Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury

Clin Exp Nephrol. 2017 Jun;21(3):436-445. doi: 10.1007/s10157-016-1308-2. Epub 2016 Jul 12.

Abstract

Background: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models.

Methods: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats.

Results: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued.

Conclusion: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

Keywords: APAC; Acute kidney injury; Ischemia–reperfusion injury; Unfractionated heparin.

Publication types

  • Comparative Study

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Acute-Phase Proteins
  • Angiopoietin-2 / blood
  • Animals
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology*
  • Biomarkers / blood
  • Biotransformation
  • Blood Coagulation / drug effects
  • Blood Urea Nitrogen
  • Creatinine / blood
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Heparin / analogs & derivatives*
  • Heparin / pharmacokinetics
  • Heparin / pharmacology*
  • Hyaluronic Acid / blood
  • Immunity, Innate / drug effects
  • Kidney / drug effects*
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Lipocalins / blood
  • Male
  • Partial Thromboplastin Time
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Function Tests
  • Positron Emission Tomography Computed Tomography
  • Proteoglycans / pharmacokinetics
  • Proteoglycans / pharmacology*
  • Prothrombin Time
  • Proto-Oncogene Proteins / blood
  • Rats, Sprague-Dawley
  • Reperfusion Injury / blood
  • Reperfusion Injury / immunology
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Syndecan-1 / blood
  • Tissue Distribution

Substances

  • Acute-Phase Proteins
  • Angiopoietin-2
  • Anticoagulants
  • Biomarkers
  • Lcn2 protein, rat
  • Lipocalins
  • Platelet Aggregation Inhibitors
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Syndecan-1
  • heparin proteoglycan
  • Hyaluronic Acid
  • Heparin
  • Creatinine