Kidney Week

Abstract: PO2359

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

Session Information

• Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

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

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

Authors

• Zager, Richard A., Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

Richard A. Zager,

• Johnson, Ali C.m., Fred Hutchinson Cancer Research Center, Seattle, Washington, United States

Ali C.m. Johnson,

• Guillem, Alvaro F., Renibus Therapeutics, Southlake, Texas, United States

Alvaro F. Guillem,

• Keyser, Donald Jeffrey, Renibus Therapeutics, Southlake, Texas, United States

Donald Jeffrey Keyser,

• Singh, Bhupinder, Renibus Therapeutics, Southlake, Texas, United States

Bhupinder Singh,

Background

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.

Methods

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).

Results

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.

Conclusion

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.

Funding

• Commercial Support –