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Acute Kidney Injury Richard Sinert Peter R. Peacock, Jr. INTRODUCTION AND EPIDEMIOLOGY Acute kidney injury (AKI) is the deterioration of renal function over hours or days, resulting in the accumulation of toxic wastes and the loss of internal homeostasis. Definitions based on renal function are listed in Table 88-1 1-4; AKI is classified using the Risk, Injury, Failure, Loss, and End-Stage Renal Failure (RIFLE), 2 the Acute Kidney Injury Network (AKIN),3 and the Kidney Disease: Improving Global Outcomes (KDIGO)4 classifications. These definitions assume that renal function has reached a steady state, which limits their applicability to ED patients with AKI whose renal function may be deteriorating. Reversible mechanisms, such as volume depletion, medications, infection, or urinary obstruction, 5-9 cause the majority of communityacquired AKI cases presenting to the ED (55% to 79%). 5,6,10-12 Despite favorable renal recovery rates, community-acquired AKI is associated with significant hospital mortality, from 7.3% to 19.6%, 13,14 and 3-year mortality is as high as 45% to 66%.7,14,15 Hospital-acquired AKI by definition occurs or worsens in the hospital, where mortality ranges from 27% to 62%. 6,10,12 For both types of AKI, mortality has a graded relationship with advancing age and severity of AKI.8,16 PATHOPHYSIOLOGY The functions of the kidneys are glomerular filtration, tubular reabsorption, and secretion. Normal glomerular filtration rate (GFR) in early adulthood is approximately 120 mL/min/1.73 m 2 and typically decreases by 8 mL/min/1.73 m 2 every decade thereafter. The driving force for glomerular filtration is glomerular capillary pressure, which depends on renal blood flow and autoregulation. For most causes of AKI, global or regional decrease in renal blood flow is the final common pathway. Recovery from AKI first depends on restoration of renal blood flow. Renal insult is classified as prerenal (decreased perfusion of a nor mal kidney), intrinsic (pathologic change within the kidney itself), or postrenal (also called postobstructive, due to obstruction of urine outflow). In prerenal AKI, tubular and glomerular functions are initially maintained. Timely restoration of circulating blood volume or discon tinuation of an implicated medication restores function in most cases. Postrenal AKI causes increased tubular pressure, which decreases the driving force for filtration. This pressure gradient soon equalizes; thereafter, the maintenance of the depressed GFR depends on vasocon strictors. Rapid relief of urinary obstruction in postrenal AKI results in a prompt decrease of vasoconstriction and a return to normal renal function. Diseases of the glomerulus, small vessels, interstitium, and tubule cause intrinsic AKI; all are associated with the release of renal vasoconstrictors. The most common cause of intrinsic AKI is ischemic injury or ischemic tubular necrosis (also historically called acute tubular necrosis), when renal perfusion is decreased so much that the kidney parenchyma is affected. During the period of depressed renal blood flow, the kidneys are especially vulnerable to further insults. Exposure at this time to known nephrotoxins such as NSAIDs or aminoglycosides can cause iatrogenic AKI. Figure 88-1 illustrates the cellular and subcellular events leading to ischemic tubular necrosis.
s affected. During the period of depressed renal blood flow, the kidneys are especially vulnerable to further insults. Exposure at this time to known nephrotoxins such as NSAIDs or aminoglycosides can cause iatrogenic AKI. Figure 88-1 illustrates the cellular and subcellular events leading to ischemic tubular necrosis. In intrinsic AKI, clearance of tubular toxins and initiation of therapy for glomerular diseases decrease vasoconstriction and help restore renal blood flow. Once the cause of injury is resolved, the remaining func tional nephrons increase filtration and eventually hypertrophy. Depending on the size of the remnant nephron pool, GFR will proportionately recover. If the number of remaining nephrons is below some critical number, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to nephron loss. A vicious cycle of nephron loss then ensues until complete AKI occurs. This sequence explains the commonly observed scenario in which progressive AKI occurs after initial recovery from AKI, contributing to delayed mortality. CLINICAL FEATURES HISTORY AND COMORBIDITIES AKI itself has few symptoms until severe uremia develops. Uremia causes nausea, vomiting, drowsiness, fatigue, confusion, and if untreated, coma. Patients are more likely to present with symptoms related to the underlying cause of AKI, which should prompt assessment of renal function. See Table 88-2 for risk factors for community-acquired AKI. 6-10,12,16-19 Patients with prerenal AKI from volume depletion commonly develop thirst, orthostatic lightheadedness, and decreased urine output. Excessive vomiting, diarrhea, urination, hemorrhage, fever, or sweating can reduce circulating volume sufficiently to precipitate AKI. Causes of endothelial leak and third spacing, such as sepsis, pancreatitis, burns, and hepatic failure, can also result in prerenal AKI, although these settings may also be associated with renal parenchymal injury. Progression of heart failure from any cause or overdiuresis