Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Molecular Profile of Mitochondrial Dysfunction in Kidney Transplant Biopsies Is Associated With Poor Allograft Outcome.

BACKGROUND: In kidney transplantation (KT), progression of chronic histological damage with subclinical inflammation is associated with poor long-term allograft survival. The role of nonimmunological pathways in chronic allograft injury has not been fully assessed. METHODS: We analyzed a public microarray dataset that used 1-year protocol kidney transplant biopsy specimens to investigate whether nonimmunological genes and pathways might influence long-term allograft outcome. The selected microarray dataset included 3 patient/sample groups based on their histological findings: normal histology (n = 25), interstitial fibrosis alone (IF alone, n = 24), and interstitial fibrosis with inflammation (IF+i, n = 16). The IF+i group had lower death-censored graft survival and renal function in patients with a mean follow-up of 4 years. We performed statistical analysis comparing gene expression patterns in the 3 group samples. RESULTS: Gene cluster enrichment and group-specific expression patterns demonstrated a divergent pattern between mitochondrial and immune response genes, with downregulation of mitochondrial genes in the IF+i group. Gene ontological analysis of the downregulated mitochondrial genes identified generation of precursor metabolite and energy, and response to oxidative stress as the most significant biological processes. The transcription regulation pathway analysis of downregulated gene cluster demonstrated transcription factors involved in mitochondrial biogenesis. CONCLUSIONS: The molecular signature of mitochondrial dysfunction reflects mitochondrial energetic insufficiency, and inadequate antioxidant response involved in mitochondria biogenesis pathways is associated with IF+i and worse long-term allograft survival. Thus, mitochondria function impairment appears to be an important nonimmune factor involved in chronic allograft injury.