Supplementary Material for: Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. Methods: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. Results: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 μmol/24 h, p = 0.007, and 0.29 vs. 0.53 μmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 μmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. Conclusions: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

背景：具有常染色体显性多囊肾病（ADPKD）的病患，通过使用血管加压素V2受体拮抗剂（V2RA）来延缓疾病进展。该药物显著增加了这些已具有升高基线水平的病患体内的血管加压素水平。血管加压素通过V1和V3受体激活而刺激下丘脑-垂体-肾上腺（HPA）轴，而V2RA治疗期间血管加压素的增加是否会影响糖皮质激素的生成尚不明确。方法：对27例ADPKD病患在给予V2RA治疗前后进行研究，并将其与年龄和性别相匹配的健康对照者以及IgA肾病病患进行比较，后者在肾功能方面也进行了匹配。通过其替代指标copeptin来测量血管加压素。测量了24小时尿液中皮质醇、皮质酮、四氢皮质醇、四氢皮质酮、异四氢皮质酮和总糖皮质激素的排泄量。结果：在基线水平，与健康对照者相比，ADPKD病患表现出更高的copeptin浓度，而皮质醇和皮质酮的尿排泄量较低（中位数分别为0.23 vs. 0.34 μmol/24 h，p = 0.007，以及0.29 vs. 0.53 μmol/24 h，p < 0.001，分别）。与IgA肾病病患相比，皮质醇和皮质酮的排泄量无差异。皮质醇、皮质酮和总糖皮质激素的排泄量与肾功能相关（相关系数分别为R = 0.37、0.58和0.19，所有p < 0.05）。尽管V2RA治疗导致copeptin水平增加3倍，但仅皮质酮的排泄量增加（中位数为0.44 vs. 基线0.29 μmol/24 h，p < 0.001），而皮质醇或总糖皮质激素的排泄量未见变化。结论：在基线和V2RA治疗期间，ADPKD病患血管加压素的浓度增加并未导致HPA轴的激活。这些病患糖皮质激素生成受损与其肾功能损害程度相关。