Regulation of renal urate excretion: A critical review

The Official Journal of the

National Kidney Foundation

AJKD

American Journal of Kidney Diseases

VOL 32, NO 6, DECEMBER 1998

IN-DEPTH REVIEWS

Regulation of Renal Urate Excretion: A Critical Review John K. Maesaka, MD, and Steven Fishbane, MD ● Uric acid metabolism is reviewed as it relates mainly to kidney and electrolyte disorders, with emphasis on the difficulties in understanding urate transport because of its bidirectional transport and the species differences in which animal data may not have relevance to the human condition. A critical review of the effects of pyrazinamide and extracellular volume expansion on urate transport raises questions about the current popular teachings that pyrazinamide exclusively blocks tubule urate secretion and extracellular volume expansion has a major role in controlling urate excretion. There appears to be a renal salt-wasting syndrome with overlapping clinical features that make it indistinguishable from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), except possibly for extracellular volume depletion. Hypouricemia and the elevation in the fractional excretion of urate (%E/Furate) are extensively reviewed with a proposal to use the persistence of hypouricemia and elevated %E/Furate after the correction of hyponatremia to differentiate these patients from those with SIADH. An algorithm is proposed to differentiate one group from the other. A plasma natriuretic factor has been shown in some with probable renal salt wasting, which includes patients with AIDS, cancer, and pulmonary and intracranial diseases. The natriuretic factor may have etiologic implications and diagnostic and therapeutic applications. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Uric acid metabolism; urate transport; urate excretion; hypouricemia; renal salt wasting; cerebral salt wasting; natriuretic factor.

I

N CONTRAST to animals of the lower kingdom, humans and humanoids must contend with elevated serum levels of an insoluble and toxic end product of purine metabolism, uric acid.1 This elevation in serum uric acid level exists, in part, because of the absence of hepatic uricase and relatively low urinary excretion rates. Deficiency of the enzyme uricase leads to uric acid as the final degradation product of purine metabolism compared with the more soluble and less toxic end product, allantoin, that results when the enzyme is present. The combination of the absence of uricase and lower urinary excretion rates of urate contribute in large part to the higher blood levels in humans. The fractional excretion of urate, defined as the percent of urate filtered at the glomerulus that is excreted in urine (%E/Furate), is normally less than 10% and rarely exceeds 100%. There is, therefore, a net reabsorp-

tion of more than 90% of the urate that is filtered at the glomerulus. In contrast to humans, urate excretion rates in some animals exceed the rates at which it is being filtered.1-4 Urate excretion that exceeds the amount being filtered at the glomerulus could occur only if urate was secreted into the tubule lumen. The low blood levels of uric acid and the From the Department of Medicine, Division of Nephrology, Winthrop-University Hospital, Mineola; and the State University of New York Medical School at Stony Brook, NY. Received August 26, 1997; accepted in revised form March 10, 1998. Address reprint requests to John K. Maesaka, MD, Department of Medicine, Division of Nephrology and Hypertension, Winthrop-University Hospital, 222 Station Plaza North, Suite 510, Mineola, NY 11501. E-mail: [email protected]

r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3206-0003$3.00/0

American Journal of Kidney Diseases, Vol 32, No 6 (December), 1998: pp 917-933

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presence of hepatic uricase in many experimental animals limit our ability to study urate transport in vivo under ambient conditions. The available methods are not sensitive enough to measure these low concentrations of uric acid accurately, and the rapid conversion of uric acid to allantoin by endogenous uricase interferes with our ability to increase serum uric acid levels artificially by infusing uric acid. Moreover, the changes in purine and uric acid metabolism that have evolved in vertebrates and the bidirectional mode of urate transport underscore the complexity of not only designing studies to understand basic metabolic and transport issues, but of relating data that have been obtained in animals to the human condition. This review of uric acid metabolism in humans will not be a thorough compendium, but will hopefully provide insight into the complexity, confusion, and controversy over basic issues and review some new directions and insights in uric acid metabolism in humans. The chemical determination of uric acid consists of three major categories. All these categories are spectrophotometric methods; two are manual and the other is automated. One manual method uses the reduction of phosphotungstate by uric acid. It is known to have interfering substances, especially in urine, and is not recommended for routine use.5,6 The second and most reliable as the reference method is that of differential spectrophotometry, which uses the reduction in uric acid absorbance in the ultraviolet spectrum after the degradation of uric acid by uricase.7 The third, an automated method, uses the molar for molar generation and color formation of hydrogen peroxide that is produced from the degradation of uric acid by uricase. The automated method is used most commonly today and is quite satisfactory in its reproducibility and sensitivity, which encompass most, if not all, clinical situations.5 There are, however, some pitfalls that can affect the determination of uric acid. Uric acid is generally stable for 2 days after being frozen.8 What is not often stressed is the determination of urinary uric acid after refrigeration. Because uric acid is relatively insoluble, particularly at a low pH, high concentration, and low temperature, erroneously low uric acid levels can result unless the pH is increased, the urine heated to 60°C for 10 minutes, or the urine

MAESAKA AND FISHBANE

sample is shaken before pipeting the sample for measurement.8 Uric acid in blood exists primarily as monohydrogen sodium urate and is saturated at 6.4 to 6.8 mg/dL at ambient conditions, with the upper limit of solubility generally placed at approximately 7 mg/dL.9,10 Stable supersaturated solutions frequently occur in diverse clinical conditions, including excessively high levels of greater than 30 mg/dL in the tumor lysis syndrome.11 The solubility of uric acid increases as sodium concentration decreases and body temperature increases and, conversely, decreases as sodium concentration increases or body temperature decreases.9 Normally, approximately 5% of uric acid is bound to plasma proteins.12 Blood levels of uric acid are lower in neonates and prepubertal children than in adults, averaging approximately 3.6 mg/dL. Urate levels are approximately 1.2 times greater in adult men compared with women until menopause, when blood levels become similar.13,14 Blood levels of uric acid depend on the balance between the rates of breakdown of endogenous and exogenous purines to uric acid and the rates of uric acid excretion. In two studies, urate excretion decreased from 550 to 340 mg/d, or approximately 5 mg/kg of body weight, when purine was eliminated from the diet, indicating that there is a significant endogenous purine load.15,16 Increased endogenous purine loads, as in tumor lysis, can significantly increase uric acid excretion. In adults, approximately 30% of the uric acid that is produced daily is excreted through the biliary and gastrointestinal tract and degraded by gastrointestinal bacteria by a process called uricolysis.17 The kidneys excrete the remaining 70%.17 With advancing renal failure, however, the amount being excreted by the gastrointestinal tract increases and urate excretion rates per nephron increase to attempt to maintain normal serum urate levels.18,19 The ingestion of large quantities of the precursors of urate, however, usually results in a large increase in urinary urate excretion with only a modest increase in serum urate concentration.20,21 The kidneys can thus protect against significant increases in the highly insoluble solute by increasing excretion when the urate load increases either by exogenous purine intake or endogenous urate production.22

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RENAL EXCRETION OF URIC ACID

