) is the principal inorganic anion of the ECF; changes in chloride

concentration are usually related to sodium concentration in an effort to maintain a

neutral charge. Serum chloride has no real diagnostic significance. The relationship

between serum concentrations of sodium, bicarbonate, and chloride is described by

Equation 2-2, where R represents the anion gap (AG):

As with bicarbonate, chloride contributes to maintaining acid–base balance. A

decreased serum chloride often accompanies metabolic alkalosis, whereas an

increased serum chloride may indicate a hyperchloremic metabolic acidosis. The

serum chloride, however, can also be slightly decreased in acidosis if organic acids

or other acids are the primary cause of the acidosis. Hyperchloremia, absence of

metabolic acidosis, is seldom encountered, because chloride retention is usually

accompanied by sodium and water retention. Hypochloremia can result from

excessive GI loss of chloride-rich fluid (e.g., vomiting, diarrhea, gastric suctioning,

and intestinal fistulas). Because chloride ions are excreted with cations by the

kidneys, hypochloremia may also result from significant diuresis.

Anion Gap

Reference Range: 7–16 mEq/L or mmol/L

The R factor, or AG, represents the contribution of unmeasured acids, such as

lactate, phosphates, sulfates, and proteins. As displayed in Equation 2-2, a patient’s

AG is determined by subtracting the primary anions (Cl

− and HCO3

−

) from the

primary cation (Na

+

). Some clinicians include potassium in this determination and

subtract the anions from both major cations (Na

+ and K+

). If potassium is not

incorporated in the calculation, a normal AG is typically 5 to 12 mEq/mL. If

potassium is considered, a normal AG would be less than 16 mEq/mL.

An elevated AG may be indicative of a metabolic acidosis caused by an increase

in lactic acids, ketoacids, salicylic acids, methanol, or ethylene glycol. A low AG

may be the result of reduced concentrations of unmeasured anions (e.g.,

hypoalbuminemia) or from systematic underestimation of serum sodium (e.g.,

hyperviscosity of myeloma). See Chapter 26, Acid–Base Disorders, for a more

detailed discussion of the clinical use of the AG.

Blood Urea Nitrogen

Reference Range: 8–20 mg/dL or 2.8–7.1 mmol/L

Urea nitrogen is a waste product that comes from protein breakdown. It is

produced solely by the liver, transported in the blood, and excreted by the kidneys.

The serum concentration of urea nitrogen (i.e., BUN) is reflective of renal function

because the urea nitrogen in blood is filtered completely at the glomerulus of the

kidney and then reabsorbed and tubularly secreted within nephrons. Acute or chronic

renal failure is the most common cause of an elevated BUN. Although the BUN is an

excellent screening test for renal dysfunction, it does not sufficiently quantify the

extent of renal disease. In addition, several nonrenal factors such as unusually high

protein intake, disease states that increase protein catabolism (or upper GI bleeding),

and glucocorticoid therapy can increase the BUN concentration. Liver disease and

low protein diet will lead to lower BUN concentration. A patient’s hydration status

will also influence BUN; a water deficit tends to concentrate the urea nitrogen, and a

water excess dilutes the urea nitrogen. The ratio of BUN to SCr can also be of

clinical use. A normal ratio is roughly 15:1. Ratios greater than 20:1 are observed in

patients with decreased blood flow to the kidney (e.g., prerenal disease such as

dehydration or conditions involving reduced cardiac output) or conditions involving

increased protein in the blood (e.g., dietary intake or an upper GI bleed). Situations

in which the BUN:SCr ratio is less than 15:1 are seen in patients with renal failure,

significant malnourishment (decreased intake of protein), or severe liver disease in

which the liver is no longer able to form urea. It is important to note that BUN can

change independent of the renal function and therefore SCr is more useful in

estimating renal function.

Creatinine

Reference Range: ≤1.5 mg/dL or ≤133 µmol/L

Creatinine is derived from the creatine and phosphocreatine metabolism in the

skeletal muscle. Its rate of formation for a given individual is remarkably constant

and is determined primarily by an individual’s muscle mass or lean body weight.

Therefore, the SCr concentration is slightly higher in muscular subjects, but unlike the

BUN, it is less directly affected by exogenous factors or liver impairment. Once

creatinine is released from muscle into plasma, it is excreted renally almost

exclusively by glomerular filtration and is not reabsorbed or metabolized by the

kidney. A decrease in the glomerular filtration rate (GFR) results in an increase in

the SCr concentration. Thus, careful interpretation of the SCr concentration is used

widely in the clinical evaluation of patients with suspected renal disease. However,

SCr concentration on its own should not be utilized to assess the level of kidney

function in an individual.

A doubling of the SCr level roughly corresponds to a 50% reduction in the GFR.

This general rule of thumb only holds true for steady-state creatinine levels.

10

Of importance, as patients become older, there is a reduction in muscle mass and

creatinine production is progressively decreased. Furthermore, the SCr concentration

in female patients is generally 0.2 to 0.4 mg/dL (85%–90%) less than for males

because females have less muscle mass.

