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Kidney Week

Abstract: PO2359

A Pharmacologic "Stress Test" for Assessing Select Antioxidant Defenses in Patients with CKD

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)


  • Zager, Richard A., Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
  • Johnson, Ali C.m., Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
  • Guillem, Alvaro F., Renibus Therapeutics, Southlake, Texas, United States
  • Keyser, Donald Jeffrey, Renibus Therapeutics, Southlake, Texas, United States
  • Singh, Bhupinder, Renibus Therapeutics, Southlake, Texas, United States

Oxidative stress is a hallmark and mediator of CKD. Diminished antioxidant defenses are thought to be partly responsible. However, there is currently no way to prospectively assess antioxidant defenses in humans. RBT-6 (stannous protoporphyrin; SnPP) induces mild, transient oxidant stress in animal models, triggering increased expression of select antioxidant proteins (eg, heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that RBT-6 can also variably increase these proteins in humans and can thus serve as a pharmacologic “stress test” for gauging gene responsiveness and antioxidant reserves.


A total of 18 healthy volunteers and 24 participants with stage 3 CKD (n=12; eGFR 30–59 ml/min per 1.73m2) or stage 4 CKD (n=12; eGFR 15–29 ml/min per 1.73m2) received a single dose of RBT-6 at 9, 27, or 90 mg administered intravenously. Plasma and/or urinary antioxidant proteins were measured at baseline and for up to 4 days post-dosing. Kidney safety was assessed by serial measurements of BUN, creatinine, eGFR, albuminuria, and urinary AKI biomarkers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, cystatin C, and N-acetyl glucosaminidase).


Plasma HO-1, ferritin, p21, and urine NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (r=-0.85 to -0.95). All four proteins manifested statistically significant dose- and time-dependent elevations after RBT-6 infusion. However, marked inter-subject differences were observed. p21 responses to high-dose RBT-6 and HO-1 responses to low-dose RBT-6 were significantly suppressed in participants with CKD versus healthy volunteers. RBT-6 was well tolerated by all participants, and no evidence of nephrotoxicity was observed.


RBT-6 can be safely administered and, after its infusion, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease. Additionally, baseline values of these markers may also be indicative of oxidative stress at baseline, especially in patients in CKD.


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