Long-term Furosemide Therapy Research Articles

Is furosemide a nephrotoxic for hospitalized patients?

Introduction: Acute kidney disease (AKI) is preventable in certain situations. Long-term and/or high dose furosemide may lead to acute kidney injury. Objectives: We aimed to find the risk of AKI among hospitalised patients who were exposed to furosemide. Patients and Methods: This is a retrospective cohort study of hospitalised patients who received furosemide therapy during the admission between 2019 and 2021. Exposure to furosemide was grouped into low dose (≤ 40 mg/d) or high dose (>40 mg/d) and short-term use (≤ 72 hours) or long-term use (>72 hours). Risk of acute kidney injury was calculated as odds ratios with a 95% confidence interval (CI). A P value <0.05 was considered statistically significant. Results: Of 314 patients who received furosemide intravenously or orally, 197 patients (62.7%) had acute kidney injury. Of 197 patients with acute kidney injury, 110 patients (55.9%) received the dosage of >40 mg/d and 121 patients (61.4%) were on furosemide for >7 days (odds ratios [ORs]: 5.46, 95% CI: 3.17 to 9.39, P≤0.001 and ORs: 7.72, 95% CI: 4.4 to 13.52, P≤0.001). In comparison, the 87 (44.1%) patients who received ≤40 mg/d of furosemide had a lower incidence of AKI (ORs: 0.25, 95% CI: 0.13 to 0.48, P≤0.001) and only 21 of the patients (10.6%) who received furosemide for < 7 days were found to have acute kidney injury (ORs: 0.08, 95% CI: 0.04 to 0.14, P≤0.001). The combined effect of high dose and long-term furosemide therapy is more consequential as we found that 100 (31.8%) patients who received furosemide >40 mg for >72 hours, 96 patients (30.6%) developed AKI (ORs: 26.8, 95% CI: 9.53 to 75.63, P≤0.001). Conclusion: Among hospitalised patients, exposure to high dose furosemide or prolonged use of furosemide is associated with AKI. The risk is more when high dose furosemide is administered for longer than 72 hours. Presence of underlying diabetes, hypertension, cardiac failure and chronic kidney disease, are also associated with furosemide -induced hospital-acquired acute kidney injury.

Potentially inappropriate use of furosemide in a very elderly population: An observational study.

Little is known about furosemide prescription modalities in elderly people. We describe furosemide prescription in ambulatory elderly patients. All patients aged over 80years, affiliated to Mutualité Sociale Agricole de Bourgogne, a French regional health insurance plan, with a medical prescription delivered in March 2015, were retrospectively included. Among 15141 patients with a median age of 86years, comprising 61.3% of women, 3937 patients (26%) had a prescription for furosemide. Severe heart failure was the most common chronic comorbidity (27.7%). Furosemide was considered a long-term therapy for almost all patients (98.7% with prescriptions for 3months or more). Recommended indications for long-term furosemide therapy included severe heart failure (50.9%), chronic nephropathy (3%) and cirrhosis (0.1%). The furosemide prescription rate increased with age (81-85: 20.4%, 86-90: 28.5%, 91-95: 35.6%, >95: 42.7%, P<.001), and the increase was associated with a decrease in recommended heart failure therapeutics (beta-blockers, angiotensin-conversion-enzyme-inhibitors or angiotensin-receptor-blockers). Prescribers were mostly general practitioners (81.3%). Plasma electrolytes were controlled in less than a half of the patients with furosemide. In this large study, long-course furosemide was prescribed in a quarter of ambulatory patients. Half of those taking furosemide suffered from severe heart failure. Age was associated with a linear increase in furosemide use and a decrease in recommended heart failure therapeutic prescriptions. A large part of these prescriptions do not seem to be in accordance with recommendations.

Does medical therapy influence the size of the syrinx in dogs with Chiari‐like malformation/syringohydromyelia complex?

