Supplementary Material for: Heterogeneity of Effect of Net Ultrafiltration Rate among Critically Ill Adults Receiving Continuous Renal Replacement Therapy

Introduction: In continuous renal replacement therapy (CRRT)-treated patients, a net ultrafiltration (NUF) rate >1.75 mL/kg/h has been associated with increased mortality. However, there may be heterogeneity of effect of NUF rate on mortality, according to patient characteristics. Methods: To investigate the presence and impact of heterogeneity of effect, we performed a secondary analysis of the “Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy” (RENAL) trial. Exposure was NUF rate (weight-adjusted fluid volume removed per hour) stratified into tertiles (1.75 mL/kg/h). Primary outcome was 90-day mortality. Patients were clustered according to baseline characteristics. Heterogeneity of effect was assessed according to clusters and baseline edema and related to the additional impact of baseline cardiovascular Sequential Organ Failure Assessment (SOFA) score. We excluded patients with missing values for baseline weight and/or treatment duration. Results: We identified 2 clusters. The largest (cluster 1; n = 941) included more severely ill patients, with more sepsis, more edema, and more vasopressor therapy (all p Conclusions: In CRRT patients, both high and low NUF rates may be harmful, especially in those with edema, sepsis, and greater illness severity. Cardiovascular SOFA scores modulate this association. Additional studies are needed to test these hypotheses, and targeted trials of NUF rates based on risk stratification appear justified. Trial Registration: ClinicalTrials.gov identifier: NCT00221013.

引言：在接受连续性肾脏替代治疗（continuous renal replacement therapy, CRRT）的患者中，净超滤（net ultrafiltration, NUF）速率>1.75 mL/kg/h与死亡率升高相关。然而，NUF速率对死亡率的影响可能因患者特征而异，存在效应异质性。

方法：为探究效应异质性的存在及其影响，我们对“正常与强化级别肾脏替代治疗随机评估试验（Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy, RENAL）”进行了二次分析。本研究的暴露因素为NUF速率（每小时按体重校正的超滤液体量），并将其按三分位分层（以1.75 mL/kg/h为截断值）。主要结局为90天死亡率。研究对象依据基线特征进行聚类分析。我们依据聚类分组及基线水肿情况评估效应异质性，并分析其与基线心血管序贯器官衰竭评估（Sequential Organ Failure Assessment, SOFA）评分的额外关联。本研究排除了基线体重和/或治疗时长缺失的患者。

结果：我们共识别出2个聚类组。规模最大的组（组1；n=941）包含病情更危重的患者，其脓毒症发生率更高、水肿程度更严重且血管活性药物使用比例更高（所有p）。

结论：在接受CRRT的患者中，高、低两种NUF速率均可能带来危害，尤其在合并水肿、脓毒症及病情更危重的患者中。心血管SOFA评分可调节这一关联。后续需开展更多研究以验证上述假说，基于风险分层的NUF速率靶向试验也具备开展合理性。

试验注册：ClinicalTrials.gov 标识符：NCT00221013。