Mycophenolate mofetil‐related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs

Abstract

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

Mycophenolic acid pharmacogenomics in kidney transplantation

“…This review explores the pharmacogenomic studies that investigated polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of MPA in kidney transplantation and the main clinical outcomes and adverse events. confirmed by Varnell et al [27] in a case-control study with children and young adult kidney transplant recipients. On the other hand, CYP2C8 rs11572076GG genotype was associated with reduced risk of leukopenia (GG vs. GA; OR: 0.14, 95%CI: 0.03-0.59, P = 0.008) with no association with AR, diarrhea or anemia [29] .…”

“…As described in Table 1, UGT1A8 c.518C>G and c.830G>A variants were not associated with AR, diarrhea, leukopenia or anemia in other investigations with kidney recipients [27,29,39,43] .…”

“…Four other studies evaluated the impact of UGT1A7 variants in kidney transplant recipients. In three cohorts, UGT1A7 rs7586110 (-57T>G), UGT1A7*2 and UGT1A7*3 did not influence MPA pharmacokinetics or MMF-related gastrointestinal adverse events or leukopenia [27,33,34] . However, UGT1A7 c.622CC (rs11692021) genotype was associated with an accumulation of MPAG (higher AUC 0-12 ) without detectable changes in MPA exposure (AUC 0-12 ) in Chinese patients [35] .…”

“…Regarding the clinical outcomes, many investigations showed that the UGT1A9 c.-2152C>T, -665C>T, c.-275T>A, c.-440C>T, and c.98T>C variants were not associated with AR and MPA-related adverse events [13,22,27,29,34,[47][48][49] .…”

“…On the contrary, MMF apparent oral clearance (CL/ F) was significantly higher in pediatric patients with UGT2B7 802T allele compared to UGT2B7 802CC genotype carriers, early after transplantation (60 days) [40] . It is important to consider here that differences in metabolism between adults and children may modify the effect of the genetic variants [27,57] .…”