Limonte Christine P, Gao Xiaoyu, Bebu Ionut, Seegmiller Jesse C, Lorenzi Gayle M, Perkins Bruce A, Karger Amy B, Arends Valerie L, Paterson Andrew, Molitch Mark E, de Boer Ian H
Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
Kidney Research Institute, University of Washington, Seattle, Washington, USA.
Kidney Int Rep. 2024 Feb 18;9(5):1406-1418. doi: 10.1016/j.ekir.2023.11.030. eCollection 2024 May.
Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage.
We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia.
At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]).
Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.
肾小管生物标志物可能有助于深入了解肾小管间质病理的进展，这对肾小球功能和损伤的传统测量方法起到补充作用。
我们在1型糖尿病（T1D）的糖尿病控制与并发症试验以及糖尿病干预与并发症流行病学研究（DCCT/EDIC研究）中研究了肾小管生物标志物的变化轨迹。在26年中的7个时间点对220名参与者的一个子集进行了生物标志物测量。测量指标包括：肾损伤分子1（KIM-1）、血清或血浆中的可溶性肿瘤坏死因子1（sTNFR1）、表皮生长因子（EGF）、定时尿中的单核细胞趋化蛋白-1（MCP1）以及一个复合肾小管分泌评分。我们描述了生物标志物的变化轨迹，并研究了强化降糖治疗和血糖水平对其的影响。
在基线时，参与者的平均年龄为28岁，45%为女性，50%被分配接受强化降糖治疗。平均估计肾小球滤过率（eGFR）为每1.73平方米125毫升/分钟，90%的参与者尿白蛋白排泄率（AER）<30毫克/24小时。生物标志物随时间的平均变化（百分比/十年）为：KIM-1：27.3%（95%置信区间[CI]：21.4 - 33.5），sTNFR1：16.9%（14.5 - 19.3），MCP1：18.4%（8.9 - 28.8），EGF：-13.5%（-16.7至-10.1），EGF - MCP1比值：-26.9%（-32.2至-21.3），以及肾小管分泌评分-0.9%（-1.8至0.0），而eGFR为-12.0%（CI：-12.9至-11.1），AER为10.9%（2.5 - 20.1）。强化降糖治疗与传统降糖治疗相比，sTNFR1的升高较慢（变化的相对差异：0.94[0.90 - 0.98]）。较高的糖化血红蛋白（HbA1c）与sTNFR1（变化的相对差异：HbA1c每升高1%为1.06[1.05 - 1.08]）和KIM-1（1.09[1.05 - 1.14]）的更快升高相关。
在基线时eGFR正常的T1D参与者中，肾小管生物标志物在长期随访中发生了显著变化。纵向随访时，高血糖与血清或血浆中sTNFR1和KIM-1的更大升高相关。
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