Emilee Willhem-Leen and Glenn Chertow
Acute kidney injury (AKI) is common in critical illness. A recent, large, multinational prospective study reported that 5.7% of critically ill patients will develop AKI during their illness.1 AKI in the setting of critical illness also confers a poor prognosis. In-hospital or short-term (90-day) mortality rates for critically ill patients who develop AKI range from 45% to 60%.1–3 Fortunately, the majority of critically ill patients who develop AKI during their hospitalization and who survive to discharge do not require long-term dialysis.1 This chapter reviews common definitions and classifications of AKI, etiologies of the disease, and appropriate emergency department (ED) diagnostic and therapeutic interventions for patients with AKI.
Critically ill patients may have AKI at presentation or may develop it during the course of their illness. While there is no consensus definition for AKI, the diagnosis is commonly made based on the following:
Classification of AKI
sCr concentration is not an optimal early marker of AKI because (1) it does not accurately reflect kidney function in patients whose glomerular filtration rate (GFR) is acutely changing and (2) it may be lowered by muscle wasting that accompanies critical illness. Given this limitation, several criteria have been proposed to classify the severity of AKI.
The RIFLE criteria (Risk, Injury, Failure, Loss, ESRD [end-stage renal disease]) consist of three levels of injury that are useful in ED assessment of kidney injury (R, I, and F) and two levels (L and E) that are more typically applied during inpatient evaluation:
Acute Kidney Injury Network Criteria
The Acute Kidney Injury Network (AKIN) criteria are based on the RIFLE criteria but simplify the system for ease of use and clarity:
o Stage 1: 1.5 times increase in sCr from baseline, ≥0.3 mg/dL increase in sCr, or urine output of <0.5 mL/kg/h for 6 hours
o Stage 2: 2 times increase in sCr or urine output of <0.5 mL/kg/h for 12 hours
o Stage 3: 3 times increase in sCr, sCr of ≥4 mg/dL (with an acute rise of ≥0.5 mg/dL), or urine output of <0.3 mL/kg/h for 24 hours or anuria for 12 hours
o Stage 1 equivalent to RIFLE RISK
o Stage 2 equivalent to RIFLE INJURY
o Stage 3 equivalent to RIFLE FAILURE
The Kidney Disease Improving Global Outcome Criteria
The Kidney Disease Improving Global Outcome (KDIGO) criteria consist of three levels of renal injury based on either sCr or urine output:
For simplicity, we recommend use of either the AKIN or KDIGO classification. Unfortunately, precise classification of AKI stage may not be possible in the ED setting; often, baseline sCr is not available, and observation of urine output takes 6 to 24 hours. However, providing critical care or nephrology colleagues with this information, as available, aids in rapid triage and prognosis. For example, if a patient with a known baseline sCr of 1.0 mg/dL presents to the ED with sepsis and an initial sCr of 2.5 mg/dL and makes <50 mL of urine during the first 2 hours of evaluation and management, he or she likely has sustained at least a stage 2 AKI (per AKIN and KDIGO criteria). No stage of AKI, alone, necessitates admission to the intensive care unit, but nephrology consultation in the ED should be considered for patients presenting with likely stage 2 or 3 AKI.
ETIOLOGY OF AKI
AKI is a heterogeneous disease that can be caused by many factors. Typically, these factors are grouped into prerenal, intrarenal, and postrenal etiologies.
Prerenal AKI is caused by a reduction in renal perfusion. Precipitating conditions include hypovolemic shock (usually from gastrointestinal losses or severe burns), cardiogenic shock (usually from left-sided or biventricular failure), cirrhosis (including hepatorenal syndrome), and sepsis/systemic inflammatory response syndrome. Diuretic therapy and other drugs like ACE inhibitors and NSAIDs can exacerbate a prerenal state, especially in patients with additional risk factors. Typically, the urine sodium is low (<20 mmol/L), with a fractional excretion of sodium (FENa) <1% indicating a sodium-avid state in which the body is attempting to retain or replace lost volume.
Etiologies of intrarenal AKI include vascular, glomerular, and tubular/interstitial disease. Common vascular diseases associated with AKI include atheroemboli (typically associated with angiographic or surgical/endovascular procedures), vasculitis, thromboembolic disease including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) malignant hypertension, and scleroderma renal crisis. Glomerular diseases that result in AKI include the nephritic (generally accompanied by active sediment on urinalysis [UA], i.e., red cells, white cells, and/or cellular casts) and nephrotic (generally accompanied by heavy proteinuria) syndromes (Table 40.1). Tubular and interstitial diseases are the most common causes of AKI in hospitalized patients; they include acute tubular necrosis (ATN), acute interstitial nephritis (AIN), and, less commonly, multiple myeloma cast nephropathy and tumor lysis syndrome.
