ModifiedExcellus Health Plan IncPolicy 2.02.55

Laboratory Testing for Transplantation Rejection

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Coverage of gene-expression profiling and other laboratory or molecular tests used to evaluate transplant rejection or graft dysfunction, including medical-necessity criteria for AlloMap after heart transplantation and investigational classifications for several other tests.

Policy Summary

PayerExcellus Health Plan Inc

PolicyLaboratory Testing for Transplantation Rejection

Policy CodePolicy 2.02.55

Change TypeModified

Effective DateJuly 16, 2026

Last ReviewJul 17, 2025

Next Review DateJuly 1, 2027

Key ActionDocument the individual's age, time since heart transplantation, cardiac function, rejection history, and absence of antibody-mediated rejection when requesting AlloMap.

SourceLink

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ModifiedExcellus Health Plan IncPolicy 2.02.55

Laboratory Testing for Transplantation Rejection

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Policy Summary

PayerExcellus Health Plan Inc

PolicyLaboratory Testing for Transplantation Rejection

Policy CodePolicy 2.02.55

Change TypeModified

Effective DateJuly 16, 2026

Last ReviewJul 17, 2025

Next Review DateJuly 1, 2027

Key ActionDocument the individual's age, time since heart transplantation, cardiac function, rejection history, and absence of antibody-mediated rejection when requesting AlloMap.

SourceLink

POLICY UPDATE CHANGES

Added CPT code 0576U for quantitative donor-derived cell-free DNA testing in liver transplantation.

The July 2025 annual review documented that policy intent remained unchanged.

15+Minimum age for AlloMap

55 days–5 yearsAlloMap post-transplant interval

≥45%Required LVEF

MultipleInvestigational transplant-rejection tests

<34Very-low-risk AlloMap score

Medical Necessity and Investigational Classifications

AlloMap After Heart Transplantation

Gene expression profiling (GEP), including AlloMap, is medically appropriate for management after heart transplantation when ALL of the following criteria are met:

ALL of the following

The individual is age 15 years or older.>= 15 years
The individual is 55 days to five (5) years post-heart transplantation.55 days to 5 years post-transplant
Heart allograft function is stable as demonstrated by ALL of the following
- Absence of signs or symptoms of congestive heart failure.
- Current echocardiogram with left ventricular ejection fraction (LVEF) ≥ 45%.LVEF >= 45%
- Absence of severe cardiac allograft vasculopathy.
- No more than one (1) episode of moderate or severe (grade 3A [2R]) cellular rejection within the past year.<= 1 episode in past year
- No history or evidence of antibody mediated rejection with associated hemodynamic compromise.

Heart-Transplant Gene-Expression Profiling

Guideline-supported use of peripheral blood GEP is limited to selected heart-transplant populations:

The selected population meets ALL of the following

The individual is an adult heart-transplant recipient who is clinically stable and at low risk for acute cellular rejection.
The individual is more than 55 days (approximately two months) to five years post-heart transplantation.> 55 days and <= 5 years post-transplant
GEP, as in AlloMap Heart, is used as a noninvasive diagnostic tool to rule out current acute cellular rejection and may reduce the frequency of surveillance endomyocardial biopsies.

Donor-Derived Cell-Free DNA Guideline-Supported Populations

Guideline-supported dd-cfDNA use includes the following transplant populations:

ANY of the following populations

A kidney-transplant recipient experiencing acute allograft dysfunction, particularly when dd-cfDNA (as in AlloSure Kidney) is used to exclude rejection, including antibody-mediated rejection.
A heart-transplant recipient in whom dd-cfDNA (as in AlloSure Heart) is used to rule out subclinical rejection.

Evidence Sufficiency

The evidence conclusions for reviewed transplant-rejection testing applications are as follows:

Evidence conclusions

For heart-transplant GEP, including AlloMap, the evidence is sufficient to determine improvement in health outcomes; one large randomized controlled trial (IMAGE) found GEP noninferior to endomyocardial biopsy.
For dd-cfDNA, the evidence is insufficient to determine improvement in health outcomes. Available studies have limited methodological quality, are primarily retrospective or prospective cohorts, and leave uncertainty regarding detection of subclinical graft injury, validated thresholds, monitoring intervals, and impact on clinical outcomes.
For other tests for detection of transplant rejection, including donor- or third-party-induced CD154+ T-cytotoxic memory-cell testing and microarray-based systems, the evidence is insufficient to determine improvement in health outcomes.

Measurement of donor-derived cell-free DNA (dd-cfDNA) (e.g., AlloSure, myTAIHEART, Prospera, Viracor TRAC, Clarava, Tuteva) is considered investigational for the management of individuals after organ transplantation, including but not limited to the detection of acute transplant rejection or transplant graft dysfunction.

