Perioperative Acute Kidney Injury

Sam D. Gumbert, M.D.; Felix Kork, M.D., M.Sc.; Maisie L. Jackson, M.D.; Naveen Vanga, M.D.; Semhar J. Ghebremichael, M.D.; Christy Y. Wang, M.D.; Holger K. Eltzschig, M.D., Ph.D.


Anesthesiology. 2019;132(1):180-204. 

In This Article

Pathophysiology of Perioperative Acute Kidney Injury

Historically, acute kidney injury was categorized into prerenal, renal, and postrenal causes. Prerenal acute kidney injury is a functional response to renal hypoperfusion, where intrinsic renal tubular function remains intact. Prerenal acute kidney injury results from a hypovolemic or low circulating volume or low cardiac output state. Postrenal acute kidney injury is caused by the blockage of urinary flow downstream in the urinary tract, inducing a backup into the kidney and consequent hydronephrosis. Like prerenal acute kidney injury, there is no inherent renal disease present if urinary flow is reestablished before permanent structural damage develops. In contrast, intrinsic acute kidney injury results from a disease process of the renal vascular, glomeruli, tubules, or interstitium.[26] This traditional classification provides a convenient but somewhat simplistic framework, because acute kidney injury often crosses these boundaries. For example, prolonged prerenal acute kidney injury can lead to secondary intrinsic acute tubular necrosis.[27]

Perioperative acute kidney injury and the ways in which it develops is multifaceted and complex. Hypoperfusion, inflammation, and neuroendocrine response to surgery are the frequent mechanisms affecting renal perfusion.[28,29] Reduction of blood pressure and renal hypoperfusion are frequent consequences of perioperative hypovolemia, as well as the vasodilatory and cardiodepressant effects of anesthesia. In a low-perfusion state, the kidneys can exhibit remarkable autoregulation, maintaining constant renal blood flow and consequently glomerular filtration rate despite fluctuating mean arterial pressure and volume status. Prostaglandin signaling decreases afferent arteriolar resistance, which increases blood flow to the glomeruli and sustains the glomerular capillary pressure in a low-perfusion state. The activation of the renin–angiotensin–aldosterone systems and release of angiotensin II raises efferent arteriolar resistance, sustaining the glomerular capillary pressure.[26] If renal hypoperfusion persists or drops below the autoregulatory range, endogenous vasoconstrictors released from the renal sympathetic system result in afferent arteriolar vasoconstriction. This effectively reduces renal blood flow leading to renal tubular ischemia and reduced glomerular filtration rate.[26,30–32] The diminishing of oxygen balance induces renal tissue hypoxia and ATP starvation that stimulates extracellular matrix production, collagen deposition, and fibrosis.[33] As a metabolic product of ATP,[34] adenosine binds to kidney cell surface receptors to match blood flow with energy consumption.[2,35] The interstitial concentration of adenosine rises when neighboring cells are in a negative energy balance.[35] To recover from a negative energy balance and high oxygen demand, it is unnecessary to increase blood flow, but rather to lower the glomerular filtration fraction. This phenomenon has been termed "acute renal success."[36,37] By reducing the filtration rate, the number of sodium ions that must be transported per oxygen delivered is reduced, conserving energy and improving the energy balance.[35] Renal perfusion is capitalized to a rate that is adequate to promote healing while maintaining excretory function without the risk of inhibiting volume conservation.[36]

Renal autoregulation can also be disrupted by using nonsteroidal antiinflammatory drugs during the perioperative period. These inhibit the enzyme cyclooxygenase and prohibit the production of renal prostaglandins. This leads to the unopposed constriction of both the afferent and efferent arterioles by angiotensin II in a state of persistent renal hypoperfusion, decreasing renal perfusion flow and glomerular filtration rate (Figure 1).

Figure 1.

Glomerular filtration as a function of glomerular blood flow. (A) Normal glomerular blood flow with normal glomerular filtration rate (GFR). (B) Reduced renal perfusion pressure within the autoregulatory range, caused by intraoperative conditions such as anesthesia and medication induced hypotension or hypovolemia. Normal GFR is maintained with prostaglandin-mediated afferent arteriolar vasodilation and angiotensin II–mediated efferent arteriolar vasoconstriction. (C) Persistent reduction in renal perfusion pressure below the autoregulatory range. This can be seen intraoperatively with protracted systemic hypotension or severe hypovolemia caused by hemorrhage and blood loss. In this state, endogenous vasoconstrictors released from the renal sympathetic nerves increase the afferent arteriolar resistance, which results in a rapid decline in GFR and a decrease in renal blood flow. This eventually leads to tubular cell damage and cell death. (D) Effect of angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB). Loss of angiotensin II decreases both the afferent and efferent arteriolar resistance, relaxing the efferent arteriole significantly more. The net clinical effect is unchanged or slightly decreased GFR. (E) Reduced GFR with nonsteroidal antiinflammatory drug (NSAID) use because of loss of vasodilatory prostaglandin. (F) Effect of chronic hypertension on the preglomerular arterial vessels, primarily the afferent arterioles. Chronic hypertension eventually leads to thickening of arteriole walls and narrowing of lumen, a process known as arteriolosclerosis. This results in inadequate blood flow through the glomeruli and may produce glomerular and tubulointerstitial ischemia. Conditions displayed in D–F can contribute to the development of "normotensive" perioperative acute kidney injury. MAP, mean arterial pressure.

