Drug Change May Aid Islet Transplant Patients

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Tacrolimus-mycophenolate mofetil is a good option for recipients unable to tolerate sirolimus.

SAN FRANCISCO—Nephrologists should consider a switch to tacrolimus and mycophenolate mofetil (TacMMF) in diabetic patients undergoing clinical islet transplantation (CIT) who are unable to tolerate sirolimus, Canadian researchers said. 

Their data, presented here at the American Diabetes Association annual meeting, showed that the switch to TacMMF was associated with albuminuria regression and also helped curb the decline in estimated glo-merular filtration rate (eGFR) that started after CIT and continued until about three months after sirolimus withdrawal. In addition, the strategy was effective in maintaining graft function without interfering with glycemic control.

“Close monitoring is important since calcineurin inhibitors alter renal hemodynamics, and acute renal decline can occur if the GI side effects of MMF cause dehydration,” said Peter A. Senior, MD, assistant professor of medicine at the University of Alberta in Edmonton. “The long-term impact of TacMMF remains to be seen.”

He and his colleagues reviewed the charts of 47 patients who underwent CIT at their institution over a recent 6.5-year period and later had to stop immunosuppression with sirolimus. “Despite the use of sirolimus and avoidance of high-dose tacrolimus, eGFR falls after CIT and albuminuria progression is common,” Dr. Senior pointed out.

In the study, eGFR was calculated according to the Modified Diet in Renal Disease study formula and albumin excretion rates measured at CIT, at the time of sirolimus withdrawal, and again three, six, and 12 months later. The investigators examined outcomes in 34 patients switched to high-dose tacrolimus (trough levels 8-10 ng/mL) and mycophenolate mofetil (1 g twice daily as tolerated) because of sirolimus-related side effects and in 13 patients who stopped all im-munosuppression (NoIS) because of graft loss.

Edema was the main reason for sirolimus withdrawal, followed by GI complaints and graft loss. Renal dysfunction led to the switch to TacMMF in some patients, however.

Consequently, compared with pre-CIT, eGFR had fallen significantly (about 20 mL/min/1.73 m2) at the time of sirolimus withdrawal in the TacMMF but not in the NoIS group. The decrease in eGFR in the TacMMF cohort continued until about three months after sirolimus withdrawal but then stabilized and remained stable at final assessment.

The eGFR remained largely unchanged after sirolimus was withdrawn in the NoIS group.

Compared with the NoIS group, the TacMMF group was older, had diabetes longer, had a lower baseline eGFR, and used more ACE inhibitors with or without angiotensin receptor blockers.

The groups were similar with respect to male-to-female ratio, weight, time to sirolimus withdrawal, systolic BP, and the number of patients with normo-, micro-, and macroalbuminuria and with retinopathy. 

Seven of 34 TacMMF patients had albuminuria when evaluated at baseline. At the time sirolimus was withdrawn, 14 patients had albuminuria (seven new cases), nine of which were progressing, according to investigators. Regression eventually occurred in seven of nine patients.

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