a. Definition. In general, acute kidney injury (AKI) is defined as a rapid decrease in glomerular filtration that results in abnormal fluid and electrolyte balance and inappropriate waste accumulation (azotemia). The diagnosis is often made when the serum creatinine (SCr) level rises abruptly. The most recent classification scheme developed by the Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Disease Workgroup defines AKI as (1) an increase of serum creatinine by 0.3 mg/dL in 48 hours; (2) increase in serum creatinine by 1.5 times baseline within 7 days; or (3) a decrease in urine output to less than 0.5 mL/kg/hr for 6 hours.
Although SCr is almost solely filtered by the glomerulus and therefore provides a good estimate of the glomerular filtration rate (GFR), small amounts are also secreted by the tubules. Some drugs (e.g., cimetidine or trimethoprim) can block secretion to raise the SCr, leading to an underestimation of the actual GFR and renal function.
b. Epidemiology. Approximately 2% of all hospitalized patients are diagnosed with AKI. In the intensive care unit (ICU), AKI may complicate the course of as many as two-thirds of patients.
c. Clinical manifestations. AKI is largely an asymptomatic disease. However, hypertension and volume overload may be present. Symptoms of uremia usually occur when the blood urea nitrogen (BUN) exceeds 100 mg/dL but may occur at lower values if rapid accumulation occurs. Clinical manifestations of uremia include constitutional symptoms (e.g., malaise, anorexia), cardiovascular complications (e.g., arrhythmias, pericarditis), neurologic abnormalities (e.g., altered mental status, seizures), or gastrointestinal complications (e.g., bleeding, nausea, vomiting).
B. Causes of Acute Kidney Injury. The causes of AKI should be classified as prerenal, postrenal, or intrarenal.
a. Prerenal causes account for more than half of AKI cases. Prerenal causes are actually preglomerular. Any disease state that results in a decrease in blood flow to the glomerulus will result in decreased glomerular filtration and, consequently, an elevated serum creatinine level. One way to remember the causes of prerenal AKI is to begin with the left ventricle and work your way toward the glomerulus.
i. Decreased filling of the left ventricle results in decreased cardiac output and, therefore, decreased flow to the glomerulus. Hypovolemia is the most common cause, but right ventricular failure and mitral stenosis can also result in poor left ventricular filling and subsequent prerenal azotemia.
ii. Decreased left ventricular function results in decreased cardiac output even with normal or elevated left ventricular filling.
iii. Aortic stenosis. Even with normal left ventricular filling and function, critical aortic stenosis can block forward flow to the kidney. As left ventricular function declines in the setting of aortic stenosis, AKI may become more apparent.
iv. Renal artery stenosis from atherosclerotic disease or fibromuscular dysplasia decreases flow to the glomerulus. Fibromuscular dysplasia, most often seen in young women, is less common than atherosclerotic disease.
v. Narrowing of the afferent arteriole from vasoconstriction, inflammation, or thrombosis can result in prerenal azotemia.
1. Sepsis can lead to constriction of the afferent arteriole by inflammatory mediators.
2. Nonsteroidal antiinflammatory drugs (NSAIDs) can lead to narrowing of the afferent arteriole by inhibiting prostaglandins, which normally dilate the vessel. This most often occurs in states of volume depletion.
3. Contrast dye can also lead to constriction of the afferent arteriole.
4. Microangiopathic hemolytic anemias (see Chapter 62) are rare causes of a prerenal azotemia.
5. End-stage liver disease results in shunting of blood away from the afferent arteriole (e.g., from splanchnic bed vasodilation and arteriovenous malformations).
b. Postrenal causes account for less than 10% of all cases of AKI. Because one kidney can adequately compensate for the other, AKI will only become apparent if both kidneys are not functioning properly.
i. Bladder rentention is the most common postrenal cause of AKI. Common causes include:
1. Prostatic hypertrophy or malignancy leading to bladder outlet obstruction
2. Neurologic disorders (e.g., neuropathy either primary or secondary to diabetes leading to bladder atonia or dysfunction)
3. Anticholinergic medications
ii. Ureteral obstruction
1. Unilateral ureteral obstruction (e.g., from stones, blood clots, or pus) can result in AKI in a patient with only one kidney.
