Medical Policy

Policy Num:      11.001.048
Policy Name:    Urinary Test for Renal Allograft Rejection
Policy ID:          [11.001.048]  [Ac / B / M- / P-]  [7.03.15]

Last Review:      August 18, 2025
Next Review:     August 20, 2026
 

Related Policies: NONE

Urinary Test for Renal Allograft Rejection

Summary

Description

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.

In transplant recipients, despite the progress in immunosuppressant therapy, the risk of rejection still remains. Diagnosis of allograft rejection continues to rely on clinical monitoring and histologic confirmation by tissue biopsy. However, due to limitations of tissue biopsy, including a high degree of interobserver variability in the grading of results and its potential complications, less invasive alternatives have been investigated. A laboratory developed test, One Lambda Laboratories CXCL10 assay, uses a noninvasive urine-based biomarker (CXCL10 protein) to support routine monitoring of graft dysfunction. One Lambda laboratories CXCL10 assay measures the concentration of the CXCL10/IP-10 protein within a urine sample.

Summary of Evidence

For individuals with a renal transplant who are undergoing surveillance or have clinical suspicion of allograft rejection and receive testing for urinary CXCL10 chemokine to assess renal allograft dysfunction, the evidence includes 1 systematic review, 1 randomized controlled trial (RCT), and an array of observational studies. Relevant outcomes are overall survival (OS), death-censored graft survival, test validity, morbid events, and hospitalizations. The systematic review, RCT, and observational studies reported urinary chemokine levels are indicative of alloimmune injury and/or infection with diagnostic accuracy, sensitivity, and specificity scores that highlight the ability of these chemokines to potentially be used to reduce the number of indication and surveillance biopsies.However, the diagnostic performance of CXCL9 and CXCL10 biomarkers have yet to demonstrate clinical validity. No studies included comparators of urinary CXCL10 or CXCL9 testing. There are no RCTs or other clinical studies in which urinary CXCL10 testing was used to diagnosis the type of allograft dysfunction or guide treatment decisions upon identification of the dysfunction and no study reported management changes made for kidney transplant recipients in response to CXCL10 urine testing results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether the measurement of various selected urine biomarkers improves the detection of renal allograft dysfunction or the management of kidney transplant recipients, thus improving net health outcomes.

Policy Statements

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.

Policy Guidelines

Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Monitoring of kidney transplantation rejection is a specialized procedure that may require an out-of-network referral. Specifically, the One Lambda CXCL10 test is only performed in the company’s laboratory.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

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.^1, 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%.^2,3,

Surveillance of transplant kidney function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis.^4, 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.^5,6, 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.^7,8,9,

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. ^10, 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. ^11, If kidney function returns to baseline, acute rejection does not necessarily cause irreparable damage or impact long-term graft survival. ^12,13, 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. ^14,15,16,

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:^15,

• 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. ^14,15,16, 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. ^14,

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. ^17, 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). ^18, 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. ^19,

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. ^20,21,22,23,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. ^24,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%. ^25,26, 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. ^27,

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. ^28, 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). ^29, 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. ^30, 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. ^31, Profiling urine miRNA and chemokines are able to discriminate kidney transplant rejection from stable graft conditions demonstrating the utility of miRNA as noninvasive biomarkers. ^32,

Urinary immune-related proteins have been identified as biomarkers of acute rejection in kidney allografts. ^33,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. ^34, 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. ^24, 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. ^35, 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. ^36, 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. ^37, 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. ^38, 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. ^{39,40,41,42,43,44,}

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. ^45,

Regulatory Status

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.

Rationale

This evidence review was created in May 2025 with a search of the PubMed database. The most recent literature update was performed through July 10, 2025.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Population Reference No. 1

CXCL10 Chemokine Testing for Renal Transplant

Clinical Context and Test Purpose

The purpose of CXCL10 testing in individuals with renal transplant who are undergoing surveillance or have clinical suspicion of allograft rejection is to detect allograft dysfunction.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with renal transplants who are undergoing surveillance or who have a clinical suspicion of allograft rejection.

Clinical suspicion of allograft rejection may be indicated by clinical symptoms (eg, pain) or dynamic changes in laboratory parameters.

Allograft dysfunction is typically asymptomatic and has a broad differential, including graft rejection. Diagnosis and rapid treatment are recommended to preserve graft function and prevent loss of the transplanted organ

Interventions

The test being considered is urinary CXCL10 testing by One Lambda Labatories to assess for renal allograft dysfunction (One Lambda Laboratories CXCL10 assay).