Although approximately 5% of the uric acid in blood is bound to plasma proteins,12 micropuncture studies have shown urate to be freely filtered at the glomerulus.23-25 This information simplifies investigations of urate transport because it eliminates the need to measure or factor in the assumed ultrafilterable fraction of serum urate, as we must do with calcium. What has greatly hampered our understanding of urate handling by the kidneys, however, has been the bidirectional transport of urate in the nephron and the species differences. On the basis of several reports in humans, it is evident that urate is secreted by the kidneys. One study reported a man with a serum urate level of less than 0.6 mg/dL and %E/Furate of 146%, indicating that 46% more urate was being excreted than was being filtered at the glomerulus.26 This was only possible if urate was being secreted into the urine by the tubule epithelium. Similarly, %E/Furate greater than 100% has been accomplished after urate loading under conditions of mannitol loading and probenecid treatment.27 A recent report of a patient with Fanconi’s syndrome secondary to multiple myeloma had evidence of a net secretion of urate with an %E/Furate of 106%.28 Additional evidence of urate secretion in humans was reported by Podvein et al29 when they rapidly microinjected inulin, PAH, 42K, and uric acid 14C simultaneously and collected small quantities of ureteral urine sequentially to detect these constituents in the urine samples. The labeled uric acid was noted to appear in the urine after PAH and 42K but before inulin, suggesting that uric acid must have been secreted into the tubule at sites distal to the glomerulus and proximal to PAH secretion in the proximal tubule and 42K secretion in the distal tubule. There was no evidence of tubule secretion in the distal tubule.29 Based on these and other observations, urate excretion has been characterized as a three-component system of filtration, reabsorption, and secretion,30 and by others as a four-component system31 in which a postsecretory reabsorptive site is added to the three-component system (Fig 1). Although there is general agreement that there is tubule reabsorption and secretion of uric acid in human kidneys, precise measurements of reabsorption and secretion are virtually impossible to make with any degree of certainty by the avail-

Fig 1. Model of the four-component system of urate handling by the human kidney. (Right) Filtration, reabsorption, secretion, and postsecretory reabsorption. (Arrows) Indicate the density and predominant direction of reabsorption and secretion along the S1, S2, and S3 segments of the proximal tubule. The numbers in the boxes to the left of the figure indicate the fraction of the filtered urate being reabsorbed. The numbers within the tubule indicate the fraction of the filtered urate remaining in the tubule. Reprinted with permission.32

able methods in tubule cells or sites within the proximal tubule. Additional factors that contribute to the state of confusion can be attributed to the limitation of performing in vitro studies in humans and to species differences, which complicate the application of data obtained from animal experimentation to the human kidney. Data obtained from birds or reptiles with a dominant secretory component would be difficult to apply to urate transport in humans. The most confounding obstacle, however, appears to be the inability to separate and quantify tubule secretion from reabsorption. Effect of Pyrazinamide on Urate Transport Much of the information gathered from studies of urate transport in humans rely on data obtained from the use of the pyrazinamide suppression test.33 This test assumes that the reduction in %E/Furate to less than 2% after the admin-

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istration of pyrazinamide is the consequence of total or almost total inhibition of the tubule secretion of uric acid. This led to the popular belief that virtually all the excreted urate was derived from secretion and that all the filtered urate must have been reabsorbed. As discussed by Holmes et al34 and Kahn,35 it is possible that pyrazinamide, which acts on urate transport after its conversion to pyrazinoic acid, might actually decrease urate excretion by increasing urate reabsorption, rather than inhibiting secretion. There is further uncertainty as to whether the effect of pyrazinamide on urate secretion is total or partial.36 Recent studies by Guggino and Aronson37 and Roch-Ramel et al38 suggest that pyrazinamide might actually increase urate reabsorption. RochRamel et al38 showed increased uptake of urate by human renal cortical brush-border membrane vesicles in the presence of pyrazinamide by the anion exchange mechanism, vide infra. These data, which were obtained from human tissue, not only have relevance to the human kidney, but are consistent with the concern of others that pyrazinamide might increase urate reabsorption rather than block the secretion to decrease urate excretion. An earlier study by Guggino and Aronson37 reported similar findings in dog renal cortical brush-border membrane vesicles but showed a paradoxical effect of pyrazinamide on urate uptake. There was increased uptake or reabsorption of urate at low doses and decreased uptake or inhibition of reabsorption at higher doses.37 Whereas these data show increased uptake or reabsorption of urate by pyrazinamide, they do not negate the possibility that urate secretion is inhibited at the same time. Such a possibility might indeed be the case from recent data obtained in the laboratory of R.G. Abramson (personal communication, May 1997), that pyrazinamide blocked the transporter channel of the voltage-dependent uniporter, which is believed to be the secretory transporter, vide infra. These newer findings raise important questions regarding the effect of pyrazinamide on urate reabsorption and secretion. It would appear from these studies that the use of pyrazinamide as a means of separating urate reabsorption from secretion in normal or diseased states should be curtailed until the disparate effects of pyrazinamide on urate transport can be resolved.

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Effect of Changes in Extracellular Volume on Urate Transport Under normal conditions, less than 10% of the filtered urate is excreted in the urine. There are many medications or agents that alter urate excretion; the reader is referred to a standard textbook for further information on this subject. One group of medications that has received a great deal of attention are the thiazide and loop diuretics. It is common to see hyperuricemia with these agents, and it is generally believed that the hyperuricemia is caused by decreased urate excretion resulting from volume depletion. When sodium losses are prevented by replacing sodium and water deficits induced by the diuretics, %E/Furate and serum urate levels remain unchanged.35,39 Moreover, decreased %E/Furate and the tendency to hyperuricemia are often found in clinical syndromes in which there is hypoperfusion of the kidneys, be it true extracellular volume depletion or volume-expanded states, such as congestive heart failure, cirrhosis, nephrosis, or preeclampsia. Increased net reabsorption of urate and other solutes in the proximal tubule can be explained by the third-factor phenomenon in which peritubular physical factors in the efferent arteriole favor solute and water reabsorption. In conditions in which the filtration fraction is increased, a higher percentage of renal blood flow is ultrafiltered and the resulting lower hydrostatic and higher oncotic pressures in the efferent arteriole have been shown to increase proximal solute and water reabsorption.34 In contrast, it is unclear whether the expansion of extracellular volume has a significant role in inducing increased %E/ Furate and hypouricemia. Abnormalities in urate transport and hypouricemia are regarded by some to reflect the status of their extracellular volume, even to the point of declaring that hypouricemia is an indicator of a volume-expanded state.40,41 A critical review of the four studies that have addressed the effect of extracellular volume expansion on urate excretion rates in humans shows %E/Furate to increase only modestly after intense volume expansion with hypotonic, isotonic, or hypertonic saline infusions.42-45 In one study, %E/Furate did not increase after the infusion of 1,600 mL of 3% saline.45 As noted in Table 1, mean %E/Furate increased by a maximum of only 6.7% greater than baseline values when %E/ Fsodium increased dramatically to levels as high as

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Table 1. Summary of Effect of Saline Infusions on Urate Transport %E/Fsodium Saline Infusion

Baseline

Hypotonic43

1.1

Isotonic42,43

1.6

Hypertonic43-45

1.04 2.9 1.4 1.0 1.6

%E/F urate

Expansion

Baseline

Expansion

2.7 6.1 3.5 8.2 4.43 11.3 18.2 14.5 6.1 10.6

4.0

5.8* 7.3† 4.9* 5.8† 9.76 9.4* 12.1† 18.7 9.1‡ 15.8§

5.0 7.98 5.4 12.5 8.7 10.2

NOTE. Summary of the effect of hypotonic, isotonic, and hypertonic saline infusions on %E/Fsodium and %E/Furate by four different studies in human subjects. The increase in %E/Furate is significant statistically but of a much lower magnitude than the reported %E/Furates noted in Table 2. Note the extremely high %E/Fsodium accompanying these small increases in %E/Furate. *One liter (10-12 mL/min infusion rate). †Two liter (10-12 mL/min infusion rate). ‡Nonresponder to saline. §Responder to saline.

