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Nephrology Committee Editor-in-Chief Michael J. Ross, MD, Section Editor Davoren Chick, MD, FACP Chief, Division of Nephrology Senior Vice President, Medical Education Albert Einstein College of Medicine American College of Physicians Montefiore Medical Center Philadelphia, Pennsylvania Bronx, New York Andrew S. Bomback, MD, MPH Senior Deputy Editor Associate Professor of Medicine Patrick C. Alguire, MD, FACP Columbia University Irving Medical Center American College of Physicians New York, New York Philadelphia, Pennsylvania Derek M. Fine, MD Associate Professor of Medicine Deputy Editor Division of Nephrology Richard S. Eisenstaedt, MD, MACP Johns Hopkins University School of Medicine Chair, Department of Medicine Baltimore, Maryland Abington Hospital, Jefferson Health Susan Hedayati, MD, MSc Abington, Pennsylvania Professor of Medicine, Division of Nephrology Yin Quan-Yuen Distinguished Professorship in Nephrology Nephrology Reviewers Associate Vice Chair for Research, Department of Internal Arshad Ali, MBBS, FACP Medicine Faris Ahmed, MD, FACP Director of Nephrology Translational and Population Ayoola Akinbamowo, MBBS, FACP Health Research Abdo Asmar, MD, FACP University of Texas Southwestern Medical Center Fahad Aziz, MD Dallas, Texas Krishna Baradhi, MD, FACP Mark G. Parker, MD, FACP Frantz Duffoo, MD, FACP

Professor of Medicine, Division of Nephrology Yin Quan-Yuen Distinguished Professorship in Nephrology Nephrology Reviewers Associate Vice Chair for Research, Department of Internal Arshad Ali, MBBS, FACP Medicine Faris Ahmed, MD, FACP Director of Nephrology Translational and Population Ayoola Akinbamowo, MBBS, FACP Health Research Abdo Asmar, MD, FACP University of Texas Southwestern Medical Center Fahad Aziz, MD Dallas, Texas Krishna Baradhi, MD, FACP Mark G. Parker, MD, FACP Frantz Duffoo, MD, FACP Vice President, Quality and Safety Mira T. Keddis, MD, FACP Division of Nephrology and Transplantation Wei Ling Lau, MD, FACP Maine Medical Center Kashif J. Piracha, MD, FACP Clinical Professor of Medicine Adrian Sequeira, MD, FACP

Vice President, Quality and Safety Mira T. Keddis, MD, FACP Division of Nephrology and Transplantation Wei Ling Lau, MD, FACP Maine Medical Center Kashif J. Piracha, MD, FACP Clinical Professor of Medicine Adrian Sequeira, MD, FACP Tufts University School of Medicine Portland, Maine Hospital Medicine Nephrology Amanda C. Raff, MD Reviewers Professor of Medicine Corinne Ahmar, MD, FACP Associate Chair of Medicine for Undergraduate Rahul Koushik, MD, FACP Medical Education Ryan Mullane, DO Albert Einstein College of Medicine Ankur Shah, MD Division of Nephrology, Montefiore Medical Center Bronx, New York Nephrology ACP Editorial Staff Harold M. Szerlip, MD, FACP Beth Goldner, Medical Editor, Assessment and Education Director, Nephrology Division Programs Baylor University Medical Center at Dallas Margaret Wells, Ed.M., Director, Assessment and Education Clinical Professor, Texas A&M College of Medicine Programs Dallas, Texas Becky Krumm, Senior Managing Editor, Assessment and Education Programs

Nephrology Clinical Evaluation cobicistat, dolutegravir, and bictegravir and result in elevated serum creatinine despite stable GFR.

Nephrology Clinical Evaluation cobicistat, dolutegravir, and bictegravir and result in elevated serum creatinine despite stable GFR. of Kidney Function Serum Cystatin C Assessment of Kidney Function Cystatin C is produced by all nucleated cells, freely filtered by glomeruli, and catabolized by tubules. Compared with serum The kidney selectively removes waste while retaining needed creatinine, serum cystatin C levels are less affected by age, sex, substrate, maintains fluid and electrolyte homeostasis, and or muscle mass, but may be increased by acute disease (such regulates blood pH. Glomerular filtration rate (GFR) measures as malignancy, hyperthyroidism, inflammation, or HIV infec- total nephron filtration of blood and correlates closely with tion). Changes in serum cystatin C may identify small decreases toxin removal and overall kidney function. Early loss of kidney in kidney function better than serum creatinine. Formulas function is difficult to detect because compensation through using cystatin C to estimate GFR are helpful for patients hypertrophy and hyperfiltration preserve GFR despite nephron in whom creatinine-based GFR may be inaccurate (such as in loss. Other markers of disordered glomerular function, such cases of drug-induced reduction of creatinine secretion as proteinuria and hematuria, are also indicators of kidney described earlier, or in those with reduced or increased muscle disease that may precede any evidence of reduced filtration. mass).

