Identification of the Causes for Chronic Hypokalemia: Importance of Urinary Sodium and Chloride Excretion.

BACKGROUND: Uncovering the correct diagnosis of chronic hypokalemia with potassium (K+) wasting from the kidneys or gut can be fraught with challenges. We identified clinical and laboratory parameters helpful for differentiating the causes of chronic hypokalemia. METHODS: Normotensive patients referred to our tertiary academic medical center for the evaluation of chronic hypokalemia were prospectively enrolled over 5 years. Clinical features, laboratory examinations-including blood and spot urine electrolytes, acid-base status, biochemistries, and hormones-as well as genetic analysis, were determined. RESULTS: Ninety-nine patients with chronic normotensive hypokalemia (serum K+ 2.8 ± 0.4 mmol/L, duration 4.1 ± 0.9 years) were enrolled. Neuromuscular symptoms were the most common complaints. Although Gitelman syndrome (n = 33), Bartter syndrome (n = 10), and distal renal tubular acidosis (n = 12) were the predominant renal tubular disorders, 44 patients (44%) were diagnosed with anorexia/bulimia nervosa (n = 21), surreptitious use of laxatives (n = 11), or diuretics (n = 12). Patients with gastrointestinal causes and surreptitious diuretics use exhibited a female predominance, lower body mass index, and less K+ supplementation. High urine K+ excretion (transtubular potassium gradient >3, urine K+/Cr >2 mmol/mmol) was universally present in patients with renal tubular disorders, but also found in >50% patients with gastrointestinal causes. Of interest, while urine sodium (Na+) and chloride (Cl-) excretions were high and coupled (urine Na+/Cl- ratio ∼1) in renal tubular disorders and "on" diuretics use, skewed or uncoupled urine Na+ and Cl- excretions were found in anorexia/bulimia nervosa and laxatives abuse (urine Na+/Cl- ratio: 5.0 ± 2.2, 0.4 ± 0.2, respectively) and low urine Na+ and Cl- excretions with fixed Na+/Cl- ratios (0.9 ± 0.2) when "off" diuretics. CONCLUSION: Besides body mass index, sex, and blood acid-base status, integrated interpretation of the urine Na+:Cl- excretion and their ratio is important to make an accurate diagnosis and treatment plan for patients with chronic normotensive hypokalemia.

Hypocalciuria in patients with Gitelman syndrome: role of blood volume.

BACKGROUND: Hypocalciuria is common in patients with Gitelman syndrome (GS), and its cause primarily is enhanced renal reabsorption of calcium in the proximal tubule in response to hypovolemia, judged by recent studies in animals. STUDY DESIGN: Uncontrolled trial in cases and controls to evaluate the effect of acute reexpansion of extracellular fluid volume (ECFV) on urine calcium excretion in patients with GS. SETTING & PARTICIPANTS: 8 patients with GS and 8 sex- and age-matched healthy control subjects (CSs) were enrolled in an academic medical center. PREDICTOR: ECFV expansion with isotonic saline at 1 L/h for 3 hours. OUTCOMES & MEASUREMENTS: Urinary calcium excretion was measured hourly for 6 hours, and subsequent 18-hour urine was analyzed as a single collection; hormones and electrolytes were measured. RESULTS: Patients with GS had hypokalemia, metabolic alkalosis, hypomagnesemia, severe hypocalciuria (urine calcium-creatinine ratio, 0.006 +/- 0.002 versus 0.08 +/- 0.02 mg/mg [0.02 +/- 0.01 versus 0.22 +/- 0.05 mmol/mmol]; P < 0.005), and a mild degree of ECFV contraction. Sodium excretion and creatinine clearance rates were similar to those in CSs. In patients with GS, saline infusion increased ECFV, which caused a significantly greater sodium excretion rate, but there was only a small increase in calcium excretion rate, in both the first 6 hours (0.04 +/- 0.02 mg/min [1.0 +/- 0.6 micromol/min]) and subsequent 18-hour period (0.02 +/- 0.01 mg/min [0.4 +/- 0.2 micromol/min]), as in CSs. Notwithstanding, their calcium excretion rate was still much less than that in CSs before volume repletion (0.13 +/- 0.04 mg/min [3.2 +/- 1.0 micromol/min]). LIMITATION: Patients with GS did not become euvolemic on a long-term sodium chloride supplementation because they excreted sodium chloride so rapidly. CONCLUSION: Hypovolemia is not the sole cause of hypocalciuria in patients with GS.

Gossypol-induced hypokalemia and role of exogenous potassium salt supplementation when used as an antispermatogenic agent in male langur monkey.

