Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients

Abstract

The hematological side effects associated with mycophenolic acid (MPA) are relatively common and have severe consequences. The majority of literature data have not shown clear consistency in the MPA exposure-neutropenia relationship. We hypothesized that (i) adult de novo kidney transplant recipients who develop neutropenia have relatively higher dose-normalized MPA exposure than patients without neutropenia, and (ii) the observed neutropenia may be explained by polymorphisms in metabolism and/or transporter genes responsible for MPA disposition. Adult kidney transplant recipients on steady-state tacrolimus and MPA, not receiving a corticosteroid, and with stable renal function were recruited for investigation at three periods post-transplant (1, 3, and 12months; n = 21, 17, and 13, respectively). Clinical variables (age, weight, MPA daily dose, albumin, serum creatinine, absolute neutrophil count), tacrolimus and MPA concentrations (for exposure calculation), and genotypes (UGT2B7 G211T, UGT2B7 C802T, UGT1A9 T-275A, UGT1A9 T98C, MRP2 C-24T, MRP2 G1249A, OATP1B1 A388G, OATP1B1 C463A) were characterized. A significant inverse association between dose-normalized MPA exposure (a surrogate marker for apparent MPA clearance) and absolute neutrophil count in all three study periods (r2 ~ 0.3-0.7) was observed. No associations between characterized single nucleotide polymorphisms and MPA exposure or absolute neutrophil count were established. However, significant alterations in the minor allele frequencies of UGT2B7*2 C802T, UGT1A9 T275A, and MRP2 G1249A were evident. These findings support the clinical strategy for conducting MPA therapeutic drug monitoring in adult kidney transplant patients on steroid-free immunosuppressant therapy. The novel population genomic analysis data warrant further epidemiological investigations in a larger study sample.