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Oral Urea for the Treatment of Chronic Syndrome of Inappropriate Antidiuresis in Children
ORAL UREA FOR THE TREATMENT OF CHRONIC SYNDROME OF INAPPROPRIATE ANTIDIURESIS IN CHILDREN ERIC A. HUANG, MD, BRIAN J. FELDMAN, MD, PHD, I. DAVID SCHWARTZ, MD, DAVID H. GELLER, MD, PHD, STEPHEN M. ROSENTHAL, MD, AND STEPHEN E. GITELMAN, MD
We report the successful use of oral urea in the management of children with chronic syndrome of inappropriate antidiuretic hormone secretion (SIAD). We performed a retrospective review of four children with chronic SIAD. After initial attempts at management with fluid restriction, each was started on a 30% to 50% oral urea solution, and the dose was titrated until normal serum sodium was achieved. Fluid intake was liberalized after serum sodium normalization. All four children normalized their serum sodium. No side effects or toxicities were experienced. Oral urea is a safe, effective treatment for chronic SIAD in children. (J Pediatr 2006;148:128-31)
he syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. Nearly half a century has passed since Schwartz et al first described the hallmarks of this syndrome1: (1) hyponatremia with corresponding hypo-osmolar serum; (2) inappropriate urinary excretion of sodium; (3) no clinical evidence of fluid volume depletion; (4) less than maximally dilute urine; (5) normal renal function; and (6) normal adrenal and thyroid function. At the time of the original clinical description of SIADH, an arginine vasopressin (AVP) radioimmunoassay was not available, but subsequent studies have shown that patients with SIADH often have inappropriately measurable or elevated AVP concentrations.2 SIADH is usually transient and self-limited, managed easily with a brief period of fluid restriction. Chronic or persistent SIADH is rare, especially in children. Only 13 published pediatric cases of chronic SIADH have been reported between 1957 and 2004.3-11 Interestingly, in four of the previously reported cases, plasma AVP was undetectable during euvolemic hyponatremia.5,9-11 Several possible mechanisms have been proposed to explain this: (1) a ‘‘reset osmostat,’’ in which AVP secretion is higher than normal for a given plasma osmolality, but response to relative changes in osmolality is maintained; (2) increased renal sensitivity to plasma AVP, which may be present at plasma concentrations below the limit of assay detection; (3) the presence of another, immunologically distinct antidiuretic substance; or (4) an AVP-independent mechanism resulting in increased renal water absorption, such as a gain-of-function mutation in the AVP receptor type 2 (AVPR2) or in the aquaporin-2 gene. Recently, two patients presented to our institution meeting the criteria for diagnosis of SIADH but with undetectable plasma AVP concentrations during periods of euvolemic hyponatremia. Sequencing of the AVPR2 gene revealed missense mutations that result in constitutively active V2 vasopressin receptors (V2R).12 Although these patients fulfill the classic criteria for diagnosis of SIADH, they are more accurately described as having a From the Department of Pediatrics, nephrogenic syndrome of inappropriate antidiuresis (NSIAD).12 Thus, we have suggested Division of Endocrinology, University of California, San Francisco School of that all patients who fulfill the classic criteria should be referred to as having SIAD until Medicine; and the Department of they can be diagnosed specifically with either SIADH or NSIAD. Pediatrics, Division of Endocrinology, Regardless of cause, the principles of management of chronic SIAD are the same. University of South Carolina School of Medicine, Columbia, SC. Fluid restriction is the mainstay of therapy. However, restricting fluids in children is chalDrs Huang, Feldman, and Geller were lenging, and doing so in young infants can result in malnutrition. Although a variety of partially supported by NIH T32 grant drugs have been used to treat SIAD, they are associated with significant side effects and # DK00716. Reprint requests: Reprints not toxicities. One therapy that has been used successfully in adults, oral urea, has been shown available. to be both safe and effective,13,14 but there are no reports of its use in children.
