Section 2: Scientific Principles
Part D: Physiology and Anesthesia
Chapter 18: Renal Physiology

Renal Clearance Techniques

Renal function is most frequently assessed by clearance techniques, 11  which provide an indirect estimate of function based on the Fick principle:

That is, the amount of substance x excreted by the kidney equals the amount delivered to the kidney by the renal arterial flow minus the amount returning from the kidney in the renal venous flow. Therefore

The amount of substance x delivered to the kidney is the product of the arterial plasma concentration (Pa x ) and RBF, and the amount returning from the kidney is the product of the venous plasma concentration (Pv x ) and RBF. The amount of substance x excreted is the product of the kidney‘s urine concentration (U x ) and the urine flow rate in milliliters per minute (V). Note that U x × V (urine concentration times flow rate) represents the urinary excretion rate of substance x. Therefore,

However, in practice, RBF and venous return are not measured, and the removal of substance x by the kidney is expressed by the concept of clearance, which is defined as the virtual volume of plasma cleared of substance x per unit time, in milliliters per minute. This allows the urinary excretion rate to be equated to the renal arterial plasma concentration:

By rearrangement, clearance of substance x may be calculated:

where U x is the concentration of substance x in the urine in mg/dL, V is the urine flow rate in milliliters per minute, and P x is the concentration of substance x in the plasma, assuming that the substance‘s concentration is identical in the renal arterial plasma and in an arm vein.

Para-Amino Hippurate Clearance

PAH is an organic anion that is almost completely cleared from the plasma in a single pass through the kidney by means of a combination of glomerular filtration and proximal tubular secretion. Calculated clearance of PAH (CPAH) therefore represents renal plasma flow. To obtain maximal PAH extraction, a steady state with a low plasma PAH level must be achieved by giving an intravenous loading dose followed by an infusion to maintain a plasma PAH concentration of about 2 mg/dL. 11  A carefully timed catheter urine collection is required. Because only 90 percent of the renal plasma flow enters the peritubular capillaries surrounding the proximal tubule, PAH clearance underestimates true renal plasma flow, and it is known as the effective renal plasma flow (ERPF).

where UPAH is the concentration of PAH in the urine, and PPAH is its concentration in the plasma. The normal effective renal plasma flow is 660 mL/min/1.73 m2 .

Effective renal blood flow (ERBF) may be derived if the hematocrit level (Hct) is known:

There are a number of circumstances in which CPAH provides misleading information about renal plasma flow. If the plasma PAH concentration exceeds the tubular maximum of 12 mg/dL, the excess PAH is returned to the renal vein, the secreted fraction declines, and renal plasma flow is underestimated. 2  About 80 percent of PAH is cleared by tubular secretion, so if proximal tubule function deteriorates, PAH clearance declines and again underestimates renal plasma flow.

These errors can be overcome if arterial and renal vein PAH levels are accessible. The renal extraction of PAH (EPAH) can be calculated and serves as an indicator of proximal tubule function:

where APAH is arterial PAH concentration, and VPAH is renal vein PAH concentration. When renal function is normal, renal vein PAH is close to zero, and PAH extraction approaches 1.0. As proximal tubule function declines, the concentration of PAH in the renal vein increases, and PAH extraction progressively decreases below 1.0. True RPF is calculated by dividing PAH clearance by PAH extraction:

PAH clearance may also misrepresent renal plasma flow in the presence of hypovolemia (PAH is sequestered in the kidney) and oliguria. Thus, despite its relative convenience as an experimental tool, PAH clearance may be an unreliable indicator of RBF during the perturbations induced by anesthesia and surgical stress.

Inulin Clearance

Inulin is an inert polyfructose sugar that is completely filtered by the glomerulus and is neither secreted nor reabsorbed by the renal tubules. The volume of plasma cleared of inulin (mL/min) represents the GFR. Inulin clearance is measured identically to PAH clearance, and an indwelling intravenous cannula and urinary catheter must be in place. After an intravenous loading dose of 30 to 50 mg/kg, a continuous infusion of inulin is given to establish a steady-state plasma concentration of 15 to 20 mg/dL. The bladder is usually flushed with air to eliminate any pooled urine. Then, a very carefully timed urine collection is made, which can be as short as 30 minutes. It is generally accepted that inulin clearance (CIN) provides the most accurate available determination of GFR (i.e., it represents the gold standard):

where UIN is urinary inulin in mg/dL, PIN is plasma inulin in mg/dL, and V is urine flow rate in mL/min. This relationship also implies that the renal excretion of inulin (urinary inulin times urine flow rate) is determined solely by the GFR and the plasma inulin concentration:

Although inulin clearance is the standard measure of GFR in experimental situations, it is seldom used clinically because its accurate measurement is laborious and requires meticulous attention to detail. The inulin assay is timeconsuming, and inulin itself is in short supply because of lack of demand. Inulin meets all the criteria of an ideal filtration marker, but large changes in blood glucose during the test may interfere with its measurement, and its accuracy in reflecting GFR cannot be directly assessed, only inferred. The predicted variability of inulin clearance is 20 percent when measurements are compared at two different times in the same individual and 40 percent when measurements are compared between two individuals. 11 

Normal values for inulin clearance are 110 to 140 mL/min/1.73m2 (males) and 95 to 125 mL/min/1.37m2 (females).

