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:
* Blood pressure measurement * Blood sample withdrawal * Urine sample collection * 12-hour urine collection
Then, one to four weeks after starting with furosemide treatment, patients will undergo the following:
* Blood pressure measurement * Blood sample prior to furosemide intake (Tmin) * Blood sample withdrawal 90 minutes after furosemide intake (Tmax: time at which the highest furosemide plasma level is expected) * Urine sample collection 60-120 minutes after furosemide intake * 12-hour urine collection
The investigators expect furosemide to increase plasma levels of PBUTs by decreasing the renal excretion of the toxins.
An age of 18 years or older
An eGFR <60 mL/min/1.73m2 for at least three months (diagnosis of CKD stage 3-5)
An indication for the start of treatment with furosemide as part of routine patient care
Willingness to participate in the study and a signed informed consent
Patients who are already on furosemide treatment
Patients with a liver disease with hyperbilirubinemia
Patients who receive any type of renal replacement therapy (peritoneal dialysis, haemodialysis)
Patients with end-stage renal failure without residual diuresis
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.
Case-only
Prospective
Invasive measurements
Diagnostic testBlood 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.
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.
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.
Plasma levels of the PBUT kynurenic acid
Kynurenic acid plasma levels (in ng/mL) will be determined before and after start of furosemide treatment.
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)
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)
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.
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
Baseline characteristics: age
Age (in years) will be documented during the first study visit.
Baseline characteristics: sex
Sex (male/female/other) will be documented 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.
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.
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UMC Utrecht
Lead sponsor
Maastricht University, MERLN Institute for Technology-Inspired Regenerative Medicine
Collaborator
Utrecht Institute for Pharmaceutical Sciences
Collaborator
