practical use of urinary fractional excretion

$: Practical use of urinary fractional excretion$
PRACTICAL USE OF URINARY FRACTIONAL

EXCRETION

Christine King, BVSc, MACVSc, MVetClinStud

Many clinical conditions involve electrolyte or mineral imbalances, either as an inciting cause or as a conse- quence of disease. Effective homeostatic mechanisms ensure that extracellular fluid (and hence serum) concentrations of electrolytes and minerals are maintained within a narrow range during all but severe disease states. This means the evaluation of serum electrolyte and mineral concentrations may be of limited use in subclinical or mild clinical conditions or early in the disease process. Normal serum electrolyte concentrations reflect successful homeostasis, not necessarily an absence of disease. <9,11

The total body concentration of a substance is determined by intake (oral, intravenous, etc) and loss (serum/blood, urine, feces, sweat, saliva, respiratory secretions, milk, etc). The kidney is a major route of excretion of sodium (Na), potassium (K), chloride (C 1), calcium (Ca), and phosphorus (P) in horses, and electrolyte homeostasis is effected mainly through changes in renal excretion.4,9,11 Measurement of these ions in the urine can give an indication of the electrolyte or mineral balance by quan- titating excretory losses. However, sim-

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because the concentration is dependent in part on the volume of urine produced, which is determined by the glo- merular filtration rate (GFR). Factors that affect the GFR include water intake and renal blood flow. 4,~'tt

METHOD

The GFR can be estimated by the clearance rate of a substance that is totally filtered and neither secreted nor absorbed by the kidney. For practical purposes, endogenous creatinine (Cr), a byproduct of muscle metabolism, is used to determine the GFR because it is produced at a fairly constant rate, and its excretion by the kidney is virtually constant. 4,9,it Expressing the urinary excretion of a substance as a percentage of Cr excretion (the fractional excretion) gives an indication of the body's efforts to conserve or excrete that substance. The fractional excretion (FE) of a substance is calculated by the follow- ing equation:

F E x = [x] urine X [Cr ]serumX 100

[x] serum [Cr] urine

where x = ion under invest igat ion

[ ] urine = urinary concentrat ion of substance [ ] serum = serum concentration of substance

A sample of blood and urine (either voided or by catheterization) should be taken at the same time and submit- ted for determination of urine and serum Cr and electrolyte concentrations. Most studies show a very good correla- tion between a single FE measurement and those averaged over a 24-hour col- lection period, z8 One study showed substantial variation between and with individual horses over a 24-hour pe-

remained within published normal ranges (Table 1) throughout the study. 9 The authors suggested that the variations may have been due to surges in the hormones that regulate these two substances (aldosterone for Na, and parathyroid hormone, calcitonin and vitamin D3 for Ca) and variations in the quantity and rate of food consumption during the 24-hour period. 9 Other authors have suggested that electrolyte excretion may also be affected by diet, exercise, and excitement, a,<s,7,1°

Traver et al. stated that the administration of diuretics such as furosemide reduces the absorption of electrolytes from the renal tubules, it This results in large increases in the FE of Na, K and C1. The FE of P after furosemide is zero, not because P is being conserved but because of the dilution effect of the increased urine ion load. It is important that diuretics are not used for procuring a urine sample for FE evaluation in horses.

A routine urinalysis, including spe- cific gravity (SG), should be performed each time urine is collected for FE evaluation. This will give added information on renal function because the GFR must be reduced by greater than 2/ 3 before renal insufficiency is reflected by elevations in serum Cr concentration. 4

Published normal FE values vary from study to study; Table 1 summarizes the findings of a number of clinical and experimental studies.

INTERPRETATION

Sodium The resorption of Na is under the

control of aldosterone, which is se-

464 JOURNAL OF EQUINE VETERINARY SCIENCE

Table 1. Normal ranges for urinary fractional excretion, FE (%), of electrolytes al and in neonatal foals.

