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Abstract: SA-OR033

PBI-4610 Improves Renal Function, Anemia, and Histopathological Abnormalities in an Adenine-Induced CKD Model

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Thibodeau, Jean-Francois, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Hince, Kathy, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Blais, Amélie, Kidney Research Centre, Ottawa, Ontario, Canada
  • Corpuz, Ramon, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Leblond, Francois A., Prometic Biosciences Inc., Laval, Quebec, Canada
  • Grouix, Brigitte, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Leduc, Martin, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Hébert, Richard L., Kidney Research Centre, Ottawa, Ontario, Canada
  • Kennedy, Chris R., Kidney Research Centre, Ottawa, Ontario, Canada
  • Gagnon, Lyne, Prometic Biosciences Inc., Laval, Quebec, Canada
Background

Adenine-supplementation is an effective tool to study the onset and progression of fibrosis and CKD-associated sequelae. Prometic’s PBI-compounds show excellent safety and efficacy in both experimental models and in human studies. Here we tested a second-generation orally active PBI compound, PBI-4610, in adenine-induced renal injury.

Methods

Six to eight-week old male C57BL/6 mice were fed a regular (Control, n=9) or custom diet consisting of regular chow supplemented with 0.25% adenine for 30 days. After 7 days, mice were administered vehicle (H2O, n=9) or PBI-4610 (100 mg/kg, n=10) by daily oral gavage. Blood sampling was done at day 0, 7 and 30. Reticulocytes were quantified by FACS analysis. Serum urea and creatinine levels were measured at endpoint by ELISA and HPLC respectively. Renal histology was assessed using H&E and Masson’s trichrome stained kidney sections.

Results

Adenine decreased bodyweight, which was significantly improved by PBI-4610 at days 17, 21 and 24. Anemia was apparent as hematocrit (Hct) began to decline as early as 7 days post-adenine, however this was significantly improved by PBI-4610 at day 14, 21 and 30. FACS revealed reduced reticulocyte counts in vehicle-treated adenine mice compared to Control mice at day 14, however at day 30, levels were increased. PBI-4610 treatment maintained reticulocyte counts to normal levels. Similarly, hemoglobin was decreased in adenine-fed mice, but levels in PBI-4610 mice trended higher (p=0.059). At endpoint, blood urea nitrogen and serum creatinine were increased by adenine-feeding, however treatment with PBI-4610 significantly reduced these levels. Tubulointerstitial fibrosis, collagen deposition, tubular dilatation and inflammation were all significantly reduced by PBI-4610. Finally, survival rate in PBI-4610 treated mice increased from 30% in the vehicle group to 80%.

Conclusion

Taken together, PBI-4610 improves several key renal functional and structural abnormalities in adenine-induced CKD including anemia, fibrosis and renal function decline leading to improved survival rates. Although the mechanism of action remains incompletely resolved, the above findings suggest treatment with PBI-4610 may represent a novel therapeutic modality in CKD.

Funding

  • Commercial Support