In our earlier study, we have observed that hypokalemia in langur monkeys, following gossypol acetic acid (GAA) treatment (5 mg dose level) when used as an antispermatogenic agent, and potassium salt supplementation partially maintained body potassium level of the animals. The aims of the present investigation was to confirm further occurrence of hypokalemia in the monkey (comparatively at two higher dose levels) and the role of potassium salt in preventing occurrence of gossypol-induced hypokalemia. Highly purified gossypol acetic acid alone at two dose levels (7.5 and 10 mg/animal/day; oral) and in combination with potassium chloride (0.50 and 0.75 mg/animal/ day; oral) was given for 180 days. Treatment with gossypol alone as well as with the supplementation of potassium salt resulted in severe oligospermia and azoospermia. Animals receiving gossypol alone showed significant potassium deficiency with signs of fatigue at both dose levels. Enhanced potassium loss through urine was found in potassium-deficient animals, whereas animals receiving gossypol acetic acid plus potassium salt showed normal serum potassium with a less significant increase in urine potassium level during treatment phases. Other parameters of the body remained within normal range except gradual and significant elevation in serum transaminases activity. The animals gradually returned to normalcy following 150 and 180 days of termination of the treatment.

PIP: An earlier study conducted by the authors indicated that body potassium levels were partially maintained in male langur monkeys treated with gossypol acetic acid (5 mg) and potassium salt supplementation. The present study sought to confirm the persistence of hypokalemia at two higher dosage levels (7.5 and 10 mg/animal/day) and assess the role of exogenous potassium salt (0.50 and 0.75 mg/animal/day) in preventing gossypol-induced hypokalemia. The two dosages of highly purified gossypol acetic acid were administered alone and in combination with potassium chloride for 180 days. All regimens produced severe oligospermia and azoospermia. However, monkeys who received gossypol alone showed significant potassium deficiency with signs of fatigue at both doses. On the other hand, animals receiving gossypol acetic acid and potassium salt supplementation showed normal serum potassium with a less significant increase in urine potassium level during treatment. Also noted was a gradual but significant elevation in the activity of serum transaminases. All parameters returned to normal 150-180 days after treatment termination. The hypokalemic effect documented in this study with gossypol alone may be due to renal leakage and gastrointestinal disturbances.

Familial hypokalemia/hypomagnesemia and chondrocalcinosis.

OBJECTIVE: Familial occurrence of Bartter's syndrome is well known, but the simultaneous occurrence of hypokalemia/hypomagnesemia and chondrocalcinosis in one family has not been described. We present the clinical, laboratory and radiological findings of a family, in which 7 members were affected by disease. METHODS: A total of 43 members of the family could be interviewed concerning their general health, past diseases and joint complaints. Serum potassium and magnesium were determined in all and radiographic studies were performed in those who had hypokalemia and hypomagnesemia or those with merely articular complaints. Urinary excretion of potassium, magnesium and calcium were determined in the affected persons. RESULTS: Seven patients were found with hypokalemia and hypomagnesemia. Urinary potassium and magnesium excretion was inappropriately high when compared to the serum levels of these electrolytes. All patients had hypocalciuria and extensive chondrocalcinosis, mainly in the knees, elbows and shoulders. In one patient, most probably as a result of magnesium supplementation, a striking reduction of chondrocalcinosis was observed during a followup of 10 years. CONCLUSION: A family with familial hypokalemia/hypomagnesemia and chondrocalcinosis is described. The reduction of chondrocalcinosis, after years of magnesium supplementation in one patient, suggests that hypomagnesemia is an important factor in the pathogenesis of chondrocalcinosis in these patients.

[Asymptomatic hypokalemia and hypomagnesemia with renal cation loss (Gitelman syndrome)]. / Asymptomatische Hypokaliämie und Hypomagnesiämie mit renalem Kationenverlust (Gitelman-Syndrom).

Hypokalemia with hyperkaliuresis was diagnosed in a 10 1/4-year-old boy, who presented with spontaneously disappearing abdominal pain. The diagnosis of Gitelman-Syndrome (asymptomatic chronic hypokalemia and -magnesemia) was established after detection of hypomagnesemia, renal magnesium losing but normal renin-angiotensin-aldosterone system and glomerular filtration rate. After oral supplementation of potassium hypokalemia persisted and hyperkaliuresis increased. The substitution was discontinued, the hyperkaliuresis diminished and the child remained asymptomatic during a 24 months follow-up. The substitution of potassium and magnesium can be avoided in children with Gitelman-Syndrome as long as they remain asymptomatic.