I wish to report on the effect of medical management on progression of syringohydromyelia (SHM) in cavalier King Charles spaniels with Chiari-like malformation (CM). Seven cavalier King Charles spaniels (age: 1 to 5 years; mean, 2·3 years) with history, clinical signs and MRI findings suggestive of Chiari malformation/syringohydromyelia received long-term (0·5 to 4·5 years; mean, 2·8 years) furosemide therapy (dose: 0·8 to 2 mg/kg twice daily; mean, 1·1 mg/kg twice daily) and had repeat MRI scans between 0·5 and 4·5 years (mean, 2·8 years) after diagnosis. Additional oral medications (gabapentin, corticosteroids and omeprazole) were prescribed when furosemide failed to control the clinical signs associated with CM/SHM complex. In all seven dogs, syrinx width and length increased at the follow-up MRI and in four cases a new syrinx had developed (Table 1). Furosemide did not prevent further syrinx expansion nor reduce the size of the syrinx but it remains unknown whether the medical treatment may have delayed the inevitable expansion of the syrinx. Studies of a larger population and prospective, randomised, blinded comparisons between different treatments (medical, surgical, medical vs surgical) are needed to ascertain which will produce the best clinical results. L. Motta Chester Gates Veterinary Specialists (CVS UK LTD), Chester, Cheshire, CH1 6LT

Renal Calcification in NICU Patients

Sequential renal ultrasonographic studies have shown renal calcifications to be more common in neonatal intensive care unit (NICU) patients than is commonly believed, especially in extremely low-birthweight (ELBW) infants. A family history of kidney stones is an independent risk factor for renal calcifications in ELBW infants. Understanding the role of inhibitors and promoters in crystal formation helps in understanding the pathophysiology of nephrocalcinosis. Identification of the presence or absence of hypercalcemia and hypercalciuria is an effective method of directing the diagnostic evaluation of infants who have nephrocalcinosis. Fortunately, ultrasonographic renal calcifications resolve spontaneously in most NICU patients. Renal calcifications can be associated with persistent abnormalities in renal function if hypercalciuria continues, such as in the rare very low-birthweight (VLBW) infant who receives long-term furosemide therapy after hospital discharge. Only in rare cases, often inborn errors of metabolism, can renal calcifications in NICU patients progress to chronic renal injury, such as in infants who have primary hyperoxaluria that involves persistence of oxalate in the urine, a potent promoter of calcium crystal formation.

Microscopic nephrocalcinosis and hypercalciuria in nephrotic syndrome

Focal calcification is an occasional tubular abnormality seen in minimal-change nephrotic syndrome. Nephrocalcinosis was also reported in premature infants as a consequence of hypercalciuria resulting from long-term furosemide therapy. We describe 4 nephrotic children (3 minimal change, 1 diffuse proliferative glomerulonephritis) with transient hypercalciuria and intraluminal calcifications in renal histopathological specimens without radiologic evidence of renal calcification. These children were resistant to corticosteroid therapy and were receiving furosemide therapy along with albumin for management of oedema. Two of the children also had urinary infection. We were concerned that children with nephrotic syndrome are at risk for nephrocalcinosis, and urinary calcium and pH should be monitored carefully during prolonged furosemide use, especially in children with nephrotic syndrome with reduced initial responsiveness to corticosteroid therapy. HUM PATHOL 31:1363:1367.

Inhaled furosemide is not effective in severe asthma in children

The purpose of the present study was to determine whether or not inhaled furosemide has any therapeutic benefit in acute asthma in children. Aerosolized furosemide (20 mg) was administered four times per day together with conventional asthma therapy for 2 days in five children with severe asthma exacerbation. The oxygen saturation with a pulse oximeter (SpO2), and the peak expiratory flow (PEF) were measured before and 10 min after furosemide inhalation. Although a little improvement in SpO2 and PEF was observed after the furosemide inhalation, the results were inferior to those with an inhaled β2-agonist (procaterol hydrochloride). Long-term furosemide therapy was performed in two cases; however, amelioration of the SpO2 levels (> 90%) and PEF (> 80% of personal best) was not observed within 8 days of medication with furosemide. It is concluded that inhaled furosemide is not of additional benefit in children with severe exacerbation of asthma.