T
AVP NSIAD
128
Arginine vasopressin Nephrogenic syndrome of inappropriate antidiuresis
SIAD V2R
Syndrome of inappropriate antidiuretic hormone secretion V2 vasopressin receptors
Submitted for publication Feb 25, 2005; last revision received Jun 21, 2005; accepted Aug 3, 2005. 0022-3476/$ - see front matter Copyright ª 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.08.031
Table 1. Presenting blood and urine studies in 4 patients with chronic SIAD Serum
Plasma
Urine
Renin Osmolality Osmolality Sodium mOsm/kg BUN Cortisol Aldosterone Free T4 TSH Activity AVP Sodium mOsm/kg mg/dL mcg/dL ng/dL ng/dL mIU/L ng/mL/hr pg/mL mEq/L H2 O Patient mEq/L H2 O 1 123 2 118 3 126 4 118 Normal 134-143 Range
252 247 256 253 285-293
,5 3 9 12 8-23
13.3 10.3 ND 28.1 4-20
10 24 ND 13 6-68
1.09 0.97 ND 1.5 0.8-1.8
0.77 4.58 ND 3.17 0.5-4.7
3.8 ,1 ND 1.4 ,15
,1 ,1 ND 1.2 NA
35 75 143 ND NA
284 390 957 543 NA
ND = not done; NA = not applicable; BUN = blood urea nitrogen; AVP = arginine vasopressin.
Table II. Blood and urine studies in 4 patients with chronic SIAD treated with oral urea Serum Patient 1 2 3 4 Normal Range
Urine
Oral Urea Dose g/kg/day
Sodium mEq/L
Osmolality mOsm/kg H2O
BUN mg/dL
Creatinine mg/dL
Sodium mEq/L
Osmolality mOsm/kg H2O
2 2 0.1 0.7 NA
137-146 137-145 137-143 134-143 134-143
283 295 284 287 285-293
25-39 31-44 17-23 22-46 8-23
,0.3 0.4 ,0.3 0.3 0.3-0.7
ND 51 37 ND NA
ND 514 508 ND NA
ND = not done; NA = not applicable; BUN = blood urea nitrogen.
CASE REPORTS Case 1 A previously healthy male presented at 3 months of age with irritability. Initial physical examination revealed mild systolic hypertension but was otherwise unremarkable. Laboratory evaluation showed a serum sodium of 123 mEq/L and normal glucose. Further blood and urine studies were consistent with the diagnosis of SIAD (Table I). Imaging of the head and chest were normal. No cause of SIAD could be found. Plasma AVP measurements were repeatedly nondetectable, and sequencing of AVPR2 revealed a missense mutation in codon 137, changing arginine to cysteine (R137C), indicating a diagnosis of NSIAD.12 Although serum sodium and osmolality improved with fluid intake restricted to urine output plus estimated insensible fluid loss, the infant’s caloric intake was significantly limited. A 30% oral urea solution was started at 0.1 g/kg/day divided into four doses and increased gradually to 2 g/kg/day. Urine output increased, and serum sodium and osmolality normalized (Table II). The patient’s fluid intake was slowly liberalized until he was allowed to drink without restriction while maintaining a normal serum sodium.
also revealed mild systolic hypertension but was otherwise unremarkable. Laboratory evaluation showed a serum sodium of 118 mEq/L and normal glucose. Further blood and urine studies were consistent with a diagnosis of SIAD (Table I). A small pars intermedia cyst was seen on magnetic resonance imaging; otherwise, imaging studies of the head and chest were normal. No cause of SIAD could be found. Plasma AVP measurements were repeatedly nondetectable. Sequencing of AVPR2 revealed a missense mutation, converting codon 137 from arginine to leucine (R137L), indicating a diagnosis of NSIAD.12 With fluid intake restricted to urine output plus estimated insensible loss, serum sodium and osmolality normalized. Despite maximizing the caloric concentration of his infant formula, the patient did not gain weight for 1 month. A 30% oral urea solution was then started at 0.1 g/kg/day divided into four doses and increased gradually to 2 g/kg/day. Serum sodium and osmolality remained normal (Table II). Fluid intake was then liberalized until he was allowed to drink without restriction while maintaining a normal serum sodium. The patient had adequate daily weight gain on this regimen.
