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History
History plays a limited role because symptoms are nonspecific. Many patients who report bloody urine have highly concentrated urine; myoglobinuria, hemoglobinuria, and bilirubinuria are also often mistaken for hematuria (see Approach to the Genitourinary Patient: Isolated Hematuria). High concentrations of urinary protein cause frothy or sudsy urine. Urinary frequency should be distinguished from polyuria in patients who report excessive urination (see Approach to the Genitourinary Patient: Polyuria and Frequency). Nocturia may be a feature of either but is often the result of excess fluid intake too close to bedtime. Family history is useful for identifying inheritance patterns and risk of polycystic kidney disease or hereditary nephropathy (Alport's syndrome).
Physical
Examination
Patients with acute renal failure may be drowsy, confused, or inattentive; speech may be slurred. Those with chronic renal failure generally appear pale, wasted, or ill. Deep (Kussmaul's) respirations signify acidemia.
Inspection:
Visual fullness of the upper abdomen is an unusual, nonspecific finding of polycystic kidney disease. Visibly asymmetric growth of one side of the body (hemihypertrophy) is a rare sign of Wilms' tumor. Chronic renal failure has several dermatologic manifestations, including xerosis due to sebaceous and eccrine sweat gland atrophy, pallor due to anemia, hyperpigmentation due to melanin deposition, sallow or yellow-brown skin due to urochrome deposition, and petechiae or ecchymoses due to platelet dysfunction. Cutaneous fibrosis can affect patients undergoing dialysis. Uremic frost, the deposition of white-to-tan urea crystals on the skin after sweat evaporation, is rare.
Auscultation:
A soft, lateralizing abdominal bruit is occasionally heard in renal artery stenosis; presence of a diastolic component increases the probability of renovascular hypertension. Pericardial and pleuritic friction rubs can be signs of uremia.
Percussion:
Pain elicited by blunt percussion of the back, flanks, and angle formed by the 12th rib and lumbar spine (costovertebral tenderness) with a fist may indicate pyelonephritis or calculi.
Palpation:
Normal kidneys are not usually palpable. However, in some women, the lower pole of the right kidney can occasionally be felt with palpation upward at the rear flank during deep inspiration, and large kidneys or masses can sometimes be felt without special maneuvers. In newborns, the kidneys can be felt with the thumbs when the thumbs are placed anterior and the fingers posterior to the costovertebral angle.
Other maneuvers:
Transillumination can distinguish solid from cystic renal masses in some children < 1 yr if the kidney and mass are manipulated against the abdominal wall. Asterixis (uremic flap), a manifestation of chronic renal or hepatic failure, can be detected in handwriting or by observation of outstretched hands maximally extended at the wrists; after several seconds in this position, a hand flap in the flexor direction is asterixis.
Testing
Urinalysis and measurement of serum creatinine are the 1st steps in evaluation of renal disorders. Other urine, blood, and imaging tests (eg, ultrasonography, CT, MRI) are done in specific circumstances.
Ideally, after the urethral meatus is cleaned, the urine specimen is collected midstream in the 1st void of the morning (clean-catch specimen); the urine should be examined immediately because delays can lead to changes in test results. When no alternatives exist, bladder catheterization or suprapubic aspiration can be used for collection, but the trauma may falsely increase the number of RBCs in the specimen. A specimen from a catheter collection bag is not acceptable for microscopic and bacteriologic tests.
Urinalysis:
A complete urinalysis includes visual inspection for color and appearance; measurement of pH, specific gravity, protein, glucose, RBCs, nitrites, and WBC esterase by dipstick reagents; and microscopic analysis for casts, crystals, and cells (urine sediment). Bilirubin and urobilinogen, although a standard part of many dipstick tests, no longer play a significant role in evaluation of renal or hepatic disorders.
