Authors' Reply: Dialysate Sodium and Mortality: 140 mmol/L at Hemodialysis Initiation by Default?
Authors: Jule Pinter, Meg Jardine, Bernard Canaud, Bernd Genser
Journal: Journal of the American Society of Nephrology (2024)

We welcome the letter from Hecking et al. titled "Dialysate Sodium and Mortality: 140 mmol/L at Hemodialysis Initiation by Default?,"1 published in this issue of JASN, regarding our publication "Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort"2 and suspect we are largely in agreement with the writers. We agree that despite careful efforts to adjust for potential confounders, residual confounding remains a concern in observational analyses such as these. As such, we feel the results of the analysis are hypothesis-generating but should not be used to change practice. We feel the results raise questions about dialysate sodium policy that can only be addressed through randomized comparisons. Hence, our strongest conclusions are the imperative for randomized evidence. We can offer the following comments in response to the particular points: Potential confounding by dialysate sodium concentrations by country: We acknowledge that completely controlling for confounding by country is impossible due to the limited variation in dialysate sodium concentrations within most participating countries. However, on the basis of our data, we do not find evidence for confounding by country. Our analysis stratified the data by country, adjusting for heterogeneity of mortality risk across countries using a country-specific baseline hazard function. The overall dialysate sodium versus high dialysate sodium effect reported in our article is a weighted average of these country-specific estimates. Only countries with both variability in dialysate sodium during follow-up and sufficient event counts contributed to the estimation of the country-specific effects. Table 1 presents these estimates: Three of five countries showed positive risk associations (hazard ratio >1), with two countries (Argentina and Portugal) demonstrating very strong and statistically significant effects. Potential confounding by fluid status: The core model used to estimate hazard ratios did not adjust for fluid overload. However, sensitivity analysis showed that including relative fluid status predialysis in the model did not substantially change the hazard ratios for low dialysate sodium ≤138 mmol/L, suggesting minimal confounding by fluid status. Potential confounding by baseline dialysate sodium prescription and limited change during follow-up: We have analyzed the data as documented in the European Clinical Database5. Dialysate sodium prescription is typically determined by country or clinic, rather than being individualized for patients. This limited variation in dialysate sodium prescription during the study could introduce confounding. To mitigate this, we exclude patients with predefined ultrafiltration and dialysate sodium prescription profiles from the analysis. Most of the dialysis clinics (78.6%) within our study were practicing a default dialysate sodium policy. It is a matter of debate which policy is feasible and subject to future randomized studies, what the best next step for outcome improvement could be, i.e., automated hemodialysis machine–based personalization of dialysate sodium on the basis of the dialysate–plasma sodium concentration gradient?3 Table 1 - Country-specific estimates of effect of low dialysate sodium versus high dialysate sodium on all-cause mortality Country % Person Months with DNa ≤138 mmol/L Patients Events HR 95% CI Argentina 7.6 4065 2346 2.48 1.91 to 3.19 Chile 6.7 2313 837 0.80 0.61 to 1.04 Poland 0.3 8717 3102 1.10 0.61 to 1.99 Portugal 1.1 3144 1529 4.38 1.64 to 11.73 Russia 0.1 5865 960 0.68 0.09 to 4.86 CI, confidence interval; DNa, dialysate sodium; HR, hazard ratio.