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A.7.03.15
Clinical assessment, routine monitoring, and noninvasive imaging of allograft function after renal transplant can be limited in accurately diagnosing individuals with acute rejection (AR) or other forms of injury because symptoms and signs poorly correlate with objective methods of assessing kidney allograft dysfunction. For management of AR, clinical signs and symptoms (eg, serum creatinine, glomerular filtration rate [GFR], and proteinuria) are relatively crude markers of renal dysfunction and occur late in the course of an exacerbation. Thus, noninvasive urine biomarkers have potential benefit in surveillance and management of renal allograft function.
Renal Allograft Dysfunction
Allograft dysfunction is typically asymptomatic and has a broad differential, including graft rejection. Allograft injury or rejection are the main reasons for transplant failures, excluding death, with graft failure rates accelerating after the first-year post-transplantation. Diagnosis and rapid treatment are recommended to preserve graft function and prevent loss of the transplanted organ. For a primary kidney transplant from a deceased donor (accounting for about 70% of kidney donors), graft survival at 1 year is 93%; at 5 years, graft survival is 74%.
Surveillance of transplant kidney function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis. Allograft dysfunction may be diagnosed by a drop in urine output or, rarely, as pain over the transplant site but if there is 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. Renal allograft 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 T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have different treatment regimens. 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, damage to other organs, infection, and/or loss of a renal transplant, but are rare with literature reporting a 0.4% to 1.0% major complication rate.
Acute Kidney Allograft Rejection
Acute kidney allograft rejection is defined as an acute dysfunction associated with specific pathophysiologic changes in the allograft and is a major cause of allograft dysfunction. The incidence of acute rejection within the first post-transplant year has decreased dramatically over the past 3 decades with the advent of more potent immunosuppressive drugs. For kidney transplants performed in 2020, the rate of acute rejection in the first post-transplant year was 9.3% for recipients aged 18 to 34 years, 7.6% for recipients aged 35 to 49 years, 6.1% for recipients aged 50 to 64 years, and 5.3% for recipients aged ≥65 years. Most episodes of acute rejection occur within the first 6 months after transplantation, with many occurring early after surgery. Acute rejection episodes are associated with a reduction in long-term graft survival even though not all rejection episodes have the same impact on long-term graft function. Factors such as timing of rejection, severity and number of acute rejections, and degree of recovery of function after treatment all affect the long-term outcome. If kidney function returns to baseline, acute rejection does not necessarily cause irreparable damage or impact long-term graft survival. However, optimizing treatment and management to prevent and minimize allograft rejection, drug toxicity, post-transplant diabetes mellitus, dyslipidemia, infection, and malignancy remains challenging.
Acute T cell–mediated (cellular) rejection
Acute TCMR is one of the most common causes of immune-mediated allograft failure after kidney transplantation. The revised Banff 2017 classification of TCMR defines acute and chronic active TCMR as conditions in which histologic evidence of acute and chronic injury is characterized by lymphocytic infiltration of the tubules, interstitium, and arterial intima via T cells which react with foreign antigens resulting in inflammation, cell damage, and, ultimately, graft dysfunction. These criteria were further refined in the Banff 2019 and 2022 Kidney Meeting Report.
The severity of acute TCMR is graded using the Banff classification, which assesses these three specific features (interstitial inflammation [i], tubulitis [t], and intimal arteritis [v]) and scores them on a scale from 1 to 3:
Borderline: ≤25% interstitial inflammation (i1) with any tubulitis (t1, t2, or t3) or >25% interstitial inflammation (i2 or i3) with mild tubulitis (t1)
Type IA: >25% interstitial inflammation (i2 or i3) with moderate tubulitis (t2)
Type IB: >25% interstitial inflammation (i2 or i3) with severe tubulitis (t3)
Type IIA: Mild to moderate intimal arteritis (v1) with or without interstitial inflammation and tubulitis
Type IIB: Severe intimal arteritis (v2) with or without interstitial inflammation and tubulitis
Type III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3)
The diagnosis of acute TCMR requires a histologic score of at least t2 and i2.
Active antibody-mediated rejection
Active ABMR is one of the most common causes of immune-mediated allograft failure after kidney transplantation. The revised Banff 2017 classification of ABMR defines active (previously called acute) and chronic active ABMR as conditions in which histologic evidence of acute and chronic injury is associated with current/recent antibody interaction with vascular endothelium and serologic data of donor-specific antibodies (DSAs) to human leukocyte antigen (HLA) or non-HLA antigens. These criteria were further refined in the Banff 2019 and 2022 Kidney Meeting Report. Antibody-mediated rejection is thought to be caused by the binding of circulating antibodies to donor alloantigens on graft endothelial cells, which results in inflammation, cell damage, and, ultimately, graft dysfunction.
The diagnosis of active ABMR is established by the presence of the following 3 criteria;
Histologic evidence of acute tissue injury (acute tubular injury, microvascular inflammation [g > 0 and/or ptc > 0], intimal or transmural arteritis [v > 0], acute thrombotic microangiopathy, etc.)
