Regardless of the significant progress, several important considerations remain poorly addressed: first, how hyperlipidemia and CKD achieve synergy in accelerating vascular inflammation; second, how intracellular gram-negative bacterial infections in CKD and elevated LPS levels derived from gut gram-negative bacteria promote intracellular inflammatory mechanisms; and third, whether TI has coupled mechanisms from the first step (CASP4/11 activation) to the second step (promotion by IL1B and other CASP4/11-GSDMD secretome) to be amplified. The gene discussed is CASP4; the disease is gram-negative bacterial infections.