RetiredCapital BluecrossPolicy AHS - M2091

Transplant Rejection Testing (gene expression profiling and donor-derived cell-free DNA)

Coverage criteria for use of gene expression profiling and donor-derived cell-free DNA (dd-cfDNA) tests to monitor transplant rejection for specified organ types and post-transplant timeframes; intended for providers ordering/performing these tests for Capital Bluecross members.

Policy Summary

PayerCapital Bluecross

PolicyTransplant Rejection Testing (gene expression profiling and dd-cfDNA)

Policy CodePolicy AHS - M2091

Change TypeRetirement

Effective Date

Next Review Date

Key ActionDocument transplant type, recipient age, and days/months post-transplant when ordering noninvasive surveillance tests to show alignment with specified covered intervals.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

heart,kidney,lungorgan types referenced

>=55dAlloMap coverage start

>=14ddd-cfDNA kidney start

TruGrafexample non-covered test

~30+

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria for Noninvasive Transplant Rejection Testing

inv-01: Covered and Not Covered Surveillance Testing

Covered when ALL of the following are met for the specified organ/test/timeframe:

AlloMap for heart transplant recipients

Frequency 2-12 months: Every month for individuals who are 2-12 months post-transplant2-12 months post-transplant
Frequency 12-36 months: Every three months for individuals who are 12-36 months post-transplant12-36 months post-transplant
Frequency >36 months: Every six months for individuals who are greater than 36 months post-transplant>36 months post-transplant

dd-cfDNA for heart transplant recipients

Frequency 1-12 months: Every month for individuals who are 1-12 months post-transplant1-12 months post-transplant
Frequency 12-36 months: Every three months for individuals who are 12-36 months post-transplant12-36 months post-transplant
Frequency >36 months: Every six months for individuals who are greater than 36 months post-transplant>36 months post-transplant

dd-cfDNA for single-kidney transplant recipients

First four months: One test per month at one, two, three, and four months post-transplantmonths 1-4: monthly
From six months onward: One test every three months beginning at six months post-transplant>=6 months: q3 months

Peripheral blood microarray-based genomic tests for kidney: For kidney transplant recipients with stable renal function, peripheral blood microarray-based genomic tests that analyze gene expression profiles to rule out kidney transplant rejection (e.g., TruGraf) are not coveredstable renal function

Not medically necessary per policy

inv-02: Noninvasive test use contexts and evidence

Noninvasive testing may be considered in selected contexts when meeting the conditions observed in supporting studies:

GEP surveillance in heart transplant: GEP was used for monitoring selected low-risk heart transplant patients beyond the early post-transplant period in randomized and registry studies (IMAGE, Kobashigawa RCT, OAR) and demonstrated similar serious outcomes with fewer biopsies when study protocols were followedGEP thresholds and timing per studies

Study-specific criteria include initiation at >=55 days post-transplant in trials and score-based biopsy triggers (e.g., >=30 between 2–6 months; >=34 after 6 months)

dd-cfDNA utility: Elevated dd-cfDNA is associated with graft injury/rejection across organs; assay-dependent thresholds reported in studies range approximately 0.2%–1.2% and performance varies by assay and organassay-dependent thresholds (0.2%–1.2%)

Combining dd-cfDNA with DSA or GEP may improve positive predictive value for ABMR in some studies

inv-03: Guideline-aligned surveillance coverage

Covered or reasonable when aligned with specialty guideline recommendations and used for surveillance in specified populations:

GEP for heart transplant surveillance: Use of peripheral blood GEP (e.g., AlloMap) is reasonable in low-risk adult heart transplant recipients from 55 days to 5 years post-transplant to identify low risk of acute cellular rejection and to reduce EMB frequency.post-op >=55 days and <=5 years

ISHLT Class IIa, Level B evidence for adults

dd-cfDNA for kidney surveillance: Serial dd-cfDNA measurement may be considered to exclude subclinical antibody-mediated rejection in kidney transplant recipients and to evaluate acute allograft dysfunction to exclude rejection.use per ASTS recommendations

