Supplementary Material for: Clinical Utility of KidneyIntelX in Early Stages of Diabetic Kidney Disease in the CANVAS Trial

<b><i>Introduction:</i></b> KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. <b><i>Methods:</i></b> We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m² or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in KidneyIntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). <b><i>Results:</i></b> We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m² and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m² in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: −6.9, −3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (<i>p</i> &lt; 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; <i>p</i> &lt; 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. <b><i>Conclusions:</i></b> KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm.

<b><i>引言：</i></b> KidneyIntelX是一种综合风险评分，整合了生物标志物与临床变量，用于预测糖尿病肾病（Diabetic Kidney Disease, DKD）的进展。目前尚不清楚该评分在钠-葡萄糖协同转运蛋白2（sodium glucose co-transporter 2, SGLT2）抑制剂治疗场景中的应用价值，以及风险评分的变化与未来肾脏结局之间的关联。
<b><i>方法：</i></b> 我们对卡格列净心血管评估研究（CANagliflozin cardioVascular Assessment Study, CANVAS）中存在基线糖尿病肾病（估算肾小球滤过率（estimated glomerular filtration rate, eGFR）30~59 mL/min/1.73 m²或尿白蛋白/肌酐比值（urine albumin-to-creatinine ratio, UACR）≥30 mg/g）的受试者的留存样本进行检测，测定了可溶性肿瘤坏死因子受体（soluble tumor necrosis factor receptor, TNFR）-1、可溶性TNFR-2以及肾损伤分子1，并在基线及第1、3、6年生成KidneyIntelX风险评分。我们评估了基线KidneyIntelX评分及其变化与后续糖尿病肾病进展（复合结局定义为：eGFR年下降≥5 mL/min[卡格列净组以6周时的eGFR作为基线值]、eGFR持续下降≥40%或肾衰竭）之间的关联。
<b><i>结果：</i></b> 我们最终纳入1325名同时患有糖尿病肾病且具备可用基线血浆样本的CANVAS受试者（平均eGFR为65 mL/min/1.73 m²，UACR中位数为56 mg/g）。在平均5.6年的随访期间，共有131名受试者（占比9.9%）发生了复合肾脏结局。参考既往验证研究中的风险截断值，KidneyIntelX将受试者分为低危组（占比42%）、中危组（占比44%）与高危组（占比15%），三组的结局累积发生率分别为3%、11%与26%（高危组相较低危组的风险比为8.4；95%置信区间（confidence interval, CI）：5.0, 14.2）。卡格列净组与安慰剂组的eGFR斜率差异在低、中、高KidneyIntelX风险分层中分别为0.66、1.52与2.16 mL/min/1.73 m²。随访第1年时，卡格列净组的KidneyIntelX风险评分下降了5.4%（95%CI：-6.9, -3.9），而安慰剂组则上升了6.3%（95%CI：3.8, 8.7）（*p* < 0.001）。在校正治疗分组后，第1年的KidneyIntelX评分变化与复合结局的未来风险相关（每降低10个单位的比值比为0.80；95%CI：0.77, 0.83；*p* < 0.001），且未观察到基线KidneyIntelX风险分层或治疗分组对该关联存在效应修正的证据。
<b><i>结论：</i></b> KidneyIntelX可成功对大型跨国外部队列的糖尿病肾病进展进行风险分层，且在基线KidneyIntelX评分更高的受试者中，卡格列净组与安慰剂组的eGFR斜率差异更为显著。随着治疗时间推移，卡格列净治疗可降低KidneyIntelX风险评分，且从基线至第1年的KidneyIntelX评分变化与糖尿病肾病进展的未来风险相关，该关联独立于基线风险评分与治疗分组。