Circulating Plasma Biomarkers in Biopsy-Confirmed Kidney Disease

Abstract

Background and objectives: Biomarkers for noninvasive assessment of histopathology and prognosis are needed in patients with kidney disease.

Design, setting, participants, & measurements: Using a proteomics assay, we measured a multimarker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semiquantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as ≥40% decline in eGFR or initiation of KRT) and death.

Results: After multivariable adjustment and correction for multiple testing, 46 different proteins were associated with histopathologic lesions. The top-performing markers positively associated with acute tubular injury and interstitial fibrosis/tubular atrophy were kidney injury molecule-1 (KIM-1) and V-set and Ig domain-containing protein 2 (VSIG2), respectively. Thirty proteins were significantly associated with kidney disease progression, and 35 were significantly associated with death. The top-performing markers for kidney disease progression were placental growth factor (hazard ratio per doubling, 5.4; 95% confidence interval, 3.4 to 8.7) and BMP and activin membrane-bound inhibitor (hazard ratio, 3.0; 95% confidence interval, 2.1 to 4.2); the top-performing markers for death were TNF-related apoptosis-inducing ligand receptor-2 (hazard ratio, 2.9; 95% confidence interval, 2.0 to 4.0) and CUB domain-containing protein-1 (hazard ratio, 2.4; 95% confidence interval, 1.8 to 3.3).

Conclusion: We identified several plasma protein biomarkers associated with kidney disease histopathology and adverse clinical outcomes in individuals with a diverse set of kidney diseases.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_12_28_CJN09380721.mp3.

Keywords: Boston; biomarkers; causality; cohort studies; histopathology; kidney biopsy; kidney disease; nephrectomy; plasma; proteomics.

Graphical abstract

Figure 1.

Circulating plasma proteins associated with histopathologic lesions. The heat map shows associations between histopathologic lesions and biomarkers after Bonferroni correction. β-coefficients are derived from multivariable linear regression models adjusted for age, sex, race, and eGFR (modeled continuously), and they are displayed as colors ranging from blue to red. Reference is none/mild lesion severity for acute tubular injury and arteriolar sclerosis. Reference is absence of lesion for mesangial expansion. Reference is 0%–10% of cortical volume or glomeruli affected for inflammation in the fibrosed and nonfibrosed interstitium and glomerular inflammation. Reference is 0%–25% of cortical volume or glomeruli affected for glomerular sclerosis and interstitial fibrosis/tubular atrophy (IFTA). Endocapillary glomerular inflammation, extracapillary cellular crescents, focal glomerular necrosis, and fibrocellular crescents were combined into a single dichotomous variable named “glomerular inflammation.”

Figure 2.

Circulating plasma proteins associated with kidney disease progression and death. (A) Kidney disease progression, (B) death. Results are derived from proportional hazards models adjusted for eGFR, race, age, sex, log(proteinuria), and primary clinicopathologic diagnosis. Horizontal dotted lines show Bonferroni-adjusted significance thresholds, and vertical dotted lines mark the hazard ratio of one.