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Clinical Evaluation of Kidney Function Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no

Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no TABLE 4. Definitions of Proteinuria and Albuminuria

Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no TABLE 4. Definitions of Proteinuria and Albuminuria Total Urine Protein

Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no TABLE 4. Definitions of Proteinuria and Albuminuria Total Urine Protein Urine Collection Method Normal Clinical Proteinuria

Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no TABLE 4. Definitions of Proteinuria and Albuminuria Total Urine Protein Urine Collection Method Normal Clinical Proteinuria 24-Hour excretion <150 mg/24h 2150 mg/24h

Urine albumin, when present at high levels, indicates glo- merular injury; conversely, the absence of albuminuria essen- e Isomorphic erythrocytes suggest a nonglomerular origin tially excludes most glomerular diseases. Smaller proteins are of blood; dysmorphic erythrocytes, particularly acan- filtered at the level of the glomerulus but are reabsorbed by the thocytes, suggest a glomerular origin. proximal tubule; their presence in urine generally indicates e Erythrocyte casts are highly suggestive of glomerulone- tubulointerstitial disease. Light chains present at high levels, phritis, leukocyte casts may be present in acute intersti- such as in monoclonal gammopathy, are detected on urine tial nephritis and infections, and granular (muddy protein electrophoresis or free light chain assay. brown) casts may be present in acute tubular necrosis. Transient, nonpathologic, usually small elevations in urine protein can occur with acute illness or fever, rigorous Measurement of Albumin and Protein Excretion exercise, and pregnancy. Orthostatic proteinuria is a benign Assessment for urine protein is indicated in patients with any proteinuria that increases when the patient is upright but suspected kidney disease. Concurrent increased serum creati- decreases when the patient is recumbent. This condition is nine or abnormal findings on urine sediment raise concern for more common in adolescents but should be considered in active kidney disease in any patient with proteinuria. those up to age 30 years. Split urine collection (daytime versus Assays to detect protein in the urine include urine dip- nighttime collection that includes first morning void) can stick, random (spot) urine protein-creatinine ratio or albumin- evaluate this diagnosis. creatinine ratio, and 24-hour urine collections. Because of the Although screening for proteinuria may be considered for challenges of 24-hour urine collections, the random urine high-risk patients, such as those with diabetes mellitus or hyper- albumin-creatinine ratio and protein-creatinine ratio have tension, screening for proteinuria or chronic kidney disease been widely adopted. Both random tests detect albuminuria, should not be done in asymptomatic adults without risk factors but the urine protein-creatinine ratio also detects nonalbumin for chronic kidney disease, as there is no proven benefit. proteins. Random collections correlate well with timed collec- In patients with diabetes, urine albumin screening is rec- tions and are sufficiently accurate for screening and monitor- ommended because of its ability to detect early disease. The ing proteinuria despite inaccuracies due to diurnal fluctuations American Diabetes Association recommends yearly assessment of urine protein and interindividual differences in urine creati- in patients with type 2 diabetes, and assessment after 5 years of nine excretion. Table 4 outlines the definitions of proteinuria disease in patients with type 1 diabetes. Once patients are taking and albuminuria as well as normal values. an ACE inhibitor or angiotensin receptor blocker, there is no TABLE 4. Definitions of Proteinuria and Albuminuria Total Urine Protein Urine Collection Method Normal Clinical Proteinuria 24-Hour excretion <150 mg/24h 2150 mg/24h Spot urine protein-creatinine ratio? <50 mg/g = $150 mg/24h 2150 mg/g =>150 mg/24h

Urine Collection Method Normal Clinical Proteinuria 24-Hour excretion <150 mg/24h 2150 mg/24h Spot urine protein-creatinine ratio? <50 mg/g = $150 mg/24h 2150 mg/g =>150 mg/24h Urine Albumin Urine Collection Method Normal? Moderately Increased Severely Increased Albuminuria®* Albuminuria>* | 24-Hour excretion <30 mg/24h 30-300 mg/24 h >300 mg/24 h Conventional spot urine dipstick Negative Negative Positive Albumin-specific spot urine <3.0 mg/dL 23.0 mg/dL Positive dipstick® : ae Negative Positive Spot urine albumin-creatinine ratio? = <30 mg/g =<30 mg/24h 30-300 mg/g ~ 30-300 mg/24h — >300 mg/g = >300 mg/24h

Albumin-specific spot urine <3.0 mg/dL 23.0 mg/dL Positive dipstick® : ae Negative Positive Spot urine albumin-creatinine ratio? = <30 mg/g =<30 mg/24h 30-300 mg/g ~ 30-300 mg/24h — >300 mg/g = >300 mg/24h *Because of the difficulty of obtaining a 24-hour urine collection, urine protein-creatinine ratio or urine albumin-creatinine ratio on random (spot) urine samples is used to estimate 24-hour excretion. Measurement of either urine protein or albumin concentration in a sample is divided by the creatinine concentration of the same sample to derive a unitless value. These ratios correlate well with the 24-hour excretion of protein or albumin. Although these calculations are technically dimensionless, they may be expressed by different laboratories with their units of calculation, such as mg/g (mg protein or albumin/g creatinine) or with units to reflect the proportional 24-hour excretion amount (mg or g protein or albumin/g creatinine). ’Chronic kidney disease classification categories A1, A2, and A3 correspond to normal (or mildly increased, moderately increased, and severely increased albuminuria, respectively). ‘The terminology of “moderately increased albuminuria” and “severely increased albuminuria” has been adopted because of the finding that even relatively low levels of urine protein have been associated with significant cardiovascular risk and risk for progression of underlying kidney disease. ¢Conventional urine dipsticks are more sensitive for detection of albumin than nonalbumin proteins; the detection limit is approximately 30 mg/dL, although they are not highly accurate for determining the degree of albuminuria if present.

‘The terminology of “moderately increased albuminuria” and “severely increased albuminuria” has been adopted because of the finding that even relatively low levels of urine protein have been associated with significant cardiovascular risk and risk for progression of underlying kidney disease. ¢Conventional urine dipsticks are more sensitive for detection of albumin than nonalbumin proteins; the detection limit is approximately 30 mg/dL, although they are not highly accurate for determining the degree of albuminuria if present. *Urine dipsticks designed specifically to detect small amounts of albuminuria. Similar to conventional urine dipsticks, these dipsticks detect albumin above a concentration threshold but are sensitive to the presence of albumin at lower levels and can be used to indicate the presence of moderately increased albuminuria.

