Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Abstract

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 biopsyconfirmed 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.

Siglec-F–expressing neutrophils are essential for creating a profibrotic microenvironment in renal fibrosis

“…Although they did not specify which CD45 + leukocytes were producing the collagen 1, they concluded that leukocytes contribute 38% to 50% of collagen 1 deposition in renal fibrosis. This is supported by a recent study that reanalyzed the single-cell RNA-Seq data from UUO-injured kidneys ( 47 ): it showed that immune cells, including neutrophils, from injured kidneys express Col1a1 as well as other collagen proteins such as Col5a2 , Col12a1 , and Col15a1 ( 48 ). Our observation that Siglec-F + neutrophils are the major collagen 1–producing leukocytes in the fibrotic kidney is thus consistent with and expands these findings.…”

Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease

“…These enriched pathways again point to cell adhesion and cell signaling as important processes altered in kidney disease, and potentially, pHTN. Studies have shown that EGF and EGF receptor (EGFR) signaling pathways are disrupted in both cardiovascular and renal pathologies, including CKD. , Several cadherins, including E-cadherin, associated here with proteinuria, eGFR < 60, and eGFR < 60 + pHTN (Table S1), have also been studied as potential biomarkers for various types of kidney disease. − Utilizing network analysis to identify modules of coordinated protein abundance associated with renal dysfunction and pHTN in SCD thus further implicates ECM and cell signaling proteins and provides specific pathways for future investigation.…”

Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

“… [43] , [44] , [45] SMOC2 has been shown to play an important role in renal fibrosis and has been suggested as a potential biomarker. 46 , 47 Whole-body Smoc2 ablation in mice ameliorated diet-induced obesity, hepatic steatosis, and fibrosis. 48 The study also showed elevated SMOC2 mRNA and protein levels in human steatotic liver biopsies and proposed a fibrogenic role for hepatocyte SMOC2 through direct intracellular interaction with TGF-β1.…”