Evidence of current/recent antibody interaction with vascular endothelium
Linear immunofluorescence or immunohistochemical staining for C4d in the peritubular capillaries
Increased expression of gene transcripts/classifiers in the biopsy tissue that are strongly associated with ABMR
At least moderate microvascular inflammation ([g + ptc] ≥2) in the kidney allograft biopsy
Serologic evidence of circulating DSAs (presence of serum antibodies against the donor's HLA class I and II antigens)
Chronic Rejection
Chronic rejection is characterized by a slow deterioration in allograft function associated with variable degrees of proteinuria and hypertension and is an important contributor to late graft loss. It usually occurs after the first year of transplantation and can occur with or without active inflammation. The 3 currently recognized types are chronic active ABMR, chronic inactive ABMR, and chronic active TCMR. Chronic active TCMR is characterized by the presence of the inflammation in areas of interstitial fibrosis (IF) and tubular atrophy (TA) in the kidney allograft. Chronic ABMR is characterized by chronic microvascular injury that leads to remodeling of the glomerular or peritubular capillaries and can be further categorized as inactive or active. Chronic active ABMR is essentially the same as active ABMR but with histopathological evidence of chronic injury and chronic inactive ABMR is characterized by chronic injury but without microvascular inflammation or evidence of antibody interaction with the endothelium.
Subclinical Rejection
Subclinical rejection (SCR) is defined as the presence of acute rejection on biopsy without any sign of allograft dysfunction or deterioration, such as an elevation in the serum creatinine concentration (variably defined as not exceeding 10%, 20%, or 25% of baseline values), decreased glomerular filtration rate (GFR), and/or proteinuria, etc. and is characterized by tubulointerstitial mononuclear infiltration. Subclinical rejection is detected by a surveillance or protocol biopsy, which is obtained at a protocol-driven, prespecified time after transplantation or upon detection of de novo DSAs rather than for an indication such as allograft dysfunction. The incidence of SCR in the first 6 months after a kidney transplantation is highly variable and depends on several factors, including degree of HLA matching, presence of DSAs, immunosuppressive protocol, and the incidence of delayed graft function. Although the cause of SCR is unclear, many studies have reported an association between SCR and decreased allograft survival and/or function.
BK Polyomavirus
BK polyomavirus (BKPyV) is a small double-stranded DNA virus that establishes lifelong infection in the renal tubular and uroepithelial cells and is typically dormant and benign. However, in immunocompromised patients, especially among kidney transplant recipients who are receiving immunosuppression medication, BKPyV can reactivate. Reactivation is frequently subclinical, although it may manifest with acute kidney injury and is associated with allograft dysfunction and premature allograft loss. Viral replication most commonly occurs during the first year after transplantation when cellular immunity is most suppressed with approximately 1% to 10% of kidney transplant recipients developing BKPyV-associated nephropathy (BKPyVAN). Kidney allograft biopsy is the gold standard for diagnosing BKPyVAN, assessing its severity, and evaluating for concomitant processes. Screening for reactivation is recommended for all kidney transplant recipients after transplantation and for those with significant reactivation, reduction of immunosuppression is the cornerstone of management, since there is no specific antiviral therapy for BKPyV. However, with the implementation of standardized screening and immunosuppression reduction protocols, rates of short-term graft loss have fallen substantially.
Urine Biomarkers for Allograft Rejection
Several urinary biomarkers, including messenger RNA (mRNA), microRNA (miRNA), proteins, and peptides, have been proposed as noninvasive biomarkers for the diagnosis and prognosis of acute rejection. Observational single-center studies of urinary cell mRNA profiling of renal allograft recipients identified potential mRNA biomarkers (eg, perforin, granzyme B, interferon [IFN]-inducible protein-10 [IP-10], CD3) that were associated with TCMR. In an observational study of 280 adult and pediatric kidney transplant recipients (Clinical Trial in Organ Transplant [CTOT1]) that evaluated multiple urinary mRNAs and proteins as biomarkers of acute rejection highlighted that elevated urinary CXCL9 mRNA and protein levels indicated immunological cause of inflammation. In urine samples collected from a large, multicenter study (Clinical Trials in Organ Transplantation 04 [CTOT4]) of 485 kidney transplant recipients, a 3-gene signature of CD3-epsilon mRNA, IP-10 (CXCL10) mRNA, and 18S ribosomal RNA (rRNA) was able to distinguish between kidney biopsy specimens showing acute TCMR and those without rejection with a sensitivity of 71% to 79% and specificity of 72% to 78%. The potential for extensive degradation of mRNAs in urine is an important limitation, for example, in the CTOT4 study only 83% of urine samples passed quality control standards. However, despite this limitation, a multicenter evaluation of a standardized protocol for urinary cell mRNA profiling demonstrated a reasonably good concordance between laboratories, confirming the potential of this technique in real-life clinical settings.