of the patient with compensated congestive heart failure may cause AKI. Decreased fluid intake from physical or cognitive disability can result in hypovolemia. Intrinsic renal diseases can often be anticipated because of symptoms of the precipitating cause. Anticipate ischemic AKI after cardiac arrest, in severe sepsis, or with other causes of systemic hypotension. AKI from crystal-induced nephropathy, nephrolithiasis, and papillary necrosis can present as flank pain and hematuria. Suspect pigment-induced AKI in rhabdomyolysis 20 (see Chapter 89, “Rhabdomyolysis”) or with hemolysis after recent blood transfusion. Darkening urine and edema, with or without constitutional symptoms such as fever, malaise, and rash, suggest acute glomerulonephritis, which may have been preceded by pharyngitis or cutaneous infection. Fever, arthralgia, and rash are com mon with acute interstitial nephritis. Acute renal arterial occlusion is usually marked by severe flank pain. Cough, dyspnea, and hemop tysis raise the possibility of Goodpasture’s syndrome or Wegener’s granulomatosis. Suspect postrenal AKI in men with prostatic disease or advanced age and patients with indwelling bladder catheters. Anuria strongly suggests obstruction, although vascular obstruction and fulminant renal disease are also possible. Alternating oliguria and polyuria is virtually pathog nomonic of obstruction. PHYSICAL EXAMINATION Assess for abnormal volume status. Evaluate mucous membranes, jugular vein distention, lung auscultation, peripheral edema, and tissue turgor to identify dehydration. Carefully assess for rashes, evidence of Renal and Genitourinary Disorders SECTION CHAPTER Tintinalli_Sec10_p0563-0606.indd 563 8/2/19 6:54 PM
XAMINATION Assess for abnormal volume status. Evaluate mucous membranes, jugular vein distention, lung auscultation, peripheral edema, and tissue turgor to identify dehydration. Carefully assess for rashes, evidence of Renal and Genitourinary Disorders SECTION CHAPTER Tintinalli_Sec10_p0563-0606.indd 563 8/2/19 6:54 PM 564 SECTION 10: Renal and Genitourinary Disorders vasculitis, jaundice, abdominal or pelvic masses, or a distended palpable urinary bladder. On cardiac exam, check for atrial fibrillation, abdominal aortic aneurysm, and signs of heart failure, and assess extremity pulses. Suspect fluid overload in patients with rapid weight gain, peripheral or facial edema, pulmonary rales, or dullness to percussion of the chest wall over the lower portions of the lungs (suggesting plural effusion). DIAGNOSIS In the ED, the goals are to identify patients at risk for AKI, correct metabolic effects, decrease ongoing renal injury, and prevent iatrogenic injury. Determine if kidney injury is prerenal, postrenal, or intrin sic through history, physical, and diagnostic testing. Obtain CBC, electrolyte levels including magnesium and phosphorus, and hepatic function tests and blood cultures as clinically appropriate. Obtain urinalysis, urine osmolality, urine sodium and urea levels, and urine culture if infection is suspected. Indicators of hypovolemia include base deficit, increased lactate level, decreased central venous pressure, or an US showing collapse of the inferior vena cava (see “Imaging” section). If acute decompensated heart failure is suspected as a contributing fac tor to worsening renal function (see “Cardiorenal Syndrome” section), obtain a B-type natriuretic peptide level or pro–B-type natriuretic peptide level. ECG is the fastest screening test for hyperkalemia, but sensitivity for a level over 6.5 mmol/L ranges from 14% to 60%. 21 Peaked T waves are only seen in 34% of patients22 (see Chapter 17, “Fluids and Electrolytes”). Chest radiography helps evaluate for increased volume, effusions, and pneumonia, all of which can result from or precipitate AKI. Obtain bedside US to assess urinary bladder volume. A large postvoid bladder residual volume (>125 mL) suggests bladder outlet obstruction, for which you would place a urethral catheter. See Chapter 92, “ Acute Urinary Retention, ” for further discussion. Anuria is defined as <100 mL of urine per day and can be present with prerenal, postrenal, or intrinsic AKI. PRERENAL ACUTE KIDNEY INJURY The causes of prerenal azotemia can be broken down into volume loss, hypotension, and diseases of the large and small renal arteries (Table 88-3). Prerenal AKI is also a common precursor to ischemic and nephrotoxic conditions, leading to intrinsic AKI. POSTRENAL ACUTE KIDNEY INJURY In the elderly population, the rate of postrenal AKI is as high as 22%. The most common cause is prostatic hypertrophy. Consider this diag nosis in elderly patients of both sexes; patients with indwelling urinary catheters, GU surgery, known or suspected abdominal malignancy, nephrolithiasis, or retroperitoneal disease; or patients on medications known to affect the urinary sphincter. See Chapter 92, “ Acute Urinary Retention, ” for a detailed list of causes. INTRINSIC ACUTE KIDNEY INJURY Intrinsic kidney injury is not common in patients with communityacquired disease, but it is the most common cause in hospitalized patients. Intrinsic AKI can result from injury to the glomerulus, tubule, interstitium, or vasculature. In community-acquired intrinsic AKI, drugs (Table 88-4), infection, and vascular events are common precipitants. Hospital AKI is due to toxic and ischemic insults in most cases.
