OBJECTIVES

After completing this chapter, the reader should be able to

  • Describe clinical situations in which blood urea nitrogen and serum creatinine are elevated

  • Discuss the evolving role of cystatin C in estimating glomerular filtration rate

  • Recognize the limitations in the usefulness of the serum creatinine concentration in estimating kidney function

  • Explain the clinical use of the Cockcroft-Gault equation, the Modification of Diet in Renal Disease equation, and the Chronic Kidney Disease Epidemiology Collaboration equation to assess kidney function

  • Determine creatinine clearance given a patient’s 24-hour urine creatinine excretion and serum creatinine

  • Estimate creatinine clearance given a patient’s height, weight, sex, age, and serum creatinine and identify limitations of the methods for estimation of kidney function

  • Recognize the classification of chronic kidney disease, glomerular filtration rate categories, and albuminuria as predictors of disease

  • Discuss the various components assessed by macroscopic, microscopic, and chemical analysis of the urine

  • Describe the role of commonly obtained urinary electrolytes and the fractional excretion of sodium in the diagnostic process

Through the excretion of water and solutes, the kidneys are largely responsible for maintaining homeostasis within the body. They also function in the activation and synthesis of many substances that affect blood pressure (BP), mineral metabolism, and red blood cell (RBC) production. The purpose of this chapter is to provide insight into the interpretation of laboratory tests in the assessment of kidney function as well as provide an overview of the interpretation of a urinalysis.

KIDNEY PHYSIOLOGY

The functional unit of the kidneys is the nephron, and each healthy kidney contains approximately 1 million nephrons. The major components of the nephron include the glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting duct. Afferent arterioles deliver blood to the glomerulus, where it undergoes filtration. Molecular weight and electrical charge affect filtration through glomerular capillary pores. Substances with a molecular weight of <7,000 Da freely cross the filtration barrier. In contrast, plasma proteins, such as albumin (MW 66,000 Da), have particularly low levels of filterability due to their size. As molecular weight increases, the ability to undergo filtration decreases. Most drugs are small enough to be freely filtered at the glomerulus, with the exception of large proteins and drugs bound to plasma proteins. Electrical charge affects macromolecule filtration because the filtration barrier contains fixed polyanions. As a result, negatively charged macromolecules are restricted by the filtration barrier, leading to a lesser extent of filtration compared with positively charged or neutral macromolecules. When there is a loss of negative ionic charge in the filtration barrier from diseases that affect the glomerulus, negatively charged macromolecules, such as albumin, are able to undergo filtration and lead to albuminuria. Smaller molecules, such as mineral anions, are not hindered by the filtration barrier and are freely filtered.1 Additionally, a drug’s volume of distribution (VD) plays a role in clearance. Drugs with a high VD are unlikely to be significantly removed by the kidneys because there are higher concentrations in the extravascular tissue than in the vascular compartment.2

The proximal tubule reabsorbs large quantities of water. As water is reabsorbed back into the blood, sodium passively follows. Other solutes primarily reabsorbed in the proximal tubule include glucose, amino acids, phosphate, uric acid, chloride, bicarbonate, urea, hydrogen, calcium, and magnesium. Water, sodium, calcium, chloride, and magnesium are further reabsorbed in the loop of Henle. The distal tubule regulates the amount of sodium, potassium, bicarbonate, phosphate, and hydrogen that is excreted, and the collecting duct regulates the amount of water in the urine through the action of antidiuretic hormone (ADH), which facilitates water reabsorption.1

Substances can enter the nephron from the peritubular blood or interstitial space via secretion. Additionally, substances may be reabsorbed from the distal tubule back into the systemic circulation via the peritubular vasculature. Tubular secretion occurs via three primary pathways in the proximal tubule: the organic acid transport system, the organic cation transport system, and the organic anion transport system.3 Although each system is somewhat specific for anions and cations, some drugs, such as probenecid, are secreted by both pathways. Creatinine enters the tubule primarily by filtration through the glomerulus. However, a small amount of creatinine is also secreted by the organic cation transport system into the proximal tubule. This becomes important when using renal clearance of creatinine to estimate kidney function.1

The rate of renal blood flow (RBF) is 1 L/min, which represents ~20% of cardiac output. The direct relationship between renal plasma flow (RPF) and RBF and hematocrit (Hct) is described by the following equation4:
RPF=RBF×(1Hct)

The normal value for RPF is ~625 mL/min.4 Of the plasma that reaches the glomerulus, ~20% is filtered and enters the proximal tubule, providing the glomerular filtration rate (GFR). A normal GFR is ~125 mL/min. The GFR is often used as a measure of the degree of kidney excretory function. In the absence of kidney disease, the kidneys filter ~180 L of fluid each day; of this amount, they only excrete ~1.5 L as urine. This amount varies widely depending on fluid intake. Regardless, more than 99% of the initial glomerular filtrate is reabsorbed into the bloodstream. Many solutes, such as creatinine, and many renally eliminated drugs are concentrated in the urine.1

DEFINITION AND CLASSIFICATION OF CHRONIC KIDNEY DISEASE

The classification of chronic kidney disease (CKD) is based on the nature or cause of the abnormality (structure, function), the GFR category (g1 through g5), and the albuminuria category (a1 through a3). The prognostic categories can be found at www.kdigo.org.5 CKD has been defined as GFR <60 mL/min/1.73 m2 for longer than 3 months.5 The use of estimating equations (eGFR) or the measurement of GFR rather than using serum creatinine (SCr) or cystatin C alone can provide the basis for the classification of kidney function. Additionally, markers of kidney damage are used for prognosis of risk, and examples include albuminuria (albumin excretion rate >30 mg/24 h, albumin-to-creatinine [ACR] ratio 30 mg/g), structural (eg, polycystic kidney disease, hydronephrosis, renal artery stenosis), or functional anomalies (eg, urinary sediment such as casts or renal tubular disorders). Risk is categorized as low risk (no markers of kidney disease), moderately increased risk, high risk, and very high risk.5 This information is useful to guide therapy and further monitor CKD complications.

ASSESSMENT OF KIDNEY FUNCTION

Classification of kidney disease and dosing of medications depend on an accurate and reliable method of assessing kidney function.5 Direct measurement of GFR using markers, such as inulin and iothalamate, is the most accurate assessment of kidney function. However, use is not routine in clinical practice because of cost and practical concerns. Measurements of timed 24-hour urine creatinine (UCr) collections are difficult by design, flawed by collection errors, and used only when determination of GFR, and more specifically creatinine clearance (CrCl), are vital and estimating equations are not reliable. Widespread availability of eGFR strengthens its use in determining renal function in pharmacokinetic studies for drug dosing.6,7 However, CrCl, as calculated through equations such as Cockcroft-Gault, is a widely accepted surrogate of GFR and may still be used to assess renal function. Serum concentrations of cystatin C, an endogenous polypeptide, have been evaluated as an alternative method to predict GFR in children and adults.8-10

Estimated GFR was initially validated using the Modification of Diet in Renal Disease (MDRD) equation and was used to stage and monitor CKD.11-15 However, the 2009 CKD Epidemiology Collaboration (CKD-EPI) equation, or an alternative creatinine-based GFR estimating equation with superior accuracy to the CKD-EPI equation, is currently recommended to estimate GFR.5 It is important to note that the MDRD is still used to estimate GFR in many laboratories, and values >60 mL/min may simply be reported as GFR >60 when this equation is used.16 In 2010, the U.S. Food and Drug Administration (FDA) Guidance to Industry draft revision proposed that both eGFR and CrCl be incorporated into package insert dosage recommendations for patients with decreased renal function.17 The use of eGFR to adjust medication doses has become commonplace, with more clinical laboratories reporting eGFR values and pharmacokinetic data referencing both eGFR and CrCl for new medications. It is important to note that use of different equations leads to variation in kidney function estimates, and renal dosing decisions require clinical judgment.

Exogenous Markers

Inulin Clearance

Inulin is a polysaccharide starch, an inert carbohydrate, with a molecular weight of 5,000 Da.1 Inulin is not bound to plasma proteins and is freely filtered through the glomerulus and into the urine without undergoing metabolism, secretion, or reabsorption. As a result, inulin is an ideal marker for measuring GFR in adults and older children.18 Neonates and younger children may present logistical problems in obtaining accurate urine flow rates.14 However, the expensive and cumbersome nature of multiple timed urine collection makes this approach largely impractical.

I-Iothalamate and Iohexol Clearance

Urinary clearance of I-iothalamate and iohexol allows measurement of GFR. Unlike I-iothalamate, iohexol is nonionic and does not undergo active secretion or absorption.19 The test involves injection of the radioactive exogenous marker, repeated blood sampling, and timed urine collection.20 The invasiveness and associated costs prohibit widespread application. As with inulin, the need for intravenous administration and plasma sampling for these markers makes them impractical for routine use.

Endogenous Markers

Cystatin C

Normal reference range21: 18–49 years: 0.63–1.03 mg/L; ≥50 years: 0.67–1.21 mg/L; 0–17 years: Reference values have not been established. Refer to eGFR.

Cystatin C is a low-molecular weight polypeptide produced at a steady state by all nucleated cells. It is filtered by the glomerulus and removed from the bloodstream through degradation via the kidneys.22 As a result, serum cystatin C concentrations are inversely proportional to GFR, and changes in serum concentrations may be an indirect reflection of GFR. It had been originally proposed that cystatin C may be more sensitive than SCr in tracking changes in kidney function because it is less affected by factors like race, age, and sex.23 Combining SCr with cystatin C, age, sex, and race in estimating GFR has provided better results than equations based on a single filtration marker.24 However, limited availability and cost of cystatin C make its use uncommon.

There is conflicting evidence regarding cystatin C in predicting different forms of acute kidney injury (AKI). Compared with creatinine, cystatin C was found to be a better predictor of contrast-induced AKI in patients with CKD.25 Cystatin C was also found to be a useful marker for detecting acute renal failure up to 2 days earlier than SCr in critically ill patients.26 However, previous studies have not captured the benefits of cystatin C to predict AKI in the settings of cardiopulmonary bypass and cardiothoracic surgery.27,28

Cystatin C concentrations have been used in equations for estimating GFR in pediatric patients.8 The use of certified cystatin C concentrations in eGFR equations is evolving rapidly with the relatively recent certification of reference material.29 The National Kidney Disease Education Program (NKDEP) recommends the use of cystatin C equations derived from data with the ERM-DA471/IFCC reference material that has been certified. Currently, it is recommended that inclusion of traceable cystatin C be used in eGFR equations rather than relying on the absolute value in the assessment of CKD.5 Data also support the correlation of elevated cystatin C levels and cardiovascular disease mortality.30 However, current data do not support implementation of cystatin c for the diagnosis of CKD in the primary care setting.31

β-Trace Protein and β-2-Microglobulin

Normal reference range32: men, 0.37-0.77 mg/L; women, 0.40 to 0.70 mg/L

β-trace protein (BTP) and β-2-microglobulin (B2M) are low molecular weight proteins. Similar to cystatin C, BTP and B2M undergo glomerular filtration before reabsorption through the proximal tubule. BTP and B2M do not undergo urinary excretion under normal conditions, and elevated serum concentrations suggest renal impairment.33 In contrast to creatinine, BTP and B2M appear less affected by age, sex, and race.34 However, current data do not support the use of BTP and B2M because they do not provide significant prognostic information and are limited by assay availability, standards, and cost.35

Serum creatinine

Normal range: adults, 0.6 to 1.2 mg/dL (53 to 106 μmol/L); young children, 0.2 to 0.7 mg/dL (18 to 62 μmol/L)

Creatinine and its precursor, creatine, are nonprotein, nitrogenous biochemicals of the blood. After synthesis in the liver, creatine diffuses into the bloodstream. Creatine is then taken up by muscle cells, where some of it is stored in a high-energy form called creatine phosphate. Creatine phosphate acts as a readily available source of phosphorus for regeneration of adenosine triphosphate and is required for transforming chemical energy to muscle action.

Creatinine, which is produced in the muscle, is a spontaneous decomposition product of creatine and creatine phosphate. The daily production of creatinine is ~2% of total body creatine, which remains constant if muscle mass is not significantly changed. In normal patients at steady state, the rate of creatinine production equals its excretion. Therefore, SCr concentrations vary little from day to day in patients with healthy kidneys. Although there is an inverse relationship between SCr and kidney function, SCr should not be the sole basis for the evaluation of renal function.14 Several issues should be considered when evaluating a patient’s SCr. Some of the factors that affect SCr concentrations include muscle mass, sex, age, race, medications, method of laboratory analysis, and low-protein diets. Additionally, acute changes in a patient’s GFR, such as in AKI, may not be initially manifested as an increase in SCr concentration because it takes time for new steady-state concentrations of SCr to be achieved. The time required to reach 95% of steady state in patients with 50%, 25%, and 10% of normal kidney function is about 1, 2, and 4 days, respectively. Steady-state concentrations of SCr become important because they are integral in clinical practice estimations of renal function.

An SCr concentration within the reference ranges as reported by clinical laboratories does not necessarily indicate normal kidney function. For example, an SCr concentration of 1.5 mg/dL in a 45-year-old man who weighs 150 lb and a 78-year-old woman who weighs 92 lb would correspond to different GFRs.

Clinicians can surmise that an increased SCr almost always reflects a decreased GFR in the absence of abnormalities in muscle mass or muscle breakdown (rhabdomyolysis), dietary protein intake, changes in hydration, and intense physical activity. The converse is not always true; a normal SCr does not necessarily imply a normal GFR. As part of the aging process, both muscle mass and renal function diminish. Decreasing amounts of creatinine coupled with a decrease in the kidney’s ability to filter and excrete creatinine may result in an SCr that remains within normal limits. Thus, practitioners should not rely solely on SCr as an index of renal function.

