Articles on Medical Diseases and Conditions

Category: Renal Function Tests

  • The Problem of Hematuria

    Major etiologies of hematuria and details of available tests were discussed in Chapter 12. The problem of hematuria is somewhat different from that of proteinuria. About 4% (range, 1.2%-9%) of asymptomatic men under age 40 have microhematuria of two or more RBCs per high-power field compared with about 15% (range, 13%-19%) of clinically healthy men over age 40 years. A major consideration is not to overlook genitourinary system cancer. Hematuria is the most frequent symptom of bladder and renal carcinoma, being reported in about 80% (range, 65%-85%) of bladder carcinoma and about 60%-70% (range, 32%-80%) of renal carcinoma. Gross hematuria comprises the majority of hematuria in both bladder and renal carcinoma. About 98% of bladder carcinoma and about 96% of renal carcinoma (not including Wilms’ tumor of childhood) occurs after age 40. Renal carcinoma is reported in about 1% (range, 0%-2.0%) of patients with hematuria of any type under age 40 years and in about 1.5%-2.0% (range, 0.4%-3.5%) in patients over age 40 years. Bladder carcinoma is reported in about 3% (range, 0.2%-8.0%) of patients with hematuria under age 40 years and in about 7%-10% (range, 0.1%-15%) of patients over age 40 years. In younger patients, several investigators have found IgA glomerulonephritis in 35%-40% of patients with gross or considerable microscopic hematuria in whom renal biopsy was performed. Over age 40, gross hematuria is much more strongly associated with cancer (although less frequently, neoplasia may present with microscopic hematuria and sometimes may be discovered with a completely normal urinalysis). Therefore, in persons under age 40 years (and especially between age 10 and 30 years) with gross hematuria, the majority of investigators do not expect cancer and do not favor extensive workup unless hematuria persists or there are other symptoms that suggest cancer. However, this opinion is not unanimous. In persons over age 40 with gross hematuria, the standard response would be, as a minimum, an IVP and cystoscopy (if the IVP results were negative).

    In persons under age 40 years with microscopic hematuria, most investigators question the need for additional investigation unless other symptoms suggest cancer or hematuria persists. In patients over age 40 years with asymptomatic microscopic hematuria only, especially if there are relatively few RBCs, opinion is divided whether to test further, and how much. Presence of other symptoms greatly increases pressure for further tests. Substantial numbers of RBCs (>10 RBCs per high-power field) also seem to influence opinions, although most studies have shown rather poor correlation in microhematuria between presence of cancer and the number of RBCs in the urine sediment. Also, it must not be forgotten that the patient may have hematuria due to carcinoma of the kidney or bladder and at the same time have other diseases, such as hypertension, which themselves are known causes of hematuria. Finding RBC casts means that the RBCs are from the kidney and that the problem is a medical disease rather than cancer.
    RBCs or hemoglobin (from lysed RBCs) in the urine may appear because of contamination during specimen collection. Female vaginal secretions may contain RBCs, WBCs, or both. A significant number of squamous epithelial cells in urine sediment (arbitrarily defined as more than 10 squamous cells per low-power field) suggests possible contamination, and the study should be repeated using a midstream voided specimen. It may be necessary to assist the patient with expert personnel.

  • The Problem of Proteinuria

    As discussed in Chapter 12, proteinuria is not itself a renal function test but almost invariably accompanies serious renal damage. Its severity does not necessarily correlate with the amount of damaged renal parenchyma or the status of any one renal function or group of systems. Its presence and degree may, in association with other findings, aid in the diagnosis of certain syndromes or disease entities whose renal pathologic findings are known. Proteinuria may be secondary to benign or extra-renal etiologies or even to contamination of the specimen.

    One question that continually arises is the significance of small degrees of proteinuria. The urine protein reference range lower limit is usually stated in textbooks to be 10 mg/100 ml (0.1 g/L). Generally speaking, values of up to 30 mg/100 ml are within normal range; 30-40 mg/100 ml may or may not be significantly abnormal. It should be noted that reference values in terms of total urinary protein output per 24 hours may be up to 100 mg/24 hours. Values stated in terms of milligrams per 24 hours may not coincide with values expressed in terms of milligrams per 100 ml due to varying quantities of diluent water. One exception to conventional reference values is diabetes mellitus, in which lesser degrees of albuminuria may reflect early renal damage and may suggest need for revised therapy (Chapter 28). It must be stressed that duration of proteinuria is even more important than quantity, especially at low values. As an example, 60 mg/100 ml (0.4 g/L) may be significant if this level persists. This becomes clear by examining the list of possible causes of proteinuria (Chapter 12). Intrinsic renal disease is usually associated with persistent proteinuria, whereas the proteinuria seen with many of the extrarenal types quickly disappears if the primary disease is successfully treated. However, this does not always hold true, and one must remember that a single disease may cause permanent damage to more than one organ. For example, arteriosclerosis or hypertension may reduce or destroy functioning kidney tissue by means of arteriolar nephrosclerosis, although cardiac symptoms due to heart damage may overshadow the renal picture.

