Medical Policy: 02.04.75
Original Effective Date: May 2019
Reviewed: May 2020
Revised: May 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Most cardiac transplant recipients experience at least one episode of rejection in the first year after transplantation. In 2005, the International Society for Heart and Lung Transplantation modified its grading scheme for categorizing cardiac allograft rejection. Revised (R) categories are as follows:
Acute cellular rejection is most likely to occur in the first 6 months, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a lifelong basis, dosing is adjusted based on graft function and the grade of acute cellular rejection determined by histopathology. Endomyocardial biopsies are typically taken from the right ventricle via the jugular vein periodically during the first 6-12 months post-transplant. The interval between biopsies varies among clinical centers. A typical schedule is weekly for the first month, once or twice monthly for the following 6 months, and several times (monthly to quarterly) between 6 months and a year post-transplant. Surveillance biopsies may also be performed after the first postoperative year e.g., on a quarterly or semi-annual basis. This practice, although common, has not been demonstrated to improve transplant outcomes.
Endomyocardial biopsy is invasive and carries a risk of adverse effects; therefore, non-invasive methods of detecting cellular rejection are being explored. Individualized adjustment of the level of immunosuppression based on the risk of rejection and risk of immunosuppression-related adverse events is challenging to implement. It has been proposed that this level of personalization may be possible with molecular diagnostic techniques. Further evidence will be needed to determine the utility of this molecular diagnostic assay as a replacement for routine biopsies and its potential role in weaning immunosuppression and other aspects of long-term management of cardiac transplant recipients.
The Heartsbreath test, is a noninvasive test that measures breath markers of oxidative stress, has been developed to assist in the detection of heart transplant rejection. In heart transplant recipients, oxidative stress appears to accompany allograft rejection that degrades membrane polyunsaturated fatty acids, and evolving alkanes and methylalkanes that are in turn excreted as volatile organic compounds in breath. The Heartsbreath test analyzes the breath methylated alkane contour , which is derived from the abundance of C4-C20 alkanes and monomethylalkanes and has been identified as a marker to detect grade 3 (clinically significant) heart transplant rejection.
A non-invasive testing approach has focused on patterns of gene expression as detected in the peripheral blood. Allomap® analyzes the expression of 20 genes in a transplant recipient’s blood sample to determine whether the patient’s immune system is launching an attack. It is intended for patients at least 15 years-old who are at least 2 months post-transplant. AlloMap® for heart transplant recipients involves measurement of a panel of genes derived from peripheral blood cells, and application of an algorithm to the results. The algorithm produces a single score with the lower scores indicating a lower risk of graft rejection.
The MMDx system uses predefined algorithms to assess the probability of rejection or injury by assessing microarrays to measure mRNA levels. The additional accuracy of biopsy testing and treatment decisions are not changed by information obtained from this testing. Current clinical trials are ongoing.
The Viracor TRAC™ dd-cfDNA assay determines the percentage of circulating cell-free DNA (cfDNA) in transplant recipients derived from donor grafts. cfDNA is extracted from plasma isolated from whole blood collected. NGS and genome-wide recipient genotype data are then analyzed by a bioinformatics pipeline that calculates the percentage of dd-cfDNA present. This test was developed and its performance characteristics determined by Viracor Eurofins.
Cell-free DNA (cfDNA), released by damaged cells, is normally present in healthy individuals. In patients who have received transplants, donor-derived cfDNA (dd-cfDNA) may also be present. It has been proposed that allograft rejection, which is associated with damage to transplanted cells, may result in an increase in dd-cfDNA. AlloSure is a commercially available, next-generation sequencing (NGS) assay which quantifies the fraction of dd-cfDNA in renal transplant recipients, relative to total cfDNA, by measuring 266 single nucleotide variants (SNVs). The myTAIHEART reports the ratio of donor specific cfDNA to total cfDNA as the donor fraction (%) and categorizes the patient as at low or increased risk of moderate/severe acute cellular rejection.
NanoString Technologies has announced the launch of nCounter Human Organ Transplant, a gene expression panel for researchers to evaluate the human immune response following organ transplantation. Created through a collaboration between NanoString and the Banff Foundation for Allograft Pathology, a global consortium of 6 transplant institutes. The customizable, 770-gene expression panel was developed specifically for use with the predominant transplant organs including kidney, heart, lung, and liver and includes genes across 37 different pathways, critical components of the immune response, tissue injury, and mechanisms of action for immunosuppressive drugs. The panel also includes probes for detection of common viral infections known to be problematic with transplants including BK polyomavirus, cytomegalovirus and Epstein-Barr virus. The Human Organ Transplant Panel is for research use only; not for use in diagnostic procedures. Veracyte system. HistoMap is being developed using the Human Organ Transplant (HOT) panel from the Banff Foundation for Allograft Pathology.
In 2010, the International Society of Heart and Lung Transplantation (ISHLT) issued guidelines for the care of heart transplant recipients which included the following:
The Kidney Disease Improving Global Outcomes (2009) issued guidelines for the care of kidney transplant recipients, The guidelines included the following recommendations.
Recommendation: "We recommend kidney allograft biopsy when there is a persistent, unexplained increase in serum creatinine.” Level 1 C
"We suggest kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection.” Level 2 D
AlloMap® molecular expression testing may be considered medically necessary as a non-invasive method of determining the risk of rejection in heart transplant recipients at least 15 years of age, between 6 months and 5 years post-transplant.
Breath test for measurement of volatile organic compounds to detect heart transplant rejection (e.g. Heartsbreath) is considered investigational.
Donor-derived cell-free DNA (dd-cfDNA) testing (e.g. Allosure, myTAIHEART, Prospera, Viracor TRAC) for transplant rejection status is considered investigational.
Microarray gene expression profiling panels for transplant rejection status (e.g. MMDx-Kidney, MMDx-Heart, kSORT) are considered investigational.
Human organ transplant panels (e.g. nCounter, HistoMAP) are considered investigational.
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