Acute Perioperative Kidney Injury

Murat Sungur

Azra Bihorac

Cengiz Utas

Joseph A. Layon

CASE SUMMARY

A 76-year old, 70-kg man underwent elective surgery for an abdominal aortic aneurysm. Baseline electrolytes were Na⁺ 138 mEq per L, Cl⁻ 96 mEq per L, and K⁺ 3.9 mEq per L. His baseline creatinine was 0.8 mg per dL and blood urea nitrogen (BUN) was 22 mg per dL. He was NPO for 10 hours preoperatively. During the 4-hour surgery, he received 5,400 mL of normal saline, four units of packed red blood cells, and two units of fresh frozen plasma. He had a 10-minute period of hypotension with a systolic blood pressure of 85 mm Hg, which responded to intravenous fluids. Infrarenal aortic cross-clamping was used for approximately 25 minutes. His total urine output (UO) was 500 mL during the surgery.

Postoperatively, he was transferred to the surgical intensive care unit (ICU) intubated with mechanical ventilation. He was stable overnight with minimal volume requirements and a UO of more than 0.5 mL/kg/hour. He began to have hypotensive episodes (systolic blood pressure <90 mmHg), tachycardia (heart rate [HR] >110 bpm), with a central venous pressure (CVP) of 2 mmHg. Hypotension persisted, with a CVP of 3 to 4 mmHg, even after 3 L of intravenous 0.9% saline solution boluses. Significant abdominal distension occurred, and rectal examination revealed bloody stool. Colonoscopy showed ischemic changes in the sigmoid colon, and he was taken back to the operating room urgently for exploratory laparotomy.

Sigmoid colectomy and colostomy were performed. The patient had hypotensive episodes during the 2 hours of surgery, requiring 5 L of intravenous crystalloids, and one liter of colloid. Postoperatively, his UO decreased to <0.25 mL/kg/hour. He was given 40 mg of intravenous furosemide, but his UO did not increase. Aggressive intravascular volume resuscitation increased the CVP to 12 mmHg and systolic blood pressure to more than 100 mmHg. UO increased to more than 0.5 mL/kg/hour. The patient’s electrolytes at that time were Na⁺ 142 mEq per L, Cl⁻ 114 mEq per L, and K⁺ 4.0 mEq per L; BUN was 40 mg per dL and creatinine was 1.4 by the next day.

Optimal intravascular volume was provided over the following days, and BUN and creatinine returned to baseline values. The patient’s trachea was decannulated 4 days later, and he was discharged from the surgical ICU to the surgical floor.

What Risk Factors for Acute Kidney Injury Were Present?

The most important risk factor for perioperative acute kidney injury (AKI) is preexistent renal insufficiency. This patient had multiple risk factors for perioperative AKI, but he did not have a history of renal insufficiency, and his baseline BUN and creatinine levels were within normal limits. Other well known risk factors are type 1 diabetes mellitus, age more than 65 years, major vascular surgeries such as coronary artery bypass graft (CABG), and major aortic procedures, as well as recent exposure to nephrotoxic agents, such as radiocontrast dye, bile pigments, aminoglycoside antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Hemodynamic instability during the perioperative period further increases the risk for AKI.

What Is Perioperative Acute Kidney Injury?

AKI is a syndrome characterized by an abrupt and sustained decrease in renal function. This change results in the retention of nitrogenous (i.e., urea and creatinine) and nonnitrogenous waste products and alteration of the kidneys’ ability to regulate water, electrolytes, and proton balance. The kidneys’ role in the initiation and maintenance of dysoxic injury is also intriguing. However, we are unable to measure and quantify the accumulation of various, poorly defined, middle and large molecules with postulated toxic effects (uremic toxins), as well
as possible immunomodulatory and proinflammatory effects of AKI on various distant organs. Depending on the severity and duration of renal dysfunction, this accumulation is accompanied by metabolic derangements including acidosis, hyperkalemia, hyperphosphatemia, disturbances in body fluid balance, and deleterious effects on distant organs such as the heart and lungs.¹

▪ ETIOLOGY

Numerous causes of AKI have been classified into three broad categories—prerenal, renal, and postrenal—in an attempt to delineate the major pathophysiologic mechanisms that underlie kidney injury. Unfortunately, most cases cannot be classified as any of the three and are likely multifactorial.