Effects of hydrochlorothiazine and furosemide diuretics on human bone marrow stromal osteoprogenitor cells

Thiazide diuretics have been shown to decrease bone loss and improve bone mineral density, while long-term furosemide therapy has been suggested to decrease bone mineral content. However, the direct effects of these diuretics on osteoblastic cells are not well established. Some investigators have reported direct effects of thiazides on osteoblastic cells but the results remain controversial, and there are few data about the direct effect of furosemide on osteoblastic cells. We investigated the effects of hydrochlorothiazide (HCTZ) and furosemide on proliferation, alkaline phosphatase activity, osteocalcin, and interleukin-6/interleukin-11 (IL-6/IL-11) secretion in cultured normal human bone marrow stromal osteoprogenitor cells (hBMSCs). Treatment with HCTZ or furosemide for 24 hours in the concentration range of 10(-6) to 10(-4) mol/L did not affect 3H-thymidine incorporation in hBMSCs. Cellular alkaline phosphatase activity and osteocalcin production were not changed significantly by treatment with HCTZ or furosemide (up to 10(-4) mol/L) during culture. There was also no significant difference in IL-6 and IL-11 production in hBMSCs. These results suggested that HCTZ or furosemide had no significant direct effect on proliferation, alkaline phosphatase activity, osteocalcin, and IL-6/IL-11 production in hBMSCs, and the effects of these diuretics on bone mass may be related to the indirect action on calcium balance.

Urinary thiamine excretion in the rat: Effects of furosemide, other diuretics, and volume load

Long-term furosemide therapy is associated with increased urinary loss of thiamine. To examine the mechanism of furosemide-induced urinary thiamine loss, we measured urinary excretion of thiamine in rats in response to increasing doses of furosemide, acetazolamide, chlorothiazide, amiloride, mannitol, and extracellular fluid (ECF) volume loading by saline infusion. All animals were in normal thiamine balance as reflected by a thiamine pyrophosphate effect (TPPE) of 2.25% ± 0.60% (mean ± SEM), and all had normal renal function. Urinary flow increased in response to diuretic administration in a dose-dependent manner, reaching (mean) peak urinary flow rates of 283 to 402 μL/min. Fractional excretion of sodium (FENa) exhibited the same pattern, reaching peak values of 12.3% to 23.2%. Urinary thiamine excretion increased in proportion to the incremental doses of diuretic agents, reaching (mean) maximal values of 7.44 to 9.34 pmol/min, with no significant difference (P = .11) between the various diuretics tested nor in response to saline loading. None of the diuretics tested differed in the effect on thiamine excretion, which was clearly flow dependent and only partially related to fractional sodium excretion. Urinary flow rate, being the single significant predictor, explained 78% (R2 = 0.78) of the variability in thiamine excretion rates. These findings indicate that urinary thiamine loss is caused by a nonspecific, flow-dependent mechanism common to all of the diuretics tested.

Non-furosemide-related renal calcifications in premature infants with bronchopulmonary dysplasia.

Renal calcification is a known complication of long-term furosemide therapy in infants with bronchopulmonary dysplasia (BPD). In a prospective study the clinical course and long-term renal sequelae of renal calcifications of 19 consecutive premature neonates (birthweight < 1250 g) with bronchopulmonary dysplasia who did not receive furosemide were examined. Infants were divided into two different groups on the basis of ultrasound evidence of renal calcifications (RC group) or absence of renal calcifications (NRC group). Serial examinations, performed at the age of 1, 2, 3, 6, 9 and 12 months, showed that 12 infants at the mean age of 68.5 +/- 12.8 days of life had renal calcifications (63%), and 3 of them had nephrolithiasis; 8 had bilateral renal calcifications. Among the 9 survivors, 2 had chronic renal calcifications at the age of 9 months; however, all normalized at the age of 12 months. Twelve infants received hydrochlorothiazide and spironolactone (63%), 17 had prolonged courses of xanthines and dexamethasone (89.5%), while furosemide was not part of the routine pharmacological administration. Statistical analysis showed that birthweight, gestational age, Apgar score and length of parenteral nutrition were comparable in the RC and NRC group infants. Mean serum creatinine, creatinine clearance, fractional sodium excretion and urinary calcium excretion values during the 12-month study period were comparable in the RC and NRC groups. Mechanical ventilation and hospital stay length were instead associated with renal calcification occurrence. The strongest indicator of renal calcification risk for this high-risk population is the severity of the unresolved acute lung disease, where different facets of respiratory management, other than the addition of furosemide, represent sufficient stimuli and renal injury to potentiate stone formation.

