A. The clearance of inulin is the most accurate measure of GFR available. However, several factors limit the use of inulin clearance in the common clinical situation. An intravenous injection followed by a constant infusion is required. Complete emptying of the bladder is necessary before the beginning of the clearance period, in order to remove all urine not containing inulin, and again at the end of the period, in order to obtain all urine produced during the period. The urine flow must be high so that enough urine may be obtained in a short period of time to permit analysis and to reduce possible errors introduced by urine remaining in the bladder at the beginning and end of the clearance period. These requirements often cannot be met in a patient with compromised renal function.

B. The use of creatinine clearance as a measure of GFR overcomes many of these practical problems, but introduces others. Creatinine (molecular weight = 113) is an end product of protein metabolism. It is always present in the blood, and its concentration (0.5 to 1.2 mg/dl) remains relatively constant over a 24-hour period. This eliminates the need for an intravenous infusion, and therefore a clearance period can extend over a long period of time, usually 24 hours, so that adequate amounts of urine can be obtained and the problem of bladder emptying minimized. Only one blood sample is needed, and it can be taken at any point during the collection period.

1. Creatinine is freely filtered, but it is also secreted into the urine by the proximal tubular epithelium. If creatinine is infused into an individual to raise the plasma concentration, its clearance exceeds the inulin clearance by 10 to 40%. There is some doubt as to whether creatinine is secreted in more than negligible amounts at normal plasma levels, but the preponderance of the evidence indicates that it is. This problem is complicated by the fact that, in the methods commonly used to measure creatinine, other substances in plasma react with the reagents. The nature of these so-called "noncreatinine chromogens" is not known, but evidently their clearance is low and their concentration in urine is nil. Thus in the clearance equation, C_cr = U_crV/P_cr, the value of the denominator is raised by the presence of these chromogens, and the value of the numerator is presumably raised by tubular secretion of true creatinine. These two factors partially cancel each other and the net result is that the clearance approximates the GFR when the kidneys are normal. In using creatinine clearance to measure GFR, the fact that creatinine is secreted should be kept in mind. It is possible that falsely high GFR values may be obtained in patients with poor glomerular function but with good blood flow and tubular function. Conversely, certain drugs (organic cations such as cimetidine and trimethoprim) inhibit tubular secretion of creatinine causing the creatinine clearance, but not the actual GFR, to decrease.

2. The measurement of the plasma creatinine concentration alone can be utilized to follow changes in GFR in a patient with chronic renal disease. The rate of production of creatinine by the body does not vary to an appreciable extent in an individual over a period of time and thus the rate of excretion also varies very little. Since creatinine is excreted primarily by filtration, GFR x P_cr = U_crV. When GFR is reduced the rate of excretion drops momentarily until P_cr rises and the rise in P_cr raises the product GFR x P_cr back to its previous level. In the long run the rate of excretion, U_crV, remains the same. Thus GFR is proportionate to 1/P_cr. In a patient in which renal disease gradually reduces GFR, the initial reductions in GFR produce only small increases in P_cr (100% to 80% of normal GFR in Fig. 4.6A) and it is difficult to discern the change in GFR from the measurement of P_cr alone. As GFR is reduced further, the change in P_cr becomes much greater (80 to 40% in Fig. 4-6A). However the reciprocal of P_cr (1/P_cr) is a straight-line function of the change in GFR (Fig4-6B); comparable changes in 1/P_cr are the result of comparable changes in GFR. Thus the use of the reciprocal makes small changes in GFR more apparent.

Fig. 4-6. Changes in plasma creatinine concentration and 1/P_cr as a function of changes in GFR.

Fig. 4-7. Illustration of the utility of measuring P_cr in a patient with chronic renal disease.

Measurement of P_cr and calculation of the reciprocal in a patient with chronic renal disease over a period of time allows one to plot the reciprocal versus time and the plot assists in determining the status of the disease (fig 4-7). If the disease process is accelerated, the reciprocal will fall at an increased rate; if treatment halts the progression of the disease, the reciprocal will stabilize. A word of caution: This tool is useful in following the progress of renal disease in a single individual. However, variations in creatinine production rates and other factors prevent its use in making comparisons among patients.

C. All the difficulties involved in measuring inulin clearance in patients are also encountered in measuring PAH clearance. In addition, a compromised or diseased kidney may not be extracting 90% of the PAH from the plasma flowing through it, so renal venous blood samples must be obtained in order to measure RPF accurately. Consequently, other means of assessing RPF in patients have been developed. In general, these methods are only semi-quantitative, but are much more easily applied to patients. In one of these methods, a substance secreted by tubular cells is labeled with a radioactive isotope (commonly ¹³¹I) and given as a single intravenous injection. An isotope counter is placed over the kidney and the amount of isotope appearing in that region of the body is measured. Following the injection, the isotope rapidly accumulates in the normal kidney as the tubules remove the substance from the plasma. After reaching a peak, the amount of isotope present falls at a slower rate as it is excreted in the urine. In other methods, the rate of disappearance of the same type of substance from the circulating plasma is measured after a single injection. This can be done by sequentially removing aliquots of blood and measuring the radioactivity present or by placing a counter over the head and measuring the radioactivity circulating through the head. The rate at which this substance disappears from the blood is largely determined by the rate at which the kidney clears it from the circulating plasma.