    A common situation is the patient who has asymptomatic proteinuria alone or in association with a disease in which it is not expected. The first step is to repeat the test after 2 or 3 days (in clinically healthy persons) or when the presenting disease is under control (in hospitalized patients) using an early morning specimen to avoid orthostatic proteinuria. This is important because orthostatic proteinuria is common; several reports indicate that it is the cause in about 20% (range, 15%-70%) of healthy young men with proteinuria on routine urinalysis. If proteinuria persists and orthostatic proteinuria is ruled out, the microscopy report should be analyzed for any diagnostic hints. Care should be taken to prevent contamination of the urine specimen, especially in female patients. The presence and degree of hematuria or pyuria suggest a certain number of diseases. If either is present, there should be a careful search for RBC or white blood cell (WBC) casts. A careful history may elicit information of previous proteinuria or hematuria, suggesting chronic glomerulonephritis, or previous kidney infection or calculi, which favors chronic pyelonephritis. Uremia due to chronic bilateral renal disease often has an associated hypertension. (Of course, hypertension may itself be the primary disease and cause extensive secondary renal damage.) In addition, a low-grade or moderate anemia, either normochromic or slightly hypochromic and without evidence of reticulocytosis or blood loss, is often found with severe chronic diffuse renal disease. The next step is to note any random specific gravities obtained. If one measurement is normal (i.e., >1.020), renal function is probably adequate. If all are lower, one can proceed to a concentration or creatinine clearance test, since low random specific gravities may simply mean high water excretion rather than lack of urine-concentrating ability. If the creatinine clearance rate is mildly or moderately reduced, the patient most likely has only mild or possibly moderate functional loss. If the creatinine clearance rate is markedly abnormal and the BUN level is normal with no hypertension or anemia present, the patient most likely has severe diffuse bilateral renal abnormality but not completely end-stage disease. When the BUN level is elevated but the serum creatinine level is still within reference range, some test or tests, such as the free water clearance, could be done to differentiate prerenal azotemia from early renal failure (acute or chronic). When both the BUN and serum creatinine levels are elevated and there is no anemia or hypertension, the differential diagnosis of prerenal azotemia or renal failure must still be made, but prerenal azotemia becomes less likely. When the BUN and serum creatinine levels are significantly elevated and there is anemia and other evidence of uremia, the prognosis is generally very bad, although some patients with definite uremia may live for years with proper therapy. There are exceptions to the situations just outlined but not too many.

  • Azotemia (Elevated Blood Urea Nitrogen Level) and Renal Failure

    Many use the term “uremia” as a synonym for azotemia, although uremia is a syndrome and should be defined in clinical terms. A BUN level of approximately 100 mg/100 ml is usually considered to separate the general category of acute reversible prerenal azotemias from the more prolonged acute episodes and chronic uremias. In general, this is an accurate distinction, but there is a small but important minority of cases that do not follow this rule. Thus, some uremics seem to stabilize at a lower BUN level until their terminal episode, whereas a few persons with acute transient azotemia may have a BUN level close to 100 mg/100 ml (36 mmol/L) and, rarely, more than 125 mg/100 ml (45 mmol/L), which rapidly falls to normal levels after treatment of the primary systemic condition. It must be admitted that easily correctable prerenal azotemia with an appreciably elevated BUN level is almost always superimposed on previous subclinical renal damage or function loss. Although the previous damage may not have been severe enough to cause symptoms, the functional reserve of these kidneys has been eliminated by aging changes, pyelonephritis, or similar conditions. The same is usually true for azotemia of mild levels (30-50 mg/100 ml [11-18 mmol/L]) occurring with dehydration, high protein intake, cardiac failure, and other important but not life-threatening situations. After the BUN level has returned to normal levels, a creatinine clearance determination will allow adequate evaluation of the patient’s renal status.

    The onset of oliguria always raises the question of possible renal failure. For a long time oliguria was considered a constant clinical sign of acute renal failure (also called acute tubular necrosis); however, it is now recognized that 30%-50% of patients with acute renal failure do not have oliguria (literature range, 20%-88%). Normal adult urine volume is 500-1,600 ml/24 hours (upper limit depends on fluid intake); a volume less than 400 ml/24 hours is considered to represent oliguria if all urine produced has actually been collected. Incomplete collection or leakage around a catheter may give a false impression of oliguria. Occasionally a patient develops oliguria and progressive azotemia, and it becomes necessary to differentiate between prerenal azotemia, which is correctable by improving that patient’s circulation, and acute renal tubular necrosis. This problem most frequently occurs after a hypotensive episode or after surgery.

    The differential diagnosis of azotemia includes prerenal azotemia, acute renal failure (acute tubular necrosis), and chronic renal failure. Two tests, filtered fraction of sodium and the free water clearance, under certain conditions, are usually capable of differentiating prerenal azotemia from renal failure. In general, if the serum creatinine level as well as the BUN level is elevated, this is more suggestive of renal failure than prerenal azotemia. However, this assumes that the BUN elevation is discovered very early after onset. Under most conditions the differentiation between prerenal azotemia and acute tubular necrosis by means of the serum creatinine level is not sufficiently reliable. A number of other tests have been proposed for the same purpose (Chapter 37). These tests have been found useful by some investigators but not useful in a sufficient number of cases by others. Part of the difference of opinion is based on the test criteria each investigator uses to differentiate prerenal azotemia from acute tubular necrosis. In general, when the test criteria are structured simply to provide best statistical separation for all cases of prerenal azotemia and acute tubular necrosis, there is considerable overlap between the two groups. When the criteria are deliberately structured to separate out either the cases of prerenal azotemia or those of acute tubular necrosis and the diagnosis is made only on the remaining cases, the test becomes insufficiently sensitive. A good example is the test using urine excretion of sodium. If one uses the urine sodium cutoff point of less than 15 mEq/L (mmol/L), the test has excellent reliability in ruling out acute tubular necrosis. However, one investigator found that 67% of patients with acute tubular necrosis and 63% of patients with prerenal azotemia had urine sodium values between 15 and 40 mEq/L (mmol/L). Therefore, if one wishes to use less than 15 mEq/L (mmol/L) as a diagnostic limit to avoid the overlap, one excludes 63% of this investigator’s prerenal azotemia cases, and the test becomes poorly sensitive for prerenal azotemia, despite excellent specificity created by ruling out nearly all cases of acute tubular necrosis.

    Part of the problem is the fact that acute tubular necrosis may be oliguric or nonoliguric. Some test criteria that enable good separation of prerenal azotemia and oliguric acute tubular necrosis are not as good in distinguishing prerenal azotemia from nonoliguric acute tubular necrosis. If the test cutoff points are restructured to include both oliguric and nonoliguric acute tubular necrosis, the overall accuracy of the test may suffer.

    In occasional cases, initial tests indicate that some renal function still remains, but the patient then develops acute tubular necrosis due to progression of the underlying disease or superimposition of some other factor.

    Urinalysis may provide useful information in patients with acute tubular necrosis. Red blood cell (RBC) or hemoglobin casts suggest glomerulonephritis, subacute bacterial endocarditis, transfusion reaction, and collagen disease. Uric acid crystals may provide a clue to uric acid nephropathy. Strongly positive urine chemical tests for hemoglobin without significant microscopic RBC raises the possibility of myoglobin.

