Supplementary Material for: Urinary Biomarkers of Tubular Health and Risk for Kidney Function Decline or Mortality in Diabetes

Introduction: Diabetes is a leading cause of end-stage kidney disease (ESKD). Biomarkers of tubular health may prognosticate chronic kidney disease (CKD) progression beyond estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Methods: We examined associations of five urinary biomarkers of tubular injury and repair (NGAL, KIM-1, IL-18, MCP-1, YKL-40) with kidney function decline (first occurrence of a decrease in eGFR≥30 ml/min/1.73 m2 if randomization eGFR≥60 or ≥50% if randomization eGFR<60; ESKD) and all-cause mortality among 1,135 VA NEPHRON-D trial participants with baseline UACR ≥300 mg/g and available urine samples. Covariates included age, sex, race, BMI, systolic BP, HbA1c, treatment arm, eGFR, and UACR. In a subset of participants with 12-month samples (n=712), we evaluated associations of KIM-1, MCP-1, and YKL-40 change (from baseline to 12 months) with eGFR decline (from 12 months onwards). Results: At baseline, mean age was 65 years, mean eGFR was 56 ml/min/1.73 m2, and median UACR was 840 mg/g. Over a median of 2.2 years, 13% experienced kidney function decline and 9% died. In fully-adjusted models, the highest vs. lowest quartiles of MCP-1 and YKL-40 were associated with 2.18- and 1.76-fold higher risks of kidney function decline, respectively. One-year changes in KIM-1, MCP-1, and YKL-40 were not associated with subsequent eGFR decline. Higher baseline levels of NGAL, IL-18, MCP-1, and YKL-40 levels (per 2-fold higher) were independently associated with 10-40% higher risk of mortality. Discussion/Conclusion: Among Veterans with diabetes and CKD, urinary biomarkers of tubular health were associated with kidney function decline and mortality.

引言：糖尿病是终末期肾病（end-stage kidney disease, ESKD）的首要致病原因。肾小管健康相关生物标志物可在估算肾小球滤过率（estimated glomerular filtration rate, eGFR）与尿白蛋白肌酐比（urine albumin-to-creatinine ratio, UACR）的基础上，进一步预测慢性肾脏病（chronic kidney disease, CKD）的进展。

方法：本研究针对1135名基线尿白蛋白肌酐比≥300mg/g且留存可用尿液样本的VA NEPHRON-D临床试验受试者，分析了5种肾小管损伤与修复相关尿液生物标志物——中性粒细胞明胶酶相关脂质运载蛋白（neutrophil gelatinase-associated lipocalin, NGAL）、肾损伤分子1（kidney injury molecule-1, KIM-1）、白细胞介素18（interleukin-18, IL-18）、单核细胞趋化蛋白1（monocyte chemotactic protein-1, MCP-1）及几丁质酶3样蛋白1（chitinase-3-like protein 1, YKL-40）——与肾功能下降（随机分组时估算肾小球滤过率≥60ml/min/1.73m²者，定义为eGFR下降≥30ml/min/1.73m²；随机分组时eGFR<60ml/min/1.73m²者，定义为eGFR下降≥50%；或发生终末期肾病）及全因死亡的关联。校正变量包括年龄、性别、种族、体质量指数（body mass index, BMI）、收缩压（systolic blood pressure, SBP）、糖化血红蛋白（glycated hemoglobin A1c, HbA1c）、治疗分组、估算肾小球滤过率及尿白蛋白肌酐比。在712名留存12个月尿液样本的亚组受试者中，本研究进一步分析了肾损伤分子1、单核细胞趋化蛋白1及几丁质酶3样蛋白1从基线至12个月的变化量与12个月后估算肾小球滤过率下降的关联。

结果：基线时，受试者平均年龄为65岁，平均估算肾小球滤过率为56ml/min/1.73m²，尿白蛋白肌酐比中位数为840mg/g。中位随访2.2年期间，13%的受试者出现肾功能下降，9%的受试者死亡。在完全校正模型中，单核细胞趋化蛋白1与几丁质酶3样蛋白1的最高四分位数组相较最低四分位数组，肾功能下降风险分别升高2.18倍与1.76倍。肾损伤分子1、单核细胞趋化蛋白1及几丁质酶3样蛋白1的1年变化量与后续估算肾小球滤过率下降无显著关联。基线时中性粒细胞明胶酶相关脂质运载蛋白、白细胞介素18、单核细胞趋化蛋白1及几丁质酶3样蛋白1水平每升高2倍，全因死亡风险独立升高10%~40%。

讨论与结论：在合并糖尿病与慢性肾脏病的退伍军人受试者中，肾小管健康相关尿液生物标志物与肾功能下降及全因死亡风险存在显著关联。