IN A RECENT issue of the American Journal

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1 JOURNAL CLUB Antidiuretic Hormone and Renal Clearance of Uric Acid Discussion: David Sheikh-Hamad, MD, and Carlos J. Ayus, MD, FACP IN A RECENT issue of the American Journal of Medicine, Decaux et al 1 presented data that support the use of serum uric acid in the differential diagnosis of polydipsia. These investigators found that all normonatremic patients who presented with primary polydipsia had a serum uric acid concentration below 5 mg/dl (mean, 3 mg/dl), while all but one of the normonatremic patients with a diagnosis of central diabetes insipidus had uric acid concentration greater than 5 mg/dl (mean, 7 mg/dl). This finding was attributed to a low clearance of uric acid in the central diabetes insipidus patients, which was enhanced on stimulation with a specific vasopressin V 1 receptor agonist. The investigators present convincing data that support the use of serum uric acid for the differential diagnosis of polydipsia, yet the data pertaining to the role of V 1 receptor stimulation in the renal clearance of uric acid are based on studies performed in only one patient. While the results of these studies support such a role, the limited scope of these studies does not permit definite conclusions. The patient with central diabetes insipidus lacks antidiuretic hormone, and as a consequence, the urine cannot be concentrated, resulting in polyuria. On the other hand, due to the compulsive water drinking in the primary polydipsia, there is appropriate suppression of antidiuretic hormone and washout of medullary concentrating gradient, resulting in polyuria. The drinking in the central diabetes insipidus lags behind, and hence is generally accompanied by serum sodium levels in the upper normal range. The mild hypertonicity generates the stimulus for the compensatory increase in water intake. By contrast, compulsive water drinkers have a From the Renal Division, Department of Medicine, Baylor College of Medicine, Houston, TX. Received and accepted as submitted February 9, Address reprint requests to Carlos J. Ayus, MD, FACP, 4 Brompton Court, Houston, TX by the National Kidney Foundation, Inc /98/ $3.00/0 This month s discussion... The Journal Club focuses on a recent article entitled Hyperuricemia as a Clue for Central Diabetes Insipidus (Lack of V 1 Effect) in the Differential Diagnosis of Polydipsia (Am J Med 103: , 1997) by Guy Decaux, Fernand Prospert, Bernard Namias, and Alain Soupart. serum sodium concentration at the lower end of normal, and the polyuria is the result of the increased drinking. Currently, the diagnosis of primary polydipsia versus central diabetes insipidus is guided by the medical history and laboratory data. In central diabetes insipidus, the plasma osmolality and sodium levels are in the high normal range, and the polyuria is abolished by vasopressin treatment but not by water deprivation. 2 In severe nephrogenic diabetes insipidus, serum osmolality is increased, but the polyuria is not abolished by water deprivation or vasopressin therapy. 2 In primary polydipsia, on the other hand, basal plasma osmolality and sodium concentration are low normal, and polyuria is abolished by water deprivation or vasopressin therapy. Frequently, however, the diagnosis can be illusive. 2 The difficulty stems from the fact that many patients have a partial defect in vasopressin secretion or action. Therefore, the availability of additional supportive laboratory testing for the differential diagnosis of the various polydipsic disorders can be useful. It has always been known that the effective blood volume affects uric acid clearance to the point at which the serum level of uric acid is considered a sensitive marker for volume status in clinical settings, such as preeclampsia and dehydration. 3,4 Notwithstanding the limitations of this report, the findings support the notion that a factor(s) other than effective blood volume may play a role in the renal clearance of uric acid. This factor(s) is presumably the stimulation of kidney V 1 receptors. While treatment with ddavp (a selective V 2 agonist) restores the effective blood volume, as judged by the normalization of 692 American Journal of Kidney Diseases, Vol 32, No 4 (October), 1998: pp