D. Clinicians often assess tubular function by measuring the fraction of the filtered amount that the tubules excrete, that is, fractional excretion. The smaller the fraction, the more efficient are the tubules in retaining filtered substances.

1. The fractional excretion of water, FE_H2O, is simply the urine flow rate, V, divided by the filtration rate, GFR (Fig. 4-8). The actual measurement is made even simpler by assuming that C_cr equals GFR, as the following equation indicates:

FE_H2O = V / GFR = V / C_cr = V / (U_crV/P_cr) = 1 / (U_cr/P_cr) =P_cr / U_cr

The utility of the ratio, P_cr/U_cr, is that timed, complete, collection of the urine is not required for this measurement. All that is required are samples of the blood and the urine. The fractional reabsorption rate, FR_H2O = 1 - FE_H2O. The values for FE and FR are usually multiplied by 100 to give the percent of the filtered water that is either reabsorbed or excreted.

Fig. 4-8. Calculation of fractional water excretion.

2. The same approach can be used to calculate the fractional excretion of a solute, FE_s. What is determined is the fraction of the filtered load of solute that is excreted:

Fig. 4-9. Calculation of the fractional excretion of a solute, FE_s.

(The mnemonic that results, you pee/you pee, is one that any student should be able to remember in association with the kidney.) All that is required to measure the fractional excretion of a solute is a sample of the blood and a sample of the urine and measurements of the solute concentration and creatinine concentration in the two samples. The fractional reabsorption rate, FR_s is equal to 1 - FE_s. FE_s and FR_s are usually multiplied by 100 to give the percent of the filtered amount of the substance that is either reabsorbed or excreted. This measurement is most used to express the fractional excretion of Na:

The measurement of FE can be used with any solute that the kidney excretes. It is used most often in connection with Na (You pee Na/You pee creatinine). Na is one of the most plentiful solutes in the filtrate and it is reabsorbed by active tubular transport that requires substantial energy consumption. Thus, FE_Na is an index of the activity and health of the tubules. Normally FE_Na is usually less than 1%, physiologically it seldom goes above 3%. Thus, in the absence of drugs that inhibit salt reabsorption, values above 3% usually indicate significant impairment of tubular function.

E. Clinicians evaluating renal function may often have different objectives in mind and the type of measurement to perform depends on the objective. In a patient suspected or known to have renal disease, it may be important to evaluate glomerular or tubular function. Then the various uses of creatinine described above can be used to measure glomerular function and the concentration ratios can be used to evaluate tubular function. In other instances, e.g., a bed-ridden patient receiving a significant volume of intravenous fluids, the physician may be interested in determining if the kidney is maintaining or altering body fluid balance or solute balance. In this situation measurement of the rate of excretion (V or U_sV) is important and permits comparison to the rate of intake.

QUESTIONS: 
6. What criteria must be met by a substance if it is to be used to measure GFR? Does creatinine meet all these criteria? If not why can creatinine be used to measure GFR? What factors must be kept in mind in interpreting measurements of GFR with the use of creatinine?

7. Why is it possible to follow qualitatively changes in a patient's glomerular function over a period of time by simply measuring plasma creatinine concentration?

8. Consider that glomerular disease causes the loss of 25% of the glomerular filtering capacity of a patient before the disease is caught and arrested. If the rate of creatinine production remains constant will the plasma creatinine concentration continue to rise after the disease process is stopped?

9. The values in the table were obtained from a patient who was in salt and water balance. 

(a) Calculate: C_cr

(b) Calculate the rate of Na filtration:

(c) Calculate the rate of Na excretion:

(d) Calculate FE_H2O and FE_Na:

(e) Calculate FE_urate:

10. A patient with chronic, slowly progressive renal failure was found to have these laboratory values. Calculate (a) C_cr and (b) the fractional excretion of Na, K, PO₄.

11. Compare and contrast the following for the patients described in problems 9 and 10:

(a) P_cr

(b) GFR:

(c) the rate of creatinine excretion:

(d) absolute water excretion rate and fractional reabsorption of water:

(e) absolute Na excretion and fractional Na reabsorption rates:

Use these data to answer questions 12-16.

12. Which patient has the poorest glomerular function? Why isn't this reflected by a low rate of water and salt excretion?

13. Patient A is hypertensive and has been given a diuretic agent in order to reduce extracellular volume. What measurements indicate that the drug is having an effect? What measurements indicate that the drug has inhibited tubular function?

14. Patient D is hypertensive and edematous. It is necessary to restrict salt intake so that the amount of salt in the extracellular compartment does not increase. What should be the upper limit of her salt intake?

15. Patient C underwent extensive surgery, lost a considerable amount of blood, and was very hypotensive for a period of time. The surgeons are concerned that the kidneys may have been damaged by ischemia. Evaluate the patient's glomerular and tubular function.

16. Patient B is in a state of diuresis. How large a volume intake/day would be required to maintain fluid balance?

Homer W. Smith, "Renal Physiology Between Two Wars". Lectures on the Kidney. University Extension Division. University of Kansas, Lawrence, 1943.

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