TABLE 31.1 Common Causes of Acute Kidney Injury (AKI) among Surgical Patients

1.	Multifactorial
2.	Prerenal
	a.	Hypovolemia
		(1)	Preoperative
			Fluid depletion secondary to poor intake (routine nil by mouth)
		(2)	Effects of surgery
			Blood losses
			Extracellular fluid losses
			Insensible losses (major abdominal surgery up to 10 mL/kg/h)
			Insensible losses due to mechanical ventilaton
	b.	Reduced “effective” extracellular volume
		Extravasation of fluid out of the vascular compartment (the “third space effect”), especially intra-abdominal and intrathoracic operations
		Heart failure
		Liver failure
	c.	Systemic vasodilation
		(1)	Effect of anesthesia
			Peripheral vasodilation
			Myocardial depression
			Renal efferent arteriolar vasodilation (especially in patients taking angiotensin-converting enzyme inhibitor or angiotensin receptor blocker)
			Increase in antidiuretic hormone
		(2)	Sepsis
		(3)	Liver failure
3.	Renal
	a.	Ischemic acute tubular necrosis
		Renal ischemia
		Inflammation
		Gut ischemia
		Impaired visceral perfusion
		Portal endotoxemia (open abdominal aortic aneurysm surgery)
		Ischemia-reperfusion injury (open abdominal and thoracic vascular surgery)
	b.	Toxic ATN
		Endogenous toxins
		Exogenous toxins
		Radiocontrast nephropathy
		Drugs
		Nonsteroidal anti-inflammatory drugs
		Antibiotics
		Aminogycosides
		Amphothericin
		Antivirals (acyclovir)
		Inorganic fluorides from volatile agents (enflurane)
	c.	Interstitial
		Drugs
		Autoimmune
		Viruses
		Acute bacterial pyelonephritis
		Malignant infiltration
	d.	Intrarenal obstruction
		Casts
		Crystals
	e.	Renal artery occlusion
		Aortic clamping during vascular surgery
	f.	Renal vein occlusion
	g.	Intrarenal vascular
	h.	Atheroembolic
		Following release of the aortic clamp
		Vascular surgery
		Endoluminal procedures
		Stent placement
		Coronary artery bypass graft
	i.	Vasculitis
	j.	Thrombotic microangiopathies
		Pregnancy
		Hemolytic uremic syndrome
		Scleroderma
		Acelerated hypertension
		Glomerulonephritis
4.	Postrenal
	a.	Urinary tract obstruction
		Ureters
		Bladder neck
		Urethra
ATN, acute tubular necrosis.

In the surgical ICU, the full spectrum of possible causes, irrespective of the difficulty in classification, may be appreciated by reference to Table 31.1. Here, AKI in the setting of multiple system organ failure, sepsis, and ischemia is encountered. Nephrotoxic AKI is less commonly seen because of the judicious use and monitoring of aminoglycosides and amphotericin B and the increased availability of less toxic alternatives that have recently emerged. Prerenal azotemia due to volume depletion,
hemorrhage, or inadequate resuscitation can be easily identified and corrected with proper monitoring. It has become less common because of the new guidelines for volume resuscitation that promote early, goal-directed therapy for patients with sepsis and the systemic inflammatory response syndrome (SIRS).²

▪ EPIDEMIOLOGY

AKI is a common problem in hospitalized patients and is associated with a high morbidity and mortality rate.³ It affects 5% of all hospitalized patients and between 10% and 25% of all critically ill patients.⁴,⁵ Acute tubular necrosis (ATN) after surgery accounts for 20% to 25% of all cases of hospital-acquired AKI, many with prerenal causes.⁶ Despite the significant advances in perioperative and intraoperative patient care, AKI is still a significant complication that increases the postoperative mortality rate.² The perioperative incidence varies according to the etiology and definition of AKI, as well as the type of surgery. AKI is common after cardiac surgery, occurring in 7.7% to 42% of patients with previously normal renal function, once again depending on how AKI is defined.⁷,⁸,⁹ Patients undergoing liver and cardiac transplantation also carry a higher risk for AKI.⁸ The incidence of severe postoperative AKI requiring renal replacement therapy (RRT) is reported between 0.6% and 2.7%.⁷,¹⁰ In the ICU, 35% to 50% of cases of AKI are attributed to sepsis.¹¹,¹²,¹³,¹⁴