2 JOURNAL CLUB 693 plasma renin activity, it did not significantly alter the renal clearance of uric acid. The addition of triglycyl-lysine-vasopressin, a selective V 1 receptor agonist, enhances the clearance of uric acid in the patient who was studied. Hence, it may be speculated that the default state without antidiuretic hormone stimulation is increased uric acid reabsorption and that antidiuretic hormone acts to decrease the fraction of uric acid that is absorbed by the kidney through V 1 receptor stimulation. The expression of V 1 receptors has been thoroughly studied in rat kidney, 5-7 although agreement about their exact localization is lacking. Using the reverse transcription polymerase chain reaction method, V 1 receptors were localized to the glomeruli, arcuate artery, and the entire collecting duct, 7 while in situ hybridization studies point to their expression in short segments of cortical distal tubules and vascular elements of the medulla. 6 On the other hand, examination of the binding of labeled V 1 antagonists (OPC and SR 49059) to kidney tissue showed that V 1 receptors were visualized in glomeruli, interstitial cells, and vascular elements but not in tubular structures. 5,8 Uric acid absorption is mostly proximal and is coupled to water absorption, 9 while a minimal portion of its absorption is distally regulated. 4 Based on the renal distribution of V 1 receptors in rat kidney, and assuming that their distribution is similar in human kidney, it would be reasonable to speculate that the differences in serum uric acid concentrations in patients with central diabetes insipidus compared with patients with primary polydipsia result from stimulation of V 1 receptors in one of the following sites: distal nephron segments, blood vessels, or both. This finding suggests the presence of uric acid transporters in distal segments of the nephron or that hemodynamic factors contribute to the renal clearance of uric acid. V 1 receptor stimulation has been associated with natriuresis as well as renal vasoconstriction. 10,11 The natriuretic effects combined with enhanced uric acid clearance during V 1 receptor stimulation suggest an effect on sodium coupled uric acid transport, possibly in the distal nephron segment. As to how the V 1 -induced hemodynamic changes may alter the renal handling of uric acid remains to be determined. In summary, notwithstanding the contribution of the report by Decaux et al, 1 the initial serum sodium and osmolality generally allow the discrimination between primary compulsive water drinkers, who tend to have mild hyponatremic values and are predominantly females, compared with the patients with central diabetes insipidus, in whom serum sodium and osmolality are either normal or slightly high. 12 REFERENCES 1. Decaux G, Prospert F, Namias B, Soupart A: Hyperuricemia as a clue for central diabetes insipidus (lack of V1 effect) in the differential diagnosis of polydipsia. Am J Med 103: , Robertson GL, Berl T: Pathophysiology of water metabolism, in Brenner BM (ed): The Kidney, vol 1 (ed 5). Philadelphia, PA, Saunders, 1996, pp Schewitz LJ: Hypertension and renal disease in pregnancy. Med Clin North Am 55:47-69, Sica D, Schoolwerth AC: Renal handling of organic anions and cations and renal excretion of uric acid, in Brenner BM (ed): The Kidney, vol 1 (ed 5). Philadelphia, PA, Saunders, 1996, pp Mimura Y, Ogura T, Hayakawa N, Otsuka F, Hashimoto M, Yamauchi T, Makino H, Ogawa N: In vitro macroand microautoradiographic localization of V1 and V2 receptors in the rat kidney using OPC and OPC Nephron 76: , Ostrowski NL, Young WS III, Knepper MA, Lolait SJ: Expression of vasopressin V1a and V2 receptor messenger ribonucleic acid in the liver and kidney of embryonic, developing and adult rats. Endocrinology 133: , Terada Y, Marumo F: Recent advances in vasopressin receptors and signal transduction system. Nippon Rinsho 51: , Serradeil-Le