Nonapoptotic cell death in acute kidney injury and transplantation

Kidney Int. 2016 Jan;89(1):46-57. doi: 10.1016/j.kint.2015.10.008.


Acute tubular necrosis causes a loss of renal function, which clinically presents as acute kidney failure (AKI). The biochemical signaling pathways that trigger necrosis have been investigated in detail over the past 5 years. It is now clear that necrosis (regulated necrosis, RN) represents a genetically driven process that contributes to the pathophysiology of AKI. RN pathways such as necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-induced regulated necrosis (MPT-RN) may be mechanistically distinct, and the relative contributions to overall organ damage during AKI in living organisms largely remain elusive. In a synchronized manner, some necrotic programs induce the breakdown of tubular segments and multicellular functional units, whereas others are limited to killing single cells in the tubular compartment. Importantly, the means by which a renal cell dies may have implications for the subsequent inflammatory response. In this review, the recent advances in the field of renal cell death in AKI and key enzymes that might serve as novel therapeutic targets will be discussed. As a consequence of the interference with RN, the immunogenicity of dying cells in AKI in renal transplants will be diminished, rendering inhibitors of RN indirect immunosuppressive agents.

Keywords: MLKL; RIP1; RIP3; RIPK1; RIPK3; apoptosis; ferroptosis; mitochondrial permeability transition; programmed cell death; regulated cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology*
  • Acute Kidney Injury / therapy
  • Animals
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Kidney Transplantation
  • Kidney Tubules / pathology*
  • Necrosis / drug therapy
  • Necrosis / genetics
  • Necrosis / metabolism
  • Necrosis / pathology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction


  • Immunosuppressive Agents
  • Receptor-Interacting Protein Serine-Threonine Kinases