Case simulation · Thermo Fisher Scientific

Expert’s Corner

Case · Presentation

Less urine, more creatinine. Rejection?

George, a 47-year-old Hispanic American man, underwent a kidney transplant one month ago for end-stage renal disease secondary to diabetic nephropathy. At this follow-up visit, he reports a decrease in urine output over the past several days, along with mild fatigue and bilateral lower limb swelling.

Medical history: diabetes mellitus and hypertension, both well controlled; no other significant medical history. Past surgical history: renal transplant performed four weeks ago.

Current medications: metformin 500 mg QD, tacrolimus 4 mg BID, mycophenolate mofetil (MMF) 500 mg QD, prednisone 20 mg QD, and lisinopril 10 mg daily.

He has no significant family history of kidney disease or autoimmune disorders. A former social drinker and smoker, he stopped both when he was diagnosed with ESRD 10 years ago.

On examination he is conscious and alert, well oriented x3, albeit nervous, and not in acute distress. He is afebrile and anicteric, and he is not pale. There is bilateral pitting pedal edema up to the distal third of the leg. BP 160/100 mmHg, RR 20 breaths/min, HR 90 bpm.

Case · Workup

The exosome assay is negative. The tacrolimus is 15.

These are the investigations ordered at today’s visit, with the findings and the reasoning for each.

  • Tacrolimus (blood)

    Today's result: 10 ng/mL.

    It is appropriate to order a blood test to determine George’s tacrolimus levels. Current KDIGO 2024 guidelines recommend maintaining tacrolimus trough levels of 8–12 ng/mL during the first 1–3 months post-transplant, then 5–8 ng/mL after stabilization, while individualizing based on pharmacogenomics and intra-patient variability (KDIGO 2024; Kim H, et al. 2023). Studies may target the higher end of the range (8-12 ng/mL) in the early post-transplant period to reduce the risk of rejection (Passey C, et al. 2011).

    This result suggests that George's tacrolimus levels are appropriate, but further investigations are needed to evaluate his symptoms and rule out other causes, such as rejection or graft dysfunction.

    Please note:

    Tacrolimus is the drug of choice in immunosuppressive maintenance therapy. However, it is also associated with nephrotoxicity. Between 17 and 44% of renal-transplant patients experience tacrolimus nephrotoxicity (Randhawa PS, et al. 1997). This nephrotoxicity usually depends on the dosing regimen and also previous clinical experience with the drug. So higher doses, usually >15 ng/mL, are associated with higher risks of nephrotoxicity (Randhawa PS, et al. 1997).

    When a rise in blood urea or serum creatinine levels cannot be explained by other factors (prerenal, renal, or postrenal), then acute tacrolimus nephrotoxicity may be suspected clinically (Randhawa PS, et al. 1997). Calcineurin inhibitor–related nephrotoxicity may occur even when trough concentrations fall within the target therapeutic range (Hardinger K, et al. 2024).

  • Renal ultrasound

    Today's result: Normal findings. These results suggest that the current symptoms are unlikely due to acute rejection.

    It is appropriate to order a renal ultrasound.

    Renal ultrasound findings in acute rejection include one or more of the following findings on sonogram: transplant swelling, increased conspicuity of the medullary pyramids, medullary pyramid enlargement, decreased renal-sinus fat, and pelvi-infundibular thickening (Linkowski G, et al. 1987).

    Recent KDIGO 2024 guidance highlights that while ultrasound remains useful to exclude obstruction, it should always be complemented by molecular biomarkers or cfDNA when available, as ultrasound alone lacks specificity for rejection (KDIGO, 2024). Accordingly, renal ultrasound is primarily used to evaluate for structural causes of allograft dysfunction, such as obstruction, perinephric fluid collections, or vascular complications, rather than to definitively diagnose rejection (Hardinger K, et al. 2024).

  • One Lambda™ Exosomes Kidney Transplant Assay

    Today's result: Negative, indicating George is unlikely to be undergoing an acute early rejection.

    It is appropriate to order a One Lambda™ Exosomes Kidney Transplant Assay.

    The One Lambda™ Exosomes Kidney Transplant Assay can help the clinician to make a better-informed decision on the patient’s acute rejection status. In patients such as George, it can eliminate the need to perform a renal biopsy, with all its attendant complications such as pain and bleeding. This noninvasive test enhances the accuracy of diagnosing kidney transplant rejection, contributing to improved patient outcomes.The One Lambda™ Exosomes Kidney Transplant Assay is a product of analysis of 112 target genes that identified an exosomal mRNA signature that significantly correlates with active rejection (Fekih RE, et al. 2021). The any-cause rejection signature and the signature to distinguish between TCMR and ABMR demonstrated excellent correlation with histopathologic diagnosis (Fekih RE, et al. 2021), assisting in the diagnosis or exclusion of acute rejection, potentially reducing the need for a renal biopsy.

