Supplementary Material for: Dose of Hemodialysis and Survival: A Marginal Structural Model Analysis

Background: Observational studies have consistently demonstrated the survival benefits of a greater dialysis dose in maintenance hemodialysis (MHD) patients, whereas randomized controlled trials have shown conflicting results. The possible causal impact of dialysis dose on mortality needs to be investigated using rich cohort data analyzed with novel statistical methods such as marginal structural models (MSMs) that account for time-varying confounding and exposure. Methods: We quantified the effect of delivered dose of hemodialysis (HD) [single-pool Kt/V (spKt/V)] on mortality risk in a contemporary cohort of 68,110 patients undergoing HD 3 times weekly (7/2001-9/2005). We compared conventional Cox proportional hazard and MSM survival analyses, accounting for time-varying confounding by applying longitudinally modeled inverse-probability-of-dialysis-dose weights to each observation. Results: In conventional Cox models, baseline spKt/V showed a weak negative association with mortality, while higher time-averaged spKt/V was strongly associated with lower mortality risk. In MSM analyses, compared to a spKt/V range of 1.2-<1.4, a spKt/V range of <1.2 was associated with a higher risk of mortality [HR (95% CI) 1.67 (1.54-1.80)], whereas mortality risks were significantly lower with higher spKt/V [HRs (95% CI): 0.74 (0.70-0.78), 0.63 (0.59-0.66), 0.56 (0.52-0.60), and 0.56 (0.52-0.61) for spKt/V ranges of 1.4-<1.6, 1.6-<1.8, 1.8-<2.0, and ≥2.0, respectively]. Thus, MSM analyses showed that the greatest survival advantage of a higher dialysis dose was observed for a spKt/V range of 1.8-<2.0, and the dialysis dose-mortality relationship was robust in almost all subgroups of patients. Conclusions: Higher HD doses were robustly associated with greater survival in MSM analyses that more fully and appropriately accounted for time-varying confounding.