Gal C, Raufaste D, Marty E, Garcia C, Maffrand JP, Le Fur G: Autoradiographic localization of vasopressin V1a receptors in the rat kidney using [3H]-SR Kidney Int 50: , Kahn AM: Indirect coupling between sodium and urate transport in the proximal tubule. Kidney Int 36: , Barthelmebs M, Krieger JP, Grima M, Nisato D, Imbs JL: Vascular effects of [Arg8]vasopressin in the isolated perfused rat kidney. Eur J Pharmacol 314: , Hirata Y, Hayakawa H, Kakoki M, Tojo A, Suzuki E, Nagata D, Kimura K, Goto A, Kikuchi K, Nagano T, Hirobe M, Omata M: Receptor subtype for vasopressin-induced release of nitric oxide from rat kidney. Hypertension 29:58-64, de Wardener HE, Herxheimer A: The effect of high water intake on the kidney s ability to concentrate the urine in man. J Physiol (Lond) 139:42, 1957

3 694 JOURNAL CLUB Authors Reply: Guy Decaux, MD, PhD, Alain Soupart, MD, PhD, and Fernand Prospert, MD AN EXCESS or deficit of antidiuretic hormone (ADH) affects renal urate clearance. The level of serum uric acid is known to be partially dependent on this renal clearance, which is influenced by different factors, one of the most important being effective volemia (EV). 1 By controlling renal water excretion, ADH is generally considered to influence the EV. It seems likely that regulation of renal sodium excretion and retention to maintain extracellular volume influences renal uric acid and urea clearance in a similar way. 2 Dorhout Mees et al 3 were the first to report that hyponatremia induced in volunteers by the administration of AVP and water was associated with a larger decrease in serum uric acid (approximately 50%) than expected for the degree of dilution (approximately a 10% decrease in serum sodium concentration). The decrease in serum uric acid concentration mainly resulted from high uric acid clearance (proportionally higher than the increase in glomerular filtration). 3 These investigators showed in two patients with an inappropriate secretion of ADH (SIADH) that normalizing natremia by water restriction normalized the fractional uric acid excretion and serum uric acid level, despite persistence of the initial disease. This finding suggests that expansion of the extracellular volume was responsible for the increase in fractional uric acid excretion. The increase in uric acid fractional excretion in the SIADH is due to a decrease in tubular reabsorption, 4 mainly localized at presecretory and postsecretory sites of the tubule, while urate secretion seems to be appropriate for the level of uricemia. 5 Beck 6 reported that hyponatremia secondary From the Service de Médecine Interne Générale, Hôpital Universitaire Erasme, Brussels, Belgium; the Service de Médecine Interne, Hôpital de Nivelles, Nivelles, Belgium; and the Service de Néphrologie, Centre Hospitalier du Luxembourg, Grand Duché du Luxembourg. Received and accepted as submitted June 25, Address reprint requests to Guy Decaux, MD, PhD, Service de Médecine Interne Générale, Hôpital Universitaire Erasme, 808 Route de Lennik, 1070 Brussels, Belgium. guy.decaux@skynet.be 1998 by the National Kidney Foundation, Inc /98/ $3.00/0 to SIADH is generally associated with a serum uric acid level lower than 4 mg/dl. 6 However, values are higher than 5 mg/dl in patients with hyponatremia associated with a decrease in the EV. 6 Since this initial observation, hyponatremia associated with hypouricemia ( 4 mg/dl) and a high fractional uric acid excretion ( 12%; 16% in the elderly) has been reported in other conditions, such as hypocorticism, 7 diuretics, 7 potomania, 7 and renal salt wasting. 8 In cirrhosis, this finding could be due to low synthesis and/or high clearances In cases of SIADH, urea levels also may be disproportionately low for the degree of dilution. This results from a high urea clearance, mainly secondary to a decrease in tubular urea reabsorption due to increased volemia. 12 Hypouricemia ( 4 mg/dl) is more frequently observed than hypouremia in cases of SIADH, as high salt excretion is associated with a normal urea clearance. 13 Uric acid clearance, however, is not influenced by salt excretion (at least in the normal range for salt excretion). 