18.2%. The results of these saline infusion studies on urate excretion rates in healthy human subjects correlate very poorly with hypouricemic conditions that have been reported under various clinical situations. In our own studies, %E/Furate was 24.0%, 34.2%, and 29.8% with %E/Fsodium of 0.5%, 1.2%, and 2.19%, respectively.46 Decaux et al47 reported %E/Furate and %E/ Fsodium in two groups of patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with mean %E/Furate of 20% and 17.3% and mean %E/Fsodium of 0.88% and 0.34%, respectively.47 Representative %E/ Furates of more than 20% that have been reported in the literature are listed in Table 2 in various clinical settings, including cancer, inborn errors of metabolism, acquired immunodeficiency syndrome (AIDS), and SIADH. Moreover, as noted in Table 3, %E/Furate in volume-depleted patients with AIDS who had postural hypotension that was responsive to saline infusions and central venous pressures (CVPs) of 0 cm H2O were unexpectedly high.48 These data in patients with AIDS suggest the presence of a significant tubule transport defect for uric acid, because mean %E/Furate in volume-depleted subjects is approxi-

mately 4%.39 It would appear, therefore, that extracellular volume expansion might significantly increase urate excretion rates, but at levels that are far less than those reported in many disease states, including SIADH. Hypouricemia and abnormally elevated %E/Furate do not appear to indicate a volume-expanded state. It is also questionable whether volume expansion per se is a major physiological variable that increases urate excretion rates in humans.48,49 RENAL TRANSPORT OF URATE

It is generally agreed that urate reabsorption occurs mainly in the proximal tubule with little or no transport in the distal tubule.50-53 Although there is agreement that urate is reabsorbed and secreted by the human nephron, the sites and Table 2. Examples of Elevated %E/Furate in Different Disease States Author

Morales and Garcia-Nieto86 Izumi et al112 Zamkoff et al80 Bennett et al78 Kay and Gottlieb79 Afzal Mir and Delamore77 Michaelis et al108 Magoula et al83 Dwosh et al72

Maesaka et al48 Tofuku et al114

Beck67 Sonnenblick and Rosin102

Disease

Retroperitoneal sarcoma Primary biliary cirrhosis Hodgkin’s disease Hodgkin’s disease Hodgkin’s disease Acute myelogenous leukemia Lae¨nnec’s cirrhosis Liver cell carcinoma Adenocarcinoma of lung Morbid obesity Light-chain myeloma Primary hypoparathyroidism AIDS

%E/Furate

37.5 44, 40, 26, 39, 33 36, 30, 63, 20, 21 40, 34 55 51 32, 39, 57 51, 42, 33 23.7 32.8 104 27.2

5 patients between 21-34 Renal calculus 34.1 Proteinuria/hyper- 39.4 tension SIADH 24.2, 38 SIADH 34, 28, 46, 26, 23, 37

NOTE. Representative %E/Furates exceeding 20% by different investigators in a wide spectrum of diseases. The comparison of these values with those noted in Table 1 shows the discrepancy in magnitude between these values and those even after extreme extracellular volume expansion.

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Table 3. %E/Furate in Patients With AIDS, Postural Hypotension, and Low CVPs

Patient No.

Serum Uric Acid (mg/dL)

CVP (cm H2O)

%E/Furate

1* 2* 3* 4* 5* 6* 7 8

2.5 3.6 3.9 2.2 3.0 5.2 4.8 6.3

0 0 0 0 0 0-1 0 0

26.9 13.3 18.6 25.5 16.7 12.2 15.0 13.2

NOTE. Clearance studies with CVP monitoring. Reprinted with permission.48 *Patients who were hypouricemic with serum uric acid levels ⱕ3 mg/dL at some time during the course of their illness. Two patients had normal and six patients had elevated plasma renin activity.

extent of this bidirectional transport are not precisely known. Each proximal tubule cell might engage in the reabsorption and secretion of urate at any given moment, but more direct studies in animals suggest that urate reabsorption is probably predominantly in the S1 segment, as it is for other solutes.50,51 Urate appears to be secreted in the S2 segment of the proximal tubule and reabsorbed between the late proximal and early distal tubules, probably the S3 segment of the proximal tubule (Fig 1).50,51,53-55 Urate reabsorption is indirectly coupled to sodium transport by an electroneutral anion exchanger. Anions, such as chloride and organic acid anions, first enter the proximal tubule cell through a sodium-dependent cotransport and move back into the tubule lumen in exchange for uric acid; hence, the indirect coupling of urate transport to sodium (Fig 2).37,56,57 Pyrazinamide increases the reabsorption of urate by first entering the proximal tubule cell with sodium and then exits the cell in exchange for uric acid through the anion exchanger (Fig 2).37,38 Pyrazinamide also appears to inhibit the voltage-sensitive transporter channel for secretion (R.G. Abramson, personal communication, May 1997). Urate enters the peritubular space, possibly through the basolateral membrane, by a voltagesensitive pathway and an anion exchanger.58,59 Urate secretion from cell to lumen presumably occurs through a voltage-sensitive transporter that is located in the luminal membrane, but the

mechanism by which urate enters the cell through the basolateral membrane from peritubular space is not known.60,61 Studies emanating from Abramson’s laboratory recently showed an electrogenic urate uniporter that was located on the brush-border membrane of rat and human proximal tubule. Earlier studies suggested that the uniporter was a uricase-like protein that transported urate into liposomes and served as a specific channel for urate when inserted in lipid bilayers.62 They produced polyclonal antibodies to pig hepatic peroxisomal uricase that were immunoreactive with and inhibited the uniporter.61,62 Later studies used the polyclonal antibody to pig liver uricase to screen a rat renal complementary DNA library and clone the urate transporter. The novel complementary DNA transporter surprisingly had no homology to uricase, but to galectins. Placement of the transporter in planar lipid bilayers showed it to be a voltage-sensitive channel/ transporter that was specific to urate.61 These investigators postulate other important housekeeping functions of the uniporter, such as the secretion of urate into the gastrointestinal tract or exit from cells after enzymatic production.61 The presence of the uniporter in human proximal tubule cells suggests that the uniporter might contribute to bidirectional urate transport on the apical and basolateral membranes of the proximal tubule in humans (R.G. Abramson, personal communication, May 1997). HYPOURICEMIA

