Abstract
Rationale & Objective: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. Study Design: Prospective observational cohort study. Setting & Participants: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Exposure: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. Outcome: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. Analytical Approach: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. Results: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. Limitations: Low prevalence of some descriptors and biopsy at a single time point. Conclusions: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 807-819.e1 |
| Journal | American Journal of Kidney Diseases |
| Volume | 79 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2022 |
Keywords
- Clinical outcomes
- disease classification
- focal segmental glomerulosclerosis (FSGS)
- gene expression
- glomerular disease
- glomerular structure
- kidney biopsy
- minimal change disease (MCD)
- molecular analysis
- morphologic features
- nephrotic syndrome
- precision medicine
- proteinuria
- renal pathology
- transcriptomics
ASJC Scopus subject areas
- Nephrology
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In: American Journal of Kidney Diseases, Vol. 79, No. 6, 06.2022, p. 807-819.e1.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Quantification of Glomerular Structural Lesions
T2 - Associations With Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome
AU - Nephrotic Syndrome Study Network (NEPTUNE)
AU - Hodgin, Jeffrey B.
AU - Mariani, Laura H.
AU - Zee, Jarcy
AU - Liu, Qian
AU - Smith, Abigail R.
AU - Eddy, Sean
AU - Hartman, John
AU - Hamidi, Habib
AU - Gaut, Joseph P.
AU - Palmer, Matthew B.
AU - Nast, Cynthia C.
AU - Chang, Anthony
AU - Hewitt, Stephen
AU - Gillespie, Brenda W.
AU - Kretzler, Matthias
AU - Holzman, Lawrence B.
AU - Barisoni, Laura
AU - Dell, K.
AU - Sedor, J.
AU - Schachere, M.
AU - Negrey, J.
AU - Lemley, K.
AU - Lim, E.
AU - Srivastava, T.
AU - Garrett, A.
AU - Sethna, C.
AU - Laurent, K.
AU - Canetta, P.
AU - Pradhan, A.
AU - Greenbaum, L.
AU - Wang, C.
AU - Kang, C.
AU - Adler, S.
AU - LaPage, J.
AU - Athavale, A.
AU - Itteera, M.
AU - Atkinson, M.
AU - Boynton, S.
AU - Fervenza, F.
AU - Hogan, M.
AU - Lieske, J.
AU - Chernitskiy, V.
AU - Kaskel, F.
AU - Ross, M.
AU - Flynn, P.
AU - Kopp, J.
AU - Blake, J.
AU - Trachtman, H.
AU - Zhdanova, O.
AU - Modersitzki, F.
N1 - Funding Information: Enrolling Centers (∗Principal Investigator; †Co-investigator; ‡Study Coordinator): Cleveland Clinic, Cleveland, OH: K. Dell,∗ J. Sedor,† M. Schachere,‡ and J. Negrey‡; Children's Hospital, Los Angeles, CA: K. Lemley∗ and E. Lim‡; Children's Mercy Hospital, Kansas City, MO: T. Srivastava∗ and A. Garrett‡; Cohen Children's Hospital, New Hyde Park, NY: C. Sethna∗ and K. Laurent‡; Columbia University, New York, NY: P. Canetta∗ and A. Pradhan‡; Emory University, Atlanta, GA: L. Greenbaum,∗ C. Wang,† and C. Kang‡; Harbor-University of California Los Angeles Medical Center: S. Adler,∗ and J. LaPage‡; John H. Stroger Jr. Hospital of Cook County, Chicago, IL: A. Athavale∗ and M. Itteera; Johns Hopkins Medicine, Baltimore, MD: M. Atkinson∗ and S. Boynton‡; Mayo Clinic, Rochester, MN: F. Fervenza,∗ M. Hogan,† J. Lieske,∗ and V. Chernitskiy‡; Montefiore Medical Center, Bronx, NY: F. Kaskel,∗ M. Ross,∗ and P. Flynn‡; NIDDK Intramural, Bethesda, MD: J. Kopp∗ and J. Blake‡; New York University Medical Center, New York, NY: H. Trachtman,∗ O. Zhdanova,† F. Modersitzki,‡ and S. Vento‡; Providence Medical Research Center, Spokane, WA: M. Bray,‡ M. Kelton,‡ and A. Cooper‡; Stanford University, Stanford, CA: R. Lafayette∗ and K. Mehta‡; Temple University, Philadelphia, PA: C. Gadegbeku∗ and S. Quinn-Boyle‡; University Health Network Toronto, Toronto, ON: M. Hladunewich,† H. Reich,† P. Ling,‡ and M. Romano‡; University of Miami, Miami, FL: A. Fornoni∗ and C. Bidot‡; University of Michigan, Ann Arbor, MI: M. Kretzler,∗ D. Gipson,∗ A. Williams,‡ and J. LaVigne‡; University of North Carolina, Chapel Hill, NC: V. Derebail,∗ K. Gibson,∗ E. Cole,‡ and J. Ormond-Foster‡; University of Pennsylvania, Philadelphia, PA: L. Holzman,∗ K. Meyers,† K. Kallem,‡ and A. Swenson‡; University of Texas Southwestern, Dallas, TX: K. Sambandam,∗ Z. Wang,‡ and M. Rogers‡; University of Washington, Seattle, WA: A. Jefferson,∗ S. Hingorani,† and K. Tuttle†; Wake Forest University Baptist Health, Winston-Salem, NC: J.J. Lin∗ and Stefanie Baker.