Key Clinical Questions
How does interpretation of the urinalysis and urine electrolytes guide clinical decision making?
What are the limitations of urinalysis and urine electrolytes?
When is it helpful to measure the urine osmolality, the fractional excretion of sodium and the fractional excretion of urea?
Urine tests can be a valuable diagnostic tool, especially since they are easily obtained and can provide a wide range of information. When interpreted in the context of a thorough history and physical examination, the clinician can use the information obtained from urinalysis to narrow the differential diagnosis and guide treatment. For example, in a patient presenting with kidney disease, the presence of significant proteinuria and red blood cell (RBC) casts in the urine suggests glomerulonephritis as a diagnosis.
This chapter will review how the major components of the urinalysis—including the appearance of the urine, urine dipstick, urine microscopy, and urine electrolytes—can guide clinical decision making. Unlike blood tests, which usually have discrete normal ranges, the “normal” range for many urine parameters is a function the patient’s clinical status and any metabolic or volume perturbations to which the kidney may be responding.
URINE COLOR AND APPEARANCE
The gross appearance of the urine may provide clues about volume status, source of bleeding, presence of infection, and medication use, as shown in Table 111-1.
TABLE 111-1Urine Appearance and Associated Medications and Conditions ||Download (.pdf) TABLE 111-1 Urine Appearance and Associated Medications and Conditions
Centrifugation of the urine can help distinguish hematuria from other causes. A red-colored pellet suggests intact RBCs, whereas a red supernatant may suggest myoglobinuria or hemoglobinuria. The gross appearance of the urine may suggest significant proteinuria (foamy urine) or lipiduria (greasy urine). Foul-smelling urine may suggest infection. Sweet-smelling urine raises the possibility of ketonuria.
URINE REAGENT STRIP (DIPSTICK) TESTING
SPECIFIC GRAVITY (AND URINE OSMOLALITY)
Specific gravity, which is measured using a urine dipstick, is the density of the urine relative to the density of water. This is a measure of the concentration of the urine. A related measure of urine concentration that is measured by the laboratory is urine osmolality, which the concentration of particles per kilogram of solution. Assessing the concentration of the urine is important when diagnosing primary polydipsia as the cause of hyponatremia and evaluating a patient with polyuria. The usual physiologic range of urine specific gravity is 1.005 to 1.030 and for urine osmolality is 50 to 1200 mOsmol/kg. Unlike osmolality, which measures the solute concentration and is not a function of the size of the particles in solution, specific gravity is affected by the mass of the particles in the urine. Therefore, large particles that are excreted in the urine, such as radiocontrast material, can cause an increase in the specific gravity. Nonetheless, under most conditions, urine specific gravity usually correlates fairly well with osmolality. Urine specific gravities of 1.001, 1.010, and 1.030 are approximately equal to a urine osmolality of 40, 320, and 1200 mOsmol/kg, respectively. In addition to the presence of radiocontrast in the urine, glucose and protein in the urine can also elevate the specific gravity.
Clinically, urine osmolality—and so also urine specific gravity—will be elevated in cases in which antidiuretic hormone (ADH) is elevated.
A urine osmolality > 100 mOsm/kg is inappropriate as in SIADH; the urine osmolality frequently will be higher than this and typically higher than the serum osmolality.
A urine osmolality < 100 mOsm/kg in a hyponatremic patient suggests primary polydipsia.
Patients with acute kidney injury (AKI) from acute tubular necrosis (ATN) will usually have a urine osmolality < 400 mOsm/kg due to compromise of the kidney’s urinary concentrating ability.
Patients with prerenal azotemia will usually have a urine osmolality that is >500 mOsm/kg.
ADH can be elevated appropriately in cases of hypovolemia, or inappropriately, as in cases of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In SIADH, the urine osmolality may not be absolutely high, but it is inappropriately high relatively speaking, given that the adaptive response to hyponatremia is to excrete free water.
In cases of polyuria, the urine osmolality can help distinguish a water diuresis from a solute diuresis. A urine osmolality >300 mOsm/kg is consistent with a solute diuresis, whereas a urine osmolality <150 mOsm/kg is suggestive of a water diuresis. In cases of a higher urine osmolality (>300 mOsm/kg) suggestive of a solute diuresis, possible causes include high salt intake, glucosuria, or mannitol. In cases of low urine osmolality (<150 mOsm/kg) suggesting a water diuresis, possible causes include diabetes insipidus or excessive water intake, as with primary polydipsia.