of Kidney Function Serum Cystatin C Assessment of Kidney Function Cystatin C is produced by all nucleated cells, freely filtered by glomeruli, and catabolized by tubules. Compared with serum The kidney selectively removes waste while retaining needed creatinine, serum cystatin C levels are less affected by age, sex, substrate, maintains fluid and electrolyte homeostasis, and or muscle mass, but may be increased by acute disease (such regulates blood pH. Glomerular filtration rate (GFR) measures as malignancy, hyperthyroidism, inflammation, or HIV infec- total nephron filtration of blood and correlates closely with tion). Changes in serum cystatin C may identify small decreases toxin removal and overall kidney function. Early loss of kidney in kidney function better than serum creatinine. Formulas function is difficult to detect because compensation through using cystatin C to estimate GFR are helpful for patients hypertrophy and hyperfiltration preserve GFR despite nephron in whom creatinine-based GFR may be inaccurate (such as in loss. Other markers of disordered glomerular function, such cases of drug-induced reduction of creatinine secretion as proteinuria and hematuria, are also indicators of kidney described earlier, or in those with reduced or increased muscle disease that may precede any evidence of reduced filtration. mass). Biochemical Markers of Kidney Function Blood Urea Nitrogen Although numerous methods for estimating kidney function Blood urea nitrogen (BUN) is a product of protein metabolism. are available (Table 1), serum creatinine and serum cystatin C Levels increase with reduced GFR and with increased urea are the primary biomarkers used to estimate GFR. reabsorption caused by renal hypoperfusion. BUN is also affected by protein intake and catabolic rate. Lower levels are Serum Creatinine noted in starvation and in patients with liver disease. BUN will Serum creatinine is the most extensively used measure of kid- increase with glucocorticoids, hemorrhage, or trauma. BUN ney function. Creatinine is freely filtered by the glomerulus and may be useful in detecting renal hypoperfusion when eleva- is also secreted into the urine by the proximal tubule. The rela- tion of BUN from increased reabsorption is disproportionate to tionship of serum creatinine to GFR is nonlinear; significant the rise in serum creatinine level. losses in kidney function at higher GFR may be masked by only small changes in serum creatinine, whereas small filtration Estimation of Glomerular Filtration Rate changes at lower GFR are associated with large fluctuations in Creatinine-based formulas are used to estimate GFR by adjust- serum creatinine (Figure 1). The contribution of tubular secre- ing for factors that affect serum creatinine and creatinine tion as a proportion of total creatinine excretion increases as clearance. These formulas take into account the effects of age, GFR declines. Therefore, when urinary creatinine clearance is race, sex, and muscle mass (estimated by weight) on serum used to estimate GFR, secreted creatinine will contribute to creatinine levels (see Table 1). overestimation of true GFR. With complete loss of kidney func- The Chronic Kidney Disease Epidemiology (CKD-EPI) tion (anuria), serum creatinine may increase by up to 1.0 mg/dL Collaboration creatinine equation is the most widely used (88.4 umol/L) per day in patients with average muscle mass. method for estimating GFR and is the most accurate equation Creatinine is a metabolite of creatine, which is mostly for most persons, particularly in older persons and those present in skeletal muscle. Persons with higher muscle mass witha GFR>60 mL/min/1.73 m2. Anewer CKD-EPI creatinine- (such as younger people, men, and Black persons) have a cystatin C equation is the most accurate, but requires cysta- higher serum creatinine compared with less muscular persons tin C data and works optimally in patients of normal body with the same GFR. Loss of muscle mass seen with aging, mass.

Biochemical Markers of Kidney Function Blood Urea Nitrogen Although numerous methods for estimating kidney function Blood urea nitrogen (BUN) is a product of protein metabolism. are available (Table 1), serum creatinine and serum cystatin C Levels increase with reduced GFR and with increased urea are the primary biomarkers used to estimate GFR. reabsorption caused by renal hypoperfusion. BUN is also affected by protein intake and catabolic rate. Lower levels are Serum Creatinine noted in starvation and in patients with liver disease. BUN will Serum creatinine is the most extensively used measure of kid- increase with glucocorticoids, hemorrhage, or trauma. BUN ney function. Creatinine is freely filtered by the glomerulus and may be useful in detecting renal hypoperfusion when eleva- is also secreted into the urine by the proximal tubule. The rela- tion of BUN from increased reabsorption is disproportionate to tionship of serum creatinine to GFR is nonlinear; significant the rise in serum creatinine level. losses in kidney function at higher GFR may be masked by only small changes in serum creatinine, whereas small filtration Estimation of Glomerular Filtration Rate changes at lower GFR are associated with large fluctuations in Creatinine-based formulas are used to estimate GFR by adjust- serum creatinine (Figure 1). The contribution of tubular secre- ing for factors that affect serum creatinine and creatinine tion as a proportion of total creatinine excretion increases as clearance. These formulas take into account the effects of age, GFR declines. Therefore, when urinary creatinine clearance is race, sex, and muscle mass (estimated by weight) on serum used to estimate GFR, secreted creatinine will contribute to creatinine levels (see Table 1). overestimation of true GFR. With complete loss of kidney func- The Chronic Kidney Disease Epidemiology (CKD-EPI) tion (anuria), serum creatinine may increase by up to 1.0 mg/dL Collaboration creatinine equation is the most widely used (88.4 umol/L) per day in patients with average muscle mass. method for estimating GFR and is the most accurate equation Creatinine is a metabolite of creatine, which is mostly for most persons, particularly in older persons and those present in skeletal muscle. Persons with higher muscle mass witha GFR>60 mL/min/1.73 m2. Anewer CKD-EPI creatinine- (such as younger people, men, and Black persons) have a cystatin C equation is the most accurate, but requires cysta- higher serum creatinine compared with less muscular persons tin C data and works optimally in patients of normal body with the same GFR. Loss of muscle mass seen with aging, mass. muscle wasting, malnutrition, or amputation will result in The Modification of Diet in Renal Disease (MDRD) study lower serum creatinine despite stable GFR. In persons with equation does not accurately estimate high GFRs. It performs decreased muscle mass, serum creatinine therefore tends to similarly to the CKD-EPI equation at GFRs <60 mL/min/1.73 m2. overestimate the GFR. Clinical laboratories that use the MDRD do not report GFRs Some medications reduce proximal tubule secretion of >60 mL/min/1.73 m?; therefore, physicians may not be aware creatinine. These drugs include cimetidine, trimethoprim, of the presence of kidney disease. In this context, an

