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We enrolled participants from three UNC-affiliated outpatient dialysis clinics between October 2020 and January 2021, with the last follow-up on June 1, 2021. Study inclusion criteria were: age ≥18 years, treatment with thrice-weekly maintenance hemodialysis for ≥60 days, and urine volume of at least one cup (250 mL) of urine/24 hours by self report. Major exclusion criteria were: a) allergy to loop diuretic; b) use of a non-loop diuretic; c) use of a medication or substance that can interact with loop diuretics (e.g., aminoglycosides, cisplatin, methotrexate, lithium, natural licorice); d) pre-dialysis serum potassium <3.5 mEq/L, magnesium <1 mg/dL, or corrected calcium <8 mg/dL in the 30 days before enrollment; e) cirrhosis; f) pregnancy or breastfeeding; g) known hearing impairment; h) history of poor adherence to hemodialysis; i) ≥1 hospitalization in the 30 days before enrollment; and j) frequent hypotension defined as a systolic blood pressure <80 mmHg in >30% of hemodialysis sessions in the 30 days before enrollment.
Intervention and Treatment AlgorithmThe study consisted of a 6-week dose titration period of oral furosemide and a 12-week follow-up period (Figure 1). During the dose titration period, participants who were not taking a loop diuretic at study enrollment received 80 mg oral furosemide two times per day (BID) for 14 days and then, if the dose was tolerated, 120 mg BID for 14 days and then, if the dose was tolerated, 160 mg BID for 14 days. Participants who were taking a loop diuretic at study enrollment received their baseline furosemide dose (or furosemide-equivalent dose for those taking bumetanide or torsemide) for 14 days. If the starting furosemide dose was tolerated, the dose was increased by 50% for 14 days, and then, if tolerated, the new dose was increased by 50% for 14 days. The maximum furosemide dose for any participant was 320 mg/day. During the 12-week follow-up period, participants remained on the maximally tolerated furosemide dose achieved during the dose titration period. Furosemide was dispensed in 20, 40, and 80 mg strength tablets by the UNC Health Investigational Drug Services.Figure 1Study design. a During the 6-week dose titration period, participants who were not taking a loop diuretic at study entry received 80 mg furosemide twice a day for 14 days and then, if the dose was tolerated, they received 120 mg oral furosemide twice a day for 14 days and then, if the dose was tolerated, they received 160 mg oral furosemide twice a day for 14 days. During the 6-week dose titration period, participants who were taking a loop diuretic at study entry received their baseline furosemide dose (or furosemide equivalent dose for those receiving non-furosemide loop diuretics) for 14 days. If tolerated, the baseline furosemide dose was increased by 50% for 14 days, and then, if the dose was tolerated, the dose was increased by 50% for 14 days. The maximum dose for any participant was 320 mg/day. During the 12-week follow-up period, participants remained on their maximally tolerated dose from the dose titration period.
During the dose titration period there were no further dose increases if any of the following events occurred: 1) pre-dialysis serum potassium 15Mohan S. Corrales C.E. Yueh B. Shin J.J. Assessment of Disease-Specific and General Patient-Reported Outcome Measures of Hearing Health., 16Yueh B. McDowell J.A. Collins M. Souza P.E. Loovis C.F. Deyo R.A. Development and validation of the effectiveness of [corrected] auditory rehabilitation scale., 17Jessen A. Ho A.D. Corrales C.E. Yueh B. Shin J.J. Improving Measurement Efficiency of the Inner EAR Scale with Item Response Theory. and 8) intradialytic systolic blood pressure 18Flythe J.E. Xue H. Lynch K.E. Curhan G.C. Brunelli S.M. Association of mortality risk with various definitions of intradialytic hypotension. Upon the occurrence of a dose-limiting event, participants returned to the prior tolerated furosemide dose. If an event occurred at the lowest administered dose, furosemide was discontinued.Study Visits and Data CollectionAll study visits occurred during routine hemodialysis sessions. Medical history, hemodialysis prescription, medications, laboratory values, symptoms, and Inner EAR assessments were recorded at baseline. Twenty-four-hour urine collections were performed at baseline, the end of the dose titration period, and at the mid-point and end of the follow-up period for a total of four collections. Laboratory, symptom, and pill count assessments were performed on a weekly basis during the dose titration period. During the follow-up period, laboratory assessments were performed every 4 weeks, and symptom and pill count assessments were performed every 2 weeks. Symptoms were assessed with a questionnaire measuring 12 patient-reported symptoms with 5-point Likert scales (response options: none, mild, moderate, severe, very severe). The Inner EAR instrument was administered every 2 weeks during the dose titration period and every 4 weeks during the follow-up period. Information about each hemodialysis session (blood pressures, weights, ultrafiltration volumes, treatment length) and hospitalizations were extracted from the electronic health record.