The initial test commonly used to evaluate for hematuria is the urine dipstick. The different cutoffs used for hematuria account, in part, for the different test characteristic numbers. Urine dipsticks have sensitivities of 91% to 100%, using 2 to >5 RBCs per high power field (HPF) on sediment microscopy as the reference standard. Urine dipsticks have specificities in the 65% to 99% range, using microscopy as the reference standard. There are a number of conditions that can cause positive results for hematuria in the absence of hematuria. Myoglobinuria and hemoglobinuria, from rhabdomyolysis and hemolysis, respectively, cause urine dipsticks to register positive for heme. The absence of RBCs on urine microscopy in the setting of a urine dipstick positive for heme suggests the possibility of rhabdomyolysis or hemolysis. In one series by Grover et al, examining patients with rhabdomyolysis, a urine dipstick showing moderate or large urine heme in the absence of hematuria had a sensitivity of 81% for detecting creatine kinase levels greater than 10,000 U/L. Another condition that can lead to false positives for heme on urine dipsticks includes some bacteria with pseudoperoxidase activity, such as certain species of staphylococci and streptococci. Ascorbic acid can result in false negative results for glucosuria due to its inhibition of the glucose oxidase reaction.
It is important to consider that urine dipsticks and microscopy signal hematuria, not necessarily disease. Epidemiological studies looking at the proportion of patients with hematuria who have serious disease have yielded inconsistent results, with rates of significant urologic disease among patients with microscopic hematuria varying from 17% to 56% in different studies. Mariani et al, evaluated 1000 consecutive adults with asymptomatic hematuria (microscopic or macroscopic). Of these patients, 9.1% had what was deemed a life-threatening condition, most commonly bladder transitional cell cancer or renal adenocarcinoma. Significant findings, such as nephrolithiasis or cystitis, occurred in 22.8% of patients. In 56.4% of patients, only insignificant findings resulted from the evaluation of their hematuria, and in the remaining 11.7% of patients, no diagnosis to explain the hematuria was obtained. The authors of this study assert that there is no lower limit to the number of RBCs in the urine that rules out serious underlying disease, given that 18.6% of patients with life-threatening conditions produced a urinalysis with fewer than three RBCs/HPF within 6 months of the cancer diagnosis.
Unexplained hematuria requires further evaluation. The most important goal of this further evaluation is to assess for the presence of cancer affecting the kidney or urinary tract. In general, patients with unexplained hematuria should undergo imaging, such as a CT scan, urine cytology testing, and also be referred to a urologist for cystoscopy and further evaluation.
Detection of hematuria should prompt the clinician to do the following:
Review any prior abdominal imaging performed in the hospital to assess for the presence of cancer affecting the kidney or urinary tract.
Consider whether the patient had any procedures including Foley catheter insertion that might account for hematuria.
Include information about the presence of hematuria in the discharge summary, and communicate this information to the patient’s PCP. In the majority of patient in whom hematuria is detected while in the hospital, further evaluation for this hematuria will occur as an outpatient, and so the need for this workup must conveyed to the patient’s PCP.
Inform the patient of the hematuria and further evaluation is required.
Most urine dipsticks can detect albumin concentrations of 200 to 300 mg/L. There are semi-quantitative assays, usually reporting the amount of proteinuria as 1+ to 3+ or 4+. A limitation of urine dipstick testing for albuminuria is that it is affected by the concentration of the urine sample being used. Using the albumin-to-creatinine ratio as the reference standard, a study of 310 general hospitalized patients by Pugia et al, found that dipstick assessment for albuminuria had a positive predictive value of 82% and a negative predictive value of 99%. The authors concluded dipstick testing had good agreement with the quantitative albumin-to-creatinine ratio. Microalbuminuria refers to urinary albumin excretion of 30 to 300 mg/d. Microalbuminuria is commonly used to detect early renal disease in diabetic patients, and so is mainly used in the primary care setting rather than the inpatient setting.
Urine dipsticks are insensitive for nonalbumin proteinuria, such as the light chains that may occur in the setting of myeloma kidney (Bence Jones proteins).
When there is a suspicion of nonalbumin proteinuria, other methods of assessing for proteinuria besides a dipstick should be used, such as a spot urine protein-to-creatinine ratio performed by the clinical laboratory.
Sulfosalicylic acid, when added to a urine sample, will cause turbidity in the presence of protein in the urine (both albumin and nonalbumin protein) and so can be used as a point-of-care test to detect nonalbumin proteinuria (with a reported sensitivity of 76.7% and specificity of 75.4%).
Measuring proteinuria is an important part of evaluating any patient with known or suspected renal disease, as heavy proteinuria can signal significant glomerular disease, or can be a consequence of renal involvement in a systemic disease, such as multiple myeloma. Proteinuria >150 mg/d is considered abnormal. When proteinuria exceeds 3.5 g/d, it is in the nephrotic range, and when accompanied by hypoalbuminemia, edema, and hyperlipidemia, full-blown nephrotic syndrome is present. Not only is the level of proteinuria diagnostically useful, but it is also a risk factor for progression of chronic kidney disease in both diabetic and nondiabetic patients. There are three different methods of assessing for proteinuria: (1) a 24-hour urine collection for protein excretion; (2) a spot (ie, untimed) urine protein-to-creatinine ratio; and (3) a urine dipstick.
