Biomarkers of inflammation and repair in kidney disease progression
Jeremy Puthumana, … , Lloyd G. Cantley, Chirag R. Parikh
Jeremy Puthumana, … , Lloyd G. Cantley, Chirag R. Parikh
Published December 8, 2020
Citation Information: J Clin Invest. 2021;131(3):e139927. https://doi.org/10.1172/JCI139927.
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Clinical Research and Public Health Inflammation Nephrology

Biomarkers of inflammation and repair in kidney disease progression

Abstract

INTRODUCTION Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODS We enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTS Higher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONS Biomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDING NIH.

Authors

Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G. Coca, Amit X. Garg, Jonathan Himmelfarb, Pavan K. Bhatraju, T. Alp Ikizler, Edward D. Siew, Lorraine B. Ware, Kathleen D. Liu, Alan S. Go, James S. Kaufman, Paul L. Kimmel, Vernon M. Chinchilli, Lloyd G. Cantley, Chirag R. Parikh

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Figure 4

Kidney fibrosis and atrophy are preceded by upregulation of Ccl2 and Chi3l1.

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Kidney fibrosis and atrophy are preceded by upregulation of Ccl2 and Chi...
Wild-type mice were subjected to 27 minutes of unilateral IRI with contralateral kidney intact (atrophy model) or unilateral IRI with contralateral nephrectomy (repair model). The mice were sacrificed on days 1, 7, 14, and 30 after injury. Contralateral, atrophy, and repair kidneys were harvested at 30 days after injury, and kidney sections were stained with Picrosirius red to detect collagen deposition and immunostained with anti-PDGFRβ antibody to detect interstitial myofibroblasts. (A and B) Representative images of kidney sections. Scale bars: 500 μm. (C–E) Quantification of cortical and medullary thickness, Picrosirius red area, and PDGFRβ-positive area, respectively. n = 10 kidneys/model. P < 0.0001 among group means and ***P < 0.001, ****P < 0.0001 by 2-way ANOVA in the indicated subgroup analyses. (F and G) Quantitative RT-PCR analysis for Col1a1, Fn1, Pdgfrb, Ccl2, Chi3l1, and Umod was performed on whole-kidney RNA harvested on days 0, 1, 7, 14, and 30 after injury. n = 10 kidneys/time point/model. Two-way ANOVA summarized in Supplemental Table 5. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 at the indicated time point. NS, not significant.