Laboratory parameters were measured pre-dialysis during the mid-week dialysis session, and 24-hour urine collections occurred between the first and second dialysis sessions of the week (i.e., in the 24 hours before the Wednesday session for Monday-Wednesday-Friday patients, and in the 24 hours before the Thursday session for Tuesday-Thursday-Saturday patients). Serum furosemide levels were determined in batched measurements by liquid chromatography mass spectrometry (AB Sciex Triple Quad LC-MS/MS Systems, Framingham, MA).
OutcomesThe primary efficacy outcome was defined as: either a) an increase from baseline 24-hour urine volume of ≥25% for participants with a baseline 24-hour urine volume ≥200 mL, or b) an increase from baseline 24-hour urine volume of ≥50 mL to at least 100 mL for participants with a baseline 24-hour urine volume <200 mL. Exploratory efficacy outcomes included interdialytic weight gain (kg), delivered ultrafiltration rate (mL/hour/kg), difference between target weight and post-dialysis weight (kg), and pre-dialysis systolic blood pressure (mmHg).
Safety outcomes included: serum potassium <3.2 mEq/L, serum magnesium <0.8 mg/dL, serum corrected calcium <7 mg/dL, serum furosemide level >12 mcg/L, dialysis-associated hypotension requiring hospital treatment not attributable to other causes, rash attributable to furosemide, tinnitus attributable to furosemide, hearing change attributable to furosemide, and ≥10-point decline from baseline in Inner EAR score. Tolerability outcomes included cramping, dizziness/pre-syncope, unusual tiredness/weakness, chest pain, nausea, vomiting, and diarrhea. Acceptability was assessed by the question, “If recommended, would you be willing to stay on the dose of furosemide you have received during the last week?” Adherence to furosemide was assessed with pill counts, with “adherent” defined as returning <20% of the dispensed tablets.
Statistical AnalysesAll statistical analyses were performed using R (3.6.3 R Foundation, Vienna, Austria). Baseline characteristics are presented as count (%) for categorical variables and as mean ± standard deviation or median [quartile 1, quartile 3] for continuous variables. Categorical outcome variables are presented as the number (%) of participants with an event of interest during the specified period. In addition, we determined the number (%) of participants that experienced ≥1 outcome event during the dose titration and follow-up periods, separately, and computed the rate of outcome events per 100 person-weeks in each period. Hemodialysis session-related exploratory efficacy outcomes were reported as the median [quartile 1, quartile 3] of individual participant median values during the baseline, dose titration, and follow-up periods. Analyses were performed as intention-to-treat (i.e., all patients included regardless of study furosemide use) and, where specified, as on-treatment (i.e., patients taking study furosemide at the time of outcome ascertainment).
DiscussionPrescribing diuretics to maximize urine output is a plausible strategy for reducing volume overload, interdialytic weight gains, and ultrafiltration rates and, in turn, mitigating hemodynamic-related symptoms and cardiovascular complications in hemodialysis care. In this open label, single-arm, 18-week, dose titration pilot study among individuals with hemodialysis-dependent kidney failure who reported ≥1 cup urine output per day, we found that oral furosemide appeared to be safe and generally well-tolerated and was modestly efficacious for increasing urine output among about one-third of participants. However, the clinical significance and durability of the efficacy findings beyond 18 weeks are uncertain.
While diuretics promote urine output and may support more consistent volume control in patients with kidney failure and residual kidney function, evidence supporting the effectiveness of loop diuretics in the hemodialysis setting is weak compared to evidence in the settings of advanced chronic kidney disease and peritoneal dialysis.2Flythe J.E. Chang T.I. Gallagher M.P. et al.Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.,6St Peter W.L. Sozio S.M. Shafi T. et al.Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months.,19Usrds. 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. 2013.