2. Bilateral ureteral obstruction may result from retroperitoneal fibrosis, malignancy, or lymphadenopathy.
c. Renal causes. It’s convenient to break intrinsic causes of AKI into anatomic components of a kidney (i.e., glomeruli, tubules, interstitium, vessels).
i. Acute glomerulonephritis affects the glomeruli. The many causes of acute glomerulonephritis are discussed in Chapter 39.
ii. Acute tubular necrosis (ATN) affects the tubules.
1. Ischemia and shock from all causes, but particularly septic shock, can lead to ATN.
2. Contrast dye agents used for radiographic studies are toxic to the tubules but most commonly cause kidney injury in patients who have underlying kidney disease (e.g., diabetic patients).
3. Endogenous pigments (e.g., myoglobin, hemoglobin), crystals, and proteins. Myoglobinuria (from rhabdomyolysis) or hemoglobinuria (from intravascular hemolysis), uric acid deposition (from tumor lysis), and Bence Jones proteins (from multiple myeloma) can all cause tubule injury and result in ATN.
4. Medications (e.g., aminoglycosides) and toxins (e.g., heavy metals) can be directly nephrotoxic.
iii. Acute interstitial nephritis affects the interstitium. Medications (e.g., β-lactam antibiotics, sulfa antibiotics, furosemide, thiazide diuretics, NSAIDs) are the most common causes of acute interstitial nephritis. Acute interstitial nephritis is sometimes hypersensitivity mediated; thus, it can often be called allergic interstitial nephritis.
iv. Vasculitis and microangiopathic hemolytic anemias affect the blood vessels (see Chapters 62 and 75). Do not be confused by the fact that many of the vasculitides are listed as causes of glomerulonephritis (i.e., inflammation of the glomerulus). Remember that the glomerulus contains a capillary bed, so small vessel vasculitis can result in glomerulonephritis.
C. Approach to the Patient. Using data gleaned from the patient history, physical examination, and basic laboratory tests and procedures, begin by classifying the injury as prerenal, intrarenal, or postrenal, or a combination of these types.
The same disorder may cause more than one type of AKI.
a. Obtain a patient history
i. Prerenal. A history of congestive heart failure (CHF), dehydration, hemorrhage (e.g., hematemesis), or new or increased use of diuretics or NSAIDs can help pinpoint a prerenal etiology.
ii. Postrenal. A history of benign prostatic hypertrophy, kidney stones, nephrectomy, anticholinergic medication use, neurologic disease, diabetes, or a retroperitoneal malignancy may alert you to postrenal causes.
1. Glomerulonephritis. The causes of glomerulonephritis can help guide your questions regarding relevant symptoms. For example, a recent sore throat or skin infection may suggest postinfectious glomerulonephritis.
2. ATN or acute interstitial nephritis. The medication history, particularly recent changes (including use of over-the-counter NSAIDs or antibiotics), may raise suspicion for a tubular or interstitial etiology.
3. Vasculitis. The presence of new rashes, symmetric arthralgias, hematuria, and fevers may indicate a vasculitis etiology (see Chapter 75).
b. Perform a physical examination. Always assess the patient’s vital signs, oxygen saturation, and urine output.
i. Blood pressure. Hypotension can denote a prerenal cause, but long-standing hypotension can also lead to ATN. On the other hand, hypertension may be a sign of glomerulonephritis. Additional evaluation and treatment are aimed at the underlying etiology.
ii. Temperature. High or low temperatures can indicate sepsis (although interstitial nephritis, glomerulonephritis, or vasculitis may also be associated with temperature abnormalities).
iii. Oxygen saturation. Hypoxemia may signal impending pulmonary edema (e.g., from kidney injury with volume overload or pulmonary renal syndromes).
iv. Urine output measurements will help classify the AKI as oliguric (<400 mL/day or 0.3 mL/kg/hr) or nonoliguric (>400 mL/day or 0.3 mL/kg/hr). Nonoliguric AKI is associated with lower mortality and dialysis rates. In patients with oliguric ATN, increased urine output often heralds the return of renal function.
v. Heart and lung examination. A complete physical examination is important, with special attention given to the heart and lungs. Heart and lung examination may provide information about the cause of the AKI (e.g., critical aortic stenosis, severe left ventricular dysfunction) and also permits assessment of some of the consequences of AKI (e.g., volume overload, pericarditis).
vi. Abdomen. Auscultation of renal bruits suggests renal artery obstruction or stenosis. Palpation of increased bladder size and tenderness or the presence of large prostate on digital rectal examination can be suggestive of postrenal obstruction.