Filtration Fraction

The filtration fraction (FF) is the fraction of the RPF that is filtered by the glomerulus:

Normally, GFR is about 125 mL/min, and RPF is about 660 mL/min so that the FF approximates 125/660, or about 0.2. Changes in FF are considered to represent changes in periglomerular arteriolar tone. An increase in FF indicates that GFR is increased relative to RPF. This could be achieved by efferent arteriolar constriction or afferent arteriolar dilation and maintains glomerular filtration pressure in the face of decreased RPF. Conversely, a decrease in FF implies that GFR is decreased relative to RPF by afferent arteriolar constriction or efferent arteriolar dilation.

Creatinine Clearance

Creatinine is the endogenous end product of creatine phosphate metabolism, is normally generated from muscle at a very uniform rate, and is handled by the kidney in a manner similar to that of inulin. Thus, creatinine clearance (CCR) provides a simple, inexpensive bedside estimate of GFR. A single blood sample is drawn at the midpoint of a carefully timed urine collection:

where UCR is the urinary creatinine concentration in mg/dL, PCR is the plasma creatinine concentration in mg/dL, and V is urine flow rate in mL/min.

Bedside use of creatinine clearance has been restricted by the belief that a prolonged (12–24-hour) urine collection is necessary to eliminate error induced by residual urine in the bladder neck after spontaneous voiding, a practice both tedious and cumbersome. The estimated creatinine clearance depends on when the blood sample is drawn, so if the serum creatinine changes rapidly during the time of urine collection, a misleading result may be obtained.

It is not the duration of urine collection that is critical, but rather the fact that its timing is precise. 12  The variability of creatinine clearance with a 1-hour urine collection is no greater than of 24-hour collection if a good urine flow is induced by diuresis, and care is taken to empty the bladder. 13  In catheterized patients with urine flow rates of more than 15 mL/h, creatinine clearance obtained with 2-hour urine collections gives values equivalent to those obtained with 12- to 24-hour collections. 14, 15  Moreover, a 2-hour creatinine clearance enables rapid, repeated estimates of GFR to be obtained. This not only makes it a viable bedside test in critically ill patients but also implies that a changing GFR can be closely tracked by serial estimations of creatinine clearance (Figs. 18–8, 18–9, and 18–10). For example, in trauma patients, a 1-hour creatinine clearance of less than 25 mL/min determined within 6 hours of surgery reliably predicted postoperative acute renal failure, despite the absence of oliguria. 16 

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FIGURE 18–8 Creatinine clearance: 2- versus 22-hour values. There is a close and significant correlation in creatinine clearance estimation from a 2-hour and a 22-hour urine collection. CC02, 2-hour urine collection; CC22, 22-hour urine collection. (From Sladen, Endo, and Harrison15 )

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FIGURE 18–9 New-onset acute renal failure. In a patient developing acute renal failure in the intensive care unit, the exponential decline in creatinine clearance is tracked equally well whether a 2-hour (CC02) or a 22-hour (CC22) urine collection is used. However, data from the 2-hour collection are available well before those from the 22-hour collection.

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FIGURE 18–10 Renal revascularization. Patient with renovascular hypertension and renal insufficiency admitted to the intensive care unit for preoperative monitoring and stabilization. Bilateral renal revascularization was performed, and following return from the operating room there was a substantial decline in renal function. These changes were tracked equally well by creatinine clearance derived from a 2-hour (CC02) and a 22-hour (CC22) collection.

There is considerable variation in the normal range of creatinine clearance, as wide as the range of normal values of body size. 13  Tobias et al 12  reported a variation in creatinine clearance between 88 and 148 mL/min and in serum creatinine between 0.9 and 1.5 mg/dL in a single healthy individual over 5 years. There is a diurnal variation in creatinine clearance, with higher values in the afternoon and a variance of up to 25 percent around mean values. 17  It is prudent to obtain short-collection creatinine clearance estimations at the same time each day to minimize diurnal variability. “Normal” creatinine clearance is related to body surface area and weight, so values may fluctuate widely in patients with cachexia or edema.

