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.
AU - Vento, S.
AU - Bray, M.
AU - Kelton, M.
AU - Cooper, A.
AU - Lafayette, R.
AU - Mehta, K.
AU - Gadegbeku, C.
AU - Quinn-Boyle, S.
AU - Hladunewich, M.
AU - Reich, H.
AU - Ling, P.
AU - Romano, M.
AU - Fornoni, A.
AU - Bidot, C.
AU - Kretzler, M.
AU - Gipson, D.
AU - Williams, A.
AU - LaVigne, J.
AU - Derebail, V.
AU - Gibson, K.
AU - Cole, E.
AU - Ormond-Foster, J.
AU - Holzman, L.
AU - Meyers, K.
AU - Kallem, K.
AU - Swenson, A.
AU - Sambandam, K.
AU - Wang, Z.
AU - Rogers, M.
AU - Jefferson, A.
AU - Hingorani, S.
AU - Tuttle, K.
AU - Lin, J. J.
AU - Barisoni, L.
AU - Bixler, J.
AU - Desmond, H.
AU - Eddy, S.
AU - Fermin, D.
AU - Gillespie, B.
AU - Kurtz, V.
AU - Larkina, M.
AU - Li, S.
AU - Lienczewski, C. C.
AU - Liu, J.
AU - Mainieri, T.
AU - Mariani, L.
AU - Sampson, M.
AU - Smith, A.
AU - Zee, J.
AU - Avila-Casado, Carmen
AU - Bagnasco, Serena
AU - Hodgin, Jeff
AU - Lemley, Kevin
AU - Mariani, Laura
AU - Palmer, Matthew
AU - Rosenberg, Avi
AU - Royal, Virginie
AU - Thomas, David
AU - Nast, Cynthia
N1 - 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
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 -