vii. Skin. Rashes, particularly palpable purpura and livedo reticularis, may occur in patients with vasculitides and glomerulonephritis. Dry skin with tenting, on the other hand, may be a sign of volume depletion.
viii. Neurologic examination. Asterixis often occurs in the setting of uremia. Coma or seizures can result from advanced uremia. Neuropathies can occur in the setting of vasculitis and concurrent glomerulonephritis.
c. Rule out obstruction
i. Postvoid residual (PVR). A PVR is often performed before laboratory tests because if obstruction is the cause, a diagnosis can be made quickly and an extensive workup is avoided. This procedure is especially useful in older men, in whom obstruction from benign prostatic hypertrophy is common. The PVR is measured by catheterization after the patient has “emptied” the bladder. In the inpatient or clinic setting, a portable bladder ultrasound scanner can be used to estimate PVRs without need for catheterization. However, these scanners are automated and can mistake any fluid-filled cavity for the bladder, which may lead to falsely elevated PVRs in obese patients or those with cystic pathology of the bladder, or in patients with ascites.
1. If the PVR is greater than about 300 mL (the exact cutoff is controversial), retention is likely and a Foley catheter (or frequent intermittent catheterization) should be considered.
2. If the patient already has an indwelling catheter, flush the catheter to rule out obstruction that might be caused by encrusted materials or blood clots.
ii. Ultrasound. The PVR does not help you evaluate the upper urinary tract. In patients with one kidney or suspected bilateral obstruction, renal ultrasound should be performed early in the workup. Occasionally, a computed tomography (CT) scan may be necessary depending on the patient’s history. CT can also visualize the lower urinary tract.
d. Perform laboratory studies to help determine the diagnosis and the consequences of the kidney injury.
i. Complete blood count (CBC) with platelets. The white blood cell (WBC) count helps evaluate for infection or interstitial nephritis. Anemia may indicate more chronic kidney disease or bleeding from uremia. Eosinophilia is associated with allergic interstitial nephritis.
ii. Electrolyte panel (including Na+, K+, Cl–, HCO–3, Ca2+, PO43–, Mg2+, and glucose). Common electrolyte or metabolic derangements include hyponatremia, hyperkalemia, hypocalcemia, hyperphosphatemia, and hypermagnesemia as well as a mixed anion and nonanion gap acidosis.
iii. Blood urea nitrogen/creatinine (BUN/Cr) ratio. The normal BUN/Cr ratio is about 10. In prerenal states, urea gets passively reabsorbed along with sodium and water from the proximal tubules, whereas creatinine does not. Therefore, a BUN/Cr ratio greater than 10 (and certainly one greater than 20) helps support a prerenal diagnosis. Remember, an important factor that can influence this ratio is the rate of BUN production, which can be increased by resorption of blood, steroid use, or a high protein diet.
An isolated elevation of BUN with normal creatinine should prompt consideration of gastrointestinal bleeding.
iv. Urinalysis. A urinalysis is an essential part of the evaluation because an active urinary sediment (i.e., one that has red or white cells or associated cellular casts), implies an intraparenchymal cause of kidney disease.
1. Red blood cell (RBC) casts or dysmorphic red cells suggest glomerulonephritis.
2. WBC casts are usually a sign of infection (i.e., pyelonephritis) or inflammation (i.e., interstitial nephritis).
3. Coarse granular or “muddy” brown casts may signify ATN.
v. Urine electrolytes can be a useful diagnostic test in patients with AKI.
1. Urinary sodium and chloride can be used to help delineate a prerenal cause from an intrarenal one. Values less than 20 mEq/L imply a prerenal etiology; values lower than 10 mEq/L are even more specific for prerenal kidney injury.
a. Early obstruction and contrast dye nephropathy can also result in a low urine sodium or chloride level.
b. In the setting of metabolic alkalosis, the urinary chloride is a better indicator of a prerenal state because sodium may be excreted with bicarbonate to maintain electroneutrality. In this situation, the urinary sodium may be falsely increased, although prerenal physiology is present.
2. Fractional excretion of sodium (FENa). FENa is another way of diagnosing prerenal physiology and can also help evaluate tubulointerstitial dysfunction when a patient is oliguric. To calculate the FENa, remember “UP . . . UP” with “sodium over creatinine”:
FENa = Urine Na+/Plasma Na+/Urine Cr/Plasma Cr × 100%
a. A value less than 1% usually signifies prerenal physiology, whereas one greater than 1%–2% usually indicates tubulointerstitial disease (because there is a defect in sodium reabsorption).
