Transtubular potassium gradient and dyskalemia risk in heart failure and chronic kidney disease
M B C Maria Belen Contreras, R De La Espriella, J M Jorge Montiel, E R Enrique Rodriguez, A C Arturo Carratala, M G Miguel Gonzalez, M M Marco Montomoli, E S Enrique Santas, G M Gema Minana, M L Miguel Lorenzo, G N Gonzalo Nunez, S V Sandra Villar, J L G Jose Luis Gorriz, J N Julio NunezAbstract
Background
Dyskalemia is common in ambulatory patients with heart failure (HF) and/or chronic kidney disease (CKD), is associated with adverse outcomes, and often complicates the introduction of disease-modifying therapies. Biomarkers that capture renal potassium-handling capacity may help anticipate future hypo- and hyperkalemia events. We aimed to determine whether baseline transtubular potassium gradient (TTKG) predicts recurrent dyskalemic events and modifies the prognostic association between longitudinal serum potassium and all-cause mortality.
Methods
Retrospective single-centre cohort study of 1,092 ambulatory adults with HF and/or CKD (January 2020–December 2024) with at least one laboratory-reported TTKG and 6,220 longitudinal serum potassium measurements. TTKG ≥7 defined a higher distal potassium secretory capacity. Recurrent hypo- (<3.5 mmol/L) and hyperkalemia (>5.0 mmol/L) were analyzed using marginal Cox regression for interval-censored recurrent events. The association between time-updated potassium and mortality was modelled using mixed-effects flexible parametric survival analysis.
Results
Mean age was 76.3±10.0 years; 38% were women; 71.6% had established HF, and 80.2% had eGFR <60 ml/min/1.73m². The longitudinal potassium trajectory showed an overall stable trend over time (P=0.119), with modest fluctuations within the normokalaemic range. Patients with a TTKG ≥7 maintained significantly lower potassium concentrations throughout follow-up compared to those with a baseline TTKG <7 (β = -0.31 mmol/L, 95% CI: -0.38 to -0.24; P<0.001), yet the rate of change over time did not differ between groups (time-interaction P=0.807). Over a median 2.29-year follow-up, 1,311 dyskalemic events occurred (904 hyperkalemia and 404 hypokalemia events). Baseline TTKG ≥7 was associated with lower hyperkalemia risk (HR 0.57; 95% CI 0.37–0.87; P=0.010) and a trend toward higher hypokalemia risk (HR 1.50; 95% CI 0.77–2.94; P=0.234), which became significant when TTKG was modelled as time-varying (HR 3.47; 95% CI 1.19–10.12; P=0.023). A significant interaction between TTKG and MRA use was observed for hypokalemia (P=0.039): TTKG ≥7 predicted hypokalemia only in patients not receiving MRAs (HR 3.57; P=0.020), whereas MRA therapy attenuated this risk (HR 0.94; P=0.880). During follow-up, 225 patients (20.6%) died; time-updated potassium showed a U-shaped mortality association relative to 4.4 mmol/L (P<0.001). TTKG modified this relationship (P interaction=0.003): among patients with TTKG ≥7, both hypokalemia and hyperkalemia carried increased mortality risk, whereas the hyperkalemia-mortality gradient was attenuated in those with TTKG <7.
Conclusions
Baseline TTKG identifies distinct dyskalemia risk phenotypes and modifies the prognostic interpretation of longitudinal potassium in ambulatory HF/CKD patients. MRA therapy may mitigate TTKG-associated hypokalemia risk, supporting physiology-informed monitoring strategies.Dyskalemia Event Burden by Baseline TTKGFor image description, please refer to the figure legend and surrounding text.Dyskalemia-Free Survival by TTKGFor image description, please refer to the figure legend and surrounding text.