Early mycophenolate dose reduction puts transplants at risk

Transplantation

By Mardi Chapman

3 Jul 2024

Early mycophenolate dose reduction is associated with an increased risk of subsequent rejection and graft failure in kidney transplant recipients initiated on a contemporary tacrolimus-based immunosuppression regimen, Australian research shows.

While mycophenolate dose reduction (MDR) is often necessary for the first year post-transplant due to haematological and GI toxicity and infective complications, renal transplant physicians have sought to identify an optimal dose that balances the risk of underimmunosuppression against these complications.

A retrospective study, published in Transplantation Direct [link here], analysed data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry comprising 3,590 adult recipients of kidney-only transplants performed between 2005 and 2017.

All were initiated on a daily mycophenolate dose of 2 g/d (or an equivalent dose of mycophenolate sodium 1.44 g/d), tacrolimus, and prednisolone, and had a ≥12-month follow-up.

The proportion of patients remaining on ≥2 g/d mycophenolate decreased to 72% at 1 month post-transplant, 47% at 3 months, 34% at 6 months, and 17% at 2 years.

Most patients who discontinued mycophenolate remained off the medication and for those who discontinued mycophenolate early – within the first 6 months – a switch to azathioprine was common.

The study found the risk of rejection increased in a dose-dependent manner as the total mycophenolate dose reduced.

Patients taking <1 g/d had double the risk of rejection compared with the ≥2 g/d group (hazard ratio [HR] 2.06; 95% confidence interval [CI], 1.36-3.13; P = 0.001), the study found.

As well, early MDR to <1.5 g/d within the first 6 months post-transplant was associated with an lower patient survival (P = 0.001), overall graft survival (P = 0.0007), and death-censored graft survival (P = 0.03).

“In the multivariable models, MDR remained an independent risk factor for death-censored graft loss (HR 1.32; 95% CI, 1.05-1.66; P = 0.016) but not for death (HR 1.18; 95% CI, 0.97-1.44; P = 0.10),” the study said.

Increasing recipient age (OR 1.06 per 10 y increase; 95% CI, 1.00-1.13; P = 0.045), increased donor age (OR 1.08 per 10 y increase; 95% CI, 1.03-1.13; P = 0.003), the use of T cell–depleting induction therapy (OR 1.74; 95% CI, 1.22-2.47; P = 0.002), and delayed graft function (OR 1.69; 95% CI, 1.40-2.03; P < 0.001) were factors associated with MDR.

“We identified a possible minimum effective mycophenolate maintenance dose threshold of 1.5 g/d, below which there was an association with subsequent rejection.”

The investigators, including renal transplant physician Associate Professor William Mulley from Monash Health, said it was possible that kidney transplant recipients (KTRs) requiring early MDR reflected a cohort more susceptible to adverse events and inferior outcomes.

“It is also difficult to ascertain the proportion of early MDR being a reactive response to adverse events or a proactive measure to minimize immunosuppression-related complications, either targeting at-risk KTRs or adhering to center-specific protocols, with or without MPA [mycophenolic acid] exposure measurements.”

“Given the wide interindividual pharmacokinetic variability, the use of MPA exposure measurements, either routinely early to avoid overimmunosuppression or after a proactive or reactive dose reduction to avoid underimmunosuppression, could be a useful tool to help define the tailored mycophenolate dose,” they said.

“However, the optimal target concentrations to minimise complications remain unclear in the maintenance phase with tacrolimus cotreatment, and this tool is yet to be accessible in all jurisdictions globally.”

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