Besides aging and alterations in muscle mass, some pathophysiological changes can affect the relationship between SCr and kidney function. For example, renal function may be overestimated based on SCr alone in patients with cirrhosis. In this patient population, the low SCr is due to a decreased hepatic synthesis of creatine, the precursor of creatinine. In patients with cirrhosis, it is prudent to perform a measured 24-hour CrCl. If a patient also has hyperbilirubinemia, assay interference by elevated bilirubin may also contribute to a low SCr.

Laboratory measurement and reporting of serum creatinine

Historically, the laboratory methods used to measure SCr included the alkaline picrate method, inorganic enzymatic methods, and high-pressure liquid chromatography. The alkaline picrate assay (Jaffe) was the most commonly used method to measure SCr; however, interfering substances, such as noncreatinine chromogens, often led to underestimation of kidney function. Causes of falsely elevated SCr results included unusually large amounts of noncreatinine chromogens (eg, uric acid, glucose, fructose, acetone, acetoacetate, pyruvic acid, and ascorbic acid) in the serum. For example, an increase in glucose of 100 mg/dL (5.6 mmol/L) could falsely elevate SCr by 0.5 mg/dL (44 μmol/L) in some assays. Likewise, serum ketones high enough to spill into the urine may falsely increase SCr and UCr. In patients with diabetic ketoacidosis, a false elevation in SCr could prompt unnecessary evaluation for renal failure when presenting with ketoacidosis. Like ketones, high levels of acetoacetate may cause a falsely elevated SCr after a 48-hour fast or in patients with diabetic ketoacidosis Another endogenous substance, bilirubin, may falsely lower SCr results with both the alkaline picrate and enzymatic assays. At low GFRs, however, creatinine secretion overtakes the balancing effects of measuring noncreatinine chromogens, causing an overestimation of GFRs by as much as 50%.36

Reliable and accurate measurement and subsequent reporting of SCr concentrations is important. The MDRD and CKD-EPI equations use SCr concentrations as one of the variables to stage kidney damage based on the estimation of GFR. The Cockcroft-Gault equation, which depends greatly on the SCr concentration, has been used as the accepted methodology for drug dosing based on an estimation of CrCl.37 The greater the imprecision of the assay, the less accurate the resultant GFR or CrCl estimations. The primary source of measurement errors includes systematic bias and interlaboratory, intralaboratory, and random variability in daily calibration of SCr values. Interlaboratory commutability is also problematic secondary to the variations in assay methodologies. A report from the Laboratory Working Group of the National Kidney Disease Program made recommendations to improve and standardize the measurement of SCr.38,39As of 2011, creatinine standardization is reported to be nationwide (in the United States), and calibration should be traceable to isotope dilution mass spectrometry (IDMS). Of note, SCr concentrations are lower than had been previously reported with older methods. This discrepancy may present a limiting factor in drug dosing for older medications when previous assays had yielded higher creatinine concentrations.

Urea (Blood Urea Nitrogen)

Normal range 8 to 23 mg/dL (2.9 to 8.2 mmol/L)

Blood urea nitrogen (BUN) is the concentration of nitrogen (as urea) in the serum and not in RBCs, as the name implies. Although the renal clearance of urea can be measured, it cannot be used by itself to assess kidney function. Its serum concentration depends on urea production (which occurs in the liver), glomerular filtration, and tubular reabsorption. Therefore, clinicians must consider factors other than filtration when interpreting changes in BUN.

When viewed with other laboratory and clinical data, BUN can be used to assess or monitor hydration, renal function, protein tolerance, and catabolism in numerous clinical settings (Table 10-1).40 Also, it is used to predict the risk of uremic syndrome in patients with severe renal failure. Concentrations above 100 mg/dL (35.7 mmol/L) are associated with this risk.

TABLE 10-1.
Common Causes of True BUN Elevations (Azotemia)

Prerenal causes

 Decreased renal perfusion: dehydration, blood loss, shock, severe heart failure

Intrarenal (intrinsic) causes

 Acute kidney failure: nephrotoxic drugs, severe hypertension, glomerulonephritis, tubular necrosis

 Chronic kidney dysfunction: pyelonephritis, diabetes, glomerulonephritis, renal tubular disease, amyloidosis, arteriosclerosis, collagen vascular disease, polycystic kidney disease, overuse of NSAIDs

Postrenal causes

 Obstruction of ureter, bladder neck, or urethra

Elevated blood urea nitrogen

Urea production is increased by a high-protein diet (including amino acid infusions), upper gastrointestinal (GI) bleeding, and the administration of corticosteroids, tetracyclines, or any other drug with antianabolic effects. Usually, ~50% of the filtered urea is reabsorbed, but this amount is inversely related to the rate of urine flow in the tubules. In other words, the slower the urine flows, the more time the urea has to leave the tubule and reenter surrounding capillaries (reabsorption). Urea reabsorption tends to change in parallel with sodium, chloride, and water reabsorption. Because patients with volume depletion avidly reabsorb sodium, chloride, and water, larger amounts of urea are also absorbed.

Likewise, a patient with a pathologically low BP may develop diminished urine flow secondary to decreased RBF with a subsequently diminished GFR. Congestive heart failure and reduced RBF, despite increased intravascular volume, are common causes of elevated BUN. Types of renal failure that can cause an abnormally high BUN (also called azotemia) are listed in Table 10-1.

Decreased blood urea nitrogen

In and of itself, a low BUN does not have pathophysiological consequences. BUN may be low in patients who are malnourished or have profound liver damage (due to an inability to synthesize urea). Intravascular fluid overload may initially dilute BUN and result in low concentrations. However, many causes of extravascular volume overload, which are associated with third spacing of fluids into tissues (eg, congestive heart failure, renal failure, and nephrotic syndrome), result in an increase in BUN because effective circulating volume is decreased.

Blood urea nitrogen to serum creatinine ratio

Simultaneous BUN and SCr determinations are commonly made and can furnish valuable information to assess kidney function. This is particularly true for AKI. In AKI caused by volume depletion, both BUN and SCr are elevated. However, the BUN:SCr ratio is often >20:1. This observation is due to the differences in the renal handling of urea and creatinine. Recall that urea is reabsorbed with water, and under conditions of decreased renal perfusion, both urea and water reabsorption are increased. Because creatinine is not reabsorbed, it is not affected by increased water reabsorption. Thus, the concentrations of both substances may increase in this setting, but the BUN would be increased to a greater degree, leading to a BUN:SCr >20:1.

In summary, when acute changes in kidney function are observed and both BUN and SCr are greater than normal limits, BUN:SCr ratios >20:1 suggest prerenal causes of acute renal impairment (Table 10-1), whereas ratios from 10:1 to 20:1 suggest intrinsic kidney damage. Furthermore, a ratio >20:1 is not clinically important if both SCr and BUN are within normal limits (eg, SCr = 0.8 mg/dL and BUN = 20 mg/dL) (Minicase 1).

Measurement of Creatinine Clearance

A complete 24-hour urine collection to measure CrCl is preferred over creatinine-based estimating equations in clinical situations of unstable SCr.41 It important to note that if kidney function is unstable, measurement of CrCl by urine collection only reflects the function at the time of the measurement. The National Kidney Foundation indicates that these measured CrCls are not better than the estimates of CrCl provided through recommended equations.5 However, a 24-hour timed urine measurement of CrCl may be useful in the following clinical situations: patients starting dialysis, patients with comorbid medical conditions, evaluation of patient dietary intake, patients with extremes in muscle mass, health enthusiasts taking creatine supplementation, vegetarians, patients with quadriplegia or paraplegia, and patients who have undergone amputation.5

Interpreting Creatinine Clearance Values With Other Renal Parameters

As noted previously, the most common clinical uses for CrCl and SCr are as follows:

  • Assessing kidney function in patients with CKD

  • Monitoring the effects of drug therapy on slowing the progression of kidney disease

  • Monitoring patients on nephrotoxic drugs

  • Determining dosage adjustments for renally eliminated drugs

Because the relationship between SCr and CrCl is inverse and geometric as opposed to linear (Figure 10-1), significant declines in CrCl may occur before SCr rises above the normal range. For example, as CrCl slows, SCr rises little until there is a significant reduction in renal function. Therefore, SCr alone is not a sensitive indicator of early kidney dysfunction.

FIGURE 10-1.
FIGURE 10-1.
This plot represents the inverse relationship between SCr and CrCl. Relatively small changes in SCr at lower levels represent significant change in kidney function as assessed by CrCl.
Calculating creatinine clearance from a timed urine collection

Although shorter collection periods (3 to 8 hours) appear to be adequate and may be more reliable, CrCl is routinely calculated using a 12-hour or 24-hour urine collection. Creatinine excretion is normally 20 to 28 mg/kg/24 h in men and 15 to 21 mg/kg/24 h in women. In children, normal excretion (mg/kg/24 h) should be approximately 15+ (0.5 × age), in which age is in years.

Estimating Equations for GFR

Marisela F., a 58-year-old woman (non–African American), arrives for routine follow-up after a recent diagnosis of type 2 diabetes mellitus. Her laboratory test results were as follows:

  • Sodium, 138 mEq/L (136 to 145 mEq/L)

  • Potassium, 4 mEq/L (3.5 to 5 mEq/L)

  • Chloride, 102 mEq/L (96 to 106 mEq/L)

  • Carbon dioxide, 25 mEq/L (24 to 30 mEq/L)

  • Magnesium, 1.8 mEq/L (1.5 to 2.2 mEq/L)

  • Glucose, 280 mg/dL (70 to 110 mg/dL)

  • BUN, 19 mg/dL (8 to 20 mg/dL)

  • SCr, 0.9 mg/dL (0.7 to 1.5 mg/dL)

  • Urinary albumin: 1 mg

  • Urinary creatinine: 18.5 g

  • HbA1c, 11.4 (4% to 5.6%)

She is currently taking the following medications:

  • Chlorthalidone 25 mg PO daily

  • Metformin 1,000 mg PO twice daily

Her vital signs and information were as follows: height 5′5″; weight 125 lb; body mass index 20.8; BP 160/96 mm Hg; heart rate 94 beats/min; respiratory rate 18 beats/min; and temperature 101.6°F.

QUESTION: Which equation should be used to evaluate eGFR?

DISCUSSION: The CKD-EPI equation is preferred because it has greater accuracy compared with the MDRD equation. Using the 2009 CKD-EPI equation (12), the calculated eGFR for this patient is 71 mL/min/1.73 m2 (stage G2). The MDRD equation is known to underestimate renal function for patients with an eGFR >60 mL/min/1.73 m2, which may lead to falsely identifying patients with CKD. The CKD-EPI equation is more accurate when looking at an eGFR >60 mL/min/1.73 m2.

QUESTION: How should the ACR be interpreted?

DISCUSSION: The ACR is 54 mg/g, which is elevated (≤30 mg/g). An elevated ACR may reflect damage to the glomerulus. However, the presence of fever, marked hyperglycemia as evidenced by the glucose and hemoglobin A1c, and elevated blood pressure may increase the ACR independently of kidney damage. Multiple abnormal readings are required to confirm albuminuria, and repeat testing is recommended.5 If there was documentation of several abnormal ACR results over at least 3 months, the patient’s albuminuria would be classified as category A2 (moderately increased) based on a finding of 54 mg/g.

QUESTION: How should the BUN:SCr ratio be interpreted?

DISCUSSION: The BUN:SCr ratio is >20:1. However, this ratio is not clinically significant because both the BUN and SCr are within normal limits. If one or both of the results were elevated, a BUN:SCr >20:1 would suggest a prerenal cause of acute renal impairment.

Because its excretion remains relatively consistent within these ranges, UCr is often used as a check for completion of urine collection. In adults, some clinicians discount a urine sample if it contains <10 mg of creatinine/kg/24 h and assume that the collection was incomplete. However, 8.5 mg/kg/day might be a better cutoff, especially in critically ill elderly patients. UCr assays are affected by most of the same substances that affect SCr. To interfere significantly, however, the substance must appear in the urine in concentrations at least equal to those found in the blood.

Measured CrCl is calculated using the following formula:
CrCl (mL/min/1.73m2)= [UCr×V]/[Scr×T]×1.73BSA

where CrCl is the CrCl in mL/min/1.73 m2, UCr is urine creatinine concentration (mg/dL), V is volume of urine produced during the collection interval (mL), SCr is serum creatinine concentration (mg/dL), T is time of the collection interval (minutes), and BSA is body surface area (m2).

BSA can be estimated using the standard method of Dubois and Dubois42:
BSA(m2)=0.20247×height (m)0.725×weight (kg)0.425
BSA also can be estimated using the following equations from Mosteller43:
BSA (m )=[height(cm)×weight(kg)]/3,600
BSA (m2)=[height(in)×weight(lb)]/3,131

Adjustment of eGFR to a standard BSA (1.73 m2) allows direct comparison with normal CrCl ranges because such tables are in units of milliliters per minute per 1.73 m2. The CrCl value adjusted for BSA is the number of milliliters cleared per minute for each 1.73 m2 of the patient’s BSA. Therefore, such adjustment in a large person (>1.73 m2) reduces the original nonadjusted clearance value because the assumption is that clearance would be lower if the patient were smaller. In practice, de-indexed values in which CrCl is in millimeters per minute should be used, and adjustment for body size is accomplished through a weight-based equation.

Estimation of Creatinine Clearance

In practice, dosage recommendations for medications excreted through the kidneys have been traditionally based on the Cockcroft-Gault estimation of CrCl. With the implementation of standardized reporting of creatinine values, calculated CrCl values may be 5% to 20% higher and may not correlate with dosage guidelines based on renal dose adjustments on creatinine values from older assays.

