Jip Jonker, Joost C van den Born, Daan Kremer, Marit S van Sandwijk, Armin Gelinck, Soufian Meziyerh, Dirk Jan A R Moes, Cornelis Smit, Antonio W Gomes-Neto, Marc Hilhorst, Priya Vart, Stefan P Berger, Stephan J L Bakker, Sandrine Florquin, Aiko P J de Vries, Frederike J Bemelman, Daan J Touw, Jan Stephan F Sanders
Larger studies are needed to determine whether late PTC is a better marker than WBTC to detect potential tacrolimus-related nephrotoxicity in KTR.
BACKGROUND: Tacrolimus is the cornerstone of immunosuppressive treatment after kidney transplantation. Its application requires therapeutic drug monitoring, which is routinely performed by assessment of whole blood tacrolimus concentrations (WBTC) that largely comprises a pharmacologically inactive fraction. Monitoring tacrolimus exposure using the plasma tacrolimus concentration (PTC) may better reflect the pharmacological active fraction. We hypothesized that PTC better reflects effectivity and toxicity than WBTC.
METHODS: The ALLEGRO trial randomized 295 kidney transplant recipients (KTR) to standard triple immunosuppression, lower tacrolimus exposure or withdrawal of prednisolone. PTC was measured using LC-MS/MS. Associations between tacrolimus concentrations and eGFR were analyzed using linear regression, with bootstrap resampling used to compare PTC and WBTC. Associations with biopsy results and rejection were evaluated using logistic regression, and infection risk was assessed with joint modeling.
RESULTS: Mean age was 56.5 ± 13.2 years, 95 (32%) were female. The mean PTC during the first month post-transplantation (0.31 ± 0.17 ng/mL) was negatively associated with eGFR at four weeks (st.β=-0.17 (-0.29;-0.05), P=0.006), whereas mean WBTC was not (st.β=0.09 (-0.03;0.22), P=0.15), the difference between these associations was statistically significant (P=0.004). Late mean PTC (6.5-24 months; 0.15 ± 0.07 ng/mL) was negatively associated with eGFR at two years (st.β=-0.19 (-0.35;-0.03), P=0.02), mean WBTC was not (st.β=0.04 (-0.13;0.20), P=0.66), this difference was also statistically significant (P=0.02). At two years, 10 (14%) out of the 71 protocol biopsies showed moderate-to-severe arteriolar hyalinosis. Although in a limited number of events, late mean PTC was significantly associated with risk of arteriolar hyalinosis (OR=1.96 (1.07;3.80), P=0.03), WBTC was not (OR=1.65 (0.83;3.53), P=0.17). Neither PTC nor WBTC was significantly associated with risk of infection in univariable analysis. Twenty-two KTR (7%) experienced biopsy-proven rejection, neither PTC nor WBTC was associated with rejection.
CONCLUSION: Larger studies are needed to determine whether late PTC is a better marker than WBTC to detect potential tacrolimus-related nephrotoxicity in KTR.