An observational study in Chronic Kidney Diseases and Renal Failure Chronic, sponsored by UMC Utrecht. Recruiting at 1 site in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-12-27.
Sponsored by UMC Utrecht · Observational
The goal of this observational study is to examine the interaction between the diuretic furosemide and certain toxins called protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD). The main question it aims to answer is: what is the effect of furosemide on plasma levels of PBUTs in patients with CKD? Besides, the investigators will also look at the effect of furosemide on the excretion of PBUTs via the urine.
Participants will be included in the study once they will be prescribed furosemide as part of routine patient care. Before they start with the furosemide treatment, patients will undergo the following:
Then, one to four weeks after starting with furosemide treatment, patients will undergo the following:
The investigators expect furosemide to increase plasma levels of PBUTs by decreasing the renal excretion of the toxins.
Protein-bound uremic toxins are known to accumulate in chronic kidney disease (CKD) and are associated with increased morbidity and mortality. It is therefore crucial to maintain the PBUT levels low in this patient group. Furosemide is often prescribed to CKD patients. However, based on preclinical data, furosemide could affect the renal excretion of PBUTs, either by competing for binding to albumin or by competing for the secretory system in the kidney. It is important to examine the effect of furosemide on the excretion and plasma concentration PBUTs as this might have harmful consequences for patients with CKD.
This study aims to examine the effect of furosemide PBUT plasma levels in patients with CKD as well as the renal PBUT excretion. The investigators expect furosemide to increase plasma levels of PBUTs by decreasing the renal excretion of the toxins.
This study is observational and includes invasive measurements; a prospective repeated measures cohort study design will be used in which PBUT plasma concentrations and excretion will be determined before and after the start of furosemide treatment.
The study population consists of patients with CKD stage 3-5 (\<60 mL/min/1.73m2 for at least three months) who have an indication for furosemide treatment as part of routine patient care. Participants will receive furosemide in a dosage prescribed by their nephrologist as part of their routine patient care; this treatment is not changed by the participation of patients in the study.
A power analysis for a paired samples T-Test was done using GPower (version 3.1.9.4). Data regarding PBUT plasma levels from the study of Tang et al. in 2021 was used in order to calculate the sample size; PCS plasma levels before (average ± standard deviation: 13,481 ± 12,642 nM) and after (average ± standard deviation: 23,000 ± 24,900 nM) furosemide intake were chosen, since PCS is one of the main PBUTs of interest. This calculation showed a required sample size of 34 (one-tail, power = 80%, α = 0.05, d = 0.44, correlation between samples 0.5 based on assumption).
Prior to the start of the furosemide treatment, a blood sample (three tubes/11 mL per withdrawal) and a urine sample will be collected from patients enrolled in the study. Participants will also hand in a 12-hour urine collection and their blood pressure will be measured.
After the start of the furosemide treatment (at least one week after the start of the furosemide treatment so that steady state has been reached), two blood samples, one urine sample, and a 24-hour urine collection will be obtained. Participants will be asked to obtain a 12-hour urine collection and to bring this with them on the day the of the visit. During the visit at the University Medical Center Utrecht, participants will first hand in the 12-hour urine collection and their blood pressure will be measured. Furthermore, a blood sample will be taken prior to the furosemide intake (Tmin). Then, they will take their prescribed furosemide at around the same time as they normally take their medication. 60 minutes after the furosemide intake, participants will be asked to empty their bladder and drink two glasses of water. Then, at Tmax, a blood sample will be collected. Tmax is estimated at around 90 minutes after oral intake; therefore, the target time of sample collection is 90 min with an acceptable range between 60-120 minutes after furosemide intake. Furthermore, a urine sample will be collected between 60 and 120 minutes after furosemide intake in order to best examine the effect of furosemide on PBUT excretion. The exact time of furosemide intake and the time of the blood and urine sample collection will be registered.
The main endpoints of this study are PBUT plasma levels before and 1-4 weeks after the start of furosemide treatment (in a steady state).
Baseline characteristics and study parameters will be presented as either a mean with standard deviation or a median with interquartile range for continuous data, or as a percentage for categorical data. Results with a p\<0.05 will be considered statistically significant. Analyses will be done using the statistical software platforms SPSS and R. Missing data will be excluded from the analyses via pairwise deletion.
Participants will only receive furosemide prescribed by their treating nephrologist as part of routine patient care. In addition, three blood sample drawings, two urine samples, and two 12-hour urine collections will be needed. Thus, the risk associated with participation is negligibly low. Participation to the study will include two site visits. These visits will be combined with routine check-ups as much as possible.
