DOI: 10.1542/peds.2006-2554 2007
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DOI: 10.1542/peds.2006-2554 2007

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  • 1. Serum Osmolal Gap in Patients With Idiopathic Nephrotic Syndrome and Severe Edema Gaurav Kapur, Rudolph P. Valentini, Abubakr A. Imam, Amrish Jain and Tej K. Mattoo Pediatrics 2007;119;e1404-e1407; originally published online May 7, 2007; DOI: 10.1542/peds.2006-2554 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/119/6/e1404 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from www.pediatrics.org by on October 20, 2010
  • 2. EXPERIENCE & REASON Serum Osmolal Gap in Patients With Idiopathic Nephrotic Syndrome and Severe Edema Gaurav Kapur, MD, Rudolph P. Valentini, MD, Abubakr A. Imam, MD, Amrish Jain, MD, Tej K. Mattoo, MD, FRCP Division of Nephrology and Hypertension, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan The authors have indicated they have no financial relationships relevant to this article to disclose. ABSTRACT Pseudohyponatremia in idiopathic nephrotic syndrome with severe edema is attributed to hyperlipidemia that results in displacement of a portion of water phase of plasma. Current methods of measurement of serum electrolytes are unaffected by hyperlipidemia. In this report we demonstrate that patients with idiopathic nephrotic syndrome with severe edema and true hyponatremia may have an increased rather than normal osmolal gap. We believe that this could be secondary to non-Na and non-K osmoles in response to plasma-volume contraction secondary to hypoalbuminemia. This observation has implications for management of severe edema in such patients, because fluid restriction could increase their risk for pre–renal failure. H YPONATREMIA IS A common observation in patients with idiopathic nephrotic syndrome (INS) with se- vere edema. In view of coexisting hyperlipidemia in such serum osmolality) attributable to non-Na and non-K osmoles in patients with circulatory shock.3–5 The aim of our study was to evaluate serum osmolality in patients patients, hyponatremia has traditionally been labeled as with INS who presented with hyponatremia and severe pseudohyponatremia rather than true hyponatremia. edema. Pseudohyponatremia is the method-dependent artifac- tual reduction of serum sodium attributed to measure- METHODS ment error caused by hyperlipidemia, which results in Known patients with INS who were admitted to inpa- displacement of a portion of plasma water by increased tient service (from November 2004 to January 2006) lipid concentration. Currently, direct potentiometry is with generalized edema were considered for the study. the method of choice for measuring blood electrolytes. Investigations performed included obtaining serum urea With this method, undiluted serum samples are used to nitrogen (SUN), serum creatinine, electrolyte, and albu- measure transmembrane potentials resulting from elec- min levels, serum osmolality, hemoglobin and hemato- trolyte gradients by using an ion-selective electrode. crit levels, urinalysis, and urine protein/creatinine ratio. Thus, the water content of the sample does not affect All investigations were performed at the time of admis- measurement of serum sodium, and pseudohyponatre- sion before starting treatment with dietary salt restric- mia is rarely seen.1 True hyponatremia in patients with tion ( 2 mEq/kg per day) and intravenous albumin and INS is included in the category of diseases with extracel- diuretics. Patients with fever, vomiting, or diarrhea or lular fluid volume expansion, as in congestive heart those who were already on diuretics, steroids, or immu- failure (CHF), and cirrhosis. In CHF and cirrhosis there is nosuppression for treatment of INS were excluded from plasma-volume expansion but effective circulatory vol- ume depletion secondary to primary reduction in cardiac Key Words: nephrotic syndrome, osmolal gap, hyponatremia, pre–renal failure Abbreviations: INS, idiopathic nephrotic syndrome; CHF, congestive heart failure; output or vascular resistance. However in INS, hy- SUN, serum urea nitrogen poalbuminemia leads to plasma-volume contraction. www.pediatrics.org/cgi/doi/10.1542/peds.2006-2554 Edema is secondary to compensatory retention of so- doi:10.1542/peds.2006-2554 dium and water by the kidney because of effective cir- Accepted for publication Nov 29, 2006 culatory volume depletion in CHF/cirrhosis and plasma- Address correspondence to Tej K. Mattoo, MD, FRCP, Pediatric Nephrology, Division of Nephrology volume contraction in INS.2 Studies have reported and Hypertension, 4th Floor, Carl’s Building, Children’s Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Blvd, Detroit, MI 48201. E-mail: tmattoo@med.wayne.edu increased serum osmolality and osmolal gap (defined as PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2007 by the the difference between the measured and the calculated American Academy of Pediatrics e1404 KAPUR et al Downloaded from www.pediatrics.org by on October 20, 2010
