Journal
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 15, Issue 5, Pages 633-642Publisher
AMER SOC NEPHROLOGY
DOI: 10.2215/CJN.15951219
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; human
Categories
Funding
- Fred Hutchinson Cancer Research Center
- Renibus Therapeutics, Southlake, Texas
Ask authors/readers for more resources
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; eGFR30-59ml/minper 1.73m(2)) or stage 4CKD(n=12; eGFR15-29ml/minper 1.73m(2)) 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. PlasmaHO-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 respons iveness/reserves in subjects with and without kidney disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available