Clinical Evaluation of Kidney Function TABLE 1. Methods for Estimating Kidney Function Method Applications Considerations Serum Creatinine Most frequently used assessment of kidney Nonlinear relationship with GFR function Nonkidney effects on blood levels (muscle mass, drugs affecting tubular secretion) Serum Cystatin C More accurate in older persons and patients Levels are affected by diabetes mellitus, with cirrhosis due to low muscle mass hyperthyroidism, inflammation, glucocorticoid use, malignancy, HIV More accurate in those with an increase in infection muscle mass i i Sensitive to mild changes in GFR 1 i ' f Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration Equation | i CKD-EPI Creatinine | | Variables include serum creatinine, age, More accurate than MDRD and CGE Preferred formula for calculating | race, and gender equations in older persons and in those creatinine-based GFR | i with GFR >60 mL/min/1.73 m? i 1 Self-reported race may reduce reliability of | this and all CKD-EPI equations |

| Variables include serum creatinine, age, More accurate than MDRD and CGE Preferred formula for calculating | race, and gender equations in older persons and in those creatinine-based GFR | i with GFR >60 mL/min/1.73 m? i 1 Self-reported race may reduce reliability of | this and all CKD-EPI equations | CKD-EPI Cystatin C t | Variables include serum cystatin C, age, | | Can be used as confirmatory test for CKD Helpful in estimating GFRinthose taking | | | and gender drugs that affect creatinine secretion (e.g., May be more accurate than creatinine- cobicistat, dolutegravir, bictegravir, | i i based equation in those with muscle trimethoprim, and cimetidine) | wasting, chronic illness, or high muscle mass i CKD-EPI Creatinine-Cystatin C | | Equation uses same variables as CKD-EPI Creatinine-cystatin C combination provides | creatinine but different exponents and the most accurate eGFR in most patient { |

| and gender drugs that affect creatinine secretion (e.g., May be more accurate than creatinine- cobicistat, dolutegravir, bictegravir, | i i based equation in those with muscle trimethoprim, and cimetidine) | wasting, chronic illness, or high muscle mass i CKD-EPI Creatinine-Cystatin C | | Equation uses same variables as CKD-EPI Creatinine-cystatin C combination provides | creatinine but different exponents and the most accurate eGFR in most patient { | | i includes serum cystatin C populations | | { Modification of Diet in Renal Disease (MDRD) Study Equation i | Variables include serum creatinine, age, Similar accuracy as CKD-EPI when eGFR is Most accurate when eGFR is | race, and gender 15-60 mL/min/1.73 m? 15-60 mL/min/1.73 m2 | Underestimates GFR when GFR >60 mL/min/1.73 m2 Creatinine Clearance (CrCl)

| Variables include serum creatinine, age, Similar accuracy as CKD-EPI when eGFR is Most accurate when eGFR is | race, and gender 15-60 mL/min/1.73 m? 15-60 mL/min/1.73 m2 | Underestimates GFR when GFR >60 mL/min/1.73 m2 Creatinine Clearance (CrCl) Variables include serum and urine Useful in pregnancy, extremes of age and Overestimates GFR 10%-20% creatinine and 24-hour urine volume weight, amputees, malnourished and Overestimation worsens with lower GFR cirrhotic patients (situations where (due to increased ratio of creatinine creatinine is low, so CKD-EP| and MDRD secretion to filtration) will overestimate GFR) Over- or undercollection limits accuracy Cockcroft-Gault Equation (CGE) Variables include serum creatinine, body Improved accuracy when age is <65 years Most accurate when eGFR is | weight, age, and gender 15-60 mL/min/1.73 m2 Underestimates GFR in obesity Overestimates GFR when BMI <25 Radionuclide Kidney Clearance Scanning

Variables include serum creatinine, body Improved accuracy when age is <65 years Most accurate when eGFR is | weight, age, and gender 15-60 mL/min/1.73 m2 Underestimates GFR in obesity Overestimates GFR when BMI <25 Radionuclide Kidney Clearance Scanning _ lothalamate GFR scan or Useful in kidney donor evaluation if eGFR Most precise method; expensive; diethylenetriamine pentaacetic acid is borderline for donation or other times exposure to radiation (DTPA) GFR scan when accurate prediction is essential DTPA can be used for determination of relative (differential) function of each kidney (e.g., prenephrectomy) CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; GFR = glomerular filtration rate.

