Effect of Furosemide on Proximal Tubular Secretion of Organic Solutes in Patients Receiving Hemodialysis

The kidneys clear numerous natural solutes and medications by secretion in the proximal tubule (1). Because the same secretory transport mechanisms are used, administration of medications, such as diuretics, could compete for secretion with uremic solutes (1). Such competition could reduce solute clearances and increase plasma solute accumulation. In this study, we assessed whether use of oral furosemide by patients receiving maintenance hemodialysis reduces the secretion of naturally occurring organic acids by the residual kidneys.

We performed a secondary pre-post comparison of samples from a study of oral furosemide use in patients receiving thrice-weekly hemodialysis at three University of North Carolina–associated outpatient hemodialysis clinics between October 2020 and January 2021 (2). Patients who reported urine output ≥1 cup (250 ml)/d received increasing furosemide doses up to a maximum of 320 mg/d. By week 5, patients were receiving their highest study furosemide dose. Pretreatment plasma was obtained from a midweek hemodialysis session, and 24-hour urine samples were obtained in the 24 hours before that session. Primary study results indicated that furosemide was generally well tolerated and safe and that it led to increased urine output in about one third of the 39 participants (2). Plasma and urine samples at baseline and week 5 were available for only eight participants due to limited biobanking resources. Among these eight participants, the daily furosemide dose averaged 221±109 mg at week 5 compared with 48±55 mg at baseline (P=0.01). Four organic acids normally secreted by the kidneys (phenylacetylglutamine, p-cresol sulfate, indoxyl sulfate, and hippurate) and furosemide were measured using liquid chromatography tandem mass spectrometry (3).

Residual kidney clearance for each solute was approximated as the urinary removal rate divided by the pretreatment plasma level. The GFR was estimated as the average of the urea and creatinine clearances, and fractional solute clearances were calculated relative to the GFR. For the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate, clearances were calculated in terms of the free unbound level in order to detect impaired secretion (3). Baseline and week 5 measurements were compared using the Wilcoxon rank sum test.

The urine volumes at baseline and week 5 were 220±229 and 322±394 ml/d, respectively (P=0.07). The GFRs at baseline and week 5 were 1.3±1.1 and 1.6±1.6 ml/min, respectively (P=0.33).

As summarized in Table 1, the fractional clearances for phenylacetylglutamine, p-cresol sulfate, indoxyl sulfate, and hippurate were all >1.0, indicating that these solutes were secreted by the residual kidneys. For all solutes, fractional clearances were similar at baseline and week 5, indicating that furosemide in the dose used did not impair uremic solute secretion. The free fractions for the bound solutes were similar.

Table 1.

Solute fractional clearance and free fraction (n=8)

Solute	Fractional Clearance				Free Fraction
	Baseline	Week 5	Week 5/Baseline	P Value	Baseline	Week 5	Week 5/Baseline	P Value
Phenylacetylglutamine	2.8±1.5	3.0±1.8	1.2±1.0	0.89	—	—	—	—
p-Cresol sulfate	4.1±2.2	3.3±1.5	1.0±0.5	0.78	0.05±0.02	0.06±0.02	1.4±1.1	0.78
Indoxyl sulfate	9.3±5.1	7.7±3.4	1.0±0.6	0.78	0.06±0.04	0.06±0.02	1.7±2.2	0.67
Hippurate	11±4	22±28	2.4±3.7	0.67	0.55±0.12	0.53±0.09	1.0±0.1	0.50

Results are presented as mean±SD. Among the eight participants, the mean±SD age was 72±10 years, seven were men, four were of Black race, and four were of White race. Fractional clearances were calculated as the solute clearance relative to the GFR. GFR was estimated as the average of the urea and creatinine clearances. Clearances of urea, creatinine, and the secreted solutes are likely variably underestimated because the prehemodialysis rather than time-averaged plasma concentrations were used for the clearance calculations. For the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate, fractional clearances are expressed in terms of the free unbound plasma level. Free fractions of the bound solutes were calculated as the plasma ultrafiltrate level divided by the total plasma level. —, not applicable.