Creatinine Clearance

Reference Range: 90–130 mL/minute

Because creatinine is cleared almost exclusively through the glomerulus in the

kidney, creatinine clearance (CrCl) can be used as a clinically useful measure of a

patient’s GFR. CrCl serves as a valuable clinical parameter because many renally

eliminated drugs are dose-adjusted based on the patient’s renal function. To

determine actual CrCl, the patient’s urine is collected for a 24-hour period, and the

concentration of urine creatinine (mg/dL), total volume of urine collected during the

24-hour period (mL/minute), and SCr (mg/dL) are determined. The patient-specific

measured CrCl is determined using Equation 2-3:

p. 23

p. 24

Unfortunately, urine collections are time consuming and expensive, and incomplete

collections can substantially underestimate renal function. In lieu of measuring actual

CrCl, simplistic equations are commonly used to estimate a patient’s CrCl. The

following Cockcroft–Gault formula incorporates age, body weight, and SCr.

11 This

formula can be utilized to estimate renal function when SCr is stable. Typically,

clinicians use ideal body weight (IBW) in the calculation of estimated CrCl;

however, actual body weight (ABW) may be used when ABW is less than IBW.

Equation 2-4 has the highest correlation and the greatest accuracy in patients with

SCr concentrations less than 1.5 mg/dL

12

:

The Cockcroft–Gault formula must be multiplied by 85% to calculate CrCl for

females to account for the fact that females have less muscle mass.

Another commonly used approach to estimating CrCl is the Jelliffe method

13

,

shown in Equation 2-5:

This Jelliffe formula must be multiplied by 90% to calculate CrCl for females. The

use of this method substantially underestimates CrCl for patients with SCr values less

than 1.5 mg/dL,

13 whereas Cockcroft–Gault appears to have the highest correlation

and greatest accuracy in patients with SCr values less than 1.5 mg/dL.

12 For patients

with liver dysfunction, all methods of calculating CrCl from an SCr value are

associated with significant overpredictions of CrCl.

14 Thus, methods for predicting

CrCl should be used cautiously when attempting to adjust drug dosages in patients

with liver disease. These equations should not be utilized in patients with rapidly

changing GFR (e.g., acute kidney injury) because they will not provide accurate

estimates of the GFR.

CASE 2-1

QUESTION 1: A 24-hour CrCl determination was ordered for D.B., a 72-year-old, 62-kg white man. The

following data were returned from the clinical laboratory (total collection time was 24 hours):

Total urine volume: 1,000 mL

Urine creatinine concentration: 42 mg/dL

SCr: 2.0 mg/dL

Determine both the measured and the estimated CrCl for D.B. based on the given data, and compare and

contrast these results.

Using Equation 2-3, D.B. has a 24-hour measured CrCl of approximately 15

mL/minute. His estimated CrCl is 29.2 mL/minute using the Cockcroft–Gault method

(Eq. 2-4). Based on both methods, D.B.’s ability to clear renally eliminated drugs is

impaired and adjustments to the dose/frequency will need to be made. An incomplete

collection of urine during the 24-hour period or possible mishandling of the specimen

can be explanations for the lower value seen with the measured CrCl. Because D.B.

had an elevated SCr of 2.0 mg/dL, the accuracy of the Cockcroft–Gault estimation

might also be compromised. D.B’s baseline SCr will need to be established and if it

is determined that SCr of 2.0 mg/dL is corresponding with D.B’s baseline, then

Cockroft–Gault estimation will hold true; if SCr of 2.0 mg/dL represents an acute

change, then Cockroft–Gault equation should not be used to estimate renal function in

D.B.

Estimated Glomerular Filtration Rate

An alternative approach to the Cockcroft–Gault method of estimating an adult

patient’s clearance was developed as part of the Modification of Diet in Renal

Disease (MDRD) study and has been referred to as the MDRD Equation.

15 The

originally described equation has been modified into an abbreviated format (Eq. 2-6)

as follows:

where SCr is the serum creatinine in mg/dL, age is in years, and the appropriate

additional components are included for female or African-American patients. The

above equation is applicable to laboratories reporting SCr values that have not been

standardized. Starting in 2005, laboratories began standardizing their SCr values

using an isotope dilution mass spectrometry to minimize the variation observed in

SCr results from different clinical laboratories. In settings in which the SCr results

have been standardized, the initial parameter in the MDRD equation is adjusted

downward. The following is used to estimate GFR:

When compared with the Cockcroft–Gault approach, MDRD estimations of GFR

were more consistent with actual measurements of GFR. However, because both

approaches rely on SCr, the influence of muscle mass and dietary intake still must be

taken into consideration. In certain patient populations (e.g., obese patients and

elderly patients), use of the MDRD can be less accurate, because the MDRD study

equation was primarily derived from white subjects with a mean age of 51 years who

had nondiabetic renal disease. A more detailed description of the MDRD equation to

estimate GFR is addressed in Chapter 28, Chronic Kidney Diseases.

Cystatin C

Although SCr has long been the primary marker for renal function, cystatin C is a

relatively new biomarker being investigated as a more precise measure of GFR.

Cystatin C is cleared predominantly through the kidneys and is not reabsorbed, and

elevated levels are observed in patients with declining renal function. Reference

ranges for cystatin C are similar to SCr (≤1.0 mg/L). In contrast to SCr, which is

produced from muscle cells, cystatin C is produced by the blood cells and was not

expected to be significantly influenced by factors such as muscle mass, diet, age, sex,

and race; however, higher levels of cystatin C have been observed in males and

patients with higher height and weight, and higher lean body mass. It was also

observed that cystatin C levels are increased with age.