13 Estimation of volemia on a clinical basis is difficult. 14,15 Low urinary salt excretion (U Na 20 meq/l or FE Na 0.5%) can be observed in the SIADH if salt ingestion is low. These patients, however, have high urea and uric acid excretions 13 (FE urea 55% and FE uric acid 12% [ 16% in the elderly]), whereas these fractional excretions are low or normal when U Na is determined by low volemia. 15 High volemia is associated with a decrease in proximal sodium reabsorption and indirectly affects urate reabsorption, which is located mainly in the proximal tubule. 16 The result is an increased sodium delivery distally to the proximal tubule, where further reabsorption occurs, and finally achieving sodium excretion within the normal range. Urate reabsorption, however, does not occur in a significant manner distally to the proximal tubule 1 and urate clearance remains high. We recently observed in volunteers that hyponatremia induced by the administration of ddavp (a potent V 2 agonist) increased urate clearance to a much lower extent ( 30%) than in patients with SIADH ( 100%). 17 This difference is reported

4 JOURNAL CLUB 695 despite a similar degree of hyponatremia, natriuria, and volume expansion (indirectly estimated by the level of hypoproteinemia 18 ). In one patient with central diabetes insipidus (CDI) and pre-existing hyponatremia induced by ddavp, the administration of triglycyl-lysinevasopressin (TGLV; a potent V 1 receptor agonist) produced a rapid increase of urate clearance. 17 These data suggest that the higher urate clearance observed during hyponatremia related to SIADH is the consequence of an increased EV and that V 1 receptor stimulation also contributes to it. 17 Furthermore, some evidence points to hyponatremia per se as a contributing factor to increased urate clearance in the SIADH. 19 Severe CDI is a condition of absent V 1 and V 2 receptor stimulation. The lack of V 1 receptor stimulation seems to have no clinical consequence, while the absence or deficit in V 2 receptor stimulation results in high diuresis, a trend to dehydration, and stimulation of fluid intake. In primary polydipsia, the tendency to dilution induces secondary inhibition of ADH secretion with ensuing polyuria. CDI is a state of volume depletion with a risk of hypernatremia, and primary polydipsia is the opposite state, leading to volume expansion and sometimes hyponatremia. Despite this difference in volemia, both conditions are usually associated with hypouremia due to the high urea clearance in polyuria. 7,20 No simple biological parameters allow reliable discrimination between these two conditions when serum sodium levels are normal. We observed that patients with primary polydipsia generally have a serum uric acid concentration below 5 mg/dl, while patients with severe CDI have values higher than 5 mg/dl. 20 When they were normonatremic, our patients with CDI had a low uric acid clearance despite high diuresis, which is normally known to increase renal uric acid clearance. 21 It is likely that chronic volume contraction in CDI is predominant over the effect of high diuresis on urate clearance. When patients with CDI are treated with ddavp, approximately 50% remain hyperuricemic with low urate clearance despite indirect signs of normal volemia (low plasma renin activity [PRA]). 20 As ddavp acts only on V 2 receptors, this observation could reflect the absence of V 1 receptor stimulation. In patients with untreated CDI and normonatremia (although many of them had a serum sodium level at the upper limit), serum uric acid was noteworthy and disproportionately high compared with the minor water deficit (approximately 0.5 to 1 L). Approximately 8% of this water deficit (40 to 80 ml) affects the vascular space. In comparison to the whole blood volume in a 70-kg patient (4 to 5 L), this amount is negligible (1% to 2%). Moreover, all the patients had a normal blood pressure, a normal pulse rate, and no clinical signs of dehydration. Diuretics induce preferentially extracellular fluid loss ( 1 to 2 L), severely affecting the