Benefits of mass spectrometry in monitoring immunosuppressive drugs for organ transplants

One organ donor can save up to eight lives, with estimates indicating that organ donation saves thousands of lives each year.¹ In 2022, it was reported that physicians performed over 150,000 organ transplantations worldwide and procedures continue to grow about 10% annually, with the most frequently transplanted organs being kidney, liver, heart, and lung.²

However, a major challenge in solid organ transplantation is managing the immune system response, in order to prevent organ rejection in recipients. To address this, healthcare providers will prescribe organ recipients immunosuppressant drugs (ISD), to help reduce acute rejection rates and prolong transplant survival.³

However, ISDs have a narrow therapeutic window, combined with high inter- and intrapatient variability and severe consequences for patients when being outside of the therapeutic window. If ISDs are at a sub-therapeutic level in a patient, this can cause therapeutic failure, leading to organ injury and ultimately, rejection of the transplanted organ. If concentrations are too high, this can cause serious side effects, including drug-induced organ toxicity and an increased risk for infections and malignancy due to over-immunosuppression.³ As such, labs play an integral role in monitoring ISD blood concentrations and aiding healthcare professionals in prescribing the optimal drug dose within a narrow therapeutic range. 

Over the past decades, laboratory methods for monitoring ISDs have evolved, with today, liquid chromatography-tandem mass spectrometry (LC-MS/MS) being the reference standard for TDM of ISDs. The expanding role of LC-MS/MS in TDM is not only based on its superior analytical capacities compared to other methods but also on dramatic improvements in analytical instrumentation, enabling timely access to drug-specific testing, prompt dose adjustment and safe treatment for patients.^3-6

The era of modern immunosuppression started with the immunosuppressive agent cyclosporin in the early 1980s, which led to significant improvements in survival rates over previous decades.⁷ Today, a wide array of ISDs, including tacrolimus, cyclosporine, sirolimus, everolimus, and mycophenolate mofetil, are used to suppress the immune system following organ transplants. These agents can be administered by combining two or more based on their different mechanisms of action.⁸

This multidrug approach is considered the standard of care that allows physicians to modify therapy as needed for each patient’s specific needs, accounting for drug-drug interactions, pre-existing diseases, and organ rejection risk.^8,9 Because the optimal therapeutic window is extremely narrow and may vary between patients, taking this personalized approach using TDM with ISD dosing is critical. This method helps physicians achieve the optimal balance between organ rejection and ISD adverse effects.^3,10

“In my laboratory, we are currently working in batch mode to deliver mass spectrometry results to physicians. Being able to deliver those results 24/7 and with random access, would enable physicians and patients to receive their results on demand, matching the needs of the highly dynamic hospital environment," said Prof. Dr. Pieter Vermeersch.

Measurements of ISDs need to be accurate and precise. Analytical methods for TDM of ISDs have undergone major developments over the last decades, with LC-MS/MS currently being considered as the gold- (or reference) standard for TDM of ISDs.¹¹

Since clinicians prescribe multiple ISDs that are used simultaneously in a transplant patient’s treatment regimen, there is a significant need to correctly separate and identify agents when blood concentrations can be low or structurally related compounds are administered to patients. Mass spectrometry offers a highly sensitive and selective approach for the low limit of ISD detection and quantification.¹²

Because inaccuracy of ISD dosing can lead to harmful side effects or graft rejection, clinical labs are leveraging LC-MS/MS due to its superior specificity when compared to other commonly utilized techniques. For example, reports show interference of drug metabolites when measuring ISDs using immunoassays, resulting in a positive bias of up to 20% when compared to LC-MS/MS.^13-15

Measurements of ISDs such as sirolimus, everolimus, and their metabolites, when not using a highly sensitive method, can also lead to incorrect results due to structural similarities and thus, significant cross-reactivity.^13,16 Furthermore, endogenous antibodies from patients can be a major challenge, leading to incorrect measurements with immunoassays and causing up to 4% variability in results.¹⁷

As ISDs are prescribed as a long-term therapy, it is important that the analytical performance of methods and laboratories is consistent over a long period of time. However, variability within laboratories and between labs is a major issue due to lot-to-lot variation and the heterogeneous nature of LC-MS/MS configurations.

The interlaboratory variability for lab-developed LC-MS/MS tests stems mainly from:¹⁸

• Lack of standardization

• Lack of appropriate reference materials

• Poor compliance with internationally accepted good laboratory practice (GLP) guidelines

Within laboratory medicine, the ongoing promotion of standardization and development of reference method procedures is further improving the traceability and consistency of LC-MS/MS results across laboratories.¹⁹ Efforts are currently being made by the IVD industry to improve the standardization and traceability of results, with the ultimate goal of reducing intra- and inter-lab variability.

When asked about the importance of mass spectrometry in the monitoring of ISDs in transplant patients, Prof. Dr. Pieter Vermeersch stated “Monitoring/measuring immunosuppressant drugs (ISDs) is a key application for Therapeutic Drug Monitoring (TDM) with LC-MS/MS. As the number of transplant procedures rises annually, laboratories are striving to enhance their workflows. Their aim is to support transplant patients and their physicians by delivering accurate results using the gold standard method in a standardized and consistent manner, while also ensuring these results are available quickly and on demand.

Current advancements in automation and efforts toward standardization will significantly enhance the quality and workflow of result generation, ultimately leading to improved patient care. These developments further solidify the essential role of LC-MS/MS in TDM of immunosuppressant drugs.”