Clinical Evaluation of Kidney Function evidence that monitoring proteinuria is beneficial or that Clinical Evaluation of Hematuria reduced proteinuria translates into improved outcomes. Hematuria is defined as the presence of >3 erythrocytes/hpf in Urine protein electrophoresis can characterize proteins, the urine sediment and may be microscopic (detectable only allowing for classification of the proteinuria as glomerular or on urine testing) or macroscopic (grossly visible). Hematuria tubular. It also detects monoclonal gammopathy, although it is is most often of nonglomerular origin. A glomerular origin is less sensitive than light chain assay. suggested by concurrent proteinuria, presence of dysmorphic erythrocytes, increased serum creatinine or decrease in eGFR, or systemic signs and symptoms. Evaluation of hematuria is HVC ¢ The random (spot) urine protein-creatinine ratio and outlined in Figure 5. albumin-creatinine ratio correlate with 24-hour urine Urinalysis should not be used for urothelial cancer screen- collections and are sufficiently accurate for screening ing in asymptomatic adults. However, a single incidental find- and monitoring proteinuria. ing of hematuria is sufficient to warrant further investigation. e High urine albumin levels indicate glomerular injury; Evaluation should be pursued even in patients with bleeding

evidence that monitoring proteinuria is beneficial or that Clinical Evaluation of Hematuria reduced proteinuria translates into improved outcomes. Hematuria is defined as the presence of >3 erythrocytes/hpf in Urine protein electrophoresis can characterize proteins, the urine sediment and may be microscopic (detectable only allowing for classification of the proteinuria as glomerular or on urine testing) or macroscopic (grossly visible). Hematuria tubular. It also detects monoclonal gammopathy, although it is is most often of nonglomerular origin. A glomerular origin is less sensitive than light chain assay. suggested by concurrent proteinuria, presence of dysmorphic erythrocytes, increased serum creatinine or decrease in eGFR, or systemic signs and symptoms. Evaluation of hematuria is HVC ¢ The random (spot) urine protein-creatinine ratio and outlined in Figure 5. albumin-creatinine ratio correlate with 24-hour urine Urinalysis should not be used for urothelial cancer screen- collections and are sufficiently accurate for screening ing in asymptomatic adults. However, a single incidental find- and monitoring proteinuria. ing of hematuria is sufficient to warrant further investigation. e High urine albumin levels indicate glomerular injury; Evaluation should be pursued even in patients with bleeding the absence of albuminuria excludes most glomerular diatheses or those taking antiplatelet or anticoagulation ther- apy. If menstruation, viral illness, vigorous exercise, or other diseases. benign cause is suspected, urinalysis should be repeated after HVC e There is no need to monitor urine protein excretion in the cause is resolved. If infection is confirmed, urinalysis patients who are taking an ACE inhibitor or angiotensin should be repeated after treatment to document resolution of receptor blocker. hematuria.

the absence of albuminuria excludes most glomerular diatheses or those taking antiplatelet or anticoagulation ther- apy. If menstruation, viral illness, vigorous exercise, or other diseases. benign cause is suspected, urinalysis should be repeated after HVC e There is no need to monitor urine protein excretion in the cause is resolved. If infection is confirmed, urinalysis patients who are taking an ACE inhibitor or angiotensin should be repeated after treatment to document resolution of receptor blocker. hematuria. AMH (23 erythrocytes/hpf on UA with microscopy) Vv History of gross hematuria (even if self-limited) Vv History and physical Repeated UA after + assessment for other potential treatment of < AMH causes other causes (e.g., infection, menstruation, or recent urologic procedures) Vv No further - evaluation

History and physical Repeated UA after + assessment for other potential treatment of < AMH causes other causes (e.g., infection, menstruation, or recent urologic procedures) Vv No further - evaluation \ | Nephrologic v Vv evaluation if | Renal function testing, proteinuria, erythrocyte | Vv cystoscopy, and A FIGURE 5. Summary of the American morphology, or other imaging | signs indicate College of Physicians recommendations for nephrologic causes | the evaluation of patients with hematuria. | AMH=asymptomatic microscopic hematuria; Areas of uncertainty: Age threshold for urologic evaluation (35-50 years) | UA=urinalysis. Imaging modality of choice (CT for all vs. risk-stratified | Reprinted with permission from Nielsen M, Qaseem A; High Value approach to CT vs. ultrasonography for all) Care Task Force of the American College of Physicians. Hematuria Nephrology evaluation as concurrent vs. alternative pathway | as.amarker of occult urinary tract cancer: advice for high-value ) care from the American College of Physicians. Ann Intern Med. 2016;164:488-97. [PMID: 26810935] doi:10.7326/M15-1496

Clinical Evaluation of Kidney Function TABLE 5. Additional Risk Factors for Urothelial Cancer Irritative lower tract symptoms e Evaluation of hematuria should be pursued even in Prior pelvic radiation therapy patients with bleeding diatheses or those taking anti- platelet or anticoagulation therapy. Prior chemotherapy with cyclophosphamide or ifosphamide e Evaluation of nonglomerular hematuria is based on the Family history of urothelial cancer or Lynch syndrome patient’s underlying risk for urothelial malignancy and Occupational exposure to benzene, rubber, petrochemicals, | and/or dyes ranges from repeat urinalysis in 6 months for low-risk patients to cystoscopy and CT urography for high-risk | Chronic indwelling foreign body in the urothelial tract | patients.