Color change to red, orange, or brown may indicate the presence of RBCs, myoglobin, bilirubin, or porphyrins; these changes may also be caused by some drugs (eg, levodopa, methyldopa , phenazopyridine , rifampin ) and foods (eg, beets). Cloudy white urine may reflect infection (pyuria), lymph (chyluria) due to filariasis or to obstructed retroperitoneal lymphatics, or precipitated phosphate crystals. Green urine may indicate Pseudomonas infection or use of certain drugs (eg, amitriptyline , methylene blue , propofol ). Rarely, urine in collection bags of catheterized bed-bound patients turns purple (purple urine bag syndrome) when urinary gram-negative bacteria metabolize a tryptophan metabolite (indican) in alkaline urine into indigo; this reaction is clinically insignificant. Dark brown or black urine may result from oxidation of excessive homogentisic acid or melanogen (from melanoma) when urine is exposed to air for several hours.
Odor, often unintentionally noted during visual inspection, conveys useful information only in rare cases of inherited disorders of amino acid metabolism when urine has a distinctive smell (eg, maple syrup in maple syrup urine disease, sweaty feet in isovaleric acidemia, or tomcat urine in multiple carboxylase deficiency).
pH is normally 5.0 to 6.0 (range 4.5 to 8.0). Delay in processing a specimen may elevate pH because ammonia is released as bacteria break down urea. Measuring with a glass pH electrode is recommended when precise values are necessary for decision making, as when diagnosing renal tubular acidosis; in these cases, a layer of oil should be added to the urine specimen to prevent escape of CO2. Infection with urease-producing pathogens can spuriously increase pH.
Specific
gravity provides a rough measure of urine concentration (osmolality). Normal range is 1.001 to 1.035; values may be higher in the elderly, who are less able to dilute and concentrate urine. It is measured by hydrometer or refractometer or estimated with a dipstick. Accuracy of the dipstick is controversial, but the test may be sufficient for patients who have calculi and are advised to self-monitor urine concentration to maintain dilute urine. Specific gravity by dipstick may be spuriously elevated when urine pH is < 6 or low when pH is > 7. Hydrometer and refractometer measurements may be elevated by high levels of large molecules (eg, radiocontrast, albumin, glucose, carbenicillin ) in the urine.
Protein in urine may be normal, but albumin never is. Dipsticks measure albumin, classified as negative (< 10 mg/dL), trace (15 to 30 mg/dL), or 1+ (50 to 100 mg/dL) through 4+ (> 2000 mg/dL). High pH, presence of cells, and radiocontrast cause false elevations. Dilute urine causes falsely low or negative results.
Glucose appears in urine erratically when serum glucose increases to > 180 mg/dL (10.1 mmol/L). Threshold for detection by urine dipstick is 50 mg/dL (2.8 mmol/L). Any amount is abnormal. Ascorbic acid, ketones, aspirin , and dilute urine cause falsely low or negative results.
RBCs lyse on a dipstick test strip, releasing Hb and causing a color change. Range is from negative (0) to 4+. Trace blood (3 to 5 RBCs/HPF) is normal under some circumstances (eg, exercise) in some people. Because the test strip reagent reacts with Hb, free Hb (eg, due to intravascular hemolysis) or myoglobin (eg, due to rhabdomyolysis) causes a positive result. Hemoglobinuria and myoglobinuria can be distinguished from hematuria by the absence of RBCs on microscopic examination and by the pattern of color change on the test strip. RBCs create a dotted or speckled pattern; free Hb and myoglobin create a uniform color change. Povidone iodine causes false-positive results; ascorbic acid causes false-negative results.
Nitrites are produced when bacteria reduce urinary nitrates derived from amino acid metabolism. Nitrites are not normally present and signify bacteriuria. The test is either positive or negative. False-negative results may occur with certain pathogens that cannot convert nitrate to nitrite (eg, Enterococcus faecalis
, Neisseria gonorrhoeae
, Mycobacterium tuberculosis
, Pseudomonas sp) or when time is inadequate (< 4 h) for conversion of nitrate to nitrite, when urinary excretion of nitrate is low, or when bacterial enzymes reduce nitrates to nitrogen. Nitrites are used mainly with WBC esterase testing to follow patients with recurrent urine infections, particularly children with vesicoureteral reflux.
