Urinary Epidermal Growth Factor: A Promising “Next Generation” Biomarker in Kidney Disease

Cortvrindt, Charlotte; Speeckaert, Reinhart; Delanghe, Joris; Speeckaert, Marijn M.

doi:10.1159/000524586

Cited by 14 publications

(10 citation statements)

References 108 publications

(161 reference statements)

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“…EGF is a 53-amino acid polypeptide that is produced in multiple tissues including the kidney, where it is expressed in the loop of Henle and the distal convoluted tubule. 30 EGF regulates cellular metabolism, glomerular hemodynamics, and cell growth in the kidney by binding to the extracellular domain of the EGF receptor. 31 These actions play a critical role in promoting kidney repair, as evidenced by data showing that EGF aids tubular injury recovery by upregulating regenerative pathways.…”

Section: Discussionmentioning

confidence: 99%

Associations of Urine Biomarkers of Kidney Tubule Health With Incident Hypertension and Longitudinal Blood Pressure Change in Middle-Aged Adults: The CARDIA Study

Khan

Scherzer²,

Lewis

et al. 2023

Hypertension

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BACKGROUND: Urine biomarkers of kidney tubule injury associate with incident hypertension in older adults with comorbidities, but less is known about these associations in younger adults. METHODS: In 1170 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults; mean age, 45 years; 40% Black people; 56% women) without hypertension, cardiovascular disease, or kidney disease at baseline, we examined associations of urine MCP-1 (monocyte chemoattractant protein-1), α1m (alpha-1-microglobulin), KIM-1 (kidney injury molecule-1), EGF (epidermal growth factor), IL (interleukin)-18, YKL-40 (chitinase-3-like protein 1), and UMOD (uromodulin) with incident hypertension (onset of systolic blood pressure [BP] ≥130 mm Hg or diastolic BP ≥80 mm Hg or initiation of hypertension meds) and longitudinal BP change in models adjusted for hypertension risk factors, estimated glomerular filtration rate, and albuminuria. RESULTS: After a median 9.9 (interquartile range, 5.9–10.2) years, 376 participants developed incident hypertension. In demographic-adjusted analyses, higher tertiles of EGF associated with lower risk of incident hypertension in both Black and White participants. After multivariable adjustment, the risk of incident hypertension remained lower in tertile 2 (hazard ratio, 0.70 [95% CI, 0.50–0.97]) and tertile 3 (hazard ratio, 0.58 [0.39–0.85]) of EGF versus tertile 1. In fully adjusted models, participants in EGF tertile 3 had smaller 10-year increases in systolic (−3.4 [95% CI, −6.1 to −0.7] mm Hg) and diastolic BP (−2.6 [95% CI, −4.6 to −0.6] mm Hg) than tertile 1. Other biomarkers showed inconsistent associations with incident hypertension and BP change. CONCLUSIONS: In middle-aged adults without hypertension, cardiovascular disease, or kidney disease, higher urine EGF associated with lower risk of incident hypertension and lower 10-year BP elevations.

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Section: Discussionmentioning

confidence: 99%

Associations of Urine Biomarkers of Kidney Tubule Health With Incident Hypertension and Longitudinal Blood Pressure Change in Middle-Aged Adults: The CARDIA Study

Khan

Scherzer²,

Lewis

et al. 2023

Hypertension

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“…During AKI, there is increased production of EGFR ligands and EGFR signaling [52]. Studies of chronic kidney disease show that urinary EGF (uEGF) declines with progression of renal fibrosis, and uEGF has been shown to be highly predictive of CKD progression [45][46][47]53].…”

Section: Discussionmentioning

confidence: 99%

Ribosomal s6 kinase (RSK) is a mediator of aquaporin 2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib

Babicz

Cheung

Baylor

et al. 2022

Preprint

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Vasopressin (VP) activates PKA, resulting in phosphorylation and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as the final mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in medullary principal cells in rat kidneys. RSK inhibition with BI-D1870 or siRNA blocked erlotinib-induced AQP2 S256 phosphorylation and membrane trafficking. CRISPR-generated RSK knockout cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro. Stimulation of PDK1, a known activator of RSK, caused AQP2 S256 phosphorylation and membrane accumulation similar to erlotinib and VP. We conclude that RSK is the terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib.

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“…Epidermal growth factor (EGF) is a tubule-specific kidney polypeptide which confers biological functions such as cellular metabolism and glomerular hemodynamics, cell growth, and injury repair [25]. While EGF is absent in plasma samples, urinary EGF excretion is a physiological phenomenon in healthy individuals.…”

Section: Epidermal Growth Factormentioning

confidence: 99%

Recent Advances in Urinary Peptide and Proteomic Biomarkers in Chronic Kidney Disease: A Systematic Review

Catanese

Siwy

Mischak

et al. 2023

IJMS

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Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms “marker *” OR biomarker * AND “renal disease” OR “kidney disease” AND “proteome *” OR “peptid *” AND “urin *”. English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.

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Urinary Epidermal Growth Factor: A Promising “Next Generation” Biomarker in Kidney Disease

Cited by 14 publications

References 108 publications

Associations of Urine Biomarkers of Kidney Tubule Health With Incident Hypertension and Longitudinal Blood Pressure Change in Middle-Aged Adults: The CARDIA Study

Associations of Urine Biomarkers of Kidney Tubule Health With Incident Hypertension and Longitudinal Blood Pressure Change in Middle-Aged Adults: The CARDIA Study

Ribosomal s6 kinase (RSK) is a mediator of aquaporin 2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib

Recent Advances in Urinary Peptide and Proteomic Biomarkers in Chronic Kidney Disease: A Systematic Review

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