Hypouricemia is a term that has been defined arbitrarily without physiological or clinical corre-

Fig 2. Model of indirect coupling of sodium (Naⴙ) and urate transport through the anion (A–) exchanger. Coupling of anion to sodium uptake along the luminal membrane and later exchange of the anion for urate in the proximal tubule. Note the indirect coupling of urate reabsorption to sodium reabsorption. Reprinted with permission.56

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lates and is usually defined as serum uric acid concentrations between 1.5 and 4 mg/dL.48,63-67 The prevalence of hypouricemia in the general ambulatory population has been reported to be between 0.2% and 3.38%,63-66,70,71 but is estimated to be greater in hospitalized patients.66 Hypouricemia per se is not known to produce symptoms and is usually characterized according to whether there is decreased production or increased gastrointestinal and/or renal excretion rates of uric acid. In assessing hypouricemic conditions, gastrointestinal losses are assumed to be unchanged or minimally altered and are mentioned only as a consideration without being quantitated because of technical difficulties that deter the study of gastrointestinal urate excretion. Decreased production is most often a result of an acquired or inborn defect in the enzyme xanthine oxidase (Table 4). By far the most common disease-related causes of hypouricemia are associated with increased renal excretion rates of urate because of decreased reabsorption and/or increased tubule secretion. As previously discussed, pharmacological manipulations of renal urate excretion by pyrazinamide or probenecid must be interpreted in light of recent studies that showed increased uptake of urate in exchange for pyrazinamide.37,38 There is a large list of malignant and nonmalignant diseases that have been reported with increased %E/Furate (Table 4). The hypouricemia associated with hyperalimentation has been attributed to interference with the chemical analysis of uric acid.4,11

The hypouricemia that has been reported in patients with diabetes appears to result from a defect in the tubule transport of urate and not from hyperfiltration.117,118 The transport defect can in part be attributed to the hyperglycemia and the underlying diabetic condition because it can be induced by glucose infusions in healthy subjects.119,120 The angiotensin II receptor antagonist, losartan, has been shown to increase urate excretion and decrease serum uric acid levels.121 Studies in brush-border membrane vesicles show competitive inhibition of urate by losartan for the anion exchanger (Fig 2).38,122 From the foregoing discussion of the diseases that are associated with hypouricemia, there is a sense that hypouricemia is largely caused by isolated defects in tubule urate transport in different disease states without clinical relevance, except possibly to perk the interest of the physiologist and to catalog the finding as a clinical parameter of the underlying disease. Recent interest in hypouricemic conditions, however, has placed hypouricemia and, possibly, elevated %E/ Furate as important markers in the evaluation of the patient with hyponatremia. Although hypouricemia and elevated %E/Furate had been previously described by a number of investigators in SIADH,100-107 including the experimental induction in healthy subjects,123 Beck67 made an important observation that placed hypouricemia as a possible marker of SIADH compared with most other causes of hyponatremia. He found 16 of 17 patients with SIADH to have hypouricemia of

Table 4. Diseases or Conditions Associated With Hypouricemia Hypouricemia

Xanthine oxidase deficiency Malignant causes Inborn error of metabolism63,68 Carcinomas of the lung,72-75 light-chain myeloma,72,76 acute myeloid leukemia,77 Hodgkin’s disease,46,63,78,81 carcinoma of the tongue,63,69 Allopurinol Squamous cell carcinoma of parotid gland69 cholangiocarcinoma,82 pancreatic carcinoma,46,63 liver cell carcinoma,83 medullary carcinoma of the thyroid,84,85 metastatic breast carcinoma,86 undifferentiated retroperitoneal sarcoma,86 brain tumors63,87 Nonmalignant causes Wilson’s disease,88 familial or isolated urate transport defects,89-95 sickle cell disease,96 hemochromatosis,97 AIDS,48 Alzheimer’s disease, 98,99 intracranial diseases,63,87 SIADH,67,100-107 severe jaundice, viral hepatitis, common bile duct obstruction, biliary cirrhosis,108-112 disseminated cryptococcosis,46 renal calculus,114 hypertension with proteinuria,114 Fanconi syndrome,115,116 diabetes mellitus,117-120 losartan121,122 NOTE. List of conditions or diseases that have been reported with hypouricemia, based on the underproduction and increased renal excretion rates of uric acid.

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less than 4 mg/dL with no overlap, except for one patient, when compared with other causes of hyponatremia. As in previous reports, the hypouricemia was associated with an elevated %E/Furate, which, in large part, contributed to the hypouricemia. The hypouricemia and elevated %E/Furate normalized after the correction of the hyponatremia by water restriction (Fig 3).67,100 As noted earlier regarding the limited role of volume expansion on increasing %E/Furate, the transient defect in urate transport with its associated hypouricemia remains an enigmatic abnormality that requires an explanation beyond that of a volumeexpanded state in SIADH. Decaux et al124 failed to induce hypouricemia and to elevate %E/Furate during the period of hyponatremia after the administration of DDAVP, suggesting that the urate transport abnormality required the V1 receptor stimulation by arginine vasopressin. In similar studies performed by Boer et al,123 the administration of DDAVP induced hypouricemia and elevated %E/Furate at the time of hyponatremia. At present, there is no adequate explanation for these disparate data or for the transient hypouricemia and urate transport abnormality in SIADH. We recently used the transient hypouricemia and elevated %E/Furate in SIADH to identify a separate group of patients who had identical clinical associations and laboratory parameters as patients with SIADH, except for possible extracellular volume depletion.46 The majority of these patients had pulmonary and/or intracranial diseases; coexistent hyponatremia and hypouricemia; elevated %E/Furate; normal renal, adrenal, and thyroid function; concentrated urine; and elevated urine sodium concentration. These patients appeared by these criteria to have SIADH. The first insight patient, who presented with

MAESAKA AND FISHBANE

bronchogenic carcinoma and a negative computed tomographic scan of the brain, had all the laboratory parameters noted except for postural hypotension, reflex tachycardia, and hyponatremia that responded to large volumes of saline. He received 4,100 mL of saline the first day and 3,600 mL the second day, with correction of the postural hypotension and an increase in serum sodium level from 111 to 121 mEq/L in the 2-day period. His admission urine osmolality was 323 mOsm/kg H2O and his urine sodium level was 42 mEq/L. When the serum uric acid level was 2.1 mg/dL, the diagnosis of SIADH was made and his fluids were restricted. He proceeded to develop signs of severe volume depletion with doughy skin, dry mucous membranes, sunken eyes, flat neck veins, postural hypotension, reflex tachycardia, postural dizziness, staggering, slurred speech, and somnolence. After liberally supplementing his diet with salt while he was restricted of fluid, his serum sodium level finally corrected to 138 mEq/L, but his serum uric acid level remained low at 2.2 mg/dL; the %E/Fsodium was 0.74%, %E/Furate was 14.7%, and urine sodium level was 181 mEq/L when he was severely volume depleted. These findings were inconsistent with those of SIADH, in which the hypouricemia and elevated %E/Furate would have corrected to greater than 4 mg/dL and less than 10%, respectively, after correction of the hyponatremia by water restriction (Fig 3). The postural hypotension with reflex tachycardia, physical signs of dehydration, and postural symptoms responded to saline, at which time he had a normal water-loading test with suppression of his ADH to less than 0.4 pg/mL.46 This case makes several important points that are not consistent with SIADH. The postural

Fig 3. Relation between values of serum uric acid (SUA), %E/Furate, and serum sodium (Sna) in SIADH and probable renal salt wasting before and after the correction of serum sodium levels by water restriction. Note the identical abnormalities between both groups of patients during hyponatremia and the ability to separate one group from the other after correction of the serum sodium level. Shaded areas represent normal values.