Creatinine clearance has a number of inherent limitations even if collection error is carefully avoided. Creatinine generation rate varies with muscle mass, physical activity, protein intake, and catabolism. The most commonly used serum creatinine assay is the Jaffé reaction, which is based on the red color of the creatinine complex with alkaline picrate. It also measures other normally-occurring chromogens, such as glucose, protein, ketones, and ascorbic acid, which represent about 14 percent of total creatinine when renal function is normal, although substantially less when serum creatinine is elevated. Ketoacidosis, barbiturates, and cephalosporin antibiotics may artifactually increase serum creatinine by as much as 100 percent and falsely decrease measured creatinine clearance. Unlike inulin, about 20 percent of creatinine is secreted by the proximal tubule, so that creatinine clearance overestimates GFR, and the ratio between the clearance of creatinine and inulin is 1.2:1. As the GFR declines, tubular secretion of creatinine increases. When GFR is less than 40 mL/min/1.73m2, a creatinine/inulin clearance ratio as high as 1.81 to 2.51 may be achieved. 18, 19, 20  In patients with normal renal function, the underestimate of GFR induced by the Jaffé reaction is balanced by the overestimate of GFR induced by tubular creatinine secretion, and creatinine clearance provides a reasonable representation of GFR. However, widely used drugs such as trimethoprim, H2 -antagonists, and salicylates block tubular secretion of creatinine and may elevate serum creatinine and decrease creatinine clearance. When serum levels of creatinine are very high, it is excreted into the gut and undergoes extrarenal metabolism by intestinal organisms.

For all these reasons, an isolated creatinine clearance estimation may not diagnose lesser degrees of renal dysfunction. Nonetheless, serial estimations of creatinine clearance provide a useful clinical guide to alterations in renal function and prognosis. The variability of creatinine clearance diminishes as GFR declines; in fact, loss of variability is a clue to deteriorating renal function. If the GFR is rapidly declining, the creatinine clearance alerts the physician earlier and more compellingly than the serum creatinine because it reflects creatinine excretion rate (i.e., urine creatinine content times urine flow rate [UCR · V]). Directional changes between creatinine clearance and inulin clearance show good agreement. 18  At low levels of GFR a creatinine/inulin clearance ratio as high as 2:1 (e.g., 12 versus 6 mL/min) would induce little actual difference in clinical management.

Serum Creatinine

Serum creatinine is a useful marker of stable renal function, but it is unreliable when GFR is rapidly changing. 18, 19, 20  Serum creatinine concentration depends on its volume of distribution (total body water), creatinine generation rate (muscle mass and rate of catabolism), and creatinine excretion rate (GFR). Perioperative fluid administration increases total body water and dilutes serum creatinine, which underestimates renal dysfunction. In a cachectic patient with very low muscle mass, creatinine generation may be so feeble that the serum creatinine remains subnormal even in the face of a markedly decreased GFR. In some patients with a serum creatinine of less than 0.9 mg/dL, creatinine clearance may be less than 25 mL/min. 13, 14  The relationship between serum creatinine and GFR is inverse and exponential. An increase in serum creatinine from 0.8 to 1.6 mg/dL implies a 50 percent decrease in GFR, and early renal dysfunction may be missed. A much larger increase from 4 to 8 mg/dL also represents a 50 percent decrease in GFR, but by this time renal insufficiency is well established (Fig. 18–11). After a transient renal insult, such as that caused by suprarenal aortic cross-clamping, serum creatinine may increase for a few days while GFR is actually recovering. 21  In oliguric acute renal failure, serum creatinine is directly proportional to creatinine generation rate. Creatinine clearance is reliably low but is associated with a wide variability of serum creatinine.

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FIGURE 18–11 The relationship between serum creatinine and GFR as measured by creatinine clearance is reciprocal and exponential. Doubling of the serum creatinine corresponds to halving of the GFR. Relatively large declines in GFR from normal are associated with small increases in serum creatinine until GFR decreases below 60 mL/min; further decrements are associated with large increases in serum creatinine. (From Alfrey and Chan176 )

Serum Creatinine-Based Nomograms

Cockroft and Gault 22  formulated a nomogram for the rapid estimate of creatinine clearance without urine collection. The nomogram was based on population studies incorporating serum creatinine, age, weight, and gender.

For females, the derived creatinine clearance is multiplied by 0.85.

In these formulas, the body weight that is used may substantially alter the derived creatinine clearance. In obese or edematous patients, the total body weight is much greater than the lean body mass from which creatinine is derived, and creatinine clearance is overestimated. In cachectic patients with depleted lean body mass, creatinine production is so low that serum creatinine is frequently less than 1.0 mg/dL and overestimates the true GFR. Robert et al 23  demonstrated that when the Cockroft and Gault equation incorporates ideal body weight (from a nomogram) and serum creatinine corrected to 1.0 mg/dL if it is less than 1.0 mg/dL, single measurements in hemodynamically stable patients correlate more closely with inulin clearance than either a 30-minute or a 24-hour creatinine clearance.

Serum creatinine–based nomograms are subject to the same limitations as serum creatinine itself in tracking changing renal function. Rapid alterations in GFR are reflected by rapid changes in the creatinine excretion rate, which is incorporated into measured creatinine clearance as UCR · V. In contrast, serum creatinine itself changes much more slowly and depends on the equilibrium point between creatinine production and excretion. In fact, serum creatinine does not begin to increase above normal levels until the GFR declines below 50 mL/min/1.73m2, and occasionally it will remain normal even when the GFR dips as low as 20 to 40 mL/min/1.73m2 .