Use of the One Lambda Laboratories CXCL10 testing service is recommended when there is clinical suspicion of active rejection and for regular surveillance of subclinical rejection. In a surveillance scenario, regular testing is recommended at 1, 2, 3, 4, 6, 9, and 12 months after renal transplant or most recent rejection. Thereafter, the test should be repeated quarterly. In the surveillance scenario, individuals with a negative result may avoid biopsy and it is recommended that a positive test result is incorporated with clinical findings to determine whether a biopsy is indicated. When there is clinical suspicion of rejection, testing is recommended as an adjunct to biopsy for treatment response monitoring, or as a rule-out test for biopsy.

Comparators

The following test is currently being used to confirm a clinical suspicion of allograft dysfunction or rejection: renal biopsy. The adoption of protocol (ie, surveillance) biopsies varies across transplant centers, and its use is not standardized.

Clinical suspicion of allograft rejection may be indicated by physical symptoms and/or dynamic changes in laboratory parameters (eg, serum creatinine, estimated glomerular filtration rate [eGFR], donor-specific antibodies [DSA]).

Outcomes

The general outcomes of interest are overall survival (OS), death-censored graft failure, allograft function, test validity, morbid events, and hospitalizations. Follow-up over months to years is needed to monitor for signs of allograft rejection. Most episodes of acute rejection (AR) occur within the first 6 months after transplantation, with many occurring early after surgery. Rejection after 12 months is typically from nonadherence to or overaggressive reduction in immunosuppression. For a primary kidney transplant, graft survival at 1 year is 94.7%; at 5 years, graft survival is 78.6%. ^2, Acute rejections occurring after 3 months and rejections not responding to therapy (serum creatinine not reaching 75% of baseline value) are associated with poor graft survival. ^46,3, For individuals who are being monitored for surveillance following kidney transplantation, the timepoint of interest to assess allograft dysfunction would be within 3-months and beyond post-transplantation.

Beneficial outcomes resulting from a true-negative test result are avoiding unnecessary subsequent biopsy. Harmful outcomes resulting from a false-positive result may include an unnecessary biopsy or unnecessary treatment. Harmful outcomes from a false-negative result are increased risk of adverse transplant outcomes.

In a triage scenario, the test would need to precisely identify a group of individuals that could safely forgo biopsy; therefore, the sensitivity, negative predictive value (NPV), and negative likelihood ratio are key test performance characteristics.

Study Selection Criteria

For the evaluation of clinical validity of the One Lambda Laboratories CXCL10 test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Several studies were excluded from the evaluation of the clinical validity of the One Lambda Laboratories CXCL10 test because they did not use the marketed version of the test, used serum instead of urine samples (Lazzeri et al (2005) ^47, and Rotondi et al (2004)^48,), or did not include information needed to calculate performance characteristics (Ho et al (2023). ^49,)

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Review

Janfeshan et al (2024) conducted a systematic review and meta-analysis of 10 studies (N=3035) on the potential role of urinary CXCL10 protein, on its own or in combination with creatinine ratio, in predicting kidney graft dysfunction amongst renal transplant recipients. ^50, According to the authors, the quality assessment of the included studies using the Newcastle-Ottawa Scale (NOS) was deemed satisfactory with each study adopting a case-control design, with unanimous gold standard for diagnosis across all experiments being histopathological results (renal biopsy) post-transplantation. However, there was significant heterogeneity observed amongst the studies included, indicated by an I² value exceeding 50%, and resulted in a comprehensive subgroup analyses and meta-regression of the diagnostic performance for this urinary biomarker (Table 2). Urinary CXCL10 levels were indicative of renal allograft inflammation and dysfunction but were not deemed sufficient at determining specific graft outcomes based on the sensitivity and specificity analyses. Some limitations of this systematic review and meta-analysis include the heterogeneity of studies, patient populations, methods of categorizing patients, and biomarker stratification approaches. Key characteristics of studies included in the systematic review are summarized in Table 1 with key results summarized in Table 2.

Table 1. Key Characteristics of Clinical Studies Evaluating CXCL10 Testing for Renal Allograft Dysfunction

  ABMR: antibody mediated rejection; ACR: acute cellular rejection; AR: acute rejection; ATN: acute tubular necrosis; AVR: acute vascular rejection; BKVAN: BK virus associated nephropathy; BR: borderline rejection; clin: clinical rejection; CR: chronic rejection; ELISA: enzyme-linked immunosorbent assay; graft func dec: graft function decrease; KTx: kidney transplant; Late clinical rej: late clinical rejection; MIX: mix rejection; NA: not applicable; NR: not reported; subclin: subclinical rejection; TCMR: T-cell mediated rejection; UCr: urinary creatinine ratio.

