remote sampling for kidney transplant TDM in India
by James Rudge, PhD, Technical Director, Neoteryx on Sep 19, 2022 9:00:00 AM
An article by Binu Susan Mathew et al at the Christian Medical College, Vellore, Tamil Nadu, India and Royal Brisbane and Women’s Hospital, Brisbane, Australia, published in the July-August 2022 edition of Clinical Biochemistry, described a thorough analytical and clinical validation of tacrolimus and creatinine from dried capillary microsamples. The paper is entitled “Analytical and clinical validation of dried blood spot and volumetric absorptive microsampling for measurement of tacrolimus and creatinine after renal transplantation.” The study compared venous whole blood samples, dried blood samples collected on Mitra® microsampling devices with VAMS® technology, and dried blood spot (DBS) filter cards from 152 transplant patients. The authors concluded that VAMS was the preferred single sampling option for the estimation of tacrolimus and creatinine in renal transplant patients.
Organ Transplant Statistics & Challenges in India
It was reported in 2020 that the population of India had grown to almost 1.4 billion people, which nearly matches the population of China. Furthermore, it was reported in 2021 that the number of solid organ transplants that were conducted in India in 2019 was 12,666. For context, there were 166,374 transplants conducted globally in that year. Of the transplants conducted in India, the vast majority were renal grafts (9,751). This was just under 10% of the global number of renal grafts (kidney transplants) conducted globally that year. Although there were reported to be 550 transplant centers in India in 2019, there were 29,636 patients that were still waiting for a new kidney.
According to the study paper by BS Mathew et al reviewed here, most of the transplant centers in India are in the bigger cities. However, around 70% of the population (~1 billion) live in rural areas. This means that many organ transplant patients don’t have easy access to transplant centers or therapeutic drug monitoring programs. The co-authors of the study paper commented that conducting therapeutic drug monitoring (TDM) for transplant patients living in different areas requires transport that offers cold shipping of venous blood samples to maintain temperature control. Yet, cold shipping for blood samples and other biological specimens is expensive as well as hazardous.
Investigating Remote Sample Collection to Benefit Rural Transplant Patients
For these reasons, the authors stated that collection of capillary blood for TDM of the calcineurin inhibitor tacrolimus and monitoring of the renal function biomarker creatinine, using Mitra devices with VAMS and DBS are an ideal solution to collect samples from people in rural areas. Moreover, a remote specimen collection approach is more convenient and less burdensome for patients. This approach also allows for remote interactions via telehealth between the physician and the patient for dose adjustments during their post-transplant treatment.
The Importance of Bridging Studies to Find a Feasible Solution for TDM
The group thus conducted a study to validate an LC-MS/MS assay using both VAMS dried blood samples and liquid blood samples collected from patients. They concluded that VAMS is the preferred sampling option for masurement of tacrolimus and creatinine in transplant patients. They propose that this approach ensures uninterrupted monitoring of patients at home after renal transplantation and is especially helpful when long distance travel to visit a transplant center for follow-up care is challenging.
TDM Study Findings
- Both tacrolimus and creatinine levels were determined by LC-MS/MS using Waters® Acquity™ Triple quadrupole detector (TQD) and Acquity Ultra performance liquid chromatography (UPLC®).
- Extraction methods for each device was different. For DBS, ACN ZnSO4 protein precipitation was employed. For VAMS, a mixture of just ACN and water were used (no ZnSO4).
- For reference, venous tacrolimus and creatinine were measured using accredited assays.
- Successful method validation was conducted in accordance with the European Bioanalysis Forum (EBF) and International Association of Therapeutic Drug Monitoring and Clinical Toxicology IATDMCT) guidelines. Highlights are as follows:
- Hematocrit (0.25, 0.37, 0.55 L/L) or punch location were within validation parameters for DBS.
- Good stability (<12%) was observed up to 37° C for 5 days and up to 29 days for tacrolimus. Similar results were observed for creatinine (<15%).
- For the clinical validation, 152 patients were recruited (30-49 years).
- For capillary collection, two 20 µL Mitra samples were collected, followed by the collection of two blood spots in the circles on Whatman™ 903 cards. Within five minutes, venous blood was also collected. All samples were collected by the same trained phlebotomist.
- 10.5% of the DBS spots were not analyzed due to poor sample quality on inspection (n=7) -- 23 were rejected for being too small (<0.428 cm2) or not collected (n=2). However, 148 patients had at least 1 DBS sample included for analysis.
- 3.6% of Mitra-VAMS devices were not analyzed because of incomplete wicking (n=6) or not collected (n=5). However, 151 patients had at least 1 VAMS sample included for analysis.
- Bias and imprecision for both VAMS and DBS were less than 12%.
- Predicted performance of both VAMS and DBS compared to venous whole blood were <± 15% for ~90% of the patients tested.
- For creatinine, with an agreement of 15% set, this limit was achieved with 81.6% of patients using VAMS and 69.4% of patients using DBS.
Study Authors’ Conclusions
- VAMS and DBS were comparable for the prediction of tacrolimus.
- For a single remote collection strategy, Mitra devices with VAMS were superior for determination of creatinine, though they were more expensive.
- To arrive at their final predicted results, the authors used a correction formula to predict both creatinine and tacrolimus; a similar approach would be needed by other labs when conducting method validation. The authors commented that clinicians would need to be mindful of this bias.
- Remote sampling can be used for measuring trends in both creatinine and tacrolimus to identify the need for urgent follow-up care management in a hospital setting.
- VAMS was the preferred sampling option for the estimation of tacrolimus and creatinine.
This study demonstrated the importance of a thorough analysis and validation of the parameters to allow for creation of predictive formulas to bridge between wet venous collection and capillary dried blood. It must be noted that in this study, sample collection was conducted under very controlled conditions using one phlebotomist to collect all samples. When developing a remote sampling strategy where patients will be self-collecting their samples, it is vital that clear instructions are given to reduce the chance of incorrectly collected samples.
Neoteryx, part of Trajan Scientific and Medical, has developed high-quality training materials and tools to help ensure that remotely collected samples are of the highest quality in order to deliver the highest success in studies. These tools and materials have been used effectively in many previous studies, as evidenced in the literature. The company has also developed another user-friendly sampling tool called the hemaPEN®. This newer device is designed for easy sampling from any angle. With hemaPEN, it is nearly impossible to under- or over-sample. Once the end-user finishes collecting their samples, they click the device into its plastic base. This action transfers four blood samples of 2.74 µL each into a cartridge of four pre-cut Whatman 903 DBS disks within the device.
This article was summarized for our readers by James Rudge, PhD, Neoteryx Technical Director. This is curated content. To learn more about the important research outlined in this blog, visit the original article in Clinical Biochemistry.
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