Urinary EGF: Back to the Future

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Editorial
Urinary EGF
Back to the Future
Monica Suet Ying Ng and Andrew J. Kassianos
Kidney360 6: 348–350, 2025. doi: https://doi.org/10.34067/KID.0000000720
In 1962, an injection of submaxillary gland extract into
newborn mice induced precocious eyelid opening and
incisor eruption by stimulation of epidermal growth and
keratization—leading to the discovery of EGF.
1
Unlike
mice, the kidney is the predominant source of EGF in
humans, with high concentrations of prepro-EGF mRNA
in the thick ascending limb of the loop of Henle and distal
convoluted tubule. In 1988, undetectable plasma EGF and
high concentrations of urinary EGF (uEGF) led to the
conclusion that human uEGF originates from the kidney.
Positive correlations between urine creatinine and uEGF
concentrations provided early evidence for the relation-
ship between kidney function and tubular EGF excretion.
2
Since then, a myriad of clinical studies have correlated
uEGF with kidney function, incident CKD and histologic
kidney damage across a wide range of primary kidney
diseases (systematically reviewed in ref. 3).
In this issue of Kidney360,Geurtset al. provide impor-
tant insights on uEGF as a noninvasive biomarker of
distal tubular volume, hypertension, and CKD progres-
sion risk.
4
In 20 people with donor nephrectomies, 24-
hour uEGF reduced from 28 to 14 mg(249%) compared
with eGFR, which reduced from 85.5 to 54.3 ml/min per
1.73 m
2
(236%) at 3 months. Relative reduction in 24-
hour uEGF correlated positively with calculated reduc-
tion in kidney volume. The study of the live kidney
donor cohort is an ingenious approach to link uEGF
with quantifiable reductions in kidney and therefore,
distal tubular volume. Previous studies had assessed
uEGF in people with different kidney diseases with pre-
sumed reduction in functional nephrons. These results
suggest that EGF may be excreted into urine at a similar
rate, regardless of nephrectomy status (i.e., there is no
compensatory increase in EGF excretion with reduction
in kidney volume). uEGF decreases acutely during AKI
and increases back to baseline levels with kidney func-
tion recovery.
5
Furthermore, uEGF reductions were
greater for higher stage AKI. These results confirm that
uEGF concentrations correlate with functional distal tu-
bular volume and that this relationship holds regardless
of mechanism of injury.
Geurts et al. further assessed the capacity of uEGF to
prognosticate CKD across a large general population co-
hort of over 2000 participants.
4
Lower uEGF was associ-
ated with higher risk of incident eGFR #60 ml/min per
1.73 m
2
CKD over a median of 5.4 years. This result was
consistent with the findings from the Renal Iohexol Clear-
ance Survey (n51249) and Prevention of Renal and Vas-
cular END-stage disease (n54534) population-based cohort
studies, with each 1 mg/mmol decrease in uEGF/creatinine
associated with almost two times increased risk of incident
CKD stage 3 and .25% eGFR decline from baseline.
6
The
correlation between low uEGF and kidney disease pro-
gression has also been observed in people with diabetic
kidney disease, glomerular disease, and hypertensive
nephropathy—suggesting that uEGF may be applied as
a prognostic biomarker across different kidney disease
cohorts.
3
Subgroup analysis of the Rotterdam cohort
demonstrated that the association between uEGF and
incident eGFR #60 ml/min per 1.73 m
2
CKD, incident
eGFR #45 ml/min per 1.73 m
2
CKD, or 40% loss of eGFR
or kidney failure was not statistically significant in people
with hypertension—raising concerns about the utility of
uEGF for kidney outcome prediction in hypertensive
people.
4
Conversely, in the Systolic Blood Pressure In-
tervention Trial, lower uEGF concentration was associ-
ated with 1.17 times higher risk of $30% eGFR decline in
people with treated hypertension and eGFR #60 ml/min
Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston, Queensland, Australia; Kidney Health Service, Royal
Brisbane and Women’s Hospital, Herston, Queensland, Australia; and Faculty of Medicine, University of Queensland, Herston, Queensland,
Australia
Correspondence: Dr. Monica Suet Ying Ng, email: monica.ng@health.qld.gov.au
See related article, ‘‘Urinary EGF Reflects Distal Tubular Mass and is Associated with Hypertension, Serum Magnesium, and Kidney Outcomes,’’ on
pages 451–460.
Copyright ©2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology. This is an open access
article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without
permission from the journal.
www.kidney360.org Vol 6 March, 2025348

