Role of excess volume in the pathophysiology of hypertension in chronic kidney disease

Background. The pathophysiology of hypertension in patients with chronic kidney disease (CKD) is largely attributed to positive sodium balance. It is unclear how loop diuretics affect fluid volume compartments, especially with respect to their antihypertensive effect. Methods. Subjects with CKD were administered a single therapeutically equivalent dose of an oral loop diuretic (furosemide or torsemide in randomized crossover design). We measured acute volume changes over 12 hours using biophysical and hormonal biomarkers and then 24-hour ambulatory blood pressure after daily diuretic therapy for 3 weeks. Results. Single-dose administration of loop diuretic decreased extracellular water (ECW) by 1.7 L [95% confidence interval (95% CI) 1.2, 2.2, P < 0.001], total body water (TBW) by 1.2 L (95% CI 0.5, 1.9, P < 0.001), and increased natural log (ln) plasma renin activity (PRA) from -1.2 +/- 1.3 ng/mL/hour to -0.5 +/- 1.5 ng/mL/hour (P < 0.001). Daily loop diuretic administration resulted in reduced ECW from 24.2 +/- 6.4 L to 22.3 +/- 5.2 L (P = 0.02) and TBW from 54.3 +/- 12.7 L to 51.6 +/- 11.9 L (P < 0.001) in 1 week. After 3 weeks of diuretic therapy, whereas ECW reduction persisted at 22.8 +/- 5.1 L (P = 0.05), TBW trended toward baseline level at 52.7 +/- 11.8 L. A concomitant increase in ln PRA from -1.0 +/- 1.3 ng/mL/hour to 0.4 +/- 1.9 ng/mL/hour (P < 0.001) and ln plasma aldosterone (PA) from 2.0 +/- 0.8 ng/dL to 2.3 +/- 0.8 ng/dL (P < 0.005) and fall in ln brain natriuretic peptide (BNP) from 4.3 +/- 0.9 pg/mL to 3.7 +/- 1.0 pg/mL (P < 0.01) were seen at 1 week. Despite a trend toward restoration of TBW, changes in hormonal biomarkers were maintained at 3 weeks. Over these 3 weeks, furosemide reduced 24-hour ambulatory blood pressure from 147 +/- 17/78 +/- 11 mm Hg to 138 +/- 21/74 +/- 12 mm Hg (P = 0.021) and torsemide reduced it from 143 +/- 18/75 +/- 10 mm Hg to 133 +/- 19/71 +/- 10 mm Hg (P = 0.007). Conclusion. Patients with CKD have elevated extracellular fluid volume that can be corrected acutely with loop diuretics. Persistent diuretic use results in dynamic changes in ECW and other body fluid compartments that translate into chronic blood pressure reduction.