Published online May 7, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1404-e1407 (doi:10.1542/10.1542/peds.2006-2554)

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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 and Tej K. Mattoo, MD, FRCP

Division of Nephrology and Hypertension, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan

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.

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Key Words: nephrotic syndrome • osmolal gap • hyponatremia • pre–renal failure

Abbreviations: INS, idiopathic nephrotic syndrome • CHF, congestive heart failure • SUN, serum urea nitrogen

Hyponatremia is a common observation in patients with idiopathic nephrotic syndrome (INS) with severe edema. In view of coexisting hyperlipidemia in such patients, hyponatremia has traditionally