Prior pelvic radiation therapy patients with bleeding diatheses or those taking anti- platelet or anticoagulation therapy. Prior chemotherapy with cyclophosphamide or ifosphamide e Evaluation of nonglomerular hematuria is based on the Family history of urothelial cancer or Lynch syndrome patient’s underlying risk for urothelial malignancy and Occupational exposure to benzene, rubber, petrochemicals, | and/or dyes ranges from repeat urinalysis in 6 months for low-risk patients to cystoscopy and CT urography for high-risk | Chronic indwelling foreign body in the urothelial tract | patients. e If imaging is negative when evaluating patients with In a patient with asymptomatic microhematuria, it is nonglomerular hematuria for renal malignancy, cystos- important to assess kidney function, erythrocyte morphology, copy should be performed. and urine protein to evaluate for a nephrologic cause, particu- larly glomerulonephritis. The absence of proteinuria generally rules out a glomerular process; exceptions include very mild Imaging Studies glomerular disease (most often IgA nephropathy) or thin glo- Ultrasonography is the most commonly used kidney imaging merular basement membrane disease related to a type IV col- modality. It is easily available, safe, and relatively inexpensive. lagen defect that may present as isolated hematuria. Systemic Ultrasonography can demonstrate hydronephrosis, kidney signs and symptoms raise suspicion for nephrologic disease, size and cortical thickness, echogenicity, and presence of cysts particularly those associated with rheumatologic disorders and tumors. Absence of hydronephrosis quickly rules out and rapidly progressive glomerulonephritis. obstruction in most cases. Echogenicity is the ability ofa tissue Macroscopic hematuria should prompt urology referral to “bounce back” or return the ultrasound signal and is recog- even if self-limited, with further evaluation of nephrologic nized as brighter shades on the sonogram image. Echogenicity disease and malignancy as indicated. is nonspecific but implies acute or chronic parenchymal dis- If a nephrologic cause of hematuria is not suggested, ease. Additionally, ultrasonography can measure pre- and hematuria may indicate a malignancy. The American postvoid bladder residual for evaluation of bladder dysfunc- Urological Association (AUA) guidelines recommend stratify- tion or outlet obstruction. Ultrasonography is also useful for ing patients as having low, intermediate, or high risk for an uncomplicated nephrolithiasis; a positive ultrasound may be underlying urothelial malignancy, with risk status dictating adequate for initial diagnosis. Ultrasonography is less useful in subsequent management. Low-risk patients are women evaluating diseases (including stones) of the mid or distal ure- <50 years of age and men <40 years of age who have never ter. Doppler ultrasonography may detect renal artery stenosis smoked, have 3 to 10 erythrocytes/hpf noted on a single urinaly- or renal vein thrombosis, but is highly user dependent. sis, and have no additional risk factors for urothelial cancer CT is appropriate for patients with a nondiagnostic ultra- (Table 5). Low-risk patients should have a repeat urinalysis sound or a more complicated presentation. Noncontrast helical within 6 months and, if normal, require no additional evalua- CT is the gold standard for diagnosis of nephrolithiasis, and is tion. If repeat urinalysis continues to show hematuria, these appropriate for evaluating renal colic. Most stones can be detected, patients are reclassified as intermediate risk (<25 erythrocytes/ including small stones and those in the distal ureter not detected hpf) or high risk (+25 erythrocytes/hpf). Immediate kidney on ultrasound. It may provide information regarding stone com- ultrasonography or ultrasonography plus cystoscopy is not inap- position and, because the entire urinary tract and abdomen are propriate for low-risk patients and should be performed if the visualized, alternative diagnoses may be suggested. patient prefers a more aggressive approach. High-risk patients CT urography (contrast-enhanced kidney-specific CT) is include those with any of the following features: >60 years of the test of choice for patients with unexplained hematuria and age, >30 pack-year history of smoking, >25 erythrocytes/hpf, or allows characterization of renal tumors and cysts. CT with gross hematuria. High-risk patients require cystoscopy and CT contrast is valuable for imaging the renal vasculature. The use urography, if there are no contraindications, or MR urography. of intravenous contrast confers risk for contrast-associated Intermediate-risk patients include all others and require prompt nephropathy in patients with an eGFR <30 mL/min/1.73 m2. kidney ultrasonography and cystoscopy. The American College Intra-arterial contrast confers higher risk, particularly with an of Physicians and the AUA recommend against obtaining urine eGFR <50 mL/min/1.73 m?. cytology in the initial evaluation of hematuria. MRI with contrast is an alternative for evaluation of renal masses and cysts when CT cannot be performed. MR angio- graphy for detection of renal artery stenosis, and venography HVC e Urinalysis should not be used for urothelial cancer for detection of renal vein thrombosis, can be performed with screening in asymptomatic adults. or without gadolinium-based contrast, although contrast pro- (Continued) vides optimal imaging. MR angiography and CT angiography