WBC
esterase is released by lysed neutrophils. Its presence in urine reflects acute inflammation, most commonly due to bacterial infection. Threshold for detection is about 5 WBCs/HPF, and test results range from negative (0 WBCs/HPF) to 4+. The test is not very sensitive for detection of infection. Contamination of a urine specimen with vaginal flora is the most common cause of false-positive results. False-negative results may result from very concentrated urine; glycosuria; urobilinogen; or use of phenazopyridine , nitrofurantoin , rifampin , or large amounts of vitamin C. WBC esterase is used mainly with nitrite testing to follow patients with recurrent urine infections. If both tests are negative, the likelihood of a positive urine culture is small.
Microscopic
analysis:
Detection of solid elements (cells, casts, crystals) requires microscopic analysis, ideally viewed immediately after voiding and dipstick testing. The specimen is prepared by centrifuging 10 to 15 mL of urine at 1500 to 2500 rpm for 5 min. The supernatant is fully decanted; a small amount of urine remains with the residue at the bottom of the centrifuge tube. The residue can be mixed back into solution by gently agitating the tube or tapping the bottom. A single drop is pipetted onto a slide and covered with a coverslip. For routine microscopic analysis, staining is optional. The specimen is examined under reduced light with the low-power objective and under full-intensity light with the high-power objective; the latter is typically used for semiquantitative estimates (eg, 10 to 15 WBCs/HPF). Polarized light and phase-contrast microscopy are used in special circumstances. Phase-contrast microscopy enhances identification of cells and casts.
Epithelial
cells (renal tubular, transitional, squamous) frequently appear in urine; most common are squamous cells lining the end of the urethra and contaminants from the vagina. Only renal tubular cells are diagnostically important; however, except when found in casts, they are difficult to distinguish from transitional cells. A few renal tubular cell casts appear in normal urine, but a large number suggests tubular injury (eg, acute tubular necrosis, tubulointerstitial nephropathy, nephrotoxins, nephrotic syndrome).
RBCs < 3/HPF may be normal, and any hematuria should be interpreted in clinical context (see Approach to the Genitourinary Patient: Isolated Hematuria). Microscopic analysis may be useful for distinguishing glomerular from nonglomerular RBCs. Glomerular RBCs are dysmorphic, with spicules, folding, and blebs; nonglomerular RBCs retain their normal shape.
WBCs < 5/HPF may be normal; special staining can distinguish eosinophils from neutrophils (see Approach to the Genitourinary Patient: Other urine tests). Pyuria is defined as ≥ 8 WBCs/μL of uncentrifuged urine, which corresponds to 2 to 5 WBCs/HPF in spun sediment.
Lipiduria is most characteristic of the nephrotic syndrome; renal tubular cells absorb filtered lipids, which appear microscopically as oval fat bodies, and cholesterol, which produces a Maltese cross pattern under polarized light. Lipids and cholesterol can also be free floating or incorporated into casts.
Crystals in urine are common and usually clinically insignificant. Crystal formation depends on urine concentration of crystal constituents, pH, and absence of crystallization inhibitors. The 4 most common types of crystals are Ca oxalate, uric acid, cystine, and Mg ammonium phosphate. Ca oxalate crystals occur in several shapes but are most easily recognized when they form small, octahedral, envelope-like shapes. When present in large numbers, they strongly suggest ethylene glycol poisoning or, rarely, short small bowel syndrome, hereditary oxalosis and oxaluria, and high doses of vitamin C. Ca oxalate crystals are also important in evaluation of calculi. Uric acid crystals are amorphous in acidic, highly concentrated, cool urine but may be diamond- or needle-shaped or rhomboid. They may indicate mild dehydration in newborns and tumor lysis syndrome in patients with cancer or renal failure. Cystine crystals are perfect hexagons, may occur alone as flat plates or as overlapping crystals of varying sizes, and are diagnostic of cystinuria, a rare hereditary cause of calculi. Mg ammonium phosphate crystals, which may resemble coffin lids or quartz crystals, often occur in normal alkaline urine and in urine of patients with struvite calculi. Drugs (eg, acyclovir , some sulfonamides, indinavir , high-dose methotrexate ) are an underrecognized cause of crystal formation. Crystals of acyclovir are birefringent and needle-shaped; they exist free or engulfed in leukocytes. Crystals of indinavir form a starburst shape or individual needle-shaped crystals and are best seen under polarized light. Sulfa and ampicillin crystals are also needle-shaped and best seen when polarized. Sulfa crystals can also appear in clusters.
