Clinical assessment of renal function

Measurement of renal blood flow

The RBF is measured conventionally by the clearance of infused para-aminohippurate (PAH), which is cleared almost totally from the arterial plasma by both filtration and secretion. Thus its clearance approximates the rate of renal plasma flow (RPF):

where U _PAH and P _PAH refer to urine and plasma PAH concentration, respectively, and V is the urine flow rate in milliliters per minute.

The RBF can be estimated by correction for hematocrit (Hct):

Although available, this test is rarely used in clinical practice. In fact, direct quantitation of the RPF and RBF is rarely indicated outside research studies; however, sometimes it is necessary to document that the kidneys are being perfused. In this case, one of three additional methods may be used: (1) selective arteriography, including computed tomography (CT) angiography and magnetic resonance (MR) angiography, (2) Doppler ultrasonography, and (3) external radionuclide scanning. Because the latter two methods are noninvasive, they are preferred. With respect to the nuclide study, until recently, scanning was usually performed using ¹²⁵ I-iodohippurate sodium; however, the poor radiologic characteristics of ¹³¹ I limit its use in renal imaging. More recent evidence suggests that other agents, such as ¹²⁷ I-orthoiodohippurate and ^99m Tc- l , l -ethylenedicysteine, are superior to ¹²⁵ I-iodohippurate sodium. ^,

Clinical correlates

Although a significant amount of data has been obtained to indicate a complex relationship between neurocirculatory factors and renal hemodynamics, several points can be made from a clinical perspective. Optimization of cardiac output and ECF volume, including the intravascular space, is essential for the maintenance of renal perfusion. In particular, because the effects of vasoactive compounds such as AII and catecholamines are accentuated in the presence of renal hypoperfusion and volume contraction, attention should be given to the assessment of ECF volume, with correction of any deficits, and to optimize cardiac function. Frequently, pharmacologic agents have been employed to maintain renal perfusion in situations in which this may be compromised. Specifically, there has been widespread use of the so-called low-dose or renal-dose dopamine infusions. This is based on the observation that in low doses (<3 μg/kg/min), dopamine leads to renal vasodilatation. At higher doses, renal vasoconstriction may occur.

The beneficial effects of dopamine infusion have not been documented in patients who exhibit evidence of intravascular volume depletion, and the use of dopamine has been shown to be ineffective beyond a short period of infusion. Thus although infusions of renal-dose dopamine for 24–36 hours may be beneficial under the appropriate circumstance, there is no evidence supporting the long-term use of this agent. Furthermore, reports suggest that adverse outcomes are associated with the use of dopamine. In patients with acute decompensated heart failure and renal dysfunction, the addition of low-dose dopamine did not enhance decongestion or improve renal function when added to diuretic therapy. Continuous infusions of fenoldopam mesylate, a potent dopamine A ₁ receptor agonist, have been employed in an attempt to preserve renal function in a variety of clinical settings. A meta-analysis of 16 randomized trials in critically ill patients showed that fenoldopam significantly reduced the risk of acute kidney injury, need for renal replacement therapy, and in-hospital death.

Beyond anecdotal evidence, there are no compelling data to support the use of other potential vasodilator substances such as prostaglandins. Although high-protein feeding and amino acid infusions may increase the RBF by undefined mechanisms, there is no justification in using these therapies solely from a hemodynamic point of view. ^,

Measurement of glomerular filtration rate

The GFR is classically measured as the clearance of inulin (C _In ), a fructose polymer with a mean molecular weight of approximately 5 κDa. Because this substance is not present endogenously, it must be given by constant infusion after a loading dose. Inulin is available commercially but is expensive, often difficult to obtain, and cumbersome to use. As a result, the C _In is rarely used in clinical practice except for research protocols. Although the C _In is generally measured chemically, ³ H- and ¹⁴ C-labeled inulins are also available but are expensive.

Other radiolabeled nuclides have been found to be satisfactory substitutes for inulin and have advantages in the measurement of GFR. ^{, , ,} In particular, ^99m Tc-labeled diethylenetriamine pentaacetic acid (DTPA) and ¹²⁵ I- or ¹³¹ I-labeled iothalamate clearances closely approximate C _In . ^{, 99m} Tc-DTPA has been used and found to give values that correlate closely with the C _In in ICU patients. ^, In addition, the clearance of gentamicin has been used in a limited fashion to measure GFR. ^, At the present time, it is not common for the GFR to be measured directly. Rather, the GFR is estimated by endogenous creatinine clearance (C _Cr ) or serum creatinine determination (see later discussion).

