During sepsis, multiple cell lines, cytokines, vasoactive substances as well as the coagulation and the complement cascade participate in the inflammatory response to infection [32]. Essential for host defense is the recognition of molecular patterns by so-called toll-like receptors (TLRs) localized on the membrane of different cell types. TLRs recognize molecules derived from bacteria, viruses, fungi, and parasites known as pathogen-associated molecular patterns (PAMPs). TLRs are also able to recognize molecules released during tissue injury, known as damage-associated molecular patterns (DAMPs). In the kidney, TLR-2 and TLR-4 are expressed both in endothelial, glomerular, and epithelial cells of Bowman’s capsule and the proximal and distal tubules [33]. Activation of TLRs triggers a series of events leading to the expression of pro-inflammatory genes [34]. Moreover, TLRs can be upregulated in the presence of interferon-γ and TNF.

Several studies in animal models of sepsis have demonstrated the role of TNF in the development of acute kidney injury: mice lacking a TNF receptor are resistant to endotoxin-induced acute kidney injury and TNF-receptor negative kidneys are resistant to endotoxin-induced damage when transplanted into TNF-positive mice [32]. In human sepsis, elevated serum levels of two soluble TNF-receptors are strongly associated with the development of acute kidney injury [35]. TNF is believed to induce apoptotic cell death through intracellular signaling. Renal tubular cells express cell surface ‘death receptors’ of the TNF superfamily, including TNF-receptor 1, Fas and FN14 receptor. TNF, TNF-like weak inducer of apoptosis (TWEAK) and Fas ligand can all activate caspases (cysteine-dependent aspartate directed proteases), enzymes with the ability to initiate apoptosis [36]. In a cascade-like manner, caspases activate other target caspases by cleaving away prodomains, ultimately activating effector caspases such as caspase-3, which cleaves multiple structural molecules, resulting in the morphologic changes that define apoptosis [37]. Treatment with a caspase-3 inhibitor was demonstrated to have a renoprotective effect in mice [38]. Caspase-1 has the ability to activate interleukin-1β and interleukin-18, cytokines playing an important role in the inflammatory process occurring during septic acute kidney injury. Blocking the activation of these cytokines also had a renoprotective effect in mice [39]. Moreover, in a murine sepsis model, combined inhibition of IL-1 and IL-18 protected animals against a lethal challenge with endotoxin [40].

Inflammation is an important component of both the initiation and extension of injury in AKI [41]. Endothelial injury stimulates the recruitment of leukocytes to the renal tissue and promotes leukocyte adhesion and migration. Leukocyte adhesion is mediated by adhesion molecules known as selectins, of which intercellular adhesion molecule-1 (ICAM-1) appears to be essential to the transendothelial migration of leukocytes [42]. The low microcirculatory blood flow observed during sepsis further facilitates the interaction between inflammatory cells and the endothelium through prolonged exposure to leukocytes and inflammatory mediators, which amplify the local inflammatory response and renal injury.

Coagulation plays an important role in the pathogenesis of sepsis. Inflammatory mediators such as endotoxin and cytokines may activate the coagulation cascade, which results in thrombin formation. Thrombin itself is a proinflammatory agent with the ability to activate inflammatory cells, which in turn produce cytokines, thus promoting an amplifying loop. The literature on the role of the coagulation cascade in the pathogenesis of acute kidney injury is scarce. Recently, the contribution of microparticles to various pathophysiologic processes has gained interest. Microparticles are small lipid bilayer vesicular bodies originating from activated or apoptotic cells. They often carry phosphatidylserine in their outer layer, which may act as a surface for activated clot formation. In addition, microparticle bound coagulation factors such as tissue factor may initiate coagulation during sepsis. A recent study among patients with severe sepsis showed that patients with renal injury had significantly increased numbers of circulating microparticles [43]. This finding suggests that activation of the coagulation pathway also plays a role in the pathogenesis of septic acute kidney injury.

Historically, renal tubular epithelial cell necrosis was regarded as the characteristic lesion in septic AKI. However, analysis of kidney biopsies from patients who died of septic shock showed limited evidence for acute tubular necrosis, but did show tubular and glomerular cell apoptosis and infiltration of monocytes [44]. During experimental sepsis, glomeruli and interstitium are also infiltrated by activated neutrophils [32, 45]. Tubular apoptosis rather than necrosis may thus prevail in vulnerable proximal tubules. However, the relevance of apoptosis to organ dysfunction has been debated [44].

The I/R injury of the kidney mainly occurs in clinical conditions such as cardiovascular surgery, shock, trauma, resuscitation, and other situations associated with hypotension, low cardiac output or both [46]. The time interval of complete blood flow interruption that leads to renal injury in animals is 30–45 min, but in humans the period can be longer, as observed during vascular and renal surgery [47]. Reperfusion during shock resuscitation stimulates inflammatory factors, therefore, I/R injury shares many pathways with the pathogenesis of AKI in inflammatory states.

Nephrotoxin exposure accounts for up to 25 % of the cases of AKI in the intensive care unit [72]. Nephrotoxicity may be promoted by factors relating to the patient, the kidney and the ingested toxic substance [73]. Critically ill patients are vulnerable to nephrotoxicity due to compromised renal perfusion. The kidney itself is prone for toxicity because it takes up toxins and concentrates them in interstitium and medulla. Renal tubular cells have a high metabolic rate requiring a substantial amount of energy and their environment is relatively hypoxic, increasing the risk of hypoxic injury to the tubular cells. Toxins may potentiate renal injury induced by other causes. Moreover, hypoalbuminemia often occurs in critically ill patients, leading to a higher plasma free fraction of potentially toxic agents [74].

The most important nephrotoxins are drugs frequently used in the ICU, such as antibiotics, analgesics, and radiocontrast [72–78]. However, outpatient exposure to nephrotoxins such as heavy metals and certain herbs may also cause nephrotoxicity [79, 80] (Table 4.1). All compartments of the kidney can be injured by toxic substances: renal vessels, glomeruli, tubular system, collecting ducts, and interstitium (Table 4.2). The pathophysiologic mechanisms of the injury to the different compartments of the kidney are briefly described.