  • 3. the study. Serum sodium was measured in undiluted Urine Osmolality, samples by using the principle of direct potentiometry by mOsm/kg 1036 971 900 815 585 645 ion-selective electrodes (Vitrios 250 Chemistry System; Ortho-Clinical Diagnostics, Rochester, NY). Serum so- dium was also measured in undiluted capillary blood samples by using a blood-gas analyzer by the same prin- Hematocrit Normal for ciple of direct potentiometry (ABL800 FLEX; Radiome- Age21), % 44 (37) 50 (40) 46 (40) 45 (37) 41 (40) 40 (37) (Mean ter, Westlake, OH). Serum osmolality was measured by freezing-point depression in milliosmole-per-kilogram water. Additional tests that were performed to exclude Serum Albumin, secondary causes of nephrotic syndrome included hep- atitis B and hepatitis C serology, serum complements C3 g/dL 1.5 1.4 1.4 1.6 1.8 1.7 and C4, antinuclear antibody, and HIV antibody. Calcu- lated serum osmolality was estimated by the following formula: 2 Nap glucose/18 SUN/2.8. An osmolal gap (difference between measured and calculated osmo- Osmole Gap Osmolality) (Measured Calculated lality) of 0 to 10 mOsm/kg water was accepted as being 21.8 19.8 13.3 13.0 11.3 10.5 within normal limits.2,6,7 RESULTS Calculated Osmolality Glucose/18), mOsm/L Twenty patients with INS with severe hypoproteinemia (2Na SUN/2.8 and generalized edema were admitted to our service 258.2 265.2 267.7 277.0 271.7 278.5 over a period of 15 months. Of these patients, 7 (35%) were found to have low serum sodium levels as mea- sured by direct potentiometry during routine laboratory tests. One of these patients, who had increased SUN and Measured Serum serum creatinine levels, was excluded from the study. Osmolality, The remaining 6 patients were included in the study. mOsm/kg 280 285 281 290 283 289 Their ages ranged from 2 to 11 years; there were 4 boys and 2 girls. Low serum sodium level was confirmed in each patient by capillary blood sample by using a blood- gas analyzer (Table 1). Serum Cholesterol, As shown in Table 1, the measured serum osmolality was low in patients 1, 3, and 5 (reference range: 285– mg/dL 542 435 492 430 417 295 mOsm/kg water), borderline in patient 2, and 311 within the reference range in patients 4 and 6. The calculated serum osmolality was low in all patients, and TABLE 1 Laboratory Results of the Patients at Time of Admission the osmolal gap was high in all patients. Capillary Blood Gas Sodium, mEq/L 123.0 123.4 131.1 132.4 132.8 133.2 DISCUSSION Pseudohyponatremia was originally described8 when flame photometry was used for serum-electrolyte deter- mination. Using this technique, serum samples were Serum Sodium, diluted before the actual measurement of serum electro- mEq/L 123 124 130 132 133 134 lytes, which resulted in an artificially low serum sodium level in conditions such as hyperlipidemia, wherein the aqueous phase of plasma is reduced. However, biochem- ical analyzers, such as direct potentiometry, that are Gender currently in use assay sodium concentration in the aque- M M M M F F ous phase only and result in accurate determination of serum sodium levels.9 Given this fact, it has been sug- Age, 3.4 10.2 8.6 3.0 11.2 2.8 y gested that the term “pseudohyponatremia” no longer be used.1 This argument is supported by recent reports Patient on the presence of true hyponatremia in patients with No. 1 2 3 4 5 6 multiple myeloma10 and in those who had received in- PEDIATRICS Volume 119, Number 6, June 2007 e1405 Downloaded from www.pediatrics.org by on October 20, 2010
