Receptor-Mediated Endocytosis

Husain and Mohan request clarification about our cohort study of biopsies to determine organ quality during kidney allocation. Many donated kidneys in the United States undergo biopsy, and abnormal histology is a leading reason for subsequent organ discard. Fortunately, international variation in organ allocation offers a tremendous opportunity to determine whether practices, such as donor kidney biopsy, add value. We concur with the observation that allocation kidney biopsies in the United States are often completed under time pressure and by pathologists with limited renal expertise, which impairs the accuracy of the subsequent histology data. This observation, however, has no bearing on our primary finding: highest-quality biopsy data obtained at French and Belgian centers did not improve the prediction of allograft failure beyond a robust baseline set of donor and recipient characteristics. Specifically, the French and Belgian centers obtained the biopsy specimens after organ acceptance. Expert renal pathologists then processed and interpreted the histology under no time pressure. For the matching on histology, we used the reference ranges reported in the United Network for Organ Sharing (UNOS) database for glomerulosclerosis. For assessments of interstitial fibrosis and tubular atrophy (IFTA) and the vascular compartment (cv), we used the categories of absent, minimal, mild, mild to moderate, and severe used by UNOS and assigned appropriate Banff categories. We did not impute missing values where information was missing. Husain and Mohan point out that some US centers provisionally accept biopsied kidneys and subject those kidneys to repeat biopsies, which may result in different histologic findings than those from the original biopsy. For matching, we relied solely on the original biopsy specimen data received by centers through the formal UNOS allocation process. We note that obtaining additional biopsies requires the resources to process and interpret the specimens very rapidly. Many organ procurement organizations lack these resources—and the barriers will be even higher during nights and weekends, when kidneys are at elevated discard risk, as Mohan et al. have previously demonstrated. Readers can best interpret our results in the context of the many disadvantages of allocation biopsies: they add cold ischemia time; cost; inconvenience; and occasionally lead to anatomic complications, such as arteriovenous fistulas, which must be endured by the recipients of the kidney. Allocation kidney biopsies stand in the causal pathway to discard. To justify these serious disadvantages, defenders of allocation biopsies would need to demonstrate that histologic data add major value. Instead, our analyses detected no incremental predictive value. US transplant professionals and organ procurement organizations need to pay attention to best practices from other transplant systems. Given the intense scrutiny of organ procurement and allocation by various US authorities, now is the time to innovate and improve.

Husain and Mohan request clarification about our cohort study of biopsies to determine organ quality during kidney allocation. 1 Many donated kidneys in the United States undergo biopsy, and abnormal histology is a leading reason for subsequent organ discard. Fortunately, international variation in organ allocation offers a tremendous opportunity to determine whether practices, such as donor kidney biopsy, add value. We concur with the observation that allocation kidney biopsies in the United States are often completed under time pressure and by pathologists with limited renal expertise, which impairs the accuracy of the subsequent histology data.
This observation, however, has no bearing on our primary finding: highest-quality biopsy data obtained at French and Belgian centers did not improve the prediction of allograft failure beyond a robust baseline set of donor and recipient characteristics. Specifically, the French and Belgian centers obtained the biopsy specimens after organ acceptance. Expert renal pathologists then processed and interpreted the histology under no time pressure.
For the matching on histology, we used the reference ranges reported in the United Network for Organ Sharing (UNOS) database for glomerulosclerosis. For assessments of interstitial fibrosis and tubular atrophy (IFTA) and the vascular compartment (cv), we used the categories of absent, minimal, mild, mild to moderate, and severe used by UNOS and assigned appropriate Banff categories. We did not impute missing values where information was missing.
Husain and Mohan point out that some US centers provisionally accept biopsied kidneys and subject those kidneys to repeat biopsies, which may result in different histologic findings than those from the original biopsy. For matching, we relied solely on the original biopsy specimen data received by centers through the formal UNOS allocation process. We note that obtaining additional biopsies requires the resources to process and interpret the specimens very rapidly. Many organ procurement organizations lack these resources-and the barriers will be even higher during nights and weekends, when kidneys are at elevated discard risk, as Mohan et al. 2 have previously demonstrated.
Readers can best interpret our results in the context of the many disadvantages of allocation biopsies: they add cold ischemia time; cost; inconvenience; and occasionally lead to anatomic complications, such as arteriovenous fistulas, which must be endured by the recipients of the kidney. Allocation kidney biopsies stand in the causal pathway to discard. To justify these serious disadvantages, defenders of allocation biopsies would need to demonstrate that histologic data add major value. Instead, our analyses detected no incremental predictive value. US transplant professionals and organ procurement organizations need to pay attention to best practices from other transplant systems. Given the intense scrutiny of organ procurement and allocation by various US authorities, 3 now is the time to innovate and improve.

P. Reese reports consultancy agreements with Collaborative Healthcare
Research & Data Analytics (COHRDATA): epidemiology consultation on pharmacoepidemiology analyses related to therapies for patients on dialysis, and VALHealth: identification of patients with kidney disease; Ownership Interest in Various equities, but none specifically health-focused and none directly related to his research; Research Funding as a Co-Principal Investigator for studies of medication adherence (to any statin) funded by the NIH and CVS Caremark, Co-Principal Investigator for investigator-initiated and collaborative trials involving transplantation of hepatitis C virus (HCV)-infected organs into HCV-negative recipients followed by HCV treatment, with funding and/or antiviral medication supplied by Merck, AbbVie and Gilead to his institution; Honoraria from Talks at academic centers or academic consortia including the Brown University, Health and Human Services, National Kidney Foundation, Massachusetts General Hospital, Brigham and Womens, University of Pittsburgh, Northwestern, Cedars-Sinai; Scientific Advisor or Membership as Associate editor for American Journal of Kidney Diseases, Volunteer for United Network for Organ Sharing including the role of past Chair and current member of the Ethics Committee, Volunteer ethics consultation to eGenesis related to patient selection and education; and Other Interests/Relationships as Legal consultation for plaintiffs requiring kidney disease care. All remaining authors have nothing to disclose.

FUNDING
None.