The Accumulation of Gut Microbiome–derived Indoxyl Sulfate and P-Cresyl Sulfate in Patients With End-stage Renal Disease

End-stage renal disease (ESRD) is the final stage of chronic kidney disease, which is increasingly prevalent worldwide and is associated with the progression of cardiovascular disease (CVD). Indoxyl sulfate (IS), a major uremic toxin, plays a key role in the pathology of CVD via adverse effects in endothelial and immune cells. Thus, there is a need for a transcriptomic overview of IS responsive genes in immune cells of ESRD patients. Here, we investigated IS-mediated alterations in gene expression in monocytes from ESRD patients. Transcriptomic analysis of ESRD patient-derived monocytes and IS-stimulated monocytes from healthy controls was performed, followed by analysis of differentially expressed genes (DEGs) and gene ontology (GO). We found that 148 upregulated and 139 downregulated genes were shared between ESRD patient-derived and IS-stimulated monocytes. Interaction network analysis using STRING and ClueGo suggests that mainly metabolic pathways, such as the pentose phosphate pathway, are modified by IS in ESRD patient-derived monocytes. These findings were confirmed in IS-stimulated monocytes by the increased mRNA expression of genes including G6PD, PGD, and TALDO1. Our data suggest that IS causes alteration of metabolic pathways in monocytes of ESRD patients and, thus, these altered genes may be therapeutic targets.

Download Full-text

Microbiome perturbation by oral vancomycin reduces plasma concentration of two gut-derived uremic solutes, indoxyl sulfate and p-cresyl sulfate, in end-stage renal disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfx029 ◽

2017 ◽

Vol 32 (11) ◽

pp. 1809-1817 ◽

Cited By ~ 28

Author(s):

Lama Nazzal ◽

Julia Roberts ◽

Prabhjot Singh ◽

Sachin Jhawar ◽

Albert Matalon ◽

...

Keyword(s):

Plasma Concentration ◽

Renal Disease ◽

End Stage Renal Disease ◽

Indoxyl Sulfate ◽

Oral Vancomycin ◽

Uremic Solutes ◽

Stage Renal Disease ◽

End Stage

Download Full-text

Functional Genomic Analysis Identifies Indoxyl Sulfate as a Major, Poorly Dialyzable Uremic Toxin in End-Stage Renal Disease

PLoS ONE ◽

10.1371/journal.pone.0118703 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0118703 ◽

Cited By ~ 10

Author(s):

Sachin Jhawar ◽

Prabhjot Singh ◽

Daniel Torres ◽

Francisco Ramirez-Valle ◽

Hania Kassem ◽

...

Keyword(s):

Renal Disease ◽

End Stage Renal Disease ◽

Genomic Analysis ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Functional Genomic ◽

Functional Genomic Analysis ◽

Stage Renal Disease ◽

End Stage

Download Full-text

Generation, clearance, toxicity, and monitoring possibilities of unaccounted uremic toxins for improved dialysis prescriptions

AJP Renal Physiology ◽

10.1152/ajprenal.00106.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. F890-F902 ◽

Cited By ~ 1

Author(s):

James G. Atherton ◽

David S. Hains ◽

John Bissler ◽

Bradford D. Pendley ◽

Ernő Lindner

Keyword(s):

Renal Function ◽

Renal Disease ◽

Normal Renal Function ◽

End Stage Renal Disease ◽

Blood Purification ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Stage Renal Disease ◽

End Stage ◽

Cellular Secretion

Current dialysis-dosing calculations provide an incomplete assessment of blood purification. They exclude clearances of protein-bound uremic toxins (PB-UTs), such as polyamines, p-cresol sulfate, and indoxyl sulfate, relying solely on the clearance of urea as a surrogate for all molecules accumulating in patients with end-stage renal disease (ESRD). PB-UTs clear differently in dialysis but also during normal renal function. The kidney clears PB toxins via the process of secretion, whereas it clears urea through filtration. Herein, we review the clearance, accumulation, and toxicity of various UTs. We also suggest possible methods for their monitoring toward the ultimate goal of a more comprehensive dialysis prescription. A more inclusive dialysis prescription would retain the kidney-filtration surrogate, urea, and consider at least one PB toxin as a surrogate for UTs cleared through cellular secretion. A more comprehensive assessment of UTs that includes both secretion and filtration is expected to result in a better understanding of ESRD toxicity and consequently, to reduce ESRD mortality.

Download Full-text