Medical Policy: 02.04.75
Original Effective Date: May 2019
Reviewed: May 2021
Revised: May 2021
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.
Transplant rejection involves an immune response to a transplanted organ. The recipient’s immune system recognizes the donated organ as “foreign,” thereby initiating an immune response as if the transplant organ was a foreign antigen. This response may cause the organ transplant to fail. Gene expression profiling (GEP), donor derived serum cell-free DNA (dd-cfDNA), breath testing, and urine-based assays have been proposed as a possible way to monitor organ transplant rejection non-invasively.
Solid Organ transplant requires much oversight and evaluation. Rejection, or failure of the transplant, is a potential outcome of any transplant case. At the molecular level, rejection is primarily caused by a component of the adaptive immune system, the major histocompatibility complex (MHC) proteins. These proteins must match between the donor and recipient, or the transplant can fail.
The MHC proteins’ primary function is acting as the platform on which T-cells identify antigens. Typically, these MHC proteins bind foreign antigens, which are then recognized as such by T-cells. From there, the T-cells can generate an immune response to handle the antigen. However, the MHC protein products must be identified as “self” by these T-cells as well. If an organ donor’s MHC protein does not match the recipient’s, the recipient’s T-cells may identify the MHC of donated organ as “foreign” and subsequently implement an immune response. This eventually starts the cascade of events that causes the transplant to fail.
Numerous methods mitigate this immune response such as immunosuppressants, which cause desensitization of the immune response. Other methods involve evaluating the risk of organ transplant rejection using gene expression profiling (GEP), donor derived serum cell-free DNA (dd-cfDNA), breath testing and urine-based testing evaluation which include the following:
• nCounter Human Organ Transplant Panel: Is a gene expression panel profiling 770 genes across 37 annotated pathways to discover biomarkers for organ rejection and tissue damage for kidney, heart, liver and lung. Also, identifies BK Polymavirus, Cytomegalovirus (CMV) and Epstein Barr-Virus.
• Kidney Solid Organ Response Test (kSORT): Has been developed for kidney transplant rejection to purportedly detect individuals who are at high risk for acute rejection. Polymerase chain reaction (PCR) is utilized to measure the relative 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.
Transplant clinicians benefit by stratifying patients into those who may benefit from surveillance biopsy and those who likely won’t, allowing them to eliminate a large percentage of surveillance biopsies that would likely have been negative if performed.
The purpose of gene expression profiling (GEP) tests, donor derived serum cell-free DNA (dd-cfDNA) testing, breath testing and urine- based testing evaluation are possible ways to monitor organ transplant rejection.
The relevant population of interest is individuals who have received a solid organ transplant.
Using gene expression profiling (GEP) tests, donor derived serum cell-free DNA (dd-cfDNA) testing, breath testing and urine- based testing to determine prognosis and/or predict acute cellular rejection.
Comparators of interest include organ biopsy to confirm a clinical suspicion of allograft rejection.
The general outcome interest is overall survival (OS), test validity, morbid events and hospitalizations. Follow-up over months to years is needed to monitor for signs of allograft rejection.
Most cardiac transplant recipients experience at least a single episode of rejection in the first year after transplantation. The International Society for Heart and Lung Transplantation modified is grading scheme for categorizing cardiac allograft rejection. The Revised (R) categories are listed in the below table:
| New Grade | Definition | Old Grade |
|---|---|---|
| 0R | No rejection | |
| 1R | Mild rejection | 1A, 1A and 2 |
| 2R | Moderate rejection | 3A |
| 3R | Severe rejection | 3B and 4 |
Acute cellular rejection is most likely to occur in the first 6 months after transplantation, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a life-long 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 to 12 months posttransplant. 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 1- year posttransplant. Surveillance biopsies may also be performed after the first postoperative year (eg, on a quarterly or semiannual basis). This practice, although common, has not been demonstrated to improve transplant outcomes. Some centers no longer routinely perform endomyocardial biopsies after 1 year in patients who are clinically stable.
