Figure 3: Mean (±SE) Urine Phosphorus/Creatinine Ratios 1 Among Renazorb, Sevelamer, and Control Groups of Rats (On Treatment)

Intravenous Administration of UNI-494 Ameliorates Acute Kidney Injury in Rat Model of Delayed Graft Function

Satya Medicherla1, PhD, Guru Reddy1, PhD, Shalabh Gupta1, MD

1Unicycive Therapeutics, Inc.

Background

  • There are no FDA approved drugs for the treatment of acute kidney injury (AKI), which affects 10-15% of hospitalized patients and often results in renal transplantation or lifelong dialysis
  • Inflammation and reactive oxygen species driven mitochondrial permeability transition pore (mPTP) opening causes mitochondrial dysfunction/swelling and eventual cell death over time
  • This is implicated in a wide range of acute diseases including AKI originating from ischemia reperfusion injury or delayed graft function (DGF)
  • Furthermore, unresolved inflammation exacerbates sustained mPTP opening, evident in chronic kidney diseases

OBJECTIVE

We present results from a study evaluating the in vivo efficacy of intravenous (IV) UNI-494 in the unilateral renal ischemia-reperfusion (I/R) rat model of AKI, which is a well-established model of DGF1

Methods

  • Rats were anesthetized, the right kidney was removed, and I/R was induced by clamping the renal vessels in the left kidney for 30 minutes (Figure 1)
  • UNI-494 was administered IV 30 minutes prior to I/R (Figure 1)
  • After 24 hours of reperfusion in metabolic cages, blood samples were collected for serum creatinine (sCr) and BUN levels, and urinary samples were collected for ACR and NGAL
  • The clamped left kidney was collected and processed for histology for tubular injury scores
Figure 1: UNI-494 I/R Study Design - Preventive Dosing

Results

  • In this study, I/R induced significant increases of sCr, BUN, uACR, and uNGAL in the vehicle treated I/R group vs No I/R sham group (Figure 2, 3)
  • A single IV dose of UNI-494 at 5 mg/kg/IV or 10 mg/kg/IV reduced the kidney functional markers sCr, BUN, uACR, and tubular injury marker (uNGAL) (all p<0.05) (Figure 2, 3)
Figure 2. Mean (SE) UNI-494 + I/R vs I/R vs Sham – Urinary ACR, Urinary NGAL, Serum Creatinine, BUN
Figure 3. Histological Image Where the Nature of the Proximal Tubule Injury Is Pointed with Arrows


CONCLUSIONS/Implications

  • UNI-494 prevented serum and urinary markers of AKI at 5 mg/kg
  • Proximal tubular injury scores improved in a dose-dependent manner
  • UNI-494 is a potential candidate for prevention of DGF and other AKI clinical conditions
  • Further studies are ongoing
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References:

1. Cavaillé-Coll M. et al., Am J Transplant. 2013. May.

Acknowledgments:

Writing support was provided by Xelay Acumen Group, Inc., and funded by Unicycive Therapeutics, Inc.