3,840 studies on the registry are indexed under Kidney Diseases; 500 are open to participants now.
This study's planned enrollment of 34 is below the median of 192 across 1,033 observational studies indexed under Kidney Diseases.
Browse Kidney Diseases studies →UMC Utrecht is the lead sponsor of 350 studies on the registry; 80 are open to participants now.
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The study population will consist of patients with CKD stage 3-5 (eGFR \<60 mL/min/1.73m2) of 18 years and older with an indication for starting treatment with furosemide as part of routine patient care. Participants will be recruited at the Department of Nephrology in the University Medical Center Utrecht (UMCU, Utrecht, The Netherlands) who have not yet started furosemide treatment or any renal replacement therapy.
Exclusion Criteria:
Participants with an age of 18 years or older and with CKD stage 3-5 (an estimated glomerular filtration rate of 60 mL/min/1.73m\^2 or lower for at least three months). Participants need to have an indication to start with furosemide as part of routine patient care.
Diagnostic Test: Invasive measurements
Blood and urine samples will be collected during the study.
Plasma levels of the PBUT indoxyl sulfate
Indoxyl sulfate plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT p-cresyl sulfate
P-cresyl sulfate plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three time during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT indole-3-acetic acid
Indole-3-acetic acid plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT kynurenic acid
Kynurenic acid plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT L-kynurenine
L-kynurenine plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT hippuric acid
Hippuric acid plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Plasma levels of the PBUT p-cresyl glucuronide
P-cresyl glucuronide plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Surrogate for PBUT clearance
This will be calculated for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment using the following formula: Urine PBUT concentration / (urine creatinine concentration \* plasma PBUT concentration)
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Fractional PBUT excretion
This will be calculated for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment using the following formula: (Urine PBUT concentration \* plasma creatinine concentration) / (urine creatinine concentration \* plasma PBUT concentration)
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
PBUT protein binding
This will be determined for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment by determining the total PBUT plasma concentration and the free fraction of the PBUTs.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Ratio of the surrogate PBUT clearance / CKD-EPI creatinine equation
This will be calculated for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment using the following formulas: For surrogate of PBUT concentration: Urine PBUT concentration / (urine creatinine concentration \* plasma PBUT concentration) For CKD-EPI creatinine equation: eGFR (in mL/min/1.73m\^2) = 142\* Min(Scr/K, 1)\^α \* Max(Scr/K, 1)\^-1.200 \* 0.9938\^Age (in years) \* 1.012 \[if female\] In which: eGFR = estimated glomerular filtration rate Scr = serum creatinine in mg/dL K = 0.7 for females, 0.9 for males α = -0.241 for females, -0.302 for males Min(Scr/K, 1) = the minimum of Scr/K or 1 Max(Scr/K, 1) = the maximum of Scr/K or 1
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Ratio of the surrogate PBUT clearance / CKD-EPI cystatin C equation
This will be calculated for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment using the following formulas: For surrogate of PBUT concentration: Urine PBUT concentration / (urine creatinine concentration \* plasma PBUT concentration) For CKD-EPI cystatin C equation: eGFR (in mL/min/1.73m\^2) = 133 \* Min(Scys/0.8, 1)\^-0.499 \* Max(Scys/0.8, 1)\^-1.328 \* 0.996\^Age (in years) \* 0.932 \[if female\] In which: eGFR = estimated glomerular filtration rate Scys = serum cystatin C in mg/L Min(Scys/0.8, 1) = the minimum of Scys/0.8 or 1 Max(Scys/0.8, 1) = the maximum of Scys/0.8 or 1
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Ratio of the surrogate PBUT clearance / CKD-EPI creatinine-cystatin C equation
This will be calculated for seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) before and after start of furosemide treatment using the following formulas: For surrogate of PBUT concentration: Urine PBUT concentration / (urine creatinine concentration \* plasma PBUT concentration) For CKD-EPI cystatin C equation: eGFR (in mL/min/1.73m\^2) = 135 \* Min(Scr/K, 1)\^α \* Max(Scr/K, 1)\^-0.544 \* Min(Scys/0.8, 1)\^-0.323 \* Max(Scys/0.8, 1)\^-0.778 \* 0.9961\^Age (in years) \* 0.963 \[if female\] In which: eGFR = estimated glomerular filtration rate Scr = serum creatinine in mg/dL Scys = serum cystatin C in mg/L K = 0.7 for females, 0.9 for males α = -0.219 for females, -0.144 for males Min(Scr/K, 1) = the minimum of Scr/K or 1 Min(Scys/0.8, 1) = the minimum of Scys/0.8 or 1 Max(Scr/K, 1) = the maximum of Scr/K or 1 Max(Scys/0.8, 1) = the maximum of Scys/0.8 or 1
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Baseline characteristics: age
Age (in years) will be documented during the first study visit.