While the endomyocardial biopsy is the criterion standard for assessing heart transplant rejection, it is limited by a high degree of interobserver variability in the grading of results and potential morbidity that can occur with the biopsy procedure. Also, the severity of rejection may not always coincide with the grading of the rejection by biopsy. Finally, a biopsy cannot be used to identify patients at risk of rejection, limiting the ability to initiate therapy to interrupt the development of rejection. For these reasons, an endomyocardial biopsy is considered a flawed criterion standard by many. Therefore, noninvasive methods of detecting cellular rejection have been explored. It is hoped that noninvasive tests will assist in determining appropriate patient management and avoid overuse or underuse of treatment with steroids and other immunosuppressants that can occur with false-negative and false-positive biopsy reports.
Gene expression profiling (GEP) of mononuclear cells in peripheral blood specimens has been studied as an alternative to endomyocardial biopsy (EMB) to detect cellular rejection and is used to limit the number of surveillance biopsies.
AlloMap gene expression assay (GEP) based on the literature was found to distinguish grade 0 (termed "quiescence") from moderate to severe rejection (grade ≥3A in the 1990 system; classified as ≥2 R in the 2004 system). The test correctly identified 84% of moderate to severe rejection. Patients with a score <30 at more than one-year posttransplant were highly unlikely to have moderate to severe rejection (negative predictive value 99.6 percent). This assay has been adopted clinically by many cardiac transplant programs.
The recommendation for AlloMap is based on the results of the CARGO and IMAGE trials. The current International Society of Heart and Lung Transplantation (ISHLT) recommendations for the use of AlloMap in limited clinical protocols are the results of the IMAGE trial, and input from the transplant practice community supporting the use of AlloMap to assess risk for acute cellular rejection (ACR) in clinically stable heart transplant recipients. The evidence is sufficient to determine the effects of the technology on net health outcomes.
Noninvasive laboratory testing using gene expression profiling (GEP) (nCounter Human Organ Transplant Panel, MMDX Heart, breath testing (Heartsbreath), and donor derived cell-free DNA (dd-cfDNA) testing (MyTAIHeart Tests) to aid in the diagnosis of heart transplant rejection have been developed and studied, however, further evidence will be needed to determine the utility of these molecular diagnostic assay as a replacement for routine biopsies and other aspects of long-term management of heart transplant recipients. The evidence is insufficient to determine the effects of the technology on net health outcomes
Allograft dysfunction is typically asymptomatic and has a broad differential, including graft rejection. Diagnosis and rapid treatment are recommended to preserve graft function and prevent loss of the transplanted organ. For a primary kidney transplant, graft survival at 1 year is 94.7%; at 5 years, graft survival is 78.6%.
Surveillance of transplant kidney function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis.27, Allograft dysfunction may also be demonstrated by a drop in urine output or, rarely, as pain over the transplant site. With clinical suspicion of allograft dysfunction, additional noninvasive workup including ultrasonography or radionuclide imaging may be used. A renal biopsy allows a definitive assessment of graft dysfunction and is typically a percutaneous procedure performed with ultrasonography or computed tomography guidance. Biopsy of a transplanted kidney is associated with fewer complications than biopsy of a native kidney because the allograft is typically transplanted more superficially than a native kidney. Renal biopsy is a low-risk invasive procedure that may result in bleeding complications; loss of a renal transplant, as a complication of renal biopsy, is rare.
Kidney biopsies allow for diagnosis of acute and chronic graft rejection, which may be graded using the Banff Classification. Pathologic assessment of biopsies demonstrating acute rejection allows clinicians to further distinguish between acute cellular rejection and antibody-mediated rejection, which are treated differently.
Noninvasive laboratory testing using gene expression profiling (GEP) (nCounter Human Organ Transplant Panel, Kidney Solid Organ Response Tests [kSORT, TruGraf, Molecular Microscopic Diagnostic System [MMDX)] kidney), donor derived cell-free DNA testing (Allosure Kidney, Prospear, Viracor TRAC) and urine-based test (QiSant also known as QSant) to aid in the diagnosis of kidney transplant rejection have been developed and studied, however, further evidence will be needed to determine the utility of these molecular diagnostic assay as a replacement for routine kidney biopsies and other aspects of long-term management of kidney transplant recipients. The evidence is insufficient to determine the effects of the technology on net health outcomes
Acute allograft rejection is a significant problem in lung transplantation. Despite advances in induction immunosuppression and use of aggressive maintenance immunosuppression, more than a third of lung transplant recipients are treated for acute rejection in the first year after transplant. Acute rejection is responsible for approximately 4 percent of deaths in the first 30 days following transplantation.
