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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Thiazide-induced Hyponatremia (TIH)

Intervention / Treatment
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* Other: Data and biosample collection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with newly prescribed thiazide or thiazide-like diuretic<br>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<br>* 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)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thiazide, Thiazide-like diuretics, Hyponatremia, Prostaglandin E2 (PGE2), Urinary PGE2 concentration, Plasma sodium level, Urinary prostaglandins