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hypotension with reflex tachycardia that responded to saline is consistent with volume depletion. Despite some of its pitfalls, postural hypotension supports the clinical diagnosis of volume depletion, particularly when it responds to saline. Other causes of postural hypotension, such as autonomic failure, do not usually respond to saline and do not increase pulse rates when the patient is upright. The responsiveness of postural hypotension and reflex tachycardia to saline, therefore, indicates a volume-depleted state that rules out the diagnosis of SIADH.125,126 The persistence of hypouricemia and elevated %E/ Furate after the correction of serum sodium levels by water restriction and the normal waterloading test with the appropriate suppression of ADH after volume repletion are also inconsistent with the diagnosis of SIADH.46 Moreover, the high urinary sodium concentration during the period of volume depletion is most consistent with renal salt wasting. Of the five patients reported with persistent hypouricemia and elevated %E/Furate after the correction of hyponatremia, all had high urinary sodium concentrations.46 Two had postural hypotension with reflex tachycardia, signs of dehydration, postural signs and symptoms of volume depletion, high urine sodium concentrations, and hyponatremia that responded to large volumes of saline.46 It would appear that these findings are collectively consistent with a renal salt-wasting syndrome. The persistence of hypouricemia and elevated %E/Furate after correction of the hyponatremia in all patients could provide an important clinical clue to differentiate these patients from SIADH, despite the absence of overt volume depletion (Fig 3). The coexistence of hyponatremia and hypouricemia was noted in a study of 96 patients with AIDS.48,127 At one time during the course of their illness, 31 patients had hyponatremia, 21 patients had hypouricemia, and 16 patients had coexistent hyponatremia and hypouricemia. The majority of these patients fit the usual criteria for SIADH, but eight patients had postural hypotension and hyponatremia that were responsive to saline. The CVP was measured in all eight patients and all had CVPs of 0 cm H2O, elevated %E/Furate (Table 3), inappropriately elevated mean urine sodium concentrations of 49 mEq/L, and elevated plasma renin and aldosterone lev-

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els.48,127 The diagnosis of SIADH was challenged by these studies, which extended the observations of the persistence of hypouricemia, elevated %E/Furate, and probable renal salt wasting to patients with AIDS. None of the medications the patients had been taking at the time of study could account for the hypouricemia or abnormal %E/Furate.48 Because 12 of 12 hypouricemic patients with AIDS had cortical atrophy noted on computed tomographic scans of the brain, it was postulated that the defect in tubule sodium and urate transport might be associated with their brain disease, rather than infection by the virus that causes AIDS.48 This postulation was consistent with the frequency with which renal (cerebral) salt wasting might have been present in 10 of 12 neurosurgical patients reported by Nelson et al.128 Because SIADH is commonly encountered in patients with intracranial diseases, we reasoned that the determination of renal urate transport and serum urate levels in these neurosurgical patients might help differentiate salt wasting from SIADH.48,87 For instance, the combination of a normal urate transport and absence of hypouricemia in a hyponatremic neurosurgical patient might differentiate the cerebral salt waster from the patient with SIADH. Therefore, we studied 29 neurosurgical patients and found 18 patients to have %E/Furate greater than 10%, 7 patients to be hypouricemic, and only 1 patient to have coexistent hyponatremia and hypouricemia.87 The single patient with hyponatremia was hypouricemic when her serum sodium level was normal, suggesting that the patient did not have SIADH.48,87 It was concluded that these patients were already hypouricemic and had elevated %E/Furate when the serum sodium level was normal, findings that were inconsistent with SIADH (Fig 3).48 Should they present with hyponatremia, however, the coexistent hypouricemia might lead the physician to the diagnosis of SIADH. Thus, when hyponatremic, these patients can only be differentiated from SIADH by determining their volume status or serum uric acid and %E/Furate when their serum sodium level was normal or corrected to normal.48,129 Patients with various forms of intracranial diseases have been reported to have cerebral salt wasting, a disease that fell into disfavor after the first reports of SIADH.125,126,130-132 Isolated re-

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ports, however, have appeared in the literature,131-138 including a single case of the coexistence of hyponatremia and hypouricemia by Tanneau et al139 that responded to saline. Aside from the cases of AIDS and neurosurgical diseases previously noted, serum uric acid levels of 5.8, 6.0, 4.6, and 2.6 mg/dL are the only uric acid levels reported in the literature of a hyponatremic case with cerebral salt wasting.138 These studies stress the need to consider a diagnosis other than SIADH when faced with hyponatremia and hypouricemia in a patient with intracranial disease, pulmonary disease, malignancies, or AIDS. Although many of these patients have intracranial diseases that could be in the category of cerebral salt wasting as first described by Peters et al131 in 1950, the presence of virtually identical findings with diseases that clearly do not involve the cranium make the term cerebral salt wasting inappropriate and renal salt wasting preferable. The persistence of hypouricemia and elevations in %E/Furate after the correction of hyponatremia represent a combination of abnormalities that identified a distinctly separate group of patients from SIADH. Although these abnormalities have been described in a large group of patients, the persistent hypouricemia and abnormal tubule urate transport may not exist in all patients with salt wasting. However, any case of renal salt wasting, with either normal or abnormal tubule urate transport, requires rigorous clinical verification. The most compelling support for such a proposal might come from sodium balance studies, but these studies are difficult to perform even in a clinical research setting in the hospital. Clinical assessment of the state of extracellular volume could easily differentiate the renal salt waster from the patient with SIADH, but a noninvasive assessment of the state of extracellular volume is accurate in only approximately 50% of the euvolemic and hypovolemic patients with hyponatremia.140,141 Despite our inability to assess extracellular volume accurately, it is a common practice to consider patients with hyponatremia, concentrated urine, and high urine sodium concentration to have SIADH and treat them with water restriction. We are thus faced with a diagnostic and therapeutic dilemma when faced with a patient with coexistent hyponatremia and hypouricemia who may have either SIADH or renal salt wasting. It is

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important to differentiate SIADH from salt wasting because patients with SIADH require water restriction and renal salt wasters require salt and water supplementation. In the absence of a simple test, such as a radioimmunoassay, we propose to differentiate SIADH from salt wasting by using the algorithm in Fig 4. PLASMA NATRIURETIC FACTOR