Casts are made up of glycoprotein of unknown function (Tamm-Horsfall protein) secreted from the thick ascending loop of Henle. They differ in constituents and appearance (see
Table 1: Approach to the Genitourinary Patient: Urinary Casts ).
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Table 1
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Urinary Casts
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Type
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Description
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Significance
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Plain casts
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Hyaline
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Glycoprotein matrix secreted by tubules
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Nonspecific; present in normal urine but may also appear in patients with low urine flow (eg, due to dehydration or after diuretic therapy), physiologic stress, an acute renal disorder with other abnormalities, or a chronic renal disorder (as broad casts formed in dilated tubules)
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Waxy
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Glycoprotein matrix with degraded protein; formed in atrophic tubules; highly refractile with waxy appearance
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Present in advanced renal failure; predicts a poor prognosis
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Casts with inclusions
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RBC
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Glycoprotein matrix with RBCs; often appears red-orange
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Virtually pathognomonic of glomerulonephritis; rarely occurs with cortical necrosis, acute tubular injury, or hematuria in runners
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Epithelial cell
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Protein matrix variably filled with tubular cells
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Occurs in acute tubular injury, glomerulonephritis, or nephrotic syndrome
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WBC
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Protein matrix variably filled with WBCs
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Suggests pyelonephritis but can indicate other causes of tubulointerstitial inflammation; may occur in the exudative stage of proliferative glomerulonephritis
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Granular
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Glycoprotein matrix with protein or cellular debris
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Occasionally occurs with exercise or dehydration and normal renal function; more often indicates glomerular or tubulointerstitial disorders
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Pigment
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Tubular cell or granular casts with pigment stain
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Usually occurs in acute renal failure due to hemolysis or rhabdomyolysis or in acute tubular necrosis when jaundice is present
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Fatty
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Free fat droplets or tubular cells with fat droplets in a protein matrix
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May occur in various types of tubulointerstitial disorders; in large numbers, strongly suggests nephrotic syndrome or Fabry's disease
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Mixed
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Hyaline cast with various cells (eg, RBCs, WBCs, tubular cells)
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Usually occurs in proliferative glomerulonephritis
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Miscellaneous
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Crystals or bacteria
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With crystals, may suggest a metabolic disorder or a cause of calculi; with bacteria, pathognomonic of bacterial pyelonephritis
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Pseudocasts
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Clumped urates, WBCs, bacteria, and artifacts
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Important not to confuse with true casts
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Other urine tests:
Other tests are useful in specific instances.
Sulfosalicylic acid (SSA) test strips can be used to detect protein other than albumin (eg, Igs in multiple myeloma) when dipstick urine tests are negative; urine supernatant mixed with SSA becomes turbid if protein is present. The test is semiquantitative with a scale of 0 (no turbidity) to 4+ (flocculent precipitates). Readings are falsely elevated by radiocontrast agents.
Protein
excretion can be measured in a 24-h collection or can be estimated by the protein-to-creatinine ratio, which, in a random urine sample, correlates well with values in g/1.73 m2 BSA from a 24-h collection (eg, 400 mg/dL protein and 100 mg/dL creatinine in a random sample equal 4 g/1.73 m2 in a 24-h collection).
