We highly appreciate the thoughtful comments of Pagliazzi et al.1 They raise three very important questions, which we only touched on partially in the discussion of our publication.2
Biomarker-driven management is a complex process involving a combined diagnostic and therapeutic concept. The therapeutic intervention on detection of subclinical rejection in the intervention arm was not strictly standardized, as Pagliazzi et al. correctly point out. We treated all Banff 2019–defined rejection episodes, mainly with steroid pulses plus optimization of maintenance immunosuppression, but allowing individualization of therapy by the treating physician. A more intensive intervention might have been beneficial. However, it could have also provoked deviations from the protocol on the basis of the patient's individual situation and comorbidities. Therefore, we decided to define treatment recommendations instead of a standardized treatment protocol.
An important use of noninvasive biomarkers is to avoid noninformative surveillance biopsies. Although this was not a specific aim of the study, we can provide some data. Using the urine CXCL10 cutoff of 3ng/mmol creatinine at one year to decide whether to perform a surveillance biopsy could have avoided 58% of all such one-year procedures while still detecting 70% of all subclinical rejection episodes defined according to Banff 2019. Notably, urine CXCL10 levels <3 ng/mmol also have a high negative predictive value to exclude relevant BK polyomavirus replication in urine or blood (97% and 99%, respectively).3 Therefore, low urine CXCL10 levels can exclude two of the most relevant allograft pathologies with high certainty.
Definition of appropriate trial end points is a highly relevant topic, especially if short-term outcomes are evaluated. Several surrogate end points have been elaborated in detail, and they should be selected wisely in future biomarker studies depending on the intended purpose of the investigated biomarker.4 Longer term follow-up with hard end points, such as graft failure, is essential, and we continue to collect data in the study population.
Besides providing useful information for clinical management, a biomarker must also be easy to measure, be robust across different laboratories,5 be cheap, and have a fast turnaround time, allowing for regular surveillance with timely decision making.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related letter to the editor, “Of Endpoints and Context of Use: A Reasonable Silver Lining for Urinary Chemokines Monitoring,” on pages 1765–1766 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
P. Hirt-Minkowski reports Advisory or Leadership Role: Alexion, AstraZeneca, and Novartis. All remaining authors have nothing to disclose.
Funding
S. Schaub: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32003B_169310/1).
Author Contributions
Writing – original draft: Patricia Hirt-Minkowski, Stefan Schaub, Caroline Wehmeier.
Writing – review & editing: Patricia Hirt-Minkowski, Stefan Schaub, Caroline Wehmeier.
References
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