Association Between Baseline Plasma Tonicity and eGFR Decline in Normonatremic Patients with CKD

Background: Serum sodium levels reflect body water balance and contribute to plasma tonicity (effective osmolality), which regulates water homeostasis. Although dysnatremia has been associated with poor kidney outcomes in CKD patients, it remains unclear whether variation in plasma tonicity within the normonatremic range affects kidney function decline. This study aims to examine the association between baseline plasma tonicity and eGFR decline. Methods: We analyzed data from an observational study of CKD or cardiovascular patients enrolled between December 2020 and September 2022 and followed until March 2024 at our hospital. Patients with baseline eGFR ≤ 60 mL/min/1.73m2 and normonatremia (135 ≤ serum Na [mEq/L] ≤145) were included. Plasma tonicity was calculated as 2 x Na + glucose/18 and divided into tertiles (Low, Mid, and High groups). eGFR trajectories were compared using a linear mixed-effects model. Rapid eGFR decline, defined as a decrease of ≥5 mL/min/1.73m2/year, was also analyzed using multivariable Cox regression models to compare risk across plasma tonicity tertiles. Additionally, plasma tonicity was treated as a continuous variable, and its association with the outcome was modeled using restricted cubic splines. Results: Among 1,031 patients, 620 with 10,391 blood tests were included. Median serum sodium and tonicity were 138 mEq/L and 282.7 mOsm/L (Low-group), 140 and 286.9 (Mid-group), and 142 and 291.0 (High-group). In the linear mixed-effects model, the annual eGFR decline was faster in the Mid-group (–0.35 mL/min/1.73m2/year, P = 0.008) and the High-group (–0.65, P < 0.001) compared with the Low-group. In multivariable Cox regression for rapid eGFR decline, only the High-group showed a significantly increased risk (adjusted HR 1.41, 95% CI 1.03–1.92). The adjusted survival curves are shown in Figure 1. Spline analysis showed a significantly increased risk above approximately 285 mOsm/L (Figure 2). Conclusion: In normonatremic CKD patients, higher plasma tonicity was independently associated with more rapid eGFR decline. These findings suggest that even within the normal range of serum sodium, attention to plasma tonicity may be important for preserving kidney function. Funding: Private Foundation Support