    The ESOT 2024 Consensus Statement (Park S, et al. 2024) recommends integrating validated non-invasive biomarkers—such as urinary exosomal RNA, cfDNA, and gene expression assays—alongside biopsy for transplant monitoring. When robust molecular signatures are available, they provide complementary evidence and may reduce the need for invasive procedures.

    Notably, urinary exosomal RNA panels can outperform dd-cfDNA in distinguishing nephrotoxicity from rejection, a distinction particularly relevant in George’s case.

    It should also be noted that the indication for a renal biopsy includes a 25% increase in serum creatinine above the baseline, proteinuria, and abnormal urinary sediment (Metter C, Torrealba JR, 2020). George's creatinine increase is 18%. According to KDIGO 2024, a single abnormal laboratory value (such as an isolated creatinine rise) should not trigger biopsy in the absence of corroborating molecular or clinical evidence (Stevens PE, et al. 2024). Also, studies have shown that there is no benefit to early (1–3 months post transplant) protocol biopsies in renal transplant patients receiving tacrolimus, mycophenolate mofetil, and prednisone, which George is receiving. This is due to the low prevalence of subclinical rejection in these patients (Rusha D, et al. 2007).

  • Comprehensive metabolic panel

    Today's results: Elevated creatinine and sodium, low eGFR.

    Value

  • Urinalysis

    Today's results: Proteinuria (2+), red blood cells 1+, others negative.

    It is appropriate to order a urinalysis. Today's urinalysis results show proteinuria, with all other findings negative. These results are not strongly indicative of acute rejection.

  • BK Virus Quantitative PCR

    Today's results: Negative

    It is appropriate to order a BK Virus Quantitative PCR. BK virus-associated nephropathy is a significant cause of graft loss in kidney transplant recipients (Kant S, et al. 2022). Today's findings show no evidence of BK virus-associated nephropathy. This suggests that the patient's symptoms are unlikely to be related to viral-mediated graft dysfunction. Further investigations will focus on other potential causes. Plasma BK viral loads below diagnostic thresholds support exclusion of BK virus–associated nephropathy in the absence of other suggestive findings (Hardinger K, et al. 2024).

  • 24-hour urine

    Today's results: Reduced urine output.

    It is appropriate to order a 24-hour urine test. This helps objectively quantify oliguria and can complement follow-up assessment of protein excretion if needed during ongoing allograft dysfunction evaluation (Myslak M, et al. 2006).

Considered and not ordered (3)
  • Kidney biopsyNot appropriate

    Today's results: Biopsy canceled.

    It is not appropriate to order a kidney biopsy. While George is showing signs of proteinuria, this is not enough to make a diagnosis of dysfunction in more than half of patients (Ahmad I, 2005). A less invasive method, such as the One Lambda™ Exosomes Kidney Transplant Assay, should be prioritized before considering biopsy.Indications for a renal biopsy include a 25% increase in serum creatinine above the baseline, proteinuria, and abnormal urinary sediment (Metter C, Torrealba JR, 2020). In this patient, the increment in creatinine is 18%. According to KDIGO 2024, a single abnormal laboratory value does not justify biopsy, particularly when validated molecular biomarkers (e.g., urinary exosomal RNA, cfDNA) indicate immune quiescence (Stevens PE, et al. 2024). Creatinine has a low specificity, and this increment can be due to different factors. Hence, a biopsy would be unwarranted (Park J, et al. 2017).

    Beyond diagnostic yield, systematic reviews highlight the real-world risks and limitations of renal biopsy, including bleeding, hematoma, and sampling error, which can undermine diagnostic certainty (Poggio E, et al. 2020; Schnuelle P, 2023). In line with contemporary practice, the ESOT 2024 consensus advises avoiding unnecessary early biopsies when validated non-invasive biomarkers argue against rejection, and recommends multimodal decision-making that integrates molecular assays with clinical context (Park S, et al. 2024)The One Lambda™ Exosomes Kidney Transplant Assay gave a negative response to acute rejection. Its any-cause rejection signature and ability to distinguish between T-cell–mediated rejection (TCMR) and antibody-mediated rejection (ABMR) demonstrate excellent correlation with histopathologic diagnosis, and its validated exosomal mRNA signature significantly correlates with active rejection, supporting its role as a reliable non-invasive alternative in this clinical setting (Fekih RE, et al. 2021).