FE (%)

Na K CI Ca P Adult horses 0.01-1.0 15-80 0.04-2.1 0-33 0-0.5

& ponies (majority) (<0.5) (20-50) (0,5-2) (<8) ( " )

After furosemide* 12 207 9.5

Neonatal Foals+ 0.1-0.5 9-18 0.1-0.7 0-6 0-7

Most horses fed grass hay and grain *from Traver et al. 11 +from Brewer et al. (data from 8 healthy, 4-day-old, full-term foals) 2

creted when the Na concentration of the extracellular fluid (ECF) compart- ment is reduced. Provided aldosterone production and tubule receptor sensitivity are normal, hyponatremia results in a low FENa and hypernatremia leads to an increase in the FENaJ 1 A low FENa (<0.02%) is an indication that the body is conserving Na; only an increase in the FENa is of real d iagnost ic value.4,6,9,13

An increase in the FENa may be the result of four situations:

(1) Excess dietary intake can occur with commercial rations that are high in NaC1, and diets or drinking water supplemented with electrolytes; psy- chogenic salt eaters are rare. 4

(2) Addison's disease occurs either as a result of reduced aldosterone production or areduction in the number or sensitivity of receptor sites in the distal tubules. Common presenting signs include polydypsia/polyuria and exercise intolerance. In horses with Addison's disease the FENa is increased, but the FEK and FEe are normal; the urine is dilute, but otherwise normal. 4,t 1

(3) Dehydration due to water dep- rivation or evaporative loss signals the body to excrete Na to maintain normal ECF osmolality. An increase in urine SG differentiates dehydration from other causes of increased FENa .4'9

(4) Renal tubular insufficiency results in the loss of filtered Na in the

urine, as the kidney fails to resorb Na in the distal tubules. Azotemia, and increases in the FE of K, C 1 and P are also common with renal tubular disease. The urine SG is low, and there are usually other urine abnormalities, such as proteinuria, and glycosuria without hyperglycemia. 4,6,9

The FENa is a useful diagnostic tool for differentiating prerenal and renal azotemia. Grossman et al. found that horses with prerenal azotemia had FENa values of less than 0.5 %, whereas those with renal disease had values between 0.8% and 10.1%; there was no overlap between the groups. 6 The authors stated that a FENa of >1% was indicative of renal azotemia, particu- larly if the serum electrolytes were ab- normal. For example, a high FENa despite hyponatremia is an indication of "salt-wasting"-severe renal tubular insufficiency. This example illustrates an important point: FE values should be interpreted in the light of the serum electrolyte concentration and clinical findings. Grossman et al. pointed out that human patients with acute glo- merulonephritis, acute renal failure due to sepsis, and acute renal failure con- comitant with Na-retaining conditions such as burns or liver cirrhosis, can have FENa values of less than 1%.6

In a clinical study by Harris and Colles two horses with recurrent rhabdomyolysis were found to have

very low FENa values. Supplementa- tion with 2 to 3 oz of NaC1 per day resulted in clinical improvement with no further attacks of rhabdomyolysis while on the supplement. 7

Potassium The urinary excretion of K is highly

variable, being greatly affected by K intake. Feeding very high quality al- falfa hay or lush green grass can result in FEK values of up to 150%. 4 This can be considered normal if the FE values of other electrolytes and urinalysis are normal. In theory, the FEK should increase when Na retention increases (i.e. FENa decreases), but because the normal range for FEK is so large, this change is difficult to detect. 4

A low FEK (<15%) implies a total body depletion of K. Since the plasma concentration of K is maintained in the face of substantial total body K defi- cits, a low FEK may be an early indicator of the need for K replacement therapy.4,9.11

The FEK is also dependent upon the urine and blood pH. When total body depletion of K occurs hydrogen ions (H) are excreted in the distal tubule in exchange for Na ions. If the urine is alkaline a low FEK indicates either depletion of total body K, insuf- ficient dietary K intake, or poor absorption of K in the gut. If the urine is acidic a low FEK indicates either the total

Volume 14, Number 9, 1994 465

body K is so low that H is being excreted at a greater rate, or metabolic acidosis exists and H is excreted and K retained. An assessment of the horse's clinical condition is usually sufficient to determine whether significant metabolic acidosis is present. Blood gas analysis may also be helpful in some cases.4