vascular compartment with possible orthostatic hypotension. Although this is less important in CDI patients, the extracellular fluid deficit in diuretic patients is accompanied by an increase in mean uric acid concentration of approximately 25% compared with 70% in CDI patients, 20 which suggests that in CDI patients, another factor besides a decrease in EV influences serum uric acid concentration. To differentiate the potential role of V 1 or V 2 receptor stimulation in uric acid clearance, ddavp and TGLV were administered successively in one patient with CDI and no detectable endogenous ADH secretion. Only TGLV was able to increase urate clearance. These data suggest that hyperuricemia in CDI appropriately treated with ddavp, or untreated, is related to a lack of V 1 receptor stimulation. 20 We observed a smaller increase in serum uric acid concentration in patients with nephrogenic diabetes insipidus than in patients with CDI despite a similar degree of volume contraction as suggested by high PRA. Uric acid clearance was also better preserved. 20 In nephrogenic diabetes insipidus patients, the resistance of the collecting tubule to the action of ADH is mediated by V 2 receptors. V 1 receptor stimulation is preserved, explaining why better maintenance of urate clearance in nephrogenic diabetes insipidus patients can be mediated through ongoing V 1 receptor stimulation by endogenous ADH secretion. The mechanism by which V 1 receptor stimulation affects urate clearance remains to be determined. Several hypotheses can be proposed. Arginine vasopressin (AVP), but not ddavp, at a

5 696 JOURNAL CLUB physiologic concentration is known to induce natriuresis that could not be inhibited by a specific V 1 antagonist. 22,23 According to these observations, neither V 1 nor V 2 receptor subtypes seem to be involved in AVP-induced natriuresis. Natriuresis induced by AVP is primarily a tubular effect without significant hemodynamic involvement, at least in the animal model. 22,23 Some investigators have suggested that the existence of a V 1 subtype or perhaps a novel V 3 receptor is responsible for AVP-mediated natriuresis. 22,23 Furthermore, Jung and Endou 24 suggested the existence of a novel AVP receptor subtype, called VP, in the S 1 nephron segment that is pharmacologically different from the two already well-established AVP receptor subtypes. The S 1 nephron segment is the main site of uric acid as well as sodium reabsorption. 1 We recently studied a patient with severe gout who had a very low urate excretion. The administration of TGLV in this patient increased the uricosuric effect of probenecid. This observation suggests that TGLV decreases presecretory proximal tubular urate reabsorption (the S 1 nephron segment), which is revealed only after inhibition of postsecretory reabsorption with a uricosuric drug. 25 It is possible that V 1 receptor stimulation in humans affects systemic and/or intrarenal hemodynamics, indirectly influencing proximal sodium and urate reabsorption. We observed low PRA in our patients with primary polydipsia but without hyponatremia, which probably reflects volume expansion. 20 It is likely that despite the lack of AVP, as in patients with severe CDI, the mild increase in the volemia of these patients is the major factor influencing urate clearance. It also is possible that the primary polydipsia patients presented a smaller decrease in serum AVP concentration than the patients with severe CDI, 26 which could also influence urate clearance. We have shown that the presence of a serum uric acid concentration higher than 5 mg/dl in a polyuric polydipsic patient is highly suggestive of CDI. We also have shown that the persistence of hyperuremia in a patient appropriately treated with ddavp is a frequent finding that does not implicate some residual degree of volume contraction but more likely reflects a lack of V 1 receptor stimulation by ddavp. In patients with partial diabetes insipidus, a hypersensitivity of the collecting tubule to a low circulating ADH concentration has been shown. 