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Journal of the American Society of Nephrology : JASN logoLink to Journal of the American Society of Nephrology : JASN
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. 2023 Aug 18;34(10):1765–1766. doi: 10.1681/ASN.0000000000000206

Of End Points and Context of Use: A Reasonable Silver Lining for Urinary Chemokines Monitoring

Angelica Pagliazzi 1, Elisabet Van Loon 1,2, Maarten Naesens 1,2,
PMCID: PMC10561771  PMID: 37782546

We read with great interest the article recently published in JASN by Hirt-Minkowski et al. exploring the clinical utility of urinary CXCL10 monitoring in kidney transplant recipients.1

In the sumptuous garden of research on noninvasive biomarkers for kidney transplantation, urinary CXCL10 monitoring stands out with good diagnostic accuracy for acute rejection.2 As the first randomized trial, the study by Hirt-Minkowski et al. is aimed to assess the clinical utility of this marker concerning clinical outcome at 1 year after kidney transplantation. Their conclusion was essentially negative: Urinary CXCL10-informed decision to proceed with a kidney biopsy in stable kidney transplant recipients does not improve clinical outcome at 1 year, when considering a complex composite end point (graft loss, rejection, de novo donor-specific anti-human leukocyte antigen antibodies, kidney function, interstitial fibrosis/tubular atrophy, and immunosuppression-related comorbidities).

We have to be very careful in interpreting this study, considering the context of use of noninvasive biomarkers for transplant rejection.

In this study, CXCL10-triggered biopsies in stable kidney transplant recipients showed a significantly higher yield for rejection diagnosis compared with 1-year surveillance biopsies. This confirms that urinary CXCL10 captures subclinical rejection, is useful to prompt informative biopsies, and allows timely adaptation of the immunosuppressive strategy. However, performing biopsies per se does not affect short-term outcomes; it is the therapeutic intervention based on the biopsy results that may have an effect. The lack of standardized intervention after detecting subclinical rejection in this trial potentially undermined the effect on the composite short-term end point. Longer follow-up is also needed to draw conclusions on the potential effect of timely treatment of subclinical rejection.

Next to potential relevance to detect subclinical rejection, noninvasive biomarker monitoring could aid in safely avoiding numerous noninformative surveillance biopsies.2 This clinically relevant context of use, supported by the high negative predictive value of urinary CXCL10, was not evaluated in this study.

Detection of subclinical rejection and avoidance of noninformative biopsies is the proposed context of use for other noninvasive biomarkers, such as donor-derived cell-free DNA, which has already been approved and implemented in several transplant centers in the United States, despite the lack of solid evidence of clinical utility.3

Awaiting longer term follow-up, the study by Hirt-Minkowski et al. demonstrates the importance for future clinical trials of establishing a clear definition of rejection (regarding histological diagnosis and subsequent therapeutic action) and of choosing the most appropriate trial end points to assess the performance of a biomarker considering the prespecified context of use.4

Acknowledgments

None.

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

See related article, “Authors' Reply: Of Endpoints and Context of Use: A Reasonable Silver Lining for Urinary Chemokines Monitoring,” on pages 1766–1767 and original article, “Randomized trial to assess the clinical utility of renal allograft monitoring by urine CXCL10 chemokine,” in Vol. 34, Iss. 8, on pages 1456–1469.

Disclosures

M. Naesens is involved in a clinical study with CareDx (Brisbane, CA), involving the use of donor-derived cell-free DNA in kidney transplant recipients. M. Naesens also reports Consultancy: Agomab, Aiosyn, Argenx, and Hansa; Research Funding: CareDx; Honoraria: Argenx and Hansa; and Patents or Royalties: M. Naesens is inventor of two patents related to the FWO-SBO application—EP19152365.3: mRNA-based biomarkers for antibody-mediated transplant rejection. This biomarker was licensed in September 2020 to CareDx, a precision medicine solutions company focused on solutions for transplant patients—PCT/EP2018/097044: Biomarkers for typing allograft recipients (patent application submitted in December 2018). E. Van Loon reports Patents or Royalties: Shared inventorship of European patent mRNA-based biomarker for antibody-mediated transplant rejection, filed on January 17, 2019. The remaining author has nothing to disclose.

Funding

M. Naesens is the senior clinical investigator of the Research Foundation Flanders (F.W.O.) (1844019N). A. Pagliazzi is supported by a PhD Fellowship grant from the Research Foundation Flanders (F.W.O.) (1S93023N).

Author Contributions

Conceptualization: Maarten Naesens, Angelica Pagliazzi, Elisabet Van Loon.

Writing – original draft: Angelica Pagliazzi.

Writing – review & editing: Maarten Naesens, Elisabet Van Loon.

References

  • 1.Hirt-Minkowski P Handschin J Stampf S, et al. Randomized trial to assess the clinical utility of renal allograft monitoring by urine CXCL10 chemokine. J Am Soc Nephrol. 2023;34(8):1456–1469. doi: 10.1681/ASN.0000000000000160 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Tinel C Devresse A Vermorel A, et al. Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection. Am J Transplant. 2020;20:3462–3476. doi: 10.1111/ajt.15959 [DOI] [PubMed] [Google Scholar]
  • 3.Oellerich M Sherwood K Keown P, et al. Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury. Nat Rev Nephrol. 2021;17(9):591–603. doi: 10.1038/s41581-021-00428-0 [DOI] [PubMed] [Google Scholar]
  • 4.Becker JU, Seron D, Rabant M, Roufosse C, Naesens M. Evolution of the definition of rejection in kidney transplantation and its use as an endpoint in clinical trials. Transpl Int. 2022;35:10141. doi: 10.3389/ti.2022.10141 [DOI] [PMC free article] [PubMed] [Google Scholar]

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