Concert Genetic Testing: Kidney Disorders

V1.2025
Date of Last Revision: 11/2024

CONCERT GENETIC TESTING: KIDNEY DISORDERS

[Revision log](Revision log)
[Coding Implications](Coding Implications)

See [Important Reminder](Important Reminder) at the end of this policy for important regulatory and legal information.

OVERVIEW

Inherited kidney disorders and inherited disorders that indirectly affect the kidneys can be common, such as autosomal dominant polycystic kidney disease, or rare, such as Lowe syndrome and Fabry disease. Identifying the genetic cause of an inherited kidney disorder can help direct treatment, inform family members, and contribute to the overall understanding of the genetic etiology of chronic kidney disease. More advanced next-generation sequencing, such as exome sequencing and comprehensive genetic testing panels, are emerging as a first-line diagnostic method for patients with chronic kidney disease.

With the use of donor-derived cell-free DNA (ddcfDNA), biomarker tests have been developed as an alternative to more invasive procedures for post-renal transplant care to optimize graft longevity while avoiding side effects and toxicity of immunosuppressive therapies.

POLICY REFERENCE TABLE

Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.

The tests, associated laboratories, CPT codes, and CPT codes contained within this document serve only as examples to help users navigate claims and corresponding criteria; as such, they are not comprehensive and are not a guarantee of coverage or non-coverage. Please see the [Concert Platform](Concert Platform) for a comprehensive list of registered tests.

OTHER RELATED POLICIES

This policy document provides criteria for hereditary kidney disorders. Please refer to:

• Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for criteria related to genetic disorders that affect multiple organ systems
• Genetic Testing: Hereditary Cancer Susceptibility for criteria related to von Hippel Lindau (VHL) syndrome and other hereditary cancer syndromes.
• Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related to genetic testing for kidney disease that is not specifically discussed in this or another non-general policy, including known familial variant testing.
• Genetic Testing Hematologic Conditions Non-Cancerous for criteria related to hematologic disorders that affect the kidneys.

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CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria:

POLYCYSTIC KIDNEY DISEASE PANELS

Polycystic Kidney Disease Panels

I. Genetic testing using a polycystic kidney disease panel (81404, 81405, 81406, 81407, 81408, 81479) to confirm or establish a diagnosis of polycystic kidney disease is considered medically necessary when:

A. The member/enrollee has any of the following clinical features of polycystic kidney disease:

1. Multiple bilateral renal cysts, OR
2. Cysts in organs other than the kidneys (especially the liver, seminal vesicles, pancreas, and arachnoid membrane), OR
3. Hypertension in an individual younger than age 35, OR
4. Bilaterally enlarged and diffusely echogenic kidneys

II. Genetic testing using polycystic kidney disease panels (81404, 81405, 81406, 81407, 81408, 81479) to confirm or establish a diagnosis of polycystic kidney disease is considered investigational for all other indications.

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COMPREHENSIVE KIDNEY DISEASE PANELS

Comprehensive Kidney Disease Panels

I. Genetic testing for kidney disease via a comprehensive kidney disease panel (81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479) is considered medically necessary when:

A. The member/enrollee has chronic kidney disease with an undetermined cause after undergoing standard-of-care workup studies (examples: history and physical examination, biochemical testing, renal imaging, or renal biopsy), AND
B. The member/enrollee meets at least one of the following:

1. Onset of chronic kidney disease under 40 years of age, OR
2. One or more first- or second-degree relatives with chronic kidney disease, OR
3. Consanguineous family history, OR
4. Cystic renal disease, OR
5. Congenital nephropathy, OR
6. Syndromic/multisystem features, OR
7. There is a possibility of identifying a condition amenable to targeted treatment.

II. Genetic testing for kidney disease via a comprehensive kidney disease panel (81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479) is considered investigational for all other indications.

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APOL1-MEDIATED KIDNEY DISEASE

APOL1 Targeted Variant Analysis

I. Targeted variant analysis for the APOL1 high-risk genotype (i.e., G1/G1, G1/G2, or G2/G2) (0355U, 81479) is considered medically necessary when:

A. The member/enrollee has kidney disease, AND
B. The member/enrollee meets at least one of the following:

1. The member/enrollee is of African ancestry, OR
2. The member/enrollee has a family member with a confirmed APOL1 high-risk genotype (i.e., G1/G1, G1/G2, or G2/G2).

II. Targeted variant analysis for the APOL1 high-risk genotype (i.e., G1/G1, G1/G2, or G2/G2) (0355U, 81479) is considered investigational for all other indications.

