Polycystic Kidney Disease and the Vasopressin Pathway

Abstract

Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL^-1/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake.

Osmoregulation in Polycystic Kidney Disease: Relationship with Cystogenesis and Hypertension

“…In ADPKD, this urinary concentrating impairment occurs early in the disease before renal function declines [2,4] (Fig. 1), likely due to the cystic distortion of renal architecture and a consequent disruption of osmotic gradients in the renal medulla [6]. Few studies have examined the renal concentrating ability in ARPKD patients and it is unclear whether the pathophysiology is similar.…”

“…2). Circulating AVP acts on renal V 2 receptors to accelerate cystogenesis in PKD (for a comprehensive review see: van Gastel and Torres [6]). This was clearly demonstrated by the observation that AVP-deficient PKD rats exhibited a four-fold reduction in cyst volume that was restored upon the administration of a V 2 agonist [8].…”

“…Accordingly, clinical trials have investigated the efficacy of a V 2 receptor antagonist, Tolvaptan, in ADPKD. Though clinical trials largely recapitulated the positive results shown in animal models, Tolvaptan is not without its side-effects, with safety issues noted relating to increased aquaresis and reduced liver function [6,13]. Alternative approaches that target the secretion of AVP rather than the V 2 receptor are therefore warranted.…”

“…Impaired urinary concentrating ability is an early clinical presentation of PKD [2][3][4][5]. As discussed by van Gastel and Torres [6] in the proceed- ings of the Hydration For Health 8th Annual Scientific Conference, physiological evidence indicates that in PKD, this urinary concentrating defect presents a hyperosmotic stimulus to central osmoreceptors that control arginine-vasopressin (AVP) secretion. Acting at renal V 2 receptors, AVP has been shown to accelerate cystogenesis through a cyclic adenosine monophosphate-dependent mechanism [6], and interrupting this pathway (i.e., through pharmacological or genetic AVP blockade or by increasing fluid intake) can substantially attenuate cystic pathology in rodent models of PKD [7,8].…”

Recent Advances in the Management of Autosomal Dominant Polycystic Kidney Disease

“…Water conservation in terrestrial animals promotes vasopressin-mediated cAMP increase that, in polycystic kidney disease, stimulates cyst formation and growth (45). Although vasopressin makes patients with ADPKD victims of evolution, it also makes the disease treatable by targeted therapy with V2-receptor (V2R) antagonists.…”