Case 3 Case 2 A previously healthy male presented at 2.5 months of age with two generalized seizures. Initial physical examination Oral Urea For The Treatment Of Chronic Syndrome Of Inappropriate Antidiuresis In Children
A previously healthy 33-month-old female underwent resection of a posterior fossa tumor. Postoperatively, her serum sodium fell to 126 mEq/L. Further blood and urine studies 129
(Table I) and her clinically euvolemic state were consistent with a diagnosis of SIAD. Hyponatremia persisted after 3 weeks of restricting fluid intake to urine output alone. The patient required several courses of intravenous 3% saline followed by intravenous furosemide for profound hyponatremia. A 30% oral urea solution was started at 0.1 g/kg/day divided into four doses; she was permitted solid foods ad lib, but fluid intake was limited to 50% of urine output. Serum sodium concentration and osmolality normalized (Table II). The patient remained eunatremic on this regimen. After several months, a trial off of urea without restricting fluid intake revealed resolution of SIAD.
Case 4 A previously healthy 7-month-old male developed a febrile illness and status epilepticus. Cerebral edema seen on head computed tomograhy scan and a positive blood culture were consistent with a diagnosis of meningoencephalitis. During his prolonged hospitalization, the patient’s serum sodium fell to 118 mEq/L, and further blood and urine studies were consistent with a diagnosis of SIAD (Table I). During severe hyponatremia, plasma AVP was inappropriately measurable at 1.2 pg/mL. He was managed with fluid restriction as well as oral sodium chloride and furosemide. At discharge, he had a chronic seizure disorder that required treatment with valproic acid and phenobarbital. At home, fluid restriction, oral furosemide, and sodium chloride were continued for management of chronic SIAD. At 9 months of age, he was discovered to be significantly hypernatremic with a serum sodium of 194 mEq/L. When oral sodium chloride and furosemide were stopped and he was given intravenous fluids, hyponatremia recurred. Fluid restriction and oral sodium chloride and furosemide were resumed and demeclocycline 100 mg twice daily was started. His serum sodium improved but did not normalize, remaining in the 120 to 130 mEq/L range. At 13 months of age, his clinical status remained poor despite increasing demeclocycline and sodium chloride dosing, and restricting fluid intake. At 16 months, demeclocycline was discontinued and a 50% oral urea solution at 0.7 g/kg/day divided into four doses was started. Serum sodium and osmolality normalized (Table II), and fluid intake was liberalized; after 2 months of treatment, decreased seizure activity was also noted as well as normal growth. At 4 years of age, he remains eunatremic on this regimen. Although significant gross motor and language delays remain, his seizure disorder has resolved.
METHODS For treatment of these patients, pharmaceutical grade urea powder was obtained from Spectrum Chemical (New Brunswick, NJ). For outpatient therapy, urea was supplied in 3-g packets and dissolved at home in 10-ml water before use in order to make a 30% solution. The retrospective chart review of these patients was approved by the Institutional Review Board of the University of California at San Francisco.
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DISCUSSION Two of these patients (Cases 3 and 4) represent more typical cases of SIADH, occurring in the setting of meningitis or brain tumor, and with elevation of plasma AVP as noted in Case 4. The other two patients have a recently described condition termed nephrogenic SIAD, with missense mutations causing constitutive activation of V2R.12 This receptor is expressed in the collecting duct and mediates water reabsorption.12 Aside from the early age at onset and suppressed AVP concentrations, the NSIAD cases exhibited similar clinical presentation, with profound hyponatremia in the setting of euvolemia. The cause of hyponatremia in SIAD remains unclear. Water-loading experiments in patients with SIAD show that expansion of extracellular fluid volume increases plasma atrial natriuetic factor and decreases plasma aldosterone levels.15 However, plasma aldosterone levels in patients with SIAD have been shown to be variable, with investigators reporting low, normal, and elevated levels.16 In addition, a dissociation between plasma renin activity and plasma aldosterone levels has been reported in patients with SIAD; specifically, when aldosterone