ABSTRACT
OBJECTIVES: To characterize the temporal pattern of a panel of blood and urinary biomarkers in an 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 d) rat model of sepsis (fecal peritonitis) and recovery was used to understand the temporal association of sepsis biomarkers in relation to systemic hemodynamics, inflammation, and renal function. At predefined time points (3, 6, 12, 24, 48, 72 hr), 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 proinflammatory response was maximal at 6 hours, corresponding with the nadir of stroke volume. Serum creatinine peaked late (24 hr), when clinical recovery was imminent. Histological evidence of tubular injury and cell death was minimal. After a recovery period, all biomarkers returned to levels approaching those observed in sham animals. Apart from urine clusterin and interleukin-18, all other urinary biomarkers were elevated at earlier time points compared with serum creatinine. Urine neutrophil gelatinase-associated lipocalin was the most sensitive marker among those studied, rising from 3 hours. While serum creatinine fell at 12 hours, 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 systemic and renal inflammation and recovery. Insight into the pathophysiology of acute kidney injury is gleaned from the temporal change markers of renal injury (urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, calbindin), followed by a marker of cell cycle arrest (urine insulin-like growth factor-binding protein 7) and, finally, by functional markers of filtration (serum creatinine and cystatin C). These clinically relevant findings should have significant influence on future clinical testing.
Subject(s)
Sepsis/physiopathology , Animals , Biomarkers , Cell Adhesion Molecules/urine , Cystatin C/blood , Disease Models, Animal , Hemodynamics , Inflammation Mediators/metabolism , Kidney Function Tests , Lipocalin-2/urine , Lipocalins/urine , Male , Prospective Studies , Rats , Rats, Wistar , Sepsis/blood , Sepsis/urine , Time FactorsABSTRACT
PURPOSE OF REVIEW: Major improvements in perioperative care and immunobiology have not abated the risk for severe pulmonary complications after solid-organ transplantation. The aim of this study is to update information on infectious and noninfectious pulmonary complications after solid-organ transplantation, addressing epidemiology, risk factors, diagnostic workup, and management. RECENT FINDINGS: Infectious and noninfectious postoperative pulmonary complications depend on the grafted organ and the anatomical site of transplantation. Kidney transplants have the lowest incidence of pulmonary complications, the highest being reported for heart, lung, and liver recipients. Respiratory tract infections, ranking first in heart and lung transplants and second in liver recipients, are a common cause of mortality. Risk factors include end-stage organ disease, comorbidities, perioperative procedures, and graft function. Factors specific for infections are timeline, state of immunosuppression, and graft dysfunction. Nosocomial multi-drug resistant pathogens are frequently responsible for the most severe infections. Aggressive diagnostic workup, early and broad empiric antiinfective therapy, and deescalation policy are the mainstays of their management. The role of intraoperative protective ventilation is under scrutiny. SUMMARY: Pulmonary complications after solid-organ transplantation, and particularly infections, are able to compromise the extremely good results of the transplant procedures. Solid-organ transplantation recipients challenge the ICU physician with unique aspects of their post-transplant course, adding, in an already critical patient, the immunosuppressed state and the quality of the functional recovery of the graft.
Subject(s)
Lung Diseases/etiology , Organ Transplantation , Postoperative Complications , HumansABSTRACT
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-1ß (0(0-10)(pg/mL) vs. 1671(1445-33778)(pg/mL); P < 0.001) and renal IL-1ß (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-1ß 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). P2X7 A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis-related AKI.