Renal Calcification in the First Year of Life

The introduction of renal ultrasound technology has shown renal calcification to be more common in infancy than was previously believed. Understanding the role of inhibitors and promoters in crystal formation helps elucidate the pathophysiology of nephrocalcinosis. Identification of the presence or absence of hypercalcemia and hypercalciuria is an effective way to direct the diagnostic work-up of infants with nephrocalcinosis. The sonographic image of renal calcification resolves spontaneously in many infants. Whether microscopic nephrocalcinosis persists below the threshold of ultrasonographic detection is unknown. Renal calcification can be associated with persistent renal function abnormalities if hypercalciuria continues, such as in VLBW infants who receive long-term furosemide therapy after discharge from the hospital. Renal calcification may also progress to renal failure, such as in infants with primary hyperoxaluria, owing to the persistence of hyperoxaluria, a potent promoter of calcium crystal formation.

Adjuvant thiamine beneficial in long-term furosemide therapy

Adjuvant thiamine beneficial in long-term furosemide therapy

Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy

We have previously found thiamine (vitamin B1) deficiency in patients with congestive heart failure (CHF) who had received long-term furosemide therapy. In the present study, we assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF) in patients with moderate to severe CHF who had received furosemide in doses of 80 mg/d or more for at least 3 months. Thirty patients were randomized to 1 week of double-blind inpatient therapy with either i.v. thiamine 200 mg/d or placebo (n = 15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/d as outpatients for 6 weeks. Thiamine status was determined by the erythrocyte thiamine-pyrophosphate effect (TPPE). LVEF was determined by echocardiography. TPPE, diuresis, and LVEF were unchanged with i.v. placebo. After i.v. thiamine, TPPE decreased (11.7% +/- 6.5% to 5.4% +/- 3.2%; P < 0.01). LVEF increased (0.28 +/- 0.11 to 0.32 +/- 0.09; P < 0.05), as did diuresis (1,731 +/- 800 mL/d to 2,389 +/- 752 mL/d; P < 0.02), and sodium excretion (84 +/- 52 mEq/d to 116 +/- 83 mEq/d, P < 0.05). In the 27 patients completing the full 7-week intervention, LVEF rose by 22% (0.27 +/- 0.10 to 0.33 +/- 0.11, P < 0.01). Thiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving longterm furosemide therapy.

Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: A pilot study

purpose: To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. design: (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. setting: General medical ward of a teaching community hospital. patients: Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. intervention: A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. results: A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p < 0.001). The mean (± SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 ± 2.5% and 7.1 ± 1.6%, respectively (p <0.001). Despite the high TPPE, the mean (± SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 μg/g creatinine), 410 ± 95 μg/g creatinine, even in comparison with that in the controls (n = 14): 236 ± 69 μg/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (± SE) of 27.0 ± 3.8% to 4.5 ± 1.3% (p <0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. conclusion: These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Short- and long-term effects of furosemide on lung function in infants with bronchopulmonary dysplasia

