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Sepsis-induced AKI models to test resuscitation fluids

PI: Kai Singbartl, MD

Co-PI: John A. Kellum, MD

Co-Investigator: Zhiyong Peng, PhD

Funding: Baxter Study Agreement

Severe sepsis is the leading cause of acute kidney injury (AKI) and its incidence is increasing. In the largest epidemiological study to date (>120,000), Bagshaw et al. found that AKI occurred in 36% of intensive care unit (ICU) patients and that the most common primary diagnosis was sepsis.  Similarly, we found in a large international observational study of AKI requiring renal replacement therapy (RRT) that approximately 50% of subjects had sepsis.   Severe sepsis currently affects more than 750,000 Americans each year and the incidence rises exponentially with age, suggesting that the number of cases will rise in coming years as baby boomers age. We have recently shown that AKI occurs in approximately 34% of patients hospitalized for community acquired pneumonia even though fewer than 20% we critically ill. We propose to test two resuscitation fluids  in both models. For both models we propose to assess the effect of the respective fluid on (a) survival, (b) incidence of AKI (defined by I and F criteria), (c) innate immunity, in particular neutrophil function, (d) vascular damage, and (e) acid-base status, glucose homeostasis as well as renal gluconate elimination.

Model 1: High severity, no antibiotics

In this model CLP involves 25% of the cecum and two punctures with 20 gauge needle. Approximately 93% of the animals develop AKI (14% R, 39% I and 39% F). The average one-week survival rate for this sepsis model is about 47% and mortality increases with severity of AKI just as in clinical situation in humans (see figure 1).














Model 2:  Low severity, antibiotic treated sepsis

For our low severity model we induce sepsis as in model 1 (CLP 25% ligation, two punctures with 20 gauge needle) but we also treat with antibiotics (ampicillin/sulbactam) starting 18 h after CLP and continued for three days at 125mg/kg every 12 h. One-week survival rates for this model is 90-95%. Notably, despite the low mortality, nearly all animals develop AKI with almost 50% developing RIFLE-F. Serum creatinine levels peak around 72hrs and recover gradually, returning to near baseline by day 7 (Figure 3).













Fig 3. Serum creatinine patterns over time for animals using
low mortality model 2. Data presented are mean values
for 13 animals.