Excessively High Soluble Klotho in Acromegaly: A Sensitive and Specific Serum Marker Reflecting Activity of Growth Hormone-Secreting Pituitary Adenomas

Aims: Klotho was identified as a lifespan-influencing gene after recognition that its disruption causes a syndrome resembling aging in mice. Predominantly expressed in the kidneys and choroid plexus, Klotho protein exists in a transmembrane and a soluble form. The former serves as coreceptor for fibroblast growth factor 23 which inhibits renal phosphate reabsorption and calcitriol production, the latter regulates calcium homeostasis and inhibits insulin signalling. The aim of this study is to report an interesting phenomenon, excessive soluble Klotho in acromegaly, and to assess the course of serum Klotho in the postsurgical phase.

Methods: We measured growth hormone (GH) and insulin-like growth factor 1 (IGF-1, by RIA), soluble Klotho (by sandwich ELISA) in sera of 46 previously treatment-naïve patients (19 females/27 males) with acromegaly before and 1 to 3 months after transsphenoidal surgery. Moreover, we assessed soluble Klotho in a subgroup of 12 patients with acromegaly before discharge from hospital, 2 to 7 days after surgery, in 7 patients with clinically nonfunctioning pituitary adenoma (NFA), and in 26 healthy controls (11 females/15 males).

Results: Surgery resulted in declining GH (to a nadir <1 µg/L in 33) and IGF-1 levels in all acromegaly patients. In these patients, Klotho levels were high preoperatively (mean±SEM, 4053±447, median/IQR, 3020/1865–5402 pg/mL; corresponding to approximately four times the upper limit of normal on average; reliable reference range pending); after surgery, Klotho fell in all 46 subjects (to 770±66, 661/458–899 pg/mL), as did IGF-1 (from 589±34 to 202±10 ng/mL). During short-term follow-up in acromegaly patients (the 2- to 7-day group), Klotho declined from 3727±784 to 889±135 pg/mL and IGF-1 from 551±67 to 283±37 ng/mL. In NFA patients (most of them were GH-deficient), preoperative and postoperative values were 585±29 and 486±49 pg/mL, and 83±18 and 86±17 ng/ml, for Klotho and IGF-1, respectively. In healthy controls, serum soluble Klotho was 624±42 pg/mL and serum IGF-1 was 164±14 ng/mL.

Conclusions: Both IGF-1 and Klotho tended to be and remained low in patients with NFA; highly elevated Klotho was specific to GH-producing adenomas and decreased rapidly following tumor removal. Further studies should elucidate causes and potential implications of excessive soluble Klotho in patients with acromegaly.