Renal Pathophysiology and Treatment for Perioperative Ischemia and Nephrotoxic Injury

Introduction and Acute Kidney Injury Definitions

Acute kidney injury (AKI) (previously known as acute renal failure) is characterized by rapid decline in the glomerular filtration rate (GFR) and the accumulation of nitrogenous waste products (blood urea nitrogen [BUN] and creatinine). AKI occurs in approximately 5% to 25% of all hospitalized patients, depending on the precise definition used for AKI, and with more frequent rates in patients who are critically ill in the intensive care unit (ICU) (also see Chapter 17 ). AKI is also a serious perioperative complication for patients undergoing major surgery. As the incidence of AKI varies by the definition used, the mortality of AKI ranges from 10% to 35% for mild AKI, whereas AKI in the ICU setting is associated with a 50% to 80% mortality rate. However, supportive care with dialysis has reduced mortality from AKI. Whereas the mortality rate of oliguric AKI was 91% during World War II, mortality declined to 53% during the Korean War with the provision of dialysis. AKI requiring dialysis develops in 1% to 7% of patients after cardiac or major vascular surgery and is strongly associated with morbidity and mortality in this context.

Perioperative renal failure was long defined as a requirement for postoperative dialysis. However, this concept has evolved during the past several years. First, because the implications of requiring postoperative dialysis are quite different for a patient starting with a normal baseline renal function compared with one starting with advanced chronic kidney disease and because the criteria for the use of dialysis are not standardized, the usefulness of dialysis alone to define AKI has been questioned. Second, studies are difficult to compare because of the use of nonstandard definitions for AKI. For example, in one review of 28 studies, definitions for perioperative AKI varied. Third, consensus definitions that focus on small changes in serum creatinine and on changes in urine output to define AKI have received widespread adoption. This last conclusion is based on the recognition that small changes in renal function directly relate to an increased risk of death.

As a result, recent consensus criteria are being used to define AKI in both the perioperative and other medical settings. The first proposed consensus criteria were the RIFLE ( R isk, I njury, F ailure, L oss, E nd-stage) kidney disease criteria developed by the Acute Dialysis Quality Initiative ( Table 42.1 ). These have subsequently undergone two modifications by the Acute Kidney Injury Network and in the Kidney Disease: Improving Global Outcomes (KDIGO) AKI guidelines. As detailed in Table 42.1 , the central components of these criteria are the focus on relative and absolute changes in creatinine from a baseline value and the definition of several degrees of AKI severity. Consequently, milder AKI (e.g., KDIGO, stage 1 disease) will be more common than stage 3 disease and will also be associated with a lower mortality rate. These criteria have also proposed definitions for AKI based on urine output. Overall, although there are studies demonstrating that AKI defined based on urine output is associated with adverse outcomes in the critical care setting and is more common than AKI defined based on creatinine, the urine output criteria are not as well validated. At present, there is no clear method to correct urine output for morbid obesity; in addition, urine output may be unmeasurable if a urinary bladder catheter is not present. Not surprisingly, AKI by urine output criteria is substantially more common than AKI by creatinine-based criteria; in a study of more than 4000 subjects undergoing major noncardiac surgery, the incidence of AKI increased from 8% to 64% when urine output criteria were incorporated. Although each AKI stage was associated with an increased risk of death, the association with mortality was attenuated in this analysis when urine output criteria for AKI were used. Finally, it should be noted that the importance of oliguria (<0.5 mL/kg/h) as a predictor of creatinine-based AKI is less well established in the perioperative setting than in other clinical settings. In a recent large single-center observational study, urine output of less than 0.3 mL/kg/h during major abdominal surgery was associated with an increased risk of perioperative AKI (defined as a 0.3 mg/dL rise in serum creatinine within 48 hours or a 50% increase over 7 days from baseline). However, urine output within the 0.3 to 0.5 mL/kg/h range was not associated with creatinine-based AKI.