Measurement of donor- and third-party-induced CD154+ T-cytotoxic memory cells (e.g., Pleximark) is considered investigational for the management of individuals after organ transplantation, including but not limited to the detection of acute transplant rejection or transplant graft dysfunction.

The Heart Molecular Microscope Diagnostic System (MMDx-Heart) and the Kidney Molecular Microscope Diagnostic System (MMDx-Kidney) are considered investigational for the management of individuals after organ transplantation, including but not limited to the detection of acute transplant rejection or transplant graft dysfunction.

Normal or below-threshold dd-cfDNA levels do not rule out cellular-mediated rejection. Clinically indicated biopsies should not be precluded by below-threshold dd-cfDNA results.

Codes, Thresholds, and Test Parameters

Experimental/Investigational CPT and Proprietary Laboratory Analysis CodesCPTExperimental

81479	Unlisted molecular pathology procedure; transplantation medicine and transplant-rejection molecular testing, including gene-expression or donor-derived cell-free DNA applications.
0087U	Cardiology (heart transplant), mRNA gene-expression profiling by microarray of 1,283 genes using transplant biopsy tissue; allograft rejection and injury algorithm.
0542U	Nephrology (renal transplant), urine nuclear magnetic resonance spectroscopy measuring 84 urinary metabolites, combined with patient data, quantification of BK virus using real-time PCR and serum creatinine; algorithm reported as a probability score for allograft injury status.
0544U	Nephrology (transplant monitoring), digital PCR of 48 variants using plasma cell-free DNA and donor-derived cell-free DNA; percentage reported as risk for rejection.
0576U	Transplant medicine, liver, quantitative donor-derived cell-free DNA testing; donor-derived cell-free DNA percentage reported as risk for rejection.

ICD-10 CodesICD-10

T86.10-T86.19	Complications of kidney transplant (code range).
T86.20-T86.298	Complications of heart transplant (code range).
Z48.21	Encounter for aftercare following heart transplant.
Z48.22	Encounter for aftercare following kidney transplant.
Z94.0	Kidney transplant status.
Z94.1	Heart transplant status.

HCPCS CodesHCPCS

No codes listed

Left ventricular ejection fraction

MeasureLeft ventricular ejection fraction (LVEF)

Required threshold≥ 45%

Clinical useDemonstrates stable heart allograft function for AlloMap medical appropriateness

Cellular rejection history

Rejection typeModerate or severe cellular rejection

Maximum historyNo more than one episode within the past year

Documentation and Denial-Risk Rules

Documentation Required

Document AlloMap Medical Necessity

Document the medical-necessity criteria for AlloMap (gene expression profiling) after heart transplantation. Coverage is appropriate only when all of the following requirements are met and supported in the medical record:

Individual is age 15 years or older.
Individual is 55 days to five (5) years post-heart transplantation.
Heart allograft function is stable, demonstrated by all of the following:
Absence of signs or symptoms of congestive heart failure.
Current echocardiogram showing left ventricular ejection fraction (LVEF) ≥ 45%.
Absence of severe cardiac allograft vasculopathy.
No more than one (1) episode of moderate or severe (grade 3A [2R]) cellular rejection within the past year.
No history or evidence of antibody-mediated rejection with associated hemodynamic compromise.

Clinical Context

Diagnosis of allograft rejection relies on clinical monitoring and histologic confirmation by tissue biopsy. After heart transplantation, endomyocardial biopsy remains the standard method for surveillance and identification of rejection. Blood-based and molecular tests have been investigated as less-invasive alternatives, but biopsy remains important when clinical findings indicate possible graft dysfunction or rejection.

Terms and Test Descriptions

Endomyocardial biopsy

ProcedureEndomyocardial biopsy (EMB)

RoleStandard tissue-based method for surveillance and identification of rejection after heart transplantation

Rejection gradingISHLT classifications range from 0R (no rejection) through 3R (severe rejection)

Gene-expression profiling / AlloMap

TestGene-expression profiling (GEP), including AlloMap

Specimen and methodPeripheral blood cells analyzed by polymerase-chain-reaction expression measurement of a gene panel

Reported result

Guideline-Supported and Covered Uses

AlloMap Management After Heart Transplantation

All of the following criteria must be met for management after heart transplantation using AlloMap:

Individual eligibility: The individual is age 15 years or older.≥15 years

Post-transplant timing: The individual is 55 days to five years post-heart transplantation.55 days to 5 years after heart transplantation

Stable heart allograft function

Heart-failure status: There are no signs or symptoms of congestive heart failure.

