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Abstract: PO0522

The Calcimimetic KP-2326 Alters the Gut Microbiota in a Rat Model of CKD-MBD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Biruete, Annabel, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Cross, Tzu-Wen L., Purdue University, West Lafayette, Indiana, United States
  • Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • De loor, Henriette, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • Evenepoel, Pieter, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium
  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Swanson, Kelly, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

CKD-MBD therapies, including diet and phosphate binders, can alter the gut microbiota. However, it is unknown if calcimimetics alter the gut microbiota and their derived uremic toxins.

Methods

Cy/+ rats, a slowly progressive rat model of CKD-MBD (CKD hereafter, n=13) and normal littermates (NL, n=8) consumed a diet with 0.7% phosphorus from 18 wk of age (~ 60% of NL glomerular filtration rate (GFR)) to euthanasia at 28 wk of age (~30% of NL GFR). An additional CKD group received the pre-clinical form of etelcalcetide, KP-2326 (CKD+KP; 0.6 mg/kg IP 3 times/wk, n=13) for a total of 10 wk starting at 18 wk of age. DNA was extracted from cecal samples, the V4 region of the 16S rRNA gene was sequenced via Illumina MiSeq, and data were analyzed via QIIME2. Indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide (TMAO) were quantified by ultra-performance liquid chromatography-tandem mass spectrometry.

Results

CKD or KP did not affect α-diversity, or diversity within samples. Β-diversity, or diversity between samples, assessed by unweighted UniFrac distances was different across all groups (PERMANOVA p=0.001; q<0.013 between groups). Weighted UniFrac distances (presence/absence + abundance), differed between NL vs. CKD and CKD vs. CKD+KP (q<0.04), and there was a trend between NL and CKD+KP (q=0.07). At the phyla-level, CKD rats had a lower relative abundance of Firmicutes than NL (60.6±9.4% vs. 68.7±3.4%, p=0.03), but CKD+KP rats were comparable to NL (67.9±4.5%, p=0.96). Bacteroidetes relative abundance was higher in CKD vs. CKD + KP (22.1±5.3 vs. 17.7±3.2%, p=0.03). Several bacterial genera that were lower in CKD were comparable to NL rats with KP, including Allobaculum, Bifidobacterium, and Blautia. Similarly, CKD rats had a higher relative abundance of the mucin-degrader Akkermansia compared to NL, and while KP had a lower relative abundance, it remained higher than NL. Despite the gut microbial changes, IS, PCS, and TMAO levels were higher in the CKD and CKD+KP compared to NL rats (p<0.05).

Conclusion

KP-2326 changed the gut microbial composition without altering the levels of gut-derived uremic toxins. As the calcium-sensing receptor is expressed along the gastrointestinal tract, future studies should explore the effect of calcimimetics on host-microbe interactions.

Funding

  • NIDDK Support