e If imaging is negative when evaluating patients with In a patient with asymptomatic microhematuria, it is nonglomerular hematuria for renal malignancy, cystos- important to assess kidney function, erythrocyte morphology, copy should be performed. and urine protein to evaluate for a nephrologic cause, particu- larly glomerulonephritis. The absence of proteinuria generally rules out a glomerular process; exceptions include very mild Imaging Studies glomerular disease (most often IgA nephropathy) or thin glo- Ultrasonography is the most commonly used kidney imaging merular basement membrane disease related to a type IV col- modality. It is easily available, safe, and relatively inexpensive. lagen defect that may present as isolated hematuria. Systemic Ultrasonography can demonstrate hydronephrosis, kidney signs and symptoms raise suspicion for nephrologic disease, size and cortical thickness, echogenicity, and presence of cysts particularly those associated with rheumatologic disorders and tumors. Absence of hydronephrosis quickly rules out and rapidly progressive glomerulonephritis. obstruction in most cases. Echogenicity is the ability ofa tissue Macroscopic hematuria should prompt urology referral to “bounce back” or return the ultrasound signal and is recog- even if self-limited, with further evaluation of nephrologic nized as brighter shades on the sonogram image. Echogenicity disease and malignancy as indicated. is nonspecific but implies acute or chronic parenchymal dis- If a nephrologic cause of hematuria is not suggested, ease. Additionally, ultrasonography can measure pre- and hematuria may indicate a malignancy. The American postvoid bladder residual for evaluation of bladder dysfunc- Urological Association (AUA) guidelines recommend stratify- tion or outlet obstruction. Ultrasonography is also useful for ing patients as having low, intermediate, or high risk for an uncomplicated nephrolithiasis; a positive ultrasound may be underlying urothelial malignancy, with risk status dictating adequate for initial diagnosis. Ultrasonography is less useful in subsequent management. Low-risk patients are women evaluating diseases (including stones) of the mid or distal ure- <50 years of age and men <40 years of age who have never ter. Doppler ultrasonography may detect renal artery stenosis smoked, have 3 to 10 erythrocytes/hpf noted on a single urinaly- or renal vein thrombosis, but is highly user dependent. sis, and have no additional risk factors for urothelial cancer CT is appropriate for patients with a nondiagnostic ultra- (Table 5). Low-risk patients should have a repeat urinalysis sound or a more complicated presentation. Noncontrast helical within 6 months and, if normal, require no additional evalua- CT is the gold standard for diagnosis of nephrolithiasis, and is tion. If repeat urinalysis continues to show hematuria, these appropriate for evaluating renal colic. Most stones can be detected, patients are reclassified as intermediate risk (<25 erythrocytes/ including small stones and those in the distal ureter not detected hpf) or high risk (+25 erythrocytes/hpf). Immediate kidney on ultrasound. It may provide information regarding stone com- ultrasonography or ultrasonography plus cystoscopy is not inap- position and, because the entire urinary tract and abdomen are propriate for low-risk patients and should be performed if the visualized, alternative diagnoses may be suggested. patient prefers a more aggressive approach. High-risk patients CT urography (contrast-enhanced kidney-specific CT) is include those with any of the following features: >60 years of the test of choice for patients with unexplained hematuria and age, >30 pack-year history of smoking, >25 erythrocytes/hpf, or allows characterization of renal tumors and cysts. CT with gross hematuria. High-risk patients require cystoscopy and CT contrast is valuable for imaging the renal vasculature. The use urography, if there are no contraindications, or MR urography. of intravenous contrast confers risk for contrast-associated Intermediate-risk patients include all others and require prompt nephropathy in patients with an eGFR <30 mL/min/1.73 m2. kidney ultrasonography and cystoscopy. The American College Intra-arterial contrast confers higher risk, particularly with an of Physicians and the AUA recommend against obtaining urine eGFR <50 mL/min/1.73 m?. cytology in the initial evaluation of hematuria. MRI with contrast is an alternative for evaluation of renal masses and cysts when CT cannot be performed. MR angio- graphy for detection of renal artery stenosis, and venography HVC e Urinalysis should not be used for urothelial cancer for detection of renal vein thrombosis, can be performed with screening in asymptomatic adults. or without gadolinium-based contrast, although contrast pro- (Continued) vides optimal imaging. MR angiography and CT angiography 10

Fluids and Electrolytes have mostly replaced standard angiography of renal arteries. Because of concerns for nephrogenic systemic fibrosis (NSF), Fluids and Electrolytes group I gadolinium-based contrast agents are contraindicated Osmolality and Tonicity in patients with an eGFR <30 mL/min/1.73 m?. Group II gado- The osmolality of a solution is determined by the number of linium-based contrast agents are likely safe in this population, solutes per kilogram. In serum or plasma, osmolality can be such that benefit generally outweighs the risk for NSF. See measured or calculated using the following formula: Chronic Kidney Disease for more information on NSF. Radionuclide imaging provides the most accurate meas- 2x [Na*] + Glucose (mg/dL) /18 + Blood Urea Nitrogen (mg/dL)/2.8 urement of GFR (see Estimation of Glomerular Filtration Rate). + Ethanol (mg/dL)/3.7 if present

have mostly replaced standard angiography of renal arteries. Because of concerns for nephrogenic systemic fibrosis (NSF), Fluids and Electrolytes group I gadolinium-based contrast agents are contraindicated Osmolality and Tonicity in patients with an eGFR <30 mL/min/1.73 m?. Group II gado- The osmolality of a solution is determined by the number of linium-based contrast agents are likely safe in this population, solutes per kilogram. In serum or plasma, osmolality can be such that benefit generally outweighs the risk for NSF. See measured or calculated using the following formula: Chronic Kidney Disease for more information on NSF. Radionuclide imaging provides the most accurate meas- 2x [Na*] + Glucose (mg/dL) /18 + Blood Urea Nitrogen (mg/dL)/2.8 urement of GFR (see Estimation of Glomerular Filtration Rate). + Ethanol (mg/dL)/3.7 if present If using international units: 2 x [Na*] + Urea (mmol/L) + Glucose (mmol/L) + Ethanol (mmol/L) x 1.25 HVC ¢ Ultrasonography is the most commonly used imaging modality in the evaluation of the kidneys and upper urinary Normal serum osmolality is between 275 and 295 mOsm/kg tract because of its safety, cost effectiveness, and availability. H,O. The difference between measured osmolality and calcu- ¢ CT urography is the test of choice for patients with unex- lated osmolality (the osmolal gap) should be <10 mOsm/kg plained hematuria and allows characterization of renal H,O. A greater value suggests the presence of a low-molecular- tumors and cysts; noncontrast helical CT is the gold weight alcohol. Because water moves freely between the intra- standard for diagnosis of nephrolithiasis, and CT with cellular and extracellular spaces based on the osmotic gradient, contrast is valuable in imaging the renal vasculature. the osmolality of both compartments is virtually identical. Osmolality is tightly controlled within a narrow range by thirst and antidiuretic hormone (ADH; also known as vaso- Kidney Biopsy pressin). ADH stimulates reabsorption of water in the collect- ing duct of the kidney. Increases in tonicity stimulate both Clinical and laboratory features are often insufficient for defin- thirst and ADH. As long as there is access to water, appropriate itive diagnosis of kidney disease. Kidney biopsy may therefore thirst, normal control of ADH, and a functioning nephron, be essential for diagnosis and management. Indications serum osmolality should be maintained in the normal range. include glomerular hematuria, severely increased albuminu- Disorders of osmolality reflect impaired water homeostasis. ria (formerly known as macroalbuminuria or overt proteinu- Because the body will defend volume status over tonicity, vol- ria), acute or chronic kidney disease of unclear cause, and ume depletion will stimulate ADH such that at any given kidney transplant dysfunction or monitoring. AIN and athero- osmolality, volume depletion will result in ADH release with embolic disease may require biopsy for diagnosis because they risk for hyponatremia. frequently present only with increased serum creatinine. Percutaneous kidney biopsy with ultrasonography or CT guidance is most common. Open or laparoscopic surgical Disorders of Serum Sodium biopsy is performed when percutaneous biopsy is not possible. Hyponatremia Contraindications to percutaneous biopsy include the unco- Hyponatremia is defined as a serum sodium concentration operative patient, bleeding diatheses (including antiplatelet <135 mEq/L (135 mmol/L). Evaluation begins with measure- use or anticoagulation), uncontrolled hypertension, poor kid- ment of serum osmolality. Hyponatremia is then identified as ney visualization, atrophic kidneys, and active UTI. Solitary hypertonic (osmolality >295 mOsm/kg H,O), isotonic (osmo- kidney and pregnancy require weighing of risks and benefits. lality 275-295 mOsm/kg H,O), or hypotonic (osmolality The most common and concerning risk of biopsy is retro- <275 mOsm/kg H,0) (Figure 6). peritoneal bleeding. Major bleeding complications, including the need for transfusion or angiography with or without Evaluation embolization, and hemodynamic instability occur in <3% of Symptoms caused by hyponatremia depend on both the rapid- biopsies. CT with contrast is the most effective noninvasive ity and degree of decline in serum sodium. Acute hypona- method to assess for large hematoma or an ongoing bleed. tremia in <48 hours provides inadequate time for the brain to However, angiography provides definitive diagnosis of an adapt. A sudden drop in serum sodium causes water to move ongoing bleed and allows for therapeutic intervention. Minor into brain cells, producing cerebral edema and possible head- complications, including pain and hematuria, are more fre- aches, seizures, or death. More chronic declines that allow quent. Kidney loss and death are very rare complications. cells to regulate their volume by decreasing intracellular elec- trolytes may be asymptomatic.

