Approach Considerations
Several laboratory tests, including the following, are useful for assessing the etiology of acute kidney injury (AKI) and can aid in proper management of the disease:
-
Complete blood count (CBC)
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Serum biochemistries
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Urine analysis with microscopy
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Urine electrolytes
In some cases, renal imaging is useful, especially if kidney failure is secondary to obstruction. The American College of Radiology recommends ultrasonography, preferably with Doppler methods, as the most appropriate imaging method in AKI. [67]
In early AKI, a furosemide stress test can be performed to help determine the patient's prognosis. Low urinary output after the infusion of furosemide predicts the development of stage 3 AKI (see Furosemide Stress Testing, below). [68, 69]
Kidney Function Studies
Although increased levels of blood urea nitrogen (BUN) and creatinine are the hallmarks of renal failure, the rate of rise depends on the degree of renal insult and, with respect to BUN, on protein intake. BUN may be elevated in patients with gastrointestinal (GI) or mucosal bleeding, steroid treatment, or protein loading.
The ratio of BUN to creatinine is an important finding. The ratio can exceed 20:1 in conditions in which enhanced reabsorption of urea is favored (eg, in volume contraction); this suggests prerenal AKI.
Assuming that the patient has no renal function, the rise in BUN over 24 hours can be roughly predicted using the following formula:
(24-hour protein intake in milligrams × 0.16) ÷ total body water
The result is expressed in mg/dL and added to the baseline BUN value to yield the predicted BUN.
Assuming no kidney function, the rise in creatinine can be predicted using the following formulas:
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For males: Weight in kilograms × [28 - 0.2(age)] ÷ total body water, with the result in mg/dL added to the creatinine value
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For females: Weight in kilograms × [23.8 - 0.17(age)] ÷ total body water, with the result in mg/dL added to the creatinine value
As a general rule, if serum creatinine increases to more than 1.5 mg/dL/day, rhabdomyolysis must be ruled out.
In 2014 the US Food and Drug Administration (FDA) approved NephroCheck, the first laboratory test to evaluate the risk of developing moderate to severe AKI in hospitalized, critically ill patients. The test identifies the presence of two AKI-associated proteins (insulinlike growth factor–binding protein 7, tissue inhibitor of metalloproteinases) in urine. Based on the level of these proteins, a score is derived that indicates the likelihood that a patient will develop AKI within the next 12 hours. [70]
Approval for NephroCheck was based on two studies, which compared results from the test with the clinical diagnosis of over 500 critically ill patients. In patients with AKI, NephroCheck was 92% accurate in detecting the condition in one study and 76% accurate in the other. In both studies, however, the test reported false-positives in about 50% of patients without AKI.
CBC, Peripheral Smear, and Serology
The peripheral smear may show schistocytes in conditions such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). A finding of increased rouleaux formation suggests multiple myeloma, and the workup should be directed toward immunoelectrophoresis of serum and urine.
The presence of the following, along with related findings, may help to further define the etiology of AKI:
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Myoglobin or free hemoglobin - Eg, pigment nephropathy
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Increased serum uric acid level - Eg, tumor lysis syndrome
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Elevated serum lactate dehydrogenase (LDH) - Eg, renal infarction
Although serologic tests can be informative, the costs can be prohibitive if these tests are not ordered judiciously. Possible tests include the following:
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Complement levels
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Antinuclear antibody (ANA)
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Antineutrophil cytoplasmic antibody (ANCA)
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Anti–glomerular basement membrane (anti-GBM) antibody
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Hepatitis B and C virus studies
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Antistreptolysin (ASO)
Urinalysis
Findings of granular, muddy brown casts in urine sediment are highly suggestive of acute tubular necrosis (ATN) (see the image below). The presence of tubular cells or tubular cell casts also supports the diagnosis of ATN. Often, oxalate crystals are observed in cases of ATN.
Pigmented, muddy brown, granular casts are visible in the urine sediment of a patient with acute tubular necrosis (400x magnification).
Reddish brown or cola-colored urine suggests the presence of myoglobin or hemoglobin, especially in the setting of a positive dipstick for heme and no red blood cells (RBCs) on the microscopic examination. The dipstick assay may reveal significant proteinuria as a result of tubular injury.
The presence of RBCs in the urine is always pathologic. Eumorphic RBCs suggest bleeding along the collecting system. Dysmorphic RBCs or RBC casts indicate glomerular inflammation, suggesting glomerulonephritis is present.
The presence of white blood cells (WBCs) or WBC casts suggests pyelonephritis or acute interstitial nephritis.
The presence of eosinophils, as visualized with Wright stain or Hansel stain, might suggest interstitial nephritis. However, it has poor sensitivity in AIN diagnosis and can be also seen in urinary tract infections, glomerulonephritis, and atheroembolic disease.
The presence of uric acid crystals may represent ATN associated with uric acid nephropathy. Calcium oxalate crystals are usually present in cases of ethylene glycol poisoning.
