Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia

Abstract

While the fractional excretion of solutes have long been considered excellent research tools to investigate tubular physiology, their clinical use has become common over the last 40 years in the diagnoses of many disorders; however, none have reached the clinical utility of the fractional excretion of sodium in the ability to distinguish pre-renal azotemia from acute tubular necrosis. Nevertheless, there are many drugs and medical conditions that interfere with that utility and recently other solutes, including urea, uric acid and lithium, have been recently investigated to improve the diagnostic ability in clinical situations where the fractional excretion of sodium is known to be unreliable. We review the tubular physiology of these solutes and show how the differences in tubular physiology might be exploited to develop a strategy for their optimal clinical use.

• azotemia
• renal failure
• diagnosis
• solute transport
• renal physiology

INTRODUCTION

For most of the twentieth century the urinary excretion of a solute when adjusted for the amount of that solute filtered at the glomerulus (also known as the fractional excretion of that solute) has been a useful research tool to investigate tubular physiology. The clinical use of fractional excretions only became popular three decades ago when the fractional excretion of sodium (FeNa) was first employed to help solve the common dilemma for the clinician; namely, the need to distinguish pre-renal azotemia (PRA) from intrinsic renal pathology (ATN) in patients with oliguric azotemia.¹ Since that time, the fractional excretions of other solutes such as magnesium, potassium, bicarbonate, chloride, calcium, and phosphorus have been occasionally used to diagnose cyclosporine toxicity,² distal acidification² and proximal bicarbonate wasting,³ tubular transport errors,⁴ bullemia,⁵ and familial hypocalciuric hypercalcemia⁶ and to differentiate hyperparathyroidism⁷ from vitamin D toxicity;⁸ however, none of these calculations have achieved the clinical utility of the FeNa in the differentiation of PRA from ATN in oliguric azotemia which remains commonly recommended.⁹ As assessment of hydration can be difficult¹⁰ and classical clinical signs are often lacking,¹¹ the FeNa remains an extremely valuable tool; however, many drugs and medical conditions interfere with the accuracy of the FeNa (Table 1).^12–44 More recently other solutes, including urea, uric acid, and lithium, have been investigated with the goal of improvement in the diagnostic ability to distinguish between PRA and ATN.^44–54 In an effort to evaluate these studies and the particular problems with each solute, we will briefly review the physiology of their renal handling in water deprivation states.

Table 1.  Reported clinical causes of misleading FeNa

	False elevation	False depression
Drugs	Diuretics, nesiritide, nisoldipine, aminoglycosides, dopamine, calcitonin, cisplatin, cyclosporine, caffeine, ethanol	Radiocontrast dye, indomethacin, erythropoietin, astragalus & angelica
Diseases	Cirrhosis, premature infants, Bartter's syndrome, Gitelman's syndrome, interstitial nephritis, ureteral obstruction	Nonoliguric ATN, hemoglobinuria, myoglobinuria, sepsis, obstruction, hepatorenal syndrome, glomerulonephritis, transplant rejection, burns
Metabolic	Chronic metabolic alkalosis acidosis, hypercalcemia, hypomagnesemia	Acute (but not chronic) respiratory acidosis

Note: There are many clinical situations where drugs^12–21 or disease^22–27 interfere with glomerular²⁴ or tubular function^25–29 which can result in an altered renal handling of sodium.^30–36,101Surprisingly, while use of diuretics are well known to make the FeNa unreliable,^35–38 other drugs, such as amphotericin, that are known to cause proximal tubular damage may not.³⁹ Rarely liver disease can result in pre-renal azotemia with an elevated FeNa because of sodium bicarbonate wasting from alkalosis³⁰ or alternatively because of loss of urea production that is necessary for water reabsorption and urine concentration.¹⁰¹ Similarly bicarbonate conservation in acute (but not chronic) respiratory acidosis may cause a false depression through sodium bicarbonate conservation and generation³¹ while metabolic acidosis has also been associated with an elevated FeNa regardless of volume^32,33 perhaps through hypercalcemia and hypomagnesemia may also interfere with tubular ability to conserve sodium even in the presence of hypovolemia.⁴⁰ Extremes of age both young and old can affect both sodium excretion.^41,42 In premature infants of 29–32 weeks gestation, a FeNa of >6 was required to distinguish ATN from PRA, but no satisfactory criteria were found for those infants under 29 weeks.⁴²

