Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system

Abstract

Interactions between sodium and calcium regulating systems are poorly characterized but clinically important. Parathyroid hormone (PTH) levels are increased shortly after furosemide treatment by an unknown mechanism and this effect is blunted by the previous administration of a calcimimetic in animal studies. Here, we explored further the possible underlying mechanisms of this observation in a randomized cross-over placebo-controlled study performed in 18 human males. Volunteers took either cinacalcet (60mg) or placebo and received a 20mg furosemide injection 3 hours later. Plasma samples were collected at 15 minutes intervals and analyzed for intact PTH, calcium, sodium, potassium, magnesium, phosphate, plasma renin activity (PRA) and aldosterone up to 6h after furosemide injection. Urinary electrolytes excretion was also monitored. Subjects under placebo presented a sharp increase in PTH levels after furosemide injection. In presence of cinacalcet, PTH levels were suppressed and marginal increase of PTH was observed. No significant changes in electrolytes and urinary excretion were identified that could explain the furosemide-induced increase in PTH levels. PRA and aldosterone were stimulated by furosemide injection, but were not affected by previous cinacalcet ingestion.Expression of NKCC1, but not NKCC2 was found in parathyroid tissue. In conclusion, our results indicate that furosemide acutely stimulates PTH secretion in absence of any detectable electrolyte changes in healthy adults. A possible direct effect of furosemide on parathyroid gland needs further studies. Mechanisms of furosemide-induced PTH secretion3

Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis

“…(30) However, a recent study suggests that loop diuretics may also be capable of directly stimulating PTH secretion, independent from calciuric effects, via loop diuretic-responsive NKCC1 receptors in parathyroid tissue. (31) Our observation of higher PTH levels with loop diuretics is echoed by studies in cohorts with chronic kidney disease who have higher PTH levels (16) and more recently in a cohort without kidney disease. (32) Thiazides decrease calciuria (potentially inducing positive calcium balance) and have been shown to increase bone density and are associated with a lower risk for fracture.…”

“…Recent studies have shown that dihydropyridine L-type calcium channels, loop-diuretic-responsive NKCC1 receptors, and angiotensin type 1 and mineralocorticoid receptors are all present in parathyroid tissue. (19,31,36) …”

Measurement of intact parathormone during operation for primary hyperparathyroidism

“…The persistence of increased parathormone level can be caused by vitamin D insuffi ciency as well. The injection of furosemid stimulates PTH secretion in healthy adults (Muller, 2015). The measurement of peroperative intact parathormone levels should be performed during miniinvasive approaches on parathyroid glands (Joliat et al, 2015).…”

Furosemide Increases the Risk of Hyperparathyroidism in Chronic Kidney Disease

“…In the CRIC study [3] , this difference was ascribed to the wellknown differences between TTLD and LD regarding calcium excretion [20] . However, a recent study has shown that acute administration of Furo to healthy individuals promoted an increase of PTH levels in the absence of any detectable electrolyte changes [21] , perhaps as a result of a direct effect on the Na-K-2Cl cotransporter expressed at the parathyroid gland [22] . A similar dissociation between serum calcium and PTH secretion in human subjects was observed when the administration of Furo lasted for several days [20] .…”