per 1.73 m
2
CKD.
7
However, the Systolic Blood Pressure
Intervention Trial cohort included participants in both
the control and treatment arms of the trial—potentially
confounding the results because of BP heterogeneity.
Further studies are required to investigate the relation-
ship between uEGF and kidney outcomes in hypertensive
people.
Lower uEGF is associated with increased likelihood of
hypertension, higher systolic BP, and lower serum mag-
nesium concentrations.
4
These results concur with find-
ings from 1170 participants from the Coronary Artery
Risk Development in Young Adults study, where higher
uEGF associated with lower risk of incident hypertension
and lower 10-year BP elevations.
8
The mechanism un-
derlying the correlation between uEGF and hypertension
hinges on whether uEGF levels represent functional distal
tubular volume and/or endogenous EGF levels. Lower
nephron mass has been associated with hypertension,
while EGF deficiency has been associated with epithelial
sodium channel activity, which has been linked to hy-
pertension. However, it is unclear whether uEGF levels
reflect kidney EGF concentrations. The positive correla-
tion between uEGF and serum magnesium corroborates
results from a smaller cohort of healthy adults and
children.
9
Considering that EGF regulates magnesium
reabsorption in the distal tubule by stimulating transient
receptor potential cation channel subfamily M member 6
activity, along with evidence that EGF receptor loss-of-
function mutations and EGF receptor inhibitors lead to
hypomagnesemia, the association between uEGF and se-
rum magnesium suggests that uEGF does represent en-
dogenous EGF activity to an extent.
10
Further studies are
required to elucidate (1) the mechanisms underlying
changes in uEGF levels in relation to serum magnesium,
BP, and CKD and (2) how uEGF levels correlate with
kidney EGF concentration and activity.
So uEGF levels correlate with future CKD
development—what next? The natural progression seems
to be the application of uEGF to screen for people without
hypertension who are likely to develop eGFR #60 ml/min
per 1.73 m
2
CKD. In the absence of other risk factors
of CKD, this subgroup is likely to be identified at a later
stage. Early identification could theoretically enable timely
kidney-protective therapy to prevent irreversible kidney
function decline. Several steps need to be surmounted
to develop, validate, and bring a biomarker to market
(Figure 1). First, uEGF measurement protocols need to
be standardized to enable comparison between different
studies. Further test development would establish target
population, sample collection protocol, normal range,
downstream processing, and result readout. Controlling
for urine concentration can be achieved by measuring
24-hour urine samples or using ratios (e.g., uEGF/
creatinine ratio). Downstream result processing is deter-
mined by the relationship between the proposed bio-
marker, confounders, and result readout. In this study,
demographic factors such as age, sex, body mass index,
smoking status, hypertension, and proteinuria affected
uEGF levels.
4
It is possible that uEGF level, along with
some demographic factors, need to be entered into an
algorithm to accurately predict CKD risk. In the Rotterdam
cohort, the association between uEGF and CKD risk was
present even without controlling for confounders—
suggesting that uEGF may be adequately robust to be
interpreted without demographic data input. The result
readout could be presented as 5-year moderate–severe
CKD risk; 5-year kidney failure risk; or if uEGF5x, then
5-year moderate–severe CKD risk is .y. The prototype
~7-8 years, ~20-106 million USD*
SQUARE
ONE
uEGF
Establish normal range
Downstream processing and result readout
Sample collection protocol
(E.g. 24 hours vs. random)
Establish target
population
Scalable and
standardized
EGF protocol
Establish test superiority over existing tools—broader
appliability, greater sensitivity and/or specificity, improved
access (E.g. cheaper, less resource intensive)
Intervention based on test result effect changes in clinical outcomes
Validation in target population in large clinical trials
Figure 1. Steps to developing uEGF into test for assessing CKD risk. *de Graaf et al.
11
Created in BioRender. uEGF, urinary EGF; USD, US
dollar.
Urinary EGF: Back to the future, Ying Ng and Kassianos
Kidney360 6: 348–350, March, 2025 349

then needs to be validated across multiple cohorts to
confirm the target population and establish test sensitivity
and specificity. After this point, the prototype may be
considered for regulatory approval. Further steps are re-
quired to facilitate clinical uptake of the biomarker. The
test prototype needs to establish superiority over existing
tools for predicting kidney outcomes (by demonstrating
broader applicability, greater sensitivity and/or specificity,
or improved access). Moreover, intervention on the basis of
test result needs to effect changes in clinical outcomes, such
as earlier referral to a kidney specialist and/or reduced
CKD progression. These factors drive incorporation of the
novel test into clinical guidelines, which facilitates payer
reimbursement for test and clinician uptake.
Biomarker development is an arduous process taking
approximately 7–8 years and 20–106 million US dollars
(Figure 1). Time will tell whether uEGF will blossom into a
clinically implemented predictor of moderate–severe CKD
or hypertension risk.
Disclosures
Disclosure forms, as provided by each author, are available with
the online version of the article at http://links.lww.com/KN9/
A887.
Funding
This work is supported by a Metro North Clinician Research
Fellowship (MSYN, CRF-606-2024).
Acknowledgments
Monica Suet Ying Ng is a participant of the Kidney360 Editorial
Training Program. Monica Suet Ying Ng acknowledges funding
from Queensland Health Clinical Research Fellowship. The content
of this article reflects the personal experience and views of the
authors and should not be considered medical advice or recom-
mendation. The content does not reflect the views or opinions of
the American Society of Nephrology (ASN) or Kidney360. Re-
sponsibility for the information and views expressed herein lies
entirely with the authors.
Author Contributions
Conceptualization: Monica Suet Ying Ng.
Writing –original draft: Monica Suet Ying Ng.
Writing –review & editing: Andrew J. Kassianos, Monica Suet
Ying Ng.
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