Cockcroft-Gault equation

This formula provides an estimation of CrCl.37 The patient’s age, body weight, and SCr concentration are necessary for the estimation. There is some controversy regarding which type of patient weight (total body weight [TBW], ideal body weight [IBW], adjusted body weight [ABW]) to use in the formula. Each weight affects the CrCl differently and may be preferred in certain situations over others. TBW may underestimate CrCl in underweight patients. In contrast, IBW was more accurate than TBW in normal weight patients. If TBW is less than IBW, use TBW to calculate CrCl. Lastly, ABW using a factor of 0.4 was found to be the least biased and most accurate method in patients who are obese because TBW overestimates the CrCl in this situation.44

Additional attempts to improve the Cockcroft-Gault equation include rounding the SCr when values are <1.0 mg/dL. By rounding the SCr to 1.0 mg/dL, the calculated CrCl is lower than the value given by using the actual SCr. A lower CrCl may lead to more conservative drug dosing. However, rounding of SCr has resulted in significant underestimation of CrCl.45,46 The results of a meta-analysis suggest that actual SCr most closely estimates CrCl.47 Based on the available data, rounding of SCr in elderly patients should be considered on a case-by-case basis because of limited evidence that this approach improves accuracy. Conflicting data exist for using lean body weight (LBW) to improve CrCl calculation in patients who are overweight, obese, or morbidly obese. Without clinical validation, both rounding of SCr and using lean body weight should be used cautiously.46

Additionally, this equation should be used cautiously in patients with unstable renal function. Instead, other methods, like cystatin C and the 6-variable MDRD equations, may provide more accurate results in critically ill patients with fluctuating renal function, but validation is lacking.48
CrCl(mL/min)=(140age)×weight(kg)72×SCr(mg/dL)×0.85(iffemale)

Body Weights Used with the Cockcroft-Gault Equation

Weight (kg)

Calculation

TBW

Total body weight

IBW (male)

(2.3 x inches > 5 feet) + 50 kg

IBW (female)

(2.3 x inches > 5 feet) + 45.5 kg

ABW

IBW (kg) + 0.4 x (TBW (kg) – IBW (kg))

To illustrate the variations in CrCl based on different weights, consider a 50-year-old man with the following information: height 72″ (182.88 cm); weight 115 kg; BMI 34.3; SCr 1.7 mg/dL. The CrCl would be 84.6 mL/min with TBW, 57.1 mL/min using IBW, and 68.1 mL/min using ABW. These differences may affect diagnosis of CKD and renal dose adjustments for certain medications. Because the patient is obese, CrCl using TBW may overestimate the CrCl, whereas using ABW may provide a more accurate calculation.

Estimation of Glomerular Filtration Rate–Modification of Diet in Renal Disease Equation

The MDRD equation had been developed as a tool to identify patients at risk for complications arising from CKD.14,49 (See Table 10-2 for the stages of CKD.) Although the CKD-EPI equation is largely considered more accurate and less biased than the MDRD equation, some laboratories still use the MDRD equation for reporting eGFR. The MDRD equation provides an estimated GFR, which was developed using measured GFR I-iothalamate reference values in patients with CKD. The abbreviated MDRD equation has been reexpressed to include standardized SCr traceable to IDMS values.11,39,50-52 Patients at age extremes may be particularly vulnerable to errors of estimated GFR.9,13 In addition, results of the MDRD equation should be interpreted cautiously in patients with low muscle mass (eg, cachectic patients) or those with unstable renal function.

TABLE 10-2.
Chronic Kidney Disease Stages

STAGE

GFR (ML/MIN/1.73 M2)

INTERPRETATION

1*

>90

Normal or high GFR

2*

60–89

Mildly decreased

3

A 45–59

B 30–44

Mildly to moderately decreased

Moderately to severely decreased

4

15–29

Significantly decreased

5

<15

Kidney failure

*In the absence of kidney damage, neither GFR category G1 nor G2 fulfil the criteria for CKD.

Source: Adapted with permission from Levey AS, Stevens PE, Bilous RW, et al. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. https://kdigo.org/guidelines/ckd-evaluation-and-management.

One well-known limitation identified with the MDRD equation is underestimation of renal function for patients with eGFR >60 mL/min/1.73 m2.53 Because this study did not include patients with normal kidney function, the MDRD equation is considered particularly less accurate at higher GFRs.54 This can lead to more patients being falsely identified with CKD. In these populations, the Kidney Disease: Improving Global Outcomes (KDIGO) working group recommends the measurement of cystatin C or direct measurement of CrCl when SCr concentration is less accurate.5

The original MDRD equation was also known as the 6-variable MDRD because it was based on six variables that included age, sex, ethnicity, SCr, urea, and albumin.11 The simplified 4-variable MDRD, shown below, uses four variables that include age, sex, ethnicity, and a revised calibration for SCr:
GFR(mL/min/1.73m2)=175×standardizedSCr(1.154)×age(0.203)×1.212(ifAfricanAmerican)×0.742(if female)

Estimation of Glomerular Filtration Rate–Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation 2009

Introduced in 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is also based on standardized SCr, age, sex, and race. This equation performs with the same degree of accuracy as the MDRD equation for patients with eGFR <60 mL/min/1.73 m2.55,56 However, it corrects the inadequacy of the MDRD equation, which leads to underestimations in patients with eGFR >60 mL/min/1.73 m2. Both the CKD-EPI and the MDRD equations account for age of the patient. Like all SCr-based equations, the Cockcroft-Gault, MDRD, and CKD-EPI equations succumb to the same inherent problems associated with this endogenous surrogate marker (ie, the formula should not be used in patients with unstable renal function). At the same SCr, younger patients who have more muscle mass have a higher GFR than older adults with low muscle mass. The usefulness of the CKD-EPI equation may be particularly evident in younger patients without kidney disease, younger patients with type 1 diabetes without microalbuminuria, or persons considering kidney donation with GFR rates approximating normal values. Additionally, data support its advantage over Cockcroft-Gault and MDRD in prognostic value in predicting cardiovascular mortality.57 KDIGO currently recommends the CKD-EPI equation to estimate GFR.5,55,56:
GFR (mL/min/1.73 m2)=141×min(Sc/κ,l)α×max(Sc/κ,l)1.209×0.993age×1.018(iffemale)×1.159(if African American)

where Sc = standardized SCr, κ = 0.7 for women and 0.9 for men, α = −0.329 for women and −0.411 for men, min indicates the minimum of Sc/κ or 1, and max indicates the maximum of Sc/κ or 1.

Cystatin C Equations

Recently, there has been calibration and standardization of traceable cystatin C concentrations to international reference standards. The 2012 NKF KDOQI Clinical Practice Guidelines for the Evaluation and Management of CKD recommend measuring cystatin C in adults with eGFR between 45 and 59 mL/min/1.73 m2 who do not have confirmatory kidney damage.5 The measurements of IDMS traceable cystatin C concentrations are not universally available in many community settings.

2012 Chronic Kidney Disease Epidemiology Collaboration Cystatin C Equation5:

133×min(SCysC/0.8,1)0.499×max (SCysC/0.8,1)0.1328×0.996age×0.932(if female)

where SCysC is serum cystatin C (in mg/L), min indicates the minimum of SCysC/0.8 or 1, and max indicates the maximum of SCysC/0.8 or 1.

2012 Chronic Kidney Disease Epidemiology Collaboration Creatinine–Cystatin C Equation5:

135×min (SCr/k,1)α×max (SCr/k,1)0.601×min (SCysC/0.8,1)0.375×max (SCysC/0.8,1)0.711×0.995age×(0.969 if female)×(1.08if African American)

where SCr is serum creatinine (in mg/dL), SCysC is serum cystatin C (in mg/L), k is 0.7 for women and 0.9 for men, α is −0.248 for women and −0.207 for men, min(SCr/k, 1) indicates the minimum of SCr/k or 1, max(SCr/k, 1) indicates the maximum of SCr/k or 1, min(SCysC/0.8, 1) indicates the minimum of SCysC/0.8 or 1, and max(SCysC/0.8, 1) indicates the maximum of SCysC/0.8 or 1.

Clinical controversy: Cockcroft-Gault versus estimated glomerular filtration rate equations

The appropriate dosing of renally eliminated medications is necessary to prevent overdosage or underdosage. Overdosage of a medication can cause significant clinical consequences and contribute to poor patient outcomes. Similarly, underdosing medications can lead to therapeutic failures. In both scenarios, inappropriate medication dosing can lead to increased length of stay, higher healthcare costs, and preventable medication-related problems. The MDRD equation provides a more accurate estimation of kidney excretory function than the Cockcroft-Gault equation.11,58,59 At this time, the optimal single best equation that can be used universally in all populations does not exist.

The usefulness of the MDRD equation in staging kidney disease is indisputable. Recently, manufacturers have provided some dosage guidance based on eGFR for patients with deteriorating kidney function. Recent studies support the agreement of the MDRD equation with measured GFR and FDA-assigned kidney function categories for medication dose adjustment.60 The NKDEP in 2009 suggested the use of either the CrCl as estimated by Cockcroft-Gault or the eGFR for dosing medications in CKD for most patients.61 However, this is controversial because most renal drug dosing is still based on CrCl. An important caveat that is often overlooked in the NKDEP recommendation is that the eGFR needs to be individualized in patients at the extremes in body size by multiplying the eGFR/1.73 m2 by patient BSA to convert units to milliliters per minute:
IndividualizedMDRD=eGFR/1.73m2×estimatedBSA(m2)=eGFRfordrugdosing

Alternatively, in patients who are considered to be high risk for adverse medication events, who are taking drugs that have a narrow therapeutic index, or in whom estimations of kidney function vary or are inaccurate, consider measuring CrCl or GFR using exogenous markers.5 The Nephrology Practice and Research Network of the American College of Clinical Pharmacy has suggested an algorithm for dosing medications eliminated by the kidneys using SCr-based equations.62 Additionally, safety and efficacy considerations affect decisions regarding dosing of renally eliminated medications that include both patient factors (clinical condition, cachexia) and drug-specific properties (therapeutic index). In summary, individualized patient characteristics and the specific clinical situation necessitate medication dosing decisions based on benefits and risks rather them numbers purely derived from generalized equations.

MEDICATION SAFETY

Pharmacists are responsible for optimizing the use of medications in their patients. Medications eliminated by the kidneys require caution in patients with acute kidney disease and CKD because the need for modifying the drug dose, extending the dosing interval, discontinuing use, and totally avoiding nephrotoxic drugs must be considered. Drug manufacturers provide drug information for use in patients with diminished renal function. Serum levels of medications that depend on renal elimination can be elevated, contributing to the increased likelihood of drug toxicity and subsequent adverse drug reactions. As mentioned, the use of eGFR estimating equations or direct measurements of CrCl, where appropriate, can provide important information for medication use and drug dosing. In situations in which SCr is not suitable, consider the use of a cystatin C equation (Equation 14).5 Ensuring appropriate medication use and dosing in patients with acute kidney disease and CKD is one of the major contributions made by pharmacists. In acute kidney disease, temporarily hold administration of drugs that may contribute to or exacerbate kidney damage. Table 10-3 identifies medication safety considerations for use in patients with acute or chronic kidney disease. However, specific medication recommendations from more than one reference should be reviewed before committing to dosing decisions (Minicase 2).

TABLE 10-3.

Medication Safety in Patients with CKD

AGENTS

CAUTIONARY NOTES

Antihypertensives/cardiac medications

RAAS antagonists

  (ACE-I, ARB, aldosterone antagonists, direct renin inhibitors)

  • Avoid in people with suspected functional renal artery stenosis

  • Start at lower dose in people with GFR <45 mL/min/1.73 m2

  • Assess GFR and measure serum potassium within 1 wk of starting or following any dose escalation

  • Temporarily suspend during intercurrent illness, planned IV radiocontrast administration, bowel preparation prior to colonoscopy, or before major surgery

  • Do not routinely discontinue in people with GFR <30 mL/min/1.73 m2 because they remain nephroprotective

 β-blockers

 Digoxin

  • Reduce dose by 50% in people with GFR <30 mL/min/1.73 m2

  • Reduce dose based on plasma concentrations

Analgesics

 NSAIDs

  • Avoid in people with GFR <30 mL/min/1.73 m2

  • Prolonged therapy is not recommended in people with GFR <60 mL/min/1.73 m2

  • Should not be used in people taking lithium

  • Avoid in people taking RAAS blocking agents

 Opioids

  • Reduce dose when GFR <60 mL/min/1.73 m2

  • Use with caution in people with GFR <15 mL/min/1.73 m2

Antimicrobials

 Penicillin

  • Risk of crystalluria when GFR <15 mL/min/1.73 m2 with high doses

  • Neurotoxicity with benzylpenicillin when GFR <15 mL/min/1.73 m2 with high doses (maximum 6 g/day)

 Aminoglycosides

  • Reduce dose and increase dosage interval when GFR <60 mL/min/1.73 m2

  • Monitor serum levels (trough and peak)

  • Avoid concomitant ototoxic agents such as furosemide

 Macrolides

  • Reduce dose by 50% when GFR <30 mL/min/1.73 m2

 Fluoroquinolones

  • Reduce dose by 50% when GFR <15 mL/min/1.73 m2

 Tetracyclines

  • Reduce dose when GFR <45 mL/min/1.73 m2; can exacerbate uremia

 Antifungals

  • Avoid amphotericin unless no alternative when GFR <60 mL/min/1.73 m2

  • Reduce maintenance dose of fluconazole by 50% when GFR <45 mL/min/1.73 m2

  • Reduce dose of flucytosine when GFR <60 mL/min/1.73 m2

Hypoglycemics

 Sulfonylureas

  • Avoid agents that are mainly renally excreted (eg, glyburide/glibenclamide)

  • Other agents that are mainly metabolized in the liver may need reduced dose when GFR <30 mL/min/1.73 m2 (eg, gliclazide, gliquidone)

 Insulin

  • Partly renally excreted and may need reduced dose when GFR <30 mL/min/1.73 m2

 Metformin

  • Suggest avoiding when GFR <30 mL/min/1.73 m2 but consider risk–benefit if GFR is stable

  • Review use when GFR <45 mL/min/1.73 m2

  • Probably safe when GFR ≥45 mL/min/1.73 m2

  • Suspend in people who become acutely unwell

 GLP-1 RA1

  • Renal dose adjustment required (exenatide, lixisenatide)