RENAL PHYSIOLOGY IN WATER DEPRIVED STATES

Sodium chloride

While NaCl is reabsorbed along the total nephron, the majority occurs in the proximal tubule (Figure 1). While some have postulated an opiate receptor, which is known to aid in proximal reabsorption in rats,⁵⁵ it is unclear whether such a receptor exists in humans. Usually, in water deprivation states, sodium is avidly reabsorbed from the glomerular filtrate as a result of suppression of natriuretic peptide,⁵⁶ activation of renal nervous system⁵⁷ and renin-angiotensin-aldosterone system axis, and local changes in peritubular hemodynamics⁵⁸ (Figure 1). There is also increased sodium reabsorption in the water-impermeable thick ascending limb (TAL), which provides increased medullary interstitial osmotic pressure for increased water conservation. To concentrate urine to 900 mOsm/L, a driving force in the medullary collecting duct (MCD) must be maintained to continue water reabsorption. As urea and NaCl are the main osmotic agents, their reabsorption becomes essential in water conservation. To conserve 5 L of water from the 6 L of filtrate delivered to the MCD, 1500 mOsm of NaCl must be reabsorbed from TAL.⁵⁹ Therefore the use of diuretics interferes with NaCl reabsorption in the proximal tubule, TAL, and distal tubule (Figure 2) and will deliver more NaCl to the MCD, resulting in higher intraluminal osmolality and lower interstitial osmolality which will prevent the necessary osmotic gradient and water conservation. As will be discussed later, this becomes a problem for the use of the FeNa to diagnose PRA in the presence of diuretics. Similarly, just as the kidney will preserve volume at the expense of tonicity, it will also preserve pH at the expense of volume preservation, and thus various pH changes can also cause problems for the FeNa.

Figure 1. Sodium chloride reabsorption: 97% is absorbed through the distal convoluted tubule with the remaining 2–3% reabsorbed in the collecting duct.

Figure 2. Interference with active tubular transport of sodium. Diuretics interfere with the active transport of sodium necessary for volume conservation in pre-renal states and thus alter FeNa.

Urea

Urea conservation has long been known to accompany water conservation. Early investigators demonstrated that 57% of urea is reabsorbed in the proximal tubule.⁶⁰ The fractional excretion of urea (FeUrea) drops below 50% at urine flows below 3 cc/min (4320 mL/24 h) and appears near 40% by the time urine flow falls below 0.41 cc/min (590 mL/24 h).⁶¹ While we have always understood that active transportation of NaCl was necessary for water conservation and its interference was useful for diuresis, we have only recently come to realize that urea reabsorption is also mediated by active transport. Urinary concentrating mechanisms models until recently were riddled with problems⁶² because of the assumption of a hypertonic inner medulla through passive transport of urea. Now we understand that urea movement across plasma membranes is modulated by specialized urea transporter (UT) proteins. In the collecting duct, UT-A1 and UT-A3 are active, while the isoform UT-A2 is in the pars recta⁶³ and descending thin limb, and the isoform UT-B in the descending vasa recta (Figure 3).⁶⁴ Just as diuretics can interfere with the active transport of NaCl and alter FeNa, drugs or disease entities that interfere with the active transport of urea will alter the FeUrea. Cytokines from experimental sepsis have been shown to down-regulate urea transporters in the presence of endotoxemia from experimental infection.⁶⁵ Gender,⁶⁶ aging,⁶⁷ protein,⁶⁸ liver disease,⁶⁹ hyperfiltration,⁶³ and certain drugs such as cyclosporine,¹⁸ lithium,⁷⁰ and spironolactone⁷¹ have also been suggested to interfere with the active transport of urea.

