The long-term use of torsemide has been shown to be safe and effective in edema associated with renal disease.

Andreucci et al (1) performed an open-label trial in 9 patients with chronic renal failure to evaluate the effects of torsemide on hypertension and edema. Torsemide was administered as a single dose of 0.77 mg/kg daily for 7 days. The drug significantly decreased blood pressure throughout the study period and significantly increased sodium excretion and urine volume. These findings confirmed that torsemide is a potent diuretic and is useful in the treatment of edema and hypertension associated with chronic renal failure.

In a double-blind, randomized group comparative study, the efficacy of daily oral administration of 100 mg and 200 mg torsemide were compared with that of 250 mg of frusemide over 2 weeks in 20 patients with advanced chronic renal failure, who had been pretreated with a maintenance therapy of 500 mg frusemide per day (2). The volume excretion after administration of 200 mg torsemide was significantly higher than after administration of 250 mg frusemide and non- significantly higher than after 100 mg of torsemide. In comparison with baseline values under pretreatment with 500 mg frusemide, there was a slight reduction of fluid and sodium excretion in the 100 mg torsemide group and clear reduction in the 250 mg frusemide group. In contrast, in the 200 mg torsemide group, excretion of fluid and sodium increased (Table). The study demonstrated the general trend of the superiority of 200 mg torsemide to 250 mg and 500 mg frusemide and 100 mg torsemide. The tolerance was found to be good in all the groups.

In another controlled randomized double-blind clinical trial by Mourad et al (3), the diuretic efficacy of 20 and 100 mg of torsemide and 60 mg of frusemide was compared including a control group with placebo in 46 patients with advanced chronic renal failure (creatinine clearance < 30 ml/min).

Russo et al compared the diuretic effects of frusemide and torsemide in patients with chronic renal failure complicated by nephrotic syndrome using fractional collections of urine (1). Seven patients, maintained on a restricted sodium diet with a protein intake equal to 0.5 g/kg/day plus the amount of protein lost in urine, were randomly assigned to receive either torsemide or frusemide, 2.2 mg/kg body weight, as a single oral dose at 8.00 hours and followed 2 days later by a single oral dose of the other diuretic. Urine was collected daily from the day before the first diuretic until 2 days after the second drug.

Sodium excretion and urine output were significantly increased after both diuretics, but torsemide exerted significantly greater effect than frusemide. The authors concluded that in patients with chronic renal insufficiency complicated by nephrotic syndrome, the natriuretic potency of torsemide is significantly greater (Figure) than that of frusemide and is of longer duration.

Franz et al studied torsemide in 13 patients with edema due to nephrotic syndrome, proteinuria >3.5 g/24 h and serum creatinine <2 mg/dl (1). 6 patients were kidney graft recipients and 7 patients had chronic renal failure of various origins. In 10 patients, nephrotic syndrome had persisted for more than 1 year and edema had already been treated more or less effectively with frusemide or in combination with spironolactone. 3 patients presented with untreated edema for 3-4 months. Therapy was initiated with an empirical dose of torsemide 5 mg + spironolactone 50 mg and titrated to a maximal dose torsemide 20 mg + spironolactone 200 mg (oral administration), if necessary.

All patients responded with regression of peripheral edema, even the 2 patients who had severe edema which was previously found to be resistant to very high doses of frusemide and spironolactone. Reduction of extracellular fluid volume was associated with a significant decrease in body weight and mean arterial blood pressure. Also, interestingly, torsemide was associated with a significant reduction in proteinuria (Table).

Changes in protein loss are usually attributed to alterations of the permeability of the capillary wall, or alternatively to changes of interglomerular hemodynamics. Fractional protein clearance (proteinuria creatinine clearance ratio) was calculated, which significantly decreased during the treatment period. This indicates that the amelioration of urinary protein excretion was not directly related to changes in GFR. Also, there was no correlation between fall of proteinuria and decline in blood pressure or body weight (fall in proteinuria could be due to better diuretic-induced control of blood pressure or reduction of extracellular fluid volume). Also, reduction of proteinuria was not caused by partial recovery of the glomerular disease since renal disease had been controlled for more than 1 year in the majority of the patients and mainly nephropathies with a low incidence of spontaneous recovery were included. Also, no changes were made in the immunosuppressive drug regime of kidney-graft recipients; none of the other patients received any immunosuppressive agents and angiotensin-converting-enzyme inhibitors were not administered.

