Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease
Abstract Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumula...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-07248-3 |
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| author | Sabbir Ahmed Rolf W. Sparidans Robin W. M. Vernooij Silvia M. Mihaila Roel Broekhuizen Roel Goldschmeding Tri Q. Nguyen Rosalinde Masereeuw Karin G. F. Gerritsen |
| author_facet | Sabbir Ahmed Rolf W. Sparidans Robin W. M. Vernooij Silvia M. Mihaila Roel Broekhuizen Roel Goldschmeding Tri Q. Nguyen Rosalinde Masereeuw Karin G. F. Gerritsen |
| author_sort | Sabbir Ahmed |
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| description | Abstract Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p-cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD. |
| format | Article |
| id | doaj-art-948ca5996dca4cf29d3b367933f80938 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-948ca5996dca4cf29d3b367933f809382025-08-20T03:45:30ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-07248-3Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney diseaseSabbir Ahmed0Rolf W. Sparidans1Robin W. M. Vernooij2Silvia M. Mihaila3Roel Broekhuizen4Roel Goldschmeding5Tri Q. Nguyen6Rosalinde Masereeuw7Karin G. F. Gerritsen8Department of Pharmaceutical Sciences, Utrecht UniversityDepartment of Pharmaceutical Sciences, Utrecht UniversityDepartment of Nephrology and Hypertension, University Medical Center UtrechtDepartment of Pharmaceutical Sciences, Utrecht UniversityDepartment of Pathology, University Medical Center UtrechtDepartment of Pathology, University Medical Center UtrechtDepartment of Pathology, University Medical Center UtrechtDepartment of Pharmaceutical Sciences, Utrecht UniversityDepartment of Nephrology and Hypertension, University Medical Center UtrechtAbstract Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p-cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD.https://doi.org/10.1038/s41598-025-07248-3Diabetic kidney diseaseTubular function markerProtein-bound uremic toxinsIndoxyl sulfateHippuric acid |
| spellingShingle | Sabbir Ahmed Rolf W. Sparidans Robin W. M. Vernooij Silvia M. Mihaila Roel Broekhuizen Roel Goldschmeding Tri Q. Nguyen Rosalinde Masereeuw Karin G. F. Gerritsen Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease Scientific Reports Diabetic kidney disease Tubular function marker Protein-bound uremic toxins Indoxyl sulfate Hippuric acid |
| title | Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| title_full | Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| title_fullStr | Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| title_full_unstemmed | Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| title_short | Protein-bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| title_sort | protein bound uremic toxin clearance as biomarker of kidney tubular function in diabetic kidney disease |
| topic | Diabetic kidney disease Tubular function marker Protein-bound uremic toxins Indoxyl sulfate Hippuric acid |
| url | https://doi.org/10.1038/s41598-025-07248-3 |
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