  • Caution when initiating or increasing dose due to potential risk of AKI

  • Benefit in slowing progression of diabetic kidney disease with liraglutide

 SGLT2i1

  • Renal dose adjustment required

  • Benefit in slowing progression of diabetic kidney disease with canagliflozin, empagliflozin, dapagliflozin

  • Talk about cutoffs with the four

Lipid-lowering

 Statins

  • No increase in toxicity for simvastatin dosed at 20 mg per day or simvastatin 20 mg/ezetimide 10-mg combinations per day in people with GFR <30 mL/min/1.73 m2 or on dialysis83

  • Other trials of statins in people with GFR <15 mL/min/1.73 m2 or on dialysis also showed no excess toxicity

 Fenofibrate

  • Increases SCr by ~0.13 mg/dL (12 μmol/L)

Chemotherapeutic

 Cisplatin

  • Reduce dose when GFR <60 mL/min/1.73 m2

  • Avoid when GFR <30 mL/min/1.73 m2

 Melphalan

  • Reduce dose when GFR <60 mL/min/1.73 m2

 Methotrexate

  • Reduce dose when GFR <60 mL/min/1.73 m2

  • Avoid if possible when GFR <15 mL/min/1.73 m2

Anticoagulants

 Low-molecular-weight heparins

  • Halve the dose when GFR <30 mL/min/1.73 m2

  • Consider switch to conventional heparin or alternatively monitor plasma antifactor Xa in persons at high risk for bleeding

 Warfarin

  • Increased risk of bleeding when GFR <30 mL/min/1.73 m2

  • Use lower doses and monitor closely when GFR <30 mL/min/1.73 m2

 DOAC

  • Edoxaban is not approved for patients with poor renal function (CrCl <30 mL/min) or upper range renal function (CrCl >95 mL/min)

  • Renal dose adjustment needed at different CrCl levels based on each DOAC and specific indication due to lack of clinical trial data on safety or efficacy in patients with advanced CKD

Miscellaneous

 Lithium

  • Nephrotoxic and may cause renal tubular dysfunction with prolonged use even at therapeutic levels

  • Monitor GFR, electrolytes, and lithium levels monthly or more frequently if the dose changes or the patient is acutely unwell

  • Avoid using concomitant NSAIDs

  • Maintain hydration during intercurrent illness

  • Risk–benefit of drug in specific situation must be weighed

 Radiocontrast agents

  • Use with caution in advanced renal disease

  • Iodinated and ionic iodinated contrast media may cause acute renal failure as serious adverse effect

  • Iodinated and ionic iodinated contrast media contraindicated in severe CKD (GFR <30 mL/min/1.73 m2) or in AKI

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; DOAC = direct oral anticoagulant; GLP-1 RA = glucagon-like peptide-1 receptor agonists; KDIGO = Kidney Disease: Improving Global Outcomes; RAAS = renin-angiotensin-aldosterone system.

Data as of January 2013.

Source: Reproduced with permission from KDIGO5; adapted from References 6368.

URINALYSIS

Urinalysis is a commonly used clinical tool for the evaluation of various renal and nonrenal problems (eg, endocrine, metabolic, and genetic). A routine urinalysis is performed as a screening test during many hospital admissions and initial physician visits. It is also performed periodically in patients in nursing homes and other settings. The most common components of the urinalysis are discussed here.

An accurate interpretation of a urinalysis can be made only if the urine specimen is properly collected and handled. Techniques are fairly standardized and, keeping in mind that urine is normally sterile, aim to avoid contamination by normal flora of the external environment (mucous membranes of the vagina or uncircumcised penis or by microorganisms on the hands). Therefore, these areas are cleansed and physically kept away from the urine stream. During menses or heavy vaginal secretions, a fresh tampon should be inserted before cleansing.

A first-morning, midstream collection is customarily used as the specimen.69 Once voided, the urine should be brought to the laboratory as soon as possible to prevent deterioration. If the sample is not refrigerated, bacteria multiply and use glucose (if present) as a food source. Subsequently, glucose concentrations decrease and ketones may evaporate with prolonged standing. Another problem is that formed elements (see Microscopic Analysis section) begin decomposing within 2 hours. With excessive exposure to light, bilirubin and urobilinogen are oxidized. Unlike other substances, however, protein is minimally affected by prolonged standing.

Heart Failure

Elle K., an 83-year-old woman with a long history of congestive heart failure, is admitted to the hospital with reports of shortness of breath (she has been sleeping in her recliner and is unable to sleep in her bed despite using two pillows), a 15-lb weight gain, and fluid retention in her lower extremities. She also has anorexia, nausea, fatigue, and weakness. All have worsened over the past 2 weeks.

Physical examination reveals a frail (5′3″, 78 kg) woman in moderate distress; heart rate 108 beats/min; BP 96/60 mm Hg; S3/S4 heart sounds; and +3 pitting edema bilateral lower extremities. Chest radiograph reveals bilateral pleural effusions. Past medical history is significant for hypertension, osteoarthritis of the knee, and atrial fibrillation.

Her current medications include the following:

  • Lisinopril, 20 mg PO daily

  • Metoprolol succinate, 100 mg PO daily

  • Furosemide, 40 mg PO daily

  • KCl, 10 mEq PO twice daily

  • Ibuprofen, 400 mg PO four times daily PRN for knee pain

Laboratory test results are as follows:

  • Sodium, 130 mEq/L (136 to 142 mEq/L)

  • Potassium, 3.2 mEq/L (3.8 to 5 mEq/L)

  • Chloride, 96 mEq/L (95 to 103 mEq/L)

  • Carbon dioxide, 30 mEq/L (24 to 30 mEq/L or mmol/L)

  • Magnesium, 1.6 mEq/L (1.3 to 2.1 mEq/L)

  • Glucose, 78 mg/dL (70 to 110 mg/dL)

  • Hgb, 11.5 g/dL (12.3 to 15.3 g/dL)

  • BUN, 76 mg/dL (8 to 23 mg/dL)

  • SCr, 2.5 mg/dL (0.6 to 1.2 mg/dL)

  • BNP, 1,200 pg/mL (<100 pg/mL)

  • Urinalysis, normal

Over the next 2 days, Elle K. receives aggressive diuretic therapy (intravenous [IV] furosemide 80 mg twice a day), and all electrolyte abnormalities were corrected. Her physical exam results were much improved, and she was no longer short of breath.

On the morning of day 4, her laboratory results were as follows:

  • Sodium, 135 mEq/L

  • Potassium, 3.2 mEq/L

  • Chloride, 100 mEq/L

  • Carbon dioxide, 34 mEq/L

  • Magnesium, 1.4 mEq/L

  • Glucose, 80 mg/dL

  • Hgb, 11.4 g/dL

  • BUN, 40 mg/dL

  • SCr, 1.9 mg/dL

  • BNP, 400 pg/mL

QUESTION: What type of renal dysfunction was this patient experiencing on admission to the hospital? What are the likely causes of her elevated BUN and SCr? Which formula would be best to estimate CrCl or eGFR?

DISCUSSION: This is a rather complex case because of the involvement of the kidneys in heart failure. Initially, the elevated BUN and SCr could be attributed to a prerenal state secondary to increased edema (hypervolemia) caused by worsening heart failure. This is supported by her clinical presentation (weight gain, symptoms of heart failure, chest X-ray, elevated BNP, and an elevated BUN:SCr ratio with a ratio of >20:1). A normal urinalysis would not reveal any cells that may indicate an intrinsic AKI (see Urinalysis section). Additionally, diuretics may increase BUN, which may complicate the picture, but the other evidence supports the diagnosis of prerenal azotemia. Assessment of kidney function on day 1 is difficult because the Cockcroft-Gault, MDRD, or CKD-EPI equation should not be used in patients with acute alterations in kidney function. In suspected cases of AKI and when there is a need to assess GFR, measurement of CrCl through collection of urine may be considered; however, this technique is associated with significant limitations in the setting of rapidly changing renal function.

QUESTION: What factors may have contributed to this patient’s heart failure exacerbation?

DISCUSSION: She has several risk factors that can worsen heart failure. She has a history of hypertension and atrial fibrillation. If her osteoarthritis has worsened, she may have been using more ibuprofen more frequently and for an extended period of time. Additional risk factors that could also contribute to exacerbation of heart failure include nonadherence to medications (eg, furosemide) and noncompliance with fluid (2 L) and diet (2 g sodium/day) restriction recommendations.

QUESTION: What other electrolyte abnormalities have resulted?

DISCUSSION: Several electrolyte abnormalities were identified during initial presentation and subsequent laboratory analysis: increased BUN and SCr, increased serum bicarbonate, hypokalemia, hypomagnesemia, and hyponatremia. On admission, worsening heart failure resulted in decreased RBF. As with creatinine, there will be a reduction in BUN filtration at the glomerulus; however, urea is avidly reabsorbed in the proximal tubule (following sodium and water), resulting in an elevated ratio of BUN out of proportion to the creatinine (>20:1). This patient also presented initially with hypervolemic hyponatremia, most likely caused by worsening heart failure, diminished blood flow to the kidneys, peripheral edema, and subsequent weight gain. As she becomes euvolemic, the hyponatremia will gradually be corrected. After aggressive diuresis with IV furosemide, hypokalemia and hypomagnesemia require replacement therapy. Loop diuretics can also cause metabolic alkalosis (increased serum bicarbonate). Overaggressive diuresis can cause elevations in BUN and SCr without evidence of overt heart failure.

After a urine sample is collected, it may undergo three types of testing: macroscopic, microscopic, and chemical (dipstick).

Macroscopic Analysis (General Appearance)

The color of normal urine varies greatly—from totally clear to dark yellow or amber—depending on the concentration of solutes. Color comes primarily from the pigments urochrome and urobilin. Fresh normal urine is not cloudy or hazy, but urine may become cloudy if urates (in an acid environment) or phosphates (in an alkaline environment) crystallize or precipitate out of solution. These salts become less soluble as the urine cools from body temperature.

Turbidity may also occur when large numbers of RBCs or white blood cells (WBCs) are present. An unusual amount of foam may be from protein or bile acids. Table 10-4 lists causes of different urine colors. Some of the changes noted may be urine pH–dependent. In general, drug-induced changes in urine color are fairly rare. Drugs that cause or exacerbate any of the medical problems listed in Table 10-4 can also be considered indirect causes of discolored urine.

TABLE 10-4.

Potential Causes of Various Urine Coloring

COLOR

CAUSE

POSSIBLE UNDERLYING ETIOLOGIES

Red to orange

Myoglobin

Crush injuries, electric shock, seizures, cocaine-induced muscle damage, rhabdomyolysis

Hemoglobin/erythrocytes

Hemolysis (malaria, drugs, strenuous exercise), menstrual contamination; kidney stones

Porphyrins

Porphyria, lead poisoning, liver disease

Drugs/chemicals

Drugs/chemicals causing previously mentioned diseases; as dyes: rifampin, isoniazid, riboflavin, sulfasalazine, warfarin, chlorpromazine, thioridazine, phenazopyridine, daunorubicin, doxorubicin, phenolphthalein, phenothiazines, senna, chlorzoxazone, hydroxocobalamin

Food

Beets, rhubarb, blackberries, cold drink dyes, carrots

Blue to green

Biliverdin

Oxidation of bilirubin (poorly preserved specimen)

Bacteria

Pseudomonas or Proteus in urinary tract infections (rare), particularly in urine drainage bags

Drugs/chemicals

As dyes: amitriptyline, azuresin, methylene blue, Clorets abuse, Clinitest ingestion, mitoxantrone, triamterene, resorcinol, promethazine, cimetidine, amitriptyline, metoclopramide, indomethacin, and propofol

Brown to black

Myoglobin

Crush injuries, electric shock, seizures, cocaine-induced muscle damage, rhabdomyolysis

Bile pigments

Hemolysis, bleed into tissues, liver disease

Melanin

Melanoma (prolonged exposure to air)

Methemoglobin

Methemoglobinemia from drugs, dyes

Porphyrins

Porphyria and sickle cell crisis

Drugs/chemicals

As dyes: cascara, chloroquine, clofazimine, emodin, senna; as chemicals: ferrous salts, methocarbamol, metronidazole, nitrofurantoin, sulfonamides, sorbitol, α-methyldopa, statins, l-dopa

Source: Adapted from References 7073.

Microscopic Analysis (Formed Elements)

Microscopic analysis typically involves the following steps71:

  • Centrifuging the urine (12 mL) at 2,000 revolutions per minute for 5 minutes

  • Pouring off all “loose” supernatant

  • Mixing the sediment with the residual supernatant

  • Examining the resulting suspension under 400 to 440× magnification (also described as high-power field)

Microscopic analysis can be done either routinely or selectively. In either case, one should look for the three “Cs”—cells, casts, and crystals.

Cells

Theoretically, no cells should be seen during microscopic examination of urine. In practice, however, an occasional cell or two is found. These cells include microorganisms, RBCs, WBCs, and tubular epithelial cells.

Microorganisms (normal range: zero to trace)

If bacteria are found in the urine sediment, contamination should be the first consideration. Of course, fungi, bacteria, and other single-cell organisms can be seen in patients with a urinary tract infection (UTI) or colonization. Even if ordered, some laboratories do not perform urine cultures unless there is significant bacteriuria. Significant bacteriuria may be defined as an initial positive dipstick screen for leukocyte esterase and nitrites (Chemical Analysis section). Likewise, some laboratories do not process cultures further (eg, identification, quantification, and susceptibility) if more than one or two different bacterial species are seen on initial plating. Additionally, some laboratories do not perform susceptibility testing if more than one organism (some more than two) is isolated or if <100,000 (some use 50,000 as the cutoff) colony-forming units (CFU) per milliliter per organism are measured with a midstream, clean-catch sample. The common cutoff for urine obtained through a catheter is <10,000 CFU/mL/organism. If multiple types of bacteria are present, contamination by flora from vaginal, rectal, hand, skin, or other body site is assumed.

