The pathophysiology of CSA-AKI is multifactorial and thus far is not fully understood. Several major pathways may be involved in the development of CSA-AKI, including renal hypoperfusion, ischaemia‒reperfusion injury (IRI), activation of the inflammatory cascade, oxidative stress, nephrotoxin exposure, and genetic polymorphisms, which can occur at any time during the perioperative period.
Renal hypoperfusion and reperfusion injury
The renal medulla has high metabolic demands but lower partial oxygen pressure (PaO
2) than the rest of the kidney (10 to 20 mmHg) [
49], making it vulnerable to hypoxic injury. Therefore, renal hypoperfusion is usually the initial factor of CSA-AKI. In cardiac surgery, cardiopulmonary bypass (CPB)-related low flow, low pressure, non-pulsatile perfusion [
50], haemodilution, emboli [
51], rewarming [
52] and intravascular haemolysis [
53] are all risk factors for renal ischaemia. Continuous renal ischaemia may lead to damage to tubular structures and tubular epithelial cells, resulting in tubular dysfunction. Renal hypoperfusion and tubular cell injury are accompanied by oxidative damage and inflammatory events [
54].
The low cardiac output is a common cause of early postoperative AKI [
55]. Prolonged low cardiac output or hypotension leads to the activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system, resulting in systemic vasoconstriction, which reduces renal blood flow and leads to renal damage [
49]. Apart from arterial perfusion pressure, obstruction of return attributing to venous congestion is another haemodynamic determinant of renal insufficiency during cardiac surgery [
56]. Evidence continues to support that perioperative high venous pressure is an independent risk factor for CSA-AKI [
57], even more important than hypotension [
58]. To ensure adequate renal blood flow and glomerular filtration, the difference between arterial driving pressure and venous outflow pressure must be maintained sufficiently large. Increased central venous pressure due to various causes, such as excessive fluid therapy or tricuspid valve disease, will lead to renal venous hypertension, increasing renal resistance, and ultimately impinging renal perfusion. At the beginning of the decrease in renal arterial perfusion, the renin level increases, causing the contraction of the efferent arterioles and the increase of glomerular pressure; thus, maintaining the filtration rate. Later, when renal venous pressure increases and renal blood flow decreases, the compensatory increase in filtration rate is destroyed, GFR decreases, and renal injury is aggravated [
7].
The essence of renal hypoperfusion injury is insufficient tissue oxygen supply. Oxygen delivery to the renal medulla is a complex interactive process involving pressure, flow, and oxygen content. According to an increasing number of studies, the kidneys may suffer from an imbalance in oxygen supply and demand during CPB. Ranucci et al. showed that the nadir of oxygen supply during CPB, with a critical threshold of < 272 mL/min/m
2, was the best predictor of AKI after cardiac surgery [
59]. The effects of decreased haemoglobin concentration and haemodilution during CPB on the incidence of AKI are probably due to decreased oxygen-carrying capacity. At the start of CPB, haemodilution occurs as an inevitable result of mixing the patient's blood with the prefilling fluid in the CPB circuit, but it is believed that reduced blood viscosity and improved microcirculation perfusion may attenuate the risk of reduced blood oxygen-carrying capacity, and oxygen supply is prone to meet the demands of tissue metabolism [
60]. Although moderate haemodilution to a haematocrit of less than 25% is acceptable, extreme haemodilution to a haematocrit of less than 21% or transfusion are not desirable, both of which are associated with AKI and increased risk of dialysis [
61]. The elements of oxygen delivery during CPB include pump flow, haemoglobin, oxygen saturation, and arterial oxygen tension [
62]. The use of goal-directed oxygen delivery during CPB has been proven to reduce CSA-AKI by approximately 50% [
63].
In addition to CPB-induced changes, a low cardiac output is also a common cause of early postoperative AKI [
55]. Prolonged low cardiac output or hypotension leads to activation of the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), resulting in systemic vasoconstriction, which reduces renal blood flow and leads to renal damage [
49]. Apart from arterial perfusion pressure, obstruction of return attributed to venous congestion is another haemodynamic determinant of renal insufficiency during cardiac surgery [
56]. In addition, bleeding complications and inflammatory responses, which are common during cardiac surgery, may contribute to renal hypoperfusion.