  • TruGraf® KidneyNot appropriate

    Today's results: Test canceled.

    It is not appropriate to order a TruGraf® Kidney. TruGraf® is a 57-gene microarray-based gene expression profile (Westphal SG, Mannon RB, 2024). However, it is not appropriate for George, because it can only be used from 90 days post-kidney transplant (First MR, et al. 2019).

  • Prospera™Not appropriate

    Today's results: Test canceled.

    It is not appropriate to order the Prospera™. Prospera™ is a dd-cfDNA assay with high specificity and sensitivity. However, it may give false positives due to non-rejection causes, such as recent surgery or infection, complicating the interpretation of George’s case (Danovitch GM, et al. 2021).

Case · Diagnosis

Rejection, or the drug preventing it?

Declining urine output, a rising creatinine and oedema, one month after transplant. Two explanations fit the picture; the assay separates them.

DecisionWhat is causing George’s graft dysfunction?

Select an answer to continue

  • AAcute early graft rejectionIncorrect
  • BNephrotoxicity due to tacrolimus therapyCorrect

A · incorrect

This is incorrect. The One Lambda™ Exosomes Kidney Transplant Assay results indicate that this scenario is not due to acute rejection of the renal transplant. The assay, which analyzes 112 target genes to detect an exosomal mRNA signature, demonstrated no correlation with active rejection in this case. This sensitive and specific test has been shown to reliably diagnose or exclude acute rejection, as its any-cause rejection signature and ability to distinguish between T-cell mediated rejection (TCMR) and antibody-mediated rejection (ABMR) align closely with histopathologic findings (Fekih et al., 2021).

In light of these results and the broader clinical picture:

- Normal Tacrolimus Levels (10 ng/mL): The patient’s immunosuppression is well-managed, reducing the likelihood of acute rejection due to inadequate drug levels.- Renal Ultrasound Findings: The ultrasound revealed no signs of acute rejection, such as abnormal kidney size, loss of corticomedullary differentiation, or vascular abnormalities.

- Urinalysis Results: Proteinuria (2+) and red blood cells (1+) are present, but there is no significant leukocyturia or other markers indicative of inflammatory or infectious processes.

- BK Virus-Associated Nephropathy: Negative findings for BK virus exclude this common post-transplant viral cause of graft dysfunction.

Given the combination of these findings, the evidence strongly supports that the patient’s decreased urine output is not related to acute rejection. This conclusion is reinforced by the high sensitivity and specificity of the One Lambda™ Exosomes Kidney Transplant Assay.

KDIGO 2024 reaffirms that the absence of molecular rejection signatures (urinary exosomal RNA, cfDNA) should be given equal diagnostic weight as a negative biopsy, reducing misclassification and avoiding overtreatment (Park S, et al. 2024; Stevens PE, et al. 2024).Other potential causes should be considered.

B · correct

This is correct.

Based on the findings, the patient’s decreased urine output is most likely due to nephrotoxicity associated with tacrolimus therapy. While the tacrolimus level is within the therapeutic range (10 ng/mL), tacrolimus is well-known for its potential to cause dose-independent nephrotoxicity (Thölking G, et al. 2014), particularly in the early post-transplant period. This conclusion is supported by the presence of proteinuria (2+), red blood cells (1+), and the absence of significant findings for acute rejection, BK virus nephropathy, or other structural abnormalities on renal ultrasound. Recent evidence shows that intra-patient variability (IPV) in tacrolimus trough levels predicts nephrotoxicity, independent of absolute drug concentrations. A 2023 study (Kim H, et al. 2023) found that high IPV was linked to greater risk of calcineurin inhibitor toxicity and poorer graft outcomes, emphasizing that nephrotoxicity may occur even at therapeutic levels such as George’s (10 ng/mL). Moreover, slow metabolizers—with higher dose-adjusted troughs—are especially prone to renal injury (Thölking G, et al. 2014; Kim H, et al. 2023). These findings support a strategy of titrating down tacrolimus, rather than discontinuing immunosuppression, to balance efficacy with nephroprotection.

Tacrolimus-induced nephrotoxicity may result from vasoconstriction of the afferent arterioles, leading to reduced renal perfusion and potential tubular damage (Randhawa PS, et al. 1997; Thölking G, et al. 2014; Wu Q, et al. 2018). KDIGO 2024 emphasizes minimizing calcineurin inhibitor exposure when nephrotoxicity is suspected, while maintaining adequate immunosuppression through antiproliferatives and steroids, supported by non-invasive biomarker monitoring to confirm immune quiescence (Stevens PE et al., 2024; Park S et al., 2024). Thus, careful adjustment of the tacrolimus dosing regimen, or consideration of alternative immunosuppressive strategies, should be evaluated to mitigate further renal impairment while maintaining graft protection.