Additional challenges for the identification of AKI in the intraoperative setting include large blood volume loss and fluid shifts, which may artificially dilute serum creatinine. Unlike the postoperative or critical care setting where renal monitoring can involve periodic evaluation of kidney function under relatively stable conditions, intraoperative renal monitoring involves a briefer unstable period, often involving significant blood loss, major fluid shifts, wide hemodynamic fluctuations, and even direct compromise to renal artery blood flow. Therefore the anesthesia provider is likely the first monitor (in a sense) required for preserving renal function by recognizing and treating factors that may contribute to or exacerbate AKI; for example, the toxic effects of aminoglycosides and iodinated contrast materials are exacerbated by intravascular volume depletion.

As medical populations shift toward older and more critically ill patients undergoing increasingly high-risk procedures, patients are at an increased risk of AKI in the perioperative setting, and the role of the anesthesia provider becomes even more critical. Indeed, a recent study of dialysis after elective major surgery suggests that the incidence of dialysis-requiring AKI is rising from 0.2% in 1995 to 0.6% in 2009, with the majority of the increase occurring after vascular and cardiac surgery. Although ischemic causes may be primarily responsible for perioperative AKI, the successful development of renoprotective strategies has not occurred. Furthermore, other pathophysiologic contributors to perioperative AKI may include contrast-induced nephropathy, pigment nephropathy (e.g., hemoglobin, myoglobin), cholesterol emboli (e.g., atheroembolic renal disease), aminoglycoside toxicity, and sepsis. Animal studies of such pure nephropathies treated with logical renoprotective interventions often demonstrate success; unfortunately, this success has not extended to equivalent renoprotection in humans. It may not be surprising that a specific treatment for a pure nephropathy nonselectively applied to a mixture of nephropathies, variably expressed in different patients, would be unsuccessful. Postoperative AKI, rather than being a single entity, is likely a mosaic of several pure nephropathies, each of varying importance for a particular patient and procedure ( Fig. 42.1 ).

Pathophysiologic Processes of Ischemic Acute Kidney Injury

In general, the causes for AKI can be divided into prerenal, intrinsic renal, and postrenal sources. In the perioperative setting, patients may be at increased risk for prerenal AKI, either attributable to volume depletion or to exacerbation of associated chronic prerenal physiologic conditions, such as congestive heart failure, which may be exacerbated by volume overload. Intraoperatively, hypotension due to vasodilation and negative inotropy/chronotropy from anesthetic agents may lead to prerenal physiology. Depending on the nature of the surgical procedure, the patient may also be at increased risk of postrenal AKI attributable to obstruction of the ureters, bladder, or urethra. However, the primary cause of perioperative AKI is acute tubular necrosis (ATN). Defining the cause of AKI is also critical because treatment of the underlying cause is critical for the reversal of AKI and potential renal recovery.

The two primary mechanisms of ATN are ischemia-reperfusion and nephrotoxic effects, with three sources of insult common to many surgical procedures during which postoperative AKI is prevalent: hypoperfusion, inflammation, and atheroembolism. Other sources of renal insult in selected patients may include rhabdomyolysis and specific drug-related effects. Certain classes of medications may also contribute to hypoperfusion by virtue of their hemodynamic effects (notably angiotensin-converting enzyme [ACE] inhibitor 1, angiotensin-receptor blockers [ARBs], and nonsteroidal antiinflammatory drugs [NSAIDs]), and, consequently, the risk of ATN.

Ischemic renal failure related to shock or severe dehydration is always preceded by an early compensatory phase of normal renal adaptation (e.g., pre-prerenal failure), followed by a condition termed prerenal azotemia during which the kidney maximizes activities at the expense of the retention of nitrogenous end-products to preserve the internal environment through retention of solutes and water ( Fig. 42.2 ). In studies of community-acquired AKI, the incidence of prerenal azotemia may be as frequent as 70%. In contrast, in a classic study of hospital-acquired AKI, although hypoperfusion accounted for 42% of cases of AKI, only 41% of these cases of hypoperfusion were attributable to inadequate intravascular volume.