Patients with preexisting renal impairment, hypertension, cardiac disease, peripheral vascular disease, diabetes mellitus, jaundice, and advanced age have a significantly higher risk for developing AKI. Preoperative renal dysfunction was the single, most consistent predictor of postoperative renal failure.¹⁵ The nature of the surgical procedure also significantly affects the occurrence of postoperative AKI, with the highest incidence after CABG and vascular surgeries involving the aorta. For patients undergoing cardiac surgery, factors such as advanced age, emergency surgery, low ejection fraction, requirement for intra-aortic balloon pump, redo cardiac surgery, diabetes mellitus, mitral valve surgery, duration of cardiopulmonary bypass (CPB), and preoperative renal disease were independently associated with AKI.¹⁶ The development of postoperative renal dysfunction is also accompanied by a higher incidence of gastrointestinal bleeding, respiratory infections, and sepsis.¹⁷ Strategies directed toward the early recognition of patients with an increased risk for postoperative AKI, and use of known preventive therapies in the perioperative and postoperative periods, are of great importance, considering the high prevalence of AKI and its detrimental effect on morbidity and mortality among this group of patients.

▪ MORTALITY

The mortality rate for patients with postoperative AKI is reported between 14% and 19%.⁷,¹⁰,¹⁸ Patients requiring RRT have a mortality rate as high as 28% to 69%.⁷,¹⁰,¹⁹ The odds ratio for death in the first 30 days postoperatively is 9.2 for patients who develop postoperative AKI compared with those who do not.²⁰ The mortality rate for contrast media-induced AKI is reported to be 34% compared with 7% for patients who do not develop AKI after exposure to contrast media.²¹ In the ICU, the mortality rate of AKI is 10% to 15% if it is an isolated organ failure, and increases to as high as 40% to 90% if it is associated with other organ failure.²²

What Is the Pathophysiology of Acute Kidney Injury?

Prerenal azotemia—reversible renal insufficiency due to renal hypoperfusion—and ATN, or a combination of both, are among the most common causes of AKI among surgical patients.¹,²³

▪ ACUTE TUBULAR NECROSIS

ATN results from a variety of synergistic combinations of ischemic and nephrotoxic insults rather than from any single insult.¹,²⁴ It is characterized by a complex interaction between the injured tubular epithelial cells and the vascular smooth muscle and endothelial cells, most likely genetically determined by the capacity of each group of these cells to regenerate and recover.²⁵,²⁶,²⁷ Pioneering studies of ATN pathophysiology in the early 1940s indicated a uniform pattern of disturbed renal function, which was characterized by gross tubular dysfunction and extreme diminution in renal blood flow (RBF), coupled with anatomic evidence of tubular necrosis and regeneration.²⁸ Recently, new data emerged that supported the existence of discrete phases of ischemic ATN: Prerenal, initiation, extension, maintenance, and repair (see Fig. 31.1).²⁷,²⁸,²⁹

Prerenal Phase

Renal hypoperfusion plays a role in the pathogenesis of prerenal azotemia and ATN. In experimental studies, AKI progressed from renal vasoconstriction and intact tubular function (prerenal azotemia) to established AKI with tubular dysfunction if the renal ischemia was prolonged.³⁰ Moreover, early intervention with fluid resuscitation was shown to prevent the progression from prerenal azotemia to established AKI in some instances.

