The Molecular Microscope Diagnostic System (MMDx) Interpretation of Solid Organ Allograft Biopsies: Restoring the Perspective

Key points

• The Molecular Microscope^®Diagnostic System (MMDx^®) has been shown to help refine the histopathologist’s findings; MMDx Kidney may add interpretation that is not possible through light microscopy and support ABMR diagnosis where C4d or DSA results are either unavailable or negative
• By analyzing over a thousand genes, MMDx Kidney may reduce subjective interpretation
• MMDx Kidney has been shown to detect ABMR in renal medulla samples and changes associated with chronic lung allograft disease in mucosal biopsies, which cannot be detected using histology
• The value of MMDx Kidney in clinical practice and its benefit in early diagnosis of rejection was recognized during the 2019 Banff meeting

Summary

MMDx Kidney simultaneously analyzes the expression of 1,494 genes in a biopsy sample. Machine learning algorithms then classify the genetic profile in relation to type of rejection or other forms of graft injury.

The MMDx Kidney test is not an alternative to traditional biopsy. In this letter to the editor by Chris McCloskey et al. of the Thermo Fisher Scientific Transplant Diagnostics team, the system may be used to enhance and refine the histopathologist’s findings. MMDx Kidney demonstrates interpretation that is not possible through light microscopy and supports ABMR diagnosis where C4d or DSA results are either unavailable or negative. The complete MMDx Kidney report is available within 48 hours after the sample is received at the laboratory; this ensures the results can be viewed at a similar time as the more diagnostic elements of histology.

Whilst histopathologists clearly agree when disease is present or absent, there may be less agreement on the type of disease or stage of rejection. Where rejection lesions are focal, there is a possibility they will be missed on the biopsy section selected for microscopy. When reading slides, histopathologists apply their experience and their understanding of the current Banff criteria to a small section of the biopsy core, and therefore, it has been shown there are, naturally, variations in the specific diagnosis given by different histopathologists.

MMDx Kidney demonstrates that it can significantly reduce subjective interpretation by analyzing over a thousand genes that are variably affected by the specific disease processes and then applying machine-based learning to interpret these results against a database of classic cases. MMDx Kidney has shown excellent correlation in results across the biopsy core, and other diagnostic tests such as cell-free DNA (cfDNA) correlate better with MMDx Kidney than with histopathology in detecting ABMR.

MMDx Kidney resolves the gene pattern into 12 different result interpretations with excellent correlations with classic ABMR and TCMR. Compared with histopathology, genetic profiling as defined by MMDx Kidney has been shown to improve diagnosis of ABMR in 16% of cases and, in 20% of cases, has been shown to downgrade results to no molecular evidence of rejection.

Inadequate biopsy samples can confound the ability to diagnose rejection using light microscopy, but MMDx Kidney has been shown to detect ABMR in renal medulla samples, which cannot otherwise be diagnosed using histology.

The value of MMDx Kidney in clinical practice, its benefit in early diagnosis of rejection, and its subsequent health and economic impacts are already becoming evident. Indeed, the 2019 Banff meeting recognized the importance of molecular diagnostics to support histopathology. MMDx Kidney is a test available today to support the clinician in the accurate and timely diagnosis of post-transplant disease.

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