The 24-hour urine collection, while often used as a reference standard, has a limited role in routine inpatient clinical practice. Under many circumstances, a spot urine can be obtained for a protein-to-creatinine ratio, which gives an estimate of the 24-hour protein excretion in the urine. Populations with a lower muscle mass—such as the elderly, underweight individuals, and women—are more likely to have a low urine creatinine. Consequently, a spot protein-to-creatinine ratio may overestimate the 24-hour urinary protein excretion in these populations.
One study by Lane, et al, which looked at 103 patients in a renal and hypertension clinic, concluded that as the level of proteinuria increased, the accuracy of the spot urine protein-to-creatinine ratio decreased, and that at levels of proteinuria above 1 g/24 h, the spot measurement was inadequately accurate, and a 24-hour collection should be used instead. The authors argue that the spot measurement is helpful in answering whether the patient has significant proteinuria, but if the exact amount of that significant proteinuria needs to be known (such as for following the effect of treatment), then a 24-hour urine collection should be used. Nonetheless, in the inpatient setting, a spot urine protein-to-creatinine ratio will in most cases provide the necessary information.
LEUKOCYTE ESTERASE, NITRITE, AND THE DETECTION OF INFECTION IN THE URINE
The urine dipstick features used to diagnose a urinary tract infection (UTI) include the presence of leukocyte esterase and nitrites. White blood cells (WBCs) on urine microscopy and an organism isolated on urine culture help confirm the diagnosis. Leukocyte esterase is an enzyme contained in WBCs, while nitrites are a product resulting from the metabolism of nitrates by certain bacteria. Bacteria that can convert nitrates to nitrites include Escherichia coli and other bacteria in the family Enterobacteriaceae. However, a number of important urinary pathogens do not produce nitrites, including S. saprophyticus, Pseudomonas, and enterococci. Certain factors can cause a misleading negative nitrite test on dipstick testing, including insufficient nitrates in the diet to be converted by the bacteria and a dipstick that has been exposed to the air for a prolonged period. It takes at least 4 hours for bacteria to convert nitrates to detectable levels of nitrite, and so this test may be negative in patients with UTIs whose urinary frequency does not provide adequate time for bacterial conversion of nitrates to nitrites. The presence of urine eosinophils or Trichomonas in the urine can lead to false positive results. Factors that can lead to false negative results include the presence of ascorbic acid, high levels of glucose or protein, and certain antibiotics, including cephalexin and tetracycline.
A systematic review by Hurlbut et al, of the test characteristics of dipstick leukocyte esterase and nitrite to detect UTI, which used >100,000 cfu/mL on the urine culture as the reference standard, found that considering either positive leukocyte esterase or positive nitrite to denote a positive test for UTI yielded the greatest area under the ROC curve. Considering either leukocyte esterase positive or nitrite positive to be a positive result for UTI yielded a sensitivity of 75% and a specificity of 82%. This review and other reviews concluded that in the setting of a high clinical suspicion, a dipstick negative for both leukocyte esterase and nitrite is not sufficient to exclude a UTI. A study of 408 women by Little et al, found similar results. Using either a dipstick positive for nitrite or positive for both leucocytes and blood to be a positive test yielded a sensitivity of 77% and a specificity of 70%, using culture data as the reference standard.
In assessing the relationship between the degree of pyuria and likelihood of bacteriuria, measuring the leukocyte excretion rate is the most diagnostically useful. However, this method is cumbersome, and so the method employed in most clinical laboratories to measure pyuria is counting the number of WBCs per HPF in the centrifuged urine sample. A common break point used by clinical laboratories is ≥10 WBCs/HPF as being abnormal pyuria, though the break points used by clinical laboratories vary. In general, the higher the number of WBCs, the more likely there is to be significant bacteriuria. One older study by Holm et al, found that among patients with 0 to 1 WBCs/HPF, 3% of patients had urine cultures with >103 bacteria/mL, whereas among patients with >9 WBCs/HPF, 87% had >103 bacteria/mL urine. A more recent study by Al-Daghistani et al, examining the diagnostic characteristics of pyruia, using >50,000 cfu/mL as representing a true UTI, found that of ≥10 WBCs/HPF has a sensitivity of 34% and a specificity of 86.5%. Pyuria on microscopy, as currently performed by most clinical laboratories, cannot by itself be used to make the diagnosis of a UTI, and must be used in conjunction with other diagnostic information. Pyuria with a negative urine culture (“sterile pyuria”) can be seen in the setting of partially treated UTIs and UTIs due to Chlamydia trachomatis, Ureaplasma urealyticum, and Mycobacterium tuberculosis. Other settings in which sterile pyuria can be seen include polycystic kidney disease, urolithiasis, papillary necrosis, Kawasaki disease, and tubulointerstitial diseases.