levels are normal or elevated, plasma renin is relatively suppressed or undetectable.16 The usual therapy for SIAD is water restriction; however, such treatment is difficult in children with chronic SIAD, especially in infants because they receive nearly all of their calories as liquids. Various medications have been used to treat chronic SIAD. Furosemide, a loop diuretic, has been used successfully in some adults.17 Two drugs that induce nephrogenic diabetes insipidus by adversely affecting the vasopressin receptor, lithium carbonate and demeclocycline, have also been used with some success in adults.18 Unfortunately, all of these therapies are associated with significant side effects and potential toxicities in children. Furosemide can cause hypokalemia, metabolic alkalosis, and nephrocalcinosis19; lithium can cause hypothyroidism and arrhythmias20; demeclocycline can cause staining of the teeth21 and inhibition of bone growth.22 Currently, several nonpeptide V2R antagonists are undergoing Phase III clinical trials, and these may eventually prove to be effective treatments for chronic SIAD.23 In contrast to other pharmacological therapies, oral urea is extremely safe and effective. Studies in patients with chronic renal failure demonstrate urea’s lack of toxicity, even at high serum levels.24 Theoretically, excess blood urea because of exogenous administration or increased endogenous protein catabolism could cause hypernatremia by excessive osmotic diuresis, especially when there is no compensation via increased free-water intake. Although this problem was not encountered during our use of urea, we recommend close monitoring of electrolytes and serum urea, especially while initiating therapy. There have also been concerns raised about urea’s taste, but this did not limit administration in any of our patients. No additives were required to camouflage the taste. The effectiveness of oral urea may be explained by the pathogenesis of hyponatremia in SIAD, which is a result of a combination of dilution of the serum by free-water and
The Journal of Pediatrics January 2006
inappropriate natriuresis. In 1980, Decaux et al noted a strong correlation between low serum sodium and low blood urea in 20 patients with SIADH, suggesting another mechanism of increased natriuresis.25 Endogenous urea plays an important role in the urinary concentrating mechanism in the inner renal medulla, which has an indirect effect on passive sodium reabsorption along the thin ascending limb.26 Water-loading studies in patients with chronic SIAD treated with oral urea have shown that at low doses, oral urea decreases natriuresis without significantly affecting urine flow, and at higher doses, oral urea increases urine flow by inducing an osmotic diuresis.25 Thus, treatment of SIAD with oral urea may be effective because it can work via these two mechanisms simultaneously.
CONCLUSIONS All four of our pediatric patients demonstrated rapid correction of hyponatremia using oral urea. Urea was well tolerated and did not have any side effects. We suggest oral urea as an extremely safe, inexpensive, effective treatment for children with chronic SIAD. We suggest starting with a 30% solution at 0.1 g/kg/day divided into four doses, then titrating to effect. We used a maximum dose of 2 g/kg/day as this is comparable to the maximum dose used in adult studies to date,13,14 although there are no data indicating a dose ceiling.
REFERENCES 1. Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:529-42. 2. Zerbe R, Stropes L, Robertson G. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980;31:315-27. 3. Sklar C, Fertig A, David R. Chronic syndrome of inappropriate secretion of antidiuretic hormone in childhood. Am J Dis Child 1985;139:733-5. 4. Skowsky WR, Fisher DA. Intermittent, idiopathic, inappropriate vasopressin secretion in a child. J Pediatr 1973;83:62-8. 5. Fyhrquist F, Holmberg C, Perheentupa J, Wallenius M. Inappropriate secretion of antiduretic hormone, hypertension, and hypoplastic corpus callosum. J Clin Endocrinol Metab 1977;45:691-4. 6. Friedman AL, Chesney RW, Bargman GJ, Segar WE. Lack of inhibition of vasopressin release in midfacial hypoplasia. J Pediatr 1979;94:591-4. 7. Baker RS, Hurley RM, Feldman W. Treatment of recurrent syndrome of inappropriate secretion of antidiuretic hormone with lithium. J Pediatr 1977;90:480-1. 8. Anmuth CJ, Ross BW, Alexander MA, Reeves GD. Chronic syndrome of inappropriate secretion of antidiuretic hormone in a pediatric