ASTS suggests serial dd-cfDNA for kidney recipients

dd-cfDNA and GEP for heart transplant: dd-cfDNA may be utilized to rule out subclinical rejection in heart transplant recipients; peripheral blood GEP may be used as a noninvasive tool to rule out acute cellular rejection in stable, low-risk adult heart transplant recipients (>55 days post-transplant).

inv-04: Clinical use and limitations

Clinical guidance and limits

Liver rejection diagnosis: Diagnosis of liver rejection requires liver histology; biopsy should be obtained before treatment and classified according to Banff criteria.

AASLD/AST guidance

HLA/serology risk stratification: Single antigen bead (SAB) testing is the gold standard to establish presence of anti-HLA donor-specific antibodies and patients should be stratified by sensitization status with local cutoffs determined by transplant centers.

ESOT recommendations

Molecular mismatch and novel assays: Molecular HLA mismatch analysis and other novel assays may inform future risk stratification but currently lack consensus on algorithms and cutoffs and are not ready for routine standalone clinical integration.

ESOT statement

Simultaneous peripheral blood gene expression profiling and donor-derived cell-free DNA (dd-cfDNA) testing for heart transplant recipients (combination panels such as HeartCare®) does not meet coverage criteria and therefore is not covered under this policy.

Heartsbreath (a breath volatile organic compound test) is FDA-cleared only as an adjunct to biopsy and the Centers for Medicare & Medicaid concluded the evidence does not adequately define the test’s technical characteristics or demonstrate improved health outcomes; use may therefore be considered excluded or denied when proposed as a substitute for standard diagnostic evaluation.

Replacement of histologic renal biopsy as the sole diagnostic method for rejection in kidney transplant recipients is not supported. Society guidance and this policy emphasize that all suspected rejections should be verified by renal biopsy unless contraindicated or the biopsy would substantially delay treatment; peripheral blood assays cannot replace biopsy when biopsy is indicated.

Routine screening assays that measure non-HLA innate or non‑HLA donor‑specific antibody (DSA) markers should not be relied upon to evaluate immunologic risk in transplantation in the absence of clinical validation and consensus cutoffs; these tests are not recommended for routine clinical decision‑making.

The cited reference sections present guideline and study citations but do not themselves list additional explicit coverage exclusions beyond those summarized in policy text; they serve as supporting evidence for the coverage positions above.

Peripheral blood gene expression profiling tests and dd‑cfDNA assays for organ types not specifically listed as covered in the policy (for example, some uses in lung or liver transplantation) are identified in the policy as not meeting coverage criteria; proprietary and laboratory‑developed dd‑cfDNA assays are described in the document but coverage is limited to the organ‑ and timeframe‑specific rules in this policy.

Heartsbreath is explicitly not supported as a replacement for endomyocardial biopsy: the FDA describes it as adjunctive only, and CMS reviewers determined available evidence does not demonstrate improved clinical outcomes when used in lieu of biopsy.

The American Society of Transplant Surgeons (ASTS) does not recommend blood gene expression profiling (GEP) to diagnose or exclude subclinical rejection in kidney transplant recipients due to insufficient evidence; therefore use of peripheral blood GEP for this purpose is considered unsupported by current ASTS guidance.

Tests that purport to measure innate immune alloreactivity are currently considered unreliable for routine clinical practice; ESOT notes that no reliable test for innate immune alloreactivity is available for routine use at this time.

