Potassium supplementation in patients with chronic kidney disease and healthy subjects: effects on potassium and sodium balance

Rationale:
Potassium is the most abundant cation in the intracellular fluid and its gradient across the cell membrane is pivotal for normal cell function. Under normal conditions, the kidney is primarily responsible for maintaining total body K+ (TBK) by matching potassium intake with potassium excretion. Yet, in kidney patients our understanding of potassium handling after a potassium load is incomplete. It is known, that as kidney function declines, the risk of hyperkalemia increases. At the same time, advanced chronic kidney disease (CKD) is often characterized by depleted TBK. Changes of the internal potassium balance might become the most important regulator of the serum potassium concentration in progressive CKD, but data to support this are lacking. Of further interest is that potassium and sodium balance are closely related. Under normal conditions, potassium supplementation increases sodium excretion, but it is unknown whether this potassium-induced natriuresis remains intact in CKD. In summary, better understanding of potassium homeostasis in response to potassium loading in CKD is highly relevant, specifically in the context of exploring the potentially beneficial effects of potassium supplementation in patients with CKD.

Objectives:
1. To analyze how potassium handling, volume and sodium status will change in healthy and CKD stage 3b/4 subjects after an acute oral potassium load.
2. To analyze how the response to an acute oral potassium load changes during renin-angiotensin-aldosterone (RAAS) blockade in healthy and CKD stage 3b/4 subjects.
3. To analyze how supplementation with two different potassium salts (potassium chloride vs. potassium citrate) influences potassium balance in CKD 3b/4.

Study design: Double blind and placebo-controlled cross-over study.

Study population: Outpatients (age ≥ 18 years) with CKD 3b/4 and hypertension (using single RAAS inhibitor treatment) and sex-matched healthy subjects, serving as controls.

Intervention: Patients and healthy subjects will be randomized to a 8-week period with RAAS inhibitor treatment (Lisinopril 10 mg once daily) followed by a 8-week period without RAAS inhibitor treatment (or vice versa). After 6, 7 and 8 weeks an acute oral dose of potassium chloride (40 mmol), potassium citrate (40 mmol) or matching placebo will be administered in random order.

Main study parameters/endpoints:
The primary study endpoint will be serum potassium (in mmol/L). Secondary endpoints will include Red Blood Cell (RBC) potassium (in mmol/L), renal potassium excretion, serum sodium, renal sodium excretion, total body water, and systolic blood pressure, as well as changes in serum bicarbonate, insulin, and plasma aldosterone.

Overall: when kidney function deteriorates, regulation of the potassium balance in response to potassium loading switches from renal to non-renal mechanisms.
1. Serum potassium in CKD is mainly influenced by alterations in the internal potassium balance.
2. Potassium supplementation in CKD restores TBK.
3. The increase in TBK by potassium supplementation reduces total body sodium stores in CKD.

3 study visits without Lisinopril (one week apart) and 2 study visits with Lisinopril (one week apart).

Patients and healthy subjects will be randomized to a 8-week period with RAAS inhibitor treatment (Lisinopril 10 mg once daily) followed by a 8-week period without RAAS inhibitor treatment (or vice versa). After 6, 7 and 8 weeks an acute oral dose of potassium chloride (40 mmol), potassium citrate (40 mmol) or matching placebo will be administered in random order.