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）的首要致病诱因。肾小管健康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）之外，对慢性肾病（chronic kidney disease, CKD）的进展开展预后评估。
方法：本研究针对1135名基线UACR≥300mg/g且留存可用尿液样本的VA NEPHRON-D试验参与者，分析了5种肾小管损伤与修复相关尿液生物标志物（NGAL、KIM-1、IL-18、MCP-1、YKL-40）与肾功能下降及全因死亡的关联，其中肾功能下降定义为：随机分组时eGFR≥60ml/min/1.73m²者出现eGFR下降≥30ml/min/1.73m²，随机分组时eGFR<60ml/min/1.73m²者出现eGFR较基线下降≥50%，或进展为终末期肾病（ESKD）。协变量涵盖年龄、性别、种族、体质量指数（body mass index, BMI）、收缩压、糖化血红蛋白（hemoglobin A1c, HbA1c）、治疗分组、基线eGFR及UACR。在712名留存12个月随访尿液样本的亚组参与者中，我们评估了KIM-1、MCP-1及YKL-40的水平变化（基线至12个月）与12个月后eGFR下降的关联。
结果：基线状态下，参与者平均年龄为65岁，平均eGFR为56ml/min/1.73m²，UACR中位数为840mg/g。中位随访时长2.2年期间，13%的参与者出现肾功能下降，9%发生死亡。在完全校正模型中，MCP-1与YKL-40最高四分位组相较于最低四分位组，肾功能下降风险分别升高2.18倍与1.76倍。KIM-1、MCP-1及YKL-40的1年水平变化与后续eGFR下降无显著关联。基线NGAL、IL-18、MCP-1及YKL-40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CKD的退伍军人群体中，肾小管健康相关尿液生物标志物与肾功能下降及死亡风险存在显著关联。