Oral Urea For The Treatment Of Chronic Syndrome Of Inappropriate Antidiuresis In Children
patient after traumatic brain injury. Arch Phys Med Rehabil 1993;74: 1219-21. 9. Thiagarajan R, La Gamma E, Dey S, Blethen S, Wilson TA. Hyponatremia caused by a reset osmostat in a neonate with cleft lip and palate and panhypopituitarism. J Pediatr 1996;128:561-3. 10. Gupta P, Mick G, Fong CT, Jospe N, McCormick K. Hyponatremia secondary to reset osmostat in a child with a central nervous system midline defect and a chromosomal abnormality. J Pediatr Endocrinol Metab 2000;13:1637-41. 11. Tanaka Y, Sugita K, Saito T, Muroya K, Ishikawa SE, Awazu M, et al. Impaired urinary water excretion in a three-generation family. Pediatr Nephrol 2001;16:820-2. 12. Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005;352:1884-90. 13. Decaux G, Prospert F, Penninckx R, Namias B, Soupart A. 5-year treatment of the chronic syndrome of inappropriate secretion of ADH with oral urea. Nephron 1993;63:468-70. 14. Decaux G, Genette F. Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone. Br Med J (Clin Res Ed) 1981;283:1081-3. 15. Cogan E, Debieve MF, Pepersack T, Abramow M. Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis. Am J Med 1988;84:409-18. 16. Fichman MP, Michelakis AM, Horton R. Regulation of aldosterone in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). J Clin Endocrinol Metab 1974;39:136-44. 17. Decaux G. Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea, or furosemide. Am J Med 2001;110:582-4. 18. Forrest JN Jr, Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1978;298: 173-7. 19. Eades SK, Christensen ML. The clinical pharmacology of loop diuretics in the pediatric patient. Pediatr Nephrol 1998;12:603-16. 20. Dietrich A, Mortensen ME, Wheller J. Cardiac toxicity in an adolescent following chronic lithium and imipramine therapy. J Adolesc Health 1993;14: 394-7. 21. Sanchez AR, Rogers RS III, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol 2004;43:709-15. 22. Smilack JD. The tetracyclines. Mayo Clin Proc 1999;74:727-9. 23. Verbalis JG. Vasopressin V2 receptor antagonists. J Mol Endocrinol 2002;29:1-9. 24. Boure T, Vanholder R. Biochemical and clinical evidence for uremic toxicity. Artif Organs 2004;28:248-53. 25. Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med 1980;69:99-106. 26. Imai M, Kokko JP. Sodium chloride, urea, and water transport in the thin ascending limb of Henle: generation of osmotic gradients by passive diffusion of solutes. J Clin Invest 1974;53:393-402.
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We report the successful use of oral urea in the management of children with chronic syndrome of inappropriate antidiuretic hormone secretion (SIAD). We performed a retrospective review of four children with chronic SIAD. After initial attempts at management with fluid restriction, each was started on a 30% to 50% oral urea solution, and the dose was titrated until normal serum sodium was achieved. Fluid intake was liberalized after serum sodium normalization. All four children normalized their serum sodium. No side effects or toxicities were experienced. Oral urea is a safe, effective treatment for chronic SIAD in children. (J Pediatr 2006;148:128-31)
he syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. Nearly half a century has passed since Schwartz et al first described the hallmarks of this syndrome1: (1) hyponatremia with corresponding hypo-osmolar serum; (2) inappropriate urinary excretion of sodium; (3) no clinical evidence of fluid volume depletion; (4) less than maximally dilute urine; (5) normal renal function; and (6) normal adrenal and thyroid function. At the time of the original clinical description of SIADH, an arginine vasopressin (AVP) radioimmunoassay was not available, but subsequent studies have shown that patients with SIADH often have inappropriately measurable or elevated AVP concentrations.2 SIADH is usually transient and self-limited, managed easily with a brief period of fluid restriction. Chronic or persistent SIADH is rare, especially in children. Only 13 published pediatric cases of chronic SIADH have been reported between 1957 and 2004.3-11 Interestingly, in four of the previously reported cases, plasma AVP was undetectable during euvolemic hyponatremia.5,9-11 Several possible mechanisms have been proposed to explain this: (1) a ‘‘reset osmostat,’’ in which AVP secretion is higher than normal for a given plasma osmolality, but response to relative changes in osmolality is maintained; (2) increased renal sensitivity to plasma AVP, which