  • 4. travenous immunoglobulin infusions,11 conditions that of intravascular volume depletion with a preshock state. previously were associated with pseudohyponatremia. Thus, patients with INS who are admitted with severe The exact incidence of hyponatremia in patients with edema and hyponatremia would initially need slow vol- INS and severe edema is not known. It is reported that ume expansion. Initial fluid restriction and diuresis in serum sodium concentration is usually within the refer- such patients could further exacerbate their volume con- ence range in patients with INS unless it is influenced by traction and increase the risk of pre–renal failure or vigorous diuretic measures or during acute water ischemic acute tubular necrosis. load.12–14 Of the 20 such patients admitted to our service, Our observations assume relevance when viewed in 7 (35%) had low serum sodium concentrations as mea- the context of recent work by Nguyen and Kurtz,18,19 sured by direct potentiometry and confirmed by blood- who have highlighted the role of physiologic parame- gas analysis. ters, besides Nae Ke/TBW (Nae total exchangeable Wang et al15 reported significantly decreased serum sodium, Ke total exchangeable potassium, and TBW sodium concentrations in 5.8% of their patients with total body water),20 that play a role in modulating serum INS who presented with hypovolemic shock and in sodium and in the generation of dysnatremias. These 12.5% of their patients with INS who presented with factors include osmotic coefficient of sodium salts, Gibbs- symptomatic hypovolemic episodes without hypoten- Donnan equilibrium, osmotic equilibrium, osmotically sion. Our patients were not on diuretics, and they were inactive Nae and Ke, and osmotically active non-Na and clinically stable with no clinical evidence of cardiovas- non-K osmoles.18,19 The effect of these additional pa- cular decompensation. rameters in the setting of hypoalbuminemia and severe Despite true hyponatremia in all 6 of our patients, the edema in patients with INS needs to be studied in detail. measured serum osmolality was low in only 3 patients However, on the basis of the Nguyen-Kurtz formula, it (patients 1, 3, and 5); the remaining 3 patients had has been shown that Gibbs-Donnan equilibrium has an serum osmolality that was either borderline (patient 2) incremental effect on serum sodium, and the presence of or within the reference range (patients 4 and 6). The osmotically active non-Na and non-K osmoles in the calculated osmolality was low in all patients, and all had plasma has a depressive effect on serum sodium, which an increased osmolal gap. Under normal circumstances, may explain the presence of a relatively low serum in otherwise healthy individuals, low serum sodium sodium concentration and measured osmolality with the concentration (true hyponatremia) is associated with higher osmolal gap in our patients. Hypoalbuminemia in low measured and calculated serum osmolality and a patients with INS could cause a decrease in the Gibbs- normal osmolal gap. The presence of an increased osmo- Donnan effect in these patients, contributing to hypona- lal gap in all of our patients and normal measured serum tremia.19 osmolality in 2 of our patients (patients 4 and 6) is intriguing. CONCLUSIONS The most common settings in which low serum so- Our results show that in children with INS and severe dium concentration is not associated with a decrease in edema, the measurement of serum sodium by current serum osmolality occurs when there are additional os- methods indicates true hyponatremia, not pseudohy- molytes in the extracellular fluid such as ethanol, meth- ponatremia. Identification of true hyponatremia is im- anol, or ethylene glycol.2,12 The coexistence of hypona- portant, because the additional presence of an increased tremia with an increased osmolal gap, as noted in our serum osmolal gap in these patients is indicative of vol- patients, has implications in understanding the patho- ume contraction. These patients need slow plasma-vol- physiology and management of severe edema in patients ume expansion, because fluid restriction would increase with INS. We believe that the increase in the osmolal gap their risk of pre–renal failure. Additional studies are in patients with INS is caused by the presence of uniden- needed to elucidate in detail the role of additional phys- tified non-Na and non-K osmoles that try to maintain iologic parameters in the generation of dysnatremias in the intravascular volume in patients with volume con- such patients. traction, as indicated in most of our patients by increased hematocrit levels and urine osmolality at the time of REFERENCES admission (Table 1). An increase in the osmolal gap 1. Trachtman H. Sodium and water. In: Avner ED, Harmon WH, ranging from 30 to 100 mOsm/kg water has been re- Niaudet P, eds. Pediatric Nephrology. 