Leijte, G. (Guus) (2015) Randomised double-‐blinded placebo-‐controlled phase one trial to evaluate the effect of escalating single intravenous doses of EA-‐230on the kidney function using iohexol plasma clearance during experimental endotoxemia in healthy males. thesis, Medicine.
Full text available on request.Abstract
1 Abstract Introduction: Systemic inflammation induced acute kidney injury (AKI) has a high incidence on the intensive are unit (ICU) and is associated with prolonged hospitalization and significant mortality rates. Current management consists of a mainly supportive nature; no therapies for modulating the causative pro-inflammatory cascade are proven to be effective. EA-230 is a novel agent for future management of the systemic inflammatory response and associated acute kidney failure. EA-230 has proven to be safe in humans and preliminary studies both in vitro and in vivo show promising results. As a modulator of systemic inflammation, no research has yet been conducted to prove the expected kidney protective effect of EA-230 during systemic inflammation. To prove the kidney protective effect of single escalating doses of EA-230 during systemic inflammation, a model of experimental human endotoxemia (LPS) is used to evaluate kidney function. To determine the kidney function accurately, the glomerular filtration rate (GFR) is assessed with iohexol plasma clearance. Materials and Methods: We conducted a monocentric, prospective, randomised, placebocontrolled, double-blinded phase one trial in 36 healthy male volunteers. The effect of 2-hour infusion of EA-230 (30, 90 and 180 mg/kg) on kidney function was evaluated using the iohexol plasma clearance, endogenous creatinine clearance (ECC) and the modification of diet in renal disease (MDRD). Kidney function was assessed on baseline, the following day during LPS-induced endotoxemia and the day hereafter. The iohexol plasma clearance was calculated using a slope interception method with samples taken at 90, 120, 240 and 360 minutes after administration of iohexol. The GFR was corrected according to Bröchner- Mortensen. Results: With iohexol plasma clearance, no significant difference was found in GFR for the different dosing groups mutually and compared to the placebo group (p=0.284). At baseline, the iohexol clearance was 99 ± 2 ml/min compared to an overestimated ECC of 153 ± 3 ml/min. During endotoxemia, an augmented renal clearance was observed using the iohexol clearance with an increase in GFR of 19 ± 2 ml/min. This hyperfiltration normalised to baseline GFR the day after. The MDRD detected a hyperfiltration of only 4 ml/min. Conclusion: During endotoxemia, EA-230 did not significantly alter the kidney function measured with iohexol clearance. An augmented renal filtration was seen during endotoxemia. We have demonstrated iohexol plasma clearance to be accurate and feasible for determining GFR in acute kidney function changes during endotoxemia, and showed once again important clinical limitations of the current clinical standards (MDRD and ECC).
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Faculty supervisor and Jagernath, Drs. D. Internist - Critical Care Physician |
| Supervisor name: | Secondary supervisors and Groenendael, Drs. R. van MSc - Research Physician and Pickkers, Prof. P. Head of Research Department of the Intens and Care, Internist - Critical Care Physician |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:03 |
| Last Modified: | 25 Jun 2020 11:03 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2288 |
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