the most common cause in hospitalized patients. Intrinsic AKI can result from injury to the glomerulus, tubule, interstitium, or vasculature. In community-acquired intrinsic AKI, drugs (Table 88-4), infection, and vascular events are common precipitants. Hospital AKI is due to toxic and ischemic insults in most cases. 16,17 Contrast-Induced Nephropathy Contrast-induced nephropathy is defined by a relatively small change in serum creatinine (25% increase from baseline or an absolute increase of 0.5 milligram/dL [44 µmol/L] 48 to 72 hours after infusion). The studies documenting contrastinduced nephropathy incidence, risks, and outcomes suffer biases common to many observational studies: confounding bias and selection bias. Confounding bias occurs when an exposure is inappropriately causally linked to an outcome, when a separate exposure (the confounding variable) other than the one of interest better explains the observed outcome. To account for this potential selection bias, multiple studies have compared the incidence of AKI between contrast-exposed and unexposed patients using propensity scoring matching to balance baseline outcome risks between groups. 23 These studies failed to find a statistically higher incidence of AKI in the contrast-exposed group compared to the unexposed group of hospitalized patients with similar comorbidities. 24-29 These studies also found no differences in mortality, development of chronic kidney disease, or need for dialysis or renal transplantation in the future between contrast-exposed patients and unexposed patients. 24-29 Prevention of worsening renal function due to contrast exposure continues to serve as an indication for hydration prior to contrast-enhanced imaging for patients with preexisting chronic kidney disease 30-32 (see “Preventing Renal Injury” section). Crystal-Induced Nephropathy Crystal-induced nephropathy is the precipitation of crystals within the renal tubules, resulting in mechani cal and inflammatory injuries of the tubular epithelium. Chronic renal insufficiency and hypovolemia predispose patients to this form of renal injury, and urinary pH affects the formation of many of these crystals. Elevated uric acid levels in the setting of tumor lysis syndrome and some medications—in particular, acyclovir, sulfonamides, indinavir, and triamterene—are the most common causes of crystal-induced acute kidney injury. Angiotensin-Converting Enzyme Inhibitors Angiotensin-converting enzyme inhibitors can simultaneously decrease the GFR and increase renal blood flow, resulting in a 10% to 20% increase in serum creatinine. Because they inhibit angiotensin II, they cause a preferential efferent arteriolar vasodilation in the renal glomerulus. These arteriolar changes may precipitate significant AKI in a patient with undiagnosed bilateral renal artery stenosis , a condition that typically requires angioplasty and stenting or bypass surgery. Volume depletion and concomitant use of vasoconstricting medications are other common precipitators of angiotensin-converting enzyme inhibitor–induced AKI. Angiotensin receptor blockers have similar effects. Hyperkalemia, which is usually mild, is a relatively common complication of angiotensin-converting enzyme inhibitor administration. NSAIDs NSAIDs may cause AKI because they decrease both GFR and renal blood flow (prerenal AKI). With chronic use, they may cause interstitial nephritis (intrinsic AKI).
ve similar effects. Hyperkalemia, which is usually mild, is a relatively common complication of angiotensin-converting enzyme inhibitor administration. NSAIDs NSAIDs may cause AKI because they decrease both GFR and renal blood flow (prerenal AKI). With chronic use, they may cause interstitial nephritis (intrinsic AKI). Risk factors for adverse reactions to these medications are older age, chronic renal insufficiency, congestive TABLE 88-1 AKIN and RIFLE Criteria for Acute Kidney Injury AKIN Stage RIFLE Category Change in Creatinine/GFR Criteria Urine Output Criteria Stage 1 Risk Serum Cr increased 1.5 times * or (AKIN only) Cr increase >0.3 milligram/dL (≥26.5 µmol/L) over <48 h * GFR decrease 25%–50% * 0.5 mL/kg/h for 6 h Stage 2 Injury Serum Cr increased 2.0–3.0 times * GFR decrease 50%–75% * 0.5 mL/kg/h for 12 h Stage 3 Failure Serum Cr increased >3.0 times* Cr >4 milligrams/dL (≥354 µmol/L) and acute increase >0.5 milligram/dL (44 µmol/L) * GFR decrease >75%* 0.3 mL/kg/h for 24 h Anuria for 12 h N/A Loss Complete loss of kidney function for >4 weeks End-stage renal disease Need for renal replacement therapy for >3 months Abbreviations: AKIN = Acute Kidney Injury Network; Cr = creatinine; GFR = glomerular filtration rate; N/A = not applicable; RIFLE = Risk, Injury, Failure, Loss, End Stage. *All changes are relative to the patient’s premorbid baseline. Tintinalli_Sec10_p0563-0606.indd 564 8/2/19 6:54 PM