To date, there have been no rigorous interventional studies of loop diuretics in hemodialysis care. Two observational studies found associations between diuretic use (vs. non-use) and lower rates of volume-related morbidity and mortality in hemodialysis-dependent kidney failure,7Bragg-Gresham J.L. Fissell R.B. Mason N.A. et al.Diuretic use, residual renal function, and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Pattern Study (DOPPS).,9Sibbel S. Walker A.G. Colson C. Tentori F. Brunelli S.M. Flythe J. Association of Continuation of Loop Diuretics at Hemodialysis Initiation with Clinical Outcomes. but potential confounding from residual kidney function and other factors limits conclusions from these data. There are also concerns about the safety and tolerability of loop diuretics. Furosemide at any dose can lead to hypokalemia, hypomagnesemia, and hypocalcemia, and high-dose furosemide can cause ototoxicity and bullous dermatosis.10Clinical Pharmacology in Diuretic Use.,12Huang X. Dorhout Mees E. Vos P. Hamza S. Braam B. Everything we always wanted to know about furosemide but were afraid to ask. While ototoxicity has not been observed with oral furosemide administered at recommended doses in the absence of interacting medication use (e.g., cisplatin, aminoglycosides),20Ototoxicity of loop diuretics. uncertainty about optimal dosing remains. The dearth of clinical trial data on furosemide effectiveness and safety is a barrier to broader use of furosemide in hemodialysis care.Although our study was small, the findings suggest that oral furosemide, up to doses of 320 mg/day, increases urine output in some patients. Approximately one-third of participants met the study definition of efficacy in the intention-to-treat analysis, with the proportion meeting the efficacy definition declining over the course of the study. While this decline could reflect decrements in response to furosemide, it is also possible that adherence to the study drug and/or completeness of 24-hour urine collections declined over the 18-week study period. In the on-treatment analysis, compared with the intention-to-treat analysis, a higher proportion of participants met the primary efficacy outcome, suggesting that the observed increase in urine output was potentially attributable to study furosemide use. In exploratory efficacy analyses, we did not detect changes from baseline in mean interdialytic weight gains, delivered ultrafiltration rates, or achievement of target weight post-dialysis. These results raise question about whether furosemide, dosed per our study protocol, can induce clinically important changes in volume-related outcomes, and whether such changes can be sustained over time. However, these findings should be considered in the context of study furosemide dosing. Because the dose of study furosemide received by participants was contingent on pre-study loop diuretic use and dose, participants achieved a range of maximum average daily study furosemide doses (69 to 320 mg/day) during the study. Almost 20% of participants had a per-protocol maximum average daily study furosemide dose of <120 mg/day. The protocol-specified dosing algorithm may have resulted in the administration of furosemide doses that were too low to trigger a physiologic response in the setting of dialysis-dependent kidney failure.
In general, furosemide appeared in our study to be safe and generally well tolerated by patients receiving maintenance hemodialysis. There were no safety events meeting the study definitions of hypokalemia, hypomagnesemia, hypocalcemia, high serum furosemide level, rash, or patient-reported hearing change. Our selection criteria excluding patients with similar events in the 30 days preceding enrollment may have reduced the risk of these events, but confirmation in future studies with broader selection criteria is warranted. One participant experienced severe tinnitus, and three participants had clinically important declines (≥10 points) from baseline in Inner EAR scores. The participant with tinnitus reported a long-standing history of this issue, and the tinnitus persisted despite discontinuation of furosemide for other reasons. The participants with Inner EAR score declines all showed improvement in scores at later timepoints while still taking study furosemide, and none reported subjective changes in their hearing. While we cannot determine if these hearing-related events were attributable to furosemide, monitoring for furosemide-induced ototoxicity is prudent, particularly when prescribing higher doses (>300 mg/day).20Ototoxicity of loop diuretics. If hearing changes are reported, patients should be evaluated with audiometry and potentially referred for otolaryngological evaluation.In addition to studying safety, we examined furosemide tolerability. Severe or very severe cramping was the tolerability event that occurred most frequently, affecting 10 participants and approximately 10% of study dialysis sessions. However, cramping may be precipitated by a range of hemodynamic, electrolyte, and neural factors and is a common intradialytic symptom, affecting approximately 50% of U.S. patients and 7% of hemodialysis sessions.21Moledina D.G. Perry Wilson F. Pharmacologic Treatment of Common Symptoms in