Donald is a 42-year-old male who underwent a kidney transplant four months ago due to end-stage renal disease (ESRD) secondary to glomerulonephritis. He presents at his four-month follow-up, remaining asymptomatic with normal laboratory results. However, a gradual increase in CXCL10 levels has been observed, warranting further evaluation and discussion of its clinical significance.
Past medical history: ESRD secondary to glomerulonephritis. No other significant medical history. Past surgical history: kidney transplant four months ago.
Current medications: mycophenolate mofetil 1000 mg twice daily (BID), tacrolimus target range of 6–8 ng/mL, prednisone 5 mg once daily (QD).
On examination he is conscious, alert, and well oriented to person, place, and time, with mild irritability but no acute distress. He is afebrile and anicteric, but he is not pale. There is no swelling or palpable lymph nodes. BP 120/80 mmHg, RR 18 breaths/min, HR 80 bpm, temperature 36.6 °C. No abnormalities were noted in the head, eyes, ears, nose, throat, neck, heart, chest, abdomen, extremities, neurologic system, or skin examination.
Although Donald is asymptomatic, asymptomatic rises in CXCL10 have been associated with subclinical immune activation and early graft injury.
Case · Workup
Creatinine normal. CXCL10 climbing.
These are the investigations ordered at today’s visit, with the findings and the reasoning for each.
One Lambda™ CXCL10 Assay
Today’s results: 24.97 pg/mL (this patient’s baseline appears to be 4.99 pg/mL).
Measuring the patient's CXCL10 levels using the One Lambda™ CXCL10 Assay is appropriate. Although no universal reference ranges exist for CXCL10 (Baresi G, et al. 2021), non-detectable to 9.99 pg/mL is considered normal, while 10-30 pg/mL is elevated. Recent systematic reviews and meta-analyses (Janfeshan S, et al. 2024; Mačionienė E, et al. 2024) demonstrate that urinary CXCL10, particularly when normalized to creatinine, can predict biopsy-proven rejection with sensitivity ranging from ~71-77% and specificity ranging from ~73-85%. While Donald did not undergo a biopsy due to normal graft function, these studies confirm that CXCL10 elevation often reflects underlying graft inflammation even before conventional markers change. Significantly, rises in CXCL10 frequently occur before serum creatinine changes, supporting its role as an early warning biomarker in transplant surveillance.Regular monitoring of CXCL10 can aid in the early detection of potential allograft dysfunction, complementing conventional biomarkers.The patient’s CXCL10 levels initially declined in the first three months post-transplant but have consistently increased over time, increasing from the patient's baseline of 4.99 pg/mL to 24.97 pg/mL today. All other laboratory parameters have remained within normal limits, and the patient is asymptomatic. This isolated rise in CXCL10 highlights the need for further investigation to assess potential underlying immune activation or allograft dysfunction despite the absence of abnormalities in other routine biomarkers.Rising CXCL10 levels are associated with renal inflammation, which may indicate acute rejection due to T-cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR). However, it is essential to recognize that elevated CXCL10 levels are not exclusively linked to rejection; they are also observed in cases of BK virus infection and leukocyturia (Haller J, et al. 2023). This highlights the importance of using CXCL10 testing as a part of broader ongoing active surveillance.Since CXCL10 results are available within 24 hours, they provide faster insights than conventional tests used for kidney graft monitoring (GenomeWeb,2024)
Donald’s rising CXCL10 levels suggest underlying renal inflammation. Further diagnostic evaluation is warranted to determine the cause of this inflammatory response.
Comprehensive metabolic panel (CMP)
Today's result: All within the normal range.
Value
Complete blood count (CBC)
Today's result: All within the normal range.
Value
Tacrolimus (blood)
Today's result: 12 ng/mL is elevated (his tacrolimus target range is 6–8 ng/mL)
It is appropriate to check the patient’s tacrolimus (blood) levels.
Target trough for tacrolimus at 3–6 months post-transplant is generally 5–8 ng/mL per KDIGO 2020 and reinforced by 2023 consensus; Donald’s level of 12 ng/mL is above this and increases the risk of nephrotoxicity and BK viremia (KDIGO, 2020; Wojciechowski D, et al 2021).
Significantly, supra-therapeutic tacrolimus exposure has been independently associated with BK viral replication, even in the absence of other risk factors, as shown in large cohort studies (Wojciechowski D, et al. 2021; Kant S, et al. 2022). This underscores the need for careful trough-level monitoring to balance rejection prevention with the risk of opportunistic infection.
Renal ultrasound
Today's result: No abnormalities noted
It is appropriate to order a renal ultrasound.