Laboratory testing in patients with suspected acute lung transplant rejection is generally nonspecific. Peripheral eosinophilia may be present; however, specific blood markers for rejection are not available. As infection is in the differential diagnosis, microbiologic stains and cultures are obtained from sputum, and bronchoalveolar lavage or bronchial washing samples. Cytomegalovirus (CMV) viral load testing is performed on peripheral blood.
The diagnosis of acute cellular rejection in lung transplant recipients is based on the presence of characteristic histopathologic changes on transbronchial lung biopsy specimens and exclusion of infection. Transbronchial lung biopsies need to be interpreted by a pathologist with experience in lung transplantation. For symptomatic patients, additional support for a diagnosis of acute cellular rejection includes the absence of airway stenosis at the time of flexible bronchoscopy and confirmation of negative microbiologic assays, stains, and cultures.
Clinical assessment without transbronchial biopsy is frequently inaccurate, as noted in a study from an experienced center in which only a 54 percent concordance rate was found between the clinical impression and the final pathologic diagnosis. Transbronchial lung biopsies improve the yield for a specific diagnosis to approximately 70 percent.
If the transbronchial biopsy does not yield a specific diagnosis and the patient has progressive respiratory impairment, repeat transbronchial biopsy, a video-assisted thoracoscopic lung biopsy, or, in the setting of acute lung injury, empiric therapy may be needed.
Noninvasive laboratory testing using gene expression profiling (GEP) (nCounter Human Organ Transplant Panel, Molecular Microscopic Diagnostic System [MMDX)] lung) and donor derived cell-free DNA testing (Allosure Lung) to aid in the diagnosis of lung transplant rejection have been developed and studied, however, further evidence will be needed to determine the utility of these molecular diagnostic assay as a replacement for routine lung biopsies and other aspects of long-term management of lung transplant recipients. The evidence is insufficient to determine the effects of the technology on net health outcomes
Acute liver allograft rejection is an important cause of allograft dysfunction. Acute rejection episodes can have an impact on long-term graft survival, even among patients who recover. The use of potent immunosuppressive agents for induction and maintenance therapy for liver transplantation has reduced the incidence of acute rejection, which is defined as liver allograft dysfunction associated with specific pathologic changes in the graft.
Acute rejection can be categorized into T- cell mediated (cellular) rejection (TCMR) and antibody-mediated (previously known as humoral) rejection. However, antibody-mediated rejection rarely occurs in liver transplantation recipients, while acute TCMR has been commonly reported. Acute T-cell mediated (cellular) rejection (TCMR) has been reported in approximately 10 to 30 percent of liver transplantation recipients.
Most episodes of acute T-cell mediated (cellular) rejection (TCMR) occur within three to six months after liver transplantation, although some episodes occur beyond six months. In addition, acute rejection after 12 months post-transplant is typically related to medication noncompliance, reduction in immunosuppression, or other factors interfering with calcineurin inhibitor trough levels (e.g,, drug-drug interaction).
Most patients who have acute TCMR are asymptomatic. However, some patients present with fever, malaise, abdominal pain, hepatosplenomegaly, and rarely, increasing ascites. Because most patients are asymptomatic, acute TCMR is suspected primarily by an increase in liver biochemical tests which may include elevations of any of the following: serum aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin levels.
For patients with suspected acute TCMR, further evaluation is typically performed within one week and includes:
The diagnosis of acute TCMR is made by examining liver allograft histology. The liver biopsy specimen is used for grading the severity of rejection and excluding other causes of elevated liver biochemical tests. A classification system for acute TCMR was developed by a panel of expert hepatologists who agreed on a nomenclature and histopathologic criteria for grading acute rejection i.e., Banff classification.