Renal perfusion may improve after CPB; however, IRI may subsequently occur and may lead to the opening of mitochondrial permeability transition pores in the kidney [
64], regulating mitophagy [
65] and thereby leading to AKI. IRI can also increase the production of reactive oxygen species (ROS) [
65], which can induce inflammation and promote the occurrence of AKI.
Inflammation and oxidative stress
During cardiac surgery, systemic inflammation occurs as a result of the contact of blood components with the surface of the CPB circuit, IRI, and oxidative damage. The inflammatory response consists of activation of the vascular endothelium and immune system and release and recruitment of proinflammatory cytokines and free radicals, contributing to tubular damage [
66]. Due to biological incompatibility, CPB circuit materials provide a significant stimulus for proinflammatory pathways, activation of the complement system, and haemolysis [
67]. An increase in the level of proinflammatory cytokines is observed in CPB surgery when compared with that in off-pump surgery [
68]. Increased postoperative plasma inflammatory cytokine concentrations are associated with increased CSA-AKI occurrence and mortality [
5]. Reperfusion of hypoxic tissue after CPB produces ROS, which in turn promote inflammation by upregulating proinflammatory transcription factors [
69], further exacerbating cellular dysfunction and renal injury [
70].
Tissue hypoxia resulting from renal hypoperfusion due to decreased CO and GFR is also responsible for the inflammatory response and subsequent oxidative stress. Ischaemia causes tissue inflammation by causing endothelial cell damage [
71]. The recruited leukocytes adhere to endothelial cells and cause endothelial damage, which in turn initiates a cascade of inflammatory responses [
72]. This inflammatory cascade eventually leads to dysfunction of the renal endothelium nitric oxide system, which plays an important role in renal oxygen delivery [
73]. Neutrophils, macrophages, and lymphocytes activated during inflammation migrate to the renal parenchyma and exacerbate renal injury, thereby promoting AKI and possibly causing fibrosis [
74].
The CPB procedure exposes the blood components to shear stress and oxidative stress, causing the lysis of red blood cells and the release of free haemoglobin and iron [
75]. The accumulated free iron is involved in pro-oxidative reactions that produce oxygen free radicals, leading to tissue damage. IRI may also exacerbate oxidative inflammatory stress during CPB, leading to an increase in circulating free labile iron [
76]. Labile catalytic iron can damage renal epithelial cells, impair cell proliferation, and induce lipid peroxidation and protein oxidation [
77].
Nephrotoxins
Perioperative use of nephrotoxic drugs is common in patients undergoing cardiac surgery, including medications for comorbidities such as antibiotics, blood pressure medications, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and radiocontrast agents used in medical diagnostic procedures.
NSAIDs inhibit cyclooxygenase, which may lead to reversible renal ischaemia and decreased GFR, worsening renal function in susceptible individuals [
78]. By blocking prostaglandin synthesis, the irrational use of NSAIDs has been shown to cause persistent severe outer medullary hypoxia [
79].
Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) can cause volume depletion and vasodilation of renal efferent arterioles, respectively [
49], thereby promoting AKI [
80]. Patients taking ARBs and diuretics in combination have an increased risk of hypovolemia, which exacerbates renal failure [
81].
Aminoglycosides exhibit several favourable pharmacokinetic and pharmacodynamic properties, but dose-dependent nephrotoxicity may cause direct injury to the kidney, resulting in drug-induced AKI. The risk of AKI attributable to aminoglycosides can be sufficiently high [
82], and perioperative use of gentamicin is associated with an increased risk of postoperative dialysis [
83]. The KDIGO AKI Guideline Working Group recommends cautious use of aminoglycosides during the perioperative period [
82].
Randomized controlled trials have shown that prophylactic use of cyclic diuretics, such as furosemide, during the perioperative period in patients planning cardiac surgery is ineffective and even harmful [
84]. The KDIGO AKI Guideline Working Group recommends not using furosemide as a prophylactic for the prevention of AKI and avoiding diuretics in the treatment of AKI [
82].