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DONOR-DERIVED CELL-FREE DNA FOR KIDNEY TRANSPLANT REJECTION

Donor-Derived Cell-free DNA for Kidney Transplant Rejection

I. The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation (81479, 0493U, 0118U, 0508U, 0509U) is considered medically necessary when:

A. The member/enrollee has undergone kidney transplantation, AND
B. The test has not been performed in the previous 12 months, AND
C. The member meets at least one of the following:

1. The member has clinical signs of acute rejection, OR
2. A biopsy was done to check for signs of acute rejection and is inconclusive, OR
3. The member is being monitored for adequate immunosuppression.

II. The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation (81479, 0493U, 0118U, 0508U, 0509U) is considered investigational for all other indications.

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OTHER COVERED KIDNEY DISORDERS

Other Covered Kidney Disorders

The following is a list of conditions that have a known genetic association. Due to their relative rareness, it may be appropriate to cover these genetic tests to establish or confirm a diagnosis.

I. Genetic testing to establish or confirm one of the following genetic kidney disorders to guide management is considered medically necessary when the member demonstrates clinical features* consistent with the disorder (the list is not meant to be comprehensive, see II below):

A. Alport Syndrome
B. C3 Glomerulopathy
C. Congenital nephrotic syndrome
D. Cystinosis
E. Cystinuria
F. Fabry Disease
G. Genetic (familial) atypical hemolytic-uremic syndrome (aHUS)
H. Primary Hyperoxaluria

II. Genetic testing to establish or confirm the diagnosis of all other kidney disorders not specifically discussed within this or another medical policy will be evaluated by the criteria outlined in General Approach to Genetic and Molecular Testing (see policy for criteria).

*Clinical features for a specific disorder may be outlined in resources such as GeneReviews, OMIM, National Library of Medicine, Genetics Home Reference, or other scholarly source.

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DEFINITIONS

1. Close relatives include first, second, and third degree blood relatives on the same side of the family:

   a. First-degree relatives are parents, siblings, and children
   b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half siblings
   c. Third-degree relatives are great grandparents, great aunts, great uncles, great grandchildren, and first cousins

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BACKGROUND AND RATIONALE

Polycystic Kidney Disease Panels

GeneReviews: Polycystic Kidney Disease, Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease - PKHD1

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes through a rigorous editing and peer review process before being published online.

The recommended polycystic kidney disease testing for autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) is as follows:

“ADPKD should be suspected in individuals with the following:

• Multiple bilateral renal cysts and the absence of manifestations suggestive of a different renal cystic disease
• Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane…
• Hypertension in an individual younger than age 35 years

“Autosomal recessive polycystic kidney disease – PKHD1 (ARPKD-PKHD1) should be suspected in probands with the following age-related clinical and ultrasonographic findings at presentation….

Infantile presentation (age 4 weeks to 1 year)

• Bilaterally enlarged kidneys (in relation to age-, height-, or weight-based normal range) that usually retain their typical shape

Note: (1) Bilaterally enlarged kidneys can be interspersed with macrocysts. (2) During later disease stages relative kidney length may decrease again.

• Increased echogenicity…
• High-resolution ultrasonography may demonstrate innumerable very small cysts (rarely exceeding 1-2 mm) in the cortex and medulla.

Childhood/Young Adulthood Presentation (age >1 year)

• Imaging findings typically are the following:
  ○ Enlarged kidneys with multiple macrocysts, increased echogenicity, and reduced or absent corticomedullary differentiation…”

Comprehensive Kidney Disease Panels

Hays et al (2020)

“We propose the following approach, based on a review of current literature and our practical experience. This approach assumes individuals have already undergone an initial nephrologic workup, including biochemical and serologic testing, imaging of the kidneys, and renal biopsy if indicated.

…[A]fter a negative or inconclusive initial workup, a patient is considered to have KDUE [kidney disease of unknown etiology] and may then be stratified according to the probability of a genetic disease. We consider higher probability patients as those with the following risk factors: early-onset disease (age <40 years), a positive family history of CKD [chronic kidney disease], consanguinity, extrarenal anomalies, cystic renal disease, or congenital nephropathy”. (p. 594)

Kidney Disease: Improving Global Outcomes (KDIGO)

KDIGO developed a Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease in 2024. The guideline states the following:

