Continuing Education Activity

Perioperative acute kidney injury (AKI) is a multifactorial complication that is seen in the context of surgical interventions. AKI is associated with significant morbidity, mortality, and prolonged hospital stays, and therefore, causes a substantial burden to the healthcare system. Perioperative AKI is characterized by a sudden and significant decline in renal function occurring within the perioperative period. The management strategies for perioperative AKI are multifaceted, encompassing preventive measures, intraoperative protocols, and postoperative care. This review examines the epidemiology, etiology, and pathophysiology of perioperative AKI, focusing on the interplay between risk factors such as age, preexisting renal dysfunction, comorbidities, and type of surgical procedure. The intricate relationship between hemodynamic alterations, inflammatory responses, and nephrotoxic insults, which collectively contribute to the development of AKI during the perioperative phase, are discussed. Furthermore, the interprofessional team's role in caring for patients with this condition is highlighted.

Objectives:

• Identify risk factors for developing perioperative acute kidney injury.

• Apply the understanding of the pathophysiology of perioperative acute kidney injury in screening patients at risk of developing AKI.

• Select appropriate strategies for managing patients with acute kidney injury in the context of surgical interventions.

• Collaborate effectively with the interprofessional team, including surgeons, anesthesiologists, nurses, and pharmacists, to coordinate care and ensure timely response to perioperative AKI development.

Introduction

Acute kidney injury (AKI) is a sudden decline in kidney function, often due to hemodynamic changes or a systemic nephrotoxic insult.[1] Traditionally, kidney function has been measured by serum creatinine levels and urine output. However, in the setting of surgery, creatinine levels may not begin to rise until GFR has decreased by half, and urine output is usually decreased for various reasons. This has prompted the classification of AKI into the following types: 1) subclinical AKI, in which lab values and urine output do not meet the current classification systems and 2) functional AKI, in which lab values and urine output do meet the current classification systems.[2] 

The main classification systems used to define acute kidney injury are as follows: Acute Kidney Injury Network (AKIN); Risk, Injury, Failure, Loss, ESKD (RIFLE); and Kidney Disease Improving Global Outcomes (KDIGO).[3] These criteria utilize serum creatinine (sCr) levels, glomerular filtration rate (GFR), and urine output. The criteria for each classification system are discussed below.

Acute Kidney Injury Network 

AKIN classifies AKI if any of the following occurs within 48 hours: increased sCr x 1.5, sCr increase of 0.3 mg/dL or more, or urine output less than 0.5 mL/kg/h for over 6 hours. Some studies report that AKIN criteria are relatively less sensitive in capturing all episodes of AKI.[2]

Risk, Injury, Failure, Loss, ESKD

RIFLE classifies AKI if any of the following occurs within 7 days: doubled sCr, decrease in GFR of more than 50%, or urine output less than 0.5 mL/kg/h.[4][2]

Kidney Disease Improving Global Outcomes

KDIGO classifies AKI if any of the following occurs: increase in sCr by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 hours; increase in sCr to 1.5 times baseline, which is presumed to have occurred within the prior 7 days; or urine volume less than 0.5 mL/kg/h for 6 hours.[2][5]

In terms of the time period of AKI versus acute kidney disease, the Acute Dialysis Quality Initiative Group states that acute kidney injury occurs within 48 hours or less, and acute kidney disease occurs when AKI lasts 7 or more days.[2][6]

The identification of AKI is now possible using several novel biomarkers, even at values that do not meet the conventional diagnostic criteria, a condition referred to as "subclinical AKI." Some of these markers represent structural damage to the kidney which may or may not affect its filtration capacity.[6][7] Traditional criteria, such as plasma creatinine level, urine output, and less commonly cystatin C, measure the kidney's filtration ability rather than structural damage and, as such, can be labeled as "functional AKI."[6]

Although it might be tempting to dismiss AKI cases that don't align with traditional functional criteria as clinically insignificant, current evidence indicates that even a slight rise in perioperative creatinine levels is associated with a 50% rise in perioperative mortality and prolonged hospitalization.[2]

Perioperative acute kidney injury (AKI) is a serious yet underrecognized problem in patients who have recently undergone surgery. Due to increasing age and number of comorbidities, perioperative AKI is increasing in incidence and has significant associated morbidity and mortality.[3] Postoperative AKI raises specific concerns as it elevates the risk of short- and long-term mortality, escalates hospitalization costs, and substantially increases resource utilization compared to patients without postoperative AKI. Early recognition of AKI and implementation of early goal-directed therapy is critical to reducing the incidence of progression to chronic kidney disease, renal replacement therapies (RRT), and death.[8]

Etiology

Perioperative AKI is an abrupt decline in renal function within hours to days of surgery.[9] AKI has a multifactorial etiology, but the following is a list of possible risk factors associated with perioperative acute kidney injury:[3]