TABLE 40.1 Clinical Significance of Findings on UA or Urine Microscopy
ATN is the most common cause of AKI in hospitalized patients and accounts for nearly 45% of in-hospital AKI.2 Renal ischemia, sepsis, and nephrotoxins, including radiocontrast media, heme pigment (e.g., in patients with rhabdomyolysis or hemolysis), selected cancer chemotherapeutic agents (e.g., platinum-based agents), and antibiotics (e.g., amphotericin B, aminoglycosides), are all common causes of ATN. Because ATN can occur after prolonged or severe prerenal physiology, it can at times be difficult to distinguish the two processes. In general, prerenal disease, unless it is due to hemodynamic derangements associated with heart failure, cirrhosis, or sepsis, will resolve with the correction of hypovolemia or hypotension. When the cause of injury is uncertain, urine studies can help distinguish the two etiologies; ATN will demonstrate an FENa >1% (as opposed to <1% seen in prerenal conditions) and the presence of muddy brown casts. In the future, ATN may be more rapidly identified by the detection of urinary neutrophil gelatinase-associated lipocalin (NGAL) and other renal tubular injury markers, discussed below.
AIN is another cause of tubular/interstitial AKI, but it is significantly less common than ATN. AIN is typically the result of exposure to drugs; common offenders include NSAIDs and antibiotics, including penicillins and cephalosporins. Less commonly, AIN can result from infection or systemic illness (e.g., sarcoidosis, Sjogren's, systemic lupus erythematosus [SLE]). A diagnosis of AIN requires the presence of pyuria and white cell casts on UA or urine microscopy.
Postrenal AKI is caused by obstruction to the flow of urine, typically from ureteral compression and occasionally from other causes (e.g., stones, papillary necrosis). Pelvic malignancies (e.g., colorectal carcinoma, ovarian or cervical carcinoma, retroperitoneal lymphadenopathy) are relatively common culprits. Generally, unless the patient has preexisting chronic kidney disease (CKD), the obstruction must affect both kidneys in order for changes in sCr to be detected.
HISTORY AND PHYSICAL EXAM
Because renal disease can impact all organ systems, a comprehensive history and physical exam should be taken. Special priority should be given to the assessment of urgent or emergent indications for dialysis, such as volume overload (shortness of breath, edema) and clinical uremia (myoclonus or asterixis, pericardial rub) (Table 40.2).
TABLE 40.2 Targeted Medical History and Physical Exam
ED patients with AKI require the following diagnostic workup:
EMERGING BIOMARKERS FOR AKI
Cystatin C is an alternative filtration marker to sCr for the estimation of GFR that is being evaluated for its ability to improve the accuracy of prognosis and prediction of mortality in CKD.4 Although a recent study did not demonstrate improved estimation of GFR using cystatin C alone when compared to sCr, the combined use of the two markers did provide a more accurate estimation of GFR.5 Cystatin C is currently not available for clinical use in the United States.
Neutrophil Gelatinase-Associated Lipocalin
Urinary and serum NGAL is another promising potential biomarker for AKI. Produced by renal tubular epithelial cells, NGAL is released into the serum and urine in response to cellular injury; NGAL levels rise in the serum and in the urine in AKI. NGAL is currently not available for clinical use in the United States.
In patients with severe AKI and hyperkalemia, a rapidly rising serum potassium, or a reasonable clinical expectation of impending hyperkalemia (e.g., patients with crush injury or an ischemic limb), medical therapy is an important, but temporizing, intervention that is followed in the majority of cases by hemodialysis (HD) or continuous renal replacement therapy (CRRT). Medical therapy includes antagonism of the effect of potassium on the cardiac myocyte (e.g., intravenous administration of calcium), extra- to intracellular flux of potassium (e.g., insulin and glucose, sodium bicarbonate, β2-agonism), and removal of potassium from the body via the kidneys and gut (e.g., loop diuresis and use of cation exchange resins). In some patients with hyperkalemia and AKI, these therapies may actually perform multiple functions; for example, the use of loop diuretics helps correct hyperkalemia, hyperchloremic metabolic acidosis, and volume overload.
Volume Overload in a Patient Responsive to Diuresis
Patients with AKI who are oliguric or anuric may present to the ED already volume overloaded. The degree of kidney injury and associated metabolic abnormalities determine which patients require immediate dialysis. If dialysis is not immediately indicated, the patient should be given a trial of intravenous loop diuretics; a nonresponse (urine output of <0.5 mL/kg/h or insufficient urine output to improve volume overload) usually indicates more severe renal injury and a greater diagnostic and therapeutic urgency. In patients with evolving renal injury, the sCr may not reflect the extent of impaired function, and the required dose of diuretics may be higher than expected.
Acidemia in a Nonanuric Patient
Metabolic acidosis is a common finding in patients with AKI. The metabolic acidosis observed in AKI can mimic that seen in genetic or chronic tubular dysfunction, with the location of the tubular dysfunction determined by the etiology of the AKI. For example, patients with obstructive nephropathy can develop distal (type 2) RTA. Fortunately, in the acute setting, the treatment of the patient with AKI and metabolic acidosis is nearly always the same.