Potassium has an important role in neuromuscular function, including va- sodilatation of muscle arterioles during exercise. This has led some researchers to surmise that total body depletion of K may result in alterations in intracel- lular metabolism, local muscle isch- emia, and exercise-induced rhabdomyolysis. 1'7 In a study by Beech et al. horses with recurrent myositis had lower FEK than clinically normal horses, although the values for all horses in the study were within the published normal range. The horses with recurrent myositis had lower semimembranosus muscle K concentrations than the normal horses, although the FEK was not significantly correlated with the muscle K. These results led the authors to con- clude that depletion of total body K may be associated with the occurrence of exercise-induced rhabdomyolysis in horses. 1 In another study one horse with recurrent myositis had an FEK of 18%, which was considered very low for the type of diet the horse was fed. The horse continued to have mild attacks ofmyositis even after the electrolyte content of the diet was balanced; the attacks ceased once 3 oz of NaC1 per day was added to the balanced ration. 7

Horses with chronic laminitis of- ten have very low FEK (eg. 3%), which is suggestive of depletion of total body K. Although the mechanism is un- known, supplementation with K report- edly results in clinical improvement in lameness.4.11

Chloride Chloride is the major urinary an-

ion, and its excretion is closely linked

Table 2. Effects of dietary calcium (Ca) and phosphorus (P) concentrations on the urinary fractional excretion, FE (%), of Ca and P in adult horses.*

Diet Dietary Intake FE (%) (g/day)

Ca P Ca:P Ca P 28 (estimate) 13 (estimate) 2.2:1 3.7+0.9 0.08_+0.03 10.8 9.0 1.2:1 2.1+1.4 0.4+0.2 9.0 41.4 1:4.6 1.9+0.4 19.9+1.9 35.1 38.7 1:1.1 4.6+0.3 5.5_+1.0

A: pasture B: oaten chaff# C: B+oats & bran D: C+90g CaCO3

*from Caple et al. 3 #oaten chaff is oaten hay that is cut up into small particles (generally includes the whole oat plant, without roots, including the seed head)

with that of Na and K. The FEc~ can be variable within individual animals, and it does not appear to have much diagnostic value in horses. 4,9

Calcium Horses normally excrete about 30%

of the absorbed Ca in their urine, a Be- cause herbivores have alkaline urine, calcium carbonate (CaCOa) crystals form and precipitate in the bladder. Unless these crystals are dissolved with acid before the urine Ca concentration is measured the FEca may be quite inaccurate. Furthermore, the settling of CaCO3 crystals in the bladder means the Ca in the urine is not evenly distrib- uted, and this can add another source of error to the interpretation of the FEca when only a portion of the voided volume is analyzed. 4 Nevertheless, some researchers have found the use of FECa to be of value in horses, a'5'9

Calcium and P metabolism are closely associated, being controlled by parathyroid hormone (PTH), calcitonin and vitamin D3. Slight reductions in the serum Ca concentration result in an increase in PTH, which causes an increase in Ca resorption from bone, gut and kidneys, and an increase in P excretion via a lowered renal P threshold, a,s,9 The renal excretion of Ca appears to vary with breed, activity level, and diet. In one study Thoroughbreds in training and ponies (not exerc ised) had interquartile ranges for the FEca of between 7% and 21%, whereas the FEca fl)r Thoroughbreds not in training were

in the range of 14% to 33%. The authors suggested that exercise causes calcium retention in horses, s

Table 2 summarizes some of the results of a study by Caple et al., in which diets containing various amounts of Ca and P, from low to excessive, were fed to adult horses. The authors advocated the use of FE of Ca and P for the determination of Ca and P balance in mature horses because detailed dietary analysis can be costly and time- consuming, and it may be inaccurate when estimates must be made of the amount and quality of pasture con- sumed. Furthermore, dietary analysis cannot provide information about the availability and absorption of nutrients. When horses were fed a low Ca, high P diet (oaten chaff, oats and bran) the FEca dropped and the FEe increased; supplementation with CaCO3 resulted in an increase in FEca and a decrease in FEp within 72 hours. The serum Ca and P did not change despite variations in dietary Ca and P. This study showed that horses receiving adequate dietary Ca and P (3g Ca/kg drywt, and 2g P/kg drywt) had FEca values >2.5 % and FEp values <4%. a