The most commonly used break point for the diagnosis of bacteriuria is ≥105 cfu/mL of urine. Some authors have suggested that it would be preferable to use a lower threshold, such as ≥104 cfu/mL of urine to define significant bacteriuria, with other authors suggesting thresholds as low as ≥102 cfu/mL of urine. Three or more isolates each present in quantities of ≥105 cfu/mL suggest contamination. A single isolate present in quantities of <102 cfu/mL is also a probable contaminant. Squamous epithelial cells seen on urine microscopy should raise suspicion of contamination.
Assess for symptoms of a UTI in deciding whether antibiotic treatment is warranted.
In pregnant women, in patients undergoing urologic procedures in which mucosal bleeding is expected, and in patients undergoing transurethral resection of the prostate, treatment of asymptomatic bacteriuria is indicated.
Outside of these circumstances, treatment of asymptomatic bacteriuria is generally inappropriate.
The diagnosis of a UTI in patients with indwelling urinary catheters (Foley catheters) presents a challenge. In patients with indwelling urinary catheters, the association between pyruia and actual UTIs is weaker than in patients without such catheters. Therefore, in patients with indwelling urinary catheters, pyuria cannot be used to reliably diagnose a UTI. Moreover, many patients with indwelling urinary catheters who have UTIs may have minimal symptoms or be asymptomatic. According to a 2009 Infectious Diseases Society of America clinical practice guideline on catheter-associated UTIs by Hooton et al, a catheter-associated UTI is “defined by the presence of symptoms or signs compatible with UTI with no other identified source of infection along with ≥103 colony forming units (cfu)/mL of ≥1 bacterial species in a single catheter urine specimen or in a midstream voided urine specimen from a patient whose urethral, suprapubic, or condom catheter has been removed within the previous 48 hours.”
Once serum glucose levels increase above about 180 mg/dL, glucose will start to appear in the urine. The presence of ascorbic acid and bacteria may cause false negative glucosuria readings on dipsticks. Dipsticks that are left uncapped and so exposed to the air for extended periods may provide false positive glucosuria results. Glucosuria may occur in the absence of hyperglycemia (known as renal glucosuria) in certain inherited disorders and in patients with Fanconi syndrome, which is a syndrome of renal proximal tubular dysfunction. Causes of Fanconi syndrome include medications—such as antiretroviral drugs (especially tenofovir), aminoglycosides, ifosfamide, and cisplatin. As part of the syndrome of proximal tubular dysfunction, wasting of bicarbonate, phosphate, calcium, and amino acids also occurs. Elevated levels of these substances in the urine support the diagnosis of Fanconi syndrome.
Case 111-1 shows how urine dipstick and urine microscopy testing can be used together to help arrive at a diagnosis.
CASE 111-1 USING URINE DIPSTICK AND URINE MICROSCOPY RESULTS TO SUGGEST A DIAGNOSIS
A 68-year-old female with a history of coronary artery disease, hypertension, and hyperlipidemia presents with malaise, weakness, and diffuse muscle aches that have been present for the past 3 days. Medications the patient is taking include metoprolol, aspirin, atorvastatin, and gemfibrozil. She notes that her urine has seemed darker than usual, but she denies any dysuria, urinary hesitancy, or foul-smelling urine. She also denies any fevers. Her urinalysis shows a specific gravity of 1.014, and is negative for glucose, protein, leukocyte esterase, and nitrites. The urinalysis is positive for hematuria. Urine microscopy detects no RBCs or WBCs.
A urinalysis positive for hematuria with no RBCs found on urine microscopy raises the possibility of myoglobinuria from rhabdomyolysis or hemoglobinuria from hemolysis. In this patient with muscle aches who is on atorvastatin and gemfibrozil, a drug combination that is a known cause of rhabdomyolysis, this is the most likely diagnosis. It would be appropriate to start IV hydration with isotonic fluids while awaiting the results of serum tests, which can confirm the suspected diagnosis. This patient’s serum tests showed a creatine kinase level of 15,125 U/L, confirming the diagnosis of rhabdomyolysis.
Urinary casts can provide important information corroborating a suspected diagnosis. In some cases, a careful examination of the urine sediment can point to a possible diagnosis that may not have initially been given prominent consideration. Urine that is to be examined for casts and other urinary elements should be fresh and should be examined as soon as possible after it is obtained. The procedure for preparing urine for examination is as follows. Ten milliliters of urine is centrifuged at 1500 to 2000 rpm for 5 to 10 minutes. Suction is used to remove 9.5 mL of the supernatant. The sediment at the bottom of the tube is resuspended in the remaining 0.5 mL of supernatant by tapping on the tube. Using a pipette, a single drop of the resuspended urine is placed on a slide and then a coverslip is placed on the urine drop. The sample should be examined under the low-power objective and the high-power objective of the microscope.
