Li Z, Li N: Epigenetic Modification Drives Acute Kidney Injury-to-Chronic Kidney Disease Progression. Nephron DOI 10.1159/000517073
Little doubt exists that a variable fraction of patients with acute kidney injury (AKI; defined by the creatinine-based KDIGO criteria) can eventually develop new-onset chronic kidney disease (CKD; again defined by KDIGO criteria), even when no (recognizable) underlying kidney disease preceded the episode of AKI. This evolution depends highly on the cause of the AKI: urinary tract obstruction, acute renal ischemia, nephrotoxins, thrombotic microangiopathy, inflammatory interstitial nephritis, vasculitis or glomerulonephritis. Hypoxia of renal parenchyma can lead to tubular injury and apoptosis, capillary rarefaction, and maladaptive repair, and renal fibrosis is a common end result.
The role of epigenetics, via DNA methylation/demethylation, histone modification, chromosomal re-configuration, and transcriptomic or translational activity, is likely important for the AKI to CKD transition. Reductions in peri-tubular capillary density, apoptosis, and stimulation of pro-fibrotic (myo-fibroblast-dependent) processes (MCP-1, TGF-β, CTGF mediated) seem to be a common final pathway.
Li and Li comprehensively review the role and mechanisms for epigenetic modifications in the AKI to CKD transition. Histone modification (methylation/acetylation) and chromatin remodeling has been established as mechanistically involved in the AKI to CKD transition in animal models. Preliminary data suggest that interventions directed to these epigenetic pathways may have salutary effects. Similarly, DNA methylation/demethylation seems to play crucial roles, acting via genes for such entities, including klotho, erythropoetin, and GTPase-activating proteins. Furthermore, non-coding RNA (mainly microRNA) and/or long non-coding RNA also likely play key roles in promoting fibrosis in the AKI to CKD transition.
These findings open up new avenues for mitigating the AKI to CKD evolution, but translation from animal models to human disease will be both challenging and difficult. Many obstacles must be overcome before epigenetic modification becomes a practical intervention in the AKI to CKD transition, not the least of which is the extreme heterogeneity of the pathogenesis of AKI, as presently defined. Subjects with AKI at highest and lowest risk for a clinically significant AKI to CKD transition will have to be prospectively characterized, using both serum and urine biomarkers and biopsy-determined morphology. This will be an arduous task, in my opinion. The well-written and comprehensive review by Li and Li provides a glimpse at a road map for the future, and engenders cautious optimism that the AKI to CKD transition may be beneficially modifiable in the not too distant future.