Fractional Excretion of Sodium and Urea
Sodium
Urine electrolyte findings also can serve as valuable indicators of functioning renal tubules. The fractional excretion of sodium (FENa) is the commonly used indicator. However, the interpretation of results from patients in nonoliguric states, those with glomerulonephritis, and those receiving or ingesting diuretics can lead to an erroneous diagnosis.
FENa can be a valuable test for helping to detect extreme renal avidity for sodium in conditions such as hepatorenal syndrome. The formula for calculating the FENa is as follows:
FENa = (UNa/PNa) / (UCr/PCr) × 100
Calculating the FENa is useful in AKI only in the presence of oliguria. In patients with prerenal azotemia, the FENa is usually less than 1%. In ATN, the FENa is greater than 1%. Exceptions to this rule are ATN caused by any of the following:
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Radiocontrast nephropathy
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Severe burns
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Acute glomerulonephritis
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Rhabdomyolysis
In patients with liver disease and heart failure, FENa can be less than 1% in the presence of ATN. On the other hand, because administration of diuretics may cause the FENa to be greater than 1%, these findings cannot be used as the sole indicators in AKI.
Urea
In patients who are receiving diuretics, a fractional excretion of urea (FEUrea) can be obtained, since urea transport is not affected by diuretics. (FEUrea of less than 35% is suggestive of a prerenal state.) The formula for calculating the FEUrea is as follows:
FEUrea = (Uurea/Purea) / (UCr/PCr) × 100
Bladder Pressure
An intra-abdominal pressure of less than 10 mm Hg is considered normal and suggests that abdominal compartment syndrome is not the cause of AKI. An intra-abdominal pressure above 10 mm Hg is abnormal, but patients who have pressures of 15-25 mm Hg are at particular risk for abdominal compartment syndrome, and those with bladder pressures above 25 mm Hg should be suspected of having AKI as a result of abdominal compartment syndrome.
Emerging Biomarkers
Creatinine elevation is a late marker for kidney dysfunction and reflects a severe reduction in glomerular filtration rate (GFR). Consequently, a number of biomarkers are being investigated to risk stratify and predict AKI in patients at risk for the disease.
One of the most promising biomarker to date is urinary neutrophil gelatinase-associated lipocalin (NGAL), which has been shown to detect AKI in patients undergoing cardiopulmonary bypass surgery. [71]
Breidthardt et al studied a model that combined the markers plasma B-type natriuretic peptide (BNP) and NGAL and found it to be a strong predictor of early AKI in patients with lower respiratory tract infection. The presence of a BNP level of over 267 pg/mL or an NGAL level of greater than 231 ng/mL correctly identified 15 of 16 early AKI patients, with a sensitivity of 94% and a specificity of 61%. [72]
A study of adults on the first day of meeting AKI criteria found that urine protein biomarkers and microscopy findings offer a significant improvement over clinical determination of prognosis. In this study, the risk for worsened AKI stage or inhospital death was approximately 3-fold higher for upper values than it was for lower ones for NGAL, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and microscopy score for casts and tubular cells. [73]
In addition, multiple studies have suggested that when stress biomarkers such as insulinlike growth factor–binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP-2) are positive after a kidney insult, timely initiation of preventive strategies is effective at preventing AKI and decreasing the need for renal replacement therapy (RRT). [74, 75, 76] Supported by this data, the current recommendation by the Acute Disease Quality Initiative (ADQI) encourages the use of validated biomarkers to identify patient populations for whom preventive interventions have been shown to improve outcomes (grade A recommendation). [77] However, there are still multiple limitations for their routine use in clinical practice, including the variable cutoff values in published articles and lack of standardization, risk of confounding by comorbidities, and high expenses. [78]
Cystatin C is another biomarker that has been studied for potential early detection of AKI and prediction of disease outcomes. [79] In multiple studies of patients undergoing cardiac surgery, cystatin C was found to have modest to moderately good discrimination ability for development of AKI, with the area under the receiver operating characteristic curve ranging from 0.63 to 0.77. [80, 81, 82]
In addition, several studies reported similar performance of cystatin C compared with serum creatinine for AKI detection postoperatively. [81, 83, 84] Similarly, cystatin C level performed comparably to serum creatinine level in predicting dialysis requirement and in-hospital death in hospitalized patients. In a heterogeneous emergency department population, a single-center prospective cohort study that included 616 patients found that cystatin C outperformed serum creatinine in early detection of AKI and and differentiated between prerenal azotemia and AKI. [85]
For more information, see Novel Biomarkers of Renal Function.