The FEca can be greater than normal in horses with acute renal disease, but there is considerable overlap between normal values and those from horses with renal disease. Horses with chronic renal failure can have hyper- calcemia due to a reduction in the excretion of Ca, as a result of failure of the kidney to degrade PTH. 9


Calcium is required for normal muscle function and to maintain the Na concentration in nerve cells. 7 In a clinical study of horses affected by recurrent rhabdomyolysis, 2 racehorses in training were found to have higher than normal FEe values (1.7% and 8.5%). Clinical improvement and a reduction in FEp were seen as long as the diets were supplemented with 2 to 3 oz CaCO3 per day and fresh grass. The serum Ca and P concentrations were normal both before and after supplementation.7

Magnesium Magnesium (Mg) is closely asso-

ciated with Ca both in functional role and in the homeostatic mechanisms that control the plasma concentrations of these ions. Thus, the urinary excretion of Mg parallels that of Ca. The FEMg in normal horses appears to be quite variable, ranging from 15% to 53% in a study by Gray et al. In that study Thor- oughbreds in training had a FEMg interquartile range of 15% to 42%; Thoroughbreds not in training had a range of 21% to 32%; and ponies (not exercised) had a range of 30% to 53%. The FEMg interquartile range in horses with chronic myositis was quite low: 3% to 14%. However, Mg supplementation was not addressed in this study, leaving the practical interpretation of this finding open to speculation. 5 There may be some value in measuring the FEMg instead of the FEoa because of the potential errors inherent in the accurate measurement of urinary Ca concentration. However, given the wide range of FEMg values reported for normal horses, more research is warranted before adopting this approach to evaluating the Ca balance.

Phosphorus The FEp has been suggested to be

a sensitive diagnostic indicator of the Ca and P balance in horses, a,8,1°'11 Traver et al. gave two examples of its clinical application. An 11-month-old

Quarter Horse filly was presented with a history of knuckling and with filling in the rear fetlocks. The horse was on a high-grain diet and was overweight. The serum Ca and P concentrations were normal, but the FEe was 4%. A diagnosis of nutritional secondary hy- perparathyroidism (NSH) was made, and the horse responded well to dietary Ca supplementation. The second case involved a 12-month-old Quarter Horse colt, with similar history and presenting signs. Again, the serum Ca and P concentrations were normal, although in this case the FEp was 0.06%. The diagnosis made was excess caloric intake, and the horse responded to a reduction in feed without mineral supplementation. 1

An increase in the FEp may be associated with four conditions:

(1) Primary or pseudohyperpara- thyroi~ism, causing an increase in PTH production. Both conditions are rare (pseudohyperparathyroidism is the result of ectopic production of PTH or PTH-like peptides from a neoplasm of non-parathyroid origin). These conditions can cause an increase in serum Ca, a reduction in serum P, and an increase in the FEp. 4'1°

(2) Renal tubular disease. 4 (3) P-wasting nephropathy, a vague

condition affecting mature horses and causing chronic, obscure, multifocal lameness. The FEe is much greater than expected for the type of diet, and the recommended therapy is supplementation with Na-monophosphateYl

(4) NSH-this can occur when the P: Ca in the ration exceeds 3:1, regard- less of whether the Ca content of the diet is sufficient. Even in horses with a positive Ca balance, high P diets de- press the intestinal absorption of Ca and increase the removal of Ca from bone. In NSH the serum Ca concentration is normal or slightly depressed, but the FEp can be as high as 60% in severe cases.4,~0,11

Urine/Serum creatinine ratios

Comparing the urine and serum Cr concentrations (Ucr:Scr)provides some information on tubular excretory function, and this can be useful in differentiating prerenal and renal azotemia. 6 In a study by Grossman et al. horses with prerenal azotemia had Ucr:Scr values between 51 and 242 (most were between 50 and 110). In contrast, horses with renal azotemia had Uor:Scr values between 2.6 and 37 (most were between 3 and 20). This measurement was accurate even during the oliguric phase of renal failure because the abil- ity to excrete Cr was reduced despite the body still being able to regulate the Na and water balance, e