replacement therapy for >3 months Abbreviations: AKIN = Acute Kidney Injury Network; Cr = creatinine; GFR = glomerular filtration rate; N/A = not applicable; RIFLE = Risk, Injury, Failure, Loss, End Stage. *All changes are relative to the patient’s premorbid baseline. Tintinalli_Sec10_p0563-0606.indd 564 8/2/19 6:54 PM CHAPTER 88: Acute Kidney Injury 565 Proinflammatory and chemotactic cytokines Oxygen depletion ATP depletion Metabolic changes Increased intralumenal sodium Polymerizing of Tamm-Horsfall protein Decreased renal function Leukocyte infiltration Necrotic cell Thick ascending limb Peritubular capillaries Collecting ducts Distal convoluted tubule Proximal convoluted tubule Mislocation of + K+ ATPase Loss of microvilli Tubular injuryC ast obstructing lumen Cytoskeleton disruption Release of cytokines, enzymes, and reactive oxygen species Denuded tubular walls Apoptotic cell Mislocation of integrins Endothelial injury Increase in adhesion molecules Backleak of fluid Increased vasoconstrictors Decreased vasodilators Congestion Hypoperfusion FIGURE 88-1. Ischemic tubular necrosis. Tubular injury is a direct consequence of vasoconstriction, inflammation, endothelial changes, disruption of cell–cell and cell–matrix connections, and apoptotic changes. ATP = adenosine triphosphate. Tintinalli_Sec10_p0563-0606.indd 565 8/2/19 6:54 PM
rs Congestion Hypoperfusion FIGURE 88-1. Ischemic tubular necrosis. Tubular injury is a direct consequence of vasoconstriction, inflammation, endothelial changes, disruption of cell–cell and cell–matrix connections, and apoptotic changes. ATP = adenosine triphosphate. Tintinalli_Sec10_p0563-0606.indd 565 8/2/19 6:54 PM 566 SECTION 10: Renal and Genitourinary Disorders or a nephritis syndrome with hematuria, red blood cell casts, decreased urine output, and hypertension. Glomerulonephritis may be postinfec tious, be associated with toxic exposure, or occur in association with an immune disorder, such as systemic lupus erythematosus. DIAGNOSTIC TESTING Creatinine and GFR Creatinine is the mainstay for measuring renal function; it is a breakdown product of the skeletal muscle protein creatine, and its level is thus linked to muscle mass. In patients with no renal function (GFR = 0), serum creatinine level increases 1 to 3 milligrams/dL (88 to 265 µmol) a day. Lesser increases in creatinine indicate residual renal function, whereas faster increases suggest rhab domyolysis. Elevation of serum creatinine may take 48 hours after onset of decreased function, and a patient with a very low baseline creatinine heart failure, diabetes, volume depletion, and concomitant use of diuretics or angiotensin-converting enzyme inhibitors. Antibiotics Antibiotics, particularly aminoglycosides, are another important cause of iatrogenic renal injury. Other antibiotics frequently implicated are vancomycin, ceftriaxone, sulfamethoxazole/trimethoprim, amoxicillin, cefazolin, and fluoroquinolones. 9,33-35 The most common antiviral medications implicated in AKI are the antiretrovirals, acyclovir, and valacyclovir. Pigment Nephropathy Hemoglobin and myoglobin from hemolysis or rhabdomyolysis are deposited and concentrated in the renal tubules. Renal injury occurs through tubular obstruction and direct toxicity (pigment nephropathy). Glomerulonephritis Glomerulonephritis is an uncommon cause of acute kidney injury. Glomerulonephritis may present as a nephrotic syndrome with edema, proteinuria, hypoalbuminemia, and hyperlipidemia, TABLE 88-2 Risk Factors for Acute Kidney Injury Dehydration* Sepsis* Advanced age* Medications • Diuretics * • NSAIDs * • ACE inhibitors* • Angiotensin receptor blockers* • Antiretroviral therapy • Acyclovir, valacyclovir • Statins • Rhabdomyolysis • Trimethoprim/sulfamethoxazole • Aminoglycosides, vancomycin Immunosuppressive drugs, kidney transplantation • Tacrolimus • Cyclosporine, others Failure to dose medications for CKD • Antibiotics, metformin, proton pump inhibitors Drugs of abuse • Cocaine, ethanol, ethylene glycol Systemic disease • CKD (preexisting)* • Cardiovascular disease* • CAD, heart failure, hypertension, vascular disease • Diabetes • Hepatic disease • Autoimmune/rheumatologic disease • Gout, elevated uric acid • Outflow obstruction: prostatic/urethral disease • Malignancy • Renal parenchymal invasion, bladder obstruction • Multiple myeloma/hypercalcemia • Eclampsia and preeclampsia Contrast agents • Iodinated contrast media • Gadolinium • Nephrogenic systemic fibrosis Abbreviations: ACE = angiotensin-converting enzyme; CAD = coronary artery disease; CKD = chronic kidney disease. *Most common risks for community-acquired disease.