Quantification of miRNA in urine samples has emerged as an alternative noninvasive method to assess allograft status in renal transplant recipients. A pilot study profiled urinary miRNAs of stable transplant patients and transplant patients with acute rejection and identified miR-210 expression differed between patients with acute rejection with lower miR-210 levels associated with higher decline in GFR 1 year after transplantation when compared to stable transplant patients with urinary tract infection or transplant patients before/after rejection. In a prospective study, urine samples from chronic allograft dysfunction (CAD) in patients with IF and TA were evaluated for miRNAs indicative of graft function and 5 miRNAs were able to distinguish patients with CAD-IF/TA from patients with stable allografts (miR-142-3p, miR-204, miR-107 and miR-211; p<.001 and miR-32; p<.05). An initial and longitudinal validation study demonstrated that a subset of miRNAs was differentially expressed in CAD-IF/TA as compared to samples of normal allograft highlighting the potential of miRNA profiling as a noninvasive marker of IF/TA and for monitoring renal allograft function. Furthermore, in a prospective observational study the correlation of miR-155-5p and CXCL10 levels with AR and graft function in kidney transplant recipients was evaluated and it was determined that these biomarkers could discern between AR and renal transplant patients with normal allograft function. Profiling urine miRNA and chemokines are able to discriminate kidney transplant rejection from stable graft conditions demonstrating the utility of miRNA as noninvasive biomarkers.
Urinary immune-related proteins have been identified as biomarkers of acute rejection in kidney allografts. One study, for example, found that urinary concentration of chemokine (C-C motif) ligand 2 (CCL2, also known as monocyte chemoattractant protein 1 [MPC1]) at 6 months posttransplant was a predictor of severe IF/TA and graft dysfunction at 2 years post-transplant. In another observational study of 280 adult and pediatric kidney transplant recipients (Clinical Trial in Organ Transplant [CTOT1]) that evaluated multiple urinary proteins as biomarkers of acute rejection highlighted that elevated urinary CXCL9 levels indicated immunological cause of inflammation. Additionally, proteins and peptides that are differentially expressed in patients with acute rejection have been identified and reported in the literature, including fragments of collagens, beta-2-microglobulin, alpha-1-antichymotrypsin, and uromodulin. High-throughput methods have been used to characterize proteomic and peptidomic signatures of acute rejection in urine samples and have the potential to diagnose acute rejection with high sensitivity and specificity. The current literature is supportive of the notion that proteomic profiling is capable of uncovering key pathogenic processes and molecular mechanism of renal allograft rejection.
CXC Chemokine Protein Biomarker
Urinary CXC chemokine protein biomarkers have elicited interest as a potential aid to predict prognosis and manage therapy of acute rejection in kidney allografts. Chemokines are small peptides divided into C, CC, CXC, and CX3C families and provide signals for the recruitment of different subsets of T cells through 7-transmembrane-spanning, G-protein-coupled receptors. The CXC chemokine family, named after the conservative sequence Cys-X-Cys in their C-terminal tail, are ligands of the CXC-receptor 3 (CXCR3) which is commonly expressed in lymphocytes and other immune related cells. CXCR3, a receptor predominantly expressed by activated T- and natural killer cells, binds to the three CXC chemokines, C-X-C motif chemokine ligand 11 (CXCL11), 10 (CXCL10/IP-10) and 9 (CXCL9), and are markers for T cells associated with Th-1 type inflammatory processes. CXCL9 and CXCL10 are inducible pro-inflammatory cytokines that are normally excreted at low levels in urine, but their levels rapidly increase at the onset of an inflammatory response. They are secreted by infiltrating immune cells in response to IFN-γ and are involved in the recruitment of alloantigen-primed T cells to the site of inflammation and for enhancing proinflammatory cytokine production. In the clinic, urine concentrations of C-X-C motif chemokines CXCL9 and 10 have been investigated as noninvasive biomarkers and increased levels of CXCL9 and CXCL10 within urine are indicative of allograft inflammation resulting from TCMR, ABMR, BKPyV infections or HLA-DQ eplet mismatch.
Multiple observational studies have demonstrated that elevated CXCL10 levels are associated with inflammation and leads to early graft dysfunction and potentially, acute allograft rejection. One Lambda Laboratories (ThermoFisher Scientific) CXCL10 testing is a commercially available high-throughput immunoassay able to detect and quantify CXCL10 chemokine levels in urine samples. The One Lambda Laboratories CXCL10 testing service reports CXCL10 protein concentration in the patient’s urine as a predictor of allograft dysfunction, although the protein concentration threshold is not described by the manufacturer.
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 Act (CLIA). The One Lambda Laboratories CXCL10 assay (ThermoFisher Scientific) is available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the Food and Drug Administration has chosen not to require any regulatory review of this test.
The use of urine samples in the measurement of CXCL10/IP-10 for the management of individuals after renal transplantation, including but not limited to the detection of acute renal transplant rejection or dysfunction, is considered investigational.
Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary.
For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
12/01/2025: New Policy added. Approved by the Medical Policy Advisory Committee.
Blue Cross Blue Shield Association policy # 7.03.15
This may not be a comprehensive list of procedure codes applicable to this policy.
Code Number | |
CPT-4 | |
0526U | Nephrology (renal transplant), quantification of CXCL10 chemokines, flow cytometry, urine, reported as pg/mL creatinine baseline and monitoring over time (PLA for CXCL10 Urine Test, One LambdaTM, Inc) |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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