Uremic toxins are conditional danger- or homeostasis-associated molecular patterns

We mined novel uremic toxin (UT) metabolomics/gene databases, and analyzed the expression changes of UT receptors and UT synthases in chronic kidney disease (CKD) and cardiovascular disease (CVD). We made the following observations: 1) UTs represent only 1/80^th of human serum small-molecule metabolome; 2) Some UTs are increased in CKD and CVD; 3) UTs either induce or suppress the expression of inflammatory molecules; 4) The expression of UT genes is significantly modulated in CKD patients, and coronary artery disease (CAD) patients; 5) The expression of UT genes is upregulated by caspase-1 and TNF-alpha pathways but is inhibited in regulatory T cells. These results demonstrate that UTs are selectively increased, and serve as danger signal-associated molecular patterns (DAMPs) and homeostasis-associated molecular patterns (HAMPs) that modulate inflammation. These results also show that some UT genes are upregulated in CKD and CAD via caspase-1/inflammatory cytokine pathways, rather than by purely passive accumulation.