TREATMENT WITH DIANNEXIN POST-REPERFUSION DECREASES DGF AND IMPROVES GFR IN RENAL TRANSPLANT RECIPIENTS OF MARGINAL KIDNEY DONORS

EXPERIMENTAL ISCHEMIA AND REPERFUSION INJURY

M. Cooper¹, S. Kapur², R. Stratta³, A. D'alessandro⁴, S. Mulgaonkar⁵, A. Allison⁶, M. Russell⁶, S. Knechtle^7
1Surgery, University of Maryland, Baltimore/UNITED STATES OF AMERICA, ², New York- Presbyterian, New York/UNITED STATES OF AMERICA, ³, Wake Forest University School of Medicine, Winston-Salem/UNITED STATES OF AMERICA, ⁴Surgery, University of Wisconsin, Madison/WI/UNITED STATES OF AMERICA, ⁵, St. Barnabas Medical Ctr, Livingston/NJ/UNITED STATES OF AMERICA, ⁶, Alavita Inc, Mountain View/CA/UNITED STATES OF AMERICA, ⁷, Emory University, Atlanta/UNITED STATES OF AMERICA

Body: Purpose: Diannexin is a novel ischemia reperfusion (IR) agent that binds to phosphotidyl serine translocated to the cell surface following anoxia and prevents the early attachment of mononuclear cells and platelets that initiate the IR injury cascade. Early results from a phase 2 study involving renal transplant recipients of marginal donors showed that the highest dose of Diannexin was associated with increases in urine output, decreases in need for post-transplant dialysis, and/or fewer days on dialysis. This study also evaluated changes in glomerular filtration rate following the first year post transplant in a high-risk donor population. Methods: A 5-center Phase 2 study enrolled 58 renal transplant recipients of an expanded-criterion donor, a donor after cardiac death with £36 hours cold ischemia time (CIT) or a standard-criterion donor with 24-36 hours CIT to examine safety and estimate efficacy. A single IV Diannexin dose (0, 200, or 400 µg /kg) was administered via IV push at 15 min upon reperfusion. Urine output, need for dialysis, episodes of BPAR, post-operative complication, and hospital readmissions were collected. Immunosuppression was per center practice with all patients maintained on CNI throughout the course of the trial. GFR was estimated from serum creatinine using the MDRD calculation at the time points indicated. Results: Dose escalation proceeded without evidence of dose- or time-dependent increases in adverse event incidence or severity. Efficacy results are demonstrated below:

Dose	0 µg/kg	200 µg/kg	400 µg/kg
N=	9	20	21
HD 1st 7d (N,%)	5, 56%	11, 55%	7, 33%
GFR (ml/min/1.73 m2)mean (SD)
Day 15	22.4 (15.7)	30.2 (17.8)	31.5 (18.5)
Day 29	30.9 (19.4)	35.7 (18.8)	40.5 (22.5)
Month 6	38.8 (22.6)	39.6 (21.0)	45.2 (17.4)
Month 12	34.9 (21.0)	36.2 (19.6)	50.1 (25.0)

Conclusion: In renal transplant recipients of marginal donor kidneys, single IVB doses of Diannexin demonstrated improvements in urine output and decreased incidence of delayed graft function. In the 400 µg /kg cohort, the mean GFR was significantly improved with placebo at each follow-up period. At this dose, the higher GFR and lower DGF rate support the concept that attenuation of ischemia reperfusion responses in the immediate operative period may improve both early tubular injury and improve long term graft function. Further clinical trials are warranted to determine the utliziation of Diannexin across a broader donor and recipient population.

Disclosure: All authors have declared no conflicts of interest.