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Tacrolimus-based Steroid Withdrawal Safe and Effective for Renal Transplant Patients With Stable Serum Creatinine: Presented at WCN

By Bruce Sylvester

BERLIN, GERMANY -- June 16, 2003 -- Two post-transplant, tacrolimus-based regimens show potential to help patients with stable serum creatinine achieve withdrawal from steroids while avoiding acute rejection or diminished kidney function, researchers reported here on June 10^th at the World Conference on Nephrology.

"This was a big study," said presenter and lead researcher Leszek Paczek, MD, a transplant surgeon and chairman of the department of immunology, transplantation, and internal medicine at the Transplantation Institute, in Warsaw, Poland.

"We know from prior research that steroid withdrawal has been possible using tacrolimus-based regimens. But we wanted to look specifically at two regimens from a steroid withdrawal point of view -- tacrolimus plus azathioprine triple regimen and tacrolimus plus mycophenolate mofetil [MMF] triple regimen in adult transplant recipients," he explained.

The investigators enrolled 489 subjects in this 6-month, prospective and multicentre study. They randomised 243 subjects in Group 1 to receive tacrolimus and MMF and 246 in Group 2 to receive tacrolimus and azathioprine plus steroids.

Baseline dosing of oral tacrolimus was 0.2 mg/kg/day; MMF dose was 1 g/day. The investigators administered azathioprine at 1-2 mg/kg/day.

Over the first 3 months, the researchers tapered steroids from 20 mg/day to 5 mg/day. "From month 3 onwards, steroids were withdrawn in patients who were free from steroid-resistant rejection and who had serum creatinine concentrations below 160 mcmol/L," they noted.

At end point, patient survival was 98.3% in Group 1 and 98.4% in Group 2. Likewise, end point graft survival was 95.0% and 93.5%, respectively.

Six-month incidence of biopsy-proven acute rejection was 18.9% in Group 1 compared with 26.8% in Group 2 (P=0.038), the authors found. Six-month incidence of steroid-resistant acute rejection was 2.1% and 4.9%, respectively (P=NS).

By the end of the third month, steroid withdrawal was achieved in 60.5% of Group 1 subjects and 48.8% of Group 2 subjects (P<0.01).

The researchers reported that from months 4-6, 2.7% of patients in the tacrolimus/MMF group experienced an acute and biopsy-confirmed transplant rejection; 0.8% of patients in the tacrolimus/azathioprine group experienced such rejection in the same time period.

Among patients who continued to receive steroids, 3.5% of patients in Group 1 had biopsy-proven acute rejections during months 4-6 compared with 7.1% of patients in Group 2. In the steroid-maintaining groups, most patients had had a rejection during the first 3 months (3 in Group 1 and 7 patients in Group 2), they noted.

At end point, the steroid-free cohort as a whole achieved excellent kidney function, with a median serum creatinine concentration of 119.5 mcmol/L compared with 115.1 mcmol/L in the group that received tacrolimus/azathioprine.

At end point, median serum creatinine in the study group as a whole was 130.5 mcmol/L in the MMF group and 132.8 mcmol/L in the azathioprine group.

The most frequent adverse events were abnormal kidney function (18.5% vs 27.2%, P=0.019), ATN (9.5% vs. 15.9%, P=0.033), and urinary tract infection (11.5% vs 13.8%, P=NS) for the tacrolimus/MMF/steroid group and the tacrolimus/azathioprine/steroid group, the authors wrote.

Mean tacrolimus whole blood trough levels were similar in all treatment groups and decreased from 15.9 ng/mL and 14.4 ng/mL, respectively, during Week 1 to 8.9 ng/mL in Group 1, 9.4 ng/mL in Group 2, 9.4 ng/mL in Group 1, and 8.6 ng/mL in Group 2 at study end.

The combination of tacrolimus and MMF achieved a lower rate of rejection and permitted a higher proportion of steroid-free patients. The overall incidence of acute rejection was low and kidney function was good.

"We found that both tacrolimus regimens used here were efficacious and safe," said Dr. Paczek.

The authors added that freedom from rejection and a serum creatinine measure below 160 mcmol/L appear to be especially useful criteria for clinical decision making regarding steroid withdrawal.

The study was undertaken without corporate financial support.


[Absence of Rejection And Stable Serum Creatinine Are Excellent Criteria For Steroid-Withdrawal In Kidney Transplant Patients Receiving Tacrolimus Treatment. Abstract 745]

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