The literature citations collected in the referenced sections summarize available studies and society statements but do not themselves label specific additional tests as not medically necessary beyond the policy’s stated positions; they provide the evidence base informing those determinations.

inv-56: Organ-specific candidate criteria

Organ- and test-specific coverage criteria summarized from the policy:

Heart - AlloMap: AlloMap covered for heart transplant recipients age >=15 and >=55 days post-transplant with specified surveillance frequencyage >=15; >=55 days

See frequency nodes

Heart - dd-cfDNA: Donor-derived cfDNA covered for heart recipients >=28 days post-transplant with specified surveillance frequency>=28 days

Examples: AlloSure Heart, Prospera Heart

Kidney - dd-cfDNA (single kidney): Donor-derived cfDNA covered for single-kidney recipients age >=18 and >=14 days post-transplant with specified early monthly and later quarterly scheduleage >=18; >=14 days

Organ- and Test-Specific Candidate Criteria

inv-56: Organ-specific candidate criteria

Organ- and test-specific coverage criteria summarized from the policy:

Heart - AlloMap: AlloMap covered for heart transplant recipients age >=15 and >=55 days post-transplant with specified surveillance frequencyage >=15; >=55 days

See frequency nodes

Heart - dd-cfDNA: Donor-derived cfDNA covered for heart recipients >=28 days post-transplant with specified surveillance frequency>=28 days

Examples: AlloSure Heart, Prospera Heart

Kidney - dd-cfDNA (single kidney): Donor-derived cfDNA covered for single-kidney recipients age >=18 and >=14 days post-transplant with specified early monthly and later quarterly schedule

Post-Transplant Surveillance Schedules and Test Use

Surveillance schedules (organ/test/time windows)

AlloMap (heart) surveillance frequencyAge ≥15 and ≥55 days post-transplant; monthly for 2–12 months, every 3 months for 12–36 months, every 6 months >36 months

dd-cfDNA (heart) surveillance frequency≥28 days post-transplant; monthly for 1–12 months, every 3 months for 12–36 months, every 6 months >36 months

dd-cfDNA (single-kidney) surveillance frequencyAge ≥18 and ≥14 days post-transplant; one test monthly at months 1–4, then every 3 months beginning at month 6

Peripheral blood microarray-based genomic tests (kidney)Not covered for kidney recipients with stable renal function (e.g., TruGraf) to rule out rejection

Study-derived surveillance timing and contexts

GEP surveillance study timing

Procedure and Test Codes

Applicable CPT/HCPCS Procedure Codesmixed

No codes listed

Listed CPT/HCPCS codes (selection)CPT

81558	Transplantation medicine (allograft rejection, kidney), mRNA, gene expression profiling by quantitative polymerase chain reaction (qPCR) of 139 genes, utilizing whole blood, algorithm reported as a binary categorization as transplant excellence or not
81595	Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score (Proprietary test: AlloMap®)
81599	Unlisted multianalyte assay with algorithmic analysis
84999	Unlisted chemistry procedure
0055U	Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma (Proprietary test: myTAIHEART)
0087U	Cardiology (heart transplant), mRNA gene expression profiling by microarray of 1283 genes, transplant biopsy tissue, allograft rejection and injury algorithm reported as a probability score

