The management of chronic disease remains challenging on multiple fronts, requiring patients’ insight into their chronic disease; their compliance with medications and laboratory tests, regular follow-up with medical providers; and appropriate financial support through healthcare system. Kidney transplant recipients represent a distinctive model population with chronic disease where transplantation is limited by an inadequate organ supply, resulting in long wait times for a precious opportunity, the safeguarding of which then requires frequent, ongoing laboratory tests to monitor allograft function and drug levels. Transplantation is an immunological disease entity where the inability to achieve clinical transplant tolerance has left transplant physicians to rely solely on blood tests to assess allograft function and to manage therapeutic drug dosing. Kidney transplant recipients require regular testing of serum creatinine (sCr) and levels of cyclosporine A (CsA) or tacrolimus (TAC). Lapses in laboratory testing can lead to kidney graft dysfunction through missed opportunities to detect subtherapeutic dosing causing rejection and failure to identify drug toxicity. The processes of blood collection, testing methodologies, and reporting have not changed substantially over the past several decades.
The term “Disruptive Innovation” was coined by Clayton M. Christensen in 1995 to refer to a discovery “that creates a new market and value network and eventually disrupts an existing market and value network, displacing established market leading firms, products and alliances.” Unfortunately, the medical industry unlike other industries, in our opinion, has not welcomed “disruptive innovations.” However, in this issue of Transplantation, in their article entitled “Dried Blood Spot bio sampling to Follow TAC, cyclosporine A and creatinine levels in Kidney Transplant Patients”, Veenhof et al1 validate the use of Dried Blood Spot (DBS), a potential disruptive innovation, for the measurement of CsA, TaC, and sCr.
The technique of DBS has been in widespread use as a screening tool since the American microbiologist Robert Guthrie first introduced the “Guthrie card” in the 1960s to screen neonates for the metabolic disorder phenylketonuria.2 Recent advances have significantly improved the sensitivity and specificity of testing and have led to automation technology, allowing its use for an increasing range of tests, including screening for sickle cell and human immunodeficiency virus, and for measuring levels of vitamin D, TSH, lipids, testosterone, and various drugs.3 DBS sampling presents many important advantages over traditional whole blood sampling by venipuncture. DBS is less invasive than traditional phlebotomy, particularly important for patients with limited venous access due to the alterations and trauma of repeated phlebotomy and dialysis access. It offers the potential to collect samples outside of a laboratory facility without need for refrigeration, which could potentially decrease cost to the patient and allow appropriate timing of drug trough levels without need to consider laboratory business hours, transportation, and life constraints such as work, school, or childcare. DBS also presents less of a biohazard risk to handlers and is easier to transport than traditional laboratory vials and has the potential to be more economical both in terms of time and finances due to its ease, efficiency, rapid turnaround time for results and decreased need for laboratory equipment and personnel.
In a simple, innovative study, Veenhof et al1 examined the use of DBS in 210 paired samples from adult kidney transplant patients in a single transplant center. DBS samples were collected during routine visits and were allowed to dry for 1 to 7 days at room temperature, then stored in a −20°C freezer until analyzed. Linear regression analysis showed a significant correlation for sCr, TAC, and CsA levels between DBS and plasma derived from whole blood obtained by venipuncture. A fixed bias was noted for sCr that was easily overcome with the use of a conversion factor [DBS plasma creatinine in μmol/L divided by 0.73]. The differences in CsA and TAC level between DBS and conventional venipuncture testing were not clinically significant and required no correction formula. Their results are in keeping with previous studies evaluating the correlation of CsA and TaC levels in DBS compared to venous whole blood, although the use of different sampling paper may explain some of the variation in the fixed bias noted between the studies.4,5 Thus, the study by Veenhof et al supports the feasibility of using DBS sampling in routine clinical care of kidney transplant recipients to replace conventional blood testing.
The logistical challenges for adopting DBS are many. The authors have acknowledged some of the aspects related to technology including the time lapse between sampling and the arrival of samples to the laboratory, its stability beyond the range of temperatures and duration of storage studied (−20°C to 25°C for at least 30 days and up to 60°C for at least 5 days)1,6 and damage during shipping. In addition, both phlebotomy as well as DBS samples were obtained by trained phlebotomists, and it remains to be seen if patients can be taught to accurately and reliably obtain and prepare their own blood samples.
Healthcare systemwide barriers to the adoption of routine DBS will also need to be overcome. Corporations that derive profit from their phlebotomy centers and laboratories and some academic institutions may have financial stake in maintaining the status quo. In addition, legal barriers from state and federal regulations, with influence from lobbyists supporting special interests groups, will need to be addressed. However, we expect that healthcare payers such as private insurance companies, and government supported healthcare systems such as Medicare, might be very interested in adopting DBS testing as a means to decrease the cost of caring for kidney transplant recipients. Ultimately, money will talk!
In summary, the article by Veenhof et al is scientifically sound and validates a method of blood testing that appears simple to implement and has the potential to improve the care and lessen the burden to patients and decrease cost, but its widespread implementation is likely to face hindrances from government agencies and special interest groups. We are living in an era of “Disruptive Innovation”; the utility of the typewriter has vanished, the pay phone has nearly disappeared, and UBER has disrupted conventional transportation technology. One can only hope that the medicinal industry will begin to embrace technologically innovative approaches toward patient care.
1. Veenhof H, Koster RA, Alffenaar JC, et al. Clinical Validation of Simultaneous Analysis of Tacrolimus, Cyclosporine A, and Creatinine in Dried Blood Spots in Kidney Transplant Patients. Transplantation
2. Lesser AJ. Phenylketonuria and the Guthrie test. Pediatrics
3. Parker SP, Cubitt WD. The use of the dried blood spot sample in epidemiological studies. J Clin Pathol
4. Wilhelm AJ, Klijn A, den Burger JC, et al. Clinical validation of dried blood spot sampling in therapeutic drug monitoring of ciclosporin A in allogeneic stem cell transplant recipients: direct comparison between capillary and venous sampling. Ther Drug Monit
5. Hinchliffe E, Adaway J, Fildes J, et al. Therapeutic drug monitoring of ciclosporin A and tacrolimus in heart lung transplant patients using dried blood spots. Ann Clin Biochem
6. Sadilkova K, Busby B, Dickerson JA, et al. Clinical validation and implementation of a multiplexed immunosuppressant assay in dried blood spots by LC-MS/MS. Clin Chim Acta