Not all casts are pathologic. For instance, hyaline casts can be a normal finding. The presence of most casts, however, suggests renal disease. The absence of casts cannot be used to exclude a diagnosis, as casts may be missed or may degrade due to specimen processing. In general, casts are composed of the diagnostic element within a matrix of Tamm-Horsfall glycoprotein. Hyaline casts, which are composed primarily of Tamm-Horsfall glycoprotein, are faint, nearly colorless casts that can be seen in patients without renal disease. Renal tubular epithelial cell casts, which are composed of renal tubular epithelial cells shed in the setting of tubular injury, are most commonly seen in patients with ATN. Granular casts represent a degradation product that can contain broken down renal tubular epithelial cells and also other cellular elements. Thus granular casts may be seen in ATN, but are nonspecific and may also be seen in other types of renal disease. A scoring system by Perazella et al, based on the number of renal tubular epithelial cells and granular casts was found to be useful in distinguishing prerenal AKI from ATN, as well as in predicting the worsening of either prerenal AKI or ATN. RBC casts are seen in pathologic states in which there is blood of glomerular origin, such as glomerulonephritis or vasculitis affecting the kidney. When reported, the morphology of any RBCs seen on microscopy can be helpful. Dysmorphic RBCs—particularly acanthocytes (ringform RBCs with blebs protruding off)—suggest the hematuria is glomerular in origin.
Leukocyte casts occur in pyelonephritis and acute interstitial nephritis, as well as in glomerulonephritis. Fatty casts, which contain lipid droplets and have a “Maltese cross” appearance under polarized light, may be seen in the setting of lipiduria, such as in patients with nephrotic syndrome. Table 111-2 summarizes different casts and their clinical significance.
An important limitation in the use of casts as a diagnostic tool relates to the skill it takes to correctly identify urinary casts. One study by Tsai et al, comparing the performance of nephrologists with that of the clinical laboratory found that the nephrologists were more likely to identify renal tubular epithelial cells, granular casts, renal tubular epithelial cell casts, and dysmorphic RBCs, as compared to the clinical laboratory. The clinical laboratory identified more squamous epithelial cells than the nephrologists, raising the possibility that the clinical lab was incorrectly identifying other urinary elements, such as renal tubular epithelial cells, as squamous epithelial cells.
Overall, nephrologists performed better than the clinical laboratory in deriving information from the urinalysis.
Therefore, it is advisable to review a urine sediment with a nephrologist, rather than relying on the clinical laboratory, if the results of the sediment examination are crucial.
Testing for urine eosinophils is frequently used to aid in the diagnosis of acute interstitial nephritis (AIN). Older data supporting the use of urine eosinophils in diagnosing AIN have not been borne out by more recent reports. A 1986 study by Nolan et al of 92 patients, focusing on the technical advantages of using Hansel stain rather than Wright stain to detect urine eosinophils, found that 10 of 11 patients with AIN were positive for urine eosinophils using Wright stain. Notably, however, eosinophiluria was also seen in cases of acute prostatitis, rapidly progressive glomerulonephritis, postinfectious glomerulonephritis, and acute cystitis. No eosinophiluria was detected among patients with ATN or acute pyelonephritis. Corwin et al, in 1989 reviewed 183 patients who had been tested for eosinophiluria, to evaluate the test characteristics of eosinophiluria in diagnosing AIN. The sensitivity (using Hansel stain) was 63% and the specificity was 93%. Eosinophiluria was also seen in two patients with UTIs, one patient with membranoproliferative glomerulonephritis, and in one patient with no diagnosis. The authors concluded that eosinophiluria was a good test for AIN.
Arriving at a different conclusion, a 1994 study by Ruffing et al, tested 148 patients with pyuria for eosinophiluria. Considering only those patients in whom testing for urine eosinophils had been recommended by a nephrologist because of a suspicion of AIN, the authors found eosinophiluria had a sensitivity of 40% and a specificity of 72%. Conditions beside AIN in which eosinophiluria was detected included glomerulonephritis and chronic renal failure. The conclusion from this study was that eosinophiluria alone was inadequate to make the diagnosis of AIN, and that both false positive and false negative test results are a problem. An influential 2008 study of the value of eosinophiluria in diagnosing AIN by Fletcher included 534 quantitative urinary eosinophil tests and reported a sensitivity of 25% and a positive predictive value of 3%. A common methodological problem in studies assessing the test characteristics of eosinophiluria for diagnosing AIN is that many of the cases of AIN were established based on clinical criteria, rather than the gold standard of renal biopsy.