However, while a renal ultrasound is usually the first-line imaging modality in evaluating a renal transplant, renal transplant rejection is not a radiologic diagnosis (Campos A, 2021).
BK virus quantitative polymerase chain reaction (PCR)
Today’s result: Positive
It is appropriate to order a BK virus quantitative PCR.BK virus quantitative PCR indicates that Donald is positive for BK virus.Despite normal routine labs, Donald’s rising CXCL10 levels were an early indicator of immune activation. BK virus replication can begin silently without immediate impact on renal function.Rising CXCL10 may indicate immune activation, potential allograft dysfunction, leukocyturia, or BK viremia (Haller J, et al. 2023) before routine labs reveal abnormalities, permitting timely intervention before significant abnormalities are detected in standard biomarkers. This highlights its value in routine surveillance and guides early investigation.If left unchecked, BK viremia can progress to BK virus-associated nephropathy (BKVAN), a significant cause of graft loss in kidney transplant recipients (Kant S, et al. 2022).
BK virus is the most likely cause of Donald’s rising CXCL10 levels.
Urinalysis
Proteinuria: Negative
Red blood cells: Negative
Others: Negative
It is appropriate to order a urinalysis. While rising CXCL10 levels may signal immune activation or potential allograft dysfunction, they can also be influenced by conditions like localized urinary tract inflammation or infection (Haller J, et al. 2023).By confirming the absence of proteinuria or hematuria, the urinalysis supports the interpretation that the rise in CXCL10 is more likely related to BK viremia or early immune activation rather than a urinary tract issue. This underscores the importance of integrating urinalysis findings into the broader diagnostic evaluation to refine clinical decisions.
Considered and not ordered (2)
Kidney biopsyNot appropriate
Today's result: Test canceled
It is not appropriate to order a kidney biopsy. Indications for a renal biopsy include a 25% increase in serum creatinine above baseline, proteinuria, and abnormal urinary sediment (Metter C, Torrealba JR. 2020). In this patient, all laboratory parameters, including creatinine, proteinuria, and urinary sediment, remain within normal limits. A renal biopsy is, therefore, unwarranted, as invasive diagnostic procedures are not justified in the absence of clinical or laboratory evidence of renal dysfunction.While the rising CXCL10 levels indicate potential immune activation, they are not specific or diagnostic enough to justify a biopsy alone.
ProsperaNot appropriate
Today's result: Test canceled
It is not appropriate to order a Prospera. Prospera is a donor-derived cell-free DNA assay with high specificity and sensitivity. However, at about $3000, it would be too costly for this patient. It may also give false positives due to non-rejection causes, such as recent surgery or infection, complicating the interpretation of Donald’s case (Danovitch GM et al, 2021).
Case · Diagnosis
What is the rising marker telling you?
Normal creatinine, no symptoms, and a marker that has been climbing for weeks.
This is the correct diagnosis. The BK virus test was positive, confirming the diagnosis, in the context of rising CXCL10 levels detected through the One Lambda™ CXCL10 Assay. Donald’s increasing CXCL10 levels are consistent with immune activation due to BK virus infection, rather than early acute rejection or leukocyturia, which can also cause a rise in CXCL10 levels (Haller J, et al. 2023).
Documenting this stage is critical because timely immunosuppression adjustment can prevent progression to biopsy-proven nephropathy, as confirmed in multicenter cohorts (Kant S, et al. 2022; Ali N, et al. 2025).
BK virus–associated immune activation is an early phase distinct from BK virus nephropathy. KDIGO 2020 and Viruses 2022 review emphasize the importance of identifying and documenting this stage, as immunosuppression reduction at this point can prevent progression to BK virus nephropathy (BKVN) and reduce the risk of graft loss (Kant S, et al. 2022).
B · incorrect
This is not the correct diagnosis: The BK virus test was positive, confirming the diagnosis of rising CXCL10 levels detected through the One Lambda™ CXCL10 Assay. Donald’s increasing CXCL10 levels are consistent with immune activation due to BK virus infection, rather than early acute rejection or leukocyturia (Haller J, et al. 2023). Additionally, a kidney biopsy was not performed due to normal routine laboratory results, and therefore, histologic confirmation of nephropathy is lacking.
While BKVN may develop over time if the infection progresses, it is currently more accurate to describe this as early BK viremia without nephropathy, as there is no evidence of kidney dysfunction or structural damage at this stage (Kant S, et al. 2022).The correct diagnosis is BK virus-associated immune activation (ICD Z48.22).
Review the other options
Case · Treatment
Immune activation, not yet nephropathy.
He is on MMF 1000 mg BID, tacrolimus targeted to 6–8 ng/mL and prednisone 5 mg daily.
