The Author Replies
Authors: Sanjeev Kumar
Journal: Kidney International (2018)

Editor’s noteThe Kidney Precision Medicine Project, a major initiative from the National Institute of Diabetes, Digestive Diseases and Kidney Diseases, is underway and will in part focus on the molecular interrogation of kidney biopsies from patients with AKI. The Kidney Precision Medicine Project is expected to provide major insights into the pathogenesis of AKI and will help address many of the questions raised in these letters.4Zuk A, Palevsky P, Fried L, et al. Overcoming translational barriers in acute kidney injury: a report from an NIDDK workshop [e-pub ahead of print]. Clin J Am Soc Nephrol. https://doi.org/10.2215/CJN.06820617.Google ScholarIn their letter, Rosen and Heyman remind us of the widely appreciated morphological differences between human versus mice warm ischemia reflow–induced acute kidney injury (AKI), and highlight the lack of attention to distal tubule and vascular injury responses.1Rosen S. Heyman S. Concerning cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int. 2018; 94: 218Scopus (6) Google Scholar First, it was clarified from the outset that the main focus of the basic science review was on the cellular and molecular pathways involved in renal repair leading to kidney function recovery after AKI, and not on the immediate/early injury responses that contribute to the initiation of AKI syndrome.2Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int. 2018; 93: 27-40Google Scholar To this end, word count permitting, this review attempted to cover the majority of the published research work including the vascular responses regulating renal repair (references 91–131 in Kumar).2Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury.Kidney Int. 2018; 93: 27-40Google Scholar Second, I agree that extensive proximal tubular epithelial cell necrosis is not regularly observed in human ischemic AKI, and more often than not the proximal tubular epithelial cell morphological changes are subtle and patchy. A key point to consider while understanding this apparent dissociation is how often a critically ill patient with the high possibility of ischemic AKI undergoes renal biopsy to gain deep insights into the injury/repair responses. In such patients, the kidney biopsy procedure–related risks far outweigh the benefit involved, which serves as a major deterrent to biopsy such kidneys. In consideration of the major challenges to developing an in-depth understanding of AKI in a heterogeneous patient population including reluctance to biopsy an ischemic kidney and obtaining a truly adequate and representative sample, rodent ischemia reperfusion injury models remain a valuable tool with the expectation that some, but not all, of the renal pathophysiological consequences will have human parallels.3Liu J. Kumar S. Dolzhenko E. et al.Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion.JCI Insight. 2017; 2: e94716Google Scholar Indeed, we need to develop and refine the current preclinical murine AKI models with a hope that the latter will aid in overcoming the translational barriers in AKI.4Zuk A, Palevsky P, Fried L, et al. Overcoming translational barriers in acute kidney injury: a report from an NIDDK workshop [e-pub ahead of print]. Clin J Am Soc Nephrol. https://doi.org/10.2215/CJN.06820617.Google Scholar Fully cognizant of the current limitations of the two approaches, an unbiased, critical integration of the two with cutting-edge tools to discover high-value targets in the acutely injured/repairing human kidneys coupled with thorough mechanistic studies in the preclinical long-term survival–compatible mice AKI models represents a promising way forward. The Kidney Precision Medicine Project, a major initiative from the National Institute of Diabetes, Digestive Diseases and Kidney Diseases, is underway and will in part focus on the molecular interrogation of kidney biopsies from patients with AKI. The Kidney Precision Medicine Project is expected to provide major insights into the pathogenesis of AKI and will help address many of the questions raised in these letters.4Zuk A, Palevsky P, Fried L, et al. Overcoming translational barriers in acute kidney injury: a report from an NIDDK workshop [e-pub ahead of print]. Clin J Am Soc Nephrol. https://doi.org/10.2215/CJN.06820617.Google Scholar Cellular and molecular pathways of renal repair after acute kidney injuryKidney InternationalVol. 93Issue 1PreviewThe acutely injured mammalian kidney mounts a cellular and molecular response to repair itself. However, in patchy regions such intrinsic processes are impaired and dysregulated leading to chronic kidney disease. Currently, no therapy exists to treat established acute kidney injury per se. Strategies to augment human endogenous repair processes and retard associated profibrotic responses are urgently required. Recent studies have identified injury-induced activation of the intrinsic molecular driver of epithelial regeneration and induction of partial epithelial to the mesenchymal state, respectively. Full-Text PDF Open ArchiveConcerning cellular and molecular pathways of renal repair after acute kidney injuryKidney InternationalVol. 94Issue 1PreviewThe review by Kumar, though well written and beautifully illustrated,1 further strengthens conceptual errors regarding human acute kidney injury (AKI), that are based on the evaluation of a murine tissue destructive process in ischemia reperfusion models, which does not parallel the human situation. Warm ischemia reflow is almost never the basis for AKI in the native kidney,2 and in the transplant situation the human kidney is very resistant to complete cessation of blood flow. Furthermore, the anatomy of the murine kidney3 and its tubular molecular signature (anchor genes)4 are very different from those of the human. Full-Text PDF Open Archive