Blocking of human anti‐pig xenoantibodies by soluble GALα1‐3GAL and Galα1‐2GAL disaccharides; studies in a pig kidney in vitro perfusion model

Abstract Depletion of anti‐pig xenoantibodies reduces cell cytotoxicity of human serum to pig endothelial cells and lymphocytes. The aim of this study was to test, in a pig kidney xenoperfusion model, the ability of soluble αGal terminated disaccharides to prevent the hyperacute rejection process in an organ. Porcine kidneys were perfused with whole human blood lacking saccharide and blood supplemented with Galα1‐3GAL, Galα1‐2Gal and lactose. Parameters evaluated were, urine production, renal blood flow, vascular resistance, renal clearance, blood cell counts, xenoantibody titers, complement activation and histopathology. The blood flow was higher in the Galα1‐3Gal (155 ± 31 ml/min × 100 g‐1 kidney tissue) group compared to Galα1‐2Gal (138 ± 16), lactose (92 ± 78) and controls (69 ± 16). When calculated as percent of the blood flow value at 1 min, the blood flow at 30 min was 157% for the Galα‐3Gal and for 187% the Galα1‐2Gal. The corresponding values for the lactose and control groups were 102% and 74%, respectively. Urine production in the lactose/control groups was lower (0.7 ml/min × 100 g‐1 kidney tissue) compared to Galα1‐3Gal (3.0) and Galα1‐2Gal (3.7). Urine sodium excretion was reduced in the lactose/control groups, compared to the Galααl ‐ groups during the perfusions. An increase in urine potassium excretion was found in the Galαα1‐groups while a reduction occurred in the lactose/control experiments. An initial 40–50% reduction in platelet count was observed in all groups while the leukocyte count showed a continuous decrease. Immunohistochemistry revealed less deposition of IgM, IgG, C3 and C1 q in the Galαα1‐saccharide groups compared to the lactose/control groups. Soluble Galαa1‐disaccharides improved both functional and histological parameters. However, significant pathological changes were still present indicating that this approach to inhibit HAR must be used in combination with additional therapeutic approaches such as solid phase xenoantibody immunoadsorption and blocking of complement activation.