The bottom line is that testing for eosinophiluria as a means of diagnosing AIN needs to be done with extreme caution, as its utility in diagnosing AIN is very limited. The presence or absence of eosinophiluria is not adequate to either establish or exclude the diagnosis of AIN. The results of testing for urine eosinophils must be viewed in the larger clinical context, and the presence of other clinical features typical of AIN, such as, in addition to kidney injury, fever, rash, eosinophilia, and arthralgias, need to be considered. Renal biopsy remains the gold standard for diagnosing AIN.
Crystals, which are typically visualized in the urine using polarizing light microscopy, can precipitate in the kidney, resulting in AKI. For example, tumor lysis syndrome can occur with treatment of lymphoma or leukemia, in which cell death may lead to hyperuricemia and AKI as a result of the uric acid precipitating as crystals that obstruct the renal tubules.
Precipitation of crystals, due to limited medication solubility, is also an important mechanism of medication-induced AKI. The archetype is acyclovir, with one study finding nearly 50% of patients had an increase in their creatinine in the setting of receiving high-dose IV acyclovir. Principles of prevention of AKI as a result of medication precipitation include maintaining a high urine output, slowly infusing the medication, using caution in patients who have CKD, and adjusting the medication dose based on the patient’s renal function. These same principles are generally applicable to other medications that may precipitate as crystals and cause AKI. Other culprit medications include indinavir, sulfonamides (such as sulfamethoxazole and sulfasalazine), and foscarnet. There have also been case reports of crystal nephropathy in association with ciprofloxacin.
URINE SODIUM AND OTHER URINE ELECTROLYTES
The urine sodium and fractional excretion of sodium (FENa) are of particular value in helping to determine the etiology of oliguric AKI and in assessing a patient’s volume status, such as in a patient with hyponatremia. However, as will be discussed below, these indices have a number of important limitations.
In oliguric patients, a urine sodium <20 mEq/L suggests renal hypoperfusion, as can occur with intravascular volume depletion. This condition is what is commonly referred to as a “prerenal” state. The low urine sodium results from the hypoperfused kidney responding by retaining sodium, so as to maximize intravascular volume. In the setting of ATN, the renal tubular cells are damaged, and so are unable to retain sodium, resulting in a higher urine sodium, usually >40 mEq/L. Urine sodium values between 20 and 40 mEq/L are indeterminate.
A urine sodium >40 mEq/L may be seen in the following circumstances despite the presence of intravascular volume depletion:
Renal salt wasting
In patients with metabolic alkalosis, the urine chloride can be checked instead of the urine sodium, as the chloride should be more reflective of the patients’ volume status. A major limitation of the urine sodium is that it reflects free water handling in addition to sodium handling, which is why using the fractional excretion of sodium is generally preferred.
FRACTIONAL EXCRETION OF SODIUM
The fractional excretion of sodium (FENa) (%), calculated as [(urine sodium x plasma creatinine)/(plasma sodium × urine creatinine)] × 100, takes into account both filtration and reabsorption of sodium. In the setting of AKI, an FENa <1% suggests renal hypoperfusion (analogous to a urine sodium <20 mEq/L), whereas an FENa >2% suggests ATN (analogous to a urine sodium >40 mEq/L).
The FENa has a number of limitations. In patients with normal renal function with a moderate salt diet, an FENa <1% may be normal because, with a normal GFR, a large amount of sodium is filtered, and an FENa <1% may reflect the moderate sodium intake of the patient.
Prolonged hypoperfusion itself may lead to ATN, and so a higher urine sodium. Thus an elevated FENa may represent a late consequence of renal hypoperfusion prolonged and severe enough to result in hypotension and ATN. There are certain clinical situations that are thought to be due to ATN, but when a low FENa often exists—including contrast induced nephropathy, AKI from myoglobinuria or hemoglobinuria, and glomerulonephritis. In patients with cirrhosis, congestive heart failure, and sepsis, the FENa may be low, due to decreased effective circulating volume.
Another major limitation in using the FENa is that its accuracy diminishes in patients receiving diuretics, a treatment commonly used in hospitalized patients. A study of 99 patients by Pepin et al, looked at the performance of the FENa in predicting which cases of AKI were transient (<7 days, and so likely the result of renal hypoperfusion), as opposed to prolonged AKI (which is more likely the result of ATN) in patients on diuretics and in patients not on diuretics. The sensitivity and specificity of the FENa in predicting transient AKI in patients not on diuretics was 78% and 75%, respectively. On diuretics, the sensitivity of the FENa goes down to 58%, but the specificity is not markedly changed at 81%. The area under the curve (AUC) for the FENa in patients without diuretics is 0.83, whereas in patients with diuretics, the AUC falls to 0.75. It is worth noting that in patients receiving diuretics, a low FENa can be helpful, because patients with a low FENa despite receiving diuretics clearly have kidneys that are sodium avid, and so likely have renal hypoperfusion. However, in patients receiving diuretics, an FENa that is high is unhelpful, because it is impossible to distinguish whether the high FENa reflects the effect of the diuretics or the actual lack of sodium avidity by the injured renal tubules (as would be expected in ATN).
