The new chronic kidney disease model and role of cytokine accumulation in the sepsis susceptibility of chronic kidney disease

Abstract

Chronic kidney disease (CKD), the progressive worsening of kidney functon resulting from the decrease in nephron (functional kidney unit) number, leadng to end-stage renal failure and death. The 2 million end stage renal disease patients by 2010 plaes a substantial burden on global health care delivery systems. CKD was reported as an important prognostc factor in the patient with sepsis, CKD patients have a higher prevalence, severity and mortality of sepss compared with normal. Knowing the cause of immune compromised in CKD should ntiate better patient management. The study on sepsis in predisposng CKD should be more resemble human sepsis conditon and results n better opportunity of successful translation. We conducted the seres of experiments to initiate proper CKD model and use that model for sepsis studies. Concerning CKD in human definition, we could not find proper CKD model from prevous literatures. Then we established new modified kidney remnant model. We found this model in Cd-1 or 129 S3 but not C57BL/6 showed progressive worsening in kidney function (serum creatinine, glomerular filtration rate), histology, albuminuria, blood pressure and other comorbdity characters. The hypertension treatment by Olmesartan but not hydralazine reduced kidney fibrosis, in part, reciprocal to human condition. Additionaly, the resistance of C57BL/6 overcame by Angitensin II but not DOCA-salt hypertension. We proposed modified kidney remnant model in CD-1 and in C57BL/6 with Angiotensin II as a proper CKD models. Subsequently, we used this model in CD-1 in sepsis study. We found the accumulation of several cytokines followed kidney njury. However, HMGB1 but not VEGF of other cytokines in CKD causes spleen apoptosis and worsen sepsis condition. The anti HMGB1 treatment in sepss with pre- existing CKD but not in previously healthy mice was effective. In conclusion, we invented new proper CKD model and reported spontaneous spleen apoptoss after CKD. Then we found that HMGB1 is an important modulator for sepss severty in CKD. HMGB1 might be an nterestng treatment target in sepsis with pre-existng CKD.