5th ed. Philadelphia, PA: ported in clinical and experimental models of shock,3–5 Lippincott Williams & Wilkins; 2004:125–146 although a detailed identification of these endogenous 2. Rose BD, Post TW. Hypoosmolal states. In: Rose BD, Post TW, osmoles is lacking.16 The increase in osmolal gaps in our eds. 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  • 5. postoperative patients in intensive care. Lancet. 1987;1(8546): renal water excretion in nephrotic syndrome: the relationship 1331–1335 between renal water excretion and kidney function, arginine 5. Boyd DR, Folk FA, Condon RE, Nyhus LM, Baker RJ. Predic- vasopressin, angiotensin II and aldosterone in plasma before tive value of serum osmolality in shock following major and after oral water loading. Eur J Clin Invest. 1985;15:24 –29 trauma. Surg Forum. 1970;21:32–33 15. Wang SJ, Tsau YK, Lu FL, Chen CH. Hypovolemia and hypo- 6. Erstad BL. Osmolality and osmolarity: narrowing the terminol- volemic shock in children with nephrotic syndrome. Acta Pae- ogy gap. Pharmacotherapy. 2003;23:1085–1086 diatr Taiwan. 2000;41:179 –183 7. McQuillen KK, Anderson AC. Osmol gaps in the pediatric 16. Dorwart WV, Chalmers L. Comparison of methods for calcu- population. Acad Emerg Med. 1999;6:27–30 lating serum osmolality from chemical concentrations, and 8. Albrink MJ, Hald PM, Man EB, Peters JP. The displacement of prognostic value of such calculations. Clin Chem. 1975;21: serum water by the lipids of hyperlipemic serum: a new 190 –194 method for the rapid determination of serum water. J Clin 17. Niaudet P. Steroid sensitive idiopathic nephrotic syndrome. In: Invest. 1955;34:1483–1488 Avner ED, Harmon WH, Niaudet P, eds. Pediatric Nephrology. 9. Croal BL, Blake AM, Johnston J, Glen AC, O’Reilly DS. Ab- 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004: sence of relation between hyponatremia and hypothyroidism. 543–556 Lancet. 1997;350:1402 18. Nguyen MK, Kurtz I. New insights into pathophysiology of the 10. Sachs J, Fredman B. The hyponatremia of multiple myeloma is dysnatremias: a quantitative analysis. Am J Physiol Renal true and not pseudohyponatremia. Med Hypotheses. 2006;67: Physiol. 2004;287:F172–F180 839 – 840 19. Nguyen MK, Kurtz I. Quantitative interrelationships between 11. Nguyen MK, Rastogi A, Kurtz I. True hyponatremia secondary Gibbs-Donnan equilibrium, osmolality of body fluid compart- to intravenous immunoglobulin. Clin Exp Nephrol. 2006;10: ments, and plasma water sodium concentration. J Appl Physiol. 124 –126 2006;100:1293–1300 12. Abraham WT, Schrier RW. Renal sodium excretion. In: Schrier 20. Edelman IS, Leibman J, Omears MP, Birkenfeld LW. Interre- RW ed. Edematous Disorders and Diuretic Use in Renal and Elec- lationships between serum sodium concentration, serum os- trolyte Disorders. 5th ed. New York, NY: Lippincott-Raven; 1997: molality, and total exchangeable sodium, total exchangeable 72–129 potassium and total body water. J Clin Invest. 1958;37: 13. Dorhout EJ, Roos JC, Boer P, Yoe OH, Simatupang TA. Obser- 1236 –1256 vations on edema formation in the nephrotic syndrome in 21. Nathan D, Oski FA. In: Nathan D, Oski FA, eds. Hematology of adults with minimal lesions. Am J Med. 1979;67:378 –384 Infancy and Childhood. 4th ed. Philadelphia, PA: WB Saunders; 14. Pedersen EB, Danielsen H, Madsen M, Jensen T. Defective 1993:1908 PEDIATRICS Volume 119, Number 6, June 2007 e1407 Downloaded from www.pediatrics.org by on October 20, 2010
  • 6. Serum Osmolal Gap in Patients With Idiopathic Nephrotic Syndrome and Severe Edema Gaurav Kapur, Rudolph P. Valentini, Abubakr A. Imam, Amrish Jain and Tej K. Mattoo Pediatrics 2007;119;e1404-e1407; originally published online May 7, 2007; DOI: 10.1542/peds.2006-2554 Updated Information including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/119/6/e1404 References This article cites 16 articles, 3 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/119/6/e1404#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genitourinary Tract http://www.pediatrics.org/cgi/collection/genitourinary_tract Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org by on October 20, 2010