Amiloride 10mg/5ml / Furosemide 125mg/5ml oral suspension

AIM: In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. METHODS: The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. RESULTS: Median baseline OH was +26.4 (interquartile range 15.5-35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1-29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80-6.40) and 5.15 (0.90-8.30)% ECW after 8 days, respectively, and by 10.10 (1.30-14.40) and 7.40 (2.80-10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. CONCLUSION: The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).

Abstract licence: CC BY-NC-ND

Background: Data on diuretic treatment in nephrotic syndrome (NS) are scarce. Our goal was to assess the non-inferiority of the combined oral diuretics (furosemide/hydrochlorothiazide/amiloride) compared to intravenous (i.v.) furosemide in patients with NS and resistant edema. Methods: We conducted a prospective randomized trial on 22 patients with resistant nephrotic edema (RNE), defined as hypervolemia and a FENa < 0.2%. Based on a computer-generated 1:1 randomization, we assigned patients to receive either intravenous furosemide (40 mg bolus and then continuous administration of 5 mg/h) or oral furosemide (40 mg/day) and hydrochlorothiazide/amiloride (50/5 mg/day) for a period of 5 days. Clinical and laboratory measurements were performed daily. Hydration status was assessed by bioimpedance on day 1 and at the end of day 5 after treatment initiation. The primary endpoint was weight change from baseline to day 5. Secondary endpoints were hydration status change measured by bioimpedance and safety outcomes (low blood pressure, severe electrolyte disturbances, acute kidney injury and worsening hypervolemia). Results: Primary endpoint analysis showed that after 5 days of treatment, there was a significant difference in weight change from baseline between groups [adjusted mean difference: −3.33 kg (95% CI: −6.34 to −0.31), p = 0.03], with a higher mean weight change in the oral diuretic treatment group [−7.10 kg (95% CI: −18.30 to −4.30) vs. −4.55 kg (95%CI: −6.73 to −2.36)]. Secondary endpoint analysis showed that there was no significant difference between groups regarding hydration status change [adjusted mean difference: −0.05 L (95% CI: −2.6 to 2.6), p = 0.96], with a mean hydration status change in the oral diuretic treatment group of −4.71 L (95% CI: −6.87 to −2.54) and −3.91 L (95% CI: −5.69 to −2.13) in the i.v. diuretic treatment group. We observed a significant decrease in adjusted mean serum sodium of −2.15 mmol/L [(95% CI: −4.25 to −0.05), p = 0.04]), favored by the combined oral diuretic treatment [−2.70 mmol/L (95% CI: −4.89 to −0.50) vs. −0.10 mmol/L (95%CI: −1.30 to 1.10)]. No statistically significant difference was observed between the two groups in terms of adverse events. Conclusions: A combination of oral diuretics based on furosemide, amiloride and hydrochlorothiazide is non-inferior to i.v. furosemide in weight control of patients with RNE and a similar safety profile.

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Abstract It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non‐anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8 h post‐treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post‐treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide‐induced diuresis.

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Abstract In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/d, max. 15 mg/d) in nephrotic patients in comparison to standard therapy with the loop diuretic furosemide (40 mg/d, max. 120 mg/d) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (Body Composition Monitor, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (start 12.5 mg/d, max. 25 mg/d). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. Median baseline OH was + 26.4 (interquartile range 15.5–35.1) % extracellular water (ECW) in the amiloride arm and + 27.9 (24.1–29.4) % ECW in the furosemide arm and decreased by 1.95 (0.80–6.40) and 5.15 (0.90–8.30) % ECW after 8 days, respectively, and by 10.10 (1.30–14.40) and 7.40 (2.80–10.10) % ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. In conclusion, the AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Thus, amiloride emerges as an alternative to the standard therapy with furosemide.

Abstract licence: CC BY