Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Background 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 preclinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity, and disease progression in human ADPKD.Methods Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. The associations between urinary PGE2 and PGEM excretions, markers of osmoregulation, eGFR and height-adjusted total kidney volume were assessed using linear regression models. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression defined as 40% eGFR loss or kidney failure, and change in eGFR over time. In two intervention studies, we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions.Results In 562 patients with ADPKD (61% female, eGFR 63±28 ml/min per 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. Participants with higher baseline urinary PGE2 and PGEM excretions had a higher risk of 40% eGFR loss or kidney failure (hazard ratio, 1.28; 95% confidence interval [CI], 1.13 to 1.46 and hazard ratio, 1.50; 95% CI, 1.26 to 1.80 per two-fold higher urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (−0.39 [95% CI, −0.59 to −0.20] and −0.53 [95% CI, −0.75 to −0.31] ml/min per 1.73 m2 per year). In the intervention studies, urinary PGEM excretion was higher after starting tolvaptan, while urinary PGE2 excretion was higher after adding hydrochlorothiazide to tolvaptan.Conclusions Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with impaired osmoregulation, disease severity, and progression

Exit event from a metastable state and Eyring-Kramers law for the overdamped Langevin dynamics

International audienceIn molecular dynamics, several algorithms have been designed over the past few years to accelerate the exit event from a metastable region of the configuration space. Some of them are based on the fact that the exit event from a metastable region is well approximated by a Markov jump process. In this work, we present recent results on the exit event from a metastable region for the overdamped Langevin dynamics obtained in [17, 18, 49]. These results aim in particular at justifying the use of a Markov jump process parametrized by the Eyring-Kramers law to model the exit event from a metastable region

Nonlinear Dielectric Relaxation in AC and DC Electric Fields

International audienc