Cellular Response to Acute Kidney Injury

Acute Kidney Injury as a Systemic Disease

Over the past decade, the perception of AKI as just another complication has been transformed into one of a systemic disease with significant, often fatal, clinical consequences. As a systemic disease, AKI is a disease process with several remote sequelae and extrarenal organ damage. In particular, interactions between AKI and the immune system have become the focus of intense research. Findings that patients with AKI have higher rates of infections have fueled current research efforts. Patients with AKI requiring RRT are affected especially by infections. Almost half of the infections become apparent shortly before initiation of RRT, 40% during RRT, and approximately 10% in the period after discontinuation of RRT. Similar data have been described for the development of sepsis in AKI. RRT does not seem to alter the AKI-associated risk of infection.

Acute Kidney Injury and Cytokines

Inflammatory changes, in particular systemic cytokine release, are a key factor in the pathogenesis of AKI. AKI, on the other hand, has profound effects on cytokine homeostasis. AKI leads to a sharp decline in or lack of cytokine clearance, which becomes easily apparent during systemic inflammation. AKI modulates underlying inflammation by impairing cytokine clearance, indirectly increasing the systemic load of inflammatory mediators. Experimental studies comparing renal ischemia reperfusion (IR) with corresponding sham surgery demonstrate this clearly. Here, animals with AKI after renal IR but not those undergoing sham surgery develop drastic increases in plasma cytokine levels (e.g., interleukin-6 [IL-6] or tumor necrosis factor-alpha [TNF-α]).

Experimental data further reveal that the decrease in renal function during AKI closely precedes the decline in plasma cytokines clearance and subsequent rise in plasma cytokine concentrations.

In vitro studies also suggest that renal tubular cells can produce inflammatory cytokines during AKI, denoting another potential mechanism of AKI-induced systemic cytokine accumulation. In vivo, IR-induced AKI increases renal production of cytokines, which in turn spill over into the systemic circulation to levels that are higher than those observed after bilateral nephrectomy.

Among the numerous inflammatory cytokines with elevated plasma/serum concentrations during AKI, TNF-α, IL-6, and IL-8 are the best known and most intensely studied.

• TNF-α:

  • Both TNF-α and its receptor (TNF receptor 1) are upregulated early after the onset of experimental AKI. Together, they lead to proinflammatory changes in various tissues and cells, endothelial dysfunction, and endothelial cell apoptosis.

• IL-6:

  • Experimental studies have shown a rise in plasma IL-6 as early as 2 hours after the induction of experimental AKI. IL-6 causes activation and dysfunction of endothelial cells, leading to production of IL-8, neutrophil recruitment, and increased endothelial permeability.

• IL-8:

  • IL-8, which also increases early after the onset of AKI, is a neutrophil-specific chemokine that mediates recruitment of neutrophils as well as their activation during inflammatory processes.

The effects of elevated systemic cytokine concentrations on remote tissues and cells remain the focus of intense research efforts. The lungs, heart, brain, and gastrointestinal tract are among the best-studied remote organ systems.

Acute Kidney Injury, Cytokines, and the Lungs

In healthy rodent lungs, IR-induced AKI increases vascular permeability, interstitial edema, and wet/dry weight ratio as well as expression of proinflammatory mediators and leukocyte adhesion molecules. This eventually is followed by interstitial infiltration with leukocytes. IR injury of the kidney stimulates a distinct pattern of enhanced inflammatory gene expression that is substantially different from that seen with bilateral nephrectomy. However, data assessing the clinical relevance of these changes are still missing (e.g., gas exchange or pulmonary function tests).

Acute Kidney Injury, Cytokines, and the Heart

Cellular changes similar to those discovered in the lungs also occur in the healthy heart after experimental AKI. Renal IR leads to upregulation of proinflammatory mediators, including TNF-α and IL-1, and recruitment of neutrophils. Moreover, renal IR but not bilateral nephrectomy provokes apoptosis of cardiac myocytes. Renal IR also results in functional echocardiographic changes, such as increasing left ventricular diameters and decreasing fractional shortening.