The potential of protein-bound uremic toxins as biomarkers of kidney tubular function

Chronic kidney disease (CKD) affects about 10% of the global population, leading to end-stage kidney disease (ESKD) requiring expensive treatments like dialysis or kidney transplantation. High mortality rates and decreased quality of life are common in these patients, especially those on dialysis. Early detection of CKD is crucial to slowing disease progression and minimizing complications. Protein-bound uremic toxins (PBUTs), like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), accumulate in the blood as kidney function declines, contributing to CKD progression. Since PBUTs rely on tubular secretion for elimination, they can serve as biomarkers for tubular dysfunction in CKD. This thesis explores the potential of PBUTs as markers for tubular function by studying six PBUTs: IS, hippuric acid (HA), kynurenic acid (KA), p-cresyl glucuronide (PCG), PCS, and indole-3-acetic acid (IAA).

The thesis research first developed a reliable method for measuring these toxins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and then analysez PBUTs in different disease models. Results indicated that plasma IS levels, in particular, could serve as sensitive biomarkers for tubular function in CKD, better than traditional markers. Additionally, PBUTs, especially IS, HA, and KA, were more closely associated with tubular atrophy and inflammation in diabetic nephropathy (DN), a major cause of ESKD. These findings were confirmed in a cohort of DN patients, where PBUT clearance was linked with urinary tubular damage markers.

Overall, the thesis supports the use of PBUT clearance, particularly IS and HA, as biomarkers for tubular dysfunction in CKD and DN, offering new insights into disease progression and potential therapeutic strategies.