If using international units: 2 x [Na*] + Urea (mmol/L) + Glucose (mmol/L) + Ethanol (mmol/L) x 1.25 HVC ¢ Ultrasonography is the most commonly used imaging modality in the evaluation of the kidneys and upper urinary Normal serum osmolality is between 275 and 295 mOsm/kg tract because of its safety, cost effectiveness, and availability. H,O. The difference between measured osmolality and calcu- ¢ CT urography is the test of choice for patients with unex- lated osmolality (the osmolal gap) should be <10 mOsm/kg plained hematuria and allows characterization of renal H,O. A greater value suggests the presence of a low-molecular- tumors and cysts; noncontrast helical CT is the gold weight alcohol. Because water moves freely between the intra- standard for diagnosis of nephrolithiasis, and CT with cellular and extracellular spaces based on the osmotic gradient, contrast is valuable in imaging the renal vasculature. the osmolality of both compartments is virtually identical. Osmolality is tightly controlled within a narrow range by thirst and antidiuretic hormone (ADH; also known as vaso- Kidney Biopsy pressin). ADH stimulates reabsorption of water in the collect- ing duct of the kidney. Increases in tonicity stimulate both Clinical and laboratory features are often insufficient for defin- thirst and ADH. As long as there is access to water, appropriate itive diagnosis of kidney disease. Kidney biopsy may therefore thirst, normal control of ADH, and a functioning nephron, be essential for diagnosis and management. Indications serum osmolality should be maintained in the normal range. include glomerular hematuria, severely increased albuminu- Disorders of osmolality reflect impaired water homeostasis. ria (formerly known as macroalbuminuria or overt proteinu- Because the body will defend volume status over tonicity, vol- ria), acute or chronic kidney disease of unclear cause, and ume depletion will stimulate ADH such that at any given kidney transplant dysfunction or monitoring. AIN and athero- osmolality, volume depletion will result in ADH release with embolic disease may require biopsy for diagnosis because they risk for hyponatremia. frequently present only with increased serum creatinine. Percutaneous kidney biopsy with ultrasonography or CT guidance is most common. Open or laparoscopic surgical Disorders of Serum Sodium biopsy is performed when percutaneous biopsy is not possible. Hyponatremia Contraindications to percutaneous biopsy include the unco- Hyponatremia is defined as a serum sodium concentration operative patient, bleeding diatheses (including antiplatelet <135 mEq/L (135 mmol/L). Evaluation begins with measure- use or anticoagulation), uncontrolled hypertension, poor kid- ment of serum osmolality. Hyponatremia is then identified as ney visualization, atrophic kidneys, and active UTI. Solitary hypertonic (osmolality >295 mOsm/kg H,O), isotonic (osmo- kidney and pregnancy require weighing of risks and benefits. lality 275-295 mOsm/kg H,O), or hypotonic (osmolality The most common and concerning risk of biopsy is retro- <275 mOsm/kg H,0) (Figure 6). peritoneal bleeding. Major bleeding complications, including the need for transfusion or angiography with or without Evaluation embolization, and hemodynamic instability occur in <3% of Symptoms caused by hyponatremia depend on both the rapid- biopsies. CT with contrast is the most effective noninvasive ity and degree of decline in serum sodium. Acute hypona- method to assess for large hematoma or an ongoing bleed. tremia in <48 hours provides inadequate time for the brain to However, angiography provides definitive diagnosis of an adapt. A sudden drop in serum sodium causes water to move ongoing bleed and allows for therapeutic intervention. Minor into brain cells, producing cerebral edema and possible head- complications, including pain and hematuria, are more fre- aches, seizures, or death. More chronic declines that allow quent. Kidney loss and death are very rare complications. cells to regulate their volume by decreasing intracellular elec- trolytes may be asymptomatic. ¢ Indications for kidney biopsy include glomerular hematuria, Hypertonic Hyponatremia severely increased albuminuria, kidney disease of unclear Hypertonic hyponatremia (osmolality >295 mOsm/kg H,O) cause, and kidney transplant dysfunction or monitoring. results from an increased concentration of effective osmotic

¢ Indications for kidney biopsy include glomerular hematuria, Hypertonic Hyponatremia severely increased albuminuria, kidney disease of unclear Hypertonic hyponatremia (osmolality >295 mOsm/kg H,O) cause, and kidney transplant dysfunction or monitoring. results from an increased concentration of effective osmotic 11