“Genetic testing is emerging as a valuable component for evaluation of cause. In some studies, >10% of people with CKD, regardless of family history, were observed to carry genetic pathogenic and likely pathogenic variant(s) that represent a plausible molecular cause for the development or progression of CKD. In some cases, identification of actionable genes through genetic testing can impact the clinical management of people with CKD. A recent KDIGO Controversies Conference listed the following recommendations for when genetic testing can be particularly informative: (i) high prevalence of monogenic subtypes within the clinical category, (ii) early age of onset of CKD, (iii) syndromic/ multisystem features, (iv) consanguinity, (v) possibility of identifying a condition amenable to targeted treatment, and (vi) CKD/ kidney failure of unknown etiology when kidney biopsy would not be informative due to advanced disease.” (p. S173)

Additionally, the guideline lists the following genes as examples for genetic testing evaluation: APOL1, COL4A3, COL4A4, COL4A5, NPHS1, UMOD, HNF1B, PKD1, PKD2. It goes on to say this is “evolving as a tool for diagnosis, increased utilization is expected. Recognition that genetic causes are more common and may present without classic family history”. (p. S150)

APOL1 Targeted Variant Analysis

Freedman et al (2021)

A multidisciplinary group of experts and patient advocates performed a systematic review and created consensus-based guidelines in 2021 to guide health care providers in APOL1-associated neuropathy. The guidelines recommend the following:

“…APOL1 testing should be considered in all patients of African ancestry with kidney disease and in any patient with kidney disease and a family member with a confirmed APOL1 high-risk genotype.” (p. 1768)

Regarding the definition of “high-risk phenotype”: “Two copies of the APOL1 variants (G1/G1, G1/G2, G2/G2) are commonly referred to as a ‘high-risk’ genotype…” (p. 1765)

Donor-Derived Cell-Free DNA for Kidney Transplant Rejection

Centers for Medicare and Medicaid Services

The CMS local coverage determination (LCD) entitled “MolDX: Molecular Testing for Solid Organ Allograft Rejection” states the following regarding donor-derived cell-free DNA tests in individuals who have had solid organ transplantation:

“This Medicare contractor will provide limited coverage for molecular diagnostic tests used in the evaluation and management of patients who have undergone solid organ transplantation. These tests can inform decision making along with standard clinical assessments in their evaluation of organ injury for active rejection (AR).

These tests may be ordered by qualified physicians considering the diagnosis of AR affiliated with a transplant center, helping to rule in or out this condition when assessing the need for or results of a diagnostic biopsy. They should be considered along with other clinical evaluations and results and may be particularly useful in patients with significant contraindications to invasive procedures.

The intended use of the test must be:

• To assist in the evaluation of adequacy of immunosuppression, wherein a non-invasive or minimally invasive test can be used in lieu of a tissue biopsy in a patient for whom information from a tissue biopsy would be used to make a management decision regarding immunosuppression, OR
• As a rule-out test for AR in validated populations of patients with clinical suspicion of rejection with a non-invasive or minimally invasive test to make a clinical decision regarding obtaining a biopsy, OR
• For further evaluation of allograft status for the probability of allograft rejection after a physician-assessed pretest, OR

Concert Genetic Testing: Kidney Disorders
V1.2025
Date of Last Revision: 11/2024

• To assess rejection status in patients that have received a biopsy, but the biopsy results are inconclusive or limited by insufficient material.”

European Society of Organ Transplantation

The European Society of Organ Transplantation (ESOT, published in 2024) published a Consensus Statement on Testing for Non-Invasive Diagnosis of Kidney Allograft Rejection, which states the following:

“Recommendation 1.1: We suggest that clinicians consider measuring serial plasma dd-cfDNA in patients with stable graft function to exclude the presence of subclinical antibody mediated rejection. (p. 5)

Recommendation 2.1: We recommend that clinicians measure plasma dd-cfDNA in patients with acute graft dysfunction to exclude the presence of rejection, particularly antibody mediated rejection.” (p. 6)

American Society of Transplant Surgeons (ASTS)

The ASTS issued a statement on donor derived cell-free DNA (dd-cfDNA) in 2023. At this time, there are no evidence-based screening recommendations for frequency of testing mentioned in this statement.

Concert Note

For routine monitoring of patients post-transplant, absent clear, specific and evidence-based guideline recommendations for a particular regimen of screening, a default frequency of coverage of once every 12 months will be adopted.

Important Reminder

This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care and are solely responsible for the medical advice and treatment of member/enrollees. This clinical policy is not intended to recommend treatment for member/enrollees. Member/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, member/enrollees, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, member/enrollees and their representatives agree to be bound by such terms and conditions by providing services to member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs and LCDs and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information.

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