    Differentiation of acute tubular necrosis and chronic renal failure is extremely difficult without clinical evidence of acute onset. If the patient does not have an elevated serum creatinine level when first investigated, or if the creatinine level is only mildly elevated and there is no anemia or other evidence of uremia, the evidence is more in favor of acute tubular necrosis than chronic renal failure. Even more difficulty exists when a patient develops acute tubular necrosis and the question is raised as to whether the patient’s renal function is likely to recover. Radioisotope studies with a scintillation camera may be helpful. Bilateral poor uptake, poor cortex-pelvis transit, and decreased blood flow suggest chronic diffuse renal disease. Good cortex uptake, poor cortex-pelvis transit, and good blood flow are more indicative of acute tubular necrosis or prerenal azotemia. Isotope techniques can demonstrate postrenal obstruction and frequently can visualize the kidneys when the IVP cannot.

    In a patient with uremia (chronic azotemia), there is no good way to determine prognosis by laboratory tests. The degree of azotemia does not correlate well with the clinical course in uremia except in a very general way.

    Other diagnostic tests

    Addis count. This procedure is used in suspected subclinical cases of chronic glomerulonephritis to demonstrate 12-hour abnormally increased rates of RBCs and cast excretion too small to exceed the normal range in ordinary random specimen microscopic examinations. If the random urine specimen already shows hematuria or pyuria, and if contamination can be ruled out by catheter or clean catch collection technique, the Addis count cannot do anything more than show the same abnormality. Addis counts are very rarely necessary with a good history and adequate workup.

    Renal biopsy. This procedure is now widely used. It may be the only way to find which disease is present, but it should be reserved for patients whose treatment depends on exact diagnosis. The general category of most renal disease entities can be inferred using routine methods. Because of the random sample nature of renal biopsies, ordinary light microscopy more often than not shows only nonspecific changes reflecting the result rather than the etiology of the disease process, and frequently renal biopsies are requested only for academic rather than for practical diagnostic or therapeutic reasons. In children, electron microscopy and immunofluorescent techniques are more useful than light microscopy.

  • Tests of Predominantly Tubular Function

    These include specific gravity, osmolality, urine excretion of electrolytes, the free water clearance test, and certain substances secreted by renal tubules.

    Phenolsulfonphthalein (PSP) excretion

    Phenolsulfonphthalein is excreted mainly by the renal tubules. In general, results give about the same clinical information as the creatinine clearance rate since glomerular and tubular dysfunction usually occur together in acute and chronic kidney damage. Creatinine clearance tests seem to have mostly replaced PSP tests in the relatively few situations in which this type of information is needed.

    Specific gravity

    Specific gravity (defined and described in Chapter 12) is important in the evaluation of chronic diffuse parenchymal disease (chronic glomerulonephritis, chronic pyelonephritis, etc.). As such conditions progress, tubular ability to concentrate urine is often affected relatively early and slowly decreases until the urine has the same specific gravity as the plasma ultrafiltrate—1.010. This usually, but not always, occurs in advance of final renal decompensation. For concentration tests to be accurate, the patient must be deprived of water over a long time period to exclude influence from previous ingestion. The usual test should run 16-17 hours. If forced fluids were given previously, a longer time may be necessary. This may be impossible in patients with cardiac disease, those with renal failure, aged persons, or those with electrolyte problems. Under these test conditions, the average person should have a urine specific gravity over 1.025; at least as high as 1.020. Concentration tests are also impaired in patients with diabetes insipidus, the diuretic phase of acute tubular necrosis, and occasionally in hyper-thyroidism, severe salt-restricted diets, and sickle cell anemia. These conditions may result in failure to concentrate without the presence of irreversible renal tubular damage. Ten grams of protein per liter raises specific gravity by 0.003; 1% glucose raises specific gravity by 0.004. In addition, the radiopaque contrast media used for IV pyelograms (IVPs) considerably increase urine specific gravity; this effect may persist for 1-2 days. Proven ability to concentrate urine does not rule out many types of active kidney disease, nor does absence of ability to concentrate necessarily mean closely approaching renal failure. Adequate ability to concentrate is, however, decidedly against the diagnosis of chronic severe diffuse renal disease. A relatively early manifestation of chronic diffuse bilateral renal disease is impairment of concentrating ability (on a concentration test), which becomes manifest before changes in other function tests appear. (This refers to beginning impairment, not to fixation of specific gravity.)

    Clinically, fixation of specific gravity is usually manifested by nocturia and a diminution of the day/night urine excretion ratio (normally 3:1 or 4:1) toward 1:1. Other causes must be considered: diabetes mellitus and insipidus, hyperparathyroidism, renal acidosis syndrome, early congestive heart failure, and occasionally hyperthyroidism. True nocturia or polyuria must be distinguished from urgency, incontinence, or enuresis.

    One improvement on the standard concentration procedure is to substitute for water deprivation a single injection of vasopressin tannate (Pitressin Tannate in Oil). Five units of this long-acting preparation is given intramuscularly in the late afternoon, and urine collections for specific gravity are made in the early morning and two times thereafter at 3-hour intervals. One danger of this procedure is the possibility of water intoxication in certain patients who are receiving a substantial amount of fluids and because of the Pitressin are now temporarily prevented from excreting much of the fluid (such as infants on a liquid diet).

    Urine at refrigerator temperature may have a falsely decreased specific gravity. Urinometers of the floating bulb type exhibit a specific gravity change of 0.001 for each 3°C above or below the calibration temperature indicated for the instrument. A refractometer also may be affected outside the temperature range of 16°C-38°C.

    Osmolality

    Another way to obtain information about renal concentrating capability is to measure urine osmolality (sometimes incorrectly called osmolarity) instead of conventional specific gravity. Osmolality is a measure of the osmotic strength or number of osmotically active ions or particles present per unit of solution. Specific gravity is defined as the weight or density per unit volume of solution compared to water. Since the number of molecules present in a solution is a major determinant of its weight, it is obvious that there is a relationship between osmolality and specific gravity. Since the degree of ionic dissociation is very important in osmolality but not in specific gravity, values of the two for the same solution may not always correspond closely. The rationale for using urine osmolality is that specific gravity is a rather empirical observation and does not measure the actual ability of the kidney to concentrate electrolytes or other molecules relative to the plasma concentration; also, certain substances are of relatively large molecular weight and tend to disproportionately affect specific gravity. The quantity of water present may vary, even in concentration tests, and influence results.