Fluids and Electrolytes Hyponatremia (serum sodium <135 mEq/L[135 mmol/L]) 1 Measure | serum osmolality i Hypotonic lsotonic Hypertonic (<275 mOsm/kg H,O) (>295 mOsm/kg H,O) (275-295 mOsm/kg H,O) (e.g., hyperglycemia) (e.g., hypertriglyceridemia, multiple myeloma) | y | | Hypervolemic || lsovolemic | | Hypovolemic | y | <100 mOsm/kg H,O | c urine osmolality Measure > >100 mOsm/kg H,O | Excessive water intake SIADH FIGURE 6. Evaluation of hyponatremia. SIADH = Decreased solute intake syndrome of inappropriate antidiuretic hormone secretion.

| y | | Hypervolemic || lsovolemic | | Hypovolemic | y | <100 mOsm/kg H,O | c urine osmolality Measure > >100 mOsm/kg H,O | Excessive water intake SIADH FIGURE 6. Evaluation of hyponatremia. SIADH = Decreased solute intake syndrome of inappropriate antidiuretic hormone secretion. solute (typically glucose). The increase in osmolality pulls H,O indicates excessive water intake, as seen with psychogenic water out of cells, diluting the sodium. For every 100-mg/dL polydipsia or poor solute intake. Because the kidney cannot excrete (5.6 mmol/L) increase in glucose, sodium decreases by 1.6 to pure water, a minimal solute concentration of 50 mOsm/kg 2.2 mEq/L (1.6-2.2 mmol/L). H,O is required. If solute intake is low while liquid intake remains high (as seen in beer potomania or chronic low food intake), water Isotonic Hyponatremia excretion is limited by available urinary solute. Isotonic hyponatremia (osmolality 275-295 mOsm/kg H,0) is a Isovolemic hypotonic hyponatremia with urine osmolal- laboratory artifact. Normally, plasma is 93% water (in which sol- ity >100 mOsm/kg H,O can occur in patients with late-stage utes are dissolved) and 7% solids (proteins and lipids). Conditions chronic kidney disease because of impairment of urine dilu- such as severe hypertriglyceridemia or multiple myeloma that tion, causing hyponatremia after excessive dietary fluid intake. increase the solid phase component of plasma will decrease the Urine osmolality >100 mOsm/kg H,O also occurs in isov- sodium concentration in plasma. Measurement of sodium using olemic hypotonic hyponatremia due to the syndrome of inap- a direct ion-selective electrode will avoid this artifact. propriate antidiuretic hormone secretion (SIADH) (Table 6). Medications are the most common cause of SIADH, with Hypotonic Hyponatremia antidepressants and thiazide diuretics being the most com- Hypotonic hyponatremia (osmolality <275 mOsm/kg H,O) mon. 3,4-Methylenedioxymethamphetamine (ecstasy) can reflects excess water for the sodium present and is further also cause hyponatremia. This drug stimulates ADH and, categorized by volume status into hypovolemic, hypervolemic, because of the associated fever and dry mouth, induces thirst. or isovolemic. A frequent finding in SIADH is a low serum urate level In hypovolemic hypotonic hyponatremia, volume depletion (<4.0 mg/dL [0.24 mmol/L]). Cortisol and thyroid hormone leads to renal sodium and water reabsorption stimulated by are required to suppress ADH; therefore, deficiencies of these sympathetic outflow, angiotensin, aldosterone, and ADH, result- hormones should be evaluated. ing in urine sodium concentration <20 mEq/L (20 mmol/L) and urine osmolality >300 mOsm/kg H,O (except if taking diuretics Management or if secondary to renal salt wasting). Treatment of hypotonic hyponatremia is determined by the In hypervolemic hypotonic hyponatremia from heart fail- underlying pathogenesis. In patients with volume overload, ure or cirrhosis, effective circulating blood volume is inade- treatment is targeted to the underlying disease process along quate despite total volume overload, resulting in urine with water restriction. In hypovolemia, volume expansion chemistries similar to hypovolemic hyponatremia. with isotonic saline will suppress ADH, thereby increasing Isovolemic hypotonic hyponatremia is secondary either to water excretion with correction of the hyponatremia. impaired dilution of urine or to water intake that exceeds the kid- Treatment of isovolemic hypotonic hyponatremia is ney’s ability to excrete dilute urine. Urine osmolality distinguishes determined by the severity of symptoms and the rapidity of between these two entities. Urine osmolality <100 mOsm/kg the decline.

solute (typically glucose). The increase in osmolality pulls H,O indicates excessive water intake, as seen with psychogenic water out of cells, diluting the sodium. For every 100-mg/dL polydipsia or poor solute intake. Because the kidney cannot excrete (5.6 mmol/L) increase in glucose, sodium decreases by 1.6 to pure water, a minimal solute concentration of 50 mOsm/kg 2.2 mEq/L (1.6-2.2 mmol/L). H,O is required. If solute intake is low while liquid intake remains high (as seen in beer potomania or chronic low food intake), water Isotonic Hyponatremia excretion is limited by available urinary solute. Isotonic hyponatremia (osmolality 275-295 mOsm/kg H,0) is a Isovolemic hypotonic hyponatremia with urine osmolal- laboratory artifact. Normally, plasma is 93% water (in which sol- ity >100 mOsm/kg H,O can occur in patients with late-stage utes are dissolved) and 7% solids (proteins and lipids). Conditions chronic kidney disease because of impairment of urine dilu- such as severe hypertriglyceridemia or multiple myeloma that tion, causing hyponatremia after excessive dietary fluid intake. increase the solid phase component of plasma will decrease the Urine osmolality >100 mOsm/kg H,O also occurs in isov- sodium concentration in plasma. Measurement of sodium using olemic hypotonic hyponatremia due to the syndrome of inap- a direct ion-selective electrode will avoid this artifact. propriate antidiuretic hormone secretion (SIADH) (Table 6). Medications are the most common cause of SIADH, with Hypotonic Hyponatremia antidepressants and thiazide diuretics being the most com- Hypotonic hyponatremia (osmolality <275 mOsm/kg H,O) mon. 3,4-Methylenedioxymethamphetamine (ecstasy) can reflects excess water for the sodium present and is further also cause hyponatremia. This drug stimulates ADH and, categorized by volume status into hypovolemic, hypervolemic, because of the associated fever and dry mouth, induces thirst. or isovolemic. A frequent finding in SIADH is a low serum urate level In hypovolemic hypotonic hyponatremia, volume depletion (<4.0 mg/dL [0.24 mmol/L]). Cortisol and thyroid hormone leads to renal sodium and water reabsorption stimulated by are required to suppress ADH; therefore, deficiencies of these sympathetic outflow, angiotensin, aldosterone, and ADH, result- hormones should be evaluated. ing in urine sodium concentration <20 mEq/L (20 mmol/L) and urine osmolality >300 mOsm/kg H,O (except if taking diuretics Management or if secondary to renal salt wasting). Treatment of hypotonic hyponatremia is determined by the In hypervolemic hypotonic hyponatremia from heart fail- underlying pathogenesis. In patients with volume overload, ure or cirrhosis, effective circulating blood volume is inade- treatment is targeted to the underlying disease process along quate despite total volume overload, resulting in urine with water restriction. In hypovolemia, volume expansion chemistries similar to hypovolemic hyponatremia. with isotonic saline will suppress ADH, thereby increasing Isovolemic hypotonic hyponatremia is secondary either to water excretion with correction of the hyponatremia. impaired dilution of urine or to water intake that exceeds the kid- Treatment of isovolemic hypotonic hyponatremia is ney’s ability to excrete dilute urine. Urine osmolality distinguishes determined by the severity of symptoms and the rapidity of between these two entities. Urine osmolality <100 mOsm/kg the decline. 12

