Tamargo Christina L, Coca Steven G, Thiessen Philbrook Heather, Hu David G, Ix Joachim H, Shlipak Michael G, Fried Linda F, Gutierrez Orlando M, Waikar Sushrut S, Schrauben Sarah J, Schelling Jeffrey R, Ganz Peter, Kimmel Paul L, Greenberg Jason H, Deo Rajat, Takakura Ayumi, Vasan Ramachandran S, Bonventre Joseph V, Parikh Chirag R
Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Barbara T. Murphy Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
JCI Insight. 2025 Jun 23;10(12). doi: 10.1172/jci.insight.186836.
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.
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.
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.
Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD.
gov NCT00555217.
NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.
背景
虽然尿生物标志物在预测糖尿病肾病（DKD）进展方面显示出前景，但远端肾小管标志物仍研究不足。我们在退伍军人事务部糖尿病肾病（VA NEPHRON - D）临床试验中研究了远端肾小管标志物表皮生长因子（EGF）和尿调节素（UMOD）与DKD进展的关联。
我们使用Cox回归模型评估每种生物标志物与DKD进展之间的关联以及生物标志物随时间变化与DKD进展之间的关系。我们使用混合模型研究基线、12个月及随时间变化的生物标志物水平及其与纵向估算肾小球滤过率（eGFR）变化的关系。
参与者（n = 1116）患有2型糖尿病，尿白蛋白与肌酐比值（UACR）≥300 mg/g，eGFR为30 - 89.9 mL/min/1.73 m²。平均年龄为65岁，平均eGFR为56（标准差19）mL/min/1.73 m²，UACR中位数为840（四分位间距424 - 1780）mg/g。在中位随访2.2（1.3 - 3.1）年期间，144名参与者（13%）发生了DKD进展。较高的基线EGF和UMOD分别与较低的DKD进展风险独立相关（调整后风险比0.68，95%置信区间0.47，0.99；以及0.85，[0.75，0.98]，分别对应EGF和UMOD浓度每升高2倍）。在基线和12个月时进行了系列生物标志物测量，在根据基线生物标志物水平进行调整后，生物标志物下降较慢与较低的DKD进展风险相关。
尿EGF和UMOD可能是DKD中有价值的预后生物标志物。
gov NCT00555217。
美国国立卫生研究院U01DK102730、U01DK103225、K23 DK118198、R01DK137087、U01DK103225、R37DK039773、U01DK114866、U01DK106962、U01DK129984和R01DK093770；国家糖尿病、消化和肾脏疾病研究所合同U01DK106965。