Although a decrease in RBF with diminished oxygen and substrate delivery to the tubule cells is an important ischemic factor, the relative increase in oxygen demand by the tubules also plays a role in renal ischemia.³⁰ Although the kidney receives 20% to 25% of cardiac output, most of that flow is directed to the renal cortex, with only a small fraction reaching the vasa recta of the renal medulla.²³ This area of low blood flow influences the concentration of urine but, ironically, places the medulla at risk of further ischemic damage. Unlike the renal cortex that has a partial pressure of O₂ of approximately 50 mmHg, the
outer medulla has a partial pressure of oxygen in the range of 10 to 20 mmHg.³¹ Perturbations in medullary blood flow and oxygen delivery can, therefore, lead to anoxic injury if they exceed the critical thresholds when they are not reversed by timely therapy. Cell injury and ATN can result.²³ The precise threshold for this injury and its clinical measurement are unclear. Persistent inadequate blood flow to the kidneys and progression to AKI following successful resuscitation and restored global hemodynamic parameters in severe sepsis and septic shock clearly indicate that the current means for measurements of end-organ perfusion, including that of the kidneys, are inadequate.³²

FIGURE 31.1 Cellular events, renal blood flow and GFR in different phases of ischemic acute kidney injury. GFR, glomerular filtration rate. (Adapted from the following references: Cochrane Injuries Group Albumin Reviewers: human albumin administration in critically ill patients: systematic review of randomized controlled trials. Brit Med J 1998;317:235; Choi PT, Yip G, Quinonez LG, et al. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med 1999;27:200; Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomized study. Lancet 2001;357:911.)

Initiation Phase

After the initial insults, parenchymal injury develops, and kidney function may deteriorate. Experimental and human studies indicate that tubular epithelial cells can suffer one of three distinct fates after ischemic AKI: Cell death (apoptosis), sublethal cell injury, or escape from injury.²⁶

Apoptosis occurring in both distal and proximal tubular cells is emerging as the major mechanism of early and late cell death in ischemic and nephrotoxic forms of AKI. Necrosis of the tubular cells is restricted to the highly susceptible, outer medullary regions following severe renal injury.³³ However, most cells remain viable, either entirely escaping injury or undergoing sublethal injury and subsequent recovery. Severe reduction in RBF induces characteristic, rapidly occurring, and duration-dependent effects in numerous renal cell types, although these effects are seen most prominently in proximal tubular cells.³⁴,³⁵,³⁶

In sublethal tubule cellular injury, alterations in the apical cytoskeleton result in loss of the brush border and cell polarity, and produce disruption of tight and adherens junctions.²⁶,³⁴ Loss of basolateral Na⁺/K⁺-ATPase impairs proximal tubular sodium reabsorption, with a consequent increase in the fractional excretion of sodium.³⁷ Redistribution of integrins to the apical membrane results in detachment of viable cells from the basement membrane and promotes tubular obstruction.²⁶ Loss of surface membrane, tubular obstruction resulting from sloughing of viable and dead tubular cells into the lumen, and cast formation decrease the glomerular filtration rate (GFR).³⁰,³⁸ Obstruction of the tubular lumen eliminates glomerular filtration within that nephron by increasing intratubular pressures to levels inconsistent with filtration.³⁴

Unfortunately, human studies using forced diuresis with furosemide or mannitol fail to demonstrate an impact on the survival and renal recovery in patients with AKI, indicating that obstruction alone accounts only for minor dysfunction.³⁹,⁴⁰ Tubular “backleak” of glomerular filtrate into the circulation results from denudation of the tubular basement membrane, intratubular obstruction, loss of cell polarity, and disruption of tight and adherens junctions, further contributing to the decline of GFR in AKI.³⁰

Several important mechanisms underlie changes in the tubular cell structure. A profound reduction in intracellular adenosine triphosphate (ATP) content occurs early after ischemic renal injury, leading to several critical metabolic consequences. A rapid degradation of ATP results in the accumulation of adenine nucleotides and hypoxanthine, contributing to the generation of reactive oxygen molecules that cause renal tubule cell injury by oxidation of proteins, peroxidation of lipids, damage to DNA, and induction of apoptosis.²⁶ A rise in free intracellular calcium causes protease and phospholipase activation, with resultant cytoskeletal degradation.³⁰ Ischemic activation of nitric oxide (NO) synthase and NO generation in tubule cells further promotes cellular damage through oxidant injury, as well as protein nitrosylation.⁴¹ Even with resolution of the initial ischemic insult, a steady decline in RBF continues, caused by hemodynamic and vascular abnormalities that are incompletely understood.²⁸,⁴² Tubuloglomerular feedback may be partly responsible for the renal vasoconstriction observed in AKI, although its role is not completely clear.²⁶,⁴²

