P2X7 receptor antagonism ameliorates renal dysfunction in a rat model of sepsis

Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP‐sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid‐resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time‐points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A‐438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham‐operated animals, septic animals had significant increases in heart rate (−1(−4 to 8)% vs. 21(12–26)%; P = 0.003), fever (37.4(37.2–37.6)°C vs. 38.6(38.2–39.0)°C; P = 0.0009), and falls in serum albumin (29(27–30)g/L vs. 26(24–28); P = 0.0242). Serum IL‐1β (0(0–10)(pg/mL) vs. 1671(1445–33778)(pg/mL); P < 0.001) and renal IL‐1β (86(50–102)pg/mg protein vs. 200 (147–248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham‐operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham‐operated animals at 24 h (23(22–25) μmol/L vs. 28 (25–30)μmol/L; P = 0.0321). Renal IL‐1β levels were significantly lower in A‐438079‐treated animals compared with untreated animals at 6 h (70(55–128)pg/mg protein vs. 200(147–248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A‐438079‐treated animals had more rapid resolution of tachycardia (22(13–36)% vs. −1(−6 to 7)%; P = 0.019) and fever (39.0(38.6–39.1)°C vs. 38.2(37.6–38.7)°C; P < 0.024), higher serum albumin (23(21–25)g/L vs. (27(25–28)g/L); P = 0.006), lower arterial lactate (3.2(2.5–4.3)mmol/L vs. 1.4(0.9–1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25–30)μmol/L vs. 22(17–27)μmol/L; P = 0.019). P2X7A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis‐related AKI

Sequential analysis of a panel of biomarkers and pathologic findings in a resuscitated rat model of sepsis and recovery

Objective : To characterize the temporal pattern of a panel of blood and urinary acu te kidney injury (AKI) biomarkers in a n animal model of fecal peritonitis and recovery Design : Prospective observational animal study Setting : University research laboratory Subjects : Male Wistar rats Interventions : A fluid - resuscitated, long - term (3 day) rat model of sepsis (fecal peritonitis) and recovery was used to understand the temporal association of AKI biomarkers in relation to systemic hemodynamics, inflammation, and renal function . At pre - defined time points (3, 6, 12, 24, 48, 72h), animals (≥6 per group) underwent echocardiography, blood and urine sampling, and had kidneys taken for histological analysis. Comparison was made against sham - operated controls and naïve animals . Measurements and main results : The systemic pro - inflammatory response wa s maximal at 6 hours, corresponding with the nadir of stroke volume. Serum creatinine peaked late (24h), when clinical recovery was imminent. Histological evidence of tubular injury and cell death was minimal . After a recovery period, all biomarkers return ed to levels approaching those observed in sham animals. Apart from urine clusterin and IL - 18, all other urin ary biomarkers were elevated at earlier time - point s compared to serum creatinine. Urine NGAL was the most sensitive marker among those studied, ris ing from 3h. While serum creatinine fell at 12h, serum cystatin C increased, suggestive of decreased creatinine production. Conclusions : Novel information is reported on the temporal profile of a panel of renal biomarkers in sepsis in the context of system ic and renal inflammation and recovery. I n sight into the pathophysiology of AKI is gleaned from the temporal change m arkers of renal injury (urine NGAL, KIM - 1, c albindin) , followed by a marker of cell cycle arrest (urine IGFBP7) and , finally , by functional markers of filtration (serum creatinine and cy s tatin C). These clinically relevant findings should have significant influence on future clinical testing