The normal values for the GFR obtained previously apply for individuals from teenage years through approximately 35 years. Thereafter, the GFR declines in most individuals. Although this decline was formerly thought to occur at a relatively constant rate of approximately 10 mL/min per decade, more recent data obtained in a longitudinal manner indicate that this reduction is not so predictable. In addition, a circadian rhythm for GFR has been described. ^, GFR is maximal in the day, whereas a minimal value during the night has been found in normal individuals. It is not known whether this circadian pattern of GFR occurs in critically ill hospitalized patients.

Creatinine clearance

The C _Cr enjoys widespread use as a reasonable gauge of GFR when great precision is not demanded, which it rarely is in clinical practice. The use of creatinine as a marker of the GFR has the advantage that creatinine is endogenously produced and easily measured by inexpensive methods. Creatinine, like inulin, is freely filtered and absorbed minimally, if at all, by the tubules. However, creatinine is secreted, and the contribution of secretion to total excretion is greater as the GFR decreases and serum creatinine rises. At GFRs below 40 mL/min, the C _Cr exceeds the C _In by 50%–100%. ^, When GFR is significantly depressed and it is deemed important to get a more precise measurement of GFR, one of the previously mentioned methods to estimate the GFR directly might be used. Additionally, because the C _Cr overestimates the GFR and the clearance of urea underestimates the GFR, the mean value of simultaneously obtained creatinine and urea clearances has been shown to provide a close estimation of the C _In when the latter is below 20 mL/min.

Because cimetidine competes with creatinine for tubular secretion (see later), administration of cimetidine may increase the accuracy of both creatinine clearance in 24-hour collections (when given for several days beforehand) and 4-hour, water-loaded clearances. Taking advantage of this effect results in a more accurate estimate of the GFR. Specifically, the C _Cr obtained in the presence of cimetidine (400 mg as a priming dose followed by 200 mg every 3 hours) yielded values that closely approximate C _In . ^, Volume expansion in humans causes a small rise in the GFR, whereas volume depletion, severe heart failure, hypotension, anesthesia, surgery, trauma, sepsis, and even mild intestinal bleeding without frank hypotension may depress the GFR substantially.

Various methods are available to measure creatinine. Creatinine is frequently measured using the Jaffé alkaline picric acid reaction. Although this method is widely used, this reaction also measures other chromogens, which may lead to a false elevation in the estimated serum creatinine (S _Cr ) measurement. Substances such as acetoacetate (in ketoacidosis), pyruvate, ascorbate, 5-flucytosine, certain (but not all) cephalosporin antibiotics, and very high urate artifactually raise S _Cr in normal subjects by 0.5–2 mg/dL. These substances are excreted into the urine but contribute trivially compared with overall urine creatinine (U _Cr ). Thus noncreatinine chromogens affect the S _Cr but have little effect on the U _Cr .

In individuals with normal renal function, the contribution of serum noncreatinine chromogens in raising the S _Cr is approximately equal to the contribution of secretion to creatinine excretion, such that the C _Cr closely approximates the GFR. As the GFR decreases, the contribution of noncreatinine chromogens to the total measured S _Cr becomes less than the secreted moiety, and the C _Cr overestimates GFR to a greater extent. Direct enzymatic creatinine measurements are not affected by noncreatinine chromogens. Very high levels of serum glucose (>1000 mg/dL) and 5-flucytosine may interfere with the enzymatic reaction, whereas high levels of bilirubin (>5 mg/dL) affect the autoanalyzer method and lead to falsely low S _Cr values. The use of catecholamines—particularly dopamine and dobutamine—can underestimate serum creatinine concentrations by some enzymatic methods. It is therefore important to know the method by which a given laboratory measures S _Cr . Competing for the same proximal tubular organic base secretory site as creatinine, certain pharmacologic agents may suppress this process and lead to a rise in the S _Cr . Trimethoprim, probenecid, dronedarone, pyrimethamine, salicylate, antiretroviral agents, cobicistat, many chemotherapeutic agents (olaparib, rucaparib, imatinib, bosutinib, sorafenib, sunitinib, crizotinib, gefitinib, pazopanib), and cimetidine, but not ranitidine, are organic bases that inhibit creatinine secretion competitively and can result in a mild elevation in the S _Cr , usually 0.5 mg/dL or less.