Red blood cells (erythrocytes) (normal range: one to three per high-power field)

Hematuria is the abnormal renal excretion of erythrocytes detected in two of three urine samples. A few RBCs are occasionally found in the urine of a healthy man or woman, particularly after exertion, trauma, or fever. If persistent, even small numbers (more than two to three per high-powered field) may reflect urinary tract pathology. Increased numbers of RBCs are seen (among others) in glomerulonephritis, infection (pyelonephritis), renal infarction or papillary necrosis, tumors, stones, and coagulopathies. In some of these disorders, hematuria may turn the urine pink or red (gross hematuria). If a specimen is not collected properly, vaginal blood may contaminate the urine.

White blood cells (leukocytes) (normal range: zero to two per high-power field)

Potentially significant pyuria has been defined as three or more WBCs per high-power field of centrifuged urine sediment. Pyuria is usually associated with UTIs (upper or lower). However, inflammatory conditions (glomerulonephritis, interstitial nephritis) may also lead to this finding.71,72

Epithelial cells (normal range: zero to one per high-power field)

Epithelial cells may be categorized as either squamous or nonsquamous. Squamous cells originate from the surfaces of external genitalia and the lower urinary tract. Presence of a large number of squamous epithelial cells usually suggests specimen contamination.74,75

Tubular epithelial cells (normal range: zero or one per high-power field)

One epithelial cell per high-power field is often found in normal subjects. Cells originating from the renal tubules are small, oval, and mononuclear. Nonsquamous epithelial cells include transitional cells and renal tubular epithelial cells, and their presence indicates acute tubular necrosis, acute interstitial nephritis, and proliferative glomerulonephritis.75 Their quantity increases dramatically when the tubules are damaged (eg, acute tubular necrosis) or when there is inflammation from interstitial nephritis or glomerulonephritis.71

Casts

Casts are cylindrical masses of glycoproteins (eg, Tamm-Horsfall mucoprotein) that form in the tubules. Casts have relatively smooth and regular margins (as opposed to clumps of cells) because they conform to the shape of the tubular lumen. Under certain conditions, casts are released into the urine (called cylindruria). Even normal urine can contain a few clear casts. These formed elements are fragile and dissolve more quickly in warm, alkaline urine. Types include hyaline, cellular, granular, and waxy (broad); their causes are listed in Table 10-5.

TABLE 10-5.
Causes of Various Types of Casts in Urine

CAST

CAUSE

Red blood cell

Classically seen with acute glomerulonephritis; can be seen in patients who play contact sports and uncommonly with tubular interstitial disease

White blood cell

Classically seen with urinary tract infections and cystitis; also seen with glomerulonephritis and interstitial nephritis

Squamous epithelial cell

Nonspecific and may not be pathologic; seen with perineal or vaginal specimen contamination in females or foreskin contamination in males

Tubular epithelial cell

Nonspecific; acute tubular necrosis, glomerulonephritis, tubulointerstitial disease; also seen with cytomegalovirus infection and toxicity from salicylates and heavy metals, ethylene glycol

Hyaline

Nonspecific and may not be pathologic; seen with prerenal azotemia and strenuous exercise

Granular

Nonspecific but pathologic; may be seen in acute tubular necrosis; volume depletion, glomerulonephritis, tubulointerstitial disease

Waxy (broad)

Nonspecific but pathologic; may be seen with advanced or chronic renal failure

Source: Adapted with permission from References 71,72,74.
Hyaline casts

Being clear, hyaline casts are difficult to observe under a microscope and are, by themselves, not indicative of disease. Hyaline casts can be seen in concentrated urine or with the use of diuretics.72,75

Cellular casts

In contrast to hyaline casts, cellular casts are seen with intrinsic renal disease. They form when leukocytes, RBCs, or renal tubular epithelial cells become entrapped in the gelatinous matrix forming in the tubule. Their clinical significance is the same as that of the cells themselves; unlike free cells, however, cells in casts originate from within the kidneys. The identification of a particular cast-type is often used to assist in diagnosis. WBC casts suggest intrarenal inflammation (eg, acute interstitial nephritis) or pyelonephritis. Epithelial cell casts suggest tubular destruction; they may also be noted in glomerulonephritis. RBC casts are seen in glomerulonephritis.71,75

Granular and waxy casts

Granular and waxy casts are older, degenerated forms of the other types. Granular (also called muddy brown) casts can be seen in many conditions, such as acute tubular necrosis, glomerulonephritis, and tubulointerstitial disease. Because waxy casts occur in many diseases, they do not offer much diagnostic information.71,75

Crystals

The presence of crystals in the urine depends on urinary pH, the degree of saturation of the urine by the substance that is forming crystals, and the presence of other substances in the urine that may promote crystallization. Numerous types of crystals can be detected in the urine (Figure 10-2). Crystalluria, if differentiated by type, can help identify patients with certain local and systemic diseases. Cystine crystals occur with the condition cystinuria, and struvite (magnesium ammonium phosphate) crystals are seen with struvite stones. Calcium oxalate, calcium phosphate, and uric acid crystals are also suggestive of stones. Many crystals can be detected in otherwise healthy patients.70,75

FIGURE 10-2.
FIGURE 10-2.
Inorganic elements that may be found in urinary sediment. Elements founds in alkaline urine are shown in the top half of the figure; those found in acidic urine are represented in the bottom half of the figure. Source: Reprinted with permission from Runge MS, Greganti MA. Netter’s Internal Medicine. 2nd ed. Philadelphia, PA: Saunders; 2008:766. Copyright© 2008. Netter medical illustration used with permission of Elsevier. All rights reserved.

CHEMICAL ANALYSIS (SEMIQUANTITATIVE TESTS, URINE DIPSTICK TESTS)

For this discussion, biochemical analysis of urine includes protein; pH; specific gravity; bilirubin, bile, and urobilinogen; blood and hemoglobin; leukocyte esterase; nitrite; glucose; and ketones. These semiquantitative tests can be performed quickly using modern dipsticks containing one or more reagent-impregnated pads. When using these strips, the clinician must carefully apply the urine to the pads as instructed and wait the designated time before comparing pad colors to the color chart. Possible results associated with various colors are displayed in Table 10-6.

TABLE 10-6.

Examples of Tests Available and Possible Results from Multitest Urine Dipstick (Bayer Multistix 10 SG)

TEST

RESULT

Leukocyte esterase

Negative

Trace

Small +

Moderate ++

Large +++

Nitrite

Negative

Positive

Urobilinogen

Normal 0.2 mg/dL

Normal 1 mg/dL

2 mg/dL

4 mg/dL

8 mg/dL

Protein

Negative

Trace

30 mg/dL +

100 mg/dL ++

300 mg/dL +++

2,000 mg/dL ++++

pH

5

6

6.5

7

7.5

8

8.5

Blood (Hgb)

Negative

Nonhemolyzed trace

Hemolyzed trace

Small +

Moderate ++

Large +++

Specific gravity

1.000

1.005

1.010

1.015

1.020

1.025

1.030

Ketones

Negative

Trace 5 mg/dL

Small 15 mg/dL

Moderate 40 mg/dL

Large 80 mg/dL

Large 160 mg/dL

Bilirubin

Negative

Small +

Moderate ++

Large +++

Glucose

Negative

1/10 g/dL (trace) 100 mg/dL

1/4 g/dL 250 mg/dL

1/2 g/dL 500 mg/dL

1 g/dL 1,000 mg/dL

2 g/dL 2,000 mg/dL

Source: Adapted with permission from Multistix (various) Reagent Strips [product information]. Elkhart, IN: Bayer HealthCare LLC; 2005.

Protein

Normal range: zero to trace on dipstick or <200 mg/g (urine protein to creatinine ratio)

The normal urinary proteins are albumin and low molecular weight serum globulins. However, albumin has a molecular weight of 66,000 Da and is typically restricted from passing through the glomerulus into the urine. The smaller serum globulins that are filtered in the nephron are generally reabsorbed in the proximal tubule. Therefore, healthy individuals excrete small amounts of protein in the urine (80 to <150 mg of protein per day). In the presence of kidney damage, larger quantities of protein may be excreted. Increased excretion of albumin is associated with diabetic nephropathy, glomerular disease, and uncontrolled hypertension. If low molecular globulins are detected, it is more likely a tubulointerstitial process. The term proteinuria is a general term that refers to the renal loss of protein (albumin and globulins). The term albuminuria specifically refers to the abnormal renal excretion of albumin. Clinical proteinuria is defined as the loss of >500 mg/day of protein urine. Patients with microalbuminuria are excreting relatively small, but still pathogenic, amounts (30 to 300 mg/day) of albumin. Common causes of proteinuria are listed in Table 10-7. It should be noted that proteinuria is sometimes intermittent and is not always pathologic (eg, after exercise and fever).

TABLE 10-7.

Causes of Proteins in Urine

Mild proteinuria (<0.5 g/day)

 High blood pressure

 Lower UTI

 Fever

 Renal tubular damage

 Exercise

Moderate proteinuria (0.5–3 g/day)

 Congestive heart failure

 Chronic glomerulonephritis

 Acute glomerulonephritis

 Diabetic nephropathy

 Pyelonephritis

 Multiple myeloma

 Preeclampsia of pregnancy

 Rhabdomyolysis

Significant proteinuria (>3 g/day)

 Glomerulonephritis

 Amyloid

 Chronic glomerulonephritis (severe)

 Diabetic nephropathy

 Lupus nephritis

 Rhabdomyolysis

Source: Adapted with permission from Sacher RA, McPherson RA. Laboratory assessment of body fluids. Widmann’s Clinical Interpretation of Laboratory Tests. 11th ed. Philadelphia, PA: FA Davis Company; 2000:924–1014; Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62–72.

Because of difficulties with overnight and 24-hour collections, KDIGO recommends spot (untimed) urine testing. The ACR ratio is convenient and accounts for urine volume effects on protein concentration and standardizes the protein or albumin excretion to creatinine excretion. The ratio of protein (or albumin) to creatinine in an untimed urine sample is an accurate estimate of the total amount of protein (or albumin) excreted in the urine over 24 hours.5 The current criteria for staging and prognosis of CKD recommends testing for albuminuria. The KDIGO working group recommends the urine ACR ratio as the preferred method to assess for kidney damage in addition to estimation of GFR. Like GFR, albuminuria should be assessed at least annually in patients with CKD and more frequently in high-risk populations in whom measurements may affect clinical decisions.5

Color indicator test strips (eg, Albustix, Multistix) used to detect and measure protein in the urine contain a buffer mixed with a dye (usually tetrabromophenol blue). In the absence of albumin, the buffer holds the pH at 3, maintaining a yellow color. If albumin is present, it reduces the activity coefficient of hydrogen ions (the pH rises), producing a blue color. Of note, these tests are fairly insensitive to the presence of low molecular globulins, including the Bence-Jones protein. Results can be affected by the urinary concentration. At both extremes of urinary concentrations, false-positive and false-negative results may occur. The potential for this can be easily assessed if specific gravity is measured concomitantly. Substances that cause abnormal urine color may affect the readability of the strips, including blood, bilirubin, phenazopyridine nitrofurantoin, and riboflavin.78 Standard dipsticks do not detect microalbuminuria; however, newer dye-impregnated strips are available that can detect lower concentrations of albumin. The KIDIGO recommends confirming positive albuminuria test strips with quantitative laboratory measurements as a ratio to creatinine when possible.5

pH

Normal range: 4.6 to 8

Sulfuric acid, resulting from the metabolism of sulfur-containing amino acids, is the primary acid generated by the daily ingestion of food. The pH is usually estimated in 0.5-unit increments by use of test strips containing methyl red and bromthymol blue indicators. These strips undergo a series of color changes from orange to blue over a pH range of 5 to 8.5. Additionally, pH can be precisely measured with electronic pH meters. Normally, the kidneys can eliminate the acid load by excreting acid itself and sodium hydroxide ions. In fact, healthy persons can acidify urine to pH 4.5, although the average pH is around 6. Any pH close to the reference range can be interpreted as normal as long as it reflects the kidneys’ attempts at regulating blood pH. Urinary pH can be affected by the various acid–base disorders. Determination of the urinary pH is often used in the setting of a UTI.74,75 In general, acidic (versus neutral) urine deters bacterial colonization. Alkaline urine may be seen with either UTIs caused by urea-splitting bacteria, such as Proteus mirabilis (via ammonia production), or tubular defects causing decreased net tubular hydrogen ion secretion, as in renal tubular acidosis.

By their intended or unintended pharmacological actions, drugs can also cause true pH changes; they do not interfere with the reagents used to estimate urine pH. Drugs that induce diseases associated with pH changes are indirect causes. These and other causes of acidic and alkaline urine are listed in Table 10-8. Persistent pHs >7 are associated with calcium carbonate, calcium phosphate, and magnesium–ammonium phosphate stones; pHs <5.5 are associated with cystine and uric acid stones.

TABLE 10-8.

Factors Affecting Urine pH

URINE PH AND FACTORS

CAUSES AND COMMENTS

Alkaline

 Postprandial

Specimens voided shortly after meals

 Vegetarianism

Vegetables do not produce fixed acid residues

 Alkalosis (metabolic or respiratory)

Hyperventilation, severe vomiting, GI suctioning

 UTI

Some bacteria (eg, Proteus) split urea to ammonia, which is alkalinizing

 Renal tubular acidosis

Impaired tubular acidification of urine and low bicarbonate and pH in blood

 Drugs

Acetazolamide, bicarbonate salts, thiazides, citrate, and acetate salts

Acidic

 Drugs

Ammonium chloride, ascorbic acid (high dose), methenamine

 Food

Cranberries, prunes, plums, fruit juices

 Ketoacidosis

Diabetes mellitus, starvation, high fever

 Metabolic acidosis

Increased ammonium excretion and cellular hypoxia with lactic acid production (shock)

 Sleep

Mild respiratory acidosis

Source: Adapted with permission from Sacher RA, McPherson RA. Laboratory assessment of body fluids. Widmann’s Clinical Interpretation of Laboratory Tests. 11th ed. Philadelphia, PA: FA Davis Company; 2000:924–1014; McPherson RA, Ben-Ezra J, Zhao S. Basic examination of urine. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 21st ed. Philadelphia, PA: Saunders Elsevier; 2007:393–425.