Noninvasive laboratory testing using gene expression profiling (GEP) (nCounter Human Organ Transplant Panel) to aid in the diagnosis of liver transplant rejection have been developed and studied, however, further evidence will be needed to determine the utility of this molecular diagnostic assay as a replacement for routine liver biopsies and other aspects of long-term management of liver transplant recipients. The evidence is insufficient to determine the effects of the technology on net health outcomes
In 2010, the International Society of Heart and Lung Transplantation (ISHLT) issued guidelines for the care of heart transplant recipients which included the following:
In 2016, the International Society of Heart and Lung Transplantation (ISHLT) issued a guideline discussing antibody-mediated rejection (AMR) of the lung, the ISHT noted the lack of specific diagnostic criteria for AMR and listed allograft dysfunction, positive histology, post C4d staining, and donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) as potential diagnostic items for AMR.
In 2013, these joint guidelines by the American Association for the Study of Liver Diseases and the American Society of Transplantation (AASLD) provided guidance on the long-term management of liver transplants. There recommendations concerning assess of rejection are as follows:
In 2017, the Renal Association (RA) published guidelines regarding post-operative care for kidney transplant patients. These guidelines have been endorsed by the British Transplant Society (BTS). The assessment of the rejection recommendations are listed below:
In the rationale, the Renal Association states: “Rejection episodes are characteristically associated with loss of graft function, but diagnosis is best established by a percutaneous biopsy since it differentiates rejection clearly from other causes of graft dysfunction.”
In 2020, the European Association of Urology (EAU) published guidelines on renal transplantation, which states the following: “The ultimate standard for the diagnosis of rejection is transplant biopsy, because it is impossible to differentiate acute rejection solely on clinical indicators from other causes of renal dysfunction (e.g., acute tubular necrosis, infection, disease recurrence or CNI nephrotoxicity. Therefore, all rejections should be verified by renal biopsy.”
The U.S. Food and Drug Administration (FDA) has cleared multiple biomarker tests for detection of heart and renal allograft rejection. The table below provides a summary of the biomarker tests currently included in this policy that have FDA clearance.
| Test | Manufacturer | FDA Clearance Type, Product Number | FDA Clearance Date | Indicated Use |
|---|---|---|---|---|
| Heartsbreath™ | Menssana Research | Humanitarian device exemption, H030004 | 2004 | To aid in diagnosing grade 3 heart transplant rejection in patients who have received heart transplants within the preceding year. The device is intended as an adjunct to, and not as a substitute for, endomyocardial biopsy and is also limited to patients who have had endomyocardial biopsy within the previous month. |
| AlloMap® Molecular Expression Testing | CareDx, formerly XDx | 510(k), k073482 | 2008 | The test is to be used in conjunction with clinical assessment, for aiding in the identification of heart transplant recipients with stable allograft function and a low probability of moderate-to-severe transplant rejection. It is intended for patients at least 15 years old who are at least 2 months posttransplant. |
There are also commercially available laboratory-developed biomarker tests for detection of heart and renal allograft rejection. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. To-date, AlloSure is regulated under the Clinical Laboratory Improvement Amendments standards and all testing is performed at the CareDx reference laboratory.
myTAIHeart is also a laboratory developed test (LDT) developed for clinical diagnostic performance exclusively in the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendment (CLIA) accredited TAI Diagnostics Clinical Reference Laboratory. This test was developed and its performance characteristics determined by TAI Diagnostics.
Not applicable.
AlloMap gene expression profiling (GEP) may be considered medically necessary as a non-invasive method of determining the risk of rejection in heart transplant recipients ≥15 years of age, who are between 6 months and 5 years post-heart transplant.
AlloMap gene expression profiling (GEP) is considered investigational for heart transplant recipients <15 years of age, because the evidence is insufficient to determine the effects of the technology on net health outcomes.
Gene expression profiling (GEP), including, but not limited to the following to aid in the diagnosis of transplant rejection is considered investigational, because the evidence is insufficient to determine the effects of the technology on net health outcomes:
The following tests to aid in the diagnosis of transplant rejection is considered investigational, because the evidence is insufficient to determine the effects of the technology on net health outcomes:
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