Dialysis Patients: A Narrative Review., 22Correa S. Pena-Esparragoza J.K. Scovner K.M. Mc Causland F.R. Predictors of Intradialytic Symptoms: An Analysis of Data From the Hemodialysis Study., 23Flythe J.E. Hilliard T. Lumby E. et al.Fostering Innovation in Symptom Management among Hemodialysis Patients: Paths Forward for Insomnia, Muscle Cramps, and Fatigue. Whether furosemide precipitated the reported cramping in our study is unknown, but it is reassuring that the rate of cramping during study treatments was similar to rates reported in the broader hemodialysis population. In one participant, severe dizziness led to reduction of furosemide dose, and severe nausea/vomiting prompted furosemide discontinuation in another participant. In both instances, the symptoms improved after the furosemide was reduced/discontinued. Two participants attributed new back pain and foot pain, symptoms that are not typical of furosemide, to the study drug and opted to reduce (for back pain) and discontinue (for foot pain) furosemide. Given the frequency of dialysis-related symptoms and challenges with distinguishing study drug-induced symptoms from routine, non-drug-related symptoms, we also assessed patient willingness to continue furosemide as a marker of treatment acceptability. Overall, furosemide was largely acceptable to participants with >90% of participants on study furosemide indicating willingness to continue furosemide at the end of the 18-week study.Our study suggests that conducting a larger-scale trial of oral diuretics among patients with hemodialysis-dependent kidney failure may be feasible. Of the 51 patients meeting the eligibility criteria, 82% expressed interest in participating in the study, and 76% began study furosemide. Adherence to study procedures, including furosemide and 24-hour urine collections, was high. In addition, the efficacy findings suggest that some but not all patients who report at least one cup of urine output/day may experience increased urine output in response to oral furosemide. Similarly, not all participants tolerated the drug. Notably, >70% of dose reduction/discontinuation events occurred among participants who were not taking a loop diuretic at baseline, suggesting that individuals newly initiating furosemide may have a higher likelihood of therapy cessation. Given the modest efficacy findings, it may be important to consider a different dosing scheme and/or use of a diuretic with different pharmacokinetic properties that may have greater efficacy and be more likely to have an important clinical effect. Results also inform other aspects of the design of future randomized clinical trials. Specifically, the incorporation of a run-in period in which patient tolerance of and urine output response to a loop diuretic are established pre-randomization may enhance trial participant retention and facilitate the selection of patients most likely to have an increase in urine output, and thus, benefit clinically from furosemide. Additionally, modification of the furosemide dosing algorithm so the target dose is not linked to a pre-trial loop diuretic dose may increase the effectiveness of the intervention. Finally, more detailed information about the urine collections, such as the timing of the collection relative to furosemide dosing, as well as consideration of collections that span the entire interdialytic interval may be informative.
Our study has several strengths. The study population was racially and ethnically diverse, composed of 59% Black and 15% Hispanic participants, and baseline 24-hour urine volumes ranged from 22 to 1,400 mL. Overall, participants were adherent to study procedures, and missing data and patient dropout were minimal. However, our findings should be considered in the context of study limitations such as the small sample size, single-arm design, relatively short duration (limiting insights into the durability of the findings), and use of unsupervised 24-hour (vs. entire interdialytic period) urine collections. In addition, as discussed above, some participants received maximum furosemide doses lower than doses expected to be effective in the setting of dialysis-dependent kidney failure. Moreover, the study was not powered to detect differences in outcomes by furosemide dose nor was it designed to examine volume-related hospitalizations or mortality. Related, increases in urine volumes that met the study definition for efficacy may not result in clinically meaningful changes to interdialytic weight gain, ultrafiltration rates, and/or blood pressure. Finally, the study was conducted among patients who reported ≥1 cup urine output per day and were cared for by one academic faculty practice in North Carolina and may not generalize to other patients and/or practices.
This study indicates that oral furosemide modestly increases urine output in a subset of patients with hemodialysis-dependent kidney failure who report urine output of at least one cup per day. However, the clinical importance of this finding is uncertain. Taken together with the acceptable safety and tolerability data, this finding suggests that larger trials designed to evaluate volume-related clinical outcomes are likely feasible.
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