    Osmolality is defined in terms of milliosmoles (mOsm) per kilogram of solution and can be easily and accurately measured by determining the freezing point depression of a sample in a specially designed machine. (In biologic fluids, such as serum or urine, water makes up nearly all of the specimen weight; since water weights 1 gm/ml, osmolality may be approximated clinically by values reported in terms of milliosmoles per liter rather than per kilogram.) Normal values for urine osmolality after 14-hour test dehydration are 800-1,300 mOsm/L. Most osmometers are accurate to less than 5 mOsm, so the answer thus has an aura of scientific exactness that is lacking in the relatively crude specific gravity method. Unfortunately, having a rather precise number and being able to use it clinically may be two different things. Without reference to the clinical situation, osmolality has as little meaning as specific gravity. In most situations, urine osmolality and specific gravity have approximately the same significance. Both vary and depend on the amount of water excreted with the urinary solids. In some cases, however, such as when the specific gravity is fixed at 1.010, urine osmolality after dehydration may still be greater than serum osmolality, which suggests that it is a more sensitive measurement. Also, urine osmolality does not need correction for glucosuria, proteinuria, or urine temperature. For example, 200 mg/100 ml of glucose increases urine osmolality about 11 mOsm/L. This magnitude of change would be insignificant in urine, since urine osmolality can vary in normal persons between 50 and 1,200 mOsm/L (depending on degree of hydration). However, adding the same 200 mg of glucose to blood could significantly increase serum osmolality, which normally varies between only 275 and 300 mOsm/L (Chapter 25).

    Intravenous pyelogram (IVP)

    Intravenous pyelogram is a radiologic technique to outline the upper and lower urinary tract that uses iodinated contrast media, most of which are tubular secreted. To be seen radiographically, once secreted the contrast media must also be concentrated. Thus, incidental to delineating calyceal and urinary tract outlines and revealing postrenal obstruction, the IVP also affords some information about kidney concentrating ability or ability to excrete the dye—two tubular functions. Renal function is usually not sufficient for visualization when the BUN level is more than 50 mg/100 ml (18 mmol/L) using ordinary (standard) IVP technique. Drip-infusion IVP methods can be used with higher BUN levels, but they are not routine and usually must be specifically requested. Radioisotope techniques using the scintillation camera are frequently able to demonstrate the kidneys when IVP fails.

    Electrolyte excretion

    Urine excretion of electrolytes may be utilized as a renal function test. Normally, the kidney is very efficient in reabsorbing urinary sodium that is filtered at the glomerulus. In severe diffuse bilateral renal damage (acute or chronic), renal ability to reabsorb sodium is impaired, and renal excretion of sodium becomes fixed between 30 and 90 mEq/L (mmol/L), whereas renal excretion of chloride is fixed between 30 and 100 mEq/L. A urine sodium or chloride concentration more than 15 mEq/L above or below these limits is evidence against acute tubular necrosis or renal failure because it suggests that some kidney tubule reabsorption or excretion ability is still present. There is considerable overlap between prerenal azotemia and acute tubular necrosis patients in the urine sodium region between 15 and 40 mEq/L. The urine sodium excretion must be less than 15 mEq/L to be reasonably diagnostic of prerenal azotemia. Values between 40 and 105 mEq/L are more difficult to interpret, since they may occur normally as well as in renal failure, depending on body sodium balance. If hyponatremia is present, evaluation is much easier. Hyponatremia prompts the kidney to reabsorb more sodium ions, normally dropping the urine sodium level to less than 15 mEq/L. In the presence of hyponatremia, urine sodium in the 40-90 mEq/L range strongly suggests renal failure. One major difficulty is the frequent use of diuretics in patients with possible renal problems, since diuretics change normal renal electrolyte patterns and may increase urine sodium excretion over what one would expect in hyponatremia. Urine sodium excretion, although it can be helpful, is no longer considered the most useful or reliable test to differentiate prerenal azotemia from renal failure.

    Free water clearance test

    Free water clearance is based on that part of renal tubule function that involves reabsorption of fluid and electrolytes with the formation of free water. This activity is one of the last kidney functions to be lost. When water reabsorption can no longer take place normally, free water excretion increases. The free water clearance test can be used to demonstrate renal concentrating ability by calculating the clearance of osmotically active particles (influenced by urine electrolyte and free water content) and relating it to the rate of urine flow to derive the fraction of excreted free water.

    The reference range for the free water clearance test is –20 to –100. In either acute tubular necrosis or chronic renal failure the values are usually near zero or are positive (+). However, certain other conditions may produce similar values, including excretion of excess water in a person with a low serum osmolality and diuresis in patients with a normal serum osmolality induced by various factors such as diuretics. However, usually a positive free water clearance value will not persist longer than 24 hours in these conditions but will persist in patients with severe kidney damage. I have personally found the free water clearance to be the most helpful of the renal function tests in differentiating prerenal azotemia from renal failure. The major drawbacks are necessity for exactly timed urine collections and interference by diuretics.

    Fraction of excreted sodium (FENa) or filtered fraction of sodium

    Several reports indicate that patients with prerenal azotemia tend to reabsorb more urine sodium after glomerular filtration than patients with severe intrinsic renal damage such as acute tubular necrosis or chronic renal failure. The formula used is the following:

    Fraction of excreted sodium
    The normal or prerenal azotemia level is said to be less than 2.0. Diuretics may inhibit sodium reabsorption and produce a falsely elevated value. Although there are several favorable reports about this test in the literature, in my limited personal experience I have not found this test to be as sensitive as the free water clearance.

