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Renal ischemia-reperfusion (I/R) injury involves several complex pathophysiological mechanisms that are incompletely understood. Broadly, cellular injury is in part due to the anoxic cell death incurred during the ischemic period, as well as the buildup of free radicals. However, with the return of blood flow comes an accumulation of inflammatory cells and mediators, reactive oxygen species (ROS) and reactive nitrogen species (RNS). The subsequent biochemical derangements in intracellular homeostasis trigger a cascade to further cell death from inflammation, apoptosis, and necrosis.1,2 These events may lead to delayed graft function in the case of transplant recipients or increases in complications, length of hospital stay, and cost of care for those experiencing I/R injury. Currently, the clinical diagnosis of acute kidney injury due to renal I/R is both difficult to confirm and likely comprised of multiple pathologies.3 Clinical indicators of renal injury range from serum creatinine, serum and urine electrolytes, fractional excretion of sodium, neutrophil gelatinase–associated lipocalin, and urine microscopy.4 The following chapter provides a cellular overview of the I/R inflammatory process and lists potential clinical biomarkers to detect clinically significant injury.


  • The kidneys receive about 1 L/min of blood flow, or roughly 20% of the total cardiac output, equating to about 605 mL/min of renal plasma flow5

  • The amount that is filtered by the glomeruli is usually 125 mL/min. Hence, the kidney receives a vastly larger supply of blood than that needed for metabolism

  • Underperfusion of the kidney occurs when the mean arterial pressure is decreased below the kidney’s autoregulatory threshold of a systolic pressure of 80 mm Hg


  • Early phase

    • Decrease in ATP and anerobic metabolism leads to increases in local phospholipases, ROS, free radicals, and calcium disregulation, associated with6:

      • Endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) imbalance

      • Alterations in intracellular pH

      • Increases in ROS and RNS

      • Cellular lipid peroxidation

      • Mitochondrial damage with activation of caspases, leading to apoptosis

      • There is subsequent activation of Toll-like receptor-2 (TLR-2), TLR-4, and peroxisome proliferator activated receptor (PPAR) binding, leading to cytokine production

      • Upregulation of inflammatory transcription factors (nuclear factor–kappa B [NF-kB], hypoxia-inducible factor-1, etc.) leads to increases in proinflammatory cytokines (TNF-a, interleukin-beta [IL-1β], IL-6, etc.)

  • Late phase

    • Increased chemotactic factors (IL-8, platelet-activating factor) and receptors (intracellular adhesion molecule-1 [ICAM], L-selectin) causing adhesion and migration

    • Increased migration of neutrophils and lymphocytes

    • Increased oxidative stress and immunologic damage

Figures 81-1 to 81-3 illustrate progression of ischemia reperfusion changes.


Progression of reperfusion injury. Initial ischemic insult leads to decreased adenosine triphosphate and cellular damage. Early changes such as mitochondrial damage and caspase activation lead to eventual apoptosis. Activation of complement and Toll-like receptors (TLRs) engage a pathway that increases inflammation and damage.12 Ultimately, neutrophil chemotaxis and migration mediate clearance of apoptotic cells. Histologically, this is manifested by:

• Cellular edema

• Flattening of ...

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