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Original ArticlesChronic Kidney Disease
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A Pharmacologic “Stress Test” for Assessing Select Antioxidant Defenses in Patients with CKD

Richard A. Zager, Ali C.M. Johnson, Alvaro Guillem, Jeff Keyser and Bhupinder Singh
CJASN May 2020, 15 (5) 633-642; DOI: https://doi.org/10.2215/CJN.15951219
Richard A. Zager
1Clinical Research Division, The Fred Hutchinson Cancer Research Center, Seattle, Washington
2Department of Medicine, The University of Washington, Seattle, Washington
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Ali C.M. Johnson
1Clinical Research Division, The Fred Hutchinson Cancer Research Center, Seattle, Washington
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Alvaro Guillem
3Renibus Therapeutics, Southlake, Texas
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Jeff Keyser
3Renibus Therapeutics, Southlake, Texas
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Bhupinder Singh
3Renibus Therapeutics, Southlake, Texas
4Department of Medicine, The University of California, Irvine, California
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Abstract

Background and objectives 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. Tin protoporphyrin (SnPP) induces mild, transient oxidant stress in mice, triggering increased expression of select antioxidant proteins (e.g., heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that SnPP can also variably increase these proteins in humans and can thus serve as a pharmacologic “stress test” for gauging gene responsiveness and antioxidant reserves.

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

Results Plasma HO-1, ferritin, p21, and 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 SnPP injection. However, marked intersubject differences were observed. p21 responses to high-dose SnPP and HO-1 responses to low-dose SnPP were significantly suppressed in participants with CKD versus healthy volunteers. SnPP was well tolerated by all participants, and no evidence of nephrotoxicity was observed.

Conclusions SnPP can be safely administered and, after its injection, 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.

Clinical Trial registry name and registration number A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3–4 Chronic Kidney Disease, NCT0363002 and NCT03893799

  • mice
  • creatinine
  • CST3 protein
  • human
  • cystatin C
  • albuminuria
  • antioxidants
  • lipocalin-2
  • tin
  • ferritins
  • tin protoporphyrin IX
  • protoporphyrins
  • hexosaminidases
  • healthy volunteers
  • exercise test
  • blood urea nitrogen
  • HAVCR1 protein
  • human
  • Received December 27, 2019.
  • Accepted March 20, 2020.
  • Copyright © 2020 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 15 (5)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 5
May 07, 2020
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A Pharmacologic “Stress Test” for Assessing Select Antioxidant Defenses in Patients with CKD
Richard A. Zager, Ali C.M. Johnson, Alvaro Guillem, Jeff Keyser, Bhupinder Singh
CJASN May 2020, 15 (5) 633-642; DOI: 10.2215/CJN.15951219

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A Pharmacologic “Stress Test” for Assessing Select Antioxidant Defenses in Patients with CKD
Richard A. Zager, Ali C.M. Johnson, Alvaro Guillem, Jeff Keyser, Bhupinder Singh
CJASN May 2020, 15 (5) 633-642; DOI: 10.2215/CJN.15951219
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Keywords

  • mice
  • creatinine
  • CST3 protein
  • human
  • cystatin C
  • albuminuria
  • antioxidants
  • lipocalin-2
  • tin
  • ferritins
  • tin protoporphyrin IX
  • protoporphyrins
  • hexosaminidases
  • healthy volunteers
  • exercise test
  • blood urea nitrogen
  • HAVCR1 protein

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