Microalbuminuria is albumin excretion persistently between 30 and 300 mg/day (20 to 200 μg/min). Normally, albumin excretion is < 20 mg/day (< 15 μg/min); > 300 mg/day (> 200 μg/min) is considered overt proteinuria. Use of the urine albumin-to-urine creatinine ratio is a reliable and more convenient screening test because it avoids timed urine specimens and correlates well with 24-h values. A value > 30 mg/g (> 0.03 mg/mg) suggests microalbuminuria. The reliability of the test is best when a midmorning specimen is used, vigorous exercise is avoided before the test, and unusual creatinine production (cachectic or very muscular patients) is not present. In diabetics, microalbuminuria usually indicates diabetic nephropathy and provides an early way to detect the disorder. Microalbuminuria is a risk factor for cardiovascular disorders and early cardiovascular mortality independent of diabetes or hypertension.
Ketones spill into urine with ketonemia, but use of test strips to measure urinary ketones is no longer widely recommended because they measure only acetoacetic acid and acetone, not β-hydroxybutyric acid. Thus, a false-negative result is possible even without an exogenous cause (eg, vitamin C, phenazopyridine , N- acetylcysteine ); direct measurement of serum ketones is more accurate. Ketonuria is caused by endocrine and metabolic disorders and does not reflect renal dysfunction.
Osmolality, the total number of solute particles per unit volume (mOsm/kg [mmol/kg]), can be measured directly by osmometer. Normally, osmolality is 50 to 1200 mOsm/kg. Measurement is most useful for evaluating hypernatremia, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and diabetes insipidus.
Electrolyte
measurements help diagnose specific disorders. Na level can help distinguish whether volume depletion (urine Na < 20 mEq/L) or acute tubular necrosis (urine Na > 40 mEq/L) is the cause of acute renal insufficiency or failure. The fractional excretion of Na (FENa), which is the ratio of excreted to filtered Na, is defined as
where UNa is urine Na, PNa is plasma Na,
is urine flow (mL/min), PCr is plasma creatinine, UCr is urine creatinine, and ClCr is the creatine clearance in mL/min. Because ClCr = (UCr)(Uvol)/PCr, the flow terms cancel out and the equation can be rewritten as
This ratio is a more reliable measure than UNa alone because UNa levels between 20 and 40 mEq/L are nonspecific. FENa < 1% suggests volume depletion; > 1% suggests acute tubular necrosis. Other useful measurements include fractional excretion of HCO3 in evaluation of renal tubular acidosis (see Abnormal Renal Transport Syndromes: Renal Tubular Acidosis (RTA)); Cl levels and urine anion gap for diagnosis of metabolic acidosis (see Acid-Base Regulation and Disorders: Diagnosis); K levels, occasionally useful in treatment of hypokalemia; and levels of Ca, Mg, and constituents such as uric acid, oxalate, citrate, and cystine in evaluation of calculi.
Eosinophils, cells that stain bright red or pink-white with Wright's or Hansel staining, most commonly indicate acute interstitial nephritis, rapidly progressive glomerulonephritis, acute prostatitis, or renal atheroembolism.
Cytology is used to screen for cancer in high-risk populations (eg, petrochemical workers), to evaluate painless hematuria due to nonrenal disorders, and to check for recurrence after bladder tumor resection. Sensitivity is about 90% for carcinoma in situ; however, sensitivity is considerably lower for low-grade transitional cell carcinomas. Inflammatory or reactive hyperplastic lesions or cytotoxic drugs for carcinoma may produce false-positive results. Accuracy for detecting bladder tumors may be increased by vigorous bladder lavage with a small volume of 0.9% saline solution (50 mL pushed in, then aspirated by syringe through a catheter). Cells collected in the saline are concentrated and examined.
Gram
stain and cultures with susceptibility testing are indicated when GU tract infections are suspected; a positive test must be interpreted in the clinical context (see Urinary Tract Infections (UTI)).
