Volume 88, Issue 6, Pages 1383-1391 (December 2015) Evidence for a gastrointestinal–renal kaliuretic signaling axis in humans  Richard A. Preston, David Afshartous, Rolando Rodco, Alberto B. Alonso, Dyal Garg  Kidney International  Volume 88, Issue 6, Pages 1383-1391 (December 2015) DOI: 10.1038/ki.2015.243 Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 1 Serum potassium concentration (mmol/l). Following 35mmol oral potassium (KCl), mean serum potassium concentration increased from baseline 4.52 (95% confidence interval: 4.401, 4.62) to a peak 5.03 (4.81, 5.25; P<0.001)mmol/l at 30min. Following the potassium-deficient meal alone (Meal), serum potassium concentration decreased from baseline 4.54 (4.31, 4.76) to 3.90 (3.78, 4.01; P<0.001)mmol/l at 60min and remained depressed. With 35mmol oral potassium plus potassium-deficient meal (Meal+KCl), serum potassium concentration did not increase at any time point during the 5-h study period. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 2 Potassium excretion (mmol/h). Following KCl alone, mean potassium excretion rapidly increased to a peak 10.0 (8.24, 11.75; P<0.001)mmol/h at 60min then returned toward baseline. With Meal alone, UKV decreased to 1.84 (1.63, 2.04; P=0.002)mmol/h at 120min. With administration of Meal+KCl UKV increased from baseline 2.54 (2.14, 2.94)mmol/h to a peak of 5.14 (3.67, 6.60; P<0.001)mmol/h at 60min and remained elevated. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 3 Cumulative potassium excretion (mmol). Cumulative potassium excretion increased rapidly and reached 40.24 (36.22, 44.27)mmol following KCl alone. Following Meal+KCl, cumulative potassium excretion reached 26.43 (22.36, 30.50)mmol. Cumulative excretion following Meal alone reached only 16.51 (14.41, 18.61)mmol. All pairwise comparisons of cumulative potassium excretion among the three experiments were statistically significant (P<0.001) including the comparison of Meal vs. Meal+KCl. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 4 Plasma aldosterone (ng/dl). In response to KCl alone, mean plasma aldosterone rapidly reached a peak of 32.1 (24.88, 39.32; P<0.001)ng/dl at 30min. Following Meal alone, plasma aldosterone did not increase at any time point throughout the collection period. Following Meal+KCl, plasma aldosterone demonstrated a small increase to 25.85ng/dl at 30min. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 5 Insulin (μIU/ml). Insulin did not increase in response to 35mmol oral KCl alone. This was a consistent finding across study subjects following KCl alone. With Meal alone, insulin increased sharply to 190.4μIU/ml at 30min and reached a peak of 242.7 (147.3, 338.1; P<0.001)μIU/ml at 90min. Following Meal+KCl, insulin increased to 192.1μIU/ml at 30min and a peak of 217.4 (134.3, 300.5, P<0.001)μIU/ml at 90min. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 6 Meal + KCL experiment following aldosterone blockade. The Meal+KCl experiment was conducted in 12 additional volunteers following aldosterone blockade with 200mg eplerenone twice on the day prior and 400mg on the day of the Meal+KCl potassium handling experiment. (a) Serum potassium in response to Meal+KCl following eplerenone 400mg. Serum potassium did not increase following Meal+KCl. (b) Potassium excretion in response to Meal+KCl following eplerenone 400mg. Potassium excretion was 2.9 mmol/h (0.393) at baseline and increased to 4.47 (0.66)mmol/h at 60min. (c) Cumulative potassium excretion in response to Meal+KCl following eplerenone. Cumulative potassium in response to Meal+KCl reached 22.6 (1.99)mmol at hour 5 of the collection period. Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions

Figure 7 Urine sodium-to-potassium ratio for subjects receiving and subjects not receiving 400mg eplerenone. The UNa/UK ratio was 2.32 (1.76, 2.89) for subjects receiving eplerenone and 0.65 (0.49, 0.81) for subjects not receiving eplerenone (P<0.001). Kidney International 2015 88, 1383-1391DOI: (10.1038/ki.2015.243) Copyright © 2015 International Society of Nephrology Terms and Conditions