Randomized Trial on the Effect of Oral Potassium Chloride Supplementation on the Thiazide-Sensitive Sodium Chloride Cotransporter in Healthy Adults.

Introduction: The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake. Methods: Healthy adults maintained on a high sodium (∼4.5 g [200 mmol]/d) low potassium (∼2.3 g [60 mmol]/d) diet underwent a 5-day run-in period followed by a crossover study, with 5-day supplementary KCl (active phase, Span-K 3 tablets (potassium 24 mmol) thrice daily) or 5-day placebo administrated in random order and separated by 2-day washout. Ambulatory blood pressure (BP) and biochemistries were assessed, and uEVs were analyzed by western blotting. Results: Among the 18 participants who met analysis criteria, supplementary KCl administration (vs. placebo) was associated with markedly higher levels of plasma potassium and 24-hour urine excretion of potassium, chloride, and aldosterone. KCl supplementation was associated with lower uEV levels of NCC (median fold change (KCl/Placebo) = 0.74 [0.30-1.69], P < 0.01) and pNCC (fold change (KCl/Placebo) = 0.81 [0.19-1.75], P < 0.05). Plasma potassium inversely correlated with uEV NCC (R2 = 0.11, P = 0.05). Conclusions: The lower NCC and pNCC in uEVs in response to oral KCl supplementation provide evidence to support the hypothesis of a functional "renal-K switch" in healthy human subjects.

In Primary Aldosteronism Acute Potassium Chloride Supplementation Suppresses Abundance and Phosphorylation of the Sodium-Chloride Cotransporter.

Background: Elevated abundance of sodium-chloride cotransporter (NCC) and phosphorylated NCC (pNCC) are potential markers of primary aldosteronism (PA), but these effects may be driven by hypokalemia. Methods: We measured plasma potassium in patients with PA. If potassium was <4.0 mmol/L, patients were given sufficient oral potassium chloride (KCl) over 24 hours to achieve as close to 4.0 mmol/L as possible. Clinical chemistries were assessed, and urinary extracellular vesicles (uEVs) were examined to investigate effects on NCC. Results: Among 21 patients with PA who received a median total dose of 6.0 g (2.4-16.8 g) of KCl, increases were observed in plasma potassium (from 3.4 to 4.0 mmol/L; P<0.001), aldosterone (from 305 to 558 pmol/L; P=0.01), and renin (from 1.2 to 2.5 mIU/L; P<0.001), whereas decreases were detected in uEV levels of NCC (median fold change(post/basal) [FC]=0.71 [0.09-1.99]; P=0.02), pT60-NCC (FC=0.84 [0.06-1.66]; P=0.05), and pT55/60-NCC (FC=0.67 [0.08-2.42]; P=0.02). By contrast, in 10 patients with PA who did not receive KCl, there were no apparent changes in plasma potassium, NCC abundance, and phosphorylation status, but increases were observed in plasma aldosterone (from 178 to 418 pmol/L; P=0.006) and renin (from 2.0 to 3.0 mU/L; P=0.009). Plasma potassium correlated inversely with uEV levels of NCC (R 2=0.11; P=0.01), pT60-NCC (R 2=0.11; P=0.01), and pT55/60-NCC (R 2=0.11; P=0.01). Conclusions: Acute oral KCl loading replenished plasma potassium in patients with PA and suppressed NCC abundance and phosphorylation, despite a significant rise in plasma aldosterone. This supports the view that potassium supplementation in humans with PA overrides the aldosterone stimulatory effect on NCC. The increased plasma aldosterone in patients with PA without KCl supplementation may be due to aldosterone response to posture challenge.

The Cl-/HCO3- exchanger pendrin is downregulated during oral co-administration of exogenous mineralocorticoid and KCl in patients with primary aldosteronism.

In primary aldosteronism (PA), the occurrence of K+ loss and hypertension suggest alterations in renal tubular transport, but the molecular basis of these alterations in humans is unclear. In this study, urinary extracellular vesicles (uEVs) isolated from patients undergoing fludrocortisone suppression testing (FST, as a means of confirming or excluding PA) were analyzed using mass spectrometry-based proteomics to determine the combined effects of an aldosterone analogue, NaCl and KCl supplementation on renal tubular protein abundance. Of quantified proteins, the Cl-/HCO3- exchanger pendrin decreased by a median 37% [-15, 57] (P < 0.01) and the potassium channel ROMK increased by a median 31% [-10, 85] (P < 0.01) during FST among 10 PA subjects. The trends remained, but to a lesser degree, in two subjects cured of PA by unilateral adrenalectomy. In PA subjects, plasma K+ increased from median 3.6 to 4.2 mM (P < 0.01) and 24 h urine K+ from 101 to 202 mmol (P < 0.01), while 24 h urine Na+/K+ decreased from 2.3 to 0.8 (P < 0.01). At baseline, pendrin negatively correlated with plasma K+ (P < 0.05) and positively correlated with plasma aldosterone (P < 0.01). There were no clear correlations between Δ pendrin (Δ = D4-D0) and changes in blood or urine variables, and no correlations between ROMK in any of the blood or urine variables either at baseline or during FST. We conclude that oral co-administration of mineralocorticoid and KCl in PA patients is associated with reduced pendrin and enhanced ROMK in uEVs. Pendrin reduction during FST suggests that the suppressive effects of oral KCl may outweigh pendrin upregulation by mineralocorticoids.

Feasibility study of colestipol as an oral phosphate binder in hemodialysis patients.

BACKGROUND: Currently available calcium- and aluminium-based phosphate binders are dose limited because of potential toxicity, and newer proprietary phosphate binders are expensive. We examined phosphate-binding effects of the bile acid sequestrant colestipol, a non-proprietary drug that is in the same class as sevelamer. METHODS: The trial was an 8 week prospective feasibility study in stable hemodialysis patients using colestipol as the only phosphate binder, preceded and followed by a washout phase of all other phosphate binders. The primary study endpoint was weekly measurements of serum phosphate. Secondary endpoints were serum calcium, lipids and coagulation status. Analyses used random effects mixed models. RESULTS: Thirty patients were screened for participation of which 26 met criteria for treatment. At a mean dose of 8.8 g/24 h of colestipol by study end, serum phosphate dropped from 2.24 to 1.96 mmol/L (P < 0.001). Three patients required calcium supplementation. LDL cholesterol dropped from 1.75 to 1.2 mmol/L (P < 0.001). Three patients dropped out because of side effects or intolerance of the required dose. CONCLUSION: The results support the feasibility of a larger trial to determine the efficacy of colestipol as a phosphate binder and that other non-proprietary anion-exchange resins may also warrant investigation.