DecisionWhat should happen to Donald’s immunosuppression?
Select an answer to continue
ALower Immunosuppression (reduce TAC trough levels to 6 ng/mL; MMF to 500mg BID; prednisone to 5mg QD)Correct
BWatchful waiting, maintain the current immunosuppressive regimenIncorrect
A · correct
This represents a valid option. Current regimen: Tacrolimus target blood trough levels 6–8 ng/mL, mycophenolate mofetil 1000 mg BID, prednisone 5 mg QDNew regimen: Tacrolimus target blood trough levels 6 ng/mL, mycophenolate mofetil 500 mg BID, prednisone 5 mg QDReducing immunosuppression is the standard first-line approach for managing BK virus-associated immune activation or early BK viremia (Kant S, et al. 2022). In patients on triple therapy (CNI + antimetabolite + prednisone), expert guidance recommends initially reducing the antimetabolite dose by ~50% (Kant S, et al. 2022). Current consensus supports stepwise reduction of immunosuppression when CXCL10 elevation coincides with BK viremia, as in this case (Kant S, et al. 2022; Janfeshan S, et al. 2024).
Recent systematic reviews and biopsy-correlated studies confirm that urinary CXCL10 often rises before changes in creatinine or histology, reinforcing its role as an early warning biomarker (Janfeshan S, et al. 2024; Mačionienė E, et al. 2024).
Donald’s rising CXCL10 levels can be attributed to a BK virus infection rather than an early acute rejection. Since no therapeutic agent is available to treat this virus-associated disease, reducing the intensity of immunosuppression is the overarching principle for managing BK viremia and BKVN. Maintaining or increasing Donald’s dose of tacrolimus can cause further nephrotoxicity and increase the risk of further infection (Kant S, et al. 2022; Haller J, et al. 2023). Experts recommend a stepwise approach for the reduction in immunosuppression (Kant S, et al. 2022):
- Reduce the dose of antimetabolite by half while continuing on the same doses of the calcineurin inhibitor and/or prednisone. - Monitor serum creatinine and serial plasma BK PCR levels from the same laboratory (to reduce inter-assay variability) every 2 weeks in the interim.
- If viral loads continue to be at similar levels or increase, proceed with complete cessation of the anti-metabolite.
- The next step is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus and 50–100 ng/L for cyclosporine).Lower Immunosuppression must be done cautiously, as excessive reduction may increase the risk of acute rejection. If serum creatinine increases by ≥25% from baseline during immunosuppression reduction, the patient should be evaluated for acute rejection. Close monitoring with BK PCR, serum creatinine, and immune activation biomarkers such as CXCL10 is essential to balance viral control and rejection risk (Kant S, et al. 2022; Haller J, et al. 2023).
B · incorrect
Reducing immunosuppression with close follow-up is the standard first-line approach for managing BK virus-associated immune activation or early BK viremia (Kant S, et al. 2022).
Immunosuppression reduction is a proactive intervention, not passive observation—it aims to restore immune control over viral replication while minimizing the risk of acute rejection.
Rather than "watching and waiting," guidelines support a structured immunosuppression reduction strategy with ongoing surveillance — BK PCR, renal function, and CXCL10 (Kant S, et al. 2022; Haller J, et al. 2023). Although Donald did not undergo a biopsy due to normal graft function, recent biopsy-correlated studies in other cohorts confirm that ignoring elevated CXCL10 is associated with a higher likelihood of histologic rejection or viral-associated nephropathy (Mačionienė E, et al. 2024). This reinforces the need for proactive management even when routine labs remain normal.
Review the other options
Case · Next steps
What Donald leaves with.
The orders that follow.
01Medication adherence. Medication adherence counseling improves understanding of the regimen, reduces missed doses, and is strongly associated with improved graft survival in kidney transplant recipients. Nonadherence is a leading modifiable risk factor for late acute rejection and graft loss, making structured adherence counseling an essential component of post-transplant care (Baker RJ, et al. 2017; Hardinger K, et al. 2024).
02Follow-Up CXCL10. The patient's CXCL10 baseline was established post-transplant (4.99 pg/mL) and is being used as a personalized target for monitoring their response to adjustments in immunosuppression. Given the recent upward trend, it is critical to track CXCL10 levels every two weeks alongside routine laboratory tests to assess immune activity and potential early rejection (Guzzi F, et al. 2024).
03Patient education. Patient education empowers early reporting of infection or rejection symptoms, improves adherence, and enhances shared decision-making, all of which are protective against graft loss.
04Follow-up appointment. Scheduled visits at least every 2–4 weeks in the setting of active BK viremia are recommended for timely intervention and early detection of complications (Malhotra D, et al. 2023).