    Other tests

    Two substances have been proposed as a marker for renal tubular function. N-acetyl-beta-D-glucosaminidase (NAG) is an enzyme that is too large to be filtered by the glomeruli and is found in high concentration in renal proximal tubule epithelium. Increased urine NAG implies release from renal tubule cells and suggests renal tubule cell damage. This information does not differentiate focal from diffuse damage, or unilateral from bilateral involvement. A variety of etiologies produce acute renal tubule damage, such as decreased renal arterial blood flow (e.g., hypotensive episode causing acute tubular necrosis), renal transplant rejection, and drug toxicity (e.g., cyclosporine or aminoglycosides). The test has been used mostly to screen for kidney transplant rejection. A marked increase from baseline (although nonspecific) would raise the question of rejection. Both enzymatic test methods and a dipstick colorimetric method are available. Another substance found only in proximal tubule cells is adenosine-deaminase-binding protein (ABP). This also has been used mostly for detection of renal transplant rejection, and has most of the same advantages and disadvantages as NAG.

    A variety of research techniques not generally available can measure one or another of the many kidney functions, such as tubular secretion of various substances, glomerular filtration of nonreabsorbed materials (e.g., inulin), and renal blood flow by clearance of substances (e.g., p-aminohippuric acid) that are both filtered and secreted.

  • Postrenal (Obstruction) Azotemia

    1. Ureteral or urethral obstruction by strictures, stones, external compression, pelvic tumors, and so forth
    2. Obstructing tumors of bladder; congenital defects in bladder or urethra
    3. Prostatic obstruction (tumor or benign hypertrophy; a very common cause in elderly men)

    Prerenal azotemia etiologies can be divided into two main categories: (1) decreased blood volume or renal circulation and (2) increased protein intake or endogenous protein catabolism.

    In azotemia due to excessive protein, some of the more common clinical situations are high-protein tube feedings or gastrointestinal (GI) tract hemorrhage (where protein is absorbed from the GI tract); low-calorie diet (as in patients receiving intravenous [IV] fluids, leading to endogenous protein catabolism); and adrenocortical steroid therapy (since these substances have a catabolic action).

    In decreased renal blood flow, etiologies include blood volume deficit, cardiac failure to pump sufficient blood, or toxic effects on blood vessels. It should be pointed out that decreased renal blood flow may produce prerenal azotemia without structural renal damage, but it may also produce severe acute renal damage (acute renal failure, also called acute tubular necrosis).

    Primary renal disease may produce azotemia due to primarily glomerular or tubular destructive conditions or to diffuse parenchymal destruction. Rarely is there glomerular damage to the point of severe azotemia (5%-10% of AGN cases) without some effect on the tubules, and vice versa. Therefore, the BUN level must be correlated with other clinical findings before its significance can be interpreted. There is nothing etiologically distinctive about the terminal manifestations of chronic kidney disease, and it is most important to rule out treatable diseases that may simulate the uremic laboratory or clinical picture. Anuria (urine output <100 ml/24 hours) always suggests urinary obstruction.

    Terminal azotemia, sometimes to uremic levels, occurs in the last hours or days of a significant number of seriously ill patients with a variety of diseases, including cancer. Often no clinical or pathologic cause is found, even microscopically. Urine specific gravity may be relatively good.

    Serum creatinine

    Serum creatinine is derived from muscle metabolism, as described earlier. Serum creatinine levels are dependent on body muscle mass; the greater the muscle mass, the higher the creatinine value, both in serum and urine. Creatinine values increase after meals, with the greatest increases (20%-50%) after meat ingestion. There is said to be a diurnal variation, with the lowest values about 7 A.M. and the peak about 7 P.M.; the late-afternoon values are reported to be about 20%-40% higher than in the morning. Some of the variation may be related to meals. Reference values for females are about 90% of those for males.

    Normally, the BUN/serum creatinine ratio is approximately 10:1. Under standard conditions a 50% decrease in the GFR produces an approximate doubling of the BUN level or serum creatinine level, and the reverse occurs when the GFR is increased. However, these relationships can be altered by many factors, including those that increase or decrease either BUN or serum creatinine level without affecting the other. Conditions that decrease creatinine production (age-related decrease, muscle wasting, low-meat diet) may partially mask serum creatinine elevation due to renal disease. The serum creatinine level has much the same significance as the BUN level but tends to rise later. Significant creatinine elevations thus suggest chronicity without being diagnostic of it.

    Laboratory methodology. Creatinine is most often assayed by a chemical method (Jaffe reaction) that includes about 20% noncreatinine substances. Elevated ketones and certain cephalosporin antibiotics (cephalothin, cefoxitin, cefazolin, cephalexin, cefaclor, cephradine) may produce false elevation of creatinine assays in serum or urine using the Jaffe reaction. Several enzymatic methods for creatinine assay are now available that are specific for creatinine and produce creatinine values that are lower and creatinine clearance results that are higher than those derived from the Jaffe reaction. Certain medications (cimetidine, probenecid, trimethoprim) interfere with tubular secretion of creatinine, increasing serum creatinine and decreasing creatinine clearance.

    Summary of glomerular function studies

    Clearance as a measurement of overall renal function impairment yields roughly the same information as that obtained from the phenolsulfonphthalein (PSP) test and has mostly replaced it in practice. Clearance tests are reliable in detecting mild to moderate diffuse renal disease, but they depend on completely collected specimens and accurate recording of the time the specimens were collected and presuppose adequate renal blood flow. If a patient is incontinent of urine, one must use either a short period of collection or a catheter or else some other test. Of course, if a Foley catheter is already in place, there is no problem. A clearance value between 60% and 80% of normal is usually taken to represent mild diffuse renal function impairment. Values between 40% and 60% of normal represent moderate decrease, and values between 20% and 40% of normal are considered severe renal function impairment, since about one half of the patients in this group also have an elevated BUN level. Most (but not all) of the causes of an increased BUN level also result in a considerable decrease in creatinine clearance. When the serum creatinine level is elevated in addition to the BUN level, a creatinine clearance rate less than 40 ml/minute (and usually < 25 ml/minute) can be predicted with reasonable assurance (Fig. 13-1). Therefore, as long as the BUN level is significantly elevated (except in unusual cases when BUN elevation is due to increased protein load), and especially if azotemia is accompanied by an elevated serum creatinine level, clearance tests usually do not provide additional information.

    Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

    Fig. 13-1 Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

    The question sometimes arises whether both the BUN and the serum creatinine should be assayed to screen for decreased renal function. In 130 consecutive patients in our hospital whose admission BUN or creatinine were elevated, 47% had elevated levels of both, 38% had elevated BUN levels only, and 15% had an elevated creatinine level only.

