A Crossover Pilot Study of the Effect of Amiloride on Proteinuria

Study Overview
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Brief Summary
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This cross-over study is designed to test the hypothesis that amiloride will reduce urinary protein excretion and protect the kidney from rapid progression in proteinuric kidney disease.

Detailed Description
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Patients with proteinuric kidney disease will be enrolled and receive either amiloride or triamterene first, a similar diuretic acting on epithelial sodium channel (ENaC) as amiloride, but not inhibiting urokinase plasminogen activator receptor (uPAR), will be used as a control. Then patients will cross over to receive another medication. We postulate that amiloride could be beneficial in the patients with proteinuric kidney diseases and could be used as an adjunct therapy to reduce proteinuria and to delay renal disease progression in this patient population. Specific Aim 1: To examine the effects of amiloride on 24 hour urine protein excretion in patients with proteinuric kidney diseases. Specific Aim 2: To study if the effect of amiloride on proteinuria reduction is mediated by suppressing soluble urokinase plasminogen activator receptor (suPAR) expression. Study Design: The study includes 3 phases. 30 patients will be recruited to this study. All patients need to be on an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) daily at least two month prior to the study. Phase 1: Patients will be randomized to receive either amiloride 5mg twice daily or triamterene 50mg twice daily for 8 weeks. Serum potassium will be monitored one week before and one week after starting phase 1. If serum potassium remains equal to or less than 5.0mmol/L, amiloride or triamterene will be continued at same dose until the end of phase 1. If serum potassium is equal to or above 5.5 mmol/L, the patient will exit the study, and an adverse event will be reported. If serum potassium is between 5.1-5.4 mmol/L, it will be monitored again in one week. If serum potassium is above 5.5 mmol/L, the patient will exit the study, and an adverse event will be reported. If serum potassium remains in the same range, the patient will continue amiloride or triamterene at the same dose to complete phase 1. Phase 2: the patients will discontinue amiloride or triamterene for a washout for 4 weeks, but continue with the ACE inhibitor or ARB. Phase 3: the patients will cross over to triamterene or amiloride for 8 weeks. Use the protocol as described in phase 1.

Official Title
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A Crossover Pilot Study of the Effect of Amiloride on Proteinuria in Patients With Proteinuric Kidney Disease

Conditions
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Proteinuria

Intervention / Treatment
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* Drug: Amiloride
* Drug: Triamterene


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with any type of proteinuric kidney diseases Aged 18-75 Proteinuria ≥1g/day estimated glomerular filtration rate (eGFR) ≥ 30ml/min/1.73m2 Exclusion Criteria: Clinical evidences of lupus nephritis, or HIV associated nephropathy eGFR <30ml/min/1.73m2 Requirement for treatment with mineralocorticoid receptor antagonists (spironolactone, eplerenone) Status post kidney transplant Received glucocorticoid steroids within six months Serum K >4.8 mmol/L Total carbon dioxide <17 mmol/L Hemoglobin <10 g/dl Contraindicated or allergic to loop diuretics or potassium sparing diuretics Abnormal liver function tests

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amiloride Phase<br>Subject receives 5mg of Amiloride twice daily for 8 weeks. | Drug: Amiloride<br>* 5mg twice a day for 8 weeks<br>|
| Active Comparator: Triamterene Phase<br>Subject receives 50mg of Triamterene twice daily for 8 weeks. | Drug: Triamterene<br>* 50mg twice a day for 8 weeks<br>|
| No Intervention: Washout Phase<br>Subject does not take any study medication for 4 weeks | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hr urine protein excretion | Identify changes in 24 hr urine protein excretion throughout the 3 phases of the study. | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| urine plasmin activity | examine urine plasmin activity during the 3 phases of the study. Serum and urine plasmin will be measured by gelatin-PAGE zymography. | 20 weeks | 
| urine plasminogen activity | examine urine plasminogen activity during the 3 phases of the study. urine plasminogen will be measured by gelatin-PAGE zymography. | 20 weeks | 
| urine suPAR concentration | examine urine suPAR concentration during the 3 phases of the study. suPAR concentration will be measured by ELISA kit. | 20 weeks | 
| serum suPAR concentration | examine serum suPAR concentration during the 3 phases of the study. suPAR concentration will be measured by ELISA kit. | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amiloride, proteinuric kidney disease, urokinase plasminogen activator receptor, proteinuria