Table 2. Key Results of Clinical Studies Evaluating CXCL10 Testing for Renal Allograft Dysfunction

  CI: confidence interval; Cr: creatinine ratio; 

Randomized Controlled Trials

Hirt-Minkowski et al (2023) conducted a randomized clinical trial (RCT) with 241 renal transplant recipients and evaluated urine samples at 1-, 3-, and 6-month post-transplant for CXCL10 chemokine levels. ^51, The primary outcome was a combined end point at 1-year post-transplant, consisting of, death-censored graft loss, clinical rejection between month 1 and 1-year, AR in 1-year surveillance biopsy, chronic active T cell–mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific human leukocyte antigen (HLA) antibodies (HLA-DSA), or eGFR <25 ml/min. Using the Banff 2015 and 2019 classifications, no significant difference was reported in the incidence of the primary outcome between the 2 groups. The cumulative inflammatory burden was investigated using the mean incidence of rejection in the 1-year surveillance biopsies (1-, 3-, 6-months) within the tertiles (high, medium, low) for CXCL10 levels and a significant association was detected for the 2019 Banff classification (p=.01) but not the 2015 classification (p=.13). The diagnostic performance of CXCL10 to detect allograft rejection was assessed using 292 paired urine-biopsy samples for the receiver operating characteristic analysis with 142 samples being excluded (no concurrent urine collected [n=108], urinary tract infection [UTI] as confounder [n=8], BK polyomavirus replication as confounder [n=26]). This analysis once again showed a significant result for the 2019 Banff classification (area under the curve [AUC]=0.73; p=.002) but not the 2015 classification (AUC=0.59; p=.17). The key observation in this study was that a urine CXCL10 monitoring strategy did not improve clinical outcomes at 1-year post-transplant. Limitations of this study were that it was not powered to detect clinically relevant differences under 2019 Banff classification criteria, and the assumed effect size was ambitiously overestimated to achieve a 50% reduction in the primary endpoint.

Observational Clinical Studies

Eighteen observational clinical studies have demonstrated that urinary chemokine CXCL9 and CXCL10 levels are correlated with renal allograft inflammation and have potential as noninvasive biomarkers for renal allograft dysfunction (Table 3). They differed in their study designs, frequency and timing of testing, outcome measures, and timing of follow up. Three of these clinical studies have demonstrated that integrating urinary CXCL9 and CXCL10 protein levels with clinical parameters improve the diagnostic value of these biomarkers.^57,54,58,A recent study by Seifert et al (2024) designed a risk-stratification algorithm (score4) combining four urinary protein biomarkers (CCL2, CXCL9, CXCL10, and vascular endothelial growth factor A [VEGF-A]) that were able to distinguish kidney transplant recipients at low- versus high-risk of allograft rejection. ^59, Nine observational studies of kidney transplant patients have reported that elevated urinary CXCL10 and CXCL9 protein levels are associated with tubulointerstitial and microvascular inflammation of the renal allograft resulting in alloimmune injury of the kidney and potential rejection.^{52,24,60,38,61,62,63,31,64,}Additionally, high levels of these urinary chemokines have been implicated in the decline of kidney function, decreased allograft survival, and worse long-term outcomes for renal transplant recipients. ^{42,65,66,56,55,}The results of testing urinary chemokines indicate clinically useful diagnostic properties (Table 3) that highlight the ability of these chemokines to potentially reduce the number of indication and surveillance biopsies by guiding decision making for the timing of a renal allograft biopsy.

Overall, these studies have identified that renal inflammation, as a result of viral infections, infiltrating immune cells, and/or other types of injury increases chemokine, specifically CXCL9 and CXCL10, production in urine but the diagnostic performance has yet to demonstrate clinical validity. Furthermore, these studies did not provide comparisons of urinary CXCL10 or CXCL9 testing with renal biopsies or any other standard method. There are no RCTs or other clinical studies in which urinary CXCL10 testing was used to diagnosis the type of allograft dysfunction or guide treatment decisions upon identification of the dysfunction and no study reported management changes made for kidney transplant recipients in response to CXCL10 urine testing results. Major limitations are synonymous with retrospective analysis, including but not limited to, clinical heterogeneity of study populations, lack of comparators, variability in data recording, different conditions under which measurements occurred, susceptibility to selection and recall bias, and inability to establish causality etc.