• Renal hyperfusion
• Systemic inflammation due to trauma and surgical stress
• Nonsteroidal anti-inflammatory drugs (NSAIDS) in the perioperative period
• Preexisting elevation of creatinine (>1.2 mg/dL) [10]
• Advanced age [11]
• African American origin [12]
• Preexisting hypertension
• Active congestive heart failure
• Chronic kidney disease [3]
• Pulmonary disease
• Insulin-dependent diabetes [13]
• Peripheral vascular disease
• Presence of ascites
• High body mass index

Epidemiology

Perioperative AKI is a common and highly underrecognized medical problem.[3] Populations with increased AKI risk include patients undergoing gastric bypass surgery, patients getting liver transplant surgery, surgical patients with preexisting CKD, advanced age, black race, preexisting hypertension, active congestive heart failure, pulmonary disease, insulin-dependent diabetes, peripheral vascular disease, presence of ascites, and high body mass index.[14][[2]

AKI is estimated to occur in approximately 12% of hospitalized patients annually.[9] As of 2017, Meersch et al. reported a prevalence of 2,147 cases of AKI per million population per year, with a significant portion, approximately 30% to 40%, occurring in surgical patients. Of these surgical patients, those receiving cardiac surgery with cardiopulmonary bypass use are at the highest risk for the development of AKI.

Kork et al retrospectively studied 39,369 surgical patients utilizing the KDIGO criteria. AKI was seen in 6% of the study population. The authors also found that even minor changes in serum creatinine levels, specifically in the range of 25% to 49% above baseline, were associated with a twofold increase in the risk of death and an extension of hospital stay by 2 days.[15] 

In 2017, O’Connor et al observed that 6.8% of patients sustained perioperative AKI, causing a 13.3% in-hospital mortality rate as opposed to 0.9% without perioperative AKI.[16] Another recent meta-analysis found the incidence of perioperative AKI in cardiac surgery patients between 25% and 30%.[17][18]

Pathophysiology

Traditionally, causes of renal injury have been categorized as prerenal, intrarenal, and postrenal causes; this remains a useful paradigm in which to visualize inciting factors. Prerenal etiologies causing hypoperfusion include hypovolemia, blood loss, decreased cardiac output, vasodilation from anesthesia, and the neuroendocrine response to surgery. Intrarenal causes of AKI are due to intrinsic disease of the renal vasculature, glomeruli, tubules, or interstitium. Postrenal causes of AKI are usually due to obstruction causing hydronephrosis. These categories can overlap, as prolonged prerenal hypoperfusion or persistent obstruction may eventually lead to intrarenal tubular necrosis.[2][3][19]

In response to prerenal insults, the kidney is capable of remarkable autoregulation which maintains constant renal blood flow and GFR despite declining mean arterial pressure and volume status. One pathway is through prostaglandin signaling, which causes afferent arteriolar vasodilation, increasing blood flow to glomeruli and sustaining the glomerular capillary pressure. NSAIDs inhibit prostaglandin production and, therefore the autoregulatory process.[2] Another mechanism that sustains the glomerular capillary pressure is the release of angiotensin II due to the activation of the renin–angiotensin–aldosterone system.[20]

In addition to hypoperfusion-induced kidney injury, systemic inflammation and cytokine production caused by trauma and surgical stress induce tubular injury and activate inflammatory cellular pathways.[21][22] The etiology of inflammation-induced AKI is multifactorial, including the following:[23]

• Renin–angiotensin–aldosterone system activation
• Renal microcirculatory dysfunction
• Increased oxidative stress
• Cytokine-induced injury
• Endothelial cell injury
• Activation of proapoptotic pathways

If renal hypoperfusion prolongs or drops below the autoregulatory threshold, the renal sympathetic system releases endogenous vasoconstrictors resulting in afferent arteriolar vasoconstriction which reduces renal blood flow, causing renal tubular ischemia and reduced GFR.[24][25] In patients with underlying chronic renal disease, autoregulation is impaired, exacerbating the effects of hypoperfusion. Additionally, surgical stimulation induces systemic inflammation, leading to microcirculatory impacts, endothelial dysfunction, and increased leukocyte migration. The net result of these inflammatory changes is damage to the renal tubules and AKI.[3]

Evidence indicates that renal dysfunction can directly impair other organ systems. For instance, AKI can activate Paneth cells in the intestine, causing them to release significant amounts of cytokines. This, in turn, can facilitate the translocation of gut bacteria into the bloodstream, thereby contributing to sepsis and multiorgan failure. Other organs affected by AKI include the heart, lung, and brain.[2]

Histopathology

A biopsy is not generally performed unless an underlying systemic process is suspected, and histopathology will depend on the cause of the AKI. For example, prerenal causes of AKI tend to show bland urine sediment and routine histopathology, while acute tubular necrosis may be present with prolonged ischemia or another nephrotoxic insult. 

