Pathophysiology of Renal Calcium Handling in Acromegaly: What Lies behind Hypercalciuria?

Abstract

Hypercalciuria is frequent in patients with acromegaly, but it is unclear how GH/IGF-I regulate renal calcium handling. Elevated fasting plasma calcium levels despite increased glomerular filtration suggest enhanced renal calcium reabsorption. The aim of this study was to investigate the impact of acromegaly on phosphocalcium metabolism. We conducted a prospective sequential study at a tertiary referral medical center and clinical investigation center (www.ClinicalTrials.gov Identifier: NCT00531908). Sixteen consecutive patients (five females/11 males) with acromegaly received a single iv infusion of 25 mg of furosemide to induce an acute increase in calcium and magnesium delivery to distal tubular segments during a high-sodium diet with stable dietary calcium, magnesium, and phosphate intake. Baseline plasma and urine electrolytes, plasma calciotropic hormones, and furosemide-induced changes in the fractional excretion and tubular reabsorption of Na, Ca, and Mg were measured before and 6 months (range, 1-12) after effective treatment of acromegaly. Serum IGF-I concentrations normalized in all the patients after acromegaly treatment. Compared with controlled acromegaly, active acromegaly was associated with higher fasting plasma (P = 0.0002) and urinary calcium (P = 0.0003) levels, lower PTH levels (P = 0.0075), higher calcitriol levels (P = 0.0137), higher phosphatemia (P<0.0001) and tubular phosphate reabsorption (P = 0.0002), and a lower calciuric (P = 0.0327) but not magnesiuric response to furosemide related to higher baseline and postfurosemide tubular calcium (P = 0.0034 and P = 0.0081, respectively), but not magnesium reabsorption. The IGF-I-mediated and PTH-independent increase in calcitriol synthesis in acromegaly is responsible for both absorptive hypercalciuria and increased fasting plasma calcium linked to enhanced distal tubular calcium reabsorption, as shown by the selectively diminished calciuric response to furosemide.