Testing Intervals and Monitoring Frequency

dd-cfDNA testing intervals

Test interval in cited studiesGenerally at least one month between dd-cfDNA tests

Early post-transplant practiceShorter intervals were reported in the early post-transplant period

Routine monitoring intervalThe optimum interval remains uncertain

Gene-expression profiling intervals

Guideline interval2 months to 5 years after heart transplantation

Early-monitoring interval55 days onward

Use evaluated

Investigational and Noncovered Services

The following services are not covered because they are classified as investigational for post-transplant management, including evaluation of acute rejection or graft dysfunction: donor-derived cell-free DNA testing (including AlloSure, myTAIHEART, Prospera, Viracor TRAC, Clarava, and Tuteva); donor- or third-party-induced CD154+ T-cytotoxic memory-cell testing (including Pleximark); and the MMDx-Heart and MMDx-Kidney Molecular Microscope Diagnostic Systems.

Policy Summary

PayerExcellus Health Plan Inc

PolicyLaboratory Testing for Transplantation Rejection

Policy CodePolicy 2.02.55

Change TypeModified

Effective DateJuly 16, 2026

Last ReviewJul 17, 2025

Next Review DateJuly 1, 2027

Key ActionDocument the individual's age, time since heart transplantation, cardiac function, rejection history, and absence of antibody-mediated rejection when requesting AlloMap.

SourceLink

On This Page

Grade 3A [2R] or higher, as stated in the policy

AlloMap cutoff and predictive value

TestAlloMap gene-expression profiling

Score cutoff30

Reported negative predictive value99.6%

AlloMap score interpretation

Very-low-risk score<34

Risk assessedModerate/severe acute cellular rejection

Score requiring biopsy≥34 prompted endomyocardial biopsy within five days

Early post-transplant GEP

Monitoring testEarly post-transplant gene-expression profiling (GEP)

Threshold at 2–6 monthsGEP ≥30

Threshold after 6 monthsGEP ≥34

Follow-up actionEither threshold prompted a follow-up biopsy

AlloSure-Heart threshold

TestAlloSure-Heart

BiomarkerDonor-derived cell-free DNA (dd-cfDNA)

Evaluated threshold0.2%

AlloSure-Kidney cutoff

TestAlloSure-Kidney

BiomarkerDonor-derived cell-free DNA (dd-cfDNA)

Evaluated cutoff1.0%

Kidney dd-cfDNA threshold

PopulationKidney transplant recipients

Threshold0.74% dd-cfDNA

Evaluated outcomesAntibody-mediated rejection and any rejection diagnosis

Kidney dd-cfDNA active-rejection threshold

BiomarkerKidney donor-derived cell-free DNA

Threshold>1.0%

Evaluated findingActive rejection

AlloMap intended-use age

TestAlloMap

Minimum intended-use ageAt least 15 years old

Regulatory statusFDA 510(k) clearance received in 2008

AlloMap post-transplant timing

TestAlloMap

Minimum post-transplant intervalAt least two months post-transplant

Intended populationHeart transplant recipients with stable allograft function and low probability of moderate-to-severe rejection

Denial Risk

Investigational Transplant-Rejection Tests

The following transplant-rejection tests are considered investigational for management after organ transplantation, including detection of acute transplant rejection or transplant graft dysfunction, and should not be represented as medically necessary under this policy.

Donor-derived cell-free DNA (dd-cfDNA), including AlloSure, myTAIHEART, Prospera, Viracor TRAC, Clarava, and Tuteva.
Donor- and third-party-induced CD154+ T-cytotoxic memory cell testing, including Pleximark.
Heart Molecular Microscope Diagnostic System (MMDx-Heart) and Kidney Molecular Microscope Diagnostic System (MMDx-Kidney).

Denial Risk

AlloMap Criteria Must All Be Met

All AlloMap medical-necessity criteria must be satisfied and documented. If any age, transplant-timing, stable-allograft-function, echocardiographic, vasculopathy, or rejection-history criterion is absent or unsupported, coverage is at risk for denial.

Verify and record every required criterion before ordering or submitting the claim.
Do not assume that meeting only some of the criteria supports coverage; the policy requires all criteria.