05Cognitive behavioral therapy. Non-pharmacological interventions, including cognitive behavioral therapy for renal transplant recipients after surgery, can reduce unhealthy psychological reactions, improve sleep quality, and enhance the self-management ability of patients (Lee H, et al. 2025). / Routine mental health support is encouraged in transplant guidelines, as anxiety, depression, and sleep disturbance negatively affect adherence and outcomes (Lee H, et al. 2025).
06Lifestyle modification counseling. This patient should be counseled on the importance of a healthy lifestyle, including eating a nutritious diet, exercising appropriately, refraining from smoking, and maintaining a healthy weight (Knoppe TJ, et al. 2025).
Case · Takeaways
Caught before the creatinine moved.
Donald, a 42-year-old male patient, underwent renal transplant surgery. CXCL10 levels of undetectable to 9.99 pg/mL served as a baseline, reflecting normal post-transplant immune activity. Despite normal routine labs, Donald’s subsequent rising CXCL10 levels from 4.99 to 24.97 pg/mL served as an early indicator of immune activation, allowing timely intervention before significant abnormalities were detected in standard biomarkers. This highlights the value of the One Lambda™ CXCL10 Assay in guiding early investigation and facilitating non-invasive monitoring in transplant recipients.
BK virus is a common post-transplant opportunistic infection, affecting approximately 15% of renal transplant recipients within the first year after transplantation. More specifically, BK viruria and viremia are detected in approximately 25–30% and ~12% of kidney transplant recipients, respectively, with ~1–10% progressing to BK virus–associated nephropathy (Limaye AP, et al. 2022). If left unaddressed, BK viremia can progress to BK virus-associated nephropathy (BKVAN), a significant cause of graft loss in kidney transplant recipients (Kant S, et al. 2022). Historically, BKVAN was associated with graft loss rates exceeding 50%, although early detection and preemptive immunosuppression reduction have substantially improved outcomes (Limaye AP, et al. 2022).
While histology remains the gold standard for definitive diagnosis, CXCL10 is a valuable adjunct for early immune activation detection and monitoring. It helps guide clinical decisions and reduces reliance on invasive procedures (Ho J, et al. 2016; Haller J, et al. 2023). Importantly, biopsy may miss early or focal BK virus–associated injury, as sampling error can occur in up to one-third of cases, reinforcing the role of non-invasive biomarkers for early detection (Limaye AP, et al. 2022).
Without the One Lambda™ CXCL10 Assay, Donald’s early BK virus may have gone undetected until more advanced stages, potentially progressing to BK virus nephropathy (BKVN). This delay could have necessitated a renal biopsy with its associated risks and costs, ultimately leading to the same management strategy for the BK virus. This highlights the assay’s value in enabling earlier, non-invasive intervention (Kant S, et al. 2022; Haller J, et al. 2023). In clinical practice, significant BK viremia (eg, plasma BK viral load ≥10,000 copies/mL) is often used to support a presumptive diagnosis and initiate intervention even in the absence of biopsy confirmation (Limaye AP, et al. 2022).The One Lambda™ CXCL10 Assay is a convenient, urine-based test. The samples can be easily collected in the physician's office. Testing can be conducted as early as 7–10 days following organ transplantation, and results can be available within 24 hours of receiving the sample (Thermo Fisher Scientific, 2024).
Current guidelines endorse a multimodal monitoring strategy: urinary CXCL10 for immune activation, BK PCR for viral reactivation, and donor-derived cfDNA or protocol biopsy if biomarker results conflict. This layered approach reduces unnecessary biopsies while detecting rejection earlier (Janfeshan et al. 2024; Ali N, et al. 2025). Routine BK virus surveillance (e.g., monthly during the first 6 months post-transplant, then every 3 months until 2 years) further supports early detection and timely intervention (Limaye AP, et al. 2022).
Economic modeling studies suggest that urine CXCL10 testing, when combined with PCR surveillance, reduces unnecessary biopsies and hospitalization costs compared with creatinine-only monitoring (Danovitch GM, et al. 2021; GenomeWeb, 2024). By enabling earlier detection of immune activation and viral reactivation, this strategy supports both improved clinical outcomes and more efficient resource utilization in transplant care.
TodayFour-month follow-up. Asymptomatic, normal laboratory results, gradually rising CXCL10.
Key results today
One Lambda™ CXCL10 AssayRisingbaseline undetectable to 9.99 pg/mL
Creatinine0.9 mg/dLnormal
Tacrolimus troughIn rangetarget 6–8 ng/mL
BK virus PCRSee workup
Kidney biopsyNot orderednot indicated at this point
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