Foals Brewer et al. found that a single FE

measurement was accurate in full-term, healthy 4-day-old foals. They found that foals had much lower FEK and much higher FEp values than adults (Table 1). The higher FEe was attrib- uted to a greater turnover of bone and muscle in foals. No relationship was found between the Na or K concentrations in the mare's milk and the foal's urine; however, there was an inverse relationship between the Ca concentration in the mare's milk and the foal's urine. No explanation was given for this finding, a

Intravenous fluid administration No information is available in the

literature regarding the effect of con- current administration of intravenous (IV) or oral fluids on FE values. Ad- ministration of IV or oral fluids should increase renal blood flow, and hence the GFR and the clearance of Cr and electrolytes. Because the FE of an electrolyte is expressed as a percentage of Cr excretion, FE measurements should still be valid during fluid therapy. In theory, isotonic, polyionic solutions should not affect the FE of electrolytes because most have a similar ionic com- position to plasma. If total body stores of an electrolyte are depleted prior to

Volume 14, Number 9, 1994 467

fluid administration, the FE of that substance would be low before, and would likely remain low during treatment as the body attempts to conserve the electrolyte. If IV fluids rich in a particular electrolyte, such as Na in physiologic or hypertonic saline, are given to an animal that is in positive balance with the ion, the FE could be expected to be greater than normal. Therefore, the type of fluid administered and the animal's clinical condition should be considered when interpreting FE results.

S U M M A R Y

In summary, the FE of electrolytes and minerals is a practical, inexpensive and useful diagnostic tool that may enable recognition of renal and meta- bofic problems before they progress to an extreme, severely debilitating de- gree. Published normal values vary widely, but several studies have dem- onstrated the clinical relevance of FE measurement in renal tubular disease, metabolic diseases (such as NSH and

low total body K), exercise-induced rhabdomyolysis, and in the determination of Ca and P balance in horses and ponies. The method is also valid in neonatal foals.

R E F E R E N C E S

1. Beech J, Lindborg S, Braund KG. Potassium concentrations in muscle, plasma and erythrocytes and urinary fractional excretion in normal horses and those with chronic intermittent exercise-associated rhabdomyolysis. Res Vet Sd 1993;55:43- 51.

2. Brewer BD, Clement SF, Lotz WS, Gronwall R. Renal clearance, urinary excretion of endogenous substances, and urinary diagnostic indices in healthy neonatal foals. J Vet Int Med 1991 ;5:28-33.

3. Caple IW, Doake PA, Ellis PG. As- sessment of the calcium and phosphorus nutrition in horses by analysis of urine. Aust Vet J 1982;58:125-131.

4. Coffman J. Clinical chemistry and pathophysiology of horses-Percent creatinine clearance ratios. Vet Med Small Anim Clin 1980;75:671-676.

5. Gray J, Harris P, Snow DH. Prelimi- nary investigations into the calcium and magnesium status of the horse. Animal Clini-

ca/Biochemistry-The future. Blackmore DJ (ed), Cambridge University Press, UK.1988; 307-317.

6. Grossman BS, Brobst DF, Kramer JW, Bayly WM, Reed SM. Urinary indices for differentiation of prerenal azotemia and renal azotemia in horses. J Am Vet Med Assoc 1982; 180:284-288.

7. Harris P, Colles C. The use of creatinine clearance ratios in the prevention of equine rhabdomyolysis: A report of four cases. Eq Vet J 1988;20:459-463.

8. Lane VM, Merritt AM. Reliability of single-sample phosphorus fractional excretion determination as a measure of daily phosphorus renal clearance in equids. Am J Vet Res 1983;44:500-502.

9. Morris DD, DiversTJ, Whitlock RH. Renal clearance and fractional excretion of electrolytes over a 24-hour period in horses. Am J Vet Res 1984;45:2431-2435.

10. Ronen N, van Heerden J,van Amstel SR. Clinical and biochemistry findings, and parathyroid hormone concentrations in three horses with secondary hyper- parathyroidism. J S Afr Vet Assoc 1992;63:134-136.

11. Traver DS, Coffman JR, Moore JN, Salem CA, Garner HE, Johnson JH, Tritschler LG. Urine clearance ratios as a diagnostic aid in equine metabolic disease. Proc Am Assoc Equine Pract 1976;22:177- 183.

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practical use of urinary fractional excretion

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