Immunologic and Infectious Complications of Acute Kidney Injury

Increased Inflammation

There is increasing evidence that AKI is caused, at least partly, by an inflammatory cascade resulting in a deterioration of organ function. This response occurs as the release of cytokines and other inflammatory mediators and seldom will be localized to one single-organ system but also will affect negatively other organs as well. As such, it is likely that this systemic inflammatory response also will cause generalized inflammation and organ dysfunction.

Inflammation is a natural defense mechanism against pathogens; however, excess or unresolved inflammation can cause tissue damage. Inflammation during ischemia-reperfusion has many similarities with inflammation caused by microbial pathogen and is pathophysiologic, divided into an early and late phase. The early phase is triggered by cell damage or death, causing a release of cytokines and recruitment of neutrophils and macrophages to the site of injury. Necrotic cells release damage-associated molecular patterns (DAMPs), which activate pattern recognition receptors, such as Toll-like receptors (TLRs). Activated renal parenchyma cells also secrete chemokines, promoting neutrophil, macrophage, and monocyte inflammatory responses. The early phase lasts minutes to hours. Overlapping with the first phase, a second phase occurs, mediated primarily by immune cells. Proinflammatory mediators are produced in the kidney by phagocytic cells as well as in the bloodstream by activated neutrophils and monocytes. The inflammatory response eventually initiates a range of antiinflammatory cytokines, induced by T cells, to repair renal damage. Ideally, pro- and antiinflammatory mechanisms should be in balance; however, prolonged hypoxia leads to an abnormal repair, renal fibrosis, and chronic loss of kidney function.

Understanding of the cellular and molecular mechanisms underlying the inflammatory response is important for future strategies in prevention and treatment of AKI. Especially, blockade of innate immune receptors, influencing parenchymal cells involved in inflammation, and molecules generated within injured cells are targets for investigation. An important discovery is that many of the triggers and cellular mediators responsible for initial organ damage are also important in the repair phase. For example, macrophages play a different role depending on the inflammatory phase; M1 leads to inflammation, whereas M2 has an antiinflammatory function. This means that interventions targeting early phase mediators can influence unintentionally negatively proinflammatory and repair mechanisms. Future targets for investigation are the parenchymal cells, because of their early role in inflammation, soluble mediators of cellular injury, cytokines, and the interaction with immune cells.

Finally, evidence is growing for what is called “organ cross-talk”; that is, infection may lead to AKI, and AKI in its turn may lead to decreased functioning of other organs, as has been demonstrated clearly for the lungs. After ischemia/reperfusion injury of the kidneys, deregulation of the salt and water channels develops, resulting in increased vascular permeability in the lungs, secondary leading to interstitial edema. In contrast to sepsis-induced acute respiratory distress syndrome (ARDS), AKI-induced ARDS generally is characterized by an induction of cytokine-induced neutrophil chemoattractant 2, a distinct expression of various heat shock proteins, and a low level of cellular infiltration.

The underlying cause for this deregulated inflammatory response is not entirely clear. Deregulation of the lung salt and water channels is related to the severity of AKI, suggesting that uremia may be responsible. Increased cytokine levels and oxidative stress in patients with end-stage renal disease additionally suggest that uremia may play a crucial role in the development of a deregulated inflammation state. Next, acidosis also may contribute to the degree of the inflammatory status in AKI patients. The effects on inflammation appear to vary according to the type of acidosis, that is, respiratory versus metabolic, and hyperchloremic versus lactic acidosis, respectively. Hyperchloremic acidosis is more proinflammatory compared with lactic acidosis. In vitro experiments demonstrated that hyperchloremic acidosis increased the IL-6/IL-10 ratio, and NF-κB DNA binding. In vivo experiments, on the other hand, demonstrated that acidosis led to increased nitric oxide levels, lower blood pressure, or even shock. Also, acidosis has been shown to worsen lung and intestinal injury and to decrease the gut barrier function, thereby facilitating systemic breakthrough of microorganisms.

Decreased Immunity

There is salient evidence for an immune-depressed state in uremic patients, especially in those with chronic renal failure treated with RRT. Several uremic retention compounds, such as leptin, advanced glycation end-products (AGEs), guanidines, and P-cresol, interfere with normal white blood cell function, phagocytosis, or endothelial function, and thus negatively affect immunity competence. Other factors that are believed to contribute to these effects in chronic uremia are (1) malnutrition, (2) iron overload, (3) anemia, and (4) bioincompatibility of dialyzer membranes. Finally, acidosis also may impair immune function by depressant effects on polymorphonuclear and lymphocyte function. Because uremia and many of the above-mentioned factors are also present in AKI patients, immune suppression seems plausible in these patients.