Clinical Evaluation of Kidney Function 13-4 Example | A Creatinine A GFR Interpretation of the Urinalysis 0.4 mg/dL (35.4 pmol/L) | 42 mL/min/1.73 m2 Urine dipstick and urine microscopy are indicated in the 1.5 mg/dL (132.6 pmol/L) | 13 mL/min/1.73 m2 [pmol/L]) evaluation of both acute and chronic kidney disease (Table 2). Analysis is best performed on a fresh specimen within 30 to 60 | minutes of voiding. Midstream collection is preferred with a foo) (mg/dL clean catch in women and uncircumcised men.

13-4 Example | A Creatinine A GFR Interpretation of the Urinalysis 0.4 mg/dL (35.4 pmol/L) | 42 mL/min/1.73 m2 Urine dipstick and urine microscopy are indicated in the 1.5 mg/dL (132.6 pmol/L) | 13 mL/min/1.73 m2 [pmol/L]) evaluation of both acute and chronic kidney disease (Table 2). Analysis is best performed on a fresh specimen within 30 to 60 | minutes of voiding. Midstream collection is preferred with a foo) (mg/dL clean catch in women and uncircumcised men. creatinine Urine Dipstick See Table 2 for details on urine dipstick. Serum 0 T = T T T a 0 20 40 60 80 100 120 Specific Gravity Glomerular filtration rate (mL/min/1.73 m2) Specific gravity measures hydration status and reflects the kidney’s ability to concentrate urine. FIGURE 1. The relationship between serum creatinine and glomerular filtration rate (GFR). Example A illustrates that a small increase in the serum creatinine level in the reference range (in this case, 0.8-1.2 mg/dL[70.7-106.1 tmol/L]) reflects a pH relatively large change in GFR (120 to 78 mL/min/1.73 m2). Example B illustrates Low urine pH may occur in persons eating high-protein diets. that a relatively greater increase in the serum creatinine level (in the high range of Alkaline urine (pH 7.0) can occur in strict vegetarians and in 3.0-4.5 mg/dL [265.2-398 rmol/L]) reflects a proportionately smaller change in persons with infections caused by urea-splitting organisms. GFR (35 to 22 mL/min/1.73 m2). Urine pH may be inappropriately high in some forms of renal tubular acidosis (type 1 distal) but may be appropriately low in increasing serum creatinine level, proteinuria, or other urine others (type 4 distal). abnormalities should alert the clinician to the presence of kidney disease. Blood When using CKD-EPI or MDRD to calculate drug dosages Dipsticks detect peroxidase activity of blood and free heme requiring adjustment for GFR, estimated GFR (eGFR) should pigments (hemoglobin and myoglobin). Three or more eryth- be multiplied by body surface area (BSA)/1.73 m2, particularly rocytes result in a positive test (1+ blood). A positive test in the in persons with very high or very low BSA. absence of erythrocytes in the urine sediment may indicate The Cockcroft-Gault equation (CGE) is the least accu- myoglobinuria (due to rhabdomyolysis) or hemoglobinuria rate method. However, it remains in use for drug dosing (due to intravascular hemolysis following transfusion, or shear because it was used in pharmacokinetic studies for most stress related to mechanical heart valve and perivalvular leak). medications. False-positive tests may occur with other substances with per- Creatinine clearance obtained by using 24-hour urine oxidase activity, including peroxidase-expressing bacteria and collection is a better measure of GFR than serum creatinine, drugs such as chloroquine. Ascorbic acid can cause a false- but it is not recommended for routine estimation of GFR negative result. Medications (rifampin, phenytoin) or food because it is affected by the accuracy of collection and by (beets) can cause heme-negative, red-colored urine. tubular creatinine secretion.