In addition to hypoperfusion-induced injury, systemic inflammation and cytokine release caused by trauma and surgical stress directly induce tubular injury and subsequent systemic inflammation.[2,34,38] The etiology of this inflammation-induced acute kidney injury is multifactorial, including renin–angiotensin–aldosterone system activation, renal microcirculatory dysfunction, increased oxidative stress, cytokine-induced injury, endothelial cell injury, and activation of proapoptotic pathways.[27–29,39,40] All these factors predispose the surgical patient to develop acute kidney injury during the perioperative period. In recent years, evidence in both basic science and clinical research has led to a new understanding that acute kidney injury is not a mere singular organ injury. Acute kidney injury is now perceived as a multifaceted systemic disease process that engenders distant organ dysfunctions, including pulmonary,[41] cardiac,[42] neurologic, immunologic, hepatic, and gastrointestinal dysfunctions (Figure 2).[43–45] Recent studies highlight that acute kidney injury can cause remote organ injury, for example, to the intestine. Lee et al.[46] provide mechanistic insight of the inflammatory activation of Paneth cells that are contained at the bottom of crypts located at the intestinal mucosa. Activation of Paneth cells leads to massive release of inflammatory mediators (such as interleukin-17A), causing a disruption of the intestinal barrier function and translocation of bacteria from the intestinal lumen into the blood stream, promoting sepsis and multiorgan failure (Figure 3).[6] These studies highlight in an elegant way a functional role of acute kidney injury beyond its filter function, suggesting that kidney injury and acute kidney injury trigger inflammation and morbidity in distal organ systems.[4]

Figure 2.

Consequences of acute kidney injury on remote organ functions. There is increasing evidence that acute kidney injury directly contributes to remote injury in the heart, lung, brain, liver, immunologic, and other organ systems. In the hepatic system, acute kidney injury causes intestinal barrier breakdown and greater gut translocation and delivery of endotoxins and microorganisms to the portal system. This results in hepatic inflammation and apoptosis along with hepatic overproduction and systemic release of proinflammatory cytokines. Acute kidney injury is also associated with cerebral dysfunction, including uremic encephalopathy. Activation of neuroinflammatory cascade results in increase in vascular permeability and breakdown of blood–brain barrier. In the cardiac system, acute kidney injury is associated with cardiorenal syndrome, which is a state of concomitant heart and kidney failure. Suggested mechanisms of acute kidney injury–induced cardiac dysfunction include fluid overload and uremia-induced decrease in myocardial contractility. In the pulmonary system, the remote effect of acute kidney injury is due to activation of inflammatory cascade leading to an increase in pulmonary vascular permeability and lung neutrophil infiltration. This leads to accumulation of fluid within the lung tissue, causing pulmonary edema. In the immunologic system, acute kidney injury has a profound impact on humoral and cellular immunity and overall immunocompetence. This is due to a combination of increase in oxidative stress, impaired clearance of the reticuloendothelial system, and decreased clearance of circulating cytokines, leading to higher rate of infections in patients with acute kidney injury. CHF, congestive heart failure; NYHA, New York Heart Association classification of heart failure.

Figure 3.

Paneth cell-mediated multiorgan systemic inflammation after acute kidney injury. Recent experimental studies indicate that acute loss of kidney function (A) causes small intestinal Paneth cells in the intestinal crypts to generate and degranulate proinflammatory interleukin (IL)-17A into the intestinal lumen, (B) which directly causes intestinal cellular injury and intestinal barrier breakdown. This allows for bacterial translocation and (C) portal delivery of IL-17A–containing macrophages, which causes (D) hepatic injury and (E) hepatic release of IL-6 and tumor necrosis factor (TNF)-α into the circulation, (F) leading to further hepatic and systemic inflammation. These studies highlight that acute kidney injury is not merely a bystander but can initiate a downward spiral triggering multiorgan failure and death.46

Many questions regarding organ "cross-talk" during acute kidney injury still remain unclear, for example how communication between the kidneys and distal organs—such as the gut, lungs, heart, or the brain—are communicated. Similarly, many mechanistic aspects of acute kidney injury continue to be the focus of basic and translational research. Experimental data suggest that during acute kidney injury, a combination of proinflammatory cytokine and chemokine release, leukocyte extravasation, induction of remote oxidative stress, and ion channels dysregulation can occur.[39,47] Similarly, a number of antiinflammatory pathways that can be targeted for acute kidney injury prevention or treatment have been identified, such as purinergic[48–50] or hypoxia-elicited antiinflammatory signaling pathways[51] or inflammatory endpoints that are under the control of microRNAs.[41,52–54]