Multiple myeloma/hypercalcemia • Eclampsia and preeclampsia Contrast agents • Iodinated contrast media • Gadolinium • Nephrogenic systemic fibrosis Abbreviations: ACE = angiotensin-converting enzyme; CAD = coronary artery disease; CKD = chronic kidney disease. *Most common risks for community-acquired disease. TABLE 88-4 Intrinsic Acute Kidney Injury Due to Drugs Reduced renal perfusion by altered intrarenal hemodynamics Amphotericin B, ACE inhibitors, cyclosporine, interleukin-2, NSAIDs, radiocontrast agents, tacrolimus Direct tubular toxicity Aminoglycoside antibiotics, amphotericin B, cisplatin, cyclosporine, foscarnet, heavy metals, IV immunoglobulin methotrexate, organic solvents, pentamidine, radiocontrast agents, tacrolimus Rhabdomyolysis Cocaine, ethanol, lovastatin Intratubular obstruction Acyclovir, chemotherapeutic agents, ethylene glycol, methotrexate, sulfonamides Interstitial nephritis Allopurinol, cephalosporins, cimetidine, ciprofloxacin, furosemide, NSAIDs, phenytoin, penicillins, sulfonamides, rifampin, thiazide diuretics Hemolytic-uremic syndrome Cocaine, cyclosporine, conjugated estrogens, mitomycin, quinine, tacrolimus Abbreviation: ACE = angiotensin-converting enzyme. TABLE 88-3 Causes of Prerenal Acute Kidney Injury Hypovolemia • GI: decreased intake, vomiting, diarrhea • Pharmacologic: diuretics • Third spacing • Skin losses: fever, burns • Miscellaneous: hypoaldosteronism, salt-losing nephropathy, postobstructive diuresis Hypotension (overt and relative) • Septic vasodilation • Hemorrhage • Decreased cardiac output: ischemia/infarction, valvulopathy, cardiomyopathy, tamponade • Pharmacologic: β-blockers, calcium channel blockers, other antihypertensive medications • High-output failure: thyrotoxicosis, thiamine deficiency, Paget’s disease, arteriovenous fistula Renal artery and small-vessel effects • Pharmacologic: NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, cyclosporine, tacrolimus (microvasculature effects that decrease renal blood flow; may lead to intrinsic AKI) • Hypercalcemia: vasoconstriction, may lead to intrinsic AKI • Embolism: thrombotic, septic, cholesterol* • Thrombosis: atherosclerosis, vasculitis, sickle cell disease* • Dissection* • Microvascular thrombosis: preeclampsia, hemolytic-uremic syndrome, disseminated intravascular coagulation, vasculitis, sickle cell disease* Abbreviation: AKI = acute kidney injury. *These causes include a component of ischemic AKI. Tintinalli_Sec10_p0563-0606.indd 566 8/2/19 6:54 PM
le cell disease* • Dissection* • Microvascular thrombosis: preeclampsia, hemolytic-uremic syndrome, disseminated intravascular coagulation, vasculitis, sickle cell disease* Abbreviation: AKI = acute kidney injury. *These causes include a component of ischemic AKI. Tintinalli_Sec10_p0563-0606.indd 566 8/2/19 6:54 PM CHAPTER 88: Acute Kidney Injury 567 level can lose more than half of the functioning nephrons before serum creatinine elevates to an abnormal level. In the ED, using automated laboratory devices, useful measures of kidney function (creatinine clearance and GFR) are estimated using equations that use information from the electronic medical record, including the measured creatinine level, age, weight, sex, and race. Patients with lower muscle mass (e.g., older patients and women) have lower actual GFRs for any given creatinine level. Acute changes in creatinine levels may be independent of renal function. For example, creatinine rises in rhabdomyolysis and fenofibrate use due to effects on muscle tissue, whereas in sepsis, creatinine production is decreased. These extrarenal changes in creatinine alter the relationship between creatinine and estimates of GFR. Glomerulonephritis increases tubular secretion of creatinine, but trimethoprim, cimetidine, and salicylates decrease tubular secretion of creatinine, thus altering the creatinine level independently of the GFR. Normal kidney function is a GFR >90 mL/ min/1.73 m 2, where 1.73 m 2 is used as the average body surface area. Stages of kidney disease are characterized in Table 88-5. Unfortunately, all GFR calculations are based on a steady-state cre atinine level, severely limiting their applicability in AKI seen in the ED. Cystatin C A protein produced by all nucleated cells has been proposed as a replacement for creatinine in estimating GFR. Cystatin C is formed at a constant rate unchanged by infections, inflammatory, and neoplastic conditions and, unlike creatinine, is not affected by diet, drugs, or body mass. Estimated GFR can be calculated by the Chronic Kidney Disease Epidemiology cystatin C equation, which corrects for age and sex. As with creatinine, elevations of cystatin C are only detected 24 to 48 hours after AKI has already occurred. Cystatin C may be more accurate in predicting death and progression to chronic kidney disease or need for dialysis. 36 Experts continue to search for a biomarker that could identify AKI early in the course of renal deterioration, but such a marker has yet to be identified. Urine Output Exact measurements of urine output require a urinary catheter to be in place for greater than 6 hours to meet the criteria of AKI as required from the Risk, Injury, Failure, Loss, and End-Stage Renal Failure (RIFLE) criteria in Table 88-1, limiting the applicability of urine output in an ED setting. BUN-to-Creatinine Ratio The ratio of BUN to creatinine can suggest hypovolemia because of differences in the way each is handled in the nephron. Both substances are passively filtered at the glomerulus, but where creatinine remains within the tubule, the renal tubule is highly permeable to urea, which is passively reabsorbed with sodium. There fore, in the setting of avid sodium retention, urea clearance is as low as 30% of GFR, whereas in the setting of adequate volume and sodium, urea clearance can increase to 70% to 100% of GFR. Thus, if the patient has normal concentrating ability, in the setting of prerenal AKI, the serum ratio of BUN to creatinine is typically >10. BUN level is depressed in patients with malnutrition and hepatic synthetic dysfunction and can be increased in the setting of protein loading, GI hemorrhage, or trauma.