In an attempt to understand mechanisms by which there might be a tubule sodium and urate transport abnormality in the patients with hypouricemia, we hypothesized that natriuretic and possibly uricosuric factors were present in the plasma of these patients. Because uric acid is transported virtually exclusively in the proximal tubule, we hypothesized further that the factor(s) affected the proximal tubule.50-53 We performed renal clearance studies in rats to study sodium and lithium transport after exposure to plasma from the same neurosurgical patients with hypouricemia and abnormal urate transport and their controls. Sodium and lithium excretion rates increased approximately 4 hours after the first exposure of the rats to the plasma of the neurosurgical patients, suggesting that a natriuretic factor(s) was present in their plasma.142 In an identical protocol, a natriuretic factor was shown in the plasma of patients with Alzheimer’s disease compared with healthy age- and sex-matched controls and patients with multiinfarct dementia.98 Patients with Alzheimer’s disease are known to be hypouricemic and were found to have increased %E/Furate when compared with controls and patients with multi-infarct dementia.98,99 As reviewed in a recent editorial, we believe that patients with Alzheimer’s disease might have a salt-wasting nephropathy, as those previously noted, with the common denominator being the presence of a tubule urate transport defect and hypouricemia.129 The demonstration of a natriuretic factor in the plasma of patients with persistent hypouricemia, elevated %E/Furate, and possible renal salt wasting raises the possibility that the tubule transport defect for sodium and urate might be accounted for by a single circulating plasma protein. It is possible that the natriuretic factor might indirectly decrease urate reabsorption through the anion exchanger by decreasing sodium reabsorption, compete with urate for the anion exchanger

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Fig 4. Proposed algorithm to differentiate SIADH from renal salt wasting. Note: %E/Furate can be determined by collecting spot urine and blood samples and calculated by the formula, %E/ Furate ⴝ (Uurate ⴛ Screatinine/ Ucreatinine ⴛ Surate) ⴛ 100. It should also be noted that a hyponatremic patient with obvious symptoms of extracellular volume (ECV) depletion should be treated with salt and water supplementation.

(Fig 2), or affect the voltage-sensitive uniporter in the direction of increased net secretion and/or decreased net reabsorption. Isolation and eventual cloning of the natriuretic factor will provide opportunities to address some of these questions. Conversely, the production of antibodies to the natriuretic factor will allow us to determine factor levels in the plasma of these patients and to test our hypothesis that the natriuretic factor is present in patients with renal salt wasting and not in those with SIADH. This latter possibility could make it easier to differentiate renal salt wasting from SIADH and be the basis on which early appropriate therapy can be instituted. Preliminary data suggest that the natriuretic factor is a protein with a molecular weight of less than 35 kd. The factor loses its natriuretic activity after boiling and protease digestion, suggesting that it is a protein (unpublished data, Maesaka JK, November 1993). The factor passes through the peritoneal membrane of rats and will probably pass through the blood-brain barrier of humans, but the site of its production is not known.

HYPERURICEMIA

Hyperuricemia is a common clinical finding that has been the subject of many clinical associations. The relation between gout and hyperuricemia dominated the study of uric acid metabolism for many years, but hyperuricemia has had other clinical applications. It has, for instance, been an important clinical marker of preeclampsia in pregnant women and has even been related to intelligence and achievement behavior in a number of reports.143,144 For many years, hyperuricemia has been more commonly seen in patients with hypertension and has been variably correlated with atherosclerotic cardiovascular disease.145-149 More recently, hyperuricemia has sometimes been included in syndrome x, a syndrome that is characterized by obesity, hyperinsulinemia, insulin resistance, non–insulin-dependent diabetes mellitus, hyperlipidemia, and atherosclerotic cardiovascular disease.150-152 It would appear from these studies that because of its frequent association with hypertension and the common use of diuretics that can induce hyperuricemia, it is important to determine

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whether hyperuricemia directly causes atherosclerotic cardiovascular disease or is merely associated without causation. Hyperuricemia and Renal Failure From a renal perspective, the role of hyperuricemia in affecting renal function is limited to acute urate nephropathy, obstructive uropathy, and genetic gouty disorder. Acute urate nephropathy is most often associated with the lysis of tumors, mainly lymphomatous or myeloproliferative, by chemotherapeutic agents. The nephropathy, however, has been seen less often with solid tumors, seizures, hypoxanthine guanine phosphoribosyltransferase deficiency (HGPRT) or hyperuricosuria associated with drugs, or tubule transport defect.11,153,154 Tumor lysis can also present with hyperphospatemia, hyperkalemia, hypocalcemia, and hyperuricemia with Burkitt’s lymphoma, acute lymphoblastic leukemia, and other tumors.155-157 The hyperphosphatemia poses a potentially dangerous situation with metastatic calcification throughout the body. The acute lysis of cells releases DNA and RNA, which are precursors of uric acid that overload the kidneys. Uric acid precipitates mainly in the distal tubule, in which the greatest concentration and acidification of urine takes place. This leads to acute intratubular precipitation of uric acid, intratubular obstruction of the kidneys, and possibly distal renal vasculature and acute renal failure.158,159 These patients do not typically present with flank pain and may not have crystals in the urine. The treatment is to inhibit the production of uric acid before chemotherapy by inhibiting xanthine oxidase with high doses of allopurinol, alkalinize the urine to increase the solubility of uric acid, and use hydration to decrease uric acid concentration. Hydration by whatever method appears to be more efficacious than the alkalinization of urine, although both are advocated.159 Acute renal failure associated with extreme hyperuricemia, however, must be differentiated from diseases in which hyperuricemia occurs as a consequence of increased uric acid reabsorption by the kidneys, as in those with severe prerenal azotemia when urate reabsorption is high. The determination of the ratio of urine uric acid to urine creatinine levels might be helpful if such a differentiation cannot be made simply; the ratio is greater than 1 in acute urate nephropathy and

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less than 1 in other hyperuricemic conditions with decreased excretion of uric acid.160 This test, however, requires caution when measuring uric acid in urine, making certain that the urate does not precipitate out of the solution and is in the solution at the time of measurement. The effect of chronic low-grade hyperuricemia on the kidney was a subject of some controversy in the past. The early reports of uric acid tophi in kidneys may have contributed in part to the opinion that uric acid was harmful to the kidneys and should be treated. Subsequent studies, particularly those relating to the long-term follow-up of patients with hyperuricemia, gout, and gout and renal failure do not implicate hyperuricemia as a cause of renal failure.161-165 Renal failure with hyperuricemia in the absence of other associated diseases, such as hypertension or renal calculi, may be caused by increased body burdens of lead.161-165 In the study reported by Batuman et al,161 gouty patients with compromised renal function had significantly higher urinary excretions of lead after the administration of ethylenediaminetetraacetic acid compared with those with normal renal function. The renal failure associated with gout in earlier times is probably a result of lead, as reviewed by Wedeen,166,167 and still requires vigilance today, particularly in selected occupations. Gout in the adult population is mainly a disease of older men, occurring rarely in women. In younger individuals, gout is seen in two inherited X-linked disorders, HGPRT deficiency and phosphoribosylpyrophosphate synthetase superactivity, in which renal failure is uncommon. Acute urate nephropathy, however, has been reported with HGPRT deficiency.168 A third familial autosomal dominant form of gout with renal failure, called familial juvenile gouty nephropathy, has been described in different countries in young men and women.169-172 Hyperuricemia is believed to result from decreased excretion rates of uric acid, and it has been debated whether it is a primary or secondary cause of the renal failure.171,173-175 Early manifestations of the disease include polyuria and the passage of dilute urines.171,175 Renal failure typically progresses to end-stage renal failure between 30 to 40 years of age, and the pathological changes are morphologically consistent with interstitial nephritis.168,171,175 Medullary cystic disease of the kidneys has been

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reported in juvenile gouty nephropathy,176 but has not been shown by others, even at necropsy.171,175 The early recognition and treatment of the hyperuricemia may or may not delay the progression of renal failure.172,173 REFERENCES 1. Abramson RG, Lipkowitz MS: Evolution of the uric acid transport mechanisms in vertebrate kidney, in Kinne RKH (ed): Basic Principles in Transport. Comp Physiol, vol 3. Basel, Switzerland, Karger, 1990, pp 115-153 2. Diamond HS, Meisel A, Kaplan D: Renal tubular transport of urate in man. Bull Rheum Dis 27:876-881, 1976 3. Gutman AB, Yu TF: Renal function in gout with a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout. Am J Med 23:600-622, 1957 4. Dantzler WH: Comparative Physiology of the Vertebrate Kidney. Berlin, Germany, Springer-Verlag, 1988 5. Watts RWE: Determination of uric acid in blood and in urine. Ann Clin Biochem 11:103-111, 1974 6. Archibald RM: Colorimetric measurement of uric acid. Clin Chem 3:102-105, 1957 7. Praetorius E, Poulsen H: Enzymatic determination of uric acid with detailed instructions. Scand J Clin Lab Invest 5:273-280, 1953 8. Soliman SA, Abdel-Hay MH, Sulaiman MI, Tayeb OS: Stability of creatinine, urea and uric acid in urine stored under various conditions. Clin Chim Acta 160:319-326, 1986 9. Wilcox WR, Khalaf A, Weinberger A, Kippen I, Klinenberg JR: Solubility of uric acid and monosodium urate. Med Mol Eng 10:522-531, 1972 10. Kippen I, Klinenberg JR, Weinberger A, Wilcox WR: Factors affecting urate solubility in vitro. Ann Rheum Dis 33:313-317, 1974 11. Kjellstrand CM, Campbell DC, von Hartitzsch B, Buselmeier TJ: Hyperuricemic acute renal failure. Arch Intern Med 133:349-359, 1974 12. Klinenberg JR, Kippen I: The binding of urate to plasma proteins determined by means of equilibrium dialysis. J Lab Clin Med 75:503-510, 1970 13. Harkness RA, Nicol AD: Plasma uric acid levels in children Arch Dis Child 44:773-777, 1969 14. Mikkelsen WM, Dodge HJ, Valkenburg H: The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia. Am J Med 39:242-251, 1965 15. Griebsch A, Zollner N: Effect of ribomononucleotides given orally on uric acid production in man, in Sperling O, De Vries A, Wyngaarden JB (eds): Purine Metabolism in Man, vol. 41B. New York, NY, Plenum, 1974 16. Coe FL, Moran E, Kavalich AG: The contribution of dietary purine over-consumption to hyperuricosuria in calcium oxalate stone formers. J Chron Dis 29:793-800, 1976 17. Sorensen LB: The elimination of uric acid in man. Scand J Clin Lab Invest 12:1-214, 1960 (suppl 54) 18. Sorensen LB: Role of the intestinal tract in the elimination of uric acid. Arthritis Rheum 8:694-706, 1965 19. Steele TH, Rieselbach RE: The contribution of re-

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sidual nephrons within the chronically diseased kidney to urate homeostasis in man. Am J Med 43:876-886, 1967 20. Nugent CA, Tyler FH: The renal excretion of uric acid in patients with gout and in nongouty subjects. J Clin Invest 38:1890-1898, 1959 21. Steele TH, Rieselbach RE: The renal mechanism for urate homeostasis in normal man. Am J Med 43:868-875, 1967 22. Rieselbach RE, Bentzel CJ, Cotlove E, Frei E III, Freireich EJ: Uric acid excretion and renal function in the acute hyperuricemia of leukemia. Pathogenesis and therapy of uric acid nephropathy. Am J Med 37:872-884, 1964 23. Bordley J III, Richards AN: Quantitative studies of the composition of glomerular urine. VII. The concentration of uric acid in glomerular urine of snakes and frogs, determined by an ultramicroadaptation of Folin’s method. J Biol Chem 101:193-221, 1933 24. Roch-Ramel F, Chomety-Diez F, De Rougemont D, Tellier M, Widmer J, Peters G: Renal excretion of uric acid in the rat: A micropuncture and microperfusion study. Am J Physiol 230:768-776, 1976 25. Weinman EJ, Steplock D, Sansom SC, Knight TF, Senekjian HO: Use of high-performance liquid chromatography for determination of urate concentrations in nanoliter quantities of fluid. Kidney Int 19:83-85, 1981 26. Praetorius E, Kirk JE: Hypouricemia: With evidence for tubular elimination of uric acid. J Lab Clin Med 35:865868, 1950 27. Gutman AB, Yu TF, Berger L: Tubular secretion of urate in man. J Clin Invest 38:1778-1781, 1959 28. Uchida S, Matsuda O, Yokota T, Takemura T, Ando R, Kanemitsu H, Hamaguchi H, Miyake S, Marumo F: Adult Fanconi syndrome secondary to ␬-light chain myeloma: Improvement of tubular functions after treatment for meyloma. Nephron 55:332-335, 1990 29. Podvein F, Ardaillou R, Paillar F, Fontanelle J, Richet G: Etude chez l’homme de la cinetique d’apparition dans l’urine de l’acide urique-2-14. Nephron 5:134-140, 1968 30. Gutman AB, Yu TF: A three-component system for regulation of renal excretion of uric acid in man. Trans Assoc Am Physicians 74:353-365, 1961 31. Diamond HS, Paolino JS: Evidence for a postsecretory reabsorptive site for uric acid in man. J Clin Invest 52:1491-1499, 1973 32. Sica DA, Schoolwerth AC: Renal handling of organic anions and cations and excretion of uric acid, in Brenner BM (ed): The Kidney (ed 5). Philadelphia, PA, Saunders, 1996, p 614 33. Gutman AB, Yu TF, Berger L: Renal function in gout. III. Estimation of tubular secretion and reabsorption of uric acid by use of pyrazinamide. Am J Med 47:575-592, 1969 34. Holmes EW, Kelley WN, Wyngaarden JB: The kidney and uric acid excretion in man. Kidney Int 2:115-118, 1972 35. Kahn AM: Effect of diuretic on the renal handling of urate. Semin Nephrol 8:305-314, 1988 36. Diamond HS: Interpretation of pharmacologic manipulation of urate transport in man. Nephron 51:1-5, 1989 37. Guggino SE, Aronson PS: Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes. J Clin Invest 76:543-547, 1985

