Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients
A 50-year-old lady of mongoloid extraction from Bhutan, with chronic kidney disease resulting from membranous proliferative glomerulonephritis pre-emptively received a renal allograft from her haplo-matched cousin sister. Her pre-transplant donor-recipient crossmatch and donor-specific antibodies were negative. She received standard immunosuppressive therapy with mycophenolate sodium (1440 mg/day), tacrolimus (5.5 mg/day), and steroid (20 mg/day) with basiliximab induction. She was also prescribed valganciclovir, cotrimoxazole, pantoprazole, and calcium. During the first 2 months post-transplant the MPA AUC0-12 ranged from 29.2 to 168.7 mg.h/L with total daily doses varying from 1440 to 1620 mg. She developed leukopenia which did not remit with reduction in dose of mycophenolate. Due to persistent leucopenia, other drugs such as valganciclovir and co-trimoxazole were stopped. Mycophenolate dose was gradually tapered but leucopenia continued to worsen therefore mycophenolate was stopped. Subsequently, leucocyte counts never increased more than 5000/cu.mm so mycophenolate could not be restarted. Renal and liver function parameters were within normal limits in the post-transplant period. The tacrolimus trough measurements (ng/ml) and the subsequent dose adjustments over time are shown in .\nDose reductions for tacrolimus were made gradually over a 1½ month period. However, the trough concentration remained above the recommended trough concentration. Tacrolimus 2 point LSS AUC within the first post-transplant year ranged between 165.6 and 140.9 μg.h/L while on 2 mg/day in two divided doses, which was within the range of exposure in the maintenance period at this center.[] Post-transplant immune monitoring with donor-specific antibody was negative throughout her follow-up. BK virus PCR screening remained negative when tested during serial visits.\nTwo years later, the two-point LSS tacrolimus AUC increased to 281.7 μg.h/L after initiation of ciprofloxacin which reduced to 217.3 μg.h/L, 1 week after discontinuation of ciprofloxacin.\nIn view of the possibility of polymorphism affecting tacrolimus metabolism, with informed consent, single nucleotide polymorphisms that could account for the elevated tacrolimus levels were tested for with PCR. She was mutant homozygous for CYP3A5*3(GG) alleles and MDR1-2677(TT) alleles, heterozygous for MDR1-1236(CT) alleles and wild-type homozygous for CYP3A5*6 (GG) and MDR1 3435C (CC) alleles.