Additional CPT/HCPCS/U codesCPT

0088U	Transplantation medicine (kidney allograft rejection), microarray gene expression profiling of 1494 genes, utilizing transplant biopsy tissue, algorithm reported as a probability score for rejection (Proprietary test: Molecular Microscope® MMDx-Kidney)
0118U	Transplantation medicine, quantification of donor-derived cell-free DNA using whole genome next-generation sequencing, plasma, reported as percentage of donor-derived cell-free DNA in the total cell-free DNA (Proprietary test: TRAC™dd-cfDNA)
0319U	Nephrology (renal transplant), RNA expression by select transcriptome sequencing, using pretransplant peripheral blood, algorithm reported as a risk score for early acute rejection (Proprietary test: Clarava™)
0320U	Nephrology (renal transplant), RNA expression by select transcriptome sequencing, using posttransplant peripheral blood, algorithm reported as a risk score for acute cellular rejection (Proprietary test: Tuteva™)
0493U	Transplantation medicine, quantification of donor-derived cell-free DNA (cfDNA) using next-generation sequencing, plasma, reported as percentage of donor-derived cell-free DNA (Proprietary test: Prospera™)
0508U	Transplantation medicine, quantification of donor-derived cell-free DNA using 40 single-nucleotide polymorphisms (SNPs), plasma, and urine, initial evaluation reported as percentage of donor-derived cell-free DNA with risk for active rejection (Proprietary test: VitaGraftTM Kidney)
0509U	Transplantation medicine, quantification of donor-derived cell-free DNA using up to 12 single-nucleotide polymorphisms (SNPs) previously identified, plasma, reported as percentage of donor-derived cell-free DNA with risk for active rejection (Proprietary test: VitaGraftTM Kidney)
0540U	Transplantation medicine, quantification of donor-derived cell-free DNA using next-generation sequencing analysis of plasma, reported as percentage of donor-derived cell-free DNA to determine probability of rejection (Proprietary test: Allsure)
0544U	Nephrology (transplant monitoring), 48 variants by digital PCR, using cell-free DNA from plasma, donor derived cell-free DNA, percentage reported as risk for rejection (Proprietary test: VitaGraftTM Kidney 2.0)

dd‑cfDNA thresholds and assay metrics (examples)

dd‑cfDNA study threshold (>1%)>1% dd‑cfDNA associated with active rejection in Bloom et al. / AlloSure Kidney study

Assay analytic limits (AlloSure) and LOQAlloSure analytic linear range 0.2%–16%; limit of detection 0.16% and limit of quantification 0.20%

dd‑cfDNA study percentile threshold (kidney)In Bromberg et al., median dd‑cfDNA 0.21% and 97.5th percentile ≈1.20% (values >1.2% considered out of range)

dd‑cfDNA clinical association rangesReference populations report baseline medians ~0.21%–0.40%; thresholds for clinical decision vary by assay and study (0.2%–1.2%)

Reported GEP and dd‑cfDNA decision thresholds

Provider Requirements, Documentation, and Billing Actions

Prior Authorization

Benefit-dependent requirement

Coverage is benefit-dependent. Verify the member's specific benefits at the time of request; medical necessity and frequency allowances are specified by test type, organ transplanted, recipient age, and time since transplant. Prior authorization may be required per the member's plan.

AlloMap coverage: heart transplant recipients ≥15 years and ≥55 days post-transplant; frequency: monthly (2–12 months), every 3 months (12–36 months), every 6 months (>36 months).
dd-cfDNA (heart) coverage: heart transplant recipients ≥28 days post-transplant; frequency: monthly (1–12 months), every 3 months (12–36 months), every 6 months (>36 months).
dd-cfDNA (kidney) coverage: single-kidney recipients ≥18 years and ≥14 days post-transplant; one test monthly at months 1–4, then every 3 months beginning at 6 months.
TruGraf and other peripheral blood GEP for kidney recipients with stable function: not covered.

Note

GEP/dd‑cfDNA surveillance use guidance

GEP (AlloMap) and dd-cfDNA surveillance are supported for specific clinical contexts: AlloMap may be used as a noninvasive surveillance alternative to routine biopsies in selected low-risk adult heart transplant recipients starting at ≥55 days post-transplant and up to 5 years post-transplant per ISHLT guidance. dd-cfDNA surveillance is supported for kidney transplant recipients at defined early and later time points and may be used to help exclude subclinical antibody-mediated rejection (ASTS).

Clinical Evaluation and Testing Requirements

Note

Center and Laboratory Requirements

Note

Contraindications and Limitations

No absolute or relative contraindications to transplant coverage are specified in this portion of the policy. The document focuses on test‑specific coverage criteria and evidence citations rather than listing contraindications to transplantation as a service.

Contraindications are not specified in the cited reference chunks; the policy and its supporting references do not define patient‑level absolute or relative contraindications within these excerpts.