Figure 3. Interference with active tubular transport of sodium urea is now known to rely upon active urea transporters that are also located in the thin descending limb, vasa recta, and the collecting duct. Interference with the active transport may also interfere with FeUrea.

Uric acid

Unlike NaCl and urea, uric acid is not an osmotic agent involved in water conservation and therefore a less obvious tool to distinguish PRA from ATN; however, increased serum uric acid levels have long been noticed to correlate with increased proximal tubular reabsorption.⁷² Normally two-thirds of uric acid is excreted by the kidneys but extra-renal excretion increases at higher levels. The complex physiologic functions that can lead to 90% net retention of filtered load are not as yet fully elucidated. Until recently renal excretion was thought to be a four-component model that sequentially involved (1) glomerular filtration, (2) tubular reabsorption, (3) tubular secretion, and (4) post-secretory reabsorption. Unfortunately, the assumptions of that model are no longer considered valid. Organic ion transporters (OAT), including URAT1 located on the apical side of renal proximal tubules, are known to mediate the clearance by exchanging urate with endogenous and exogenous anions. Once inside proximal tubular cells, a sugar transport facilitator family member protein GLUT9 (SLC2A9) functions as an efflux transporter of urate from the tubular cell.⁷³ Most drugs (Table 2) that cause uricosuria interfere with URAT1 and its binding partner PDZK1 located at the apical border of the proximal tubule.⁷⁴ Several other OAT are most likely also involved and may be related to some of the age, gender, disease, and genetic differences known to occur in serum uric acid.^75–80 Interestingly, some angiotensin II receptor blockers trans-stimulate the uptake of uric acid by URAT1 whereas others cis-inhibit such transport by URAT1 and other OAT.⁷⁷ Similarly competition from other organic anions for OAT may explain the hyperuricemia known to occur in lactic acidosis, ketoacidosis, and alcohol ingestion⁷⁸ and even by drugs with organic acid metabolites, like aspirin and fenofibrate.⁷⁹ More difficult to explain is the hyperuricemia associated with hyperinsulinemia and salt absorption. Enhanced activity of OAT is noted after 24 h of water restriction regardless of changes in effective renal plasma flow;⁸¹ however, the effect is not related to urine output or concentration,⁸² which may explain why vasopressin (ADH) has such conflicting effects, being associated with hyperuricemia with appropriate ADH and hypouricemia with inappropriate ADH (SIADH). As the high FeUA usually corrects with fluid restriction in SIADH, some authors have suggested that an FeUA that remains above 10–12% in hyponatremic and hypouricemic patients, a diagnosis other than SIADH should be considered.^83,84 Thus considered it appears that intravascular volume regulates FeUA, with even small increases such as those seen in SIADH being associated with decreased URAT1/OAT activity with increased FeUA, and decreased intravascular volume being associated with increased URAT1/OAT activity and decreased FeUA.

Table 2.  Drugs that alter uric acid reabsorption and secretion in the kidney

Probenecid

Phenylbutazone

Benzbromarone

Sulfinpyrazone

Losartan

Candesartan

Aspirin

Non-steroidal anti-inflammatory drugs

Furosemide

Hydrochlorothiazide

Metalazone

Pyrazinamide

Fenofibrate

Lithium

Lithium is freely filtered, and normally approximately 80% is reabsorbed. Reabsorption was originally thought to be limited to the proximal tubule. More recently, some investigators have found that only 60% is reabsorbed in the proximal tubule whereas another 20% reabsorption is accomplished between the late proximal convoluted tubule and early distal sites⁸⁵ with another 3% after the early distal tubule which increases to 40–50% during severe sodium restriction. The renal handling of sodium and lithium appears interrelated in the distal nephron because they share the same apical membrane entry mechanism (the amiloride-sensitive sodium channel); however, the two ions exit the cell through different transport mechanisms. Sodium exits through the Na-K-ATPase whereas lithium through the Na/H exchanger. A hypothesis has been proposed linking sodium and lithium reabsorption in the distal nephron which suggests that the absence of distal lithium reabsorption during intake of a normal diet can be explained by a negative driving force for lithium entrance across the apical membrane in those segments in which amiloride-sensitive sodium channel is active.⁸⁶