Although furosemide improves lung mechanics in some infants with broncho-pulmonary dysplasia (BPD), this may not be important unless gas exchange also improves. To determine the relationship between improvement in mechanics and improvement in gas exchange, the short- and long-term effects of furosemide therapy were studied in 16 spontaneously breathing infants with severe BPD who were both oxygen dependent and hypercarbic (mean PCO2 54 +/- 11 torr). Each infant was examined at least three times: before furosemide therapy, 1 hour after the first dose of furosemide, and after a 6- to 10-day course. Ten of the 16 infants were also examined three times during a 7-day control period. Transcutaneous PO2 and PCO2, esophageal pressure, air flow, and tidal volume were measured. Pulmonary resistance, lung compliance, and the alveolar to skin PO2 difference were calculated. After a single dose of furosemide, only compliance significantly improved. After prolonged therapy, compliance, resistance, and oxygenation significantly improved in the group as a whole, but better oxygenation was achieved in only six of 16 infants. tcPCO2 was unaffected by long-term furosemide therapy, but in all infants with decreased tcPCO2 1 hour after a single dose, there was sustained decrease in PCO2 after prolonged therapy. Changes in gas exchange were not explained by changes in lung mechanics. These data indicate that long-term diuretic therapy can improve the mechanical properties of the lungs of spontaneously breathing infants with BPD, but that gas exchange is usually unaffected.

Secondary hyperparathyroidism and bone disease in infants receiving long-term furosemide therapy.

Four preterm infants receiving long-term furosemide therapy were examined for hypercalciuria, hyperparathyroidism, renal calcification, and bone demineralization. All four infants had increased urinary calcium excretion. Three infants had high serum concentrations of parathyroid hormone, and in these three infants, bone mineral content was below the mean of "osteopenic" preterm infants of comparable gestational and postnatal age. In two of these infants, there was ultrasound evidence of renal calcification. In one infant, autopsy disclosed bone changes of hyperparathyroidism, gallstones, and calcification in the heart and kidney.

Renal Calcification in Premature Infants

To the Editor.— Hufnagle et al1 reported on ten premature infants who developed renal calcifications while receiving long-term furosemide therapy for bronchopulmonary dysplasia. A similar case has been reported,2 and I have been informed of another premature male infant with bronchopulmonary dysplasia who developed a left renal calculus while receiving chronic furosemide therapy. At six months of age, the infant developed hydronephrosis, which required nephrostomy for decompression and removal of the calculus (N. Visveshwara, personal communication, 1982).

Renal Calcifications: A Complication of Long-Term Furosemide Therapy in Preterm Infants

During the last four years ten premature infants developed renal calcifications while receiving long-term furosemide therapy. The drug was used in infants with present ductus arteriosus and later in the same infants with chronic lung disease. They had received furosemide in a dose of at least 2 mg/kg/day for at least 12 days before calcifications were noted on abdominal roentgenograms. Calcifications included small flecks, isolated stones, staghorn calculi, and nephrocalcinosis. Analysis of stones received from our infants showed calcium oxalate and calcium phosphate. Infants who were not receiving furosemide had no calcifications. The infants with renal calcifications had rates of calcium excretion ten to 20 times that of normal, age-matched premature infants in our nursery. When chlorothiazide was given to the infants, in addition to furosemide, a four- to 15-fold decrease in calcium excretion and a radiologic dissolution of the renal calcifications were documented. It is concluded that furosemide, in doses of at least 2 mg/kg/day for at least 12 days can be associated with renal calcifications. The probable mechanism of the stone formation is hypercalciuria, primarily caused by furosemide.

Renal Calcifications: A Complication of Long-Term Furosemide Therapy in Preterm Infants

During the last four years ten premature infants developed renal calcifications while receiving long-term furosemide therapy. The drug was used in infants with present ductus arteriosus and later in the same infants with chronic lung disease. They had received furosemide in a dose of at least 2 mg/kg/day for at least 12 days before calcifications were noted on abdominal roentgenograms. Calcifications included small flecks, isolated stones, staghorn calculi, and nephrocalcinosis. Analysis of stones received from our infants showed calcium oxalate and calcium phosphate. Infants who were not receiving furosemide had no calcifications. The infants with renal calcifications had rates of calcium excretion ten to 20 times that of normal, age-matched premature infants in our nursery. When chlorothiazide was given to the infants, in addition to furosemide, a four- to 15-fold decrease in calcium excretion and a radiologic dissolution of the renal calcifications were documented. It is concluded that furosemide, in doses of at least 2 mg/kg/day for at least 12 days can be associated with renal calcifications. The probable mechanism of the stone formation is hypercalciuria, primarily caused by furosemide.