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Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease
Frank Geurts1, Laixi Xue1, Bart J Kramers2
1Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Insights
Higher urinary Prostaglandin E2 (PGE2) and its metabolite (PGEM) levels in autosomal dominant polycystic kidney disease (ADPKD) patients correlate with worse kidney function and faster disease progression. These findings highlight PGE2
Area of Science:
- Nephrology
- Endocrinology
- Molecular Medicine
Background:
- Prostaglandin E2 (PGE2) is crucial for osmoregulation, a process disrupted early in autosomal dominant polycystic kidney disease (ADPKD).
- While preclinical studies suggest PGE2 involvement in ADPKD pathogenesis, human data remain limited.
- This study investigates the association between urinary PGE2 excretion and ADPKD in humans.
Purpose of the Study:
- To determine if urinary PGE2 and its metabolite (PGEM) excretion correlates with osmoregulation impairment in ADPKD patients.
- To assess the relationship between urinary PGE2/PGEM levels and ADPKD disease severity (eGFR, total kidney volume).
- To evaluate the association of urinary PGE2/PGEM excretion with ADPKD progression (eGFR decline, kidney failure).
Main Methods:
- Prospective cohort study measuring urinary PGE2 and PGEM in 562 ADPKD patients.
- Linear regression analysis to assess associations with osmoregulation markers, eGFR, and kidney volume.
- Cox regression and linear mixed models for longitudinal analysis of disease progression and eGFR change.
- Intervention studies evaluating tolvaptan and hydrochlorothiazide effects on urinary PGE2/PGEM.
Main Results:
- Higher urinary PGE2/PGEM levels were linked to impaired osmoregulation (higher copeptin, lower urine osmolality).
- Increased urinary PGE2/PGEM correlated with reduced eGFR and greater total kidney volume.
- Higher baseline urinary PGE2/PGEM predicted a greater risk of 40% eGFR loss or kidney failure and faster eGFR decline.
- Urinary PGEM increased with tolvaptan; urinary PGE2 increased with hydrochlorothiazide addition.
Conclusions:
- Elevated urinary PGE2 and PGEM excretion in ADPKD patients is associated with impaired osmoregulation.
- Higher urinary PGE2/PGEM levels indicate increased ADPKD disease severity and predict faster progression.
- These findings suggest PGE2 as a potential biomarker and therapeutic target in ADPKD.
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.
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