Trial Information

Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function: A Prospective Randomised Controlled Trial

Renal transplantation is the most effective form of treatment for end-stage renal failure.
It doubles long-term survival and has major socioeconomic and health benefits compared to
patients who remain on dialysis. Graft survival in the UK is 90% at one year and greater
than 75% at 5 years [UKTransplant, 2004], with better survival of grafts from living donors
compared with deceased. However, by 15 years post-transplantation, over 50% of recipients
who are still alive have returned to dialysis. Indeed, premature allograft failure is now
one of the leading causes of end stage renal disease. As short-term outcomes of renal
transplantation continue to improve, increasing attention is being paid to this late
attrition of renal allografts.

It is recognised that calcineurin inhibitor (CNI) nephrotoxicity is a major factor in late
renal allograft failure and dysfunction. In fact, withdrawal of CNI from patients with
deteriorating graft function may improve graft function. However, there is abundant evidence
that histological renal allograft damage may progress even in the absence of changes in
renal function - i.e. declining renal function is a late marker of renal damage, and
therefore institution of therapies (including CNI minimisation) to slow this process may be
"too little, too late".

CNI minimisation may be optimised by three major routes. Firstly, by minimising the CNI
beyond 12 months post transplantation when the risk of acute rejection is at its greatest.
Secondly, by performing a renal biopsy in patients prior to CNI minimisation and avoiding
CNI minimisation in patients with inflammation on the biopsy. Finally, converting
azathioprine to mycophenolate prior to CNI minimisation should have a renoprotective effect.

The type of CNI we will investigate is cyclosporine.

Patients who fulfill the study entry criteria will require a renal allograft biopsy prior to
randomisation to exclude acute rejection, recurrent disease or de novo glomerulonephritis.
Those patients with an acceptable biopsy will proceed to randomisation on a 1:1 basis into 2
groups:

Group 1: CNI [Cyclosporine] minimisation; Group 2: CNI [Cyclosporine] withdrawal.

At this point participants will undergo assessment of the primary and secondary outcome
measures. The treatment period comprises three stages:

Firstly, a 2 week period during which the patient will be stabilised on mycophenolate sodium
720mg twice daily (in place of azathioprine);

Secondly, a 3 month period during which the CNI [Cyclosporine} will be either targeted to a
specified low blood level of 50-100ng/ml, or withdrawn completely (depending on
randomisation);

Thirdly, a 12 month maintenance period on the new immunosuppression regimen.

During the first two stages, patients will be reviewed every 2 weeks. This 2-weekly
follow-up will continue for the first two months of the third stage of the study, and then
visits will be reduced to monthly. At these visits routine blood and urine analysis will be
performed as per routine clinical practice.

At the end of the third stage of the study (i.e. 16 months after randomisation) the
participants will undergo the second assessment of the primary and secondary outcome
measures. This will signify study end for the individual study participant.