‡ Data Analysis and Coordinating Center: M. Kretzler, L. Barisoni, J. Bixler, H. Desmond, S. Eddy, D. Fermin, C. Gadegbeku, B. Gillespie, D. Gipson, L. Holzman, V. Kurtz, M. Larkina, J. Lavigne, S. Li, S. Li, C.C. Lienczewski, J. Liu, T. Mainieri, L. Mariani, M. Sampson, J. Sedor, A. Smith, A. Williams, and J. Zee. Digital Pathology Committee: Carmen Avila-Casado (University Health Network, Toronto), Serena Bagnasco (Johns Hopkins University), Joseph Gaut (Washington University in St Louis), Stephen Hewitt (National Cancer Institute), Jeff Hodgin (University of Michigan), Kevin Lemley (Children's Hospital of Los Angeles), Laura Mariani (University of Michigan), Matthew Palmer (University of Pennsylvania), Avi Rosenberg (Johns Hopkins University), Virginie Royal (University of Montreal), David Thomas (University of Miami), and Jarcy Zee (University of Pennsylvania); Co-Chairs: Laura Barisoni (Duke University) and Cynthia Nast (Cedar Sinai). Jeffrey B. Hodgin, MD, PhD, Laura H. Mariani, MD, MS, Jarcy Zee, PhD, Qian Liu, MS, Abigail R. Smith, PhD, Sean Eddy, PhD, John Hartman, Habib Hamidi, PhD, Joseph P. Gaut, MD, Matthew B. Palmer, MD, Cynthia C. Nast, MD, Anthony Chang, Stephen Hewitt, MD, PhD, Brenda W. Gillespie, PhD, Matthias Kretzler, MD, Lawrence B. Holzman, MD, and Laura Barisoni, MD. Research idea and study design: JBH, LHM, JZ, LBH, LB; data acquisition: JBH, LHM, JZ, JPG, MBP, CCN, AC, SH, MK, LBH, LB; data analysis/interpretation: JBH, LHM, JZ, QL, ARS, SE, JH, HH, BWG, LBH, LB; statistical analysis: JZ, QL, ARS; supervision or mentorship: BWG, MK, LBH, LB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by a grant from the National Institute of Diabetes, Digestive, and Kidney Diseases R01-DK118431 (to LB, JBH, BWG, LBH, LHM, JZZ), and funding from NIH/NIDDK K08 DK115891-01 (to LHM). NEPTUNE is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International and the Halpin Foundation. All RDCRN consortia are supported by the network's Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). Funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication. Dr Barisoni has received grants from the NIH/NIDDK during the conduct of the study, and personal fees from Moderna, Protalix, Sangamo, and Vertex outside the submitted work. Dr Hodgin has received grants from the NIH/NIDDK during the conduct of the study, and personal fees from AstraZeneca, Gilead, Moderna, NovoNordisc, Eli Lilly, and Jansen outside the submitted work. Dr Holzman has received grants from the NIH/NIDDK during the conduct of the study. Dr Mariani has received grants from the NIH/NIDDK during the conduct of the study, and personal fees from Reata, Calliditas Therapeutics, and Travere Therapeutics outside the submitted work. Dr Zee has received grants from the NIH/NIDDK during the conduct of the study. The remaining authors declare that they have no relevant financial interests. A preprint version of this article was posted September 22, 2021, at medRxiv withdoi:10.1101/2021.09.16.21263706. Received August 14, 2021, as a submission to the expedited consideration track with 2 external peer reviews. Evaluated by an additional external peer reviewer, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form October 20, 2021. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies, which also provides further information on expedited consideration (AJKD Express). Funding Information: This study was supported by a grant from the National Institute of Diabetes, Digestive, and Kidney Diseases R01-DK118431 (to LB, JBH, BWG, LBH, LHM, JZZ), and funding from NIH/NIDDK K08 DK115891-01 (to LHM). NEPTUNE is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International and the Halpin Foundation. All RDCRN consortia are supported by the network’s Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). Funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication. Publisher Copyright: © 2022
PY - 2022/6
Y1 - 2022/6
N2 - Rationale & Objective: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. Study Design: Prospective observational cohort study. Setting & Participants: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Exposure: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. Outcome: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. Analytical Approach: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. Results: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. Limitations: Low prevalence of some descriptors and biopsy at a single time point. Conclusions: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.
AB - Rationale & Objective: The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies nor the clinical and molecular heterogeneity of these diseases. Study Design: Prospective observational cohort study. Setting & Participants: 221 MCD and FSGS patients enrolled in the Nephrotic Syndrome Study Network (NEPTUNE). Exposure: The NEPTUNE Digital Pathology Scoring System (NDPSS) was applied to generate scores for 37 glomerular descriptors. Outcome: Time from biopsy to complete proteinuria remission, time from biopsy to kidney disease progression (40% estimated glomerular filtration rate [eGFR] decline or kidney failure), and eGFR over time. Analytical Approach: Cluster analysis was used to group patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for associations with outcomes using adjusted Cox models and linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes between clusters and identify genes associated with individual descriptors driving cluster membership. Results: Three clusters were identified: X (n = 56), Y (n = 68), and Z (n = 97). Clusters Y and Z had higher probabilities of proteinuria remission (HRs of 1.95 [95% CI, 0.99-3.85] and 3.29 [95% CI, 1.52-7.13], respectively), lower hazards of disease progression (HRs of 0.22 [95% CI, 0.08-0.57] and 0.11 [95% CI, 0.03-0.45], respectively), and lower loss of eGFR over time compared with X. Cluster X had 1,920 genes that were differentially expressed compared with Y+Z; these reflected activation of pathways of immune response and inflammation. Six descriptors driving the clusters individually correlated with clinical outcomes and gene expression. Limitations: Low prevalence of some descriptors and biopsy at a single time point. Conclusions: The NDPSS allows for categorization of FSGS/MCD patients into clinically and biologically relevant subgroups, and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.
KW - Clinical outcomes
KW - disease classification
KW - focal segmental glomerulosclerosis (FSGS)
KW - gene expression
KW - glomerular disease
KW - glomerular structure
KW - kidney biopsy
KW - minimal change disease (MCD)
KW - molecular analysis
KW - morphologic features
KW - nephrotic syndrome
KW - precision medicine
KW - proteinuria
KW - renal pathology
KW - transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85124425737&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124425737&partnerID=8YFLogxK
U2 - 10.1053/j.ajkd.2021.10.004
DO - 10.1053/j.ajkd.2021.10.004
M3 - Article
C2 - 34864148
AN - SCOPUS:85124425737
SN - 0272-6386
VL - 79
SP - 807-819.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 6
ER -