% of GFR. Thus, if the patient has normal concentrating ability, in the setting of prerenal AKI, the serum ratio of BUN to creatinine is typically >10. BUN level is depressed in patients with malnutrition and hepatic synthetic dysfunction and can be increased in the setting of protein loading, GI hemorrhage, or trauma. Despite the use of the BUN-to-creatinine ratio by clinicians to identify prerenal disorders since the 1940s, two recent studies ques tion its accuracy. 38,39 The ratio fails to accurately identify AKI cases that resolve with volume replacement alone.38,39 Fractional Excretion of Sodium The fractional excretion of sodium (FeNa = U Na/PNa ÷ U Cr/PCr, where Na = sodium, Cr = creatinine, U = urine, and P = plasma) is another indicator that is commonly used to identify hypovolemia, but it has important limitations. For example, in the setting of intrinsic AKI in which tubular concentrating capacity is retained, as in the case of glomerulonephritis, the fractional excretion of sodium may be depressed if there is concomitant volume depletion. With tubular injury such as ischemic acute tubular necrosis, the loss of concentrating ability results in a dilute urine, with a fractional excretion of sodium >1%, even if the patient is volume depleted ( Table 88-6). Urinalysis Microscopic examination of urine is useful in establish ing the differential diagnosis. In acute glomerulonephritis, red blood cells enter the filtrate at the glomerulus and, on microscopic urinalysis, appear as casts and dysmorphic cells due to the increased tonicity of the renal medulla. In acute tubular necrosis, the tubular epithelium breaks down and allows protein to leak into the filtrate, and tubular epithelial cells may be seen in the sediment. Hyaline casts are common in prerenal AKI and can be a normal finding; pigmented granular casts are common with ischemic or toxic tubular injury. Brown granular casts are common in hemoglobinuria or myoglobinuria. The finding of hemoglobin on urine dipstick analysis with no red cells on microscopy suggests myoglobinuria. Some crystals may be present in a normal urinalysis. Crystals are best seen with polarized light microscopy. Red cell casts and proteinuria suggest glomerulonephritis or an underlying autoimmune disease. Imaging Renal US is the test of choice for urologic imaging in the setting of AKI. It has approximately 90% sensitivity and specificity for detecting hydronephrosis due to mechanical obstruction. Figure 88-2 contrasts normal kidney US findings with US findings indicating hydronephrosis. If renal US detects hydronephrosis, a secondary imag ing study to define the location of obstruction may be required. Bipolar renal length is easy to assess by US, and kidney dimension of <9 cm suggests chronic kidney disease . Renal parenchyma should be isoechoic or hypoechoic compared with that of the liver and spleen. TABLE 88-5 Stages of Chronic Kidney Disease Stage GFR Comments Stage 1 GFR ≥90 mL/min/1.73 m 2 Non-GFR evidence of kidney damage present Stage 2 GFR 60–89 mL/min/1.73 m 2 Mild disease Stage 3 GFR 30–59 mL/min/1.73 m 2 Mild to moderate disease Stage 4 GFR 15–29 mL/min/1.73 m 2 Moderate to severe disease Stage 5 GFR <15 mL/min/1.73 m2 Dialysis or transplant needed Abbreviation: GFR = glomerular filtration rate.
2 Non-GFR evidence of kidney damage present Stage 2 GFR 60–89 mL/min/1.73 m 2 Mild disease Stage 3 GFR 30–59 mL/min/1.73 m 2 Mild to moderate disease Stage 4 GFR 15–29 mL/min/1.73 m 2 Moderate to severe disease Stage 5 GFR <15 mL/min/1.73 m2 Dialysis or transplant needed Abbreviation: GFR = glomerular filtration rate. TABLE 88-6 Laboratory Findings in Conditions That Cause Acute Kidney Injury Category Dipstick Test Sediment Analysis Urine Osmolality (mOsm/kg) Fractional Excretion of Sodium (%) Prerenal Trace to no proteinuria, SG >1.015 A few hyaline casts possible >500 <1 Renal Ischemia Mild to moderate proteinuria Pigmented granular casts, renal tubular epithelial cells <350 >1 Nephrotoxins Mild to moderate proteinuria Pigmented granular casts <350 >1 Acute interstitial nephritis Mild to moderate proteinuria; hemoglobin, leukocytes White cells, eosinophils, casts, red cells <350 >1 Acute glomerulonephritis Moderate to severe proteinuria; hemoglobin Red cells and red cell casts; red cells can be dysmorphic >500 Depends on volume status Postobstrutcive or postrenal Trace to no proteinuria; hemoglobin and leukocytes possible Crystals, red cells, and white cells possible <350 >1 Abbreviation: SG = specific gravity. Tintinalli_Sec10_p0563-0606.indd 567 8/2/19 6:54 PM
Red cells and red cell casts; red cells can be dysmorphic >500 Depends on volume status Postobstrutcive or postrenal Trace to no proteinuria; hemoglobin and leukocytes possible Crystals, red cells, and white cells possible <350 >1 Abbreviation: SG = specific gravity. Tintinalli_Sec10_p0563-0606.indd 567 8/2/19 6:54 PM 568 SECTION 10: Renal and Genitourinary Disorders FIGURE 88-2. US of normal kidney and kidney showing hydronephrosis. A. Normal kidney; capsule margin at arrows. B. Hydronephrosis as would be expected in obstructive uropathy; the dilated kidney fills the majority of the screen; capsule at arrows. [Image used with permission of Michael B. Stone, MD, RDMS.] Hyperechogenicity indicates diffuse parenchymal disease. Color flow Doppler US allows assessment of renal perfusion and can allow diagnosis of large-vessel causes of AKI. Resistive index is the ratio of the difference between systolic and diastolic flow to systolic flow [(V max – V min)/ Vmax] as measured by color flow Doppler. In the vasoconstrictive phase of ischemic AKI, in which there may be no diastolic flow, the ratio may be as high as 1.0. The normal ratio is <0.7. In intermittent or partial obstruction, hydronephrosis may be present, and it may even be absent in complete obstruction in the setting of retroperitoneal fibrosis. Furthermore, functional dilatation can occur in the setting of chronic ureteral reflux. Noncontrast CT has a sensitivity for hydronephrosis that is equiva lent to that of US and has the added advantage of demonstrating the site and often the cause of obstruction. If functional obstruction is a consideration in the presence of a dilated GU tract, radionuclide scans and magnetic resonance urographs before and after administration of diuretics can be obtained. TREATMENT For the critically ill patient with AKI, resuscitation is the first priority, and multiple diagnostic and therapeutic processes advance simultane ously. Look for and treat hypovolemia, sepsis, myocardial ischemia, respiratory failure, acute decompensated heart failure, electrolyte disturbances, acidosis, volume overload, and urinary obstruction, as clinically indicated. 40-42 The initial priority is treatment of the underlying cause of AKI.40-42 While determination of the AKI type helps to determine priorities for treatment (i.e., prerenal AKI is most likely to require fluid resuscitation), this treatment section is organized based on the manifestations of AKI most likely to require acute management regardless of AKI type. See also “Cardiorenal Syndrome” under the “Special Populations” sec tion below. Rhabdomyolysis is discussed in Chapter 89. VOLUME DEPLETION Correct intravascular volume deficits with crystalloids. 43 Balanced crystalloids, such as lactated Ringers’ solution, may offer a small advantage over normal saline solution. In a large randomized trial involving 15,802 critically ill patients, subjects receiving balanced crystalloids had a lower rate of the composite outcome of death from any cause, new renal replacement therapy, or persistent renal dysfunction after dis charge (14.3%), compared to patients receiving normal saline (15.4%). A separate randomized trial involving 13,347 non–critically ill patients, did not find a mortality difference; however, patients receiving balanced crystalloids had a lower rate of adverse kidney events (4.7% vs. 5.6%). Accurate determination of volume status is essential to prevent volume overload, which has been shown to worsen AKI and increase mortality.46 Using bedside US, inspiratory collapsibility of the intrahepatic segment of the inferior vena cava is one noninvasive measure of volume status and expected fluid responsiveness 47,48 (Figure 88-3). PREVENTING RENAL INJURY Hold medications that could be causing AKI (Tables 88-3 and 88-4).
AKI and increase mortality.46 Using bedside US, inspiratory collapsibility of the intrahepatic segment of the inferior vena cava is one noninvasive measure of volume status and expected fluid responsiveness 47,48 (Figure 88-3). PREVENTING RENAL INJURY Hold medications that could be causing AKI (Tables 88-3 and 88-4). Make sure that renal dose adjustments are made for medication orders and that renal function is considered before ordering radiographic contrast studies. In general, for IV contrast studies in patients with GFR of 30 to 59 mL/min/1.73 m 2, weigh benefits of the study against the risk of renal function decline. For patients with GFR <30 mL/min/1.73 m 2, avoid IV contrast studies if possible. Emergency contrast studies for major trauma, aortic dissection, or ST-segment elevation myocardial infarction are examples in which benefits typically outweigh risk for most patients. Avoid gadolinium for GFR <30 mL/min/1.73 m 2. For patients with abnormal kidney function, for whom contrast-enhanced imaging is planned, the ideal rate and volume of fluid administration is not defined. 32 Commonly used volumes are 500 to 1000 mL of crystal loid (lactated Ringer’s or 0.9% normal saline) prior to the procedure and an equal volume after the procedure; however, significantly dehydrated patients may need additional volume. The administration rate should be determined by the patient’s comorbidities, as well as any additional needs for urgent hydration. RELIEVE URINE OUTFLOW OBSTRUCTION Timely relief of obstruction is essential for the return of normal renal function. Permanent loss of renal function develops over the course of 10 to 14 days in the setting of complete obstruction. The risk of chronic kidney disease increases significantly if obstruction is complicated by urinary tract infection. Consider both urethral and ureteral obstruction or sphincter dysfunction as potential causes. For additional discussion of postrenal AKI management, see Chapter 92, “ Acute Urinary Retention. ” FLUID OVERLOAD Diuretics are the mainstay of treatment for fluid overload in patients with normal kidney function. Fluid overload is associated with increased mortality in patients with AKI. 49 In the absence of fluid overload, diuretics are not recommended for patients with AKI, 40-42 nor have they been shown to prevent AKI. 50 However, diuretics are used in the setting of mild to moderate AKI when fluid overload is present.40-42,51 The alternative to diuretics for the treatment of fluid overload is dialysis, and failure to respond to diuretics is frequently used as an indication for dialysis. A furosemide stress test can be used in the setting of mild AKI (AKIN Tintinalli_Sec10_p0563-0606.indd 568 8/2/19 6:54 PM