Amino
acids are normally filtered and reabsorbed by the proximal tubules. They may appear in urine when a hereditary or acquired tubular transport defect (eg, Fanconi syndrome, cystinuria) is present. Measuring type and amount of amino acids may help in the diagnosis of certain types of calculi, renal tubular acidosis, and inherited disorders of metabolism.
Creatinine
clearance:
Creatinine clearance (CrCl) is a measure of GFR, the amount of blood filtered through the kidney per minute, because creatinine is produced at a constant rate by muscle metabolism and is freely filtered without reabsorption or metabolism by the kidneys. However, enough additional creatinine is secreted that CrCl overestimates GFR by about 10 mL/min/1.73 m2 BSA, or by 10 to 20%. Using a timed urine collection, CrCl can be calculated as
where UCr is urine creatinine concentration. Normal values (adjusted by dividing by BSA in m2) are 70 ± 14 mL/min/m2 for men and 60 ± 10 mL/min/m2 for women. CrCl increases throughout childhood and progressively decreases after about age 40, so that by age 80, CrCl is normally ½ what it was in young adulthood. Up to 50% of the glomerular filtering surface may be lost before the serum creatinine begins to rise because of hypertrophy of residual glomeruli. Thus, a normal CrCl cannot exclude mild renal disease and is not useful for detecting early kidney damage.
Blood
tests:
Serum creatinine levels can estimate CrCl on the premise that urine volume and creatinine in the above equation are roughly constant. Levels are affected by diet, age, and muscle mass; the last 2 are reflected in the following equation:
For women, the calculated value is multiplied by 0.85. GFR (in mL/min/1.73 m2) has been shown to be more accurately predicted by
but the difficulty of calculating this equation has limited its use. In general, serum creatinine values > 1.3 mg/dL (> 114 μmol/L) in men and > 1 mg/dL (> 90 μmol/L) in women are abnormal. Values may be falsely elevated by consumption of large amounts of meat and use of some drugs ( cimetidine , trimethoprim , cefoxitin , flucytosine ). With aging, CrCl decreases but so does creatinine production due to decreasing muscle mass and turnover; thus, serum creatinine tends to remain stable at about 1.0.
ACE inhibitors and angiotensin II receptor blockers reversibly decrease GFR and increase creatinine because they vasodilate efferent more than afferent glomerular arterioles. Creatinine levels vary inversely but nonlinearly with GFR, so that small changes just above normal in creatinine indicate a more dramatic decline in GFR than do larger changes well above normal. Thus, creatinine measurements are better used to follow changes in renal function over time rather than to detect renal disorders.
BUN/creatinine ratio is used to distinguish prerenal from renal or postrenal (obstructive) azotemia; a value > 15 is considered abnormal and may occur in prerenal and some cases of postrenal azotemia. However, BUN is affected by protein intake and by multiple nonrenal processes (eg, trauma, infection, GI bleeding, corticosteroids) and, although suggestive, is generally unreliable for evaluating renal disorders.
Serum chemistries (eg, Na, K, HCO3) may become abnormal in acute and chronic renal failure and should be monitored periodically.
CBC may detect anemia in chronic renal disorders or, rarely, polycythemia in renal cell carcinoma or polycystic kidney disease. Anemia is often multifactorial (eg, due to erythropoietin deficiency, blood loss in dialysis circuits or the GI tract); it may be microcytic or normocytic, and may be hypochromic or normochromic.
Renin, a proteolytic enzyme, is stored in the juxtaglomerular cells of the kidneys. Renin secretion is stimulated by reduced blood volume and flow in afferent renal arterioles and is inhibited by Na and water retention. Plasma renin is assayed by measuring renin activity as the amount of angiotensin I generated per hour. Specimens should be drawn from well-hydrated, Na- and K-replete patients who have been supine for at least 15 min. Plasma renin activity should be measured in evaluation of adrenal insufficiency, hyperaldosteronism, and refractory hypertension. Renal vein renin level is still occasionally measured to determine the functional significance of renal artery obstruction (see Arterial Hypertension: Renovascular Hypertension).
Last full review/revision November 2005
Content last modified November 2005
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