other hand, side effects profile was also higher with CsA-ME than FK506. More patients on CsA-ME developed hypertension and hyper-cholesterolemia. Hypertension was observed in 15.7% of FK-506 treated vs 23.2% of CsA-treated patients. Hypercholesterolemia was observed in 4.2% of FK506 treated vs 8.9% of CsA treated patients. However, incidence of post-transplant diabetes was higher with FK506 compared to CsA (4.5% vs 2%, respectively). It was concluded that FK506 was superior to CsA in preventing acute rejection. The safety profile was comparable for both drugs although FK506 appears to have less side effects in terms of hypertension and hypercholesterolemia. FK506 also reduces the switch of cornerstone immunosuppressant and reduces incidence of need for dialysis.

Another longitudinal study performed by the Welsh Transplant Research Group in 112 patients comparing two triple immunosuppressive regimens, namely Neoral, Imuran and Prednisolone versus Tacrolimus, Imuran and Prednisolone noted that 58% in Neoral group verus 77% of Tacrolimus group were rejection-free. They also noted renal function to be significantly better with Tacrolimus group after 2-year follow-up period.

Other than being a primary immunosuppressive therapy, Tacrolimus has also been evaluated as a form of rescue therapy. In the US Multi-center Randomized Crossover Study for documented refractory rejection, 205 patients were randomized to the FK506 switch to CsA arm while 207 patients were randomized to the CsA switch to FK506 arm. Rejection resolved in 76.5% of patients who were switched to FK506 arm while only 50% of rejection resolved when switched to CsA. Patients put on CsA-ME with biopsy proven rejection were randomized to either FK arm (N=61) or CsA arm (N=58) for 3 months. Second rejection was the study endpoint. 86.9% of FK arm versus 58.6% of CsA arm had steroid sensitive rejection. Only 6.6% of FK arm versus 25.9% of CsA arm had steroid resistant rejection.

The 4-year follow-up data for the European Study comparing use of FK (N=303) versus CyA (N=145) was as follows: AR was 0.3% for FK vs 2.8% for CsA. Overall incidence of CR was 5.5% for FK vs 11.3% for CsA. Most of the data available indicate that FK is superior to CsA in that acute rejection rate was reduced by about 50%, use of steroid treatment for acute rejection was reduced by 50%, recurrent rejection was reduced and it is a better rescue therapy. However, further study is needed to determine if it does result in better renal function and long-term graft survival. Both drugs have comparable safety profile though higher incidence of hypertension and hypercholesterolemia were observed with CsA.

An open-labelled multi-center randomized parallel group study in 11 Italian and 25 Spanish centers have altogether enrolled 475 recipients. The study compared double (FK506 and Prednisolone) versus triple therapy (FK506, Prednisolone and Imuran). It showed that Imuran has no additional role at all since no difference was noted in the acute rejection rate and steroid resistant rejection rate between the two groups.

Further study comparing Tacrolimus versus Tacrolimus and MMF 1g versus Tacrolimus and MMF 2g showed that the acute rejection rate was 29% for Tacrolimus alone and was reduced to 11% with combination of Tacrolimus and MMF. No difference was noted in the incidence of acute rejection between the use of 1g or 2g MMF. The area under the curve (AUC) of mycophenolic acid (MPA) following oral MMF and FK506 indicated that there is increased systemic exposure after taking the first dose of MMF up to 3 months later for both 1g and 2g MMF. But the increase in AUC is even higher with 2g compared to 1g. It is therefore advisable that when giving MMF in combination with FK506, 2g should be used for the first 14 days, then the dose should be decreased to 1g afterwards as the incidence of acute rejection was noted to be similar for both 1g and 2g MMF but the side effects were less with the use of a lower dose.

Although no relationship was observed between MPA AUC and acute rejection, FK506 AUC was clearly higher in patients with no rejection compared to patients with rejection. Hence it is important not to reduce the dose of FK506 dose when using MMF. According to the Maastricht data, target levels for FK506 should be kept around 15-20 ng/ml (Day 0-14), 10-15 ng/ml (day 15-28), 7-10 ng/ml (week 4-6 months) and 5-7 ng/ml (after 6 months).

In terms of the side effect profile for FK506 and CsA, cholesterol was found to be higher for CsA within the first year compared to FK506. More statin use was required with Cyclosporin compared to FK506. Although blood pressure was similar for both FK506 and CsA, number of anti-hypertensives was significantly greater for CsA compared to FK506. Only 6% patients on FK506 versus 50% patients on CsA required 3 or more anti-hypertensives for blood pressure control. Indeed, a CsA-FK506 4-week cross-over study switching patient from CsA to FK506 and then back to CsA noted indeed a drop in mean arterial pressure (MAP) by 10 mmHg when switching patient from CsA to FK506 and increase in MAP when switching patient back to CsA. Total cholesterol and LDL-cholesterol showed similar reduction with FK506 and increase when switched back to CsA.

There are also data to suggest that FK506 may be more cost-saving compared to CsA. Taking into account that less anti-rejection therapy is required, MMF dose is lower (1g lower for FK506 than CsA) with the use of FK506, better steroid sparing effect with Fk506 and hence no osteoporosis treatment required, less anti-hypertensives and statins use, the total running cost with FK506 may be lower compared to CsA. More recent economic analysis by the UK group comparing the use of FK506 versus CsA in kidney transplantation, however, showed no significant difference in cost per survival with either treatment. These data were presented in the British Transplantation Society Meeting in March 2001.