Contrast agents have been suggested to induce AKI in patients undergoing coronary angiography or percutaneous coronary intervention [
85]. Ranucci et al. showed that restricting angiography on the day of surgery could reduce the incidence of AKI after cardiac surgery [
86]. Performing cardiac surgery on the day of the catheterization procedure and administering a high-dose contrast agent are independently associated with an increased risk of postoperative AKI [
87]. However, another study suggested that contrast therapy within 48 h before the start of CPB in patients with cyanotic congenital heart disease did not increase the risk of AKI [
88]. Even though the results of clinical studies regarding the association between angiography and CSA-AKI are inconsistent, it is recommended to avoid angiography before cardiac surgery or to extend the interval between surgery and angiography. Contrast agent-induced AKI (CI-AKI) can cause direct renal tubular injury, but the underlying mechanism remain unclear, including direct cytotoxic effects and autocrine, paracrine and endocrine factors [
89]. Lau et al. demonstrated that CI-AKI involves a Nod-like receptor pyrin containing 3 (NIrp-3)-dependent inflammatory response between resident and infiltrating renal phagocytes, requiring tubular reabsorption of contrast media via the brush border enzyme dipeptidase 1 [
90]. Iodinated contrast agent is the main media of contrast-induced nephropathy, and its osmotic pressure is one of the influencing factors. Studies have confirmed that the risk of CI-AKI is lower in high-osmolar contrast than in low-osmolar contrast, but there is no significant difference between iso-osmolar contrast and low-osmolar contrast [
91,
92].
Cardiac surgery stimulates the SNS and the hypothalamic‒pituitary‒adrenal axis, which in turn causes the release of neurohormonal agents, including epinephrine and norepinephrine, and may increase the production of vasopressin and endothelin-1 [
93]. Studies have confirmed that plasma concentrations of epinephrine and norepinephrine reach peak levels during CPB cardiac surgery [
94]. High plasma concentrations of these endogenous hormones cause unstable haemodynamic conditions and systemic vasoconstriction [
93], which can lead to decreased renal perfusion and ultimately renal injury.
Free iron release is a common consequence of CPB. During CPB, when red blood cells come into contact with artificial surfaces or air, a degree of haemolysis is inevitable, and the accompanying prolonged cold temperatures provide the perfect environment for haemolysis and the release of free iron, leading to vasoconstriction through scavenging of nitric oxide by free haemoglobin [
95]. Free iron-mediated toxicity may also be an important mechanism for AKI in patients undergoing CPB cardiac surgery. Several novel renal biomarkers have been implicated in iron metabolism, including NGAL, L-FABP, α-1 microglobulin, and hepcidin isoforms [
96]. Free iron-related and ROS-mediated renal injury seems to be the unified pathophysiological association between these biomarkers. Iron regulation plays a role in the development of AKI after cardiac surgery and is associated with oxidative stress and IRI. Various prevention and treatment strategies related to iron regulation are being investigated for AKI [
97]. Hepcidin is an endogenous acute-phase liver hormone that prevents iron export from cells by inducing the degradation of ferroportin, the only known iron export protein. Hepcidin-induced restoration of iron homeostasis was accompanied by significant reductions in ischaemia‒reperfusion-induced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration [
98]. Several small studies have investigated iron chelation as a novel therapeutic strategy for the prevention of AKI and have shown encouraging initial results [
99].
Genetic polymorphisms
A number of studies have suggested the role of genetic polymorphisms in the development of CSA-AKI. Polymorphisms of angiotensinogen, apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), endothelial nitric oxide synthase (eNOS), erythropoietin, interleukin-6 (IL-6), interleukin-10 (IL-10), catechol-O-methyltransferase (COMT), GRM7 | LMCD1—AS1 loci and BBS9, transducer and activator of transcription 3 (STAT3), and macrophage migration inhibitory factor (MIF) genes have been proven to be associated with a higher risk of AKI after cardiac surgery [
100]. However, some studies have denied a correlation between some of these gene polymorphisms and CSA-AKI [
101,
102]. In the pathogenesis of AKI, various genes act together to generate favourable or harmful proinflammatory and anti-inflammatory cytokine environments, thereby determining the intensity of tissue damage. Genetic variations may affect how the kidney responds to injury, determining the outcome of the patient. Thus, knowledge of genetic polymorphisms can facilitate patient management by modifying risk stratification tools and detecting genetic susceptibility biomarkers [
100].