Specific Gravity

Normal range: 1.016 to 1.022 (normal fluid intake)

The kidneys are responsible for maintaining the blood’s osmolality within a narrow range (285 to 300 mOsm/kg). To do so, the kidneys must vary the osmolality of the urine over a wide range. Although osmolality is the best measure of the kidneys’ concentrating ability, determining osmolality is difficult. Fortunately, it correlates well with specific gravity when urine contains normal constituents. Specific gravity is the ratio of the weight of a given fluid to the weight of an equal volume of distilled water. Sodium, urea, sulfate, and phosphate contribute most to the specific gravity of urine. Because specific gravity is related to the weight (and not the number) of particles in solution, particles with a weight different from that of sodium chloride (the solute usually in the highest concentration there) can widen the disparity. Patients with normal kidney function can dilute urine to approximately 1.001 and concentrate urine to 1.035, which correlates to an osmolality of 50 to 1,000 mOsm/kg, respectively. A urinary specific gravity of 1.010 is considered isosthenuric; that is, the urinary osmolality is the same as plasma.71,72,74

Specific gravity can be measured by reagent strips (dipstick), a urinometer (hydrometer), or a refractometer. The reagent strips change color based on the pKa change of the strips in relation to the ionic concentration of the urine. The indicator substance on the strip changes color, which can be then correlated to the specific gravity. Specific gravity measured by reagent strips is not affected by high concentrations of substances such as glucose, protein, or radiographic contrast media, which may elevate readings with refractometers and urinometers. The urinometer is akin to a graduated buoy; it requires sufficient urine volume to float freely. The reading is adjusted according to the urine temperature. The refractometer uses the refractive index as a basis and needs only a few milliliters of urine and no temperature adjustment.71,72,74

Several conditions can affect specific gravity. In general, urinary specific gravity should be considered abnormal if it is the opposite (high versus low and vice versa) of that which should be produced based on the concurrent plasma osmolality. Patients who are volume depleted should present with a concentrated urine (specific gravity ≥1.020) as a normal compensatory mechanism. Patients with prerenal disease will likely have relatively concentrated urine, whereas patients with intrinsic damage to the renal tubules are more likely to produce urine, which is isosthenuric (the tubules are unable to dilute or concentrate the urine, so the urine is the same concentration as the filtrate). The urine of patients with diabetes insipidus has low values (<1.005) despite a relatively hypertonic plasma. On the other hand, patients with the syndrome of inappropriate syndrome of antidiuretic hormone (SIADH) have concentrated urine and relatively hypotonic serum.71,72,74

Urobilinogen

Normal range: 0.3 to 1 Ehrlich unit

Urobilinogen (formed by bacterial conversion of conjugated bilirubin in the intestine) is normally present in urine and increases when the turnover of heme pigments is abnormally rapid, as in hemolytic anemia, congestive heart failure with liver congestion, cirrhosis, viral hepatitis, and drug-induced hepatotoxicity. Elevated urobilinogen may be premonitory of early hepatocellular injury, such as hepatitis, because it is evident in urine before serum bilirubin levels increase. Alkaline urine is also associated with increased urobilinogen concentrations caused by enhanced renal elimination. Urobilinogen may decrease (if previously elevated) in patients started on antibiotics (eg, neomycin, chloramphenicol, and tetracycline) that reduce the intestinal flora producing this substance. Urobilinogen is usually absent in total biliary obstruction because the substance cannot be formed. Increased urobilinogen in the absence of bilirubin in the urine suggests a hemolytic process.

Bilirubin

Normal range: negative

A dark yellow or greenish-brown color generally suggests bilirubin in the urine (bilirubinuria). Most test strips rely on the reaction between bilirubin with a diazotized organic dye to yield a distinct color. Bilirubinuria may be seen in patients with intrahepatic cholestasis or obstruction of the bile duct (stones or tumor). False-negative results may occur in patients taking ascorbic acid.

Blood and Hemoglobin

Normal range: negative

Dipsticks for blood depend on the oxidation of an indicator dye due to the peroxidase activity of hemoglobin. A dipstick test can detect as few as one to two RBCs per high-power field. Even small amounts of blood noted on dipstick require further investigation. It is important to note that in addition to hemoglobin, myoglobin can also catalyze this reaction so that a positive dipstick result for blood may indicate hematuria (blood), hemoglobinuria (free hemoglobin in urine), or myoglobinuria. Microscopic examination of the urine is needed to distinguish hematuria. The presence of ascorbic acid in the urine may lead to a false-negative result with these tests, which is usually associated with a fairly large oral intake of vitamin C.72,74,78

Hemoglobinuria suggests the presence of intravascular hemolysis or directed damage to the small blood vessels. The presence of myoglobin in the urine is highly suggestive of rhabdomyolysis, the acute destruction of muscle cells. With rhabdomyolysis, myoglobin is cleared rapidly by the kidneys and can be detected in the urine.72

The clinical distinction between hematuria, hemoglobinuria, and myoglobinuria is important because the clinical conditions that cause them are very different. The color of the urine is not specific; all three may lead to red or dark brown urine. As noted with dipsticks for blood, all three conditions lead to a positive test result. Microscopic analysis demonstrates many more erythrocytes with hematuria, but RBCs can be seen with hemoglobinuria and myoglobinuria. Erythrocytes may be few in hematuria because of lysis of the RBCs if the urine has a low specific gravity (<1.005).

Leukocyte Esterase

Normal range: negative to trace

Many dipsticks can detect leukocyte esterase, give a semiquantitative estimate of pyuria (pus in the urine), and thus be considered an indirect test for UTIs. The presence of esterase activity correlates well with significant numbers of neutrophils (either present or lysed) in the urine. The leukocyte esterase test is important because the presence of actual neutrophils in the urine is not a specific indicator for UTI.72,74

Nitrite

Normal range: negative

The presence of nitrite in the urine is another indirect indicator of a UTI. Many organisms, such as Escherichia coli, Klebsiella, Enterobacter, Proteus, Staphylococcus, and Pseudomonas, are able to reduce nitrate to nitrite; thus, a positive urine test result would suggest a UTI. If nitrite-positive, a culture of the urine should be obtained. A first-morning urine specimen is preferred because an incubation period is necessary for bacteria to convert urinary nitrate to nitrite. A positive test result is suggestive of a UTI, but a negative test result cannot rule out a UTI (ie, the test is specific but not highly sensitive). False-positive test results may be caused by strips that are exposed to air. False-negative results occur with infections caused by non–nitrite-producing organisms (Enterococcus).72,74

Glucose and Ketones

Normal range: none

Although glucose is filtered in the glomerulus, it is almost completely reabsorbed in the proximal tubule so that glucose is generally absent in the urine. However, at glucose concentrations >180 mg/dL, the capacity to reabsorb glucose is exceeded and glycosuria occurs. Glucose in the urine is suggestive of diabetes mellitus although other less common conditions can cause glycosuria.

Additionally, certain medications may cause intentional glycosuria through their mechanism of action. One notable example includes the sodium-glucose cotransporter 2 inhibitor (SGLT2i) drug class, which is indicated primarily for type 2 diabetes mellitus but is supported by an increasing body of evidence for use in heart failure with reduced ejection fraction.79 SGLT2i are proteins located on the proximal convoluted tubule that are responsible for ~90% of filtered glucose reabsorption. SGLT2i prevent glucose reabsorption and facilitate excretion in the urine, resulting in intended glycosuria.80,81 As a result of various factors that affect or cause glycosuria, use of urinary glucose to screen and monitor for diabetes is no longer a standard of care.72,74,75

Ketones in the urine typically indicate a derangement of carbohydrate metabolism resulting in use of fatty acids as an energy source. Ketonuria in association with glucose in the urine is suggestive of uncontrolled type 1 diabetes mellitus. Ketonuria can also occur with pregnancy, carbohydrate-free diets, and starvation. Aspirin has been reported to cause a false-negative ketone test result, whereas levodopa and phenazopyridine may cause false-positive ketone results (Minicase 3).72,74,75

Urinary Electrolytes

Like most laboratory tests, urinary electrolytes are rarely definitive for any diagnosis. They can confirm suspicions of a particular medical problem from the history, physical examination, and other laboratory data. Along with the results of a urinalysis and serum electrolytes, urinary electrolyte tests allow the practitioner to rule in or out possible diseases of the differential diagnosis. These tests are relatively simple to perform and widely used in the clinical setting.

Glycosuria/Ketonuria

Mason L. is a 20-year-old man who presents to an urgent care facility with reports of fatigue and nausea. He notes losing 10 lb despite experiencing increased appetite and thirst over the past 3 months. He describes increased frequency of urination but denies any pain or burning sensations upon voiding.

URINALYSIS

RESULT

REFERENCE STANDARD/RANGES

Color

Yellow

Yellow

Specific gravity

1.020

1.016–1.022

Ketones

5+

Negative

Glucose

4+

Negative

pH

5

4.6–8

Blood

Negative

Negative

Protein

Negative

Negative

Nitrite

Negative

Negative

Leukocyte esterase

Negative

Negative-trace

Bacteria

0

0-trace

WBC

0

0-2/HPF

RBC

1/HPF

1-3/HPF

Epithelial cells

0

0-1/HPF

QUESTION: What condition is suggested by the patient’s presentation and urinalysis results?

DISCUSSION: The patient requires further evaluation for type 1 diabetes mellitus and diabetic ketoacidosis. Glycosuria suggests diabetes mellitus because glucose is usually completely reabsorbed in the proximal tubule. Reports of polyphagia, polydipsia, and polyuria are hallmark characteristics of hyperglycemia. Type 1 diabetes mellitus is typically diagnosed in children, teens, and young adults. The presence of ketones suggests uncontrolled type 1 diabetes mellitus because of improper carbohydrate metabolism. The subsequent catabolism of fatty acids for energy leads to weight loss. Along with ketonuria, the patient’s symptoms of fatigue and nausea prompt concerns for diabetic ketoacidosis.

“Normal” values for urinary electrolytes are a bit of a misnomer because the kidneys should be retaining or excreting electrolytes based on intake and any endogenous production. Any concentration in the urine is normal if it favors a normal fluid and serum electrolyte status. A related test, the urinary fractional excretion of sodium (%FENa), can assist with common diagnostic dilemmas involving the kidneys’ ability to regulate electrolytes.

Urinary Sodium and Potassium

The electrolyte that is most commonly measured in urine is sodium. Occasionally, it is useful to measure potassium and chloride. For these electrolytes, there is no conversion factor to International System (SI) units because milliequivalents per liter are equivalent to millimoles per liter.

Sodium

Normal range: varies widely

Regulation of urinary excretion of sodium maintains an effective systemic circulating volume. For this reason, the urinary sodium concentration is often used to assess volume status in a patient. Less often, a 24-hour assessment of sodium excretion (via a urine collection) can be used to assess adherence to sodium restriction in a patient with hypertension and heart failure.82,83 This is because the total urinary sodium excretion should equal the amount of sodium taken in through the diet. For example, a patient following a low-sodium diet should ingest <90 mEq (90 mmol) of sodium per day and would, therefore, have a 24-hour urine sodium <90 mEq (90 mmol) per day if the patient is following the diet accurately. Sodium and water balance is an extremely complex process, and only the most common disorders that may alter sodium and water balance (and hence urine sodium) are discussed here.

Hyponatremia is the most common electrolyte disorder seen in clinical practice, and it is most often observed in volume depletion (GI loss and diuretics) and in SIADH, which is not uncommon. In particular, SIADH can be seen in elderly patienets who are maintained on drugs known to cause excess secretion of ADH, such as selective serotonin reuptake inhibitors. Urine sodium concentrations of <20 mEq/L generally suggest volume depletion—the kidneys are responding to the low volume by reabsorbing sodium. In the case of SIADH, which is characterized by inappropriate retention of water in the distal tubule, the urine sodium is generally >20 to 40 mEq/L.

Hypernatremia is less common and occurs when there is limited access to free water because otherwise healthy adults become thirsty in the face of hypernatremia. Diabetes insipidus, which is characterized by a decreased production or response to ADH, is another cause of hypernatremia. With diabetes insipidus, the urine sodium concentration is low despite the presence of clinical euvolemia. This is due to dilution of the urinary sodium secondary to inappropriate loss of water in the urine.83,84

Urine sodium concentrations are also useful in the diagnosis of AKI. In the presence of prerenal azotemia, urine sodium concentrations are low because of the kidneys’ attempt to maintain volume and blood flow to the kidneys. On the other hand, with acute tubular necrosis, the urinary sodium is generally >40 mEq/L because the damaged renal tubules are unable to reabsorb sodium and concentrate urine.83 The fractional excretion of sodium (FENa) may be used to test the resorptive function of renal tubules. Diuretics can also interfere with the assessment of urinary sodium. Even with volume depletion, urinary sodium levels can be high due to the effect of the diuretic on renal sodium handling.83

%FENa test
Although assessment of urine sodium concentrations is useful in determining volume status, concentration of sodium in the urine is affected by the degree of water reabsorption in the tubules. The FENa is the percentage of sodium (fraction) that is filtered in the glomerulus that eventually is excreted in the urine and corrects for the amount of water in the filtrate. An FENa can be estimated from a spot (random) urine sample with a concomitant serum sample. The calculation is as follows:
FENa(%) =(UNa×SCrSNa×UCr)×100

where UNa and SNa are urine and serum sodium in milliequivalents per liter or millimoles per liter and UCr and SCr are in milligrams per deciliter or micromoles per liter.