    In the classic case of chronic diffuse bilateral renal disease, the first demonstrable test abnormality is a decrease in urine-concentrating ability in the concentration test. As the disease progresses, the creatinine clearance becomes reduced. Then the specific gravity becomes fixed, and there is a considerable decrease in creatinine clearance. Finally, clearance becomes markedly decreased, and the BUN level starts to rise, followed shortly by the serum creatinine level.

    The question sometimes is raised as to the degree of BUN increase that is possible in short periods of time. In one study, daily increase after onset of acute renal failure ranged from 10 to 50 mg/100 ml (3.5 to 18 mmol/L) during the first week, with the average daily increase being 25 mg/100 ml (9 mmol/L). After the first week, the amount of increase tended to be less.

    1.
    Ureteral or urethral obstruction by strictures, stones, external compression, pelvic tumors, and so forth

    2.
    Obstructing tumors of bladder; congenital defects in bladder or urethra

    3.
    Prostatic obstruction (tumor or benign hypertrophy; a very common cause in elderly men)
    Prerenal azotemia etiologies can be divided into two main categories: (1) decreased blood volume or renal circulation and (2) increased protein intake or endogenous protein catabolism.
    In azotemia due to excessive protein, some of the more common clinical situations are high-protein tube feedings or gastrointestinal (GI) tract hemorrhage (where protein is absorbed from the GI tract); low-calorie diet (as in patients receiving intravenous [IV] fluids, leading to endogenous protein catabolism); and adrenocortical steroid therapy (since these substances have a catabolic action).
    In decreased renal blood flow, etiologies include blood volume deficit, cardiac failure to pump sufficient blood, or toxic effects on blood vessels. It should be pointed out that decreased renal blood flow may produce prerenal azotemia without structural renal damage, but it may also produce severe acute renal damage (acute renal failure, also called acute tubular necrosis).
    Primary renal disease may produce azotemia due to primarily glomerular or tubular destructive conditions or to diffuse parenchymal destruction. Rarely is there glomerular damage to the point of severe azotemia (5%-10% of AGN cases) without some effect on the tubules, and vice versa. Therefore, the BUN level must be correlated with other clinical findings before its significance can be interpreted. There is nothing etiologically distinctive about the terminal manifestations of chronic kidney disease, and it is most important to rule out treatable diseases that may simulate the uremic laboratory or clinical picture. Anuria (urine output <100 ml/24 hours) always suggests urinary obstruction.
    Terminal azotemia, sometimes to uremic levels, occurs in the last hours or days of a significant number of seriously ill patients with a variety of diseases, including cancer. Often no clinical or pathologic cause is found, even microscopically. Urine specific gravity may be relatively good.
    Serum creatinine
    Serum creatinine is derived from muscle metabolism, as described earlier. Serum creatinine levels are dependent on body muscle mass; the greater the muscle mass, the higher the creatinine value, both in serum and urine. Creatinine values increase after meals, with the greatest increases (20%-50%) after meat ingestion. There is said to be a diurnal variation, with the lowest values about 7 A.M. and the peak about 7 P.M.; the late-afternoon values are reported to be about 20%-40% higher than in the morning. Some of the variation may be related to meals. Reference values for females are about 90% of those for males.
    Normally, the BUN/serum creatinine ratio is approximately 10:1. Under standard conditions a 50% decrease in the GFR produces an approximate doubling of the BUN level or serum creatinine level, and the reverse occurs when the GFR is increased. However, these relationships can be altered by many factors, including those that increase or decrease either BUN or serum creatinine level without affecting the other. Conditions that decrease creatinine production (age-related decrease, muscle wasting, low-meat diet) may partially mask serum creatinine elevation due to renal disease. The serum creatinine level has much the same significance as the BUN level but tends to rise later. Significant creatinine elevations thus suggest chronicity without being diagnostic of it.
    Laboratory methodology. Creatinine is most often assayed by a chemical method (Jaffe reaction) that includes about 20% noncreatinine substances. Elevated ketones and certain cephalosporin antibiotics (cephalothin, cefoxitin, cefazolin, cephalexin, cefaclor, cephradine) may produce false elevation of creatinine assays in serum or urine using the Jaffe reaction. Several enzymatic methods for creatinine assay are now available that are specific for creatinine and produce creatinine values that are lower and creatinine clearance results that are higher than those derived from the Jaffe reaction. Certain medications (cimetidine, probenecid, trimethoprim) interfere with tubular secretion of creatinine, increasing serum creatinine and decreasing creatinine clearance.
    Summary of glomerular function studies
    Clearance as a measurement of overall renal function impairment yields roughly the same information as that obtained from the phenolsulfonphthalein (PSP) test and has mostly replaced it in practice. Clearance tests are reliable in detecting mild to moderate diffuse renal disease, but they depend on completely collected specimens and accurate recording of the time the specimens were collected and presuppose adequate renal blood flow. If a patient is incontinent of urine, one must use either a short period of collection or a catheter or else some other test. Of course, if a Foley catheter is already in place, there is no problem. A clearance value between 60% and 80% of normal is usually taken to represent mild diffuse renal function impairment. Values between 40% and 60% of normal represent moderate decrease, and values between 20% and 40% of normal are considered severe renal function impairment, since about one half of the patients in this group also have an elevated BUN level. Most (but not all) of the causes of an increased BUN level also result in a considerable decrease in creatinine clearance. When the serum creatinine level is elevated in addition to the BUN level, a creatinine clearance rate less than 40 ml/minute (and usually < 25 ml/minute) can be predicted with reasonable assurance (Fig. 13-1). Therefore, as long as the BUN level is significantly elevated (except in unusual cases when BUN elevation is due to increased protein load), and especially if azotemia is accompanied by an elevated serum creatinine level, clearance tests usually do not provide additional information.