Glomerulonephritis without tubular dysfunction will not produce an abnormal FENa because sodium reabsorption is primarily a renal tubular function.
b. FENa in nonoliguric patients is difficult to interpret. A healthy adult ingesting a typical American diet’s worth of sodium that remains in sodium balance will have an FENa of about 0.5%, whereas a patient with stable chronic kidney disease type III eating a similar diet will have an FENa of about 2.5% while remaining in sodium balance.
Patients receiving diuretics may have an increased FENa despite being prerenal; on the other hand, a patient taking diuretics with a FENa less than 1% usually can be assumed to be volume depleted.
3. Fractional excretion of urea (FEUrea). There are a few instances when the FENa is unreliable. These are instances in which the patient is not in sodium homeostasis and the filtered load of sodium is artificially higher than normal. The two major clinical settings in which this will be encountered are metabolic alkalosis and ongoing diuretic therapy. In both of these instances, calculating an FEUrea can provide a better idea of whether the patient is in a prerenal state.
FEUrea = (Urine urea nitrogen/Blood urea nitrogen)/(Urine creatinine/Plasma creatinine) × 100%
a. Values less than 35% are suggestive of prerenal physiology regardless of diuretic use or metabolic alkalosis.
vi. Creatine kinase. Evaluation of the creatine kinase level is helpful if the urine dipstick is positive for blood but no or few RBCs are noted on microscopic analysis. This implies that urinary myoglobin (usually from rhabdomyolysis) or hemoglobin (from intravascular hemolysis) is present. Because rhabdomyolysis is more common and easier to detect, evaluate the possibility of rhabdomyolysis first. Creatine kinase levels greater than 6000 IU (and often more than 15,000 IU) are usually needed to cause tubular necrosis; however, creatine kinase levels may be normal if the rhabdomyolysis and ATN occurred several days before the workup.
vii. Ancillary tests. If glomerulonephritis or vasculitis is suspected or diagnosed, additional tests need to be ordered (see Chapters 39 and 75). Liver function tests are ordered when the hepatorenal syndrome or a glomerulonephritis (given association between certain glomerulonephritides and liver disease) are suspected, but the clinical diagnosis for this pathology is often obvious.
e. Perform additional diagnostic studies if the diagnosis remains unclear.
i. Renal ultrasound. In addition to ruling out obstruction, renal ultrasound helps to distinguish acute from chronic kidney disease.
1. The kidneys are usually normal in size in patients with AKI.
2. They are usually small in patients with chronic kidney disease. However, some chronic kidney diseases can lead to enlarged kidneys. A useful mnemonic for these conditions is:
MNEMONIC: (“SHAPE” is large)
Polycystic kidney disease
Endocrinopathy (i.e., diabetes mellitus, acromegaly)
ii. Renal biopsy is usually unnecessary but may be warranted for unresolving acute renal failure of unknown etiology or to define the need for potentially toxic treatment of glomerulonephritis.
a. Disease specific
i. Prerenal causes
1. Fluids are usually indicated because hypovolemia is the predominant prerenal cause of AKI.
Remember—if the cause of AKI is cardiac in origin (e.g., CHF, critical aortic stenosis), giving fluids may not be appropriate. Consider these possibilities before giving fluids!
a. Administration of small, defined boluses (e.g., 250 mL of 0.9% saline) can prevent volume overload.
b. Reevaluate the patient frequently. The goal is to normalize hemodynamic parameters (blood pressure, heart rate) and restore urine output to nonoliguric rates without causing overt fluid overload.
2. Other treatments tailored to the specific etiology may also be necessary (e.g., discontinuing medications, administering antibiotics for sepsis).
ii. Postrenal causes
1. Catheterization. A Foley catheter is often placed if one has not been placed already.
a. Clamp the catheter if more than 750 mL drains acutely to prevent bladder injury from sudden bladder decompression and systemic hypotension. If, after 30 minutes, no hypotension develops, you can allow more drainage while monitoring blood pressure.
b. Observe for postobstructive diuresis. If the blockage has been present for a few days, a postobstructive diuresis often ensues. This may result from urea accumulation with an osmotic diuresis as well as salt accumulation with a physiologic diuresis. Although this diuresis is partly a physiologic phenomenon, transient tubular dysfunction can contribute to severe volume depletion unless fluids are replaced.
i. Fluid replacement. It is customary to give back approximately half of the urinary losses with 0.45% saline, not normal saline (0.9%). Giving normal saline will only exacerbate the problem by adding to the volume overload and leading to a solute diuresis.
ii. Electrolyte replacement. Depletion of electrolytes, particularly potassium and magnesium, occurs frequently.