History and Physical

Overall, perioperative acute kidney injury presents in a nonspecific manner. Clinical signs on physical examination are related to the degree of renal function that has been lost and the underlying insult, such as hypotension or hypovolemia.[26] Intraoperative hypotension, before and after incision, and the duration and depth of the hypotension have been significantly correlated with AKI.[27] Intraoperative hypotension plays a significant role in the subsequent development of AKI. It can occur before incision, often preventable, or after incision, which is not as easily prevented.

Postincision hypotension is multifactorial and can be due to blood loss, changes in noxious stimulation, positioning, or vessel compression. One study demonstrated intraoperative hypotension in half of the patients, and hypotension occurred 4 times as often postincision.[27]

The presentation of perioperative AKI is similar to AKI due to other causes, such as:

• Oliguria
• Nausea and vomiting
• Dizziness
• Edema

Evaluation

Innovations in laboratory analysis of AKI have determined the existence of AKI biomarkers that can be detected before renal mass is lost.[9] These biomarkers are surrogates of early stress on the renal tubules. They are mobilized secondary to cardiopulmonary bypass and surgical stimulation and reflect underlying mechanisms of renal injury since different biomarkers are released in response to specific insults. Of note, insults due to G1-phase cell cycle arrest are associated with tissue-inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP-7) biomarkers and are predictive of major adverse kidney events, including death, persistent renal dysfunction, and need for dialysis.[28][29] 

Other biomarkers being studied for similar purposes are (NGAL), kidney injury molecule-1 (KIM-1), and cystatin C. NGAL has been especially well studied and is highly correlated with renal tubular injury.[30] NGAL prevents bacteria from absorbing iron, which inhibits their growth and multiplication. In AKI, NGAL levels are elevated in both plasma and urine up to 24 hours before elevated plasma creatinine levels.[30] 

Cystatin C is another molecule being studied as a substitute for creatinine. Cystatin C is a tiny, charged molecule entirely filtered at the glomerulus, where it is catabolized in proximal tubule cells. Consequently, cystatin C is virtually absent in the urine of healthy individuals.[31] Combined with a short half-life (2 hours), these characteristics have made cystatin C a potential surrogate for tubular cell integrity and glomerular filtration rate.

The main limitation of using these biomarkers is their availability outside the research sphere. Further research is needed into the use of these biomarkers as early indicators of both structural kidney damage and impairment of the kidney's filtration function, as the current indicators of serum creatinine and urine output may not show abnormalities until significant AKI has already occurred.

Treatment / Management

Developing successful treatment options for perioperative AKI has been elusive. Although various agents have shown potential, a single strategy for improving treatment options for AKI has failed to show utility in clinical care.[32][33][34] When perioperative acute kidney injury develops, goal-directed therapy to reach adequate cardiac output and oxygen delivery levels has been documented to reduce mortality resulting from AKI.[35] Unfortunately, studies have shown that developing lactic acidosis or hypotension intraoperatively is a late indicator of decreased renal perfusion. As such, cardiac output and renal blood flow should be maintained with aggressive fluid resuscitation, and when fluids alone are insufficient, inotropes are necessary. A reasonably liberal fluid administration regimen is safer than a highly restricted one for fluid resuscitation of patients in the perioperative period.[36][37] The use of hydroxyethyl starches, including low-molecular-weight starches, in the perioperative period is not recommended in patients with an increased risk of AKI.[38]

Several medications have been controversial in the treatment of AKI. Dopamine was previously thought helpful in AKI, but this has not been born out in studies, and KDIGO guidelines advise against its use. Fenoldopam is a selective dopamine-1 agonist that has been shown to reduce the need for RRT. Nonetheless, this has only been consistently demonstrated in patients having undergone cardiac surgery, and its use is limited by its ability to cause systemic hypotension. Atrial natriuretic peptide (ANP) effectively reduces the need for RRT in post-cardiac surgery patients, yet, like fenoldopam, its utility is limited by systemic hypotension.[39] KDIGO guidelines support using diuretics to treat hypovolemia but do not empirically prevent AKI.

The KDIGO bundle recommends specific measures to help prevent AKI. These include avoiding nephrotoxic substances, optimizing volume status to maintain sufficient perfusion pressures, maintaining normoglycemia, and monitoring serum creatinine, urine output, and perhaps hemodynamics. The KDIGO bundle, if implemented early based on biomarkers, reduces the development of AKI in postsurgical patients.[40]

Prompt nephrology referral is vital in the management of AKI. Studies of hospitals without nephrology coverage have demonstrated recognition of AKI was delayed with an associated increase in resulting CKD and decreased survivability.[8] Nephrology referral within 18 hours of initial insult reduces the progression of AKI and preserves renal function. Renal replacement therapy should be initiated immediately in cases of progressive AKI or life-threatening complications, such as unresponsive volume overload to diuretics, metabolic disorders, or electrolyte disturbances.[40][3] Initiation of renal replacement therapy is tailored according to each case, based on assessing various clinical parameters that demonstrate the mismatch of demand and capacity.[41][40]

There are a few experimental strategies to prevent perioperative AKI, such as remote ischemic preconditioning, in which brief periods of nonlethal ischemia are given to the peripheries to prepare them for the long and lethal episodes of ischemia from the surgery.[42] Remote ischemic preconditioning involves the application of short intervals of ischemia and reperfusion of peripheral tissues or organs, resulting in the activation of protective responses of remote organ systems. For instance, inflating a blood pressure cuff on the upper arm to 200 to 300 mm Hg for 5 minutes and then releasing the pressure, followed by several repeat cycles. The threshold of including remote ischemic preconditioning in routine clinical practice is relatively low because of the noninvasive nature, unknown adverse effects, and favorable initial findings.

Differential Diagnosis

Various perioperative AKI syndromes must be considered, including hemodynamic, nephrotoxic, damage-associated molecular pattern (DAMP)-induced inflammation, and obstruction. If oliguria develops as the presenting symptom of AKI, mechanical obstruction of the urinary tract must be considered. Obstruction is widespread in colorectal, urological, and gynecological surgical procedures.

Additionally, drug-induced urinary retention should also be excluded. If a Foley catheter is in place, it should be inspected to ensure it is not obstructed or kinked. Increased release of antidiuretic hormone secondary to pain, nausea, surgery, and other nonrenal stimulation should be considered, as should increased aldosterone secretion.[9]

Prognosis

Perioperative AKI is associated with a 10-fold increase in mortality, reduced long-term survival, and increased development of chronic kidney disease with subsequent need for hemodialysis following hospital discharge. AKI requiring renal replacement therapy is an independent risk factor for death.[14]

Complications

As previously discussed, the development of perioperative AKI places the patient at risk of progression to chronic renal disease and may require long-term renal replacement therapy.[14] The development of complications is dependent on the stage of acute kidney injury, but the following is a comprehensive list of complications that may arise in patients with perioperative AKI:

• Hyperkalemia
• Hyperphosphatemia
• Hyponatremia
• Hypermagnesemia
• Hypocalcemia
• Metabolic acidosis
• Uremic encephalopathy
• Volume overload
• Hypertension
• Circulatory collapse

Deterrence and Patient Education

Patients who have experienced perioperative AKI should receive guidance on preserving their renal function. This includes recommendations to avoid nephrotoxic agents that could further harm the kidneys. NSAIDs are known to cause prerenal hypoperfusion and interstitial nephritis, which can lead to the development of AKI or the worsening of existing AKI. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are also known to affect renal autoregulation, although avoiding these mediations in the perioperative period is currently a topic of debate.[39]

Enhancing Healthcare Team Outcomes

Early recognition of perioperative AKI is the first step in improving care. The risk-adjusted cost of caring for a patient with perioperative AKI is $42,600 per episode of care versus $26,700 per episode of care in a patient without AKI.[8] Unfortunately, a nephrology consultation is usually made after an AKI has become severe. At this point, renal replacement therapy is often required.[43]

Soares et al described the importance of nephrologists' involvement in interprofessional care teams in making early identification of AKI and implementing strategies to slow or stop the progression of AKI. AKI is also strongly associated with nutritional impairments, including negative nitrogen balance, alterations in serum concentrations of amino acids, gluconeogenesis, and insulin resistance. As such, registered dieticians are essential in ensuring that patients with AKI have adequate nutritional requirements to meet these deficiencies.[43]

Pharmacists also have an essential role in the interprofessional care team in managing perioperative AKI. Clinical pharmacists have the expertise to perform medication reconciliations to prevent drug-drug interactions. They can also adjust the dose of medications based on renal function, as needed, for changing the glomerular filtration rate, as this will be dynamic as AKI worsens or improves. Pharmacist interventions have been shown to prevent the progression of renal disease to the point of requiring RRT in patients with chronic renal disease, and it is reasonable that they can have similar outcomes in acute renal injury.[44]

Healthcare providers need to work together as a team to optimize patient care, minimize the risk of kidney injury, and promptly address any complications that arise. Healthcare providers should collaborate to enhance the quality of care and improve patient outcomes in the perioperative period. Effective collaboration, communication, and a patient-centered approach are essential to managing patients with perioperative AKI and improving patient outcomes.