TY - JOUR
T1 - Ultrastructural characterization of proteinuric patients predicts clinical outcomes
AU - Royal, Virginie
AU - Zee, Jarcy
AU - Liu, Qian
AU - Avila-Casado, Carmen
AU - Smith, Abigail R.
AU - Liu, Gang
AU - Mariani, Laura H.
AU - Hewitt, Stephen
AU - Holzman, Lawrence B.
AU - Gillespie, Brenda W.
AU - Hodgin, Jeffrey B.
AU - Barisoni, Laura
N1 - Funding Information:
This work was supported by the National Institute of Diabetes, Digestive, and Kidney Diseases through grant R01-DK-118431. The Nephrotic Syndrome Study Network Consortium is a part of the National Institutes of Health Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the National Institute of Diabetes, Digestive, and Kidney Diseases (grant U54‐DK‐083912). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International, and the Halpin Foundation.
Funding Information:
Dr. Barisoni reports personal fees from Moderna, personal fees from Pro-talix, personal fees from Sangamo, personal fees from Vertex, outside the submitted work. Dr. G. Liu reports grants from National Institutes of Health/ National Institute of Diabetes, Digestive, and Kidney Diseases (NIH/NIDDK), during the conduct of the study. Dr. Q. Liu reports grants from NIH/NIDDK, during the conduct of the study. Dr. Mariani reports grants from NIH/ NIDDK, during the conduct of the study; personal fees from Reata Pharmaceuticals, outside the submitted work. Dr. Zee reports grants from NIH/ NIDDK, during the conduct of the study.
PY - 2020/4
Y1 - 2020/4
N2 - Background: The analysis and reporting of glomerular features ascertained by electron microscopy are limited to fewparameterswith minimal predictive value, despite some contributions to disease diagnoses. Methods: We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) fromthe Nephrotic Syndrome Study Network (NEPTUNE)Digital Pathology Scoring System. Study pathologists scored 12 descriptors in NEPTUNE renal biopsies from 242 patients with minimal change disease or FSGS, with duplicate readings to evaluate reproducibility. We performed consensus clustering of patients to identify unique electron microscopy profiles. For both individual descriptors and clusters, we used Cox regression models to assess associations with time from biopsy to proteinuria remission and time to a composite progression outcome (≥40% decline in eGFR, with eGFR<60 ml/min per 1.73 m2, or ESKD), and linear mixed models for longitudinal eGFR measures. Results: Intrarater and interrater reproducibility was ≥0.60 for 12 out of 12 and seven out of 12 descriptors, respectively. Individual podocyte descriptors such as effacement and microvillous transformation were associated with complete remission, whereas endothelial cell and glomerular basement membrane abnormalities were associated with progression. We identified six descriptor-based clusters with distinct electronmicroscopy profiles and clinical outcomes. Patients in a cluster with more prominent foot process effacement and microvillous transformation had the highest rates of complete proteinuria remission, whereas patients in clusters with extensive loss of primary processes and endothelial cell damage had the highest rates of the composite progression outcome. Conclusions: Systematic analysis of electron microscopic findings reveals clusters of findings associated with either proteinuria remission or disease progression.
AB - Background: The analysis and reporting of glomerular features ascertained by electron microscopy are limited to fewparameterswith minimal predictive value, despite some contributions to disease diagnoses. Methods: We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) fromthe Nephrotic Syndrome Study Network (NEPTUNE)Digital Pathology Scoring System. Study pathologists scored 12 descriptors in NEPTUNE renal biopsies from 242 patients with minimal change disease or FSGS, with duplicate readings to evaluate reproducibility. We performed consensus clustering of patients to identify unique electron microscopy profiles. For both individual descriptors and clusters, we used Cox regression models to assess associations with time from biopsy to proteinuria remission and time to a composite progression outcome (≥40% decline in eGFR, with eGFR<60 ml/min per 1.73 m2, or ESKD), and linear mixed models for longitudinal eGFR measures. Results: Intrarater and interrater reproducibility was ≥0.60 for 12 out of 12 and seven out of 12 descriptors, respectively. Individual podocyte descriptors such as effacement and microvillous transformation were associated with complete remission, whereas endothelial cell and glomerular basement membrane abnormalities were associated with progression. We identified six descriptor-based clusters with distinct electronmicroscopy profiles and clinical outcomes. Patients in a cluster with more prominent foot process effacement and microvillous transformation had the highest rates of complete proteinuria remission, whereas patients in clusters with extensive loss of primary processes and endothelial cell damage had the highest rates of the composite progression outcome. Conclusions: Systematic analysis of electron microscopic findings reveals clusters of findings associated with either proteinuria remission or disease progression.
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U2 - 10.1681/ASN.2019080825
DO - 10.1681/ASN.2019080825
M3 - Article
C2 - 32086276
AN - SCOPUS:85082881329
VL - 31
SP - 841
EP - 854
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 4
ER -