    Fig. 13-1 Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

    The question sometimes arises whether both the BUN and the serum creatinine should be assayed to screen for decreased renal function. In 130 consecutive patients in our hospital whose admission BUN or creatinine were elevated, 47% had elevated levels of both, 38% had elevated BUN levels only, and 15% had an elevated creatinine level only.
    In the classic case of chronic diffuse bilateral renal disease, the first demonstrable test abnormality is a decrease in urine-concentrating ability in the concentration test. As the disease progresses, the creatinine clearance becomes reduced. Then the specific gravity becomes fixed, and there is a considerable decrease in creatinine clearance. Finally, clearance becomes markedly decreased, and the BUN level starts to rise, followed shortly by the serum creatinine level.
    The question sometimes is raised as to the degree of BUN increase that is possible in short periods of time. In one study, daily increase after onset of acute renal failure ranged from 10 to 50 mg/100 ml (3.5 to 18 mmol/L) during the first week, with the average daily increase being 25 mg/100 ml (9 mmol/L). After the first week, the amount of increase tended to be less.

  • Renal Azotemia

    1. Chronic diffuse bilateral kidney disease or bilateral severe kidney damage (e.g., chronic glomerulonephritis or bilateral chronic pyelonephritis)
    2. Acute tubular necrosis (glomerular or tubular injury [or both] due to hypotension or shock with renal shutdown, traumatic or nontraumatic rhabdomyolysis, transfusion or allergic reactions, certain poisons, and precipitation of uric acid or sulfa crystals in renal tubules)
    3. Severe acute glomerular damage (e.g., AGN)

  • Prerenal Azotemia

    1. Traumatic shock (head injuries; postsurgical hypotension)
    2. Hemorrhagic shock (varices, ulcer, postpartum hemorrhage, etc.)
    3. Severe dehydration or electrolyte loss (severe vomiting, diarrhea, diabetic acidosis, Addison’s disease)
    4. Acute cardiac decompensation (especially after extensive myocardial infarction)
    5. Overwhelming infections or toxemia
    6. Excess intake of proteins or extensive protein breakdown (usually other factors are also involved, such as the normally subclinical functional loss from aging)

  • Tests Reflecting Severe Glomerular Damage, Tubular Damage, or Both

    Blood urea nitrogen

    Blood urea nitrogen (BUN) is actually measured in serum rather than whole blood and can be assayed in urine. Urea can be measured biochemically or enzymatically (with the specific enzyme urease). Few substances interfere seriously with either method. Two screening methods for BUN, called Urograph and Azostix, are commercially available. Evaluations to date indicate that both of these methods are useful as emergency or office screening procedures to separate normal persons (BUN level <20 mg/100 ml [7 mmol/L]) from those with mild azotemia (20-50 mg/100 ml [7-18 mmol/L]) and those with considerable BUN elevation (>50 mg/100 ml [18 mmol/L]). If accurate quantitation is desired, one of the standard quantitative BUN procedures should be done.

    As noted previously, urea is produced in the liver and excreted by the kidneys. When the kidneys are not able to clear urea sufficiently, urea accumulates in the blood. If reasonable liver function is assumed, measurement of urea (BUN) thus provides an estimate of renal function. Elevation of BUN levels is also known as azotemia. However, elevated BUN levels are not specific for intrinsic kidney disease. Elevated BUN levels may occur from excessive quantities of urea presented to the kidney; from decreased renal blood flow, which prevents adequate glomerular filtration; from intrinsic renal disease, which affects glomerular or tubular function; or from urinary obstruction, which results in back-pressure interference with urea removal. Therefore, in some types of azotemia the kidney is not structurally affected and the azotemia is transient. In other azotemic patients the primary cause is renal parenchymal damage, and whether the BUN elevation is reversible depends on whether the kidney is able to recover a sufficient degree of function. BUN levels may be decreased below expected levels in severe liver disease (insufficient manufacture) and sometimes in late pregnancy.

    Following is a classification of azotemia based on etiology. It is subdivided into azotemia primarily due to increased urea or decreased blood flow (prerenal), intrinsic kidney disease, or postrenal obstruction.

  • Tests Predominantly of Glomerular Function

    Clearance Tests

    Clearance is a theoretical concept and is defined as the volume of plasma from which a measured amount of substance can be completely eliminated (cleared) into the urine per unit of time. This depends on the plasma concentration and excretory rate, which, in turn, involve the glomerular filtration rate (GFR) and renal plasma flow (RPF). Clearance tests in general are the best available means for estimating mild to moderate diffuse glomerular damage (e.g., acute glomerulonephritis [AGN]). Serum levels of urea or creatinine respond only to extensive renal disease. Renal clearance is estimated by UV/P, when U is the urine concentration of substance cleared (in mg/100 ml), V is the urine flow rate (in ml/minute), and P is the plasma or serum concentration of the substance cleared (in mg/100 ml). Each of the three variables in the equation can be separately or collectively influenced by extrarenal and intrarenal conditions, thus altering the clearance result (discussed in more detail later).

    Urea clearance

    Urea is a nitrogen-containing waste product of protein metabolism synthesized in the liver from ammonia (derived predominantly from the metabolism of protein by intestinal bacteria) and from various amino acids (of which alanine is the most important). Urea is filtered at the glomerulus, but approximately 40% is reabsorbed in the tubules by passive back-diffusion. Thus, under usual conditions, urea clearance values parallel the true GFR at about 60% of it. However, two factors may adversely influence this situation. First, the test is dependent on rate of urine flow. At low levels (<2 ml/minute), the values are very inaccurate, even with certain correction formulas. Second, levels of blood urea change to some extent during the day and vary according to diet and other conditions.

    Creatinine clearance

    Creatinine is a metabolic product of creatine-phosphate dephosphorylation in muscle. It has a relatively (although not completely) constant hourly and daily production and is present at fairly stable blood levels. Excretion is by a combination of glomerular filtration (70%-80%) and tubular secretion. It usually parallels the true GFR by ± 10% (however, it can exceed inulin clearance values by 10%-40%, even in normal persons). At low filtration rates (<30% of normal), creatinine clearance values become increasingly inaccurate because the tubular secreted fraction becomes a larger proportion of total urinary creatinine (sometimes comprising up to 60% of urinary creatinine in severe renal insufficiency). Creatinine clearance has an advantage over urea clearance because creatinine has a more constant production rate than urea. Since the serum value is part of the clearance formula, less fluctuation in the serum value permits larger urine time interval collections and more reproducible results. In addition, there is less non-filtered alteration of creatinine excretion than urea. Theoretical and clinical considerations have shown creatinine clearance to be a better estimate of the GFR than urea clearance. Thus, creatinine clearance has replaced urea clearance in most laboratories.

