The loss of metabolic/fluid homeostasis and excretory function characteristic of AKI is associated with the retention of metabolic waste products (i.e., uremic toxins), nonvolatile acids, and the expansion of extracellular volume. This decrement in kidney function can precipitate clinically important and adverse physiological consequences on the normal function of numerous organ systems, in particular the lung [1]. The accumulation of uremic compounds is known to contribute to lung inflammation and injury and has been termed uremic pneumonitis. However, this complication of AKI is rarely seen due to earlier initiation and more intensive application of RRT [11]. Metabolic derangement in AKI, such as abnormalities in serum phosphate and calcium level and metabolic acidosis, may also contribute to respiratory muscle weakness and dysfunction [12]. Perhaps the most common life-threatening pulmonary complication associated with AKI is alveolar edema. Expansion of extracellular volume can contribute to increased pulmonary capillary hydrostatic pressure. This coupled with alterations to pulmonary microvascular permeability and reduced serum oncotic pressure can predispose to rapid increases in extravascular lung water [13]. AKI can also contribute to lowering the threshold for accumulation of extravascular lung water [14] along with impaired clearance of alveolar fluid once present. Indeed, lung injury in AKI can occur in the absence of overt volume overload [15]. This is due, in part, to the downregulation of epithelial sodium transporters (ENaC), sodium-potassium adenosine triphosphatases (Na-K-ATPase), and aquaporins at the alveolar-capillary barrier. In further support of the hypothesis that lung injury in AKI represents more than alveolar edema, experimental models of ischemic-/reperfusion-induced AKI have shown lung injury that is characterized by not only pulmonary vascular congestion and interstitial edema but also focal alveolar hemorrhage and inflammatory cell infiltrate [16]. Indeed, the systemic inflammation incited by AKI, including the release and reduced clearance of proinflammatory mediators, is an important mechanism contributing to acute lung injury. Moreover, the magnitude of AKI, both in terms of severity and duration, can also modify the intensity of lung injury.

Naturally, this organ crosstalk and associated clinical complications may be aggravated in critical illness due to concurrent widespread systemic inflammation (i.e., sepsis, major trauma) and diminished baseline physiological reserve due to preexisting chronic lung, cardiac, or kidney disease and in response to resuscitation (i.e., large-volume resuscitation). Among patients receiving mechanical ventilation, the development of AKI has been associated with impaired or delayed weaning, higher likelihood of tracheostomy, and prolongation of ICU stay [17]. Those patients developing lung injury and respiratory failure necessitating mechanical ventilation, concurrent with or following an episode of AKI, have worse outcome and increased risk of mortality [18, 19].

Lung injury, such as acute respiratory distress syndrome (ARDS), can contribute to downstream kidney injury and dysfunction through a number of mechanisms including impaired gas exchange, systemic and regional hemodynamic alterations, systemic inflammation, and the application of mechanical ventilation (Table 6.2).

Abnormalities in gas exchange are common among critically ill patients with lung injury. These patients often receive supplemental oxygen, noninvasive ventilatory support, or invasive mechanical ventilation when respiratory failure ensues, with the aim of correcting hypoxemia and restoring near-normal gas exchange. However, this is often challenging or not possible, and many patients may have residual hypoxemia or hypercapnea in the setting of ARDS and lung-protective ventilation and/or permission hypercapnea. The exact mechanisms by which hypoxemia contributes to AKI are incompletely understood and, however, are likely multifactorial and relate to altered cardiovascular function, renal microcirculatory dysfunction, neuro-hormonal activation, and circulating systemic inflammatory mediators [20]. Small clinical studies have suggested that hypoxemia may impair renal autoregulation and glomerular filtration rate (GFR) and contribute to sodium and water retention, while reversal of hypoxemia may improve renal blood flow (RBF) [21, 22]. Hypercapnea has also been associated with impaired kidney function, attributed to alterations in RBF and renovascular resistance; however, experimental data have been inconsistent [23]. Further, acute hypercapnea can also contribute to or worsen existing acidemia. The combined impact of hypoxemia and hypercapnea may act synergistically to impair kidney function [24].

Lung injury may be the result of primary lung disease (i.e., aspiration, contusion) or a systemic process (i.e., pancreatitis, sepsis); however, the application of mechanical ventilation is well recognized as a potentially important precipitant or exacerbating factor in lung injury. Ventilator-induced lung injury (VILI) is attributable to the use of excessive end-inspiratory pressures and volumes coupled with the added effects of barotrauma, atelect-trauma, and biotrauma (Table 6.3). The mechanical disruption of the alveolar-capillary barrier from excessive pressure-volume loading during positive pressure ventilation can induce the release of local inflammatory mediators into the systemic circulation [25]. This inflammation due to VILI can contribute to downstream end-organ injury, including AKI [26]. In a murine model of lung injury, the application of injurious MV was associated with increased expression of IL-6 in kidney tissue, increased evidence of renal tubular apoptosis, and impaired kidney function [27, 28].

