TY - JOUR
T1 - Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis
AU - Kidney Precision Medicine Project (KPMP)
AU - Schmidt, Insa M.
AU - Colona, Mia R.
AU - Kestenbaum, Bryan R.
AU - Alexopoulos, Leonidas G.
AU - Palsson, Ragnar
AU - Srivastava, Anand
AU - Liu, Jing
AU - Stillman, Isaac E.
AU - Rennke, Helmut G.
AU - Vaidya, Vishal S.
AU - Wu, Haojia
AU - Humphreys, Benjamin D.
AU - Waikar, Sushrut S.
AU - Knight, Richard
AU - Lecker, Stewart H.
AU - Stillman, Isaac
AU - Bogen, Steve
AU - Amodu, Afolarin A.
AU - Ilori, Titlayo
AU - Maikhor, Shana
AU - Beck, Laurence H.
AU - Henderson, Joel M.
AU - Onul, Ingrid
AU - Verma, Ashish
AU - McMahon, Gearoid M.
AU - Valerius, M. Todd
AU - Waikar, Sushrut
AU - Weins, Astrid
AU - Greka, Anna
AU - Hacohen, Nir
AU - Hoover, Paul J.
AU - Marshall, Jamie L.
AU - Aulisio, Mark
AU - Chen, Yijiang M.
AU - Janowczyk, Andrew
AU - Jayapandian, Catherine
AU - Viswanathan, Vidya S.
AU - Bush, William S.
AU - Crawford, Dana C.
AU - Madabhushi, Anant
AU - Bush, Lakeshia
AU - Cooperman, Leslie
AU - Gonzalez-Vicente, Agustin
AU - Herlitz, Leal
AU - Jolly, Stacey
AU - Menez, Steven
AU - Parikh, Chirag R.
AU - Rosenberg, Avi
AU - Corona-Villalobos, Celia P.
AU - Wen, Yumeng
N1 - Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/9
Y1 - 2021/9
N2 - Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
AB - Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
KW - biomarker
KW - biopsy
KW - fibrosis
KW - histopathology
KW - kidney disease
UR - http://www.scopus.com/inward/record.url?scp=85110412207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110412207&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2021.04.037
DO - 10.1016/j.kint.2021.04.037
M3 - Article
C2 - 34051265
AN - SCOPUS:85110412207
SN - 0085-2538
VL - 100
SP - 672
EP - 683
JO - Kidney international
JF - Kidney international
IS - 3
ER -