Definitions and Test Descriptions

Definitions: dd‑cfDNA

Definition — dd‑cfDNADonor‑derived cell‑free DNA — circulating DNA fragments originating from the transplanted organ used as a marker of graft injury

Analytic reporting metricdd‑cfDNA is reported as the percentage of donor‑derived cell‑free DNA in the total cell‑free DNA sample

Clinical roleElevations indicate graft injury and have been associated with acute rejection and allograft dysfunction across organ types

Definitions: Gene expression profiling (GEP / AlloMap)

Definition — GEP (gene expression profiling)Analysis of expression levels of a set of genes (qRT‑PCR or microarray) from peripheral blood to assess rejection risk/status

AlloMap specificsAlloMap: peripheral blood GEP for cardiac allograft rejection surveillance, scored 0–39 and intended for recipients ≥15 years and ≥55 days post‑transplant

Supporting Evidence and References

Note

Policy Revision History

2024-08-xxevidence_update

Updated evidence reference list to include recent large studies and guideline updates through 2024 (adds multiple citations including 2024 Nat Med dd-cfDNA and 2024 ISHLT guidance).

2023-05-xxguideline_update

Incorporated ISHLT 2023 guidance supporting reasonable use of GEP (AlloMap) between 55 days and 5 years post-transplant for low-risk adult heart recipients and referenced related society positions.

2023-03-xxreview

Policy Summary

PayerCapital Bluecross

PolicyTransplant Rejection Testing (gene expression profiling and dd-cfDNA)

Policy CodePolicy AHS - M2091

Change TypeRetirement

Effective Date

Next Review Date

Key ActionDocument transplant type, recipient age, and days/months post-transplant when ordering noninvasive surveillance tests to show alignment with specified covered intervals.

SourceLink

On This Page

Heartsbreath / VOC testing:

Breath volatile organic compound testing identified grade 3 heart rejection with moderate sensitivity but low positive predictive value; regulatory review (CMS/FDA) found insufficient evidence to support replacement of biopsy

not established for clinical decision-making

FDA describes Heartsbreath as adjunctive

MMDx and microarray-based diagnostics: MMDx (molecular microscope diagnostic system) demonstrates moderate agreement with histology and high negative predictive value for some rejection types and may reclassify discordant cases, with performance varying by rejection subtypetest-specific classifier outputs

PPV/NPV differ for ABMR versus TCMR

TruGraf blood classifier: TruGraf shows potential to reduce surveillance biopsies in stable renal function cohorts with reported accuracy in select studies but evidence is limited and context-specific; predictive value in graft dysfunction is less well establishedclassifier concordance with clinical/histologic assessment

Evidence limited and context-specific

per society guidance

ASTS and ISHLT positions

Example: AlloSure Kidney

GEP studied as surveillance beginning ≥55 days post-transplant in randomized and registry studies (IMAGE, Kobashigawa RCT, OAR)

dd-cfDNA study sampling windowsdd-cfDNA sampling in studies spanned early post-transplant (1–4 months), first year monthly time points, and quarterly thereafter (examples: Pai et al.; Bromberg et al.)

Combined testing study findingsPaired dd-cfDNA + GEP surveillance in a single-center study showed similar 1‑year survival and rejection‑free survival compared with GEP alone and reduced biopsy frequency

Society guidance on noninvasive surveillance

ISHLT position on EMB and GEPISHLT: periodic EMB reasonable during first 3–12 months; peripheral blood GEP reasonable in low‑risk adult heart recipients from 55 days to 5 years to reduce EMB frequency

ASTS dd-cfDNA guidance (kidney)ASTS supports serial dd‑cfDNA to exclude subclinical AMR and to evaluate acute dysfunction in kidney recipients

Guideline integration remarkUse of dd‑cfDNA and GEP may be integrated into surveillance strategies when aligned with specialty society recommendations

Test types and organ applicability

Tests described across organsNoninvasive surveillance tests (GEP, dd‑cfDNA) and molecular biopsy (MMDx) are described for heart, kidney, lung and other solid‑organ transplant monitoring