There is concern that diuretics could impair the secretion of uremic solutes (1). Diuretics, including furosemide, are delivered in the peritubular capillaries and taken into the proximal tubule cell by transporters on the basolateral membrane. They pass through different transporters on the apical membrane into the tubule lumen, where they then act at their respective tubule sites. Numerous uremic solutes are cleared by these same secretory mechanisms, and their secretion may be impeded by competing diuretics (3). However, our study showed no impairment in secretion of four uremic solutes in the setting of furosemide use in patients receiving hemodialysis.

There are potential reasons why furosemide did not reduce the secretion of uremic solutes. First, the furosemide dose may not have achieved plasma levels sufficient to compete for secretion. Furosemide has a substantial nonkidney clearance; thus, high plasma levels are not sustained for long (4). Indeed, the average plasma furosemide level at week 5 in this study (432±347 ng/ml) was much lower than the level in a study in which 2000 mg/d furosemide elicited nearly a two-fold increase in daily urine output in ten patients on hemodialysis (27,340±13,104 ng/ml) (5). The furosemide plasma levels in this study (measured before hemodialysis) were relatively low (432±347 ng/ml) despite only limited urinary excretion (1.3±1.2 mg/24 h) because of the sizable nonkidney clearance of furosemide. Higher doses (such as those delivered intravenously) or effects of other medications and/or comorbidities might lead to higher plasma levels and the potential for secretion competition. Second, furosemide and the four studied solutes may not be secreted entirely by the same transporters. Furosemide is secreted by organic anion transporter (OAT) 1, and indoxyl sulfate, p-cresol sulfate, and hippurate are secreted by OAT3 as well as OAT1 (1). Lastly, the transporters may have greater affinity for the four uremic solutes than for furosemide, so that secretion of these solutes was maintained despite the presence of furosemide. There are many different transporters, and little is known about their specificity for medications and solutes (1).

Overall, furosemide at the doses studied did not impair the secretion of the uremic solutes phenylacetylglutamine, p-cresol sulfate, indoxyl sulfate, and hippurate. Further investigation into interactions between medications and uremic solutes during proximal tubule secretion may determine whether dose adjustments to prevent plasma accumulation of solutes are warranted.

Disclosures

In the last 3 years, J.E. Flythe has received speaking honoraria from the American Society of Nephrology and multiple universities as well as investigator-initiated research funding unrelated to this project from the Renal Research Institute, a subsidiary of Fresenius Kidney Care, North America. She serves on a medical advisory board for Fresenius Kidney Care, North America, as well as a scientific advisory board and a data and safety monitoring committee for the National Institute of Diabetes and Digestive and Kidney Diseases. She has received consulting fees from AstraZeneca and serves as the Kidney Health Initiative Patient Preferences Project Chairperson, a Kidney360 associate editor, and a Patient-Centered Outcomes Research Institute peer review associate editor. T.H. Hostetter reports consultancy agreements with the Center for Dialysis Innovation, University of Washington and Otsuka; honoraria from Otsuka; Tricida stock options; and advisory or leadership roles for the Center for Dialysis Innovation, University of Washington and Tricida. T.L. Sirich has served as a consultant for Baxter.

Funding

This work and J.E. Flythe were supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R03 DK124651. J.E. Flythe is also supported by National Heart, Lung, and Blood Institute grant R01 HL152034. T.L. Sirich is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK118426.

Author Contributions

J.E. Flythe, T.H. Hostetter, and T.L. Sirich conceptualized the study, were responsible for data curation, were responsible for investigation, were responsible for formal analysis, and were responsible for methodology. J.E. Flythe was responsible for validation, was responsible for funding acquisition, and provided supervision. J.E. Flythe, T.H. Hostetter, and T.L. Sirich wrote the original draft and reviewed and edited the manuscript.

Data Sharing Statement

All data used in this study are available in this article.