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Abstract: FR-PO148

Microbiome Modulation After Severe AKI Accelerates Recovery and Decreases Fibrosis

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Gharaie, Sepideh, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Lee, Kyungho, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Xu, Jiaojiao, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Arend, Lois J., Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Pluznick, Jennifer L., Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Noel, Sanjeev, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Rabb, Hamid, Johns Hopkins Medicine, Baltimore, Maryland, United States
Background

Most studies on modifying the microbiome to improve acute kidney injury (AKI) have focused on prevention. Effects on repair have not been well studied. We hypothesized that modifying gut microbiota with antibiotics (ABX) administered AFTER severe ischemic AKI in mice would accelerate kidney recovery and mitigate fibrosis.

Methods

C57BL6 mice underwent 50 min unilateral ischemia reperfusion injury (UIRI). Amoxicillin, metronidazole, combination of ABX (ampicillin, metronidazole, neomycin, vancomycin) or control were started after IR. Glomerular filtration rate (GFR) was measured in conscious mice via transcutaneous detection of FITC-sinistrin. Kidneys were evaluated for fibrosis with Masson’s trichrome, mRNA expression of Col1α1, TGFβ, and αSMA by qPCR, and immunophenotyped by flow cytometry. Stool 16s rRNA sequencing was performed. Germ free (GF) and CD4 KO mice with severe AKI were studied.

Results

Amoxicillin started post IRI increased GFR at 1, 2, 3 and 4 weeks compared to control (900±26 vs 749±31 μL/min/100g,P<.01; 922±28.8 vs 707±25, P<.01; 922±21 vs 811±26, P=0.021; and 931±23 vs 758±24, P<.01). Amoxicillin decreased fibrosis percentage in both cortex and outer medulla compared to control (5.5±1.2 vs 12.1±2.3, P=.015; 6.6±0.7 vs 13.9±1.2, P<.01). Amoxicillin decreased TGFβ expression compared to control (0.6±0.1 vs 1.1±0.1, P=.013). Amoxicillin decreased percentage of kidney CD4T cells (47.5±1.8 vs 61.5±2.4, P<.01), while CD8 cells (39.4±2.2 vs 26.2±2.2, P<.01) and PD1 expression on CD8 (21.1±2.3 vs 7.73±1.6, P<.01) were increased. Amoxicillin did not accelerate kidney repair in GF mice, but was effective in CD4 KO mice. Amoxicillin increased stool Alistipes, Anaerotruncus, and Lactobacillus species and reduced Holdemanella and Anaeroplasma. GFR level was increased in metronidazole (P=.02) at 1 week and in ABX at 1 (P<.01), 2 (P=.09), and 4 (P=.011) weeks. Fibrosis percentage in cortex and outer medulla was increased by metronidazole (22.3±3.1 vs 17.4±4.3 and 13.6±1.6 vs 10.6±1.2) and combination of ABX (28.7±8.7 vs 17.4±4.3 and 14.4±1.6 vs 10.6±1.2) versus control.

Conclusion

Modification of gut bacteria with amoxicillin administered after induction of ischemic AKI is a promising novel therapeutic approach to accelerate recovery of kidney function and mitigate AKI to CKD progression.

Funding

  • NIDDK Support