Study limitations are shown in Tables 4 and 5.

Table 3. Diagnostic Performance Characteristics of Urinary Chemokine Biomarkers for Detection of Kidney Allograft Dysfunction

  Adapted from Park et al (2024) 68, ABMR: antibody-mediated rejection; AR: acute rejection; AUC: area under the curve; AUROC: area under the receiver operating characteristic curve; BKI: BK polyomavirus infection; BKV: BK virus; BL: borderline rejection; CCL2: C-C motif ligand 2; CI: confidence interval; CMV: cytomegalovirus; CNI: calcineurin inhibitor toxicity; Cr: creatinine ratio; IF/TA: interstitial fibrosis and tubular atrophy; LEU: leukocyturia; NPV: negative predictive value; NR; not reported; OR: odds ratio; PPV: positive predictive value; ROC: receiver operating characteristic; scABMR: subclinical antibody-mediated rejection; SCR: subclinical rejection; scTCMR: subclinical T cell-mediated rejection; subAR: subclinical acute rejection; TCMR: T cell-mediated rejection. a Study population was for pediatric (≤ 21 years old) kidney transplant recipients b Time-dependent ROC curve; CXCL10/Cr at 3 months

Table 4. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 5. Study Design and Conduct Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Four retrospective clinical studies have published results that indicate that increased urine proteins levels of the chemokine, CXCL10, are associated with BK polyomavirus (BKPyV) replication and reactivation with 2 of these studies reporting diagnostic performance via area under the receiver operating curve values (Table 6).

Tinel et al (2020) performed 2 separate retrospective studies, a cross-sectional study (N=391) and longitudinal study (N= 60), to investigate urinary CXCL10 levels across different stages of BKPyV replication and as a prognostic and/or predictive biomarker for allograft dysfunction after BKPyV DNAemia. ^69, In the cross-sectional study, BKPyV viral load correlated with increased urinary CXCL10 levels and after excluding confounding factors, such as AR and UTIs, chemokine levels increased with viral replication (no BKPyV vs DNAemia p<.0001; no BKPyV vs polyomavirus associated nephropathy [PVAN] p<.0001; viruria vs DNAemia p<.001; viruria vs PVAN p<.0001). Furthermore, the nested case-control arm of the cross-sectional study (n=63) examined renal allograft outcomes (denoted by 50% eGFR decline) among kidney transplant recipients with BKPyV DNAemia using a Cox proportional hazard model with the multivariate analysis demonstrating that CXCL10 urine levels were associated with graft function decline (hazard ratio [HR], 1.52, 95% confidence interval [CI], 1.00 to 2.30; p≤.05) and could discriminate patients into low- and high-risk groups (p=.01). In the longitudinal cohort, patients with BKPyV DNAemia with at least a 6-month follow up were used to validate a urinary CXCL10 threshold as a prognostic biomarker for allograft dysfunction. Using regression analysis, at first instance of BKPyv DNAemia, patients in the high-risk group were associated with a sharper peak in CXCL10 concentration compared to low-risk groups and demonstrated better survival rates (p=.03). Using a Cox proportional hazards regression model including urinary CXCL10/creatinine ration [Cr], eGFR, and BK viral load (all measured at the time of first BK virus DNAemia), CXCL10 was significantly associated with 25% eGFR decrease (HR, 1.733; p<.05).

Weselindtner et al (2020) assessed CXCL10 chemokine levels in urine samples from kidney transplant recipients (N=85) who displayed different stages of BKPyV replication as it progressed to PVAN. ^70, Urine levels of CXCL10 increased proportionally as BKPyV replication increased while the virus progressed through the viral life cycle and peaked when a decrease of eGFR and/or histological evidence for PVAN was detected (baseline vs BKPyV DNAuria alone p<.023; BKPyV DNAuria vs low-level DNAemia p<.001; and low-level DNAemia vs 1000 DNA copies/ml p<.0005; 1000 DNA copies/ml vs PVAN p<.0001). Haller et al (2023) was able to corroborate that increased CXCL10 chemokine levels in urine is correlated with BKPyV pathology retrospectively in 235 patients undergoing renal allograft monitoring during a clinical trial (baseline vs viruria p<.001; viruria vs viruria + decoy cells p<.001; viruria + decoy cells vs DNAemia p<.01). ^71, Additionally, researchers were able to show that CXCL10 urine levels closely parallels BKPyV DNAemia including a return to normal levels after viral clearance. Mayer et al (2022) performed a retrospective analysis of 19 cases of patients with PVAN to evaluate donor-derived cell-free DNA and urinary chemokines, CXCL10 and CXCL9, as diagnostic biomarkers for renal injury. ^72, At time of biopsy, patients with PVAN had significantly higher levels of CXCL10 in urine samples compared to the antibody-mediated rejection (p=.0002) and control cohorts (p=.003) but not the T cell-mediated rejection cohort (p=.67), however, under further investigation there was no correlation between urinary CXCL10 levels and allograft histologic analysis or BKPyV-specific biomarkers.