Time frame: This will be collected once throughout the study participation period (between 1-4 weeks) during the first study visit.
Baseline characteristics: sex
Sex (male/female/other) will be documented during the first study visit.
Time frame: This will be collected once throughout the study participation period (between 1-4 weeks) during the first study visit.
Baseline characteristics: BMI
BMI (calculated from length and weight in kg/m\^2) will be documented during the first study visit.
Time frame: This will be collected once throughout the study participation period (between 1-4 weeks) during the first study visit.
Prescribed dosage of furosemide
The prescribed dosage of furosemide (including frequency of intake and dosage per intake) will be collected during the first study visit.
Time frame: This will be collected once throughout the study participation period (between 1-4 weeks) during the first study visit.
Comorbidities and underlying cause of renal disease
Data regarding comorbidities and underlying cause of renal disease of participants will be collected during the first study visit.
Time frame: This will be collected once throughout the study participation period (between 1-4 weeks) during the first study visit.
Medication usage
Medication usage of the participant will be assessed at both study visits.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Blood pressure measurements
Blood pressure (systolic and diastolic, in mmHg) will be measured before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Postprandial or fasting state
Postprandial/fasting state will be assessed at the time of blood and urine sample collection before and after start of furosemide treatment. This means that participants will be asked whether they have eaten prior to the sample collection (in the morning). If so: postprandial state. If not: fasting state.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Intake of prescribed medication
Intake of prescribed medication will be assessed at the time of blood and urine sample collection before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Furosemide plasma and urine levels
Furosemide plasma and urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times in plasma and four times in urine (also in 12-hour urine collections) during the study participation period (between 1-4 weeks).
Cystatin C plasma and urine levels
Cystatin C plasma and urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times in plasma and two times in urine during the study participation period (between 1-4 weeks).
Bicarbonate plasma levels
Bicarbonate plasma levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
Neutrophil Gelatinase-Associated Lipocalin (NGAL) urine levels
NGAL urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Kidney Injury Molecule-1 (KIM1) urine levels
KIM1 urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Beta-2 microglobulin urine levels
Beta-2 microglobulin urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Albumin plasma and urine levels
Albumin plasma and urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed three times in plasma and four times in urine (also in 12-hour urine collections) during the study participation period (between 1-4 weeks).
Total protein urine levels
Total protein urine levels will be determined before and after start of furosemide treatment.
Time frame: This will be assessed four times (also in 12-hour urine collection) during the study participation period (between 1-4 weeks).
Fractional urea excretion
Fractional urea excretion will be calculated before and after start of furosemide treatment. This will be calculated using the following formula: (Urine urea concentration \* plasma creatinine concentration) / (urine creatinine concentration \* plasma urea concentration)
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Urine pH
Urine pH will be determined before and after start of furosemide treatment.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Furosemide protein binding
This will be determined before and after start of furosemide treatment by determining the total furosemide plasma concentration and the free fraction of furosemide.
Time frame: This will be assessed three times during the study participation period (between 1-4 weeks).
PBUT levels in the 12-hour urine collections
Urine levels of seven PBUTs (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, kynurenic acid, L-kynurenine, hippuric acid, p-cresyl glucuronide) will be determined in the 12-hour urine collections.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Creatinine levels in the 12-hour urine collections
Urine levels of creatinine will be determined in the 12-hour urine collections.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Urea levels in the 12-hour urine collections
Urine levels of urea will be determined in the 12-hour urine collections.
Time frame: This will be assessed twice during the study participation period (between 1-4 weeks).
Plan to share: Yes — The data package will contain: the raw data, the study protocol describing the methods and materials, the script to process the data, the scripts leading to tables and figures in the publication, a codebook with explanations on the variable names, and a 'read_me.txt' file with an overview of files included and their content and use. All data and documents in the data package will be shared under restrictions. The publication will be openly assessable. The study protocol and this Data Management Plan will also be available.
Supporting information: Study protocol, Sap, Icf, Csr, Analytic code
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