A Crossover Pilot Study of the Effect of Amiloride on Proteinuria

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.

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