Fluids and Electrolytes TABLE 6. Causes of the Syndrome of Inappropriate 8.0 mEq/L (8.0 mmol/L) in 24 hours. If there is significant Antidiuretic Hormone Secretion neurologic impairment (e.g., seizures or coma), sodium can be Cause Examples acutely increased 2.0 to 4.0 mEq/L (2.0-4.0 mmol/L) using either a bolus or a continuous 30-mL/h infusion of 3% saline,

TABLE 6. Causes of the Syndrome of Inappropriate 8.0 mEq/L (8.0 mmol/L) in 24 hours. If there is significant Antidiuretic Hormone Secretion neurologic impairment (e.g., seizures or coma), sodium can be Cause Examples acutely increased 2.0 to 4.0 mEq/L (2.0-4.0 mmol/L) using either a bolus or a continuous 30-mL/h infusion of 3% saline, Selective serotonin reuptake inhibitors | Drugs? Thiazide diuretics with frequent monitoring of the urine volume and serum sodium. Simultaneous administration of desmopressin makes Phenothiazines the rate of correction resulting from 3% saline more predicta- Haloperidol ble and safer for the patient because it prevents an unexpected Clofibrate water diuresis and rapid increases in the serum sodium. In patients with asymptomatic isovolemic hypotonic Carbamazepine | Cyclophosphamide | hyponatremia or with minimal symptoms (headache, leth- argy), water restriction is safe and effective. However, limiting Tricyclic antidepressants fluid intake to <800 mL/24 h is often intolerable. If water Valproic acid restriction is not adequate, therapy is targeted at blocking 3,4-Methylenedioxymethamphetamine ADH activity or increasing water excretion. Demeclocycline (ecstasy) | inhibits ADH action and can be used chronically but is fre- |

Selective serotonin reuptake inhibitors | Drugs? Thiazide diuretics with frequent monitoring of the urine volume and serum sodium. Simultaneous administration of desmopressin makes Phenothiazines the rate of correction resulting from 3% saline more predicta- Haloperidol ble and safer for the patient because it prevents an unexpected Clofibrate water diuresis and rapid increases in the serum sodium. In patients with asymptomatic isovolemic hypotonic Carbamazepine | Cyclophosphamide | hyponatremia or with minimal symptoms (headache, leth- argy), water restriction is safe and effective. However, limiting Tricyclic antidepressants fluid intake to <800 mL/24 h is often intolerable. If water Valproic acid restriction is not adequate, therapy is targeted at blocking 3,4-Methylenedioxymethamphetamine ADH activity or increasing water excretion. Demeclocycline (ecstasy) | inhibits ADH action and can be used chronically but is fre- | Malignancy Small cell lung carcinoma quently associated with photosensitivity and gastrointestinal Squamous cell carcinoma of the head symptoms. Tolvaptan, an ADH antagonist, is effective and usu- and neck ally well tolerated, but it is cost-prohibitive and its use is lim- Central nervous Stroke, hemorrhage, infection, trauma, ited to 1 month because of potential liver toxicity. Although system disease and psychosis loop diuretics can be used adjunctively to limit urine concen- Pulmonary disease Pneumonia (viral, bacterial, tuberculous) | tration, along with increased oral sodium intake, a recent Endocrine disorders | Glucocorticoid deficiency randomized study showed no therapeutic benefit in patients treated with water restriction alone versus water restriction Myxedema plus furosemide with or without salt supplementation. Idiopathic Mostly in older patients; some cases later noted to be occult tumor | Patients treated with furosemide had a higher likelihood of (neuroblastoma, small cell carcinoma) acute kidney injury and hypokalemia. Oral urea, 15 to 30 g/d, Endurance exercise — is also effective in increasing water excretion, although its use (marathon running) is often limited because of unpalatable taste. @Drugs are the most common cause. |

Malignancy Small cell lung carcinoma quently associated with photosensitivity and gastrointestinal Squamous cell carcinoma of the head symptoms. Tolvaptan, an ADH antagonist, is effective and usu- and neck ally well tolerated, but it is cost-prohibitive and its use is lim- Central nervous Stroke, hemorrhage, infection, trauma, ited to 1 month because of potential liver toxicity. Although system disease and psychosis loop diuretics can be used adjunctively to limit urine concen- Pulmonary disease Pneumonia (viral, bacterial, tuberculous) | tration, along with increased oral sodium intake, a recent Endocrine disorders | Glucocorticoid deficiency randomized study showed no therapeutic benefit in patients treated with water restriction alone versus water restriction Myxedema plus furosemide with or without salt supplementation. Idiopathic Mostly in older patients; some cases later noted to be occult tumor | Patients treated with furosemide had a higher likelihood of (neuroblastoma, small cell carcinoma) acute kidney injury and hypokalemia. Oral urea, 15 to 30 g/d, Endurance exercise — is also effective in increasing water excretion, although its use (marathon running) is often limited because of unpalatable taste. @Drugs are the most common cause. | e Treatment of symptomatic isovolemic hypotonic hypona- Symptomatic patients with isovolemic hypotonic hypona- tremia consists of a 100-mL bolus of 3% saline.

