MMDx for Molecular Biopsy Assessment

What is the Molecular Microscope Diagnostic System? 

The MMDx Kidney, Heart and Lung are biopsy-based laboratory developed tests (LDTs) that measure the molecular expression of rejection and injury within organ transplants, estimating the probability of T-cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), and injury.

A new era of precision medicine 

MMDx uses microarray technology to measure gene expression within a biopsy sample, then analyzes this data using pre-defined machine learning algorithms to identify patterns associated with rejection and injury.


A software algorithm compares the molecular features of each new biopsy to those in an organ-specific reference set representing the global transplant population from early to greater than 30 years post-transplant in kidney and heart recipients, and greater than 19 years in lung recipients.

 

Manage post-transplant treatment with confidence


In the post-transplant setting, diagnoses relying on histopathologic assessment demonstrate poor concordance between pathologists1. However, "Molecular diagnostic assessment using microarrays combined with machine learning algorithms for interpretation have shown promise for increasing diagnostic precision via probabilistic assessements, recalibrating standard of care diagnostic methods, clarifying ambiguous cases, and identifying potentially missed cases of rejection"1.

Figure 1. Variability in TCMR Diagnosis
with Histopathology. When assessing the same organ biopsy sample, research shows that only a fraction of pathologists will agree on a TCMR diagnosis2,3,4.

Advantages of MMDx

MMDx complements conventional histopathology by providing reproducible results, enhancing diagnostic confidence.
  • Actionable data: Measures the probability of rejection and injury within an organ transplant
  • Fast turnaround: Results typically available in as little as 24-72 hours after receipt of sample*
  • Easily incorporated: Sample obtained from the existing biopsy (requires only 3 mm for kidney and 2 or more bites for heart and lung)
  • Efficient process: Sample is placed in a vial containing RNAlater solution and shipped at room temperature 

"In 82% of biopsy samples for which feedback was provided, investigators noted that MMDx would provide increased confidence for management decisions."⁵

MMDx Kidney

MMDx Kidney isolates the assessment of allograft rejection and injury. Research demonstrates parenchymal injury, not rejection, is the main determinant of allograft survival.1 Moreover, in kidney patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity, molecular assessment of rejection has been used to monitor response to treatment, evidenced by improved inflammation.8

 

A comprehensive biopsy assessment for kidney transplant patients

Assessment can be applied to a small sample of the existing biopsy. While cortical samples are preferred, the test can read samples containing both medulla and cortex, which may reduce the risk of an “inadequate” biopsy sample and, as a result, the need for a second biopsy.

 

New studies on molecular assessment for graft function

Inflammation in areas of atrophy-fibrosis (i-IFTA) has shown to be associated with increased risk of failure in kidney biopsies. A recent study has concluded that i-IFTA in indication biopsies reflect current or ongoing parenchymal injury, MMDx Kidney has demonstrated accuracy and reproducibility in kidney biopsy assessment with minimal inter-observer disagreement in reporting. As a result, MMDx may be particularly valuable in cases when pathology results are borderline or suspicious9.

MMDx Heart

MMDx Heart separates the assessment of endomyocardial rejection and injury, providing greater insight to the relationship between rejection, injury, and cardiac function. Severe injury (more often seen in TCMR than ABMR) and late atrophy fibrosis tend to associate with reduced cardiac function and lower survival. Evaluating these disease states as separate entities, may help support diagnostic accuracy and better guide patient care.

 

A comprehensive biopsy assessment for all heart transplant patients

Requires 2 or more tissue bites for robust and reproducible results. Through gene expression profiling, this test assesses the likelihood of an allograft demonstrating rejection and/or injury, providing probability scores for T-cell mediated rejection (TCMR), antibody mediated rejection (ABMR), recent injury, and late injury (atrophy fibrosis).

