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Abstract: TH-PO882

Pirfenidone May Protect Against Diabetic Kidney Disease by Reducing Fumarate

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Kim, Jiwan John, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Bhattarai, Manoj, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Miyamoto, Satoshi, Okayama University Hospital, Okayama, Japan
  • Montemayor, Daniel, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Darshi, Manjula, University of Texas Health San Antonio, San Antonio, Texas, United States
  • Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States
Background

Recent studies suggest that Pirfenidone (PFD) has anti-fibrotic effect in various diseases including diabetic kidney disease (DKD). We previously demonstrated that in type 2 diabetic animal models PFD significantly reduces the expansion of mesangial matrix. Furthermore, in a placebo-cotrolled clinical study we found that PFD treatment for 54 weeks significantly improved eGFR with a low dose. In the current study we aim to identify predictive metabolite biomarkers and potential mechanisms associated with renoprotective effects of PFD and also tested a longer acting and better tolerated version.

Methods

1) Two types of PFD (short acting and long acting) were administered to 16 week db/db and db/m control mice (n=8 each). After 4 weeks, 24 hr urine was collected and 70 urinary metabolites were quantified using GC-MS/MS. 2) Urine and plasma from our prior clincal trial was assessed for metabolite markers from samples collected every 3 months. Fumarate in human urines was also assessed with a specific fumarate assay kit.

Results

Significant changes in metabolites were observed between the db/mand db/db, and PCA plot clustered the two groups into well-defined spaces. The db/db mice treated with PFD were in closer proximity to the db/db cluster with a slight trend toward the db/m cluster. Untreated Db/db mice had lower levels of succinate, citrate, 3-methyl crotonyl glycine, 2 hydroxyglutarate, and uracil, but PFD treated db/db mice had the levels restored either partially or completely back to the levels of db/m. Interestingly, the db/db mice had three fold increase in fumarate as compared to the db/m mice (p<0.0001), while long acting PFD treatment significantly reduced the fumarate levels below that of db/m mice (p<0.0001). In the human study, the baseline urine fumarate level of placebo treated patients showed negative correlation with the rate of change in GFR at 12 months (r=-0.89, p<=0.05). The correlation was not observed in subjects treated with PFD.

Conclusion

The anti-fibrotic effects of PFD in kidney has effects on several urinay metabolites identified to be regulated in human diabetic kidney disease. Fumarate may be a useful biomarker in the mouse model of diabetic kidney disease and may be a potential marker for anti-fibrotic therapies.

Funding

  • NIDDK Support