Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study

Background: Extracellular fluid volume (ECF) is independently associated with chronic kidney disease (CKD) progression and mortality in patients with CKD, but the prognostic value of the trajectory of ECF over time beyond that of baseline value is unknown.

Objectives: To characterize ECF trajectory and evaluate its association with the risks of end-stage kidney disease (ESKD) and mortality.

Methods: From the prospective tricentric NephroTest cohort, we included 1588 patients with baseline measured glomerular filtration rate (mGFR) ≥15 mL min^-1 /1.73 m² and ECF measurement. ECF and GFR were measured repeatedly using the distribution volume and clearance of ⁵¹ Cr-EDTA, respectively. ESKD and mortality were traced through record linkage with the national registries. Adjusted shared random-effect joint models were used to analyse the association between the trajectory of ECF over time and the two competing outcomes.

Results: Patients were mean age 58.7 years, 66.7% men, mean mGFR of 43.6 ± 18.6 mL min^-1 /1.73 m² and mean ECF of 16.1 ± 3.6 L. Over a median follow-up of 5.3 [IQR: 3.0;7.4] years, ECF increased by 136 [95%CI 106;167] mL per year on average, whilst diuretic prescription and 24-hour urinary sodium excretion remained stable. ESKD occurred in 324 (20.4%) patients, and 185 (11.6%) patients died before ESKD. A higher current value of ECF was associated with increased hazards of ESKD (adjusted hazard ratio [aHR]: 1.12 [95%CI 1.06;1.18]; P < 0.001 per 1 L increase in ECF), and death before ESKD (aHR: 1.10 [95%CI 1.04;1.17]; P = 0.002).

Conclusions: The current value of ECF was associated with the risks of ESKD and mortality, independent of multiple potential confounders, including kidney function decline. This highlights the need for a close monitoring and adjustment of treatment to avoid fluid overload in CKD patients.