Letter to the AJT Editor re: Puttarajappa et al (doi:10.1111/ajt.16150)
Year: 2020
Type: letter
Abstract: To the Editor: We read with interest the manuscript entitled “Economic Analysis of Screening for Subclinical Rejection in Kidney Transplantation Using Protocol Biopsies and Non-Invasive Biomarkers” by Puttarajappa et al1Puttarajappa CM, Mehta RB, Roberts MS, Smith KJ, Hariharan S. Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.16150.Google Scholar which, based on a Markov model, concludes that protocol biopsies are superior to noninvasive biomarkers from a cost-benefit perspective. We submit that this conclusion may not be fundamentally warranted based on methodological concerns. The aggregation of the sensitivity and specificity of biomarkers tested are a point of concern. There are two categories of biomarkers: those to monitor stable patients for subclinical rejection in place of protocol biopsies (gene expression profile test) and those to monitor unstable patients for clinical rejection at the time of a “for cause” biopsy (donor-derived cell-free DNA—ddcfDNA tests). While the gene expression profile test was specifically designed and validated to monitor stable patients,2Friedewald JJ Kurian SM Heilman RL et al.Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant.Am J Transplant. 2018; 19: 98-109Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,3Marsh CL Kurian SM Rice JC et al.Application of TruGraf v1: a novel molecular biomarker for managing kidney transplant recipients with stable renal function.Transpl Proc. 2019; 51: 722-728Crossref PubMed Scopus (14) Google Scholar there are no definitive published data that support the ability of ddcfDNA tests to monitor stable patients for subclinical rejection.4Bromberg JS Brennan DC Poggio E et al.Biological variation of donor-derived cell-free dna in renal transplant recipients: clinical implications.J Appl Lab Med. 2017; 2: 309-321Crossref PubMed Scopus (47) Google Scholar With the aggregation of the sensitivities and specificities of biomarker tests with different contexts of use, it is likely that the authors have underestimated the efficacy of a biomarker test used to monitor patients with stable renal function. This is especially important as the model is used to compare the utility of biomarker tests vs surveillance biopsies for patients with stable renal function. Current state assumptions and/or values, independent of prior states, are a limiting factor of Markov models. A major assumption in the analysis conducted by the authors is the one-time utility loss from a major complication during biopsy; it is unclear how the utility loss number was derived. The subsequent lack of utility loss from minor complications, along with zero risk of graft loss and patient death, from protocol biopsies also limits the analysis conducted. This is particularly important as complications from invasive biopsies range from short-term events, such as bleeding that require hospitalization and may result in graft loss, to longer-term events such as arteriovenous fistulae.5Ahmad I. Biopsy of the transplanted kidney.Semin Intervent Radiol. 2004; 21: 275-281Crossref PubMed Scopus (36) Google Scholar In addition, the economic assumptions used in the model significantly undervalued the cost of a kidney transplant biopsy. The authors list the cost of a biopsy as a mean of $1450 with a range of $900–$2786.1Puttarajappa CM, Mehta RB, Roberts MS, Smith KJ, Hariharan S. Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.16150.Google Scholar Using CMS fee schedule data, a similar analysis discovered a cost of $3391 as the holistic cost of a protocol biopsy.5Ahmad I. Biopsy of the transplanted kidney.Semin Intervent Radiol. 2004; 21: 275-281Crossref PubMed Scopus (36) Google Scholar The use of a gene expression biomarker designed specifically for monitoring kidney transplant recipients with stable renal function resulted “in $6509 savings per year gross vs using protocol biopsies, or $1302 net per year including the cost of the biomarker tests.”6Rf M Lee D Lewis P Rose S. An economic analysis of the cost effectiveness of blood gene expression profiling in kidney transplant recipients.J Health Med Econ. 2017; 3 (https://doi.org/10.21767/2471-9927.100029)Google Scholar It is likely the authors have underestimated the potential cost-benefit of using a molecular biomarker monitoring approach compared to biopsies. Given the premise of the study, this cost underestimation is particularly important. Finally, the authors conclude that, “A one-time screening performed close to the period of peak SCR incidence appears cost-effective.”1Puttarajappa CM, Mehta RB, Roberts MS, Smith KJ, Hariharan S. Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.16150.Google Scholar However, by relying on studies with prescribed timing of biopsies, the authors cannot be certain when the peak incidence of SCR occurs, which could result in under-sampling. The potential value and benefit of noninvasive biomarkers in patients with stable renal function includes more frequent sampling to identify and treat ongoing inflammation in the kidney transplant.7Seifert ME Yanik MV Feig DI et al.Subclinical inflammation phenotypes and long-term outcomes after pediatric kidney transplantation.Am J Transplant. 2018; 18: 2189-2199Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,8Parajuli S Joachim E Alagusundaramoorthy S et al.Subclinical antibody-mediated rejection after kidney transplantation: treatment outcomes.Transplantation. 2019; 103: 1722-1729Crossref PubMed Scopus (43) Google Scholar Taken together, our methodological concerns regarding the study by Puttarajappa et al1Puttarajappa CM, Mehta RB, Roberts MS, Smith KJ, Hariharan S. Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers [published online ahead of print 2020]. Am J Transplant. https://doi.org/10.1111/ajt.16150.Google Scholar suggest that their analysis does not provide sound evidence to support their conclusion that from a cost-benefit perspective, protocol biopsy is superior to noninvasive biomarkers. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Abhijit S. Grewal is funded by the University Fellowship from The Graduate School at Northwestern University. John J. Friedewald and Michael M. Abecassis are the advisors of Transplant Genomics Inc.
DOI: 10.1111/ajt.16308
Institutions: Northwestern University, University of Arizona
Language: French
Subfield: Transplantation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
OpenAlex ID: W3087299574