Example proprietary assaysProprietary tests referenced include AlloMap, AlloSure/Prospera (dd‑cfDNA), and MMDx (molecular microscope diagnostic) with tissue or blood platforms

Code/test mappingSpecific CPT/HCPCS/U codes correspond to organ/test type (e.g., AlloMap/AlloSure/Prospera/MMDx) and should be used for billing/authorization

Evidence and guideline citations

Key evidence sourcesMajor references include randomized trials, registry analyses, multicenter dd‑cfDNA and GEP validation studies, and society guidelines (references listed 48–76)

Meta-analytic findings for dd‑cfDNAMeta-analysis documents consistent baseline dd‑cfDNA medians (~0.21%–0.40%) and diagnostic validity across >20 kidney studies

Registry and cohort dataOutcomes AlloMap Registry (OAR) and multicenter dd‑cfDNA cohorts provide real‑world surveillance outcome data cited in the references

GEP cutoffs reported

GEP cutoffs reported in studies: ≥30 between 2–6 months and ≥34 at ≥6 months in some trial algorithms

dd‑cfDNA reported thresholds (examples)Reported dd‑cfDNA decision thresholds include 0.20% (LOQ), 0.74% (kidney AMR sensitivity example), 0.88% (kidney study association), and 1.2% (97.5th percentile) depending on assay and study

GEP score metricAlloMap score range 0–39 with study‑validated cutoffs (e.g., 34 in CARGO II) used as biopsy‑trigger thresholds

dd‑cfDNA fraction thresholds and metrics

Specific dd‑cfDNA fraction threshold exampleA dd‑cfDNA fraction threshold of 0.15% was used in a heart transplant study (Prospera) with reported sensitivity 78.5% and specificity 76.9%

dd‑cfDNA fraction as reported metricdd‑cfDNA is reported as percentage of donor‑derived cell‑free DNA in total cell‑free DNA

Study median ranges supporting thresholdsStudy medians and IQRs (e.g., median 0.58% in AR samples vs 0.04% non‑AR) illustrate separation used to set thresholds

ISHLT: GEP reasonable for low-risk adult HT recipients between ~2 months and 5 years to reduce EMB frequency (Class IIa).
ASTS: suggests serial dd-cfDNA measurement in kidney recipients with stable graft function to exclude subclinical ABMR and recommends dd-cfDNA in kidney recipients with acute dysfunction.
Clinical trials: GEP may be an alternative to routine biopsy in selected low-risk patients beyond early post-transplant (IMAGE, Kobashigawa et al.).
dd-cfDNA surveillance time points (kidney): months 1–4, 6, 9, 12, then quarterly thereafter (Pai et al., Bloom et al.).

Billing Rule

Procedure code requirements

Requests for coverage and claims must reference the appropriate CPT/HCPCS and proprietary test codes. Use listed codes when requesting prior authorization or submitting claims to ensure correct adjudication.

AlloMap (proprietary): CPT 81595.
TruGraf (kidney GEP) example: CPT 81558.
dd-cfDNA proprietary and CPT-level codes: e.g., AlloSure - 0540U (CareDx), Prospera - 0493U (Natera), TRAC dd-cfDNA - 0118U (Transplant Genomics).
Unlisted assay codes: 81599, 84999 as applicable.
Ensure the lab/manufacturer name and proprietary test identifier are included on requests/claims.

Note

Evidence references (no PA rules listed)

This section lists evidence citations and guideline references for clinical support and documentation. It does not by itself establish prior authorization rules beyond the coding and benefit requirements noted elsewhere in the policy.

Selected references include ISHLT guidelines, ASTS position statement, peer-reviewed studies validating AlloMap and dd-cfDNA, and guideline statements from EAU, Renal Association, AASLD/AST, and KDIGO.
Providers should reference these publications when justifying testing strategies in clinical notes or prior authorization submissions.