    Creatinine clearance has certain drawbacks. The reference limits (90-120 ml/minute) were established for young adults. The GFR has been shown to decrease with age; one report indicates a 4 ml/ minute decrease for each decade after age 20. Several studies found creatinine clearances as low as 50 ml/minute in clinically healthy elderly persons, and one study found values between 40% and 70% of normal. Creatinine production and excretion also diminish with age, although serum creatinine usually remains within population reference limits. Whether age-related normal values should be applied depends on whether these changes are regarded as physiologic (because they occur frequently in the population) or pathologic (because they are most likely due to renal arteriolar nephrosclerosis). Several nonrenal factors influence creatinine clearance. One major problem is shared by all clearance tests: the necessity for very accurately timed urine collections without any loss of urine excreted during the collection period. Incomplete urine collection will usually falsely decrease apparent clearance values. Another factor to be considered is serum creatinine origin from muscle and therefore dependence on muscle mass, which can vary considerably in different individuals. Decreased muscle mass (as seen in the elderly, persons with chronic renal failure, or malnourished persons) can produce a decrease in apparent clearance values. This exaggerates any decrease due to glomerular filtration decrease. Conversely, dietary meat in sufficiently large quantity can potentially increase serum creatinine and also decrease creatinine clearance. Finally, there are laboratory variables. Certain substances (e.g., ketones) can interfere with the widely used Jaffe biochemical assay of creatinine. Kinetic alkaline picrate methods (used on many automated chemistry instruments) and enzymatic methods for creatinine assay produce serum creatinine values about 20 mg/100 ml (1768 µmol/L) lower than the more nonspecific Jaffe method. This results in clearance values 20-30 ml/min higher in normal persons using these assay methods than clearance values using the Jaffe creatinine assay method. Using any method, day-to-day variation in assay of the same creatinine specimen produces differences in results of 15%-20% in most laboratories (representing ±2 standard deviations from the mean value). Variation in repeated creatinine clearance is reported to be about 20%-25% (range, 20%-34%). Also, once the creatinine clearance falls to very low levels (e.g., less than 20 ml/min), the values become so inaccurate that interpretation is very difficult. To conclude, creatinine clearance is a useful estimate of the GFR, but there are problems in collection, measurement, and body physiology (normal or disease induced) that can produce inaccuracy.

    The standard urine collection time for creatinine clearance is 24 hours. Several reports indicate that a 2-hour collection period provides results that correlate reasonably well with those of 24-hour collection. The 2-hour collection should be performed in the early morning with the patient fasting, since there is a postprandial increase in creatinine blood and urine levels of 10%-40%.

    Some investigators believe that creatinine clearance results are more accurate if patient weight, surface area, age, or some combination of these variables is included in the clearance computation. One frequently used correction formula is the following:

    Renal Function Tests

    Various nomograms and formulas have been published based on serum creatinine levels alone plus some of the variables just listed to predict creatinine clearance without requiring urine collection. However, all such formulas assume that patient renal function is stable. None has been widely accepted to date. The formula of Gault and Cockcroft seems reasonably simple and is reported to be fairly reliable:

    Renal Function Tests

    Clearance values for women determined by using this formula are 90% of those for men. All predictive formulas give some results that are at variance with measured clearances.

    Creatinine clearance has been reported to be one of the most sensitive tests available to warn of renal failure, since the clearance falls swiftly to low levels. However, many conditions produce a fall in creatinine clearance, and if the clearance is already decreased, a further fall would be difficult to interpret. The most useful information would be provided if the clearance were known to be normal or close to normal before testing. A major drawback is the nonspecificity of a clearance decrease, which cannot be used to differentiate between the etiologies of abnormality.

    Creatinine clearance determinations are most commonly used in three situations: (1) in AGN, to follow the clinical course and as a parameter of therapeutic response, (2) to demonstrate the presence of acute, strictly glomerular disease in contrast to more diffuse chronic structural damage, and (3) as a measurement of overall renal functional impairment. In AGN, there frequently (but not always) is a decrease in the GFR due to primary glomerular involvement. When this is true, the clearance tests have been used to evaluate the length of time that bed rest and other therapy are necessary. However, the erythrocyte sedimentation rate (ESR) gives the same information in a manner that is cheaper, simpler, and probably more sensitive. Therefore, the ESR seems preferable in most cases. Concerning the second category, it is not so easy to demonstrate strictly glomerular disease because many diseases reduce renal blood flow and thus the GFR. Also, some patients with AGN may have some degree of tubular damage. One situation in which clearance tests may be used to diagnostic advantage is the rare case of a young person with sudden gross hematuria but without convincing clinical or laboratory evidence of AGN. Since one expects normal clearance values in a young person, a reduced creatinine clearance rate could be some evidence in favor of nephritis.

  • Renal Function Tests

    Renal function testing and liver function testing share many of the same problems. In both the kidney and the liver a multiplicity of enzyme and transport systems coexist—some related, others both spatially and physiologically quite separate. Processes going on in one section of the nephron may or may not directly affect those in other segments. Like the liver, the kidney has not one but a great many functions that may or may not be affected in a given pathologic process. By measuring the capacity to perform these individual functions, one hopes to extract anatomical and physiologic information. Unfortunately, the tests available to the clinical laboratory are few and gross compared with the delicate network of systems at work. It is often difficult to isolate individual functions without complicated research setups, and it is even more difficult to differentiate between localized and generalized damage, between temporary and permanent malfunction, and between primary and secondary derangements. One can measure only what passes into and out of the kidney. What goes on inside is all-important but must be speculated on by indirect means. A tremendous handicap that results from this situation is the inability of function tests to reveal the etiology of dysfunction; the only information obtained is whether or not a certain degree of dysfunction is present and a rough estimate of its severity. Therefore, useful information can be obtained only through knowledge of the physiologic basis for each test and by careful correlation with other clinical and laboratory data.

    Renal function tests fall into three general categories: (1) tests predominantly of glomerular function, (2) tests reflecting severe glomerular or tubular damage (or both), and (3) tests of predominantly tubular function.