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Clinical Trial
. 2025 Jun 23;10(12):e186836.
doi: 10.1172/jci.insight.186836.

The distal nephron biomarkers associate with diabetic kidney disease progression

Christina L Tamargo  1 , Steven G Coca  2 , Heather Thiessen Philbrook  1 , David G Hu  1 , Joachim H Ix  3   4 , Michael G Shlipak  5   6 , Linda F Fried  7   8 , Orlando M Gutierrez  9   10 , Sushrut S Waikar  11 , Sarah J Schrauben  12 , Jeffrey R Schelling  13 , Peter Ganz  5   14 , Paul L Kimmel  15 , Jason H Greenberg  16 , Rajat Deo  17 , Ayumi Takakura  18   19 , Ramachandran S Vasan  20   21 , Joseph V Bonventre  18   19 , Chirag R Parikh  1
Affiliations
Clinical Trial

The distal nephron biomarkers associate with diabetic kidney disease progression

Christina L Tamargo et al. JCI Insight. .

Abstract

BACKGROUNDWhile urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial.

Methods: We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change.

Results: Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30-89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424-1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3-3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels.

Conclusion: Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD.

Clinicaltrials: gov NCT00555217.

Funding: NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.

Keywords: Chronic kidney disease; Clinical Research; Diabetes; Nephrology.

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Conflict of interest statement

Conflict of interest: See supplement for conflict of interest.

Figures

Figure 1
Figure 1. Relationship between baseline urine biomarker levels and hazard of DKD progression.
Splines are truncated to the 2.5th and 97.5th percentiles, representing 95% of the data. Splines are unadjusted. EGF, epidermal growth factor; UMOD, uromodulin.
Figure 2
Figure 2. Relationship between 12-month urine biomarker levels and hazard of DKD progression.
Splines are truncated to the 2.5th and 97.5th percentiles, representing 95% of the data. Splines are unadjusted. EGF, epidermal growth factor; UMOD, uromodulin.
See this image and copyright information in PMC

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