FRACTIONAL EXCRETION OF UREA
In response to the limitations of the FENa, the fractional excretion of urea (FEurea) has been proposed as an alternative. Using the FEurea is physiologically appealing in this setting, because urea is reabsorbed primarily in the proximal portion of the nephron, and so urea handling by the kidney would be expected to be less affected by diuretic administration than would salt handling. The FEurea is calculated by the same method as the FENa, with the urine urea substituting for the urine sodium, and the plasma urea (blood urea nitrogen) substituting for the plasma sodium. The breakpoint used for the FEurea is <35%, which, analogous to the <1% breakpoint used with the FENa, suggests an avid kidney responding to renal hypoperfusion. Pepin et al, also examined the performance of the FEurea in distinguishing between transient and prolonged AKI. This study found that the FEurea did not perform well, even in patients on diuretics. The sensitivity of the FEurea for predicting transient AKI in patients on diuretics was 79% and the specificity was 33%. In patients not on diuretics, the FEurea had a sensitivity of 48% and a specificity of 75%. Overall, the test characteristics were less favorable for FEurea, which has an AUC of 0.56 for patients not on diuretics and 0.57 for patients on diuretics. This compares to an AUC for FENa of 0.83 in patients not on diuretics and 0.75 for patients on diuretics.
In contrast to the findings by Pepin et al, a study by Carvounis et al, supports the utility of the FEurea in the setting of diuretic use. In this study, 102 episodes of AKI were categorized as being due to either prerenal azotemia in patients who were not treated with diuretics, prerenal azotemia in patients who were treated with diuretics, or due to ATN. FEurea performed the best overall, with a sensitivity of 85% and a specificity of 92%. The AUC for FEurea was 0.972, while the AUC for FENa was 0.889. Among prerenal patients on diuretics, 89% of them had an FEurea <35%, whereas only 48% of them had an FENa <1%. FEurea and FENa performed similarly in prerenal patients not on diuretics, with 90% of them having an FEurea <35% and 92% having an FENa <1%.
Given these conflicting data, the FEurea should be used as a diagnostic tool with caution. Outside of the setting of diuretic use, the FENa is preferred. In the setting of diuretic use, the available data do not clearly support using one over the other. One approach is to use both and to obtain urine electrolytes at multiple time points, and see if this larger pool of data is congruent so as to support a diagnosis of renal hypoperfusion or ATN.
URINE ELECTROLYTES IN ACID-BASE DISTURBANCES
Urine sodium and urine chloride should, in theory, correlate fairly closely with each other, though one report by Sherman et al, found that a dissociation between urine sodium and urine chloride >15 mEq/L occurred in 30% of patients. Urine sodium and urine chloride will diverge in acute acid-base disturbances. In the setting of an alkalosis, a normal kidney will excrete the excess bicarbonate. In order to maintain electroneutrality, the anionic bicarbonate excreted in the urine by the kidney will be accompanied by cations, such as sodium. Therefore, in the setting of an alkalosis, an elevated urine sodium may be a reflection of the renal compensation for the alkalosis, rather than the volume status. With an acidosis, a functioning kidney should respond by eliminating excess protons in the urine, which it does by excreting ammonium. For electroneutrality, the cationic ammonium is accompanied by anionic chloride. Thus in this setting, the urine chloride may be elevated primarily as a reflection of the kidney’s effort to compensate for the acidosis, rather than the volume status. Case 111-2 shows the use of urine electrolytes in a patient having episodes of emesis.
CASE 111-2 URINE ELECTROLYTES IN A VOMITING PATIENT
A 45-year-old patient, with a history of alcoholic liver disease, presented with multiple episodes of vomiting. Initial vitals signs included a blood pressure of 100/80 mm Hg and a pulse of 90 beats/min. Serum electrolytes were notable for a blood urea nitrogen of 53 mg/dL and a creatinine of 7.0 mg/dL. Urine electrolytes showed an FENa of 2.4%.
Given the history of vomiting, intravascular volume depletion leading to AKI from a prerenal state would seem to be a leading diagnosis. However, the FENa of 2.4% suggests ATN as a cause of the AKI. This case illustrates a limitation of the FENa and how it can potentially be diagnostically misleading. In this patient, even if he does become intravascularly volume depleted because of vomiting, this vomiting will lead to a metabolic alkalosis due to the loss of gastric acid in the emesis. The resulting metabolic alkalosis will lead to a compensatory excretion of bicarbonate by the kidney, and with the excretion of bicarbonate in the urine, there will be the obligate excretion of sodium in order to maintain electroneutrality. Therefore, in this patient who is volume depleted due to vomiting, the FENa may be high because the increased urinary sodium loss as a result of compensation for the metabolic alkalosis may more than offset the sodium avidity that would be expected due to the intravascular volume depletion. In a case such as this, the urine chloride may be a more helpful guide. The urine chloride in this patient was low (<10 mmol/L), consistent with intravascular volume depletion. The patient’s AKI improved with IV isotonic fluids.
