Volumetric microsampling for simultaneous remote immunosuppressant and kidney function monitoring in outpatient kidney transplant recipients

Abstract

Immunosuppressant and kidney function monitoring are crucial for kidney transplant recipient follow-up. Microsamples enable remote sampling and minimise patient burden as compared to conventional venous sampling at the clinic. We developed a liquid chromatography-tandem mass spectrometry assay to quantify tacrolimus, mycophenolic acid (MPA), creatinine and iohexol in dried blood spot (DBS), and volumetric absorptive microsample (VAMS) samples. Methods:The assay was successfully validated analytically for all analytes. Clinical validation was conducted by direct comparison of paired DBS, VAMS and venous reference samples from 25 kidney transplant recipients. Patients received iohexol 5-15 minutes before immunosuppressant intake and were sampled 0, 1, 2 and 3 hours thereafter, enabling tacrolimus and MPA area under the concentration-time curve (AUC) and creatinine-based and iohexol-based glomerular filtration rate (GFR) estimation. Method agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and the percentages of values within 15-30% of the reference (P 15 -P 30 ) with a P 20 acceptance threshold of 80%.Results: For DBS samples, method agreement was excellent for tacrolimus trough concentrations (n = 25, P 15 = 92.0%) and AUCs (n = 25; P 20 = 95.8%) and adequate for creatinine-based GFR trend monitoring (n = 25; P 20 = 80%). DBS-based MPA AUC assessment showed suboptimal agreement (n = 16; P 20 = 68.8%), but was considered acceptable given its P 30 of 100%. The assay performed inadequately for DBS-based iohexol GFR determination (n = 24; P 20 = 75%). The VAMS technique generally showed inferior performance, but can be considered for certain situations. Conclusion:The assay was successfully validated for tacrolimus, MPA and creatinine quantification in DBS samples, enabling simultaneous remote kidney function trendThe authors confirm that the Principal Investigator for this article is Dirk Jan Moes.

Therapeutic Drug Monitoring of Tacrolimus Based on Volumetric Absorptive Microsampling Technique (VAMS) in Renal Transplant Pediatric Recipients—LC-MS/MS Method Development, Hematocrit Effect Evaluation, and Clinical Application

“…Some studies have reported that 24 h is a suitable time for drying a VAMS sampler under ambient conditions [ 24 , 25 ]. In our study, a reduction in the drying time to 1 h assured a high recovery of TAC, and no significant differences between the 2 h and 1 h period of VAMS drying were observed.…”

“…Protti et al concluded that IS should be added immediately during the analytical process [ 29 ]. In most published studies, IS was added to the solution for analyte extraction from VAMS [ 24 , 25 , 26 , 29 , 30 , 31 , 32 , 33 ]. In a survey by Kita et al [ 27 ], ASC was added after extraction from the VAMS tip, similar to our LC-MS/MS method.…”

“…Zwart et al discussed the higher imprecision of VAMS in DBS devices [ 24 ]. However, appropriate sampling with DBS is more difficult for patients than for VAMS.…”

“…In conclusion, the VAMS technique could be used in cases of stable renal transplant recipients, as well as in cases of initiation of pharmacotherapy and clinically unstable transplant patients. In the same study, it was also evaluated that in the case of hematocrit range characteristic for transplant patients (0.20–0.60), the results of TAC determination are reliable, without significant correlation between TAC and HCT levels [ 24 ].…”

Blood microsampling technologies: Innovations and applications in 2022

“…111 Microsampling has been extensively studied for the determination of tacrolimus and mycophenolic acid, two of the most commonly prescribed IMS used to prevent organ rejection in recipients of solid organ transplants. 32,63,64,112,113 samples due to poor sample quality) and costs (7 times lower than Mitra device). 32,64 Additionally, use of non-contact Hct prediction strategies such as NIR and UV/VIS spectroscopy coupled to an automated DBS workflow was found to adequately correct for Hct effect in determining IMS concentrations.…”