fluid overload is present.40-42,51 The alternative to diuretics for the treatment of fluid overload is dialysis, and failure to respond to diuretics is frequently used as an indication for dialysis. A furosemide stress test can be used in the setting of mild AKI (AKIN Tintinalli_Sec10_p0563-0606.indd 568 8/2/19 6:54 PM CHAPTER 88: Acute Kidney Injury 569 FIGURE 88-3. US of the inferior vena cava. A. Dilated inferior vena cava ( arrows) with little respiratory variation as might be expected in volume overload. B. An almost fully collapsed inferior vena cava at inspiration ( arrows) and expiration (arrowheads) as might be expected in prerenal acute kidney injury. [Image used with permission of Michael B. Stone, MD, RDMS.] stage ≤2) to determine diuretic responsiveness as well as to predict worsening renal function. Administer 1 milligrams/kg of furosemide in naive patients or 1.5 milligrams/kg in those with prior exposure; a urine output of <200 mL over 2 hours has a sensitivity of 87.1% and a specificity of 84.1% to predict progression to AKIN stage 3 AKI 52-55 (Table 88-1). Mannitol has no role in the treatment of AKI. 40 Low (“renal”)-dose dopamine does not improve renal recovery or decrease mortality.40,41 HYPERTENSION Fenoldopam and nicardipine are commonly used in this setting; see Chapter 57, “Systemic Hypertension, ” for a detailed discussion of management. METABOLIC ACIDOSIS In cases were the pH is greater than 7.1, treat the underlying cause of the AKI first. If pH is ≤7.1, consider treatment. Dialysis is preferred in the setting of anuria, or fluid overload, because safe effective use of sodium bicarbonate requires urine flow and ability to tolerate a fluid load. See Chapter 15, “ Acid-Base Disorders. ” ELECTROLYTE DISORDERS Suspected hyperkalemia should be treated in the setting of prolongation of the PR interval, peaked T waves, or widening of the QRS complex; proven hyperkalemia should be treated. For the diagnosis and management of hyperkalemia and other electrolyte abnormalities, see Chapter 17, “Fluids and Electrolytes. ” GLOMERULONEPHRITIS Management includes consultation with nephrology, plan for renal biopsy, corticosteroids, cyclophosphamide, and consideration for plasmapheresis. DISPOSITION AND CONSULTATION Patients with mild prerenal AKI (AKIN stage 1) are eligible for treat ment in ED observation protocols anticipating reversibility of renal dysfunction before discharge. Patients who do not improve or patients with more severe AKI require hospital admission for evaluation and treatment. For patients with severe AKI or for patients with uncertain etiology, nephrology should be consulted. DIALYSIS/RENAL REPLACEMENT THERAPY Timing of renal replacement therapy is controversial. The Early Versus Late Initiation of Renal-Replacement Therapy in Critically Ill Patients with Acute Kidney Injury (ELAIN) Investigators’ study of intensive care unit patients meeting KDIGO stage 2 criteria with either severe sepsis or fluid overload refractory to diuretics found reduced mortality (39.3% vs. 54.7%) and improved renal recovery (53.6% vs. 38.7%) in the group treated with early renal replacement therapy (within 8 hours of KDIGO stage 2 diagnosis) versus the group receiving delayed renal replacement therapy (within 12 hours of KDIGO stage 3 diagnosis). 57 However, two subsequent meta-analyses that included the ELAIN data found no improved mortality overall. 58,59 Indications for emergency dialysis or renal replacement therapy are listed in Table 88-7. SPECIAL POPULATIONS CARDIORENAL SYNDROME Cardiorenal syndrome is a complex pathophysiologic disorder of the heart and kidneys where acute or chronic dysfunction of one organ induces acute or chronic dysfunction of the other organ.
dications for emergency dialysis or renal replacement therapy are listed in Table 88-7. SPECIAL POPULATIONS CARDIORENAL SYNDROME Cardiorenal syndrome is a complex pathophysiologic disorder of the heart and kidneys where acute or chronic dysfunction of one organ induces acute or chronic dysfunction of the other organ. Cardiorenal syndrome type 1 is characterized by acute deterioration in cardiac function that causes AKI. Cardiorenal syndrome type 3 (also called acute renocardiac syndrome) is characterized by an AKI that causes acute cardiac injury and/or dysfunction, such as cardiac ischemia, congestive heart failure, or arrhythmias. Type 2 and 4 cardiorenal syndromes are chronic; type 5 is secondary to a separate systemic condition such as sepsis. Comparing TABLE 88-7 Indications for Emergent Dialysis or Renal Replacement Therapy • Uncontrolled hyperkalemia (potassium >6.5 mmol/L or rising) • Refractory fluid overload in association with persistent hypoxia or lack of response to conservative measures • Uremic pericarditis • Progressive uremic/metabolic encephalopathy; asterixis, seizures • Serum sodium level <115 or >165 mEq/L (<115 or >165 mmol/L) • Severe metabolic acidosis with concomitant acute kidney injury; treat underlying source of lactic acidosis and tolerate pH >7.2 in setting of permissive hypercapnia • Life-threatening poisoning with a dialyzable drug, such as salicylates, lithium, isopropanol, methanol, or ethylene glycol • Bleeding dyscrasia secondary to uremia • Excessive BUN and creatinine levels: trigger levels are arbitrary; it is generally advisable to keep BUN level <100 milligrams/dL (<37.7 mmol/L), but each patient should be evaluated individually Tintinalli_Sec10_p0563-0606.indd 569 8/2/19 6:54 PM