In the face of AKI, the FENa can be useful to discriminate between a prerenal process (ie, volume depletion) and acute tubular necrosis. In the hypovolemic, prerenal state, the kidneys conserve sodium and the FENa is <1%. With tubular damage, the FENa generally is >2% to 3%. As with the assessment of urine sodium, the FENa can be affected by diuretic therapy and may be somewhat high despite volume depletion.82,83

Potassium

Normal range: varies widely

As is the case with sodium, urinary excretion of potassium varies based on dietary intake and other factors that may affect serum potassium concentrations. For patients with unexplained hypokalemia, urinary potassium may provide useful information. Concentrations >10 mEq/L in a hypokalemic patient usually mean that the kidneys are responsible for the loss. This may occur with potassium-wasting diuretics, high-dose sodium penicillin therapy (eg, ticarcillin/clavulanate and piperacillin/tazobactam), metabolic acidosis or alkalosis, and renal tubular acidosis. Concomitant hypokalemia and low urinary potassium (<10 mEq/L) suggest GI loss (including chronic laxative abuse) as the cause of low serum potassium. In the setting of hyperkalemia, assessment of urinary potassium concentrations is less useful. Hyperkalemia is often due to kidney failure (with or without drugs that affect potassium homeostasis), so potassium concentrations in the urine would be low.83 A 24-hour urine potassium measurement or the transtubular potassium gradient (TTKG) may be used to differentiate between renal and nonrenal causes of potassium abnormalities. The TTKG measures potassium secretion by the distal nephron corrected for urine osmolality:
TTKG=(Ku/Ks)×(Sosm /Uosm)

where Ku and Ks are the concentrations of potassium in the urine and serum and Sosm and Uosm are the osmolarities of the serum and urine, respectively.85,86 A TTKG value of <6 suggests a renal cause of hyperkalemia, whereas values >6 may indicate extrarenal causes of hyperkalemia, such as increased potassium intake, acidosis, or rhabdomyolysis.87

SUMMARY

The kidneys play a major role in the regulation of fluids, electrolytes, and the acid–base balance. Kidney function is affected by the cardiovascular, pulmonary, endocrine, and central nervous systems. Therefore, abnormalities in these systems may be reflected in renal or urine tests. Urinalysis is useful as a mirror for organ systems that generate substances (eg, blood/biliary system and urobilinogen) ultimately eliminated in the urine. Urinalysis allows indirect examination without invasive procedures.

A rise in BUN without a simultaneous rise in SCr is not specific for kidney dysfunction. However, concomitant elevations in BUN and SCr almost always reflect some disturbance in the kidneys’ ability to clear substances from the body. Renal functions should be estimated based on a patient’s SCr and demographic characteristics using either the 2009 CKD-EPI or Cockcroft-Gault equation. These equations are a more reliable index of kidney function than SCr alone. Evolving evidence may show better estimation of GFR with creatinine–cystatin-C equations.88 A thoughtful examination of urine (macroscopic, microscopic, and chemical) is an indispensable tool in identifying kidney and other pathologic processes that may be present in a patient.

ACKNOWLEDGMENTS

The authors acknowledge the contributions of Dr. Dominick P. Trombetta, who authored this chapter in previous editions of this textbook.

LEARNING POINTS

1. What is the relevance in knowing the eGFR?

ANSWER: The importance is in the assessment of whether the GFR is stable or changing. Classification of kidney disease is based on estimates of GFR and ranges of albuminuria, and it identifies patients who need to be under the care of nephrologists. Also, changes in GFR may be reflective of worsening disease severity. Many medications are eliminated by renal excretion. Inappropriate use of nephrotoxic drugs or inappropriate dosing in patients with reduced renal function as evidenced by low eGFR may contribute to adverse drug reactions. The eGFR may assist the pharmacist in assessing medication use and determining dose and frequency adjustment. Lastly, staging may help identify appropriate screening for other conditions and comorbidities, such as anemia and mineral and bone disorder, and prepare patients for dialysis.

2. Which is better to use for drug dosing, the Cockcroft-Gault, MDRD, or CKD-EPI equation?

ANSWER: Either the CrCl using Cockcroft-Gault equation or the eGFR multiplied by BSA may be used to calculate drug doses for most patients. In some cases, manufacturer labeling provides specific renal dose adjustments in terms of eGFR, such as for metformin and SGLT2 inhibitors; others use CrCl as calculated by Cockcroft-Gault equation. Consider measuring CrCl for patients who are considered at high risk (very young and very old patients), for patients receiving drugs that have a narrow therapeutic index, or for patients in whom estimations of kidney function vary or are likely to be inaccurate. This is especially important in assessing patients for kidney transplant.

3. What is the clinical significance of measuring albuminuria?

ANSWER: Under normal conditions, a small amount of total body albumin is filtered by the kidneys. The filtered albumin and low molecular weight serum globulins are then generally reabsorbed in the proximal tubule, which means only small amounts are detected in the urine. The presence of albumin in the urine may suggest glomerular dysfunction, and albuminuria and GFR categories are used to classify CKD. Additionally, the category of albuminuria should be considered when assessing CKD prognosis. The ACR ratio is recommended to assess kidney damage in addition to the GFR. However, proteinuria may be intermittent and benign when caused by transient factors. As a result, evaluating other causes and arranging confirmatory testing may be recommended to distinguish between benign and pathologic albuminuria.

REFERENCES

  • 1.

    Eaton DC, Pooler J. Vander’s Renal Physiology. 9th ed. New York, NY: McGraw-Hill; 2009.

  • 2.

    Holford NHG. Pharmacokinetics and pharmacodynamics: rational dosing and the time course of drug action. In: Katzung BG, ed. Basic and Clinical Pharmacology. 14th ed. New York, NY: McGraw-Hill; 2018: Chapter 3, 41-55.

    • Search Google Scholar
    • Export Citation
  • 3.

    Dowling T. Evaluation of kidney. In: DiPiro JT, Yee GC, Posey L, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. New York, NY: McGraw-Hill; 2020: Chapter 59 Evaluation of kidney function.

    • Search Google Scholar
    • Export Citation
  • 4.

    Barrett KE, Barman SM, Brooks HL, Yuan JXJ. Ganong’s Review of Medical Physiology. 26th ed. New York, NY: McGraw-Hill; 2019.

  • 5.

    Levey AS, Stevens PE, Bilous RW, et al. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf. Accessed Apr 18, 2020.

  • 6.

    Hudson JQ, Nolin TD. Pragmatic use of kidney function estimates for drug dosing: the tide is turning. Adv Chronic Kidney Dis. 2018;25(1):14-20.PubMed

    • Search Google Scholar
    • Export Citation
  • 7.

    Matzke GR, Aronoff GR, Atkinson AJ Jr, et al.Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11):1122-1137.PubMed

    • Search Google Scholar
    • Export Citation
  • 8.

    Zappitelli M, Parvex P, Joseph L, et al.Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis. 2006;48(2):221-230.PubMed

    • Search Google Scholar
    • Export Citation
  • 9.

    Zappitelli M, Joseph L, Gupta IR, et al.Validation of child serum creatinine-based prediction equations for glomerular filtration rate. Pediatr Nephrol. 2007;22(2):272-281.PubMed

    • Search Google Scholar
    • Export Citation
  • 10.

    Shlipak MG, Mattes MD, Peralta CA. Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis. 2013;62(3):595-603.PubMed

    • Search Google Scholar
    • Export Citation
  • 11.

    Levey AS, Coresh J, Greene T, et al.Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-254.PubMed

    • Search Google Scholar
    • Export Citation
  • 12.

    Brosius FC 3rd, Hostetter TH, Kelepouris E, et al.Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney And Cardiovascular Disease Council; the Councils on High Blood Pressure Research, Cardiovascular Disease in the Young, and Epidemiology and Prevention; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: developed in collaboration with the National Kidney Foundation. Circulation. 2006;114(10):1083-1087.PubMed

    • Search Google Scholar
    • Export Citation
  • 13.

    Lamb EJ, Webb MC, Simpson DE, et al.Estimation of glomerular filtration rate in older patients with chronic renal insufficiency: is the modification of diet in renal disease formula an improvement? J Am Geriatr Soc. 2003;51(7):1012-1017.PubMed

    • Search Google Scholar
    • Export Citation
  • 14.

    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266.PubMed

    • Search Google Scholar
    • Export Citation
  • 15.

    Counahan R, Chantler C, Ghazali S, et al.Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child. 1976;51(11):875-878.PubMed

    • Search Google Scholar
    • Export Citation
  • 16.

    The Renal Association. About eGFR. https://renal.org/information-resources/the-uk-eckd-guide/about-egfr. Accessed Sep 24, 2020.

  • 17.

    U.S. Food and Drug Administration. Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on doing and labeling, draft guidance. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm204959.pdf. Accessed Apr 18, 2020.

  • 18.

    Inker LA, Levey AS. Assessment of glomerular filtration rate in acute and chronic settings. In: Gilbert SJ, Weiner DE, Gipson DS, et al., eds. Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014:26-32.

    • Search Google Scholar
    • Export Citation
  • 19.

    Delanaye P, Ebert N, Melsom T, et al.Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 1: How to measure glomerular filtration rate with iohexol? Clin Kidney J. 2016;9(5):682-699.PubMed

    • Search Google Scholar
    • Export Citation
  • 20.

    Papadakis MA, McPhee SJ, Rabow MW. Current Medical Diagnosis and Treatment 2020. 59th ed. New York, NY: McGraw-Hill; 2020.

  • 21.

    Mayo Clinic, Mayo Clinical Laboratories. Cystatin C with estimated GFR serum. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/35038. Accessed Apr 7, 2020.

  • 22.

    Perkins BA, Nelson RG, Ostrander BE, et al.Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol. 2005;16(5):1404-1412.PubMed

    • Search Google Scholar
    • Export Citation
  • 23

    , Nicoll D, Lu CM, McPhee SJ. Guide to Diagnostic Tests. 7th ed. New York, NY: McGraw-Hill; 2017.

  • 24.

    Stevens LA, Coresh J, Schmid CH, et al.Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis. 2008;51(3):395-406.PubMed

    • Search Google Scholar
    • Export Citation
  • 25.

    Briguori C, Visconti G, Rivera NV, et al.Cystatin C and contrast-induced acute kidney injury. Circulation. 2010;121(19):2117-2122.PubMed

    • Search Google Scholar
    • Export Citation
  • 26.

    Herget-Rosenthal S, Marggraf G, Hüsing J, et al.Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004;66(3):1115-1122.PubMed

    • Search Google Scholar
    • Export Citation
  • 27.

    Wald R, Liangos O, Perianayagam MC, et al.Plasma cystatin C and acute kidney injury after cardiopulmonary bypass. Clin J Am Soc Nephrol. 2010;5(8):1373-1379.PubMed

    • Search Google Scholar
    • Export Citation
  • 28.

    Koyner JL, Bennett MR, Worcester EM, et al.Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery. Kidney Int. 2008;74(8):1059-1069.PubMed

    • Search Google Scholar
    • Export Citation
  • 30.

    Menon V, Shlipak MG, Wang X, et al.Cystatin C as a risk factor for outcomes in chronic kidney disease. Ann Intern Med. 2007;147(1):19-27.PubMed

    • Search Google Scholar
    • Export Citation
  • 31.

    Shardlow A, McIntyre NJ, Fraser SDS, et al.The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: a primary care cohort study. PLoS Med. 2017;14(10):e1002400.PubMed

    • Search Google Scholar
    • Export Citation
  • 32.

    Donadio C, Bozzoli L. Urinary β-trace protein: a unique biomarker to screen early glomerular filtration rate impairment. Medicine (Baltimore). 2016;95(49):e5553.PubMed

    • Search Google Scholar
    • Export Citation
  • 33.

    DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach, 11th edition. New York, NY: McGraw-Hill; 2020.

    • Search Google Scholar
    • Export Citation
  • 34.

    Inker LA, Tighiouart H, Coresh J, et al.GFR estimation using β-trace protein and β2-microglobulin in CKD. Am J Kidney Dis. 2016;67(1):40-48.PubMed

    • Search Google Scholar
    • Export Citation
  • 35.

    Inker LA, Coresh J, Sang Y, et al.Filtration markers as predictors of esrd and mortality: individual participant data meta-analysis. Clin J Am Soc Nephrol. 2017;12(1):69-78.PubMed

    • Search Google Scholar
    • Export Citation
  • 36.

    Oh MS. Evaluation of renal function, water, electrolyte and acid-base. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by laboratory Methods. 21st ed. Philadelphia, PA: Saunders Elsevier; 2007:147-169.

    • Search Google Scholar
    • Export Citation
  • 37.

    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.PubMed

  • 38.

    Myers GL, Miller WG, Coresh J, et al.Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem. 2006;52(1):5-18.PubMed

    • Search Google Scholar
    • Export Citation
  • 39.

    Wade WE, Spruill WJ. New serum creatinine assay standardization: implications for drug dosing. Ann Pharmacother. 2007;41(3):475-480.PubMed

    • Search Google Scholar
    • Export Citation
  • 40.

    Macedo E, Mehta RL. Clinical approach to the diagnosis of acute kidney injury. In: Gilbert SJ, Weiner DE, Gipson DS, et al., eds. Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014:294-297.

    • Search Google Scholar
    • Export Citation
  • 41.

    National Institute of Diabetes and Digestive and Kidney Diseases. When not to use creatinine-based estimating equations. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/identify-manage-patients/evaluate-ckd/estimate-glomerular-filtration-rate. Accessed May 7, 2020.

  • 42.

    DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863-871.

    • Search Google Scholar
    • Export Citation
  • 43.

    Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098.PubMed

  • 44.

    Scappaticci GB, Regal RE. Cockcroft-Gault revisited: N\new deliverance on recommendations for use in cirrhosis. World J Hepatol. 2017;9(3):131-138.PubMed

    • Search Google Scholar
    • Export Citation
  • 45.

    Smythe M, Hoffman J, Kizy K, Dmuchowski C. Estimating creatinine clearance in elderly patients with low serum creatinine concentrations. Am J Hosp Pharm. 1994;51(2):198-204.PubMed

    • Search Google Scholar
    • Export Citation
  • 46.

    Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy. 2012;32(7):604-612.PubMed

    • Search Google Scholar
    • Export Citation
  • 47.