Although osmotic diuresis⁸² and sodium depletion⁸⁷ do not affect the ratio of intratubular to plasma lithium concentrations ([T/P]_Li) in the proximal tubule, diuretics such as furosemide and amiloride,^88,89 as well as prostaglandin inhibition by indomethacin,⁹⁰ do affect reabsorption indicative of substantial reabsorption beyond the proximal tubule. Indeed diuretics have been used to treat lithium overdose⁹¹ unless there is renal function impairment.⁹² Other drugs may also affect lithium reabsorption. The use of non-steroidal anti-inflammatory drugs, diuretics, renin-angiotensin inhibitors, liver disease, hypertension, theophylline, calcineurin inhibitors, and particularly antibiotics have been thought as potential determinants of the elevated lithium serum levels.^93–97

DEVELOPMENT OF THE FRACTIONAL EXCRETION OF SOLUTES AS A DIAGNOSTIC TOOL TO DISTINGUISH PRA FROM ATN

The calculation of the fraction of a urine solute that was excreted compared to the amount filtered is not a new concept. Early studies, usually that attempted to understand tubular function and normal renal physiology, would often compare sodium,^98,99 urea,^60,100,101 lithium,¹⁰² uric acid,¹⁰³ phosphorus,⁸ glucose,¹⁰⁴ and other solute clearances to inulin clearance. In 1976 the FeNa was first developed for use as a diagnostic tool from 17 patients with acute oliguria to distinguish PRA from ATN. Although it has been an excellent diagnostic tool, the ideal solute would be one that has the following properties

1. Complete excretion of filtered load under volume replete conditions (euvolemia or hypervolemia)

2. Avid reabsorption under volume deplete conditions (hypovolemia)

3. Reabsorption unaffected by drugs or aberrant medical conditions

4. All mechanisms of reabsorption are lost by tubular injury in ATN

While the present use of creatinine as a measurement of glomerular filtration exposes all present calculations to errors (Table 3), the use of solutes other than sodium may have advantages in various clinical situations, a thorough analysis of all recent attempts is warranted.

Table 3.  Causes of spurious serum creatinine values

	False elevation	False depression
Drugs	Trimethoprim, cimetidine, fenofibrate, barbiturates, ascorbic acid	Dopamine, dobutamine, acetylcysteine
Diseases/metabolic	Ketoacidosis, IgM myeloma, pyruvate, citrate, ethylene glycol	Hyperbilirubinemia

Note: Various drugs, diseases, and metabolic conditions that have been reported to give misleading serum creatinine values either by interference with the measurement of creatinine and non-creatinine chromogens in the serum or interference with its tubular secretion.

