NIV Congres

Aims Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-Antitrypsin (AAT), the major serum serine-protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy in a mouse model of renal ischemia-reperfusion (I/R) injury.

Methods Renal I/R injury was induced in male C57/Bl6 mice by bilateral clamping of the renal artery and vein for 21 min. After clamp removal, kidneys were inspected for restoration of blood flow. hAAT (80 mg/kg/day, Prolastin^®, Bayer) was administered daily i.p. from day -1. Control animals received the same amount of human serum albumin. Mice (n=8 animals per group) were placed in metabolic cages at day 1, 2, 7 or 14 after surgery to collect urine. After 24h, blood samples were obtained and animals were sacrificed by cervical dislocation. Kidneys were harvested for further analysis. Serum creatinine and urea levels were measured using standard clinical chemistry methods. Measurement of the renal injury markers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in urine and plasma was performed by ELISA.

Results Kidney ischemia significantly impaired renal function, causing a marked increase in plasma creatinine and urea levels. Furthermore, renal I/R significantly increased the protein levels of both KIM-1 and NGAL, in urine and plasma. The observed increase of these parameters peaked at days 2 and 3. hAAT treatment ameliorated renal IRI, reducing the levels of plasma creatinine (13.7 ± 1.4 vs 22.4 ± 4.1 µmol/L, P = 0.09) and urea (11.9 ± 3.8 vs 28.2 ± 6.1 mmol/L, P = 0.05) at day 2. Interestingly, treatment with hAAT significantly decreased the NGAL protein levels in urine at day 3 (626 ± 177 vs 2135 ± 536 ng/mL, P < 0.05) and in plasma at days 2 (485 ± 71 vs 901 ± 118 ng/mL, P < 0.05) and 3 (448 ± 100 vs 1101 ± 196 ng/mL, P < 0.05).

Conclusions These data indicate a protective effect of hAAT in renal ischemia reperfusion injury and support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.