An algorithm produces a score from 0 to 40; lower scores indicate lower likelihood of rejection

Donor-derived cell-free DNA

BiomarkerDonor-derived cell-free DNA (dd-cfDNA)

Measurement approachQuantifies the donor-derived fraction relative to total cell-free DNA

Alternative approachSome assays use single-nucleotide-polymorphism (SNP)-based methods

MMDx-Heart

SystemMolecular Microscope MMDx-Heart

SpecimenEndomyocardial biopsy specimens

AnalysisMicroarray-based messenger RNA gene-expression analysis to assess heart-transplant rejection

MMDx-Kidney

SystemMolecular Microscope Diagnostic System (MMDx-Kidney)

SpecimenTransplant kidney biopsy tissue

Analysis and resultmRNA analysis of 1,494 genes reports an allograft rejection and injury probability score

Clarava

TestClarava

TimingPre-transplant

Method and purposeBlood-based mRNA expression assay using a proprietary artificial-intelligence algorithm to estimate risk of early acute rejection

Tutivia

TestTutivia

TimingPost-transplant

Purpose and methodBlood-based mRNA expression assay focused on acute cellular rejection, including subclinical rejection, using a proprietary artificial-intelligence algorithm

Donor-derived cell-free DNA

OriginCell-free DNA originating from the organ donor and circulating in the transplant recipient’s blood

MeasurementReported as the donor-derived fraction of circulating cell-free DNA

Clinical evaluationElevated levels are evaluated as a marker of allograft injury or rejection

Gene-expression profiling

SpecimenPeripheral blood

MethodGene-expression profiling

Clinical purposeEstimate the risk of acute cellular rejection in heart-transplant recipients

Echocardiographic function: The current echocardiogram shows a left ventricular ejection fraction of at least 45%.LVEF ≥45%

Cardiac allograft vasculopathy: There is no severe cardiac allograft vasculopathy.

Cellular rejection history: There has been no more than one episode of moderate or severe cellular rejection, grade 3A [2R], within the past year.≤1 episode in the past year

Antibody-mediated rejection: There is no history or evidence of antibody-mediated rejection with associated hemodynamic compromise.

Peripheral-Blood Gene-Expression Profiling

Covered when the recipient is a selected stable adult heart-transplant patient:

Selected stable adult population: The recipient is an adult heart-transplant recipient who is stable and at low risk of acute cellular rejection.

Post-transplant timing: The recipient is more than 55 days post-transplant.>55 days post-transplant

The 2023 ISHLT discussion identifies low-risk individuals between two months and five years after transplantation. Pediatric data do not support a general routine recommendation.

Clinical use: Peripheral-blood gene-expression profiling is used as a noninvasive diagnostic tool to rule out acute cellular rejection and reduce the frequency of endomyocardial biopsy.

Kidney-Transplant dd-cfDNA

Donor-derived cell-free DNA may be considered in the following kidney-transplant populations:

Kidney-transplant indication

Acute allograft dysfunction: The kidney-transplant recipient is experiencing acute allograft dysfunction, and dd-cfDNA is used to help exclude rejection, particularly antibody-mediated rejection.
Surveillance for subclinical rejection: The kidney-transplant recipient is undergoing surveillance intended to exclude subclinical antibody-mediated rejection.

AlloSure-Heart dd-cfDNA

Covered as a guideline-supported use in the following population:

Heart-transplant surveillance: The recipient is a heart-transplant recipient undergoing surveillance for subclinical rejection.

Clinical purpose: AlloSure-Heart donor-derived cell-free DNA is used to help rule out subclinical rejection.

This recommendation does not establish a universal dd-cfDNA threshold.

Kidney Transplant Recipients With Acute Allograft Dysfunction

ASTS guidance recommends consideration of donor-derived cell-free DNA in this population:

Acute kidney allograft dysfunction: The recipient is a kidney-transplant recipient experiencing acute allograft dysfunction.

Purpose of testing: dd-cfDNA, such as AlloSure Kidney, is considered to help exclude rejection, particularly antibody-mediated rejection.

Heart Transplant Recipients Under Surveillance for Subclinical Rejection

ASTS guidance permits consideration of donor-derived cell-free DNA in this surveillance population:

Heart-transplant surveillance: The recipient is a heart-transplant recipient undergoing surveillance for subclinical rejection.

Purpose of testing: dd-cfDNA, such as AlloSure Heart, may be used to help rule out subclinical rejection.

Stable, Low-Risk Adult Heart-Transplant Recipients More Than 55 Days Post-Transplant

Peripheral-blood gene-expression profiling may be used in the following selected population:

Adult recipient: The recipient is an adult heart-transplant recipient.

Stable, low-risk status: The recipient is stable and at low risk of acute cellular rejection.

Post-transplant timing: The recipient is more than 55 days after heart transplantation.>55 days post-transplant

Clinical purpose: Peripheral-blood gene-expression profiling, such as AlloMap Heart, is used as a noninvasive diagnostic tool to rule out acute cellular rejection.

The ISHLT discussion identifies low-risk individuals between two months and five years after transplantation; pediatric data do not support a general routine recommendation.

Peripheral blood gene-expression profiling for post-transplant surveillance