creatinine Urine Dipstick See Table 2 for details on urine dipstick. Serum 0 T = T T T a 0 20 40 60 80 100 120 Specific Gravity Glomerular filtration rate (mL/min/1.73 m2) Specific gravity measures hydration status and reflects the kidney’s ability to concentrate urine. FIGURE 1. The relationship between serum creatinine and glomerular filtration rate (GFR). Example A illustrates that a small increase in the serum creatinine level in the reference range (in this case, 0.8-1.2 mg/dL[70.7-106.1 tmol/L]) reflects a pH relatively large change in GFR (120 to 78 mL/min/1.73 m2). Example B illustrates Low urine pH may occur in persons eating high-protein diets. that a relatively greater increase in the serum creatinine level (in the high range of Alkaline urine (pH 7.0) can occur in strict vegetarians and in 3.0-4.5 mg/dL [265.2-398 rmol/L]) reflects a proportionately smaller change in persons with infections caused by urea-splitting organisms. GFR (35 to 22 mL/min/1.73 m2). Urine pH may be inappropriately high in some forms of renal tubular acidosis (type 1 distal) but may be appropriately low in increasing serum creatinine level, proteinuria, or other urine others (type 4 distal). abnormalities should alert the clinician to the presence of kidney disease. Blood When using CKD-EPI or MDRD to calculate drug dosages Dipsticks detect peroxidase activity of blood and free heme requiring adjustment for GFR, estimated GFR (eGFR) should pigments (hemoglobin and myoglobin). Three or more eryth- be multiplied by body surface area (BSA)/1.73 m2, particularly rocytes result in a positive test (1+ blood). A positive test in the in persons with very high or very low BSA. absence of erythrocytes in the urine sediment may indicate The Cockcroft-Gault equation (CGE) is the least accu- myoglobinuria (due to rhabdomyolysis) or hemoglobinuria rate method. However, it remains in use for drug dosing (due to intravascular hemolysis following transfusion, or shear because it was used in pharmacokinetic studies for most stress related to mechanical heart valve and perivalvular leak). medications. False-positive tests may occur with other substances with per- Creatinine clearance obtained by using 24-hour urine oxidase activity, including peroxidase-expressing bacteria and collection is a better measure of GFR than serum creatinine, drugs such as chloroquine. Ascorbic acid can cause a false- but it is not recommended for routine estimation of GFR negative result. Medications (rifampin, phenytoin) or food because it is affected by the accuracy of collection and by (beets) can cause heme-negative, red-colored urine. tubular creatinine secretion. Radionuclide imaging provides the most accurate meas- Protein urement of GFR and is the gold standard in research. It is use- Although various proteins may be present in urine, the dip- ful for accurate determination of GFR during evaluation of stick preferentially detects albumin. Because dipsticks are kidney donors, evaluation of recipients for other organs, and dependent on urine concentration, false negatives may result assessment of the differential GFR of each kidney before from dilute urine and false positives from highly concen- nephrectomy. trated urine. Because moderately increased albuminuria (formerly known as microalbuminuria) may go undetected by dipstick, direct quantification of albuminuria and/or e Serum creatinine changes nonlinearly with glomerular proteinuria using a random (spot) protein-creatinine ratio or filtration rate (GFR), and significant losses in kidney albumin-creatinine ratio or a 24-hour urine collection is function at higher GFR may cause only small changes in required in high-risk patients. False-positive tests can occur serum creatinine. with highly alkaline urine specimens. e The Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration creatinine equation is the most widely Glucose used equation to estimate glomerular filtration rate Glucosuria typically occurs when plasma glucose exceeds (GFR); it is the most accurate equation for most per- 180 mg/dL (10.0 mmol/L). Glucosuria in the absence of hyper- sons, particularly in older persons and those with a glycemia suggests proximal tubular dysfunction, as seen with GFR >60 mL/min/1.73 m?. myeloma or exposure to drugs (such as tenofovir disoproxil

Radionuclide imaging provides the most accurate meas- Protein urement of GFR and is the gold standard in research. It is use- Although various proteins may be present in urine, the dip- ful for accurate determination of GFR during evaluation of stick preferentially detects albumin. Because dipsticks are kidney donors, evaluation of recipients for other organs, and dependent on urine concentration, false negatives may result assessment of the differential GFR of each kidney before from dilute urine and false positives from highly concen- nephrectomy. trated urine. Because moderately increased albuminuria (formerly known as microalbuminuria) may go undetected by dipstick, direct quantification of albuminuria and/or e Serum creatinine changes nonlinearly with glomerular proteinuria using a random (spot) protein-creatinine ratio or filtration rate (GFR), and significant losses in kidney albumin-creatinine ratio or a 24-hour urine collection is function at higher GFR may cause only small changes in required in high-risk patients. False-positive tests can occur serum creatinine. with highly alkaline urine specimens. e The Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration creatinine equation is the most widely Glucose used equation to estimate glomerular filtration rate Glucosuria typically occurs when plasma glucose exceeds (GFR); it is the most accurate equation for most per- 180 mg/dL (10.0 mmol/L). Glucosuria in the absence of hyper- sons, particularly in older persons and those with a glycemia suggests proximal tubular dysfunction, as seen with GFR >60 mL/min/1.73 m?. myeloma or exposure to drugs (such as tenofovir disoproxil 3

Clinical Evaluation of Kidney Function TABLE 2. Findings on Urinalysis | Normal Range Comments | Dipstick Specific gravity 1.005-1.030 Low: dilute urine from excess hydration; impaired urine concentration (diabetes insipidus; sickle cell nephropathy; acute tubular injury) High: volume depletion; renal hypoperfusion; excretion of hypertonic solute (glycosuria; contrast dye) pH 5.0-6.5 Low/acidic: high-protein diets; type 4 distal RTA; some type 2 proximal RTA; increases risk for uric acid and cystine calculi High/alkaline: urease-splitting organisms (most commonly Proteus species; other potential organisms include Escherichia coli and Pseudomonas, Klebsiella, and some staphylococcal species); low acid ingestion; type 1 distal RTA; some type 2 RTA; increases risk for struvite and calcium phosphate calculi Blood/heme pigments None Positive: hemoglobin or myoglobin; absence of erythrocytes suggests myoglobinuria or intravascular hemolysis False positive: alkaline urine (pH >9) Protein None to trace Dipsticks primarily detect albumin; concentration dependent (trace positive can be normal in a concentrated specimen); not sufficiently sensitive to detect moderately | | increased albuminuria Graded as trace (10-30 mg/dL), 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), | 4+(>1000 mg/dL)

