Kidney Week

Abstract: SA-OR033

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

Session Information

• Anemia and Iron Metabolism: Basic Research
  November 09, 2019 | Location: 150, Walter E. Washington Convention Center
  Abstract Time: 04:54 PM - 05:06 PM

Category: Anemia and Iron Metabolism

• 201 Anemia and Iron Metabolism: Basic

Authors

• Thibodeau, Jean-Francois, Prometic Biosciences Inc., Laval, Quebec, Canada

Jean-Francois Thibodeau, PhD



Dr. Jean-Francois Thibodeau is a early career scientist within Liminal Bioscience's R&D division. Dr. Thibodeau's research focuses on establishment of novel preclinical models of kidney injury, as well as elucidation and characterisation of signaling pathways involved in fibrogenesis and validating the effects of small therapeutic anti-fibrotic compounds in the context of kidney injury.

• Hince, Kathy, Prometic Biosciences Inc., Laval, Quebec, Canada

Kathy Hince,

• Blais, Amélie, Kidney Research Centre, Ottawa, Ontario, Canada

Amélie Blais,

• Corpuz, Ramon, Prometic Biosciences Inc., Laval, Quebec, Canada

Ramon Corpuz,

• Leblond, Francois A., Prometic Biosciences Inc., Laval, Quebec, Canada

Francois A. Leblond,

• Grouix, Brigitte, Prometic Biosciences Inc., Laval, Quebec, Canada

Brigitte Grouix,

• Leduc, Martin, Prometic Biosciences Inc., Laval, Quebec, Canada

Martin Leduc,

• Hébert, Richard L., Kidney Research Centre, Ottawa, Ontario, Canada

Richard L. Hébert,

• Kennedy, Chris R., Kidney Research Centre, Ottawa, Ontario, Canada

Chris R. Kennedy,

• Gagnon, Lyne, Prometic Biosciences Inc., Laval, Quebec, Canada

Lyne Gagnon,

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 –