2. Percutaneous drainage through a percutaneous nephrostomy tube may be needed in cases of upper tract obstruction.
iii. Renal causes are treated based on the specific pathology, but there are general treatments that are common to all.
1. General measures
a. Fluid restriction. Fluids may need to be restricted to 1–1.5 L/day. Volume status should be monitored by daily weights and input/output measurements.
b. Diet. The diet should be low salt, low potassium, and low phosphorus.
c. Adjust medication dosages. The dosages of medications that are excreted by the kidneys must be adjusted. Magnesium- and phosphorus-containing medications should be avoided because these will accumulate in the setting of limited renal function.
2. Specific measures
a. Glomerulonephritis. Treatment is discussed in Chapter 39.
i. Fluids may help prevent further ischemic insult and may also dilute the effects of certain toxins (i.e., myoglobin, contrast dye).
ii. Furosemide in high doses is sometimes successful in converting oliguric to nonoliguric renal failure, but this has not been shown to change clinical outcomes. If used, diuretics such as furosemide can be helpful to maintain a reasonable volume status in patients with ATN. They should be given to reduce or avoid overt volume overload but should not be given to such a degree that renal blood flow is compromised. They should not be used to delay the initiation of dialysis. Consider consulting a nephrologist if considering diuretics in the setting of AKI.
c. Acute interstitial nephritis is usually treated by discontinuing offending medications and administering fluids as tolerated. A short course of corticosteroids (1 mg/kg/day of prednisone to a maximum dose of 60 mg daily for 1–2 weeks with a rapid taper) is occasionally used.
d. Vasculitis. Treatment is discussed in Chapter 76.
b. Acute dialysis. The following indications often warrant dialysis, regardless of the cause of kidney disease.
MNEMONIC: Indications for Acute Dialysis (“AEIOU”)
Electrolytes (e.g., hyperkalemia, hypercalcemia)
i. Acidosis. Dialysis is usually necessary when the patient is experiencing severe complications from metabolic acidosis (e.g., arrhythmias, left ventricular dysfunction) or if the serum pH starts to fall below 7.2. Oral and/or intravenous sodium bicarbonate may be used as a temporizing measure until dialysis can be initiated.
ii. Severe, refractory hyperkalemia (usually >6.5 mEq/L) or hyperkalemia with persistent electrocardiogram (EKG) changes is an indication for acute dialysis. Temporizing measures include the following: (1) intravenous calcium gluconate, which acts as a cardiac membrane stabilizer; and (2) sodium bicarbonate, albuterol nebulizers, and/or insulin and glucose, which cause potassium to move intracellularly. Sodium polystyrene sulfonate is an exchange resin that can be given orally or rectally to decrease potassium levels—but takes several hours to work. Therefore, it is not appropriate as monotherapy in settings of severe hyperkalemia. Remember, as potassium is bound, sodium is released; thus, caution should be used when giving this medication to patients with CHF.
iii. Intoxication. Dialysis may be necessary when AKI results from a dialyzable, toxic ingestion (e.g., salicylates, ethylene glycol).
iv. Overload. Volume overload that is refractory to diuretics is an indication for dialysis. Temporizing measures such as nitrates and furosemide may be used for venodilation and decreasing pulmonary edema).
v. Uremia. Altered mental status, seizures, pericarditis, intractable nausea and vomiting, and uncontrolled bleeding from platelet dysfunction are all indications for acute dialysis.
Suggested Further Readings
Carvounis CP, Nisar S, Guro-Razuman S. Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int 2002;62:2223–9. (Classic Article.)Find this resource:
Kellum JA. Acute kidney injury. Crit Care Med 2008;36:S141–5.Find this resource:
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Workgroup. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1–138.Find this resource:
Miller TR, Anderson RJ, Linas SL, et al. Urinary diagnostic indices in acute renal failure: a prospective study. Ann Intern Med 1978;89:47–50. (Classic Article.)Find this resource:
Palevsky PM. Indications and timing of renal replacement therapy in acute kidney injury. Crit Care Med 2008;36:S224–8.Find this resource: