Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.
Humans
Female
Male
Polycystic Kidney, Autosomal Dominant
/ complications
Tolvaptan
/ therapeutic use
Dinoprostone
/ pharmacology
Prospective Studies
Osmoregulation
Disease Progression
Kidney
/ pathology
Renal Insufficiency
/ complications
Hydrochlorothiazide
/ pharmacology
Glomerular Filtration Rate
Antidiuretic Hormone Receptor Antagonists
Journal
Clinical journal of the American Society of Nephrology : CJASN
ISSN: 1555-905X
Titre abrégé: Clin J Am Soc Nephrol
Pays: United States
ID NLM: 101271570
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
received:
16
05
2023
accepted:
06
08
2023
pmc-release:
01
11
2024
medline:
9
11
2023
pubmed:
14
8
2023
entrez:
14
8
2023
Statut:
ppublish
Résumé
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. 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. In 562 patients with ADPKD (61% female, eGFR 63±28 ml/min per 1.73 m 2 ), 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 m 2 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. Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with impaired osmoregulation, disease severity, and progression.
Sections du résumé
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 m 2 ), 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 m 2 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.
Identifiants
pubmed: 37574650
doi: 10.2215/CJN.0000000000000269
pii: 01277230-202311000-00009
pmc: PMC10637469
doi:
Substances chimiques
Tolvaptan
21G72T1950
Dinoprostone
K7Q1JQR04M
Hydrochlorothiazide
0J48LPH2TH
Antidiuretic Hormone Receptor Antagonists
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1426-1434Investigateurs
Dorien Peters
(D)
Monique Losekoot
(M)
Johan de Fijter
(J)
Folkert Visser
(F)
Joost Drenth
(J)
Tom Nijenhuis
(T)
Jack Wetzels
(J)
Marieke van Gastel
(M)
Informations de copyright
Copyright © 2023 by the American Society of Nephrology.
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