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Kidney Week

Abstract: PO0940

Systemic Therapies Targeted to Ischemia in a Model of Diabetic AKI

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Cleland, Jeffrey, Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Sharma, Rishi, Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Appiani La Rosa, Santiago, Ashvattha Therapeutics, Inc, Redwood City, California, United States
  • Zhang, Jinglei, Creative Biolabs, Shirley, New York, United States
  • Chang, Audrey Qing, Creative Biolabs, Shirley, New York, United States
  • Kannan, Sujatha, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Rangaramanujam, Kannan, Ashvattha Therapeutics, Inc, Redwood City, California, United States
Background

In acute kidney injury (AKI) and chronic kidney disease (CKD), ischemia in the kidney results in inflammation and tissue damage. The initial response to injury is the infiltration of reactive macrophages into the kidney with subsequent pro-inflammatory cytokine expression. Upon systemic administration, hydroxyl dendrimers selectively target reactive macrophages in the ischemic kidney with renal clearance maximizing kidney exposure.

Methods

Diabetes was induced in Wistar rats by administration of streptozotocin (70 mg/kg) as a single intraperitoneal (IP) injection. Rats with a blood glucose of >16.7 mM were allocated to 4 groups (G1-4; n=3/group). After 6 weeks, ischemia reperfusion injury (IRI) was conducted with 60 min ischemia(I)/6 hr reperfusion (R) (G2), or 45 min I/24 hr R (G3 & G4). A sham surgery was performed as a control (G1). Hydroxyl dendrimer labeled with Cy5 (D-Cy5) was administered IP 1 hr after IRI in G1, G2 and G3 and 12 hr after IRI in G4. Renal function was assessed by clinical chemistry, glomerular filtration rate (GFR), and kidney injury biomarkers. Rats were euthanized 6 (G2) or 24 hr (G1, G3, G4) after surgery. Kidneys were evaluated for tubular damage and tubular epithelial cell necrosis and stained by DAPI and anti-CD68 antibody (macrophage).

Results

Glucose levels increased to ~30 mM prior to IRI. GFR was significantly reduced from 1.8 mL/min (sham) to <0.1 mL/min in IRI rats. Serum creatinine and blood urea nitrogen were significantly elevated in IRI groups (G4>G3>G2). The degree of kidney damage increased with the longer reperfusion time prior to sacrifice (G4, G3 > G2). In all IRI groups, renal tubular necrosis was moderate to severe and proximal tubule damage was severe. Maximal uptake of the D-Cy5 was observed in renal tubules in reactive macrophages in G2.

Conclusion

A diabetic model of AKI was successfully established to evaluate targeting of hydroxyl dendrimers to reactive macrophages. Prolonged ischemia followed by rapid reperfusion increased reactive macrophages and subsequent uptake of hydroxyl dendrimers. Given the high incidence of diabetic nephropathy and higher risk for AKI in these patients, these results provided a model and treatment strategy to evaluate targeted therapies with hydroxyl dendrimer drug conjugates to treat AKI and CKD.

Funding

  • Commercial Support