Review the other options

Case · Treatment

Take the calcineurin inhibitor down.

He is on tacrolimus 4 mg BID, MMF 500 mg and prednisone 20 mg daily.

DecisionWhich regimen should George be on now?

Select an answer to continue

  • ATacrolimus 4 mg BID, MMF 500 mg, and prednisone 20 mg qdIncorrect
  • BBelatacept 10 mg/kg at week 2, 4, 8, and 12, followed by 5 mg/kg from week 16 onwards, and MMF 1000 mg BIDIncorrect
  • CTacrolimus 4 mg BID, azathioprine 100 mg QD, and prednisone 10 mg QDIncorrect
  • DSirolimus 5 mg QD, MMF 750 mg BID, and prednisone 20 mg (tapered to 5 mg at 3 months)Incorrect
  • ECiclosporin 100 mg BID, MMF 1000 mg BID (and reduced to 500 mg BID after 30 days), and prednisone 20 mg QDIncorrect
  • FTacrolimus 3 mg BID, MMF 500 mg BID, and prednisone 20 mg QDCorrect

A · incorrect

This does not represent a valid option. This patient’s kidney appears to be very sensitive to tacrolimus. The One Lambda™ Exosomes Kidney Transplant Assay reports a result that’s negative for organ rejection. Tacrolimus 4 mg BID, MMF 500 mg, and prednisone 20 mg QD were the patient’s original dose; maintaining the original tacrolimus exposure despite evidence of nephrotoxicity would not address the underlying cause of graft dysfunction. Adjusting the tacrolimus would be the correct approach (Stevens PE, et al. 2024; Park S, et al. 2024).

B · incorrect

This does not represent a valid option. While belatacept has been associated with improved graft function and histology, it carries risks such as post-transplant lymphoproliferative disorder and progressive multifocal leukoencephalopathy. The risk of PTLD is higher in Epstein–Barr virus (EBV)–seronegative recipients, and belatacept is generally avoided in this group (Hardinger K, et al. 2024). It is therefore generally considered a second-line treatment (Baker RJ, et al. 2017). More recent studies, however, have shown that conversion from calcineurin inhibitors to belatacept can be effective in select patients with intolerance or persistent nephrotoxicity, with favorable renal outcomes and acceptable safety (Divard G, et al. 2024; Efe O, et al. 2024). These conversion strategies are typically reserved for patients with established CNI intolerance or persistent nephrotoxicity despite dose optimization (Divard G, et al. 2024; Hardinger K, et al. 2024). In George’s case, these criteria are not met, and belatacept is therefore not an appropriate option at this stage.

George does not require a second-line treatment at this stage.

C · incorrect

This does not represent a valid option. Induction therapy plus low-dose tacrolimus, MMF, and corticosteroids has produced the lowest rates of acute rejection, superior graft function, and better graft survival (Baker RJ et al, 2017).

Furthermore, MMF is more effective than azathioprine in reducing the risk of graft loss and acute rejection (Wagner M et al, 2015). Accordingly, mycophenolate is generally preferred over azathioprine unless MMF is not tolerated or contraindicated (Hardinger K, et al. 2024).

So, switching MMF for azathioprine is not necessary in this patient. George has achieved adequate immunosuppression; it would be more appropriate to manage the associated nephrotoxicity.

D · incorrect

This does not represent a valid option. Induction therapy plus low-dose tacrolimus, MMF, and corticosteroids has produced the lowest rates of acute rejection, superior graft function, and better graft survival (Baker RJ et al, 2017). Early mTOR inhibitor use may increase adverse effects (e.g., wound-healing complications and proteinuria) and is typically reserved for selected patients, often with reduced CNI exposure rather than complete substitution (Hardinger K, et al. 2024; Pascual J, et al. 2018). Mammalian target of rapamycin inhibitors are also poorly tolerated and associated with higher rejection rates. They are best used as second-line agents (Baker RJ, et al. 2017). More recent evidence suggests that mTOR-based strategies may have a role when used in combination with reduced calcineurin inhibitor exposure for patients with CNI intolerance or toxicity (Pascual J, et al. 2018; Zou ZY, et al. 2023).

George has achieved adequate immunosuppression; it would be more appropriate to manage the associated nephrotoxicity.

E · incorrect

This does not represent a valid option. Compared with ciclosporin, treating kidney transplant recipients with tacrolimus results in a substantial improvement in graft survival (Webster AC, et al. 2005).