Malignancy Small cell lung carcinoma quently associated with photosensitivity and gastrointestinal Squamous cell carcinoma of the head symptoms. Tolvaptan, an ADH antagonist, is effective and usu- and neck ally well tolerated, but it is cost-prohibitive and its use is lim- Central nervous Stroke, hemorrhage, infection, trauma, ited to 1 month because of potential liver toxicity. Although system disease and psychosis loop diuretics can be used adjunctively to limit urine concen- Pulmonary disease Pneumonia (viral, bacterial, tuberculous) | tration, along with increased oral sodium intake, a recent Endocrine disorders | Glucocorticoid deficiency randomized study showed no therapeutic benefit in patients treated with water restriction alone versus water restriction Myxedema plus furosemide with or without salt supplementation. Idiopathic Mostly in older patients; some cases later noted to be occult tumor | Patients treated with furosemide had a higher likelihood of (neuroblastoma, small cell carcinoma) acute kidney injury and hypokalemia. Oral urea, 15 to 30 g/d, Endurance exercise — is also effective in increasing water excretion, although its use (marathon running) is often limited because of unpalatable taste. @Drugs are the most common cause. | e Treatment of symptomatic isovolemic hypotonic hypona- Symptomatic patients with isovolemic hypotonic hypona- tremia consists of a 100-mL bolus of 3% saline. tremia (serum sodium typically <120 mEq/L [120 mmol/L]) e The therapeutic goal for acute isovolemic hypotonic hypona- and an acute decrease in serum sodium should be treated with tremia is an increase in serum sodium by 2.0 to 3.0 mEq/L a 100-mL bolus of 3% saline to increase the serum sodium by (2.0-3.0 mmol/L) and 4.0 to 6.0 mEq/L (4.0-6.0 mmol/L) 2.0 to 3.0 mEq/L (2.0-3.0 mmol/L). If symptoms persist, the for chronic isovolemic hypotonic hyponatremia. bolus can be repeated once or twice at 10-minute intervals as e Overly aggressive treatment of chronic isovolemic long as the serum sodium can be measured. If the acute hypotonic hyponatremia can result in osmotic decline in sodium is secondary to excess water intake, fluid demyelination. restriction will rapidly correct the hyponatremia. In isovolemic hypotonic hyponatremia with a more chronic (>48 hours’ presentation) decline in serum sodium, Hypernatremia overly aggressive treatment can result in neuronal damage and Hypernatremia is defined as a serum sodium concentration osmotic demyelination. Accordingly, unless it is documented >145 mEq/L (145 mmol/L). Although less common than that the hyponatremia is acute, all cases should be treated as hyponatremia, hypernatremia is often seen in hospitalized chronic. The osmotic demyelination syndrome is character- patients and is associated with increased mortality in the criti- ized by varied neurologic manifestations, including paresis, cally ill. movement disorders, behavioral abnormalities, seizures, and Hypernatremia can be divided into three broad catego- obtundation, which are usually irreversible. Patients at great- ries: inappropriate intake/administration of hypertonic solu- est risk have severe hyponatremia (Na* <105 mEq/L tions; loss of hypotonic fluids; and excessive water loss due to [105 mmol/L]) that is chronic and often associated with liver defects in ADH release or action. A detailed history and physi- disease, malnutrition, or hypokalemia. The goal of initial ther- cal examination combined with measurement of urine elec- apy is to increase the serum sodium by 4.0 to 6.0 mEq/L trolytes and osmolality help distinguish the pathogenesis of (4.0-6.0 mmol/L) in a 24-hour period, and not to exceed hypernatremia.

tremia (serum sodium typically <120 mEq/L [120 mmol/L]) e The therapeutic goal for acute isovolemic hypotonic hypona- and an acute decrease in serum sodium should be treated with tremia is an increase in serum sodium by 2.0 to 3.0 mEq/L a 100-mL bolus of 3% saline to increase the serum sodium by (2.0-3.0 mmol/L) and 4.0 to 6.0 mEq/L (4.0-6.0 mmol/L) 2.0 to 3.0 mEq/L (2.0-3.0 mmol/L). If symptoms persist, the for chronic isovolemic hypotonic hyponatremia. bolus can be repeated once or twice at 10-minute intervals as e Overly aggressive treatment of chronic isovolemic long as the serum sodium can be measured. If the acute hypotonic hyponatremia can result in osmotic decline in sodium is secondary to excess water intake, fluid demyelination. restriction will rapidly correct the hyponatremia. In isovolemic hypotonic hyponatremia with a more chronic (>48 hours’ presentation) decline in serum sodium, Hypernatremia overly aggressive treatment can result in neuronal damage and Hypernatremia is defined as a serum sodium concentration osmotic demyelination. Accordingly, unless it is documented >145 mEq/L (145 mmol/L). Although less common than that the hyponatremia is acute, all cases should be treated as hyponatremia, hypernatremia is often seen in hospitalized chronic. The osmotic demyelination syndrome is character- patients and is associated with increased mortality in the criti- ized by varied neurologic manifestations, including paresis, cally ill. movement disorders, behavioral abnormalities, seizures, and Hypernatremia can be divided into three broad catego- obtundation, which are usually irreversible. Patients at great- ries: inappropriate intake/administration of hypertonic solu- est risk have severe hyponatremia (Na* <105 mEq/L tions; loss of hypotonic fluids; and excessive water loss due to [105 mmol/L]) that is chronic and often associated with liver defects in ADH release or action. A detailed history and physi- disease, malnutrition, or hypokalemia. The goal of initial ther- cal examination combined with measurement of urine elec- apy is to increase the serum sodium by 4.0 to 6.0 mEq/L trolytes and osmolality help distinguish the pathogenesis of (4.0-6.0 mmol/L) in a 24-hour period, and not to exceed hypernatremia. 13