Protocol for a Preclinical Systematic Review and Meta-Analysis of Pharmacological Targeting of Peroxisome Proliferator-Activated Receptors in Experimental Renal Injury

Contributors:
  1. Yeong Huei Desmond Chuah
  2. Emer Conroy
  3. Alison Reynolds
  4. Conor Judge
  5. Francisco J. López-Hernández
  6. Carel le Roux
  7. Neil Docherty

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Description: Fatty acid oxidation (FAO) is impaired following acute kidney injury (AKI) and in chronic kidney disease (CKD), and contributes to tubular dedifferentiation and the development of tubulointerstitial fibrosis. The development of renal fibrosis is the pathologic hallmark which most strongly predicts adverse outcomes in both AKI and CKD. No anti-fibrotic therapies are currently used in the treatment of AKI or CKD in clinical practice. However, given the well-characterised deficit in tubular FAO which drives development and progression of renal fibrosis, druggable targets involved in renal lipid metabolism are sought for this purpose, with peroxisome proliferator-activated receptors (PPARs) being one of the strongest candidate targets. Pharmacologic PPAR modulation offers an attractive means of promoting FAO to oppose renal fibrosis, with potential for translatability to human AKI and CKD. Furthermore, repurposing of licensed drugs that activate PPARs, including fibrates, thiazolidinediones, and glitazars, for a renal fibrosis indication could decrease time and cost associated with the drug development pipeline. No human clinical trials examining pharmacological stimulation of FAO to mitigate renal fibrosis have yet been conducted. However, a crucial intermediary step prior to the conduct of a human clinical trial of pharmacological PPAR modulation in renal fibrosis is a systematic and rigorous evaluation of the efficacy of this approach in preclinical models, including assessment of external and construct validity. This systematic review and meta-analysis will synthesise evidence from the multiple preclinical studies performed to test the impact of pharmacological PPAR targeting in experimental renal injury, and inform the design of future preclinical and clinical studies evaluating FAO restoration through PPAR modulation in renal fibrosis.

License: CC-By Attribution 4.0 International

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