While HD or CRRT can rapidly correct metabolic acidosis (of any etiology), patients with AKI who develop hyperchloremic metabolic acidosis as a result of impaired acid secretion or bicarbonate regeneration (common in the setting of low GFR) may be conservatively managed with intravenous sodium bicarbonate–containing solutions. For a mild to moderate bicarbonate deficit, one strategy is to administer an isotonic solution containing three amps of bicarbonate (150 mEq) per liter, at a rate of 1 to 2 mL/kg/h. For patients with more severe metabolic acidosis who are awaiting dialysis, bolus administration of sodium bicarbonate may be necessary. Administering sodium bicarbonate to patients with severe lactic acidosis is generally not advised; rather, attention should be focused on reversing the primary cause of lactic acidosis (e.g., septic shock).
INDICATIONS FOR DIALYSIS IN AKI
The decision to initiate dialysis from the ED is generally made in conjunction with a consulting nephrologist. The following are the commonly accepted indications for dialysis in a patient with AKI:
Although there are no studies comparing outcomes for patients who have dialysis initiated in the ED to those who have dialysis initiated later in their hospital course, several high-quality observational and randomized controlled trials (RCTs) suggest that earlier initiation of dialysis or hemofiltration in critically ill patients may improve short-term outcomes such as length of ICU stay and overall survival. In one study of ICU patients from several academic ICUs, the odds ratio for survival to hospital discharge was 1.85 in the group that received dialysis at a lower BUN target (≤76 mg/dL) when compared to those whose BUN was allowed to climb to a higher target (>76 mg/dL).6
TYPES OF RENAL REPLACEMENT
HD is the most common form of renal replacement for hospitalized patients. Dialysis is an intermittent therapy; typically, it is performed three times per week, but it can be performed daily if necessitated by acute illness or other clinical indication. Electrolytes, solutes, and uremic toxins are removed via diffusion; the patient's blood is pumped in a countercurrent fashion along a semipermeable membrane, on the other side of which flows dialysate solution containing precise concentrations of various electrolytes. Dialysis requires venous access, typically in the form of a fistula or graft, but may also be performed by means of a temporary or permanent dialysis catheter. Dialysis rapidly addresses electrolyte, acid–base, and volume derangements; however, removal of intravascular volume in large amounts may be limited by the patient's blood pressure.
Continuous Renal Replacement Therapy
CRRT is a low-flow, continuous therapy used for critically ill patients when adequate volume removal cannot be achieved via a short intermittent session or for those patients who will not tolerate the large fluid shifts associated with dialysis. CRRT also may allow for adequate solute clearance in a patient who is highly catabolic, where intermittent dialysis may be insufficient. Clearance can be obtained via diffusion (dialysis), convection (hemofiltration), or a combination of the two. Access generally requires a catheter; CRRT cannot be performed via a patient's preexisting fistula or graft. CRRT is almost always performed in an intensive care setting.
Sustained Low-Efficiency Daily Dialysis
Sustained low-efficiency daily dialysis (SLEDD) is a hybrid therapy that combines the long treatment times and slower blood flow rates used in CRRT with the purely diffusive clearance of HD. It is used for patients who require a therapy that can provide a slower removal of volume, reduced hemodynamic perturbation, and significant solute clearance. SLEDD is used in place of CRRT in some hospitals; clinical outcomes are generally similar between the two therapies.
For many ED practitioners, the perceived risk of contrast-associated nephropathy will influence the decision to limit the use of certain imaging modalities, especially for patients with CKD or AKI. However, the true risk of contrast-associated nephropathy is likely overestimated in practice, and there is evidence that patients with kidney dysfunction are being inappropriately denied necessary and potentially lifesaving diagnostic and therapeutic procedures.7 The decision to administer or forgo contrast in a patient with AKI should be made in conjunction with a nephrologist. If contrast is administered to patients at highest risk for contrast-associated nephropathy (e.g., patients with preexisting CKD or AKI or patients with diabetes mellitus [DM]), it is reasonable to consider prophylactic pretreatment. One strategy for pretreatment is to administer a bicarbonate-containing isotonic solution at a rate of 1 mL/kg for 6 to 12 hours prior to contrast administration, continuing for 12 hours after contrast administration. Given the lack of risk, it is also reasonable to administer acetylcysteine, either by mouth or intravenously, on the day prior to, and on the day of, contrast administration. It should be noted that the evidence for this strategy is mixed and comes with little expert consensus.8
CI, confidence interval.
AKI is common in critically ill patients and confers a poor prognosis. Identifying these patients early and determining who will require HD is a priority for the emergency physician. Application of the grading systems discussed in this chapter and—since acute AKI may not mount a significant elevation in sCr in the ED—close attention to urine output can greatly expedite achieving this goal.
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