Applications of Volumetric Absorptive Microsampling in Kidney Transplant Management

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Kidney transplant medicine continues to evolve, and there are opportunities within the existing kidney transplantation landscape to optimize medication management and patient outcomes with new techniques. The most promising of these is the use of microsampling instead of traditional venous blood sampling. Many important drugs and biologic parameters in kidney transplant care can be collected and analyzed by microsample. Transforming how we approach blood sampling in kidney transplant monitoring is timely, relevant, and may address broader gaps in telemedicine and health integration. History The earliest form of microsampling is dried blood spots (DBS), these are used in kidney transplant management in some jurisdictions; however, issues such as hematocrit and lack of homogeneity in samples has limited widespread adoption.2 A ranger of newer devices have been developed that use volumetric absorptive methods of collecting a whole blood microsample (10–30 microl/L) through a lancet and a wicking process.3 Microsampling Principles and Hematocrit Considerations DBS sampling involves applying capillary whole blood onto filter paper and analyzing area-based punches from the dried spot.1 A concern with DBS is hematocrit which alters the viscosity of the blood and influences the size of the spot and therefore the amount of blood able to be analyzed in an individual punch.3 Punches may contain variable blood volumes and plasma-to-cell ratios, introducing bias unless whole-spot analysis or correction factors are applied.5 Mitra Volumetric Absorptive Microsamplers (VAMS) are an alternate device and allow an accurate volume of blood to be wicked onto polymer tips.3 VAMS and other volumetric devices (Table 1) deliver a fixed volume of blood into a porous polymer tip or microfluidic channel, reducing—but not eliminating—hematocrit-related variability.3 Residual dependencies include viscosity-driven fill kinetics, incomplete saturation, and minor evaporation effects during drying.3 Both DBS and microsamples typically measure capillary whole blood rather than plasma. Capillary blood is a mix of venous, arterial, and interstitial fluid and may have different drug concentrations when compared with plasma.4 Therefore, analytes with significant red cell partitioning (e.g., immunosuppressants) and biomarkers calibrated for plasma require matrix-specific validation and interpretation, which may require a correction factor validation to allow accurate representation from microsample.2,4 Table 1 - Comparative information of microsampling devices Devices Technology/Sampling Technique Analytea Advantages Limitations/Common Errors Sample Volume Regulatory Approvals Non volumetric devices Whatman 903 DBS Tacrolimus Cheaper and more available Sample contamination NA IVDR globally3, 8, 12 DMPK-B Mycophenolic acid Established use with many current applications Hematocrit concerns sample quality Up to six spots per card MPAG Inadequate drying time Prednisolone Volumetric devices Mitra VAMS Tacrolimus Simple device Potential to overfill device 10, 20 and 30 uL EMA Ciclosporin mycophenolic acid Range of volumes available Analyte recovery depends on HCT FDA MPAG Potential for tip contamination Canada Prednisolone Australia3,5,8,10,13 Sirolimus Everolimus Ganciclovir Creatinine Hemoglobin Tasso-M20 VAMS Tacrolimus Device designed to reduce contamination and contains lancet, drying is not required Retrieval of samples from device requires manual steps 4×17.5 uL EMA Mycophenolic acid FDA9,14 Creatinine HemaPEN Quantitative DBS Tacrolimus Four samples per device Issues with sample volume and quality control Four spots EMA Creatinine Protection against sample contamination Special device needed for lab to access sample Each 2.74 uL FDA15 CapitainerR Quantitative DBS Tacrolimus Device designed to reduce sample variation and contamination Requires sample to be removed manually from device Two spots of 10 uL or 50 uL EMA (IVDR) Ciclosporin FDA (DC1)16 Sirolimus Everolimus Ganciclovir HemaXis Quantitative DBS Tacrolimus DBS card combined with volumetric sample collection Potential for sample contamination 10 uL EMA (IVDR) Ciclosporin mycophenolic acid FDA (DC1)17 Sirolimus Everolimus DBS, Dried blood spot; EMA, European Medicines Authority; FDA, Federal Drug Authority; HCT, hematocrit; IVDR, in vitro diagnostic regulation; MPAG, mycophenolic acid glucoronide; NA, not applicable; VAMS, Volumetric Absorptive Microsamplers.aAnalytes listed here are of interest to kidney transplant community. Many more drugs and physiologic markers are being reported using these devices. Analytical Validation As with any new technology, there is a requirement to validate against existing procedures and considerations of blood sampling are no different, particularly in the kidney transplant space. Method validation must assess performance across the expected hematocrit range (e.g., 20%–65%) and include mitigation strategies for populations at risk (anemia, polycythemia).4 All microsampling devices are tested to regulatory standards and use statistical methods such as Bland-Altman or Deming approaches to assess clinical acceptance and is outlined in the International Association of Therapeutic Drug Monitoring and Clinical Toxicology guideinline.5 Applications Microsampling has been explored in an increasing number of compounds including metals and inorganic compounds, antibodies, anticonvulsants, antibiotics, lipids, and peptides.5,6 The commonly used transplant drugs collected and analyzed using microsamples include mycophenolic acid, tacrolimus, sirolimus, everolimus, ciclosporin, prednisolone, and valganciclovir and biomarkers include creatinine and hemoglobin (Table 1).5 The ability to test multiple drugs and creatinine from a microsample opens the door to both remote monitoring of both kidney function and therapeutic drug monitoring. Creatinine has also been tested in the outpatient setting simultaneously with isohexal in the same microsample allowing the possibility of a measured GFR from microsamples.6 Key applications of microsampling include trough concentration monitoring, area under the curve estimation, and adherence screening. Microsampling has also been used in pediatric populations and other jurisdictions where sample storage and transport are issues. Advantages An advantage of microsamples is that once collected and dried the samples are relatively robust and are not considered a biohazard so are able to be posted through regular mail and then stored at room temperature until analyzed.3 There is now a variety of microsampling devices (Table 1), which offer different advantages and sample volumes.3 Patients are interested in using microsampling devices and find the concept acceptable.7 In the early post-transplant period, hospital visits are burdensome with frequent visits for blood sampling and consultations being very disruptive to work and home life.8 The ability for patients to self-sample is very desirable as it reduces travel and waiting time in outpatient clinics.7,8 Another benefit to self-sampling at home is reduced exposure to the hospital environment with its nosocomial pathogens particularly when patients are immunosuppressed reducing infection risks.8 Microsamples may also assist in facilitating telemedicine. An area of particular interest and importance is pediatric transplant medicine where our vulnerable patients are often traumatized by needles and procedures microsampling has been used in this population to provide therapeutic drug monitoring.1 Disadvantages Microsampling devices are potentially open to abuse with over or underfilling or contamination; however, in an implementation study in pediatric kidney transplant patients, < 2% of samples were not able to be used due to sampling error.3 Patients do require a degree of dexterity to manage microsampling devices; this can be a concern if patients are experiencing dexterity issues or hand tremors, for example, from tacrolimus.7 In

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