Furthermore, ciclosporin causes more episodes of acute rejection than Tacrolimus (Knoll GA, Bell RC, 1999). Contemporary practice generally favors tacrolimus over ciclosporin as the preferred calcineurin inhibitor in maintenance regimens (Hardinger K, et al. 2024). George has achieved adequate immunosuppression; it would be more appropriate to manage the associated nephrotoxicity.

F · correct

This represents a valid option. This regimen with a lower dose of tacrolimus and MMF will reduce their risk of infection while reducing the risk of additional nephrotoxicity. Because mycophenolate adverse effects are dose-related, dose reduction is a common strategy to reduce toxicity while maintaining immunosuppressive efficacy (Hardinger K, et al. 2024).

This aligns with guidance to minimize tacrolimus exposure while maintaining antiproliferative and steroid backbones, using serial biomarker monitoring to verify quiescence and avoid unnecessary escalation (Baker RJ, et al. 2017; Park S, et al. 2024; Westphal & Mannon, 2024).

Review the other options

Case · Next steps

What George leaves with.

The orders that follow the regimen change.

  • 01Follow-Up Laboratory Monitoring. Regular biomarker monitoring (e.g., urinary exosomal RNA, cfDNA) provides valuable insights into disease progression and treatment response, and reduces reliance on invasive biopsy (Westphal & Mannon, 2024; Stevens PE, et al. 2024).
  • 02Medication adherence. Medication adherence counseling is critical, as non-adherence is one of the strongest predictors of graft loss; structured education improves patient understanding and adherence to complex regimens (Baker RJ, et al. 2017).
  • 03Follow-up appointment. Follow-up visits thrice weekly for the next month will allow close monitoring of renal function, tacrolimus levels, and early signs of nephrotoxicity or rejection, in line with KDIGO recommendations (Stevens PE, et al. 2024).
  • 04Patient education. Patient education should focus on recognition of early warning signs (e.g., reduced urine output, edema, fever) and reinforce when to seek medical attention, empowering patients to participate in shared care (Park S, et al. 2024).

Case · Takeaways

A negative result is an answer.

George is a 47-year-old man who underwent a kidney transplant one month ago. Despite post-transplant care, he presents with decreased urine output, elevated creatinine, and elevated blood pressure.

George has a history of controlled diabetes mellitus and hypertension. During your consultation with him, while he was keen to find out if his symptoms were due to having his transplant rejected, he expressed concerns about the pain and discomfort associated with a renal biopsy and its financial implications.

On evaluation with the One Lambda™ Exosomes Kidney Transplant Assay, the results were negative, indicating George was not undergoing an acute early rejection. The use of the One Lambda™ Exosomes Kidney Transplant Assay spared George an invasive and unnecessary biopsy. Due to its high accuracy, the clinician can confidently make a better-informed decision on patient management. This aligns with KDIGO 2024 guidance to incorporate validated non-invasive biomarkers as a first-line diagnostic adjunct when available (Stevens PE, et al. 2024). This is particularly relevant in patients like George who have already expressed anxiety about a renal biopsy and renal biopsy complications, including pain, hematuria, hematoma, and bleeding (Poggio E, et al.2020).At present, the primary methods for diagnosing rejection are invasive procedures, including surveillance and indicated biopsies. These carry potential risks such as bleeding, infection, damage to the graft or nearby organs, and, in rare cases, mortality (Park S, et al,. 2024). Furthermore, biopsies can negatively impact the overall patient experience.

Ongoing care should prioritize biomarker-guided monitoring (urinary exosomal RNA/cfDNA where appropriate) to corroborate clinical stability and detect early immune activity, reducing reliance on invasive biopsy (Park S, et al. 2024). If nephrotoxicity persists despite careful tacrolimus minimization, consider second-line conversions (e.g., mTOR- or belatacept-based) after individualized risk–benefit assessment (Baker RJ, et al. 2017). This stepwise strategy maintains graft protection while minimizing drug-related renal injury.

Explore more cases at Expert’s Corner

The case · George Sand what separates rejection from toxicity

The case 47-year-old, one month post-transplant

  • −30 dRenal transplant. IV basiliximab 20 mg on day 0 and day 4.
  • TodayDecreased urine output over several days, mild fatigue, bilateral pitting pedal oedema. BP 160/100 mmHg.

Key results today

  • One Lambda™ Exosomes AssayNegativeno acute early rejection
  • Tacrolimus trough15 ng/mLsupratherapeutic
  • Creatinine1.5 mg/dL
  • Renal ultrasoundNo obstruction
  • BK virus PCRNegative
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Age
47 years
Weight
70 kg
Height
175 cm
BMI
22.9