Although there is no explanation for the observed decrease in proteinuria, the authors concluded that proteinuria was reduced in 42% of nephrotic patients treated with torsemide.

Reference
1. Nephrol Dial Transplant 1996; 11: 2521-2522

Frusemide has been the cornerstone in therapy so far for patients undergoing hemodialysis. However, the need for a better diuretic with lesser incidence of side effects and a more favourable electrolyte pattern has always been felt. Torsemide scores over frusemide in this aspect because it is eliminated minimally by the kidney as it depends on the liver for its metabolism. Also, it prevents hypokalemia, thus decreasing chances of further electrolyte imbalance in patients of renal failure.

Two studies have compared the effects of torsemide and frusemide in patients undergoing hemodialysis (1,2). The efficacy of torsemide in reducing interdialysis weight gain and increasing water, sodium and chloride excretion was investigated in trials by Schulz et al and Stolear et al in patients with advanced renal disease and residual diuresis of at least 200-300 ml/day after hemodialysis (1,2). In the first study by Schulz et al, torsemide 200 mg daily (n=32) was compared with frusemide 500 mg (n=36) and placebo (n=34). After 14 weeks, interim evaluation revealed that torsemide produced the greatest increase in volume, and sodium and chloride excretion during the active phase, with a clear reduction in values for ionic excretion in a 2-week post-treatment follow-up. There was no negative influence on uraemia or urological symptoms.

In the second study (2), 44 patients received daily oral doses of torsemide 50 or 100 mg, or frusemide 125 mg for 2 weeks followed by double doses for an additional 14 days. All treatments caused an increase in urine volume and sodium excretion and a decrease in interdialysis weight gain. Torsemide 100 mg was at least as effective as frusemide 250 mg.

From the results of these short-term trials, torsemide would appear to be a valuable alternative to frusemide for patients with advanced renal failure.

References
1. J Cardiovasc Pharmacol 1993; 22 (Suppl 3): S59-S70
2. Drugs 1991; 41(1): 81-103

Powerful loop diuretics are useful in severely oliguric, acutely ill patients with potential or established acute renal failure. Even the most oliguric patient will respond to high dose loop diuretic with a few extra milliliters of urine, irrespective of the cause. Studies on the role of loop diuretics in patients with acute renal failure (ARF) are largely retrospective, anecdotal, and poorly controlled.

To address this issue, Shilliday et al (1,2) conducted a prospective, randomized, double-blind, placebo-controlled study in 92 patients with ARF. All patients received intravenous dopamine, 2 micrograms/kg body weight/min throughout, 20% mannitol, 100 ml every 6 h for the first 3 days, and, in a double-blind manner, either torsemide, frusemide, or placebo, 3 mg/kg body weight I.V. every 6 h for 21 days or until renal recovery or death. Results indicated that patients given a loop diuretic had a significant rise in urine flow rate in the first 24 h compared to placebo. Based on the urine flow rate during the first post-medication day, patients were divided into two groups -- oliguric (< 50 ml/h) and non-oliguric (> 50 ml/h). Non-oliguric patients had a significantly lower mortality than oliguric patients (43% vs 69%, p = 0.01). However, they were less ill and had less severe renal failure at entry (creatinine clearance 14 ml/min vs 4 ml/min, p < 0.0001). The authors concluded that although there is no evidence that these drugs can alter outcome, the use of loop diuretics in oliguric patients with ARF results in diuresis. In a detailed review, Russo et al (3) also concluded that loop diuretics do not affect the mortality rate for ARF but may facilitate the treatment of patients by reverting an oliguric form to a non-oliguric form of ARF.

References
1. J Cardiovasc Pharmacol 1993; 22 (Suppl 3): S59-S70
2. Nephrol Dial Transplant 1997; 12(12): 2592-2596
3. Clin Nephrol 1992; 38 (Suppl 1): S69-S73

Torsemide has been generally well tolerated, with only a small percentage of patients having mild, transient adverse effects. Torsemide is potassium sparing in nature and it minimizes hypokalemia: this is attributable to its aldosterone-inhibiting property.(1) Unlike frusemide, torsemide is excreted mainly via the hepatic route; hence high doses up to 100-200 mg in advanced chronic renal failure may be used without the risk of drug accumulation and toxicity. (2)

References
1. Eur J Pharmacol 1991; 205: 145
2. Cardiology 1994; 84 (Suppl): 155-161