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. 2024 Oct 16;6(12):100921.
doi: 10.1016/j.xkme.2024.100921. eCollection 2024 Dec.

Proteomics and Incident Kidney Failure in Individuals With CKD: The African American Study of Kidney Disease and Hypertension and the Boston Kidney Biopsy Cohort

Teresa K Chen  1   2   3 , Aditya L Surapaneni  4 , Insa M Schmidt  5 , Sushrut S Waikar  5 , Josef Coresh  4   6 , Hongbo Liu  7 , Katalin Susztak  7 , Eugene P Rhee  8 , Celina Liu  4 , Pascal Schlosser  6   9 , Morgan E Grams  4   6
Affiliations

Proteomics and Incident Kidney Failure in Individuals With CKD: The African American Study of Kidney Disease and Hypertension and the Boston Kidney Biopsy Cohort

Teresa K Chen et al. Kidney Med. .

Abstract

Rationale & objective: Individuals with chronic kidney disease (CKD) are at increased risk of morbidity and mortality, particularly as they progress to kidney failure. Identifying circulating proteins that underlie kidney failure development may guide the discovery of new targets for intervention.

Study design: Prospective cohort.

Setting & participants: 703 African American Study of Kidney Disease and Hypertension (AASK) and 434 Boston Kidney Biopsy Cohort (BKBC) participants with baseline proteomics data.

Exposures: Circulating proteins measured using SomaScan.

Outcomes: Kidney failure, defined as dialysis initiation or kidney transplantation.

Analytical approach: Using adjusted Cox models, we studied associations of 6,284 circulating proteins with kidney failure risk separately in AASK and BKBC and meta-analyzed results. We then performed gene set enrichment analyses to identify underlying perturbations in biological pathways. In separate data sets with kidney-tissue level gene expression, we ascertained dominant regions of expression and correlated kidney tubular gene expression with fibrosis and estimated glomerular filtration rate (eGFR).

Results: Over median follow-up periods of 8.8 and 3.1 years, 210 AASK (mean age: 55 years, 39% female, mean GFR: 46 mL/min/1.73 m2) and 115 BKBC (mean age: 54 years, 47% female, mean eGFR: 51 mL/min/1.73 m2) participants developed kidney failure, respectively. We identified 143 proteins that were associated with incident kidney failure, of which only 1 (Testican-2) had a lower risk. Notable proteins included those related to vascular permeability (endothelial cell-selective adhesion molecule), glomerulosclerosis (ephrin-A1), glomerular development (ephrin-B2), intracellular sorting/transport (vesicular integral-membrane protein VIP36), podocyte effacement (pigment epithelium-derived factor), complement activation (complement decay-accelerating factor), and fibrosis (ephrin-A1, ephrin-B2, and pigment epithelium-derived factor). Gene set enrichment analyses detected overrepresented pathways that could be related to CKD progression, such as ephrin signaling, cell-cell junctions, intracellular transport, immune response, cell proliferation, and apoptosis. At the kidney level, glomerular expression predominated for genes corresponding to circulating proteins of interest, and several gene expression levels were correlated with eGFR and/or fibrosis.

Limitations: Possible residual confounding.

Conclusions: Multimodal data identified proteins and pathways associated with the development of kidney failure.

Keywords: ESAM; Proteomics; SPOCK2; ephrin; kidney failure.

Plain language summary

Circulating proteins that underlie the development of kidney failure may be new targets for treatment. In the current study of adults with chronic kidney disease, we evaluated over 6,000 proteins detected in blood and found more than 100 proteins whose levels were associated with new-onset kidney failure. Further investigation using gene expression data showed that the genes encoding these proteins were expressed in the kidney and involved in pathways of immune responses as well as cell signaling, structure, transport, and survival.

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Figures

Figure 1
Figure 1
A volcano plot of proteins associated with kidney failure in AASK and BKBC. Models adjusted for age, sex, randomized treatment groups (AASK), race (BKBC), glomerular filtration rate (GFR in AASK; eGFR in BKBC), and log-transformed albuminuria (urine PCR in AASK; urine ACR in BKBC). The horizontal dashed line represents Bonferroni-corrected P-value threshold for significance. Colored dots represent the different modules. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; ACR, albumin-to-creatinine ratio; BKBC, Boston Kidney Biopsy Cohort; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; PCR, protein-to-creatinine ratio.
Figure 2
Figure 2
Pathways enriched in CKD progression using protein-kidney failure associations from AASK and BKBC. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; BKBC, Boston Kidney Biopsy Cohort; CKD, chronic kidney disease; NES, normalized enrichment score. Positive and negative scores indicate upregulation and downregulation of pathways, respectively. aFrom Kyoto Encyclopedia of Genes and Genomes 2021 human package. bFrom Reactome 2022 package.
Figure 3
Figure 3
Heatmap of the square of correlations (r2) between proteins, based on module assignment. The sign (+ or -) reflects correlation.
Figure 4
Figure 4
Predominant site of cognate gene expression in KPMP for proteins associated with kidney failure in meta-analysis of AASK and BKBC. Data presented are among 36 KPMP (9 healthy, 22 with chronic kidney disease, and 5 with acute kidney injury) participants with regional transcriptomics data. Predominance was determined as a beta of >1.0 when comparing one cell type to all other cell types. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; BKBC, Boston Kidney Biopsy Cohort; KPMP, Kidney Precision Medicine Project.
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