Perioperative Acute Kidney Injury

Abstract

Perioperative organ injury is among the leading causes of morbidity and mortality of surgical patients. Among different types of perioperative organ injury, acute kidney injury occurs particularly frequently and has an exceptionally detrimental effect on surgical outcomes. Currently, acute kidney injury is most commonly diagnosed by assessing increases in serum creatinine concentration or decreased urine output. Recently, novel biomarkers have become a focus of translational research for improving timely detection and prognosis for acute kidney injury. However, specificity and timing of biomarker release continue to present challenges to their integration into existing diagnostic regimens. Despite many clinical trials using various pharmacologic or nonpharmacologic interventions, reliable means to prevent or reverse acute kidney injury are still lacking. Nevertheless, several recent randomized multicenter trials provide new insights into renal replacement strategies, composition of intravenous fluid replacement, goal-directed fluid therapy, or remote ischemic preconditioning in their impact on perioperative acute kidney injury. This review provides an update on the latest progress toward the understanding of disease mechanism, diagnosis, and managing perioperative acute kidney injury, as well as highlights areas of ongoing research efforts for preventing and treating acute kidney injury in surgical patients.

Figure 1.. Glomerular Filtration as a Function of Glomerular Blood Flow.

Panel A shows normal glomerular blood flow with normal glomerular filtration rate. Panel B shows reduced renal perfusion pressure within the autoregulatory range, caused by intraoperative conditions such as anesthesia and medication induced hypotension or hypovolemia. Normal glomerular filtration rate is maintained with prostaglandin-mediated afferent arteriolar vasodilation and Angiotensin II-mediated efferent arteriolar vasoconstriction. Panel C shows persistent reduction in renal perfusion pressure below the autoregulatory range. This can be seen intraoperatively with protracted systemic hypotension or severe hypovolemia due to 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 glomerular filtration rate and decrease in renal blood flow. This eventually leads to tubular cell damage and cell death. Panel D shows reduced glomerular filtration rate with nonsteroidal anti-inflammatory drug use due to loss of vasodilatory prostaglandin. Panel E shows the effect of angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker. 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 glomerular filtration rate. Panel F shows the 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 Panel D-F can contribute to the development of “normotensive” perioperative acute kidney injury.

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. 1) 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 pro-inflammatory cytokines. 2) Acute kidney injury is also associated with cerebral dysfunction, including uremic encephalopathy. Activation of neuro-inflammatory cascade results in increase in vascular permeability and breakdown of blood-brain barrier. 3) 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. 4) 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. 5) 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.

Figure 3.. Paneth Cell-Mediated Multiorgan Systemic Inflammation after Acute Kidney Injury.

Recent experimental studies indicate that acute loss of kidney function causes small intestinal Paneth cells in the intestinal crypts to generate and degranulate proinflammatory IL-17-A into the intestinal lumen, which directly causes intestinal cellular injury and intestinal barrier breakdown. This allows for bacterial translocation and portal delivery of IL-17-A-containing macrophages, which causes hepatic injury and hepatic release of IL-6 and TNF-alpha into the circulation, 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 multi-organ failure and death.

Figure 4.. Biomarkers Over Time After Acute Kidney Injury.

Schematic representation of the levels of several biomarkers over time. The baseline (time 0) is immediately following cardiac bypass (CBP). The lines are a schematic of the predicted rise and fall of the biomarkers following CBP as a function of time and when levels become significant enough to cross the threshold for diagnosing acute kidney injury. These patterns and specifically the timeline for diagnosing acute kidney injury, represent ideal circumstances (the shortest possible time interval shown in a clinical study), and not necessarily what will prove to be clinically verifiable. neutrophil gelatinase-associated lipocalin = urinary neutrophil-associated lipocalin; kidney injury molecule-1= urinary kidney injury molecule; cystatin C= serum cystatin C; [tissue inhibitor of metalloproteinases-2]*[IGFBP7]= tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein-7 (IGFBP7); serum Cr= serum creatinine. Modified from Figure 1, from McIlroy DR, Wagener G, Lee HT: Biomarkers of Acute Kidney Injury: An Evolving Domain. Anesthesiology 2010;112(4):998-1004