Diuretic Efficacy Of Torasemide In Nephrotic Syndrome:Continuous Infusion Versus Bolus Injection

BACKGROUDCeiling dose of loop diuretics is usually used on patients with NS,in which edema treatment often meets "diuretic resistance".Torasemide,a pyridine sulfonylurea class loop diuretic,has been widely used to treat severe edema disease.One fact is that the clinical pharmacological studies of torasemide indicate that delivery of the drug to the urinary side of the nephron is the predominant determinant of response;in other words,its response most closely follows urinary rather than serum drug.A continuous infusion of furosemide can maintain an amount of diuretic at the active site and can be persistently effective,for it has a relatively shorter elimination t1/2 as 30 to 60 minutes.Theoretically,torasemide,which has a relatively longer half-life(t1/2)of 3 to 6 hours after intravenous administration[1],is also persistently effective when administered as a bolus injection.However,studies referred to intravenous time of torasemide had inconsistent results.Kim YC found that urine output and urinary excretion of sodium and chloride were significantly greater when torasemide was administered as continuous infusion than that as bolus injection in rabbits.Kramer WG revealed that administration of torasemide to patients with chronic heart failure as a continuous infusion resulted in diuresis and natriuresis that was numerically but not statistically greater than that observed in bolus administration.However,the difference of diuretic response and safety of torasemide in patients with NS between continuous infusion and bolus injection administration modes is not defined.To investigate a preferable administration mode of torasemide for the patients with NS,we designed the current 2x2 crossover study to investigate the efficacy of a continuous intravenous infusion compared with the same dose of a single bolus administration in a group of patients with NS.METHODS1.PatientsThe protocol was approved by the Research Ethics Committee,Guangdong General Hospital,Guangdong Academy of Medical Sciences[No.GDREC2014247H(R1)],and registered at Chinese Clinical Trials Registry(www.chictr.org.cn,registration number:ChiCTR-IPR-15006391).All patients provided written informed consent before the start of the study.We included 31 patients with diagnosis of NS who were 18 to 70 years of age and need of diuretic treatment.The exclusion criterion included:hypotension,acute kidney injury,estimated glomerular filtration rate(eGFR)<60 mL/min,glutamate pyruvate transaminase(GPT)or glutamic oxalacetic transaminase(GOT)>40 U/L,cirrhosis,heart failure,fever,polypnea,vomit,diarrhoea,deep vein thrombosis,serious disorders of serum K+ or Na+,receiving the glucocorticoid;the significant change of serum albumin concentration or urinary albumin creatinine ratio or fractional excretion of urea et al,body weight losing>4%per day,24-hour urine volume<400 mL.2.Study DesignThe principal investigator designed the open-label,two-treatment,randomized-controlled,2×2 crossover study.According to the pharmokinetics of torasemide as previous report,a 5 times of t1/2,that is 48-hour,was defined as washout period.All patients did not receive intravenous diuretic 48 hours before study.On day 1 and day 3 of the study,which were designed as washout period,subjects received history collecting,physical examination,blood and urine test,ultrasound,and received(before 12 AM)furosemide of the same prescribed formulation or did not receive furosemide.And all patients had the normal serum electrolyte concentration after symptomatic treatment.Unified sodium intake,diet and other treatment were in the process of test.3.Assay MethodologyThe biochemical measurement was performed using Beckman Colter UniCel DXC 800 Synchron biochemical analyzer.FEUrea and FENa was analyzed according to previous described.Plasma and urine concentrations of total and unbound torasemide were measured using liquid chromatography-tandem mass spectrometry(LC-MS/MS).The free torsemide in plasma and urine were separated by ultrafiltration on Nanosep10 KDa devices.The data were processed using Analyst 1.4.2 software(AB Sciex,Foster City,CA,USA).4.Statistical analysesThe sample size was estimated before the study with the use of nQuery Advisor software.All values were expressed as mean ±SEM.p<0.05 was considered to be statistically significant among the two means for paired data with 2 treatment sequences and 2 phases,using a General Linear Models of ANOVA program in SPSS 17.0.RESULTS1.We screened 31 patients and 23 entered the study.Patients were 18 to 63 years of age and 60 to 149 mL/min per 1.73 m2 of eGFR.Minimal change disease(MCD)and membranous nephropathy(MN)were the two main renal pathological types.2.patients received torasemide by continuous infusion exhibited significantly higher daily urinary volume(1650±126 vs 1402±92 mL,p<0.05),urinary chloride excretion(173±19 vs 131±14 mmol,p<0.05),urinary sodium excretion(152 ±18 vs 118±14 mmol,p<0.05),and the FENa within 24 hours(1.27±0.28 vs 0.92±0.19%,p<0.05)than those of the patients by bolus injection.3.Patients in the group of continuous infusion exhibited a lower but no statistically significant difference of 24-hour total torasemide excretion(6.19±0.73 mg vs 7.08±0.90 mg,p>0.05)and urinary 24-hour free-state torasemide excretion compared with those in the bolus group(3.55±0.58 vs 3.46±0.60 mg,p>0.05).However,a significantly lower amount of bound torasemide excretion was found compared to that of bolus injection group(2.55±0.37 vs 3.63±0.57 mg,p<0.05).Furthermore,the ratio of urinary volume to the total torasemide excretion,which represented diuretic efficiency,was significantly higher compared to that of bolus injection group(353±58.5 vs 260±35.5 mL/mg,p<0.05).We further determined the drug plasma concentration-time profiles,and found that patients in the group of continuous infusion presented a markedly higher area under the curve(AUC)compared to that of bolus injection group(9.50±2.38 h×mg/L vs 2.86± 0.52 h×mg/L,p<0.05).CONCLUSIONOur results suggested that 2-hour continuous infusion of torasemide provided a better diuretic effect,and was a preferable administration strategy for patients with NS compared to bolus injection.