Urinary Prostaglandin as a Potential Predictive Marker for Thiazide-induced Hyponatremia (PROPHECY)

Urinary Prostaglandin as a Potential Predictive Marker for Thiazide-induced Hyponatremia: a Prospective Cohort Study (The PROPHECY Study)

Thiazides and thiazide-like diuretics are one of the five major classes of antihypertensive drugs. This study is to investigate whether urinary PGE2 concentration at baseline (prior to thiazide initiation) is associated with the development of TIH within the first four weeks of treatment.

Study Overview

• Status: Recruiting
• Conditions: Thiazide-induced Hyponatremia (TIH)
• Intervention / Treatment: Other: Data and biosample collection

Detailed Description

Thiazides and thiazide-like diuretics are one of the five major classes of antihypertensive drugs. They act by inhibiting the apical Na+-Cl- -cotransporter in the distal convoluted tubules of the kidneys. Thiazides and thiazide-like diuretics often cause adverse effects, importantly a drop in plasma sodium levels that is called thiazide-induced hyponatremia (TIH). Data suggest a crucial role of urinary PGE2 in water reabsorption. Since urinary PGE2 concentrations were higher in patients with TIH, quantification of urinary PGE2 prior and after thiazide initiation might allow identification of patients at risk for TIH, presenting PGE2 as a potential novel predictive marker for the development of TIH.

This study is to investigate whether urinary PGE2 concentration at baseline (prior to thiazide initiation) is associated with the development of TIH within the first four weeks of treatment. Hospitalized and ambulatory patients in whom a thiazide or thiazide-like diuretic will be newly prescribed are screened for inclusion.

The study procedure contains the screening and inclusion, visit 1 before thiazide initiation, visit 2 4 weeks (+/-7days) after thiazide initiation and a 3-months follow-up (visit 3). An additional visit (visit 2.1) will only be added in case of a dose change of the thiazide or thiazide-like diuretic (4 weeks +/- 7 days after the dose change). The 2 hours- challenge is optional if the patient agrees to additional testing.

• Study Type: Observational
• Enrollment (Estimated): 232

Contacts and Locations

• Study Contact: Name: Julia Beck, Dr. med.; Phone Number: +41 61 328 54 37; Email: julia.beck@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel, Endocrinology, Diabetes and Metabolism
    • Contact: Julia Beck, Dr. med.; Phone Number: +41 61 328 54 37; Email: julia.beck@usb.ch
    • Principal Investigator: Julia Beck, Dr. med.
    • Sub-Investigator: Sophie Monnerat
    • Sub-Investigator: Thilo Burkard, Dr. med.
    • Sub-Investigator: Ewout J. Hoorn, Prof. Dr. med.
    • Sub-Investigator: Michael Mayr, PD Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Hospitalized and ambulatory patients in whom a thiazide or thiazide-like diuretic will be newly prescribed. Screening will take place at the University Hospital Basel, primarily at the Endocrine Outpatient Clinic and the Hypertension Clinic of the Medical Outpatient Clinic and is based on the patients' charts as well as consultation with the treating physician.

Description

Inclusion Criteria:

• Newly prescribed thiazide or thiazide-like diuretic
• ≥ 18 years of age
• Informed Consent as documented by signature

Exclusion Criteria:

• Intake of thiazide or thiazide-like diuretic in the preceding month
• Hyponatremia (plasma sodium <135 mmol/L) at baseline
• Acute infectious / inflammatory disease (CRP ≥ 20 mg/L [1, 11])
• Symptomatic urinary tract infection
• Chronic treatment with NSAID and / or NSAID intake 48 hours prior to urine sampling at visit 1 and 2 (intake of acetylsalicylic acid will be no exclusion criteria)
• End of life care, no informed consent or inability to follow the procedures of the study, e.g., due to language barriers, psychological disorders, dementia

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with newly prescribed thiazide or thiazide-like diuretic; As the study population of this observational study shall be as representative as possible all patients with a new thiazide or thiazide-like diuretic regardless of the indication, co-morbidities and co-medication can be included.	Other: Data and biosample collection; Collection of spot urine, blood sampling, vital parameters, body weight, medical history, patient questionnaires, drinking protocol, drug diary at at Visit 1 (before thiazide initiation), at Optional 2 hours-challenge, at Visit 2 (4 weeks after thiazide initiation), at Visit 2.1 (4 weeks after dose change), at Visit 3 (3-months after thiazide initiation)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of hyponatremia (plasma sodium <135 mmol/L)	Occurrence of hyponatremia (plasma sodium <135 mmol/L)	Within the first four weeks of treatment (at visit 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urinary Prostaglandin- concentration	Change in urinary Prostaglandin E2 (PGE2) and metabolite (PGE2M)- concentration	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in the expression of proteins involved in sodium and water transport	Change in the expression of proteins involved in sodium and water transport (AQP2, Prostaglandin transporter (PGT) and NCC) in urinary extracellular vesicles in spot urine (second morning urine)	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in systolic and diastolic blood pressure	Change in systolic and diastolic blood pressure	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Change in heart rate	Change in heart rate	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Change in body weight	Change in body weight	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Change in daily fluid intake	Change in daily fluid intake	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Change in Bioelectrical impedance analysis (BIA)	Change in Bioelectrical impedance analysis (BIA)	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Change in plasma sodium	Change in plasma sodium	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in urine sodium	Change in urine sodium	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in potassium	Change in potassium	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in chloride	Change in chloride	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in creatinine	Change in creatinine	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in urea	Change in urea	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in uric acid	Change in uric acid	Between baseline and visit 2 (and visit 2.1 if applicable), approximately 4 weeks
Change in general well-being	Change in general well-being rated on a visual analogue scale reaching from 0 to 10	Between baseline, visit 2 (visit 2.1 if applicable) and visit 3, approximately 3 months
Incidence of hyponatremia	Incidence of hyponatremia	Between baseline and visit 3, approximately 3 months
Incidence of falls	Incidence of falls	Between baseline and visit 3, approximately 3 months
Incidence of fractures	Incidence of fractures	Between baseline and visit 3, approximately 3 months
Incidence of hospitalization due to any cause	Incidence of hospitalization due to any cause	Between baseline and visit 3, approximately 3 months

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Mirjam Christ-Crain, Prof. Dr. med., University Hospital Basel, Endocrinology, Diabetes and Metabolism

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2022
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: September 12, 2022
• First Submitted That Met QC Criteria: September 12, 2022
• First Posted (Actual): September 15, 2022

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Hyponatremia; Thiazide; Thiazide-like diuretics; Prostaglandin E2 (PGE2); Urinary PGE2 concentration; Plasma sodium level; Urinary prostaglandins
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyponatremia
• Other Study ID Numbers: 2022-01241; kt21ChristCrain3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No