Denial Risk

Denial triggers for specific tests/organs

Denial triggers: Requests for certain tests or uses are not covered and may be denied when submitted for disallowed indications or organs.

Peripheral blood GEP to rule out kidney transplant rejection in recipients with stable renal function (e.g., TruGraf) — NOT COVERED.
Any dd-cfDNA testing for organ types not listed as covered (e.g., lungs, liver) — NOT COVERED.
Simultaneous combined AlloMap + dd-cfDNA commercial combination panels for heart (e.g., HeartCare) — NOT COVERED.
mRNA expression profiling of biopsied tissue (e.g., MMDx Heart, MMDx Kidney) for the listed purpose — NOT COVERED.
Volatile organic compound (Heartsbreath) testing to detect moderate grade 2R/3 heart rejection — NOT COVERED.

Documentation Required

Policy context emphasizes that biopsy is the diagnostic standard

Policy context: Histologic examination of a transplant biopsy remains the diagnostic standard for rejection across organs. Noninvasive assays may aid surveillance and decision-making but do not replace biopsy when histologic confirmation is required to establish rejection and guide therapy.

EAU: ultimate standard for diagnosis of rejection is transplant biopsy; all rejections should be verified by renal biopsy.
Renal Association: recommend biopsy before treating acute rejection unless clinically contraindicated.
AASLD/AST: rejection diagnosis for liver transplant can be reliably made only on liver histology; biopsy should be taken before treatment initiation.

Prior Authorization

Conflict with government policy

If a government policy (LCD/NCD) or applicable state Medicaid policy conflicts with this policy, the government policy supersedes and will be used for coverage determinations for affected members.

Always check for applicable Medicare LCDs/NCDs and state Medicaid rules before finalizing coverage decisions.
When in conflict, defer to the most specific government policy for the member.

Note

No denial criteria are specified in these reference lists

No additional denial criteria are specified in the reference list below; the listed citations serve as supporting literature and guidelines rather than operational denial rules.

Providers should not assume absence of coverage without verifying member benefits and any applicable LCD/NCD.
Clinical documentation and use of the correct procedure codes remain necessary for adjudication.

Documentation Required

Required clinical context for ordering

Required clinical context for ordering: When requesting testing, the ordering provider should document specific clinical details to demonstrate alignment with coverage criteria.

Transplant type (heart, kidney) and donor/recipient details as relevant.
Recipient age and exact days/months post-transplant to confirm timing thresholds (e.g., ≥55 days for AlloMap, ≥28 days for heart dd-cfDNA, ≥14 days for kidney dd-cfDNA).
Clinical indication: routine surveillance vs. clinical suspicion of rejection vs. exclusion of subclinical ABMR.
Relevant clinical data: recent creatinine/trend (kidney), symptoms, DSA status, prior biopsy results, current immunosuppression regimen, and any recent interventions.

Documentation Required

GEP result documentation

GEP (AlloMap) result documentation: When using GEP for surveillance, document the post-transplant timing, the numerical GEP score, the threshold used for the care pathway, and any subsequent action prompted by the result (e.g., biopsy performed, change in immunosuppression).

Record the test date and days/months since transplant (e.g., ≥55 days, ≥6 months when different thresholds apply).
Document the GEP score value and indicate the threshold applied (e.g., ≥30 between 2–6 months, ≥34 after 6 months per trial protocols).
If monitoring variability over serial tests, document cumulative score variability and any clinical interpretation.
Document follow-up actions such as scheduling an endomyocardial biopsy when scores exceed thresholds or change substantially.

Documentation Required

Guidelines cited state that diagnosis of rejection is reliably confirmed by histology/biopsy

Guidelines and expert statements cited emphasize that histologic confirmation by biopsy is required to reliably diagnose rejection and to guide treatment decisions for kidney, heart, and liver transplantation.

Use noninvasive tests to inform clinical assessment and risk stratification but obtain biopsy when histologic diagnosis is necessary to initiate or change rejection therapy.
ISHLT: EMB remains reasonable for surveillance early post-transplant and for higher-risk patients; routine EMB later than 5 years is not recommended except for cause.

