A New Application of Amiloride in the Treatment of Patient With Chronic Kidney Disease In Reducing Urinary PROtein

Study Overview
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Brief Summary
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Nowadays, the prevalence of chronic kidney disease (CKD) in China is about 10.8%,and nearly 120 million people suffer from CKD, which has become a serious public health problem in China. Study confirmed that proteinuria is an independent risk factor for the continuous deterioration of glomerular filtration rate (GFR) in patients with CKD. So it is of great significance to explore the strategy of reducing proteinuria. According to our previous study, Amiloride can inhibit the expression of uPAR in podocytes and reduce proteinuria, This clinical trial aims to evaluate the effect and safety of Amiloride in decreasing proteinuria for patients with Chronic Kidney Disease.

Detailed Description
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Amiloride is a Na+ channel blocker and has been used as a diuretic. It mainly inhibits the exchange of Na+-K+ and Na+-H+ in the distal tubule and collecting duct of the kidney, thus increasing the excretion of Na+ and water, reducing the excretion of K+ and H+. Recent studies have found a significant increase in urine uPA in patients with massive proteinuria.Urine uPA concentration were positively correlated with urinary protein and decreased with remission of proteinuria. In children and adults with nephrotic syndrome,as well as rat with proteinuria induced by puromycin amino-nucleoside, amiloride can inhibit uPA concentration in urine, which may be one of the mechanisms of amiloride in reducing proteinuria. This study is a prospective , crossover, open-Label study. All patients need to be on an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) daily at least four weeks prior to the study. The baseline data would be recorded. Patients enrolled will receive either amiloride or hydrochlorothiazide first for 8 weeks.Hydrochlorothiazide, a similar diuretic as amiloride, but not inhibiting urokinase plasminogen activator receptor (uPAR), will be used as a control. Then the patients will discontinue amiloride or hydrochlorothiazide for a washout for 4 weeks, but continue with the ACE inhibitor or ARB. After that patients will cross over to receive another medication for another 8 weeks. We aim to evaluate the effect and safety of Amiloride in decreasing proteinuria for patients with chronic kidney disease.

Official Title
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The Effect and Safety of Amiloride in Decreasing Proteinuria for Patients With Chronic Kidney Disease in a Prospective , Crossover, Open-label Study.

Conditions
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Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Amiloride
* Drug: Hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients at the age of more than 14 years old with chronic kidney disease Good compliance of treatment PCR≥500mg/g.cr ，more than double confirmed Patients who written informed consent Exclusion Criteria: less than 14 years of age eGFR≤30ml/min.1.73m2； poor compliance of treatment Previously intolerant or allergic to hydrochlorothiazide Patients with history of gout within six months Patients with active infection Patients with severe cardiopulmonary disease and dysfunction of central nervous system history of malignancy life expectancy is less than 1 years women who are pregnant,lactating and lack of contraception. enrolled in other clinical trials within 3 months patients who have used immunosuppressive agents or corticosteroids recently or in the past 12 weeks. patients without informed consent written or who enable or unwilling to comply with protocol approved by researchers.

Ages Eligible for Study
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Minimum Age: 14 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All patients need to be on an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) daily at least four weeks prior to the study. The baseline data would be recorded. Patients enrolled will receive either amiloride or hydrochlorothiazide first for 8 weeks.Then the patients will discontinue amiloride or hydrochlorothiazide for a washout for 4 weeks, but continue with ACEI(angiotensin-converting enzyme inhibitor ) or ARB. After that patients will cross over to receive another medication for another 8 weeks.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: amiloride<br>Amiloride first for 8 weeks, then for a washout for 4 weeks, and cross over to receive hydrochlorothiazide for another 8 weeks | Drug: Amiloride<br>* Amiloride first for 8 weeks, then for a washout for 4 weeks, and cross over to receive hydrochlorothiazide for another 8 weeks.<br>|
| Active Comparator: hydrochlorothiazide<br>hydrochlorothiazide first for 8 weeks, then for a washout for 4 weeks, and cross over to receive amiloride for another 8 weeks. | Drug: Hydrochlorothiazide<br>* hydrochlorothiazide first for 8 weeks, then for a washout for 4 weeks, and cross over to receive amiloride for another 8 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The remission of proteinuria |  | after treatment for 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| estimated Glomerular Filtration Rate | time to a 50% reduction in baseline estimated Glomerular filtration rate (according to CKD-EPI) and to doubling of baseline creatinine | after treatment for 12 weeks | 
| creatinine | time to doubling of baseline creatinine | after treatment for 12 weeks | 
| hyperkalemia | The ratio of hyperkalemia occurred at 12 weeks after treatment. | at 12 weeks after treatment |