Protein None to trace Dipsticks primarily detect albumin; concentration dependent (trace positive can be normal in a concentrated specimen); not sufficiently sensitive to detect moderately | | increased albuminuria Graded as trace (10-30 mg/dL), 1+ (30 mg/dL), 2+ (100 mg/dL), 3+ (300 mg/dL), | 4+(>1000 mg/dL) Glucose None Positive: plasma glucose exceeds ~180 mg/dL (10.0 mmol/L); proximal tubule defect (Fanconi syndrome); pregnancy (lower excretion threshold) Ketones None Detects acetone and acetoacetic acid, not B-hydroxybutyrate Positive: diabetic ketoacidosis; starvation; vomiting; pregnancy Leukocyte esterase None Enzyme found in leukocytes; indicates pyuria (possibly from UTI); positive test requires 25 leukocytes/hpf Nitrites None Produced by gram-negative bacteria from nitrates Positive: suggests UTI Negative: does not rule out UTI (specific but not sensitive) Microscopic | Erythrocytes 0-2/hpf Urine microscopy should be performed to evaluate erythrocyte morphology | Leukocytes 0-4/hpf The presence of any leukocytes may be abnormal depending on clinical circumstances Squamous epithelial cells <15/hpf Increased epithelial cells indicates contamination Casts None or hyaline Hyaline casts: indicative of poor kidney perfusion Granular casts: acute tubular necrosis Erythrocyte casts: glomerular bleeding/glomerulonephritis Leukocyte casts: infection; acute interstitial nephritis

Squamous epithelial cells <15/hpf Increased epithelial cells indicates contamination Casts None or hyaline Hyaline casts: indicative of poor kidney perfusion Granular casts: acute tubular necrosis Erythrocyte casts: glomerular bleeding/glomerulonephritis Leukocyte casts: infection; acute interstitial nephritis Crystals (see Table 3) None Most common: calcium oxalate, calcium phosphate, uric acid, and struvite RTA = renal tubular acidosis; UTI = urinary tract infection. fumarate). Sodium-glucose cotransporter-2 inhibitors, such as B-hydroxybutyrate; therefore, in diabetic ketoacidosis and empagliflozin and canagliflozin, cause glucosuria by prevent- alcoholic ketoacidosis where B-hydroxybutyrate is the primary ing reabsorption of glucose. Glucosuria may be present in ketone, the dipstick underestimates ketone excretion. False- normal pregnancy due to changes in tubular threshold for positive tests may occur with drugs containing sulfhydryl glucose reabsorption. groups, such as captopril. Ketones Leukocyte Esterase and Nitrites Ketonuria most commonly occurs in starvation, diabetic Leukocyte esterase is an enzyme present in leukocytes. A posi- ketoacidosis, and alcoholic ketoacidosis. Urine ketones are tive test suggests pyuria (5 leukocytes/hpf). also seen in salicylate toxicity and isopropyl alcohol poisoning. A positive nitrite test signifies the presence of gram- Urine dipstick detects acetone and acetoacetate but not negative bacteria (Escherichia coli; Klebsiella, Enterobacter, 4

Clinical Evaluation of Kidney Function Citrobacter, and Proteus species) capable of converting urine Leukocytes nitrates into nitrites. The test is falsely negative if there is inad- The presence of 25 leukocytes in the urine sediment indicates equate contact time for urine nitrates with the bacteria. The pyuria, which is most commonly caused by a UTI. Sterile pyu- nitrite test is negative in urinary tract infection (UTI) caused by ria is the presence of urine leukocytes in the setting of negative nonconverting organisms (Enterococcus, Staphylococcus, urine culture; common causes include vaginitis and cervicitis Streptococcus, or Haemophilus species). in women, prostatitis in men, acute interstitial nephritis (AIN), The presence of both leukocyte esterase and nitrites on kidney stones, kidney transplant rejection, and, less com- urine dipstick is highly predictive of a UTI; conversely, the monly, UTIs due to organisms that do not grow by standard absence of both has a high negative predictive value for a UTI. culture techniques (Chlamydia species, Mycobacterium tuberculosis, Ureaplasma urealyticum). The absence of leu- Bilirubin kocytes does not rule out AIN. Bilirubin should be absent from the urine when serum levels are normal. Conjugated, water-soluble bilirubin is excreted in Eosinophils the urine in severe liver disease or obstructive hepatobiliary Urine eosinophils suggest interstitial nephritis, atheroembolic disease. disease, glomerulonephritis, small-vessel vasculitis, UTI, pro- static disease, or parasitic infections. Poor sensitivity and spec-

