Description

A biopsy is considered the gold standard for the diagnosis of organ transplant rejection. Noninvasive methods for the detection and surveillance of transplant rejection have been developed with the goal of reducing the number of biopsies. These tests include, but may not be limited to, the following:

Gene Expression Profiling

• A gene expression test (eg, AlloMap) has been developed to predict the likelihood of cardiac rejection. Following a transplant, the test evaluates the quantitative measure of 20 genes using an algorithm to report a rejection risk score. The test is intended to be used in conjunction with standard clinical assessment to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection at the time of testing.
• Immune response gene expression panel (eg, nCounter Human Organ Transplant Panel) has been developed to assess immune response following organ transplant utilizing a panel of 770 genes across 37 pathways that purportedly evaluates kidney, heart, liver and lung rejection. (Refer to Coverage Limitations section)
• mDNA and mRNA gene expression assays utilize proprietary microarrays and algorithms based on a reference set of biopsies to provide scores to assess the probability of rejection by reportedly measuring cell-mediated rejection. The tests are purportedly utilized for heart, kidney, and lung transplants. Examples of mDNA and mRNA gene expression assays include, but may not be limited to:
1. Clarava pretransplant mRNA expression assay
2. Molecular Microscope Diagnostic system (eg, MMDx Heart, MMDx Kidney, MMDx Lung)
3. TruGraf Blood Gene Expression Test
4. Tutivia post-transplant mRNA expression assay
• ImmuKnow Cytotoxic T-cell Function assay (kSORT) has been developed for kidney transplant rejection to reportedly detect individuals who are at high risk for acute rejection. Polymerase chain reaction (PCR) is utilized to measure the relative messenger ribonucleic acid (mRNA) expression levels of 17 genes that have been known to be associated with acute rejection. Individuals are classified into high, low or indeterminate risk according to a correlation-based algorithm. (Refer to Coverage Limitations section)

Antigen-Specific T-cell Function Assay

• CD154+-T-cytotoxic memory cell testing has been developed to reportedly determine the likelihood of acute cellular rejection by measuring the immune response of recipient lymphocytes to donor or donor-like cells. The tests utilize an index ratio, which purportedly represents cell activity of the T-cytotoxic memory cells toward the donor cells and assesses the risk of rejection. This testing is designed for determining rejection risk in renal transplants (eg, Pleximark Tx) and for pediatric liver and small bowel transplants (eg, Pleximmune).

Molecular Diagnostic Assays and Breath Testing for Transplant Rejection Effective Date: 03/01/2023 Revision Date: 03/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0313-021 Page: 3 of 13 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Breath Testing

• Breath methylated alkane contour (BMAC) (eg, Heartsbreath) is a test that is purportedly indicated for use as an aid in the diagnosis of grade 3 heart transplant rejection in individuals who have received a heart transplant within the preceding year. It is intended to be used as an adjunct to, and not as a substitute for, an endomyocardial biopsy. The use of the test is limited to individuals who have had an endomyocardial biopsy within the previous month. By breathing into a plastic mouthpiece that is attached to a breath collecting device, the amount of methylated alkanes in the individual's breath is supposedly subtracted from that found in the room. A value is then generated and is compared to the results of a biopsy performed during the previous month to measure the probability of the implanted heart being rejected. (Refer to Coverage Limitations section)

Combined Gene Expression Profiling and Donor-Derived Cell-Free (dd-cfDNA) tests

• These tests are designed to reportedly provide a broad assessment of immune quiescence (inactivity) and graft injury by combining a gene expression profiling test and a dd-cfDNA test (eg, AlloMap and AlloSure Heart [HeartCare], TruGraf and Viracor TRAC Kidney [OmniGraf]). (Refer to Coverage Limitations section)

dd-cfDNA

• Biomarker blood tests purportedly determine allograft injury by measuring DNA fragments that are supposedly released into the bloodstream from the injured donor allograft cells. The goal of these tests is to predict active rejection using these measurements. These tests include, but may not be limited to:
• AlloSure Heart
• AlloSure Kidney
• AlloSure Lung
• Prospera Heart
• Prospera Kidney with Quantification
• Viracor TRAC (heart, kidney, liver, and lung)
(Refer to Coverage Limitations section)

Urine-Based Tests for Allograft Rejection

• Several urine-based tests have been proposed utilizing various biomarkers to aid in the diagnosis of acute rejection in kidney transplant recipients. Purportedly, the tests measure urine mRNA, urine proteins and/or urine proteomics. Some tests measure several biomarkers (eg, QiSant [also known as QSant]) to reportedly determine acute kidney transplant rejection. The biomarkers include, but may not be limited to, cfDNA, methylated cfDNA, clusterin, CXCL10, creatinine and total protein, which are integrated into an algorithm to supposedly determine kidney risk rejection scores. (Refer to Coverage Limitations section)

Molecular Diagnostic Assays and Breath Testing for Transplant Rejection Effective Date: 03/01/2023 Revision Date: 03/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0313-021 Page: 4 of 13 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. These are considered experimental/investigational as they are not identified as widely used and generally accepted for any other proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for the following tests to aid in the diagnosis of transplant rejection:

• Antigen-specific T-cell function assays (eg, CD154+T-cytotoxic memory cells [Pleximark Tx – 0018M, Pleximmune – 81560]); OR
• Breath testing (eg, Heartsbreath) (0085T); OR
• Combined Gene Expression Profiling and dd-cfDNA tests (eg, HeartCare, OmniGraf); OR
• dd-cfDNA test including, but may not be limited to:
  • AlloSure Heart
  • AlloSure Kidney
  • AlloSure Lung
  • Prospera Heart
  • Prospera Kidney with Quantification
  • Viracor TRAC (heart, kidney, liver, lung)
  OR
• Urine-based tests for allograft rejection (eg, QiSant [also known as QSant])

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Background

• American College of Cardiology
• American Heart Association
• International Society of Heart and Lung Transplantation
• National Kidney Foundation
• National Library of Medicine

Medical Alternatives

• Alternatives to molecular diagnostic assays and breath testing include, but may not be limited to, the following:
• Biopsy of the transplanted organ
• Physician consultation is advised to make an informed decision based on an individual’s health needs.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.