may be present at plasma concentrations below the limit of assay detection; (3) the presence of another, immunologically distinct antidiuretic substance; or (4) an AVP-independent mechanism resulting in increased renal water absorption, such as a gain-of-function mutation in the AVP receptor type 2 (AVPR2) or in the aquaporin-2 gene. Recently, two patients presented to our institution meeting the criteria for diagnosis of SIADH but with undetectable plasma AVP concentrations during periods of euvolemic hyponatremia. Sequencing of the AVPR2 gene revealed missense mutations that result in constitutively active V2 vasopressin receptors (V2R).12 Although these patients fulfill the classic criteria for diagnosis of SIADH, they are more accurately described as having a From the Department of Pediatrics, nephrogenic syndrome of inappropriate antidiuresis (NSIAD).12 Thus, we have suggested Division of Endocrinology, University of California, San Francisco School of that all patients who fulfill the classic criteria should be referred to as having SIAD until Medicine; and the Department of they can be diagnosed specifically with either SIADH or NSIAD. Pediatrics, Division of Endocrinology, Regardless of cause, the principles of management of chronic SIAD are the same. University of South Carolina School of Medicine, Columbia, SC. Fluid restriction is the mainstay of therapy. However, restricting fluids in children is chalDrs Huang, Feldman, and Geller were lenging, and doing so in young infants can result in malnutrition. Although a variety of partially supported by NIH T32 grant drugs have been used to treat SIAD, they are associated with significant side effects and # DK00716. Reprint requests: Reprints not toxicities. One therapy that has been used successfully in adults, oral urea, has been shown available. to be both safe and effective,13,14 but there are no reports of its use in children.
T
AVP NSIAD
128
Arginine vasopressin Nephrogenic syndrome of inappropriate antidiuresis
SIAD V2R
Syndrome of inappropriate antidiuretic hormone secretion V2 vasopressin receptors
Submitted for publication Feb 25, 2005; last revision received Jun 21, 2005; accepted Aug 3, 2005. 0022-3476/$ - see front matter Copyright ª 2006 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.08.031
Table 1. Presenting blood and urine studies in 4 patients with chronic SIAD Serum
Plasma
Urine
Renin Osmolality Osmolality Sodium mOsm/kg BUN Cortisol Aldosterone Free T4 TSH Activity AVP Sodium mOsm/kg mg/dL mcg/dL ng/dL ng/dL mIU/L ng/mL/hr pg/mL mEq/L H2 O Patient mEq/L H2 O 1 123 2 118 3 126 4 118 Normal 134-143 Range
252 247 256 253 285-293
,5 3 9 12 8-23
13.3 10.3 ND 28.1 4-20
10 24 ND 13 6-68
1.09 0.97 ND 1.5 0.8-1.8
0.77 4.58 ND 3.17 0.5-4.7
3.8 ,1 ND 1.4 ,15
,1 ,1 ND 1.2 NA
35 75 143 ND NA
284 390 957 543 NA
ND = not done; NA = not applicable; BUN = blood urea nitrogen; AVP = arginine vasopressin.
Table II. Blood and urine studies in 4 patients with chronic SIAD treated with oral urea Serum Patient 1 2 3 4 Normal Range
Urine
Oral Urea Dose g/kg/day
Sodium mEq/L
Osmolality mOsm/kg H2O
BUN mg/dL
Creatinine mg/dL
Sodium mEq/L
Osmolality mOsm/kg H2O
2 2 0.1 0.7 NA
137-146 137-145 137-143 134-143 134-143
283 295 284 287 285-293
25-39 31-44 17-23 22-46 8-23
,0.3 0.4 ,0.3 0.3 0.3-0.7
ND 51 37 ND NA
ND 514 508 ND NA
ND = not done; NA = not applicable; BUN = blood urea nitrogen.
CASE REPORTS Case 1 A previously healthy male presented at 3 months of age with irritability. Initial physical examination revealed mild systolic hypertension but was otherwise unremarkable. Laboratory evaluation showed a serum sodium of 123 mEq/L and normal glucose. Further blood and urine studies were consistent with the diagnosis of SIAD (Table I). Imaging of the head and chest were normal. No cause of SIAD could be found. Plasma AVP measurements were repeatedly nondetectable, and sequencing of AVPR2 revealed a missense mutation in codon 137, changing arginine to cysteine (R137C), indicating a diagnosis of NSIAD.12 Although serum sodium and osmolality improved with fluid intake restricted to urine output plus estimated insensible fluid loss, the infant’s caloric intake was significantly limited. A 30% oral urea solution was started at 0.1 g/kg/day divided into four doses and increased gradually to 2 g/kg/day. Urine output increased, and serum sodium and osmolality normalized (Table II). The patient’s fluid intake was slowly liberalized until he was allowed to drink without restriction while maintaining a normal serum sodium.