Citrobacter, and Proteus species) capable of converting urine Leukocytes nitrates into nitrites. The test is falsely negative if there is inad- The presence of 25 leukocytes in the urine sediment indicates equate contact time for urine nitrates with the bacteria. The pyuria, which is most commonly caused by a UTI. Sterile pyu- nitrite test is negative in urinary tract infection (UTI) caused by ria is the presence of urine leukocytes in the setting of negative nonconverting organisms (Enterococcus, Staphylococcus, urine culture; common causes include vaginitis and cervicitis Streptococcus, or Haemophilus species). in women, prostatitis in men, acute interstitial nephritis (AIN), The presence of both leukocyte esterase and nitrites on kidney stones, kidney transplant rejection, and, less com- urine dipstick is highly predictive of a UTI; conversely, the monly, UTIs due to organisms that do not grow by standard absence of both has a high negative predictive value for a UTI. culture techniques (Chlamydia species, Mycobacterium tuberculosis, Ureaplasma urealyticum). The absence of leu- Bilirubin kocytes does not rule out AIN. Bilirubin should be absent from the urine when serum levels are normal. Conjugated, water-soluble bilirubin is excreted in Eosinophils the urine in severe liver disease or obstructive hepatobiliary Urine eosinophils suggest interstitial nephritis, atheroembolic disease. disease, glomerulonephritis, small-vessel vasculitis, UTI, pro- static disease, or parasitic infections. Poor sensitivity and spec- Urobilinogen ificity limit the utility of urine eosinophils in the diagnosis of interstitial nephritis. Gut bacteria produce urobilinogen through metabolism of bilirubin. Urobilinogen is then absorbed via portal circulation Epithelial Cells and excreted in urine. Increased urobilinogen is associated Renal tubular, transitional, and squamous epithelial cells may with hemolytic anemia or parenchymal liver disease. be seen on urinalysis (see Figure 2). Renal tubular epithelial Decreased levels are seen with severe cholestasis and obstruc- tive disease. cells are round with central nuclei and are 1.5 to 3 times larger than leukocytes. Their presence in the context of granular casts suggests acute tubular necrosis. Transitional epithelial ° Because moderately increased albuminuria may go cells are slightly larger than renal tubular epithelial cells and undetected by dipstick, direct quantification using a may be binucleate; they originate anywhere from the renal random (spot) protein-creatinine ratio or albumin- pelvis to the proximal urethra. Squamous epithelial cells are creatinine ratio or a 24-hour urine collection is required the largest epithelial cells, and are flat and irregular with small in high-risk patients. central nuclei; they are derived from the distal urethra

Urobilinogen ificity limit the utility of urine eosinophils in the diagnosis of interstitial nephritis. Gut bacteria produce urobilinogen through metabolism of bilirubin. Urobilinogen is then absorbed via portal circulation Epithelial Cells and excreted in urine. Increased urobilinogen is associated Renal tubular, transitional, and squamous epithelial cells may with hemolytic anemia or parenchymal liver disease. be seen on urinalysis (see Figure 2). Renal tubular epithelial Decreased levels are seen with severe cholestasis and obstruc- tive disease. cells are round with central nuclei and are 1.5 to 3 times larger than leukocytes. Their presence in the context of granular casts suggests acute tubular necrosis. Transitional epithelial ° Because moderately increased albuminuria may go cells are slightly larger than renal tubular epithelial cells and undetected by dipstick, direct quantification using a may be binucleate; they originate anywhere from the renal random (spot) protein-creatinine ratio or albumin- pelvis to the proximal urethra. Squamous epithelial cells are creatinine ratio or a 24-hour urine collection is required the largest epithelial cells, and are flat and irregular with small in high-risk patients. central nuclei; they are derived from the distal urethra e The presence of both leukocyte esterase and nitrites on or external genitalia, and their presence in large numbers urine dipstick is highly predictive of a urinary tract (>15/hpf) denotes contamination by genital secretions.

Urobilinogen ificity limit the utility of urine eosinophils in the diagnosis of interstitial nephritis. Gut bacteria produce urobilinogen through metabolism of bilirubin. Urobilinogen is then absorbed via portal circulation Epithelial Cells and excreted in urine. Increased urobilinogen is associated Renal tubular, transitional, and squamous epithelial cells may with hemolytic anemia or parenchymal liver disease. be seen on urinalysis (see Figure 2). Renal tubular epithelial Decreased levels are seen with severe cholestasis and obstruc- tive disease. cells are round with central nuclei and are 1.5 to 3 times larger than leukocytes. Their presence in the context of granular casts suggests acute tubular necrosis. Transitional epithelial ° Because moderately increased albuminuria may go cells are slightly larger than renal tubular epithelial cells and undetected by dipstick, direct quantification using a may be binucleate; they originate anywhere from the renal random (spot) protein-creatinine ratio or albumin- pelvis to the proximal urethra. Squamous epithelial cells are creatinine ratio or a 24-hour urine collection is required the largest epithelial cells, and are flat and irregular with small in high-risk patients. central nuclei; they are derived from the distal urethra e The presence of both leukocyte esterase and nitrites on or external genitalia, and their presence in large numbers urine dipstick is highly predictive of a urinary tract (>15/hpf) denotes contamination by genital secretions. infection (UTI); conversely, the absence of both has a high negative predictive value for a UTI. Casts The backbone of all urine casts is a matrix composed of Tamm- Horsfall protein (uromodulin). These cylindrical casts form in Urine Microscopy the distal tubular lumen. Any cells or debris in casts must be Microscopic assessment of urine sediment (Figure 2) is indi- present in the tubule at the time of cast formation, having origi- cated for patients with abnormalities on dipstick and in those nated from a more proximal part of the nephron. Erythrocyte with acute kidney injury, newly diagnosed chronic kidney casts are highly suggestive of glomerulonephritis. Leukocyte disease, or suspected glomerulonephritis. See Table 2 for casts may be present in AIN and infections (pyelonephritis). details on urine microscopy. Pigmented or granular (muddy brown) casts contain tubular cell debris (Figure 4) and may be present in acute tubular necro- Erythrocytes sis. The severity of acute kidney injury correlates with the num- Erythrocyte morphology may indicate their origin (see ber of casts and presence of renal tubular epithelial cells. Figure 2). Isomorphic erythrocytes (round and of consistent size) suggest a nonglomerular origin as a result of infection, Crystals mass, cyst, or stone. Dysmorphic erythrocytes, which are frag- Crystalluria results from the supersaturation of solutes in con- mented erythrocytes with significant variability, suggest glo- centrated urine. These solutes are derived from metabolic merular bleeding. Acanthocytes, a form of dysmorphic eryth- disorders, inherited diseases, drugs, or toxins. Table 3 describes rocytes characterized by vesicle-shaped protrusions, are most features of common crystals. Certain drugs can crystallize in suggestive of a glomerular source of bleeding. Dysmorphic concentrated urine and when used in high doses, including erythrocytes should result in prompt evaluation for glomeru- sulfadiazine, sulfamethoxazole, intravenous acyclovir, metho- lonephritis (Figure 3). See Clinical Evaluation of Hematuria for trexate, and atazanavir. more information. (Text continued on page 8)

