ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

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)

Authors

  • 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
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