A complex cascade of inflammatory mechanisms is initiated in this phase and will become fully evident if the injury is not alleviated. Intrarenal protective mechanisms, such as the induction of heat shock protein (HSP) in tubular cells, are activated early and in parallel with mechanisms of renal injury. If they prevail, the injury will be diminished at this stage, with complete recovery to follow.⁴³,⁴⁴

Extension Phase

Extension of microvascular endothelial injury resulting in the perpetuation of hypoxia following the initial ischemic event and exaggeration of inflammatory cascade are the hallmarks of this stage. Regional alterations in RBF persist after the initial ischemic event and are of greater magnitude in the outer medulla than in the outer cortex or inner medulla. Medullary blood flow remains severely reduced to levels ranging from 10% to 50% of normal in both human²⁸ and animal models of ischemic AKI.⁴⁵ The mechanisms underlying this persistent alteration of renal perfusion following ischemic injury are complex and not completely understood. An imbalance between the mediators of renal vasoconstriction and renal vasodilatation, as well as congestion of the renal microcirculation secondary to endothelial injury and dysfunction, are among the major proposed mechanisms.²⁷,²⁹

Endothelial cells undergo an array of complex changes that alters their function and interaction with multiple other cell types. Endothelial cell swelling, altered cell-to-cell attachment, and reduced endothelial cell basement membrane attachment increase permeability and interstitial edema.²⁹,³⁴ Thrombin activation and generation lead to an activated coagulation cascade, and the amplification of inflammatory cascade includes white blood cell activation and cytokine generation.²⁷ Altered vascular reactivity, produced by reactive, oxygen species-mediated decreases in NO-mediated vasodilatation and endothelin-mediated vasoconstriction, potentiate the intense vasoconstriction and contribute to abnormal blood flow.²⁹ These changes are most prominent in the peritubular capillaries of the corticomedullary junction and outer medulla, and further exacerbate medullary congestion, hypoperfusion, and injury during the extension phase.²⁷

More widespread tubular cell death, desquamation, and luminal obstruction continue in the medulla. Injured endothelial and epithelial cells amplify the inflammatory cascade and produce multiple inflammatory cytokines and chemokines. Endothelial activation enhances endothelial-leukocyte interactions and leads to leukocyte infiltration, as well as further inflammatory and cytotoxic injury.²⁷ In a recent study, CD4⁺ T cells, working through both interferon-γ (IFN-γ) and costimulatory molecules, were implicated as an important modulator of AKI.⁴⁶ Complement activation may also contribute to neutrophil recruitment and tissue damage.⁴⁷ This activated inflammatory cascade exacerbates hypoperfusion in the renal microcirculation and promotes further release of cytotoxic inflammatory cytokines and reactive oxygen species.

Maintenance Phase

During this phase, GFR is maintained at its nadir while parenchymal injury is established. RBF begins
to normalize, although it may remain slightly below normal 12 to 20 weeks after the onset of ATN in spite of clinical renal recovery.²⁸ Tubular cellular injury with ongoing apoptosis coexists with regeneration during the maintenance phase, the duration and severity of which may be determined by the balance between cell survival and death.⁴⁴ Repair of both epithelial and endothelial cells is critical to overall recovery, and measures to accelerate the endogenous regeneration processes may be effective during this phase.

Although resident stem cells with tubulogenic capacity have been described in the kidneys after ischemic AKI,⁴⁸ proliferation of the native tubule epithelial cells seem to represent the primary healing source for regeneration of the tubule epithelium.⁴⁹,⁵⁰ The surviving renal tubule cells recapitulate phases and processes that are very similar to those during normal kidney development.⁴⁴,⁵¹ Viable cells dedifferentiate, proliferate, and migrate across the basement membrane to reestablish epithelial continuity. This sequence is followed by the process of redifferentiation and reestablishment of normal epithelial polarity and transport functions.⁴⁴,⁵¹ Although the beneficial effect of bone marrow-derived, mesenchymal stem cells in ATN recovery has been demonstrated, most of the evidence suggests that this protective effect is mediated through powerful anti-inflammatory and antiapoptotic mechanisms, with decreased renal tubular injury, rather than by differentiation.⁵²,⁵³

Recovery Phase

Improvement in GFR and reestablishment of tubular integrity, with full differentiation and polarization of regenerated epithelial cells, are observed in this phase. The mechanisms whereby most of the tubular cells escape cell death and recover completely after ischemic AKI are still under investigation. Induction of HSP is a highly conserved, innate cellular response and is found to be activated after ischemic AKI, likely promoting cell survival by inhibiting apoptosis.⁴³ The importance of inducing protein involved in cell cycle control has recently emerged.⁵⁴ Engagement of the cell cycle is an important determinant of whether cells survive the injury itself. Coordinated cell cycle control, initially manifested as cell cycle inhibition, is necessary for optimum recovery from ATN. Hence, the importance of cell cycle inhibitors, p21 and 14-3-3r, induced by cellular stress from the initial ischemic or nephrotoxic insult, and their combined activities to check the cell cycle at G1 and G2, can be appreciated to coordinate the cell cycle and permit cell survival.⁵⁴

In conclusion, after the initial “functional recovery” from an episode of clinical AKI, a significant proportion of patients exhibit persistent or progressive deterioration in renal function. Animal studies, and some early morphologic studies in human ATN, indicate that postischemic kidneys demonstrate various sequelae of acute injury, including reduction in renal microvasculature, interstitial fibrosis, tubular hypercellularity and atrophy, and persistent inflammation.²⁸,⁵⁵,⁵⁶,⁵⁷,⁵⁸ Future research efforts will be directed toward a better understanding of the mechanisms described and the development of a means for intervention early in the course of AKI. Perhaps more importantly will be the development of strategies to identify AKI susceptibility among individuals exposed to known ischemic and nephrotoxic injuries and to prevent injury altogether.

How Is Acute Kidney Injury Clinically Assessed and Diagnosed?

▪ GENERAL CONSIDERATIONS

Until approximately 60% of the renal mass is lost, patients are in a stage of decreased renal reserve. They generally have no signs or symptoms of renal dysfunction and present no specific problems for intensivists or anesthesiologists. The clinical diagnosis of AKI can be described as a sudden deterioration in renal function with concomitant electrolyte, acid-base, and fluid balance disturbance. Two issues are important in the clinical approach to the patient with AKI:

Treating any life-threatening features and
Identifying any cause of AKI that warrants specific treatment

Any patient with low UO should be assessed for possible prerenal causes of AKI. UO is very specific but far less sensitive to define acute renal failure (ARF). Severe ARF can exist despite normal UO (i.e., nonoliguric), but changes in UO can occur long before biochemical changes are apparent. Prerenal forms of ARF nearly always present with oliguria (<400 mL per day), although very rarely nonoliguric forms are possible. Hypotension, shock, and respiratory failure should immediately be assessed in the initial approach and treated if present. Hyperkalemia is another feature that requires urgent treatment. Dehydration secondary to gastrointestinal losses, pneumonia, bowel obstruction, and new onset impairment of functional capacity in the elderly patient are often the initial diagnoses. A definitive diagnosis of AKI is made only when laboratory parameters become available. The clinician should then ask a series of questions: Is this AKI? Are there any clues from the history? Is the etiology prerenal? Could this be an obstructive process? Is intrinsic renal disease probable? What will the initial evaluation reveal?

Anemia, hypocalcemia, and hyperphosphatemia are not good indicators of renal failure chronicity. Renal ultrasonography may reveal small kidneys, often with cortical scarring and possible cyst formation, in chronic renal disease. Normal sized kidneys, however, do not necessarily rule out current renal disease. A targeted history will often be necessary. The history should include queries concerning a recent throat infection (possible poststreptococcal glomerulonephritis). Drug history should include current and recent medications as well as over-the-counter
preparations, recreational drugs, and alternative or herbal remedies. Rash, fever, and arthralgia are suggestive of acute interstitial nephritis. Bone pain may be a feature of myeloma. Constitutional symptoms may point to systemic vasculitis. Hemoptysis suggests a pulmonary-renal syndrome. Nephrotoxic agents should also be investigated, including aminoglycosides and radiocontrast agents.

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