Furosemide Stress Testing
In early AKI, urine output after a furosemide stress test (FST) can predict the development of stage 3 AKI. Response to the FST may be used to help the clinician determine when or whether to start renal replacement therapy. [68, 69]
Candidates for FST should be euvolemic and stable. For the test, furosemide is infused intravenously, in a dose of 1.0 or 1.5 mg/kg, and urine output is measured for 2 hours afterward. A 2-hour urinary output of 200 ml or less has been shown to have the best sensitivity and specificity to predict development of stage 3 AKI. To minimize the risk of hypovolemia, urine output may be replaced mL for mL each hour with Ringers lactate or normal saline for 6 hours after the FST, unless volume reduction is considered clinically desirable. [69]
In a study by Koyner et al, FST was significantly better than any urinary biomarker tested in predicting progression to stage 3 AKI (P< 0.05), and was the only test that significantly predicted receipt of renal replacement therapy. However, these authors found that a higher area under the curve for prediction of adverse patient outcomes was achieved when FST was combined with biomarkers using specified cutoffs: urinary neutrophil gelatinase-associated lipocalin (NGAL) > 150 ng/mL or urinary tissue inhibitor of metalloproteinases (TIMP-2) × insulinlike growth factor–binding protein-7 (IGFBP-7) > 0.3. [68]
Ultrasonography
Renal ultrasonography is useful for evaluating existing renal disease and obstruction of the urinary collecting system. Obtaining images of the kidneys can be technically difficult in patients who are obese, however, as well as in those with abdominal distention from ascites, gas, or retroperitoneal fluid collection.
The degree of hydronephrosis found on an ultrasonogram does not necessarily correlate with the degree of obstruction. Mild hydronephrosis may be observed with complete obstruction if found early. Small kidneys suggest chronic kidney disease.
Doppler ultrasonography
Doppler scans are useful for detecting the presence and nature of renal blood flow. Because renal blood flow is reduced in prerenal and intrarenal AKI, findings are of little use in the diagnosis of AKI. However, Doppler scans can be quite useful in the diagnosis of thromboembolic or renovascular disease. Increased resistive indices can be observed in patients with hepatorenal syndrome.
Nuclear Scanning
Radionuclide imaging with technetium-99m-mercaptoacetyltriglycine (99m Tc-MAG3),99m Tc-diethylenetriamine penta-acetic acid (99m Tc-DTPA), or iodine-131 (131 I)-hippurate can be used to assess renal blood flow, as well as tubular function. There is, however, a marked delay in the tubular excretion of radionuclide in prerenal and intrarenal AKI, limiting the value of nuclear scans.
Aortorenal Angiography
Aortorenal angiography can be helpful in establishing the diagnosis of renal vascular diseases, including the following:
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Renal artery stenosis
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Renal atheroembolic disease
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Atherosclerosis with aortorenal occlusion
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Certain cases of necrotizing vasculitis (eg, polyarteritis nodosa)
Kidney Biopsy
A kidney biopsy can be useful in identifying intrarenal causes of AKI and can be justified if the results may change management (eg, initiation of immunosuppressive medications). See the image below. A kidney biopsy may also be indicated when kidney function does not return for a prolonged period and a prognosis is required to develop long-term management. In as many as 40% of cases, kidney biopsy results reveal an unexpected diagnosis.
Acute cellular or humoral rejection in a transplanted kidney can be definitively diagnosed only by performing a biopsy.
Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.
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Pigmented, muddy brown, granular casts are visible in the urine sediment of a patient with acute tubular necrosis (400x magnification).
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Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.
Tables
Stage |
GFR Criteria |
Urine Output Criteria |
Probability |
Risk |
SCreat increased × 1.5 or GFR decreased >25% |
UO < 0.5 mL/kg/h × 6 h |
High sensitivity (Risk >Injury >Failure) |
Injury |
SCreat increased × 2 or GFR decreased >50% |
UO < 0.5 mL/kg/h × 12 h |
|
Failure |
SCreat increased × 3 or GFR decreased 75% or SCreat ≥4 mg/dL; acute rise ≥0.5 mg/dL |
UO < 0.3 mL/kg/h × 24 h (oliguria) or anuria × 12 h |
|
Loss |
Persistent acute renal failure: complete loss of kidney function >4 wk |
High specificity |
|
ESKD |
Complete loss of kidney function >3 mo |
||
ESKD—end-stage kidney disease; GFR—glomerular filtration rate; SCreat—serum creatinine; UO—urine output Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLE-FC; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 µmol/L) and results from an acute increase of at least 0.5 mg/dL (44 µmol/L). |
|||
Stage |
Serum Creatinine Criteria |
Urine Output Criteria |
1 |
Increase of ≥0.3 mg/dL (≥26.4 µmol/L) or 1.5- to 2-fold increase from baseline |
< 0.5 mL/kg/h for >6 h |
2 |
> 2-fold to 3-fold increase from baseline |
< 0.5 mL/kg/h for >12 h |
3* |
> 3-fold increase from baseline, or increase of ≥ 4.0 mg/dL (≥35.4 µmol/L) with an acute increase of at least 0.5 mg/dL (44 µmol/L) |
< 0.3 mL/kg/h for 24 h or anuria for 12 h |
*Patients who receive renal replacement therapy (RRT) are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT. |
||