Although prerenal azotemia is ominous and typically accompanied by oliguria (<0.5 mL/kg/h), it is reversible. At a critical tilting point, as conditions go beyond the compensatory mechanisms that maintain renal perfusion, ischemia leads to irreversible renal cell necrosis or ATN. This represents the pure form of ischemic AKI. Other forms of ATN are due to toxins, including medications (e.g., aminoglycosides, cisplatinum), pigments (e.g., hemoglobin, myoglobin), and iodinated contrast dye. These forms of ATN do not involve the typical pattern of preceding prerenal azotemia with associated oliguria, since the insult is sudden. Importantly, most cases of perioperative AKI are the result of numerous renal insults, rather than being attributable to one pure source ( Fig. 42.3 ). In particular, patients with prerenal azotemia are likely at increased risk for toxic ATN.

Interruption of blood flow to the kidneys for more than 30 to 60 minutes results in ATN and irreversible cell damage. The kidneys receive 1000 to 1250 mL/min of blood or 3 to 5 mL/min/g of tissue for the average adult, and this amount far exceeds what is needed to provide the kidney’s intrinsic oxygen requirement. Intracortical blood flow may not be evenly distributed. Because the renal cortex contains most of the glomeruli and depends on oxidative metabolism for energy, ischemic hypoxia injures the renal cortical structures, particularly the pars recta of the proximal tubules. As ischemia persists, the supply of glucose and substrates continues to decrease; glycogen is consumed, and the medulla, which depends to a great extent on glycolysis for its energy sources, becomes more adversely affected. Early cell changes are reversible, such as the swelling of cell organelles, especially the mitochondria. As ischemia progresses, a lack of adenosine triphosphate interferes with the sodium pump mechanism, water and sodium accumulate in the endoplasmic reticulum of tubular cells, and the cells begin to swell. Onset of tubular damage usually occurs within 25 minutes of ischemia as the microvilli of the proximal tubular cell brush borders begin to change. Within an hour, they slough off into the tubular lumen, and membrane bullae protrude into the straight portion of the proximal tubule. After a few hours, intratubular pressure rises, and tubular fluid passively backflows. Within 24 hours, obstructing casts appear in the distal tubular lumen.

Renal Response to Hypoperfusion: Autoregulation and Distribution of Cardiac Output to the Kidneys

A common intraoperative stress that puts patients at risk for AKI is hypoperfusion due to hypotension and/or hypovolemia. The fraction of cardiac output perfusing the kidneys depends on the ratio of renal vascular resistance to systemic vascular resistance. In general, the response to renal hypoperfusion involves three major regulatory mechanisms that support renal function: (1) afferent arteriolar dilation increases the proportion of cardiac output that perfuses the kidney; (2) efferent arteriolar resistance increases the filtration fraction and preserves GFR; and (3) hormonal and neural responses improve renal perfusion by increasing intravascular volume, thereby indirectly increasing cardiac output.

The kidney produces vasodilator prostaglandins to counteract the effects of systemic vasoconstrictor hormones such as angiotensin II. In a state of low cardiac output when systemic blood pressure is preserved by the action of systemic vasopressors, RBF is not depressed because the effect of the vasopressors is blunted within the kidney. Studies using specific inhibitors of angiotensin II have shown that efferent arteriolar resistance largely results from the action of angiotensin II. At low concentrations, norepinephrine has a vasoconstricting effect on efferent arterioles, indicating that the adrenergic system may also be important for maintaining the renal compensatory response.

Reductions in cardiac output are accompanied by the release of vasopressin and by increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. These regulatory mechanisms to preserve RBF conserve salt and water. One study reported the normal response to hemorrhage in otherwise healthy patients, describing a 30% reduction in RBF with a decrease in mean perfusion pressure from 80 to 60 mm Hg. Changes known to occur at the initiation of cardiopulmonary bypass (CPB) surgery include greater reduction in renal perfusion than systemic perfusion, loss of RBF autoregulation, and stress hormone and inflammatory responses known to be harmful to the kidney. These effects may explain why the duration of CPB surgery independently predicts postcardiac surgery renal impairment.

Detection of Acute Kidney Injury