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38. Roch-Ramel F, Guisan B, Schild L: Indirect coupling of urate and p-aminohippurrate transport to sodium in human brush-border membrane vesicles. Am J Physiol 270: F61-F68, 1996 39. Steele TH, Oppenheimer S: Factors affecting urate excretion following diuretic administration in man. Am J Med 47:564-574, 1969 40. Decaux G, Schlesser M, Coffernils M, Prospert F, Namias B, Brimioulle S, Soupart A: Uric acid, anion gap and urea concentration in the diagnostic approach to hyponatremia. Clin Nephrol 42:102-108, 1994 41. Decaux G, Dumont I, Naeiji N, Mols P, Melot C, Mockel J: High uric acid and urea clearance in cirrhosis secondary to increased effective circulatory volume. Am J Med 73-328-334, 1982 42. Steele TH: Evidence for altered renal urate reabsorption during changes in volume of the extracellular fluid. J Lab Clin Med 74:288-299, 1969 43. Diamond H, Meisel A: Influence of volume expansion, serum sodium, and fractional excretion of sodium on urate excretion. Pflugers Arch 356:47-57, 1975 44. Cannon PJ, Svahn DS, Demartini FE: The influence of hypertonic saline infusions upon the fractional reabsorption of urate and other ions in normal and hypertensive man. Circulation 41:97-108, 1970 45. Manuel MA, Steele TH: Pyrazinamide suppression of the uricosuric response to sodium chloride infusion. J Lab Clin Med 83:417-427, 1974 46. Maesaka JK, Batuman V, Yudd M, Salem M, Sved AF, Venkatesan J: Hyponatremia and hypouricemia: Differentiation from SIADH. Clin Nephrol 33:174-178, 1990 47. Decaux G, Prospert F, Cauchie P, Soupart A: Dissociation between uric acid and urea clearances in the syndrome of inappropriate secretion of antidiuretic hormone related to salt excretion. Clin Sci 78:451-455, 1990 48. Maesaka JK, Cusano AJ, Thies HL, Siegal FP, Dreisbach: Hypouricemia in acquired immunodeficiency syndrome. Am J Kidney Dis 15:252-257, 1990 49. Tanneau RS, Moal M-C, Rouhart F, Dueymes JM, Bourbigot B: Hypouricemia with high urate clearance in hyponatremia: Is it always a clue for increased effective volemia. Clin Nephrol 44:128, 1995 50. Abramson RG, Levitt MF: Micropuncture study of uric acid transport in the rat kidney. Am J Physiol 228:15971605, 1975 51. Abramson RG, Levitt MF: Use of pyrazinamide to assess renal uric acid transport in the rat. A micropuncture study. Am J Physiol 230:1276-1283, 1976 52. Weinman EJ, Knight TF, McKenzie R, Eknoyan G: Dissociation of urate from sodium transport in the rat proximal tubule. Kidney Int 10:295-300, 1976 53. Roch-Ramel F, Diezi-Chomety F, DeRougemont D, Tellier M, Widmer J, Peters G: Renal excretion of uric acid in the rat: A micropuncture and microperfusion study. Am J Physiol 2340:768-776, 1976 54. Weinman EJ, Sansom SC, Bennett S, Kahn AM: Effect of anion exchange inhibitors and para-aminohippurate on the transport of urate in the rat proximal tubule. Kidney Int 23:832-837, 1983 55. Weinman EJ, Sansom SC, Steplock D, Sheth T,

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Knight F, Senekjian HO: Secretion of urate in proximal convoluted tubule of the rat. Am J Physiol 239:F383-F387, 1980 56. Guggino SE, Martin GJ, Aronson PS: Specificity and modes of the anion exchanger in dog renal microvillus membranes. Am J Physiol 244:F612-F621, 1983 57. Kahn AM, Aronson PS: Urate transport via anion exchange in dog renal microvillus membrane vesicles. Am J Physiol 244:F56-F63, 1983 58. Polkowski CA, Grassl SM: Uric acid transport in rat renal basolateral membrane vesicles. Biochem Biophys Acta 1146:145-152, 1993 59. Kahn AM, Shelat H, Weinman EJ: Urate and p-aminohippurate transport in rat renal basolateral vesicles. Am J Physiol 249:F654-F661 60. Roch-Ramel F, Werner D, Guisan B: Urate transport in brush-border membrane of human kidney. Am J Physiol 266:F797-F805, 1994 61. Leal-Pinto E, Tao W, Rappaport J, Richardson M, Knorr BA, Abramson RG: Molecular cloning and functional reconstitution of a urate transporter/channel. J Biol Chem 272:617-625, 1997 62. Knorr BA, Lipkowitz MS, Potter BJ, Masur SK, Abramson RG: Isolation and immunolocalization of a rat renal cortical membrane urate transporter. J Biol Chem 269:6759-6764, 1994 63. Ramsdell CM, Kelley WN: The clinical significance of hypouricemia. Ann Intern Med 78:239-242, 1973 64. Yanase M, Nakahama H, Mikami H, Fukuhara Y, Orita Y, Yoshikawa H: Prevalence of hypouricemia in apparently normal population. Nephron 48:80, 1988 65. Lesmes A, Diaz-Curiel M, Castrillo JM: Tumoural hypouricemia. Adv Exp Med Biol 122A:145-148, 1980 66. Ogino K, Hisatome M, Saitoh J, Miyamoto J, Ishiko R, Hasegawa J, Kotake H, Mashiba H: Clinical significance of hypouricemia in hospitalized patients. J Med 22:76-82, 1991 67. Beck LH: Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 301:528-530, 1979 68. Dent CE, Philpot GR: Xanthinuria, an inborn error (or deviation) of metabolism. Lancet 1:82, 1954 69. Mitnick PD, Beck OH: Hypourciemia and malignant neoplasms. A new case of xanthinuria. Arch Intern Med 139:1186-1187, 1979 70. Mikkelsen WM, Dodge HJ, Valkenburg H: The distribution of serum uric acid values in a population unselected as to gout or hyperuricemia: Tecumseh, Mich, 1959-1960. Am J Med 39:242-251, 1965 71. Van Peenen HJ: Causes of hypouricemia. Ann Intern Med 78:977-978, 1973 72. Dwosh IL, Roncari DAK, Marliss E, Fox IH: Hypouricemia in disease: A study of different mechanisms. J Lab Clin Med 90:153-161, 1977 73. Osterlind K, Hansen HH, Hansen M, Dombernowsky P, Andersen PK: Long-term disease-free survival in smallcell carcinoma of the lung: A study of clinical determinants. J Clin Oncol 4:1307-1313, 1986 74. Weinstein B, Irreverre F, Watkin DM: Lung carcinoma, hypouricemia and aminoaciduria. Am J Med 39:520526, 1965 75. Passamonte PM: Hypouricemia, inappropriate secre-

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