Autosomal dominant polycystic kidney disease is associated with central and nephrogenic defects in osmoregulation

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is associated with a urine-concentrating defect attributed to renal cystic changes. As PKD genes are expressed in the brain, altered central release of arginine vasopressin could also play a role. In order to help determine this we measured central and nephrogenic components of osmoregulation in 10 adults and 10 children with ADPKD, all with normal renal function, and compared them to 20 age- and gender-matched controls. Overnight water deprivation caused a lower rise in urine osmolality in the patients with ADPKD than controls, reflecting an impaired release of vasopressin and a peripheral defect in the patients. The reactivity of plasma vasopressin to water deprivation, as found in controls, was blunted in the patients with the latter showing lower urine osmolality for the same range of plasma vasopressin. The maximal urine osmolality correlated negatively with total kidney volume. Defective osmoregulation was confirmed in the children with ADPKD but was unrelated to number of renal cysts or kidney size. Thus, patients with ADPKD have an early defect in osmoregulation, with a blunted release of arginine vasopressin. This reflects expression of polycystins in hypothalamic nuclei that synthesize vasopressin, and this should be considered when evaluating treatments targeting the vasopressin pathway in ADPKD.

Copeptin Is Associated with Kidney Length, Renal Function, and Prevalence of Simple Cysts in a Population-Based Study

“…27 The positive association of copeptin levels with total kidney volume in ADPKD also reflects the cystic disruption of the medulla, leading to the defective urinary concentrating ability that is consistently observed early in the disease. 19,27 By contrast, our results suggest that AVP may also play a role in the formation of simple renal cysts in the general population. The prevalence of simple cysts tends to increase with age and may reflect kidney aging.…”

“…AVP is a small nonapeptide that must be isolated from plasma by chromatography and further concentrated before the assay, which notoriously complicates the analytical procedure. 14,19 Even with RIAs, AVP remains difficult to measure: Its plasma t 1/2 is short, it is not stable ex vivo, and it interferes with plasma components or factors such as heparin. 15,20,21 In addition, storage at 220°C and freeze-thaw cycles result in a decline of plasma AVP levels over time.…”

Hyperglycemia in the absence of cilia accelerates cystogenesis and induces renal damage

“…There was a substantial increase in urine output and some evidence of proteinuria in cilia Ϫ mice compared with cilia ϩ mice. Although we do not have a clear explanation for the substantial differences between groups, the global Ift88 knockout model exhibits hyperphagia (9), and in PKD, in general, there is a urine-concentrating defect that may include defects at the collecting duct in the kidney and the osmoreceptors/vasopressin mechanism in the brain (16,24).…”

Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology

“…CTproAVP is correlated with the severity of the disease and recent evidence suggests that ADPKD patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance [45][46][47]. AVP has a direct influence on cysts, by stimulating the formation of cAMP, a potent stimulator of cyst growth, particularly of cysts that originate from the distal nephron segments that express V2 receptors.…”