Note

Laboratory test validation and regulation

Laboratory tests: many proprietary assays are laboratory-developed tests (LDTs) and must be validated and performed under CLIA high-complexity rules. FDA clearance status varies by test and does not replace the requirement for proper clinical validation and documentation.

AlloMap: FDA-cleared IVDMIA (CareDx) for specified indication and population.
Many dd-cfDNA and multigene assays are offered as CLIA LDTs; document laboratory performing the test and validation status when relevant.
Analytic performance parameters (e.g., AlloSure limit of detection 0.16%, limit of quantification 0.20%) should be considered when interpreting low-level results.

Documentation Required

Supporting references for documentation

Supporting references for documentation: When justifying a testing strategy for transplant rejection surveillance or diagnostic evaluation, include citations to the peer-reviewed studies and guideline statements supporting the proposed use.

Key guideline citations: ISHLT (chunks 44-45), ASTS position (chunk 49), EAU/RA/AASLD guidance (chunks 52-54).
Representative studies validating performance and surveillance schedules: IMAGE, CARGO, Grskovic et al., Bloom et al., Pai et al., Oellerich et al.
Include relevant study identifiers or guideline sections in prior authorization notes when applicable.

Note

Testing as alternative to biopsy in selected patients

Testing as an alternative to biopsy in selected patients: In selected low-risk adult heart transplant recipients beyond early post-transplant periods, GEP (AlloMap) has been used as an alternative surveillance strategy to reduce the frequency of routine biopsies when accompanied by appropriate clinical assessment and predefined thresholds.

GEP surveillance considered acceptable beginning at ~55 days post-transplant in selected low-risk patients; a positive GEP above trial-specified cutoffs typically prompts confirmatory biopsy.
Document selection criteria for low-risk status and any deviation from standard EMB-based surveillance protocols.

Note

GEP surveillance considerations

GEP surveillance considerations: When using GEP in surveillance pathways, consider the timing of testing, the pre-specified thresholds that prompt further evaluation, and the role of serial variability measures in risk estimation.

Thresholds used in clinical trials: e.g., GEP ≥30 between 2–6 months, ≥34 after 6 months; however, clinical judgment and baseline patient risk should guide threshold selection.
Serial variability of GEP scores has prognostic value; document trends and how variability informs management decisions.
GEP is not generally recommended as routine in pediatric patients per current guideline data.

Note

ASTS recommends serial dd-cfDNA for kidney recipients and selective GEP use in heart recipients

ASTS recommends serial dd-cfDNA measurement in kidney transplant recipients to exclude subclinical antibody-mediated rejection and supports dd-cfDNA measurement in kidney recipients with acute allograft dysfunction to help exclude rejection. ASTS also supports use of peripheral blood GEP to rule out acute cellular rejection in selected stable, low-risk adult heart transplant recipients.

ASTS: consider serial dd-cfDNA in stable kidney recipients to detect subclinical ABMR.
ASTS: measure dd-cfDNA in kidney recipients with acute dysfunction to evaluate for rejection, particularly ABMR.
ASTS: recommends peripheral blood GEP as noninvasive tool in stable, low-risk adult heart transplant recipients >55 days post-transplant.

Clinical applicationGEP used to stratify low vs higher risk of acute cellular rejection and guide reduced EMB frequency in selected low‑risk heart recipients

Added practical guidance review discussing noninvasive surveillance approaches and cited recent review 'The End of Endomyocardial Biopsy?' (JACC Heart Fail 2023).

2019-01-01evidence_integration

Integrated prospective multicenter and registry studies on dd-cfDNA and GEP (including Moayedi et al. 2019 and Khush et al. 2019) informing surveillance recommendations.

2015-09-18policy_initialLatest

Policy initial presentation date recorded for Transplant Rejection Testing (Policy Number: AHS - M2091).