infection (UTI); conversely, the absence of both has a high negative predictive value for a UTI. Casts The backbone of all urine casts is a matrix composed of Tamm- Horsfall protein (uromodulin). These cylindrical casts form in Urine Microscopy the distal tubular lumen. Any cells or debris in casts must be Microscopic assessment of urine sediment (Figure 2) is indi- present in the tubule at the time of cast formation, having origi- cated for patients with abnormalities on dipstick and in those nated from a more proximal part of the nephron. Erythrocyte with acute kidney injury, newly diagnosed chronic kidney casts are highly suggestive of glomerulonephritis. Leukocyte disease, or suspected glomerulonephritis. See Table 2 for casts may be present in AIN and infections (pyelonephritis). details on urine microscopy. Pigmented or granular (muddy brown) casts contain tubular cell debris (Figure 4) and may be present in acute tubular necro- Erythrocytes sis. The severity of acute kidney injury correlates with the num- Erythrocyte morphology may indicate their origin (see ber of casts and presence of renal tubular epithelial cells. Figure 2). Isomorphic erythrocytes (round and of consistent size) suggest a nonglomerular origin as a result of infection, Crystals mass, cyst, or stone. Dysmorphic erythrocytes, which are frag- Crystalluria results from the supersaturation of solutes in con- mented erythrocytes with significant variability, suggest glo- centrated urine. These solutes are derived from metabolic merular bleeding. Acanthocytes, a form of dysmorphic eryth- disorders, inherited diseases, drugs, or toxins. Table 3 describes rocytes characterized by vesicle-shaped protrusions, are most features of common crystals. Certain drugs can crystallize in suggestive of a glomerular source of bleeding. Dysmorphic concentrated urine and when used in high doses, including erythrocytes should result in prompt evaluation for glomeru- sulfadiazine, sulfamethoxazole, intravenous acyclovir, metho- lonephritis (Figure 3). See Clinical Evaluation of Hematuria for trexate, and atazanavir. more information. (Text continued on page 8) 5

FIGURE 2. Findings on urine microscopy. A, Erythrocytes (black arrowheads) appear as small anucleated cells. Also shown is a leukocyte (black arrow) embedded in a cast, as well as a tubular cell (white arrow). B, Leukocytes (black arrowheads) are larger than erythrocytes and have characteristic granular cytoplasm: Note the large relative size of squamous epithelial cells (black arrows). C, Hyaline casts have a transparent, empty appearance. D, Granular casts may be coarse or fine in nature. Deeply pigmented (muddy brown) granular casts may be associated with acute tubular necrosis. E, Erythrocyte cast (black arrow). F, Leukocyte cast.

Clinical Evaluation of Kidney Function ‘ f: Ff | @. 8) nn ; FIGURE 4. Tubular injury (for example, acute tubular necrosis) may lead to deposition of pigmented epithelial tubular debris in the proteinaceous matrix of FIGURE 3. Urine microscopy demonstrating acanthocytes, indicated in the red the cast, with the formation of pigmented or granular (muddy brown) casts. circles. Acanthocytes, a form of dysmorphic erythrocytes characterized by vesicle- shaped protrusions, are most suggestive of glomerular bleeding. Courtesy of J. Charles Jennette, MD. TABLE 3. Urine Crystals Type Morphology Associated Conditions Image Calcium oxalate Envelope; dumbbell; Hypercalciuria; hyperoxaluria; calcium needle oxalate stones; ethylene glycol poisoning 4 | Me Calcium phosphate Prism; needle; star-like Distal renal tubular acidosis; urine clumps pH >6.5; tumor lysis syndrome; acute phosphate nephropathy Uric acid Rhomboid; needle; rosette, | Hyperuricemia; gout; diabetes mellitus; barrels; hexagonal plates obesity; tumor lysis syndrome; urine pH <6.0 Struvite (magnesium Coffin-lid Alkaline urine due to chronic urinary ammonium phosphate) tract infection with urease-producing organisms i i Cystine Hexagonal Cystinuria