also revealed mild systolic hypertension but was otherwise unremarkable. Laboratory evaluation showed a serum sodium of 118 mEq/L and normal glucose. Further blood and urine studies were consistent with a diagnosis of SIAD (Table I). A small pars intermedia cyst was seen on magnetic resonance imaging; otherwise, imaging studies of the head and chest were normal. No cause of SIAD could be found. Plasma AVP measurements were repeatedly nondetectable. Sequencing of AVPR2 revealed a missense mutation, converting codon 137 from arginine to leucine (R137L), indicating a diagnosis of NSIAD.12 With fluid intake restricted to urine output plus estimated insensible loss, serum sodium and osmolality normalized. Despite maximizing the caloric concentration of his infant formula, the patient did not gain weight for 1 month. A 30% oral urea solution was then started at 0.1 g/kg/day divided into four doses and increased gradually to 2 g/kg/day. Serum sodium and osmolality remained normal (Table II). Fluid intake was then liberalized until he was allowed to drink without restriction while maintaining a normal serum sodium. The patient had adequate daily weight gain on this regimen.
Case 3 Case 2 A previously healthy male presented at 2.5 months of age with two generalized seizures. Initial physical examination Oral Urea For The Treatment Of Chronic Syndrome Of Inappropriate Antidiuresis In Children
A previously healthy 33-month-old female underwent resection of a posterior fossa tumor. Postoperatively, her serum sodium fell to 126 mEq/L. Further blood and urine studies 129
(Table I) and her clinically euvolemic state were consistent with a diagnosis of SIAD. Hyponatremia persisted after 3 weeks of restricting fluid intake to urine output alone. The patient required several courses of intravenous 3% saline followed by intravenous furosemide for profound hyponatremia. A 30% oral urea solution was started at 0.1 g/kg/day divided into four doses; she was permitted solid foods ad lib, but fluid intake was limited to 50% of urine output. Serum sodium concentration and osmolality normalized (Table II). The patient remained eunatremic on this regimen. After several months, a trial off of urea without restricting fluid intake revealed resolution of SIAD.
Case 4 A previously healthy 7-month-old male developed a febrile illness and status epilepticus. Cerebral edema seen on head computed tomograhy scan and a positive blood culture were consistent with a diagnosis of meningoencephalitis. During his prolonged hospitalization, the patient’s serum sodium fell to 118 mEq/L, and further blood and urine studies were consistent with a diagnosis of SIAD (Table I). During severe hyponatremia, plasma AVP was inappropriately measurable at 1.2 pg/mL. He was managed with fluid restriction as well as oral sodium chloride and furosemide. At discharge, he had a chronic seizure disorder that required treatment with valproic acid and phenobarbital. At home, fluid restriction, oral furosemide, and sodium chloride were continued for management of chronic SIAD. At 9 months of age, he was discovered to be significantly hypernatremic with a serum sodium of 194 mEq/L. When oral sodium chloride and furosemide were stopped and he was given intravenous fluids, hyponatremia recurred. Fluid restriction and oral sodium chloride and furosemide were resumed and demeclocycline 100 mg twice daily was started. His serum sodium improved but did not normalize, remaining in the 120 to 130 mEq/L range. At 13 months of age, his clinical status remained poor despite increasing demeclocycline and sodium chloride dosing, and restricting fluid intake. At 16 months, demeclocycline was discontinued and a 50% oral urea solution at 0.7 g/kg/day divided into four doses was started. Serum sodium and osmolality normalized (Table II), and fluid intake was liberalized; after 2 months of treatment, decreased seizure activity was also noted as well as normal growth. At 4 years of age, he remains eunatremic on this regimen. Although significant gross motor and language delays remain, his seizure disorder has resolved.
METHODS For treatment of these patients, pharmaceutical grade urea powder was obtained from Spectrum Chemical (New Brunswick, NJ). For outpatient therapy, urea was supplied in 3-g packets and dissolved at home in 10-ml water before use in order to make a 30% solution. The retrospective chart review of these patients was approved by the Institutional Review Board of the University of California at San Francisco.