There has been increasing focus on the detrimental effects of elevated IAP in AKI [29]. IAP is normally between 5 and 7 mmHg in healthy individuals and ≤10 mmHg in critically ill adults, measured supine at end-expiration, zeroed at the level where the midaxillary line crosses the iliac crest [30]. By consensus, intra-abdominal hypertension (IAH) is defined as a sustained increase in IAP ≥12 mmHg, and abdominal compartment syndrome (ACS) as a sustained increase >20 mmHg with new organ dysfunction/failure [30]. The most important risk factors for these conditions are shock/hypotension, resuscitation with a large amount of fluids, and worsening respiratory status [31]. Therefore, it should not be surprising that IAH is common among critically ill patients and associated with worse outcome [32]. However, it is less clear whether the relationship between IAH and organ dysfunction represents cause and effect and if prevention/treatment of IAH might improve organ function and prognosis.

Elevated IAP influences renal function in different ways. First, IAH might lead to a significant decrease in RBF as renal perfusion pressure equals mean arterial pressure minus IAP [33]. Further, higher intrarenal vascular resistance (organ compression) shunts blood away from the kidneys. This is of particular concern for the renal medulla, which receives only ~12 % of the RBF, exacerbated by neurohumoral activation [34]. Indeed, AKI through ischemic tubular necrosis is probably the most common complication in the ICU necessitating RRT. Second, the combination of systemic venous congestion and elevated IAP decreases the glomerular filtration gradient [35]. Because the kidney is an encapsulated organ, a pressure rise in the venous system translates into a higher renal interstitial and Bowman’s capsular pressure, directly impeding glomerular filtration [36, 37]. Intriguingly, in advanced heart failure – presumably because of low renal perfusion – the kidneys are extremely sensitive to even small elevations in IAP (8–10 mmHg) [38]. Moreover, decreasing IAP in such cases, through ultrafiltration or paracentesis, can dramatically improve renal function [38]. Extrapolating these findings to the general ICU population, recent evidence suggests that a comprehensive management strategy with appropriate use of an open abdomen in patients at risk significantly improves survival from IAH/ACS [39].

A new area of research is the role of gut microbiota in AKI. It has been clearly established that bacterial fermentation processes in the large intestines are an important source of tightly protein-bound toxins such as p-cresyl sulfate and indoxyl sulfate [40]. Because of this protein binding, such toxins are difficult to clear from the circulation, even by means of hemodialysis [41]. They may accelerate kidney dysfunction, and plasma levels are correlated to all-cause mortality [42, 43]. This offers a strong rationale for targeting gut microbiota and toxin production in the bowel compartment with future therapies.

In normal circumstances, the gut has an important barrier function, preventing entrance of toxins and microorganisms into the systemic circulation. However, especially when abdominal perfusion is impaired, like in advanced heart failure or patients with IAH, this function might become compromised [44]. Indeed, it has been shown that the intestinal morphology, permeability, and function are substantially altered in heart failure [45, 46]. Consequently, leakage of lipopolysaccharides in the systemic circulation may cause further hemodynamic compromise leading to a detrimental vicious cycle [44, 47]. As the ICU clusters, the most vulnerable patients with regard to hemodynamic compromise, kidney and organ dysfunction, this is likely an underrecognized problem and should be an area of further research. Only recently, IAP has been identified as a potential missing link in patients with cardiorenal syndrome, and the term cardio-abdominal-renal syndrome (CARS) was coined [44].

AKI is a fearsome complication in patients with decompensating liver cirrhosis, where it occurs in ~20 %, and is associated with poor outcome [48]. Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state and reduced effective blood volume. Hepatorenal syndrome is initiated by portal hypertension and may be triggered by bacterial infections, nonbacterial systemic inflammatory reactions, excessive diuresis, gastrointestinal hemorrhage, diarrhea, nephrotoxic agents, or IAH [49]. Orthotopic liver transplantation is the best current treatment and leads to a gradual recovery of renal function in the vast majority of patients.

The kidneys are well-perfused organs, located inside the retroperitoneal space of the abdomen. Elevated IAP may seriously disrupt systemic and renal hemodynamics, which might cause renal dysfunction and loss of intestinal barrier function with subsequent entry of toxins into the systemic circulation. A more thorough understanding of kidney-organ interactions in the abdominal compartment may hopefully lead to new therapeutic targets to better preserve renal function in critically ill patients. Within this regard it is important to consider IAP as a missing link in patients with congestive heart failure developing worsening kidney function. This condition has been termed as CARS.