As with all clearance methods, the C _Cr is subject to errors that may amount to as much as 10%–15%. In addition to potential problems in estimating the S _Cr and U _Cr , errors in timing of urine collection, incomplete collection, and inaccurate measurement of urine volume are other factors that contribute to errors. Although 24-hour U _Cr clearances have been widely used, no specified period is required for the clearance to be obtained. In fact, shorter collection periods of several hours may be more accurate in patients passing adequate amounts of urine (not oliguric), particularly if the patient is not in a steady state (see later). To reduce errors in volume measurement, one can induce water diuresis in stable subjects before beginning the test, although this is rarely practical in the ICU setting. Nevertheless, because many ICU patients have indwelling Foley catheters, it should be possible for accurately timed urine collections to be obtained and for the C _Cr to be measured with reasonable accuracy.

Serum creatinine

Because of the practical and technical problems in obtaining estimates of the GFR by clearance methods, renal function is most commonly estimated by following the S _Cr in hospitalized patients. Creatinine is formed nonenzymatically from creatine and phosphocreatine in skeletal muscle cells and is normally present in the serum at a concentration of 0.8–1.4 mg/dL in adults and 0.3–0.6 mg/dL in children and pregnant subjects. This process is irreversible, is temperature and pH dependent, and occurs at a constant rate. The measured S _Cr depends on the method of measurement, as discussed previously, the GFR, rate of creatinine production, volume of distribution (e.g., S _Cr is lower in anasarca), and extent of its tubular secretion and intestinal degradation. Because creatinine production is closely related to muscle mass, the S _Cr is generally less in females than in males and decreases as muscle mass is lost with aging or debilitating illnesses.

The relationship between the S _Cr and C _Cr (and hence GFR) can be described by a rectangular hyperbola ; however, this relationship applies in the steady state and assumes a constant rate of creatinine production ( Fig. 95.1 ). Thus a doubling of the S _Cr reflects a 50% decrease in C _Cr , a fourfold increase in the S _Cr , a 75% drop in the GFR, and so on. Because creatinine production may not remain constant, the S _Cr may underestimate the decrease in GFR in critically ill patients who have a decrease in muscle mass secondary to an ongoing catabolic state. Moreover, it should be appreciated that the S _Cr is an insensitive marker of change early in the course of renal disease. Thus a 33% fall in the GFR may raise the S _Cr from 0.8 to 1.2 mg/dL, a value still within the normal range. If the prior value is not known, this fall in the GFR may go unrecognized.

The S _Cr provides a close estimate of the GFR only in the steady state. With an abrupt decrease in the GFR, as may occur in acute renal failure, creatinine production would be expected to continue unchanged, but because of the decrease in the GFR, creatinine excretion will be impaired. As a result, the S _Cr increases until a new steady state is obtained, at which time the amount of creatinine produced equals the amount filtered (GFR − S _Cr ) and excreted (U _Cr − V). Depending on the extent of damage and decrease in the GFR, it may take several days for a new steady state to be achieved. Therefore after an insult leading to an abrupt decrease in the GFR, the S _Cr rises progressively over the next several days. This should not be interpreted as a new insult each day, but rather that a steady state has not yet been obtained. While the S _Cr is changing, its absolute value cannot be used as an accurate measure of the decrease in the GFR. If an accurate measurement of the GFR is needed during this time, a short C _Cr can be obtained.

Many equations have been developed to estimate the C _Cr based on the S _Cr without collection of urine. ^, Box 95.1 is a compilation of the more commonly used equations. These equations generally take into consideration muscle mass (estimated as body weight), sex (males having a higher GFR than females), and age. Aging, hepatic diseases, excessive muscle wasting, severe muscular atrophy or dystrophy, hyperthyroidism, paralysis, and chronic glucocorticoid therapy are associated with reduced creatinine generation. In addition, particularly at low levels of GFR, correction for nonrenal creatinine metabolism is recommended. ^, One of the most commonly used equations is that developed by Cockcroft and Gault :