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DISCUSSION Two of these patients (Cases 3 and 4) represent more typical cases of SIADH, occurring in the setting of meningitis or brain tumor, and with elevation of plasma AVP as noted in Case 4. The other two patients have a recently described condition termed nephrogenic SIAD, with missense mutations causing constitutive activation of V2R.12 This receptor is expressed in the collecting duct and mediates water reabsorption.12 Aside from the early age at onset and suppressed AVP concentrations, the NSIAD cases exhibited similar clinical presentation, with profound hyponatremia in the setting of euvolemia. The cause of hyponatremia in SIAD remains unclear. Water-loading experiments in patients with SIAD show that expansion of extracellular fluid volume increases plasma atrial natriuetic factor and decreases plasma aldosterone levels.15 However, plasma aldosterone levels in patients with SIAD have been shown to be variable, with investigators reporting low, normal, and elevated levels.16 In addition, a dissociation between plasma renin activity and plasma aldosterone levels has been reported in patients with SIAD; specifically, when aldosterone levels are normal or elevated, plasma renin is relatively suppressed or undetectable.16 The usual therapy for SIAD is water restriction; however, such treatment is difficult in children with chronic SIAD, especially in infants because they receive nearly all of their calories as liquids. Various medications have been used to treat chronic SIAD. Furosemide, a loop diuretic, has been used successfully in some adults.17 Two drugs that induce nephrogenic diabetes insipidus by adversely affecting the vasopressin receptor, lithium carbonate and demeclocycline, have also been used with some success in adults.18 Unfortunately, all of these therapies are associated with significant side effects and potential toxicities in children. Furosemide can cause hypokalemia, metabolic alkalosis, and nephrocalcinosis19; lithium can cause hypothyroidism and arrhythmias20; demeclocycline can cause staining of the teeth21 and inhibition of bone growth.22 Currently, several nonpeptide V2R antagonists are undergoing Phase III clinical trials, and these may eventually prove to be effective treatments for chronic SIAD.23 In contrast to other pharmacological therapies, oral urea is extremely safe and effective. Studies in patients with chronic renal failure demonstrate urea’s lack of toxicity, even at high serum levels.24 Theoretically, excess blood urea because of exogenous administration or increased endogenous protein catabolism could cause hypernatremia by excessive osmotic diuresis, especially when there is no compensation via increased free-water intake. Although this problem was not encountered during our use of urea, we recommend close monitoring of electrolytes and serum urea, especially while initiating therapy. There have also been concerns raised about urea’s taste, but this did not limit administration in any of our patients. No additives were required to camouflage the taste. The effectiveness of oral urea may be explained by the pathogenesis of hyponatremia in SIAD, which is a result of a combination of dilution of the serum by free-water and
The Journal of Pediatrics January 2006
inappropriate natriuresis. In 1980, Decaux et al noted a strong correlation between low serum sodium and low blood urea in 20 patients with SIADH, suggesting another mechanism of increased natriuresis.25 Endogenous urea plays an important role in the urinary concentrating mechanism in the inner renal medulla, which has an indirect effect on passive sodium reabsorption along the thin ascending limb.26 Water-loading studies in patients with chronic SIAD treated with oral urea have shown that at low doses, oral urea decreases natriuresis without significantly affecting urine flow, and at higher doses, oral urea increases urine flow by inducing an osmotic diuresis.25 Thus, treatment of SIAD with oral urea may be effective because it can work via these two mechanisms simultaneously.
CONCLUSIONS All four of our pediatric patients demonstrated rapid correction of hyponatremia using oral urea. Urea was well tolerated and did not have any side effects. We suggest oral urea as an extremely safe, inexpensive, effective treatment for children with chronic SIAD. We suggest starting with a 30% solution at 0.1 g/kg/day divided into four doses, then titrating to effect. We used a maximum dose of 2 g/kg/day as this is comparable to the maximum dose used in adult studies to date,13,14 although there are no data indicating a dose ceiling.
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Oral Urea For The Treatment Of Chronic Syndrome Of Inappropriate Antidiuresis In Children
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