Limitations of these studies are synonymous with retrospective analysis, including but not limited to, clinical heterogeneity of study populations, variability in data recording, different conditions under which measurements occurred, susceptibility to selection and recall bias, and inability to establish causality etc. Other limitations include some studies had small or insufficient sample sizes, incomplete baseline and histological samples, and lack of controls. No study reported management changes made for kidney transplant recipients in response to CXCL10 urine testing results.

Table 6. Summary of Observational Studies of Urine Chemokines for BK Polyomavirus Infection

  AUROC: area under the receiving operating characteristic curve; CI: confidence interval; NR: not reported

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Urinary CXCL10 One Lambda Test for Renal Allograft Dysfunction

For individuals with a renal transplant who are undergoing surveillance or have clinical suspicion of allograft rejection and receive testing for urinary CXCL10 chemokine to assess renal allograft dysfunction, the evidence includes 1 systematic review, 1 RCT, and an array of observational studies. The systematic review, RCT, and observational studies reported urinary chemokine levels are indicative of alloimmune injury and/or infection with diagnostic accuracy, sensitivity, and specificity scores that highlight the ability of these chemokines to potentially be used to reduce the number of indication and surveillance biopsies.However, the diagnostic performance of CXCL9 and CXCL10 biomarkers have yet to demonstrate clinical validity. No studies included comparators of urinary CXCL10 or CXCL9 testing. There are no RCTs or other clinical studies in which urinary CXCL10 testing was used to diagnosis the type of allograft dysfunction or guide treatment decisions upon identification of the dysfunction and no study reported management changes made for kidney transplant recipients in response to CXCL10 urine testing results.

For individuals with a renal transplant who are undergoing surveillance or have clinical suspicion of allograft rejection and receive testing for urinary CXCL10 chemokine to assess renal allograft dysfunction, the evidence includes 1 systematic review, 1 randomized controlled trial (RCT), and an array of observational studies. Relevant outcomes are overall survival (OS), death-censored graft survival, test validity, morbid events, and hospitalizations. The systematic review, RCT, and observational studies reported urinary chemokine levels are indicative of alloimmune injury and/or infection with diagnostic accuracy, sensitivity, and specificity scores that highlight the ability of these chemokines to potentially be used to reduce the number of indication and surveillance biopsies.However, the diagnostic performance of CXCL9 and CXCL10 biomarkers have yet to demonstrate clinical validity. No studies included comparators of urinary CXCL10 or CXCL9 testing. There are no RCTs or other clinical studies in which urinary CXCL10 testing was used to diagnosis the type of allograft dysfunction or guide treatment decisions upon identification of the dysfunction and no study reported management changes made for kidney transplant recipients in response to CXCL10 urine testing results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

European Society of Organ Transplantation

In 2024, the European Society of Organ Transplants (ESOT) convened to address the need for improved biomarkers for kidney transplant rejection by reviewing literature pertaining to clinical and subclinical acute rejection to develop guidelines in the screening and diagnosis of acute rejection.^68, The ESOT issued 2 recommendations pertaining to the role of urinary chemokine biomarkers in kidney transplant surveillance:

• "We suggest the monitoring of a combination of urine CXCL9 and CXCL10 in stable patients to exclude subclinical rejection (TCMR [T cell-mediated rejection] or ABMR [antibody-mediated rejection]).

  • Quality of evidence - moderate

  • Strength of recommendation - weak in favor"

• "We recommend the measurement of urinary chemokines CXCL9 and CXCL10 to inform the presence or absence of clinical acute rejection (TCMR or ABMR) in patients with graft dysfunction.

  • Quality of evidence - moderate

  • Strength of recommendation - moderate in favor"

Kidney Disease Improving Global Outcomes

The Kidney Disease Improving Global Outcomes (2009) issued guidelines for the care of kidney transplant recipients. ^73, The guidelines included the following recommendations (see Table 7).

Table 7. Guidelines for Biopsy in Renal Transplant Recipients

  LOE: level of evidence; SOR: strength of recommendation.

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

  NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

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