26 Whether this also involves the V 1 receptor is unknown. Patients with partial diabetes insipidus may have uric acid concentrations that overlap more frequently than those seen in patients with primary polydipsia. Further studies are required. REFERENCES 1. Sica D, Schoolwerth AC: Renal handling of organic anions and cations and renal excretions of uric acid, in Brenner MB (ed): The Kidney, vol 1 (ed 5). Philadelphia, PA, Saunders, 1996, pp Bankir L: Urea and the kidney, in Brenner MB (ed): The Kidney, vol 1 (ed 5). Philadelphia, PA, Saunders, 1996, pp Dorhout Mees EJ, Blom van Assendelf TP, Nieuwenhuis MG: Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion. Acta Med Scand 189: 69-72, Decaux G, Dumont I, Waterlot Y, Hanson B: Mechanisms of hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. Nephron 39: , Prospert F, Soupart A, Brimioulle S, Decaux G: Evidence of defective tubular reabsorption and normal secretion of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone. Nephron 39: , Beck LH: Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 301: , 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: , Maesaka JK, Batuman Y, Yudd M, Salem M, Sved AF, Venkatesan J: Hyponatremia and hypouricemia: Differentiation from SIADH. Clin Nephrol 33: , Michelis MF, Warms PC, Fusco RD, Dais BB: Hypouricemia and hyperuricosuria in laennec cirrhosis. Arch Intern Med 134: , Decaux G, Dumont I, Naieje N, Mols P, Melot C, Mockel J: High uric acid and urea clearance in cirrhosis secondary to increased effective vascular volume. Am J Med 73: , Decaux G, Prospert F, Namias B, Schlesser M, Soupart A: Raised urea clearance in cirrhotic patients with high uric acid clearance is related to low salt excretion. Gut 33: , Decaux G, Genette F, Mockel J: Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone secretion. Ann Intern Med 93: , Decaux G, Prospert F, Cauchie P, Soupart A: Dissociation between uric acid and urea clearances in the syndrome of inappropriate secretion of ADH related to salt excretion. Clin Sci (Lond) 78: , Chung HM, Kluge R, Schrier RW, Anderson RL: Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 83: , 1987

6 JOURNAL CLUB Musch W, Thimpont J, Vandervelde D, Verhaeverbeke I, Berghmans T, Decaux G: Combined fractional excretion of sodium and urea better predicts response to saline in hyponatremia than do usual clinical and biochemical parameters. Am J Med 99: , Kahn AM: Indirect coupling between sodium and urate transport in the proximal tubule. Kidney Intern 36: , Decaux G, Namias B, Gulbis B, Soupart A: Evidence in hyponatremia related to inappropriate secretion of ADH that V 1 receptor stimulation contributes to the increase in renal uric acid clearance. J Am Soc Nephrol 7: , Namias B, Soupart A, Kornreich A, Decaux G: In human patients, vascular water retention during ddavp related hyponatremia occurs mainly in the plasma volume and not in the erythrocyte. J Lab Clin Med 128: , Decaux G, Namias B, Soupart A, Musch W: Indirect evidence to suggest that hyponatremia by itself contributes to the high urate clearance in the SIADH. J Am Soc Nephrol 7:102A, 1997 (abstr) 20. Decaux G, Prospert F, Namias B, Soupart A: Hyperuricemia as a clue for central diabetes insipidus (lack of V 1 receptor) in the differential diagnosis of polydipsia. Am J Med 103: , Diamond HS, Lazarus R, Kaphan D, Halberstra D: Effect of urine flow rate on uric acid excretion in man. Arthritis Rheum 15: , Chan WY, Hruby VJ: Natriuretic action of neurohypophysial peptides: Effects of agonists and antagonists and implication of natriuretic receptor. J Pharmacol Exp Ther 246: , Smith CP, Balment RJ: Arginine vasopressin induced natriuresis in the anaesthetized rat: Involvement of V 1 and V 2 receptors. J Endocrinol 136: , Jung KY, Endou H: A novel vasopressin receptor in rat early proximal tubule. Biochem Biophys Res Commun 180: , Decaux G, Soupart A, Musch W, Hannotier P, Prospert F: Restoration of the uricosuric effect of probenecid after triglycylvasopressine administration in a gouty patient. Clin Nephrol 1998 (in press) 26. Zerbe RL, Robertson GL: A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med 305: , 1981