 

New studies on molecular assessment for graft function

MMDx Heart has demonstrated an improved sensitivity for the detection of subclinical graft injury in heart patients6 and for the evaluation of antibody-mediated rejection (ABMR)7. Molecular assessment may also provide greater clarity for biopsies with high probability of molecular injury but no molecular rejection, a state that can often be misdiagnosed as rejection by histology.10

MMDx Lung

For lung transplant patients, MMDx provides insights into graft health by analyzing gene expression patterns to evaluate early signs of rejection. By leveraging this advanced diagnostic tool, clinicians can make informed decisions to optimize treatment.

 

The mechanisms involved in pulmonary allograft injury and rejection are poorly understood, and histological assessment of transbronchial biopsies (TBB) offer limited reproducibility and present considerable risk11. MMDx Lung may offer new insights into these disease states and generates assessment in every TBB with 2 or more tissue bites—measuring the probability of rejection as well as evaluating the molecular features associated with chronic lung allograft dysfunction (CLAD)11.

 

A comprehensive biopsy assessment for all lung transplant patients

Through allograft gene expression profiling, this test assesses the probability of a biopsy specimen demonstrating rejection, as well as CLAD related molecular changes. While five or more TBB bites are recommended for histology assessment, MMDx requires at least two of the total bites obtained for robust and reproducible molecular assessment.

"Molecular diagnostic assessment using microarrays combined with machine learning algorithms for interpretation has shown promise for increasing diagnostic precision."¹

From specimen collection to biopsy report: the MMDx process

Obtaining results starts with requesting a free Specimen Collection Kit. The following steps illustrate the process from collection kit request to analysis, and clinician engagement.

References

  1. Madill-Thomsen, K. S., & Halloran, P. F. (2024). Precision diagnostics in transplanted organs using microarray-assessed gene expression: Concepts and technical methods of the molecular microscope® diagnostic system (mmdx). Clinical Science, 138(11), 663–685.
  2. Arcasoy, S.M. et al. (2011). Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable. American Journal of Transplantation 11, 320-328.
  3. Crespo-Leiro MG, Zuckermann A, Bara C, et al. Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II). Transplantation. 2012;94(11):1172-1177.
  4. Reeve J, Sellarés J, Mengel M, et al. Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies. Am J Transplant. 2013;13(3):645-655.
  5. Halloran PF, Reeve J, Akalin E, et al. Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study. Am J Transplant. 2017;17(11):2851-2862.
  6. AP Nikolova, JA Kobashigawa. Donor-specific antibodies in heart transplantation: can we a_ord the price or is it too steep to pay? Curr Opin Organ Transplant. 2020 Dec;25(6):555-562.
  7. VP Nguyen, JA Kobashigawa. Antibody-medicated rejection after heart transplantation: diagnosis and clinical implications. Curr Opin Organ Transplant. 2020 Jun; 25(3):248-254.
  8. D Kumar et al. Impact of Belatacept Conversion on Renal Function, Histology, and Gene Expression in Kidney Transplant Patients With Chronic Active Antibody-mediated Rejection. Transplantation. 2021 Mar 1;105(3):660-667.
  9. Madill-Thomsen K et al; MMDx-Kidney Study Group. Discrepancy analysis comparing molecular and histology diagnoses in kidney transplant biopsies. Am J Transplant. 2020 May;20(5):1341-1350.
  10. PF Halloran et al. Exploring the cardiac response to injury in heart transplant biopsies. JCI Insight. 2018 Oct 18;3(20):e123674.
  11. Gauthier, P. T., et al. (2023). Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies. American Journal of Transplantation, 23(12), 1922–1938.

Order your free Specimen Collection Kit

Coverage information for MMDx

* Turnaround times are approximate and are subject to variation.

 

MMDx Heart, MMDx Kidney and MMDx Lung are tests that were developed and validated by Kashi Clinical Laboratories, LLC.  The laboratory developed tests are used for clinical purposes by the CLIA-certified laboratory performing the test. These tests have not been cleared or approved by the US FDA or CE marked in the EU as an in vitro diagnostic test.

 

MMDx and Molecular Microscope are trademarks of Transcriptome Sciences Inc.