These same principles described above underlie the urine anion gap, which is calculated as urine (Na+ + K+ – Cl–). The urine anion gap is an indirect measure of urinary ammonium excretion, since urinary ammonium is an unmeasured cation, and increased ammonium excretion in the urine is accompanied by increased chloride excretion in the urine. Therefore, as urinary ammonium excretion is increased, urinary chloride is also increased, and so the urine anion gap decreases, and will often become negative. One of the main clinical situations in which the urine anion gap may be useful is in a nonanion gap (hyperchloremic) metabolic acidosis, in which one wants to help distinguish whether the nonanion gap metabolic acidosis is from diarrhea or either a type 1 (distal) or type 4 (hyperkalemic) renal tubular acidosis (RTA). In a nonanion gap metabolic acidosis in which the kidney is functioning normally, such as in a patient with diarrhea, the kidney will respond by increasing ammonium production, and so the urine anion gap will be negative. In one series of patients with diarrhea described by Batlle, et al, the average urine anion gap was –20. In a nonanion gap metabolic acidosis caused by either a type 1 or type 4 RTA, the defect is in the kidney, and so it will not be able to mount an appropriate increase in ammonium excretion in response to the acidosis, and so the urine anion gap will be positive. Conditions that can render the urine anion gap less reliable include excretion of other unmeasured anions in the urine, such as ketoacids or lactic acid, and in certain types of dietary intake, such as cereals that provide chloride without Na+ or K+.
URINE TESTING IN THE DIFFERENTIAL DIAGNOSIS OF ACUTE KIDNEY INJURY
The results of the urinalysis and other urine testing can, in conjunction with the clinical picture, help elucidate the cause of AKI in hospitalized patients. Particularly in cases in which both prerenal and postrenal causes of AKI have been determined to be less likely, the results of urine tests can help distinguish among intrarenal causes of AKI—such as ATN, AIN, and glomerulonephritis. In ATN, the tubular cells are damaged and so are unable to reabsorb sodium, so an FENa > 2% (and an FEurea >50%) would be expected, along with minimal proteinuria and muddy brown casts in the urine sediment. Most cases of AIN have only low-level proteinuria, except in cases of NSAID-induced AIN, which commonly involves nephrotic-range proteinuria. AKI from glomerulonephritis is characterized by elevated levels of proteinuria, RBC casts, and an FENa that is typically low. The use of urinary parameters in diagnosing AKI is summarized in Table 111-3.
TABLE 111-3Urinalysis and Urine Electrolyte Findings in AKI ||Download (.pdf) TABLE 111-3 Urinalysis and Urine Electrolyte Findings in AKI
|Etiology of ARF ||Urine Na (mEq/L) ||FENa ||FEUrea ||Proteinuria ||Urine Sediment |
|Prerenal ||<20 ||<1% ||<35% ||Minimal ||Bland |
|Intrarenal || || || || || |
|ATN ||>40 ||>2% ||>50% ||Minimal ||Granular casts |
|AIN ||Variable ||Variable ||Variable ||Variable ||Eosinophils |
|GN ||<20 ||<1% ||<35% ||>150 mg/d ||RBC casts |
|Postrenal ||Variable ||Variable ||Variable ||Minimal ||Bland or RBCs |
Multiple investigations have been undertaken with the goal of finding urinary biomarkers that could herald the onset of AKI prior to an increase in the serum creatinine, analogous to how serum troponins are used in cardiology for early identification of cardiac ischemia. Among the most studied urinary biomarkers for AKI are neutrophil gelatinase-associated lipocalin, and interleukin 18. Though these and other urinary biomarkers for AKI have performed well in some individual studies and in certain populations, none is expected to soon be widely used in clinical practice. Some of the reasons that these urinary biomarkers remain limited to investigational use are that they have performed well mainly in very specific situations (such as postcardiac bypass pediatric patients) and because many are confounded by the presence of pre-existing CKD.
All the urinary parameters discussed in this chapter have limitations. However, when taken together, these parameters can be very useful in arriving at a diagnosis. Beyond this use, rinary tests can assist in determining the cause of AKI, identifying the cause of hyponatremia, diagnosing rhabdomyolysis, and determining the etiology of an acid-base disturbance. Considering the relatively low cost and ease of obtaining most urinary tests, they are an important, and often overlooked, means to obtain important diagnostic information.
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