Pathogenesis of acute kidney injury: foundation for clinical practice

Abstract

The pathogenesis of acute kidney injury (AKI) is complex, involving such factors as vasoconstriction, leukostasis, vascular congestion, cell death, and abnormal immune modulators and growth factors. Many targeted clinical therapies have failed, are inconclusive, or have yet to be tested. Given the complexity of the pathogenesis of AKI, it may be naive to expect that one therapeutic intervention would have success. Some examples of detrimental processes that can be blocked in preclinical models to improve kidney function and survival are apoptotic cell death in tubular epithelial cells, complement-mediated immune system activation, and impairment of cellular homeostasis and metabolism. Modalities with the potential to decrease morbidity and mortality in patients with AKI include vasodilators, growth factors, anti-inflammatory agents, and cell-based therapies. Pharmacologic agents that target these diverse pathways are being used clinically for other indications. Using combinatorial approaches in future clinical trials may improve our ability to prevent and treat AKI.

Figure 1

Plasma and Urine sample. Collected samples demonstrated hemolysis and free hemoglobin in the plasma, and the urine specimen tested positive for blood.

Figure 2

Immune mechanisms in kidney ischemia-reperfusion injury (IRI). The insult activates a number of targets including leukocytes, endothelial cells, and tubular epithelial cells leading to a “sterile” inflammatory response. This process is necessary to initiate repair process but overzealous activation leads to tissue injury. Invariant natural killer T (NKT) cells, neutrophils (PMN), and macrophages (MØ), which originate in the bone marrow, collect in the kidney where they are activated and release pro-inflammatory cytokines. IRI has detrimental effects on endothelial cells, resulting in greater vascular permeability, expression of adhesion molecules, and leukocyte migration into the kidney. Renal dendritic cells (DCs) produce cytokines and chemokines that respond to damage-associated molecular pattern (DAMP) signals, activate NKT cells, and produce cytokines and chemokines. Tubular epithelial cells show enhanced complement deposition and upregulate the expression of Toll-like receptors (TLRs), both of which mediate chemokine and cytokine production in the injured kidney. As a direct or indirect consequence of changes in each cell type, other cells drive inflammation after kidney IRI. These interactions between kidney and bone marrow derived cells, and innate and adaptive immunity, reflect the complexities in acute kidney injury-associate inflammation. This figure is based on a model presented in Kinsey et al(3).

Figure 3

Sites of action for selected therapeutic agents with potential use in acute kidney injury (AKI). Abbreviations: PPAR, peroxisome proliferator-activated receptor; A2aR, adenosine A2a receptor; S1PR1, sphingosine-1-phosphate receptor 1; Tregs, regulatory T cells; MSCs, multipotent stromal cells; CO, carbon monoxide; APC, activated protein C; EPO, erythropoietin.