    Wilhelm SM, Kale-Pradhan PB. Estimating creatinine clearance: a meta-analysis. Pharmacotherapy. 2011;31(7):658-664.PubMed

  • 48.

    Sunder S, Jayaraman R, Mahapatra HS, et al.Estimation of renal function in the intensive care unit: the covert concepts brought to light. J Intensive Care. 2014;2(1):31.PubMed

    • Search Google Scholar
    • Export Citation
  • 49.

    Levey AS, Bosch JP, Lewis JB, et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461-470.PubMed

    • Search Google Scholar
    • Export Citation
  • 50.

    Verhave JC, Fesler P, Ribstein J, et al.Estimation of renal function in subjects with normal serum creatinine levels: influence of age and body mass index. Am J Kidney Dis. 2005;46(2):233-241.PubMed

    • Search Google Scholar
    • Export Citation
  • 51.

    Levey AS, Coresh J, Greene T, et al.Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007;53(4):766-772.PubMed

    • Search Google Scholar
    • Export Citation
  • 53.

    National Kidney Foundation. Frequently asked questions about GFR estimates. https://www.kidney.org/sites/default/files/docs/12-10-4004_abe_faqs_aboutgfrrev1b_singleb.pdf. Accessed Apr 7, 2020.

  • 54.

    Klahr S, Levey AS, Beck GJ, et al.The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med. 1994;330(13):877-884.PubMed

    • Search Google Scholar
    • Export Citation
  • 55.

    Levey AS, Stevens LA, Schmid CH, et al.A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612.PubMed

    • Search Google Scholar
    • Export Citation
  • 56.

    Levey AS, Stevens LA. Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kidney Dis. 2010;55(4):622-627.PubMed

    • Search Google Scholar
    • Export Citation
  • 57.

    Ferreira JP, Girerd N, Pellicori P, et al.Renal function estimation and Cockcroft-Gault formulas for predicting cardiovascular mortality in population-based, cardiovascular risk, heart failure and post-myocardial infarction cohorts: The Heart ‘Omics’ in AGEing (HOMAGE) and the high-risk myocardial infarction database initiatives. BMC Med. 2016;14(1):181.PubMed

    • Search Google Scholar
    • Export Citation
  • 58.

    Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol. 2009;4(11):1832-1843.PubMed

  • 59.

    Froissart M, Rossert J, Jacquot C, et al.Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol. 2005;16(3):763-773.PubMed

    • Search Google Scholar
    • Export Citation
  • 60.

    Stevens LA, Nolin TD, Richardson MM, et al.Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis. 2009;54(1):33-42.PubMed

    • Search Google Scholar
    • Export Citation
  • 61.

    National Kidney Disease Education Program. CKD and drug dosing: information for providers. https://www.niddk.nih.gov/health-information/professionals/advanced-search/ckd-drug-dosing-providers. Accessed Apr 7, 2020.

  • 62.

    Nyman HA, Dowling TC, Hudson JQ, et al.Comparative evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy. 2011;31(11):1130-1144.PubMed

    • Search Google Scholar
    • Export Citation
  • 63.

    American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes: 2020. https://care.diabetesjournals.org/content/43/Supplement_1/S98. Accessed Sep 24, 2020.

  • 64.

    Edoxaban [prescribing information]. Tokyo, Japan: Daiichi Sankyo Co.; 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed Sep 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 65.

    Cholografin meglumine [prescribing information]. Monroe Township, NJ: Bracco Diagnostics, Inc.; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009321s030lbl.pdf. Accessed Sep 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 66.

    Cholografin meglumine and diatrizoate sodium [prescribing information]. Raleigh, NC: Liebel-Flarsheim Company; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019292s011lbl.pdf. Accessed Sep 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 67.

    Iothalamate meglumine [prescribing information]. Raleigh, NC: Liebel-Flarsheim Company; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/013295s070lbl.pdf. Accessed Sep 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 68.

    Ethiodized oil [prescribing information]. Bloomington, IN: Guerbet LLC; 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/009190s024lbl.pdf. Accessed Sep 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 69.

    Sacher RA, McPherson RA. Laboratory assessment of body fluids. In:Widmann’s Clinical Interpretation of Laboratory Tests. 11th ed. Philadelphia, PA: FA Davis Company; 2000:924-1014.

    • Search Google Scholar
    • Export Citation
  • 70.

    Wallach J. Urine. In: Interpretation of Diagnostic Tests. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:89-110.

  • 71.

    Greenberg A. Urinalysis. In: Gilbert SJ, Weiner DE, Gipson DS, et al., eds. Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014:33-41.

    • Search Google Scholar
    • Export Citation
  • 72.

    McPherson RA, Ben-Ezra J, Zhao S. Basic examination of urine. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 21st ed. Philadelphia, PA: Saunders Elsevier; 2007:393-425.

    • Search Google Scholar
    • Export Citation
  • 73.

    Gill CB. Medscape reference. Drugs, diseases, and procedures: discoloration, urine. http://emedicine.medscape.com/article/2172371-overview. Accessed May 5, 2020.

  • 74.

    Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. Am Fam Physician. 2005;71(6):1153-1162.PubMed

  • 75.

    Wald R. Urinalysis in the diagnosis of renal disease. In: UpToDate. Waltham, MA: UpToDate; 2019: 1-53.

  • 76.

    Multistix (various) Reagent Strips [product information]. Elkhart, IN: Bayer HealthCare LLC; 2005.

  • 77.

    Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury [Erratum appears in N Engl J Med. 2011;19:364(20):1982]. N Engl J Med. 2009;361(1):62-72 PubMed

    • Search Google Scholar
    • Export Citation
  • 78.

    Jayne D, Yiu V. Hematuria and proteinuria. In: Gilbert SJ, Weiner DE, Gipson DS, et al., eds. Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014:42-50.

    • Search Google Scholar
    • Export Citation
  • 79.

    U.S. Food and Drug Administration. FDA news release. FDA approves new treatment for a type of heart failure. May 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed Sep 24, 2020.

  • 80.

    Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79.PubMed

    • Search Google Scholar
    • Export Citation
  • 81.

    Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology [Erratum appears in Diabetes Ther. 2015;6(1):95]. Diabetes Ther. 2014;5(2):355-366.PubMed

    • Search Google Scholar
    • Export Citation
  • 82.

    Kamel KS, Davids MR, Lin S-H, et al.Interpretation of electrolyte and acid-base parameters in blood and urine. In: Brenner and Rector’s The Kidney. Philadelphia, PA: Elsevier; 2016:804-845.e2.

    • Search Google Scholar
    • Export Citation
  • 83

    , Rose BD. Meaning and Application of Urine Chemistries. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York, NY: McGraw-Hill Inc; 2001:405-414.

    • Search Google Scholar
    • Export Citation
  • 84.

    Foote EF. Syndrome of inappropriate antidiuretic hormone secretion and diabetes insipidus. In: Tisdale JE, Miller DA, eds. Drug-induced diseases. Bethesda, MD: American Society of Health-System Pharmacists; 2005:611624.

    • Search Google Scholar
    • Export Citation
  • 85.

    West ML, Marsden PA, Richardson RM, et al.New clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab. 1986;12(4):234-238.PubMed

    • Search Google Scholar
    • Export Citation
  • 86.

    Ethier JH, Kamel KS, Magner PO, et al.The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis. 1990;15(4):309-315.PubMed

    • Search Google Scholar
    • Export Citation
  • 87.

    Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008;19(3):424-426.PubMed

    • Search Google Scholar
    • Export Citation
  • 88.

    Inker LA, Schmid CH, Tighiouart H, et al.Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20-29.PubMed

    • Search Google Scholar
    • Export Citation

QUICKVIEW | BUN

PARAMETER

DESCRIPTION

COMMENTS

Common reference range

Adults

Children

8–23 mg/dL (2.9–8.2 mmol/L)

5–18 mg/dL (1.8–6.4 mmol/L)

BUN represents concentration of nitrogen in serum

Usually measured with creatinine to assess renal function

A normal BUN:creatinine ratio is 6:1 to 20:1; if ratio is >20:1, it suggests prerenal etiology of renal failure; if ratio is 10–20:1, it suggests intrarenal etiology of renal failure

Critical value

100 mg/dL (35.7 mmol/L)

Associated with uremic syndrome in patients with severe renal failure

Inherent activity

Extremely high BUN levels lead to uremia, which includes symptoms of nausea, vomiting, and other metabolic and endocrine abnormalities

Location

Production

Urea is byproduct of hepatic protein metabolism; source of protein can be exogenous (eg, protein in diet) or endogenous (eg, breakdown of RBCs or muscle cells)

Urea is primary way that body eliminates excess nitrogen

Storage

Not applicable

Secretion/excretion

Urea is 100% filtered by glomerulus and then undergoes proximal tubule reabsorption

Percentage that is reabsorbed by proximal tubule is inversely related to patient’s intravascular volume; if intravascular volume is lower than normal, then percentage of BUN reabsorbed in proximal tubule is increased

Causes of abnormal values

High

Prerenal causes: dehydration, blood loss, shock, congestive heart failure, hypotension, increased protein catabolism (due to fever, infection, severe burns)

Intrarenal causes: acute or chronic renal failure due to any cause, glomerulonephritis, acute tubular necrosis, severe hypertension

Postrenal causes: obstruction of ureter, bladder neck, or urethra due to stones, enlarged prostate, or stricture, respectively

Nonrenal causes: excessive amino acid infusions, upper gastrointestinal tract bleeding

Drugs with antianabolic effects or protein catabolic effects: corticosteroids, tetracyclines

Drugs that contribute to prerenal or intrarenal failure: ACE inhibitor, acetaminophen, acyclovir, diuretics, aminoglycosides, antibiotics, angiotensin II receptor blockers, NSAIDs, radiographic contract media

Low

Starving or malnourished patients with inadequate protein intake or patients with muscle-wasting disease

Excess intravascular volume (eg, congestive heart failure) or SIADH may dilute BUN and have low levels

Chloramphenicol, guanethidine, or streptomycin use

Signs and symptoms

High level

Azotemia refers to elevated BUN, which occurs when GFR is 20%–35% of normal

Uremia refers to elevated BUN plus fluid and electrolyte, endocrine, neuromuscular, hematologic, or dermatologic, and metabolic abnormalities; it occurs when patient has overt renal failure and GFR is <20%–25%

Low level

No symptoms

After event, time to….

Initial elevation

Variable, depending on etiology of increase in BUN

Peak values

Can exceed 100 mg/dL

Normalization

If prerenal or postrenal etiology of renal failure is corrected, BUN will return to normal range quickly; however, if intrarenal etiology of renal failure results in permanent nephron injury, high levels of BUN may persist; in this case, when uremia develops, patient may be dialyzed, which will reduce BUN level

Causes of spurious results

Avoid collecting blood specimens in tubes containing sodium fluoride, which inhibits urease

QUICKVIEW | Creatinine

PARAMETER

DESCRIPTION

COMMENTS

Common reference range

Adults

Children

0.6–1.2 mg/dL (53–106 µmol/L)

0.2–0.7 mg/dL (18–62 µmol/L)

Usually measured with BUN to assess renal function

Normal range for SCr varies based on patient age, muscle mass of the patient, and gender; however, usually, normal range for adults applies to both men and women

Critical value

Variable based on age, race, muscle mass, low-protein diets, and medications

SCr should not be used alone as indicator of renal function; acute decrease in GFR may not be immediately manifested as increased SCr

Inherent activity

None

Location

Production

Creatinine is produced in muscle; it is waste product of creatine and creatine phosphate

Storage

Not applicable

Secretion/excretion

70%–80% of creatinine is filtered by glomerulus, and rest undergoes tubular secretion via the organic cation pathway

Causes of abnormal values

High

Prerenal causes: dehydration, blood loss, shock, congestive heart failure, hypotension, increased intake of meat

Intrarenal causes: acute or chronic renal failure due to any cause, glomerulonephritis, acute tubular necrosis, severe hypertension

Postrenal causes: obstruction of ureter, bladder neck, or urethra due to stones, enlarged prostate, or stricture, respectively

Exposure to nephrotoxins (eg, aminoglycosides, vancomycin, loop diuretics, penicillinase- resistant penicillins)

Low

Aging: older patients have less muscle mass; therefore, SCr may be lower than in younger patients

Malnourished patients have low muscle mass; therefore, SCr may be decreased

Signs and symptoms

High level

If increased SCr is due to intrinsic renal disease, patients typically have other laboratory abnormalities; eg, when GFR is ~25 mL/min, increased serum phosphate, uric acid, potassium, and hydrogen ion result; when the GFR is <10 mL/min, increased sodium and chloride result

Low level

Signs and symptoms of underlying cause of low creatinine levels are evident (eg, malnourished patient appears cachectic)

After event, time to….

Initial elevation

Variable, depending on etiology of increase in creatinine; eg, in acute renal failure, SCr often rises within 24–48 hr; after radiocontrast media exposure, SCr rises in 3–5 days; after ischemic renal failure, SCr increases in 7–10 days

Peak values

Not applicable

Normalization

If prerenal or postrenal etiology of renal failure is corrected, creatinine returns to normal range quickly; however, if intrarenal etiology of renal failure results in permanent nephron injury, high levels of creatinine may persist; after cause has been eliminated, increase in SCr may persist if patient had irreversible renal dysfunction or may persist for 7–14 days if patient had reversible renal dysfunction

Causes of spurious results

Uric acid, glucose, fructose, acetone, acetoacetate, pyruvic acid, and ascorbic acid, cefoxitin, or flucytosine can cause false elevations in measured creatinine when using the alkaline picrate (Jaffe) assay; can lead to an underestimation of a patient’s creatinine clearance

Bilirubin can falsely lower measured creatinine when using alkaline picrate assay or enzymatic assays; can lead to an overestimation of patient’s creatinine clearance

Cimetidine, trimethoprim, pyrimethamine, dronedarone, or dapsone can compete through organic cation pathway for tubular secretin of creatinine; these drugs can cause false elevations in SCr

Hemolysis of blood sample can falsely increase creatinine measurement