FeNa

While all of the patients in the original study had a complicated clinical picture, those patients who had received diuretics, had glomerular or obstructive disease, or were nonoliguric were excluded.¹ As a result the first limitations of the use of the FeNa arose. Although it has performed remarkably well and remains the most popular laboratory aid in distinguishing PRA from ATN, time has since added a large number of drugs, diseases, and metabolic conditions to the limitations of the FeNa (Table 1). Although the clinical significance of many of these problems may be debatable, some factors can cause misdiagnoses.^105,106 Timing of the testing in relation to the ischemic event may be one factor. After the initial episode of hypotension, the kidney may still have PRA indices that only become ATN after sustained ischemia.¹⁰⁷ Similarly, one must remember that the test was designed only for oliguric patients (<20 cc/h or 480 cc/day). The large volume of solvent in nonoliguric ATN lowers the concentration to not appear to be PRA when there is neither salt nor water conservation. However, in the absence of diuretics, clinicians should not have a problem clinically confusing nonoliguric ATN with PRA. Although nonoliguric PRA can occur because of diabetes insipidus, interstitial renal disease, or loss of concentrating ability from the reduced availability of urea as an intramedullary osmole,¹⁰⁸ nonoliguric states are less often the cause of a pre-renal azotemia because the normal renal response to an acute reduction in renal perfusion (and even hypovolemia with preserved or increased renal perfusion in sepsis)^109–111 is a reduction in urine flow rate accompanied by enhanced reabsorption of sodium and urea with decreased water excretion. Unfortunately, there are many other clinical situations where drugs^12,13 or diseases¹¹² interfere with glomerular or tubular function^37,38 which can result in an altered renal handling of sodium^{14–44,108,113}, that makes the FeNa less reliable which has led some to avoid the use of the FeNa.³⁹ Many causes may not appear obvious, unless the clinician maintains a clear understanding of renal physiology. Severe metabolic alkalosis from vomiting can result in bicarbonate concentrations that exceed the tubular threshold resulting in sodium and bicarbonate wasting that occurs even while chloride conservation remains intact, that will falsely elevate the FeNa,³¹ and if the clinician is unaware of renal physiology he will be led to incorrect diagnoses. Similarly, chronic (but not acute) respiratory acidosis is associated with a decrease in FeNa because of sodium bicarbonate generation and conservation by the tubules.³² Chronic metabolic acidosis may also result in sodium wasting,^33,34 presumably because of a different mechanism where acidosis may disrupt active transport. Surprisingly, while use of diuretics are well known to make the FeNa unreliable,^36–39 other drugs, such as amphotericin, that are known to cause proximal tubular damage may not.⁴⁰

FeUrea

Despite the problems with FeNa, there has been much less experience with the use of FeUrea. Even the values considered necessary to distinguish PRA have varied between 55%^102,114,115 and 35%.^48,51 As urine flow falls below 0.41 cc/min (590 mL/24 h)⁵⁹ (which was our definition of oliguria) at about a FeUrea of 40%, we chose a cutoff of below 40% for FeUrea to reflect pre-renal azotemia. In a prospective study of 100 consecutive patients referred to our nephrology service for azotemic oliguria, we found that although the Fellrea is clearly related to the FeNa (Figure 4), the FeUrea was more accurate in patients treated with diuretics (p < 0.0001).^50,51 The FeNa, however, appeared to have an advantage in the presence of infection. Recent studies have shown that there is active transport of urea in the renal tubules. Just as diuretics can interfere with the active transport of sodium chloride and alter the FeNa, interference with active transport of urea in different clinical states may alter the FeUrea. Sepsis had been speculated to interfere with urea transport,⁶⁵ and therefore may be one clinical situation where the FeUrea becomes unreliable; however, we did not find gender, age, protein infusion, liver disease, or any drugs (even the presence of nephrogenic diabetes insipidus because of lithium) to affect the reliability of the FeUrea. Unfortunately, we did find that infectious diarrhea result in particularly low BUN levels with resulting inaccurate FeUrea, and therefore interruption of the active transport in the colon may adversely affect the accuracy in patients with infectious secretory diarrhea. In the colon and small intestine, UT-B¹¹⁶ and UT-A1 and A6¹¹⁷ transporters have been found and urea circulating in the blood can pass into the enteric lumen, where it is hydrolyzed into ammonia and carbon dioxide by the enzyme urease, produced by intestinal bacteria. Ammonia normally then can be incorporated into protein synthesized by the bacteria or be reabsorbed for the process of nitrogen recycling. Despite elevated creatinines (4.2 and 3.1 mg/dL) with low FeNa (<1.0%) and urine urea concentrations (<300 mg/dL) our patients with secretory diarrhea had inappropriately low BUN (3–10 mg/dL). As FeUrea calculation depends heavily upon BUN which varies much more significantly than serum sodium, a low BUN resulting from loss of urea cycling in the colon may be a major pitfall for the use of FeUrea when there is infection that interferes with urea transport in the colon. As UT-B can have divergent expression under abnormal conditions,¹¹⁸ it is theoretically possible that while sepsis might decrease FeUrea in the kidney even in acute renal failure (ARF), infectious diarrhea might result in increased colonic urea loss resulting in an abnormally low BUN and consequently elevated FeUrea even in pre-renal azotemia.

Figure 4. Relationship of FeNa to FeUrea. The indices did not assort independently but maintained a strong correlation (Pearson correlation = 0.503 (p <0.0001)) even in the presence of diuretics, sepsis, and liver disease⁵⁰.

FeUA

Although not related to the concentrating mechanism, the uric acid excretion appears sensitive to small volume changes as seen with its use in SIADH. Although in the absence of diuretics, one group found that its diagnostic accuracy approaches that of the FeNa,¹¹⁹ unfortunately, our limited understanding of its physiology may limit its use as well as the fact that drugs, diseases, and metabolic states interfere with OAT and will limit its effectiveness. Nevertheless, an FeUA above 10–12% remains an excellent tool for the diagnosis of SIADH.^83,84 Similarly, as most of the uromodulin-related diseases (familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease) are associated with reduced FeUA, this can be helpful in diagnosis.¹²⁰

FeLi

While its similar tubular handling to sodium gives it the potential for diagnostic use, the similar problems with the FeNa also appear to limit its potential as an alternate choice in the presence of diuretics in addition to other medical diseases.¹¹⁴

SUMMARY STRATEGY FOR OPTIMAL USE

While no single test may be able to replace clinical observation over time,¹²¹ the judicious use of laboratory test can definitely be an aid in diagnosis. Theoretically, all of the solutes studied would have advantages in certain clinical situations and disadvantages in others (Table 4). Diuretics would be most likely to affect FeNa and FeLi, while presence of organic ions or drugs that interfere with OAT would adversely affect the accuracy of FeUA and clinical situations (perhaps infection) that interfere with urea reabsorption would render the FeUrea less useful. Perhaps the solution is to create a PRA panel¹¹⁵ to be ordered and follow a diagnostic tree similar to Figure 5. While the FeUrea appears more accurate in the presence of diuretics, the FeNa may be a useful adjunct in the presence of infections, although the use of all urinary biochemistry for diagnostic purposes has been questioned,^110,122,123 and at least in the case of urea, there may be a physiologic basis. Other clinical situations where the comparison of the FeNa to the FeUrea may have an advantage is in the presence of renal artery occlusion with a functioning contralateral kidney. One group has reported that in such situations, the FeNa is markedly elevated, often approaching 100%, whereas the FeUrea merely simulates PRA.¹²⁴ Unfortunately, both may be unreliable in contrast dye-induced ARF, where both the FeNa and FeUrea are low suggestive of PRA.¹²⁵ Improved understanding of the differences in the renal handling of each solute may be quite useful in the diagnosis of other clinical situations in the future.

Table 4.  Overall guide to the use of the fractional excretion of solutes in various clinical situations

Test	Cutoff values	Best clinical use	Clinical situation most likely to mislead
FeNa	<1% pre-renal >3% ARF	Distinguish pre-renal azotemia from oliguric ARF	Pre-renal azotemia after diuretics
FeUrea	<40% pre-renal >40% ARF	Distinguish pre-renal azotemia from oliguric ARF after diuretics	Unknown but possibly infection
FeUA	12% SIADH	Hyponatremia familial juvenile hyperuricemic nephropathy	Drugs or anions that compete for OAT

Figure 5. A flow chart for efficient use of fractional excretions of solutes. See Table 1 for additional previously reported limitations to FeNa. Future limitations to FeUrea may exist.

KEY POINTS

1. The FeNa has been a popular clinical tool but various drugs and medical conditions limit its usefulness.

2. The FeUrea appears to have an advantage over the FeNa in patients treated with diuretics, however clinical situations that interfere with urea transporters and urea cycling may limit its usefulness.

3. The tubular physiology of the FeUA is both complex and as yet fully understood, but appears to have its greatest clinical value at present in the diagnosis of SIADH.

4. Comparison of the fractional excretions of a panel of solutes that included Na, urea and uric acid may provide the most insight to the diagnosis in various clinical states.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.