Acid-Base Homeostasis During Vasopressin V2 Receptor Antagonist Treatment in Autosomal Dominant Polycystic Kidney Disease Patients

Abstract

M any patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with the vasopressin V2 receptor antagonist tolvaptan to slow disease progression. By preventing binding of vasopressin to this specific receptor, tolvaptan causes a state of nephrogenic diabetes insipidus, resulting in significant polyuria, an increase in plasma sodium, and a compensatory surge in plasma vasopressin. Hypothetically, these increased levels of vasopressin set off by tolvaptan use can give rise to off-target effects via vasopressin V1 receptors, for this other type of vasopressin receptor is not blocked by this selective V2 antagonist. Potential effects of V1 activation include an increase in blood pressure via induction of vasoconstriction of the smooth muscle cells in the vascular walls, an increase of blood glucose levels by enhancing glycogenolysis in hepatocytes, an increase of glucocorticoid levels by stimulation of the adrenal cortex, and changing acid-base homeostasis in the kidneys. Considering the effect on acid-base homeostasis in particular, it should be recognized that increased V1 activation might induce a metabolic alkalosis. A recently published, meticulously executed preclinical study has demonstrated how stimulation of the V1 receptor, present on alpha-type intercalated cells in the collecting ducts of the kidneys, induces both urinary Hþ excretion and bicarbonate reabsorption into the circulation, thus increasing plasma bicarbonate levels. In case tolvaptan indeed induces a change in the acidbase homeostasis, recognition of this state is of importance, because even a subclinical metabolic alkalosis may have consequences for a patient’s well-being. To our knowledge, the effect of tolvaptan on the acid-base balance has never been addressed in prior research.