Alkaline Phosphatase Treatment of Acute Kidney Injury in an Infant Piglet Model of Cardiopulmonary Bypass with Deep Hypothermic Circulatory Arrest

Jesse A Davidson,Amy Treece,Suzanne Osorio Lujan,Scott Lawson,Justin Robison,Richard J Ing,Ludmila Khailova,James Jaggers,Danielle E Soranno

doi:10.1038/s41598-019-50481-w

Abstract

Acute kidney injury (AKI) is associated with prolonged hospitalization and mortality following infant cardiac surgery, but therapeutic options are limited. Alkaline phosphatase (AP) infusion reduced AKI in phase 2 sepsis trials but has not been evaluated for cardiac surgery-induced AKI. We developed a porcine model of infant cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA) to investigate post-CPB/DHCA AKI, measure serum/renal tissue AP activity with escalating doses of AP infusion, and provide preliminary assessment of AP infusion for prevention of AKI. Infant pigs underwent CPB with DHCA followed by survival for 4 h. Groups were treated with escalating doses of bovine intestinal AP (1, 5, or 25U/kg/hr). Anesthesia controls were mechanically ventilated for 7 h without CPB. CPB/DHCA animals demonstrated histologic and biomarker evidence of AKI as well as decreased serum and renal tissue AP compared to anesthesia controls. Only high dose AP infusion significantly increased serum or renal tissue AP activity. Preliminary efficacy evaluation demonstrated a trend towards decreased AKI in the high dose AP group. The results of this dose-finding study indicate that AP infusion at the dose of 25U/kg/hr corrects serum and tissue AP deficiency and may prevent AKI in this piglet model of infant CPB/DHCA.

Highlights

Acute kidney injury (AKI) is an increasingly recognized and important complication of pediatric cardiac surgery[8]
We combined data from all animals undergoing cardiopulmonary bypass (CPB)/deep hypothermic circulatory arrest (DHCA) regardless of treatment group and compared them to anesthesia-only controls in order to determine the cardiovascular effects of the model as well as the level of AKI produced by the model
Serum NGAL, urine NGAL, and urine NGAL/creatinine ratios were elevated in animals undergoing CPB/DHCA compared to anesthesia controls, and we found no significant difference in serum NGAL (216 ng/ml vs 196 ng/ml; p = 0.87) (Supplemental Figure S12), urine NGAL (109 ng/ml vs 109 ng/ml; p = 0.45) (Supplemental Figure S13), or urine NGAL/Creatinine ratio (0.61 vs 0.65; p = 0.60) (Supplemental Figure S14) between the high dose Alkaline phosphatases (AP) group and the remaining CPB/DHCA groups

Summary

Introduction

Acute kidney injury (AKI) is an increasingly recognized and important complication of pediatric cardiac surgery[8]. Evidence of proximal tubular injury appears within 2 hours of cardiac surgery in both animal models and human biomarker studies[11,12,13,14], followed by evolution to clinical acute kidney dysfunction over a period of hours to days[15]. Alkaline phosphatases (AP) are endogenous metalloenzymes found in serum and in multiple organs throughout the body including bone, liver, intestine, and kidney[23] These enzymes are well established as biomarkers of liver and bone disease, but their physiologic roles remain incompletely understood. There are no preclinical or human studies evaluating dosing or preliminary efficacy of systemic AP infusion for prevention of CPB/DHCA-induced AKI. In this study we sought to establish a porcine model of early infant CPB/DHCA-induced AKI and determine the serum and renal tissue AP activity achieved with escalating doses of bovine intestinal AP (BiAP) infusion in this model. We hypothesized that higher doses of BiAP would result in decreased histologic and biomarker evidence of AKI in this model

Methods

Results

Conclusion