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.


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.