Prostaglandin E2, osmoregulation and disease progression in autosomal dominant polycystic kidney disease.

Abstract

Prostaglandin E2 (PGE2) plays a physiological role in osmoregulation, a process that is affected early in autosomal dominant polycystic kidney disease (ADPKD). PGE2 has also been implicated in the pathogenesis of ADPKD in pre-clinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity and disease progression in patients with ADPKD. Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. Linear regression was used for the cross-sectional analysis of the associations between urinary PGE2 and PGEM excretions, markers of osmoregulation and disease severity. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression. In two separate intervention studies we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions. In 562 patients with ADPKD (61% female, eGFR 63 ± 28 ml/min/1.73 m2) higher urinary PGE2 or PGEM excretions were independently associated with higher plasma copeptin, lower urine osmolality, lower eGFR and greater total kidney volume. Patients with higher baseline urinary PGE2 and PGEM excretions had an increased risk of 40% eGFR loss or kidney failure (HR 1.28 and 1.47 for each doubling in urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (-0.39 and -0.53 ml/min/1.73 m2/year for each doubling in urinary PGE2 or PGEM excretions). In the intervention studies, inducing polyuria by tolvaptan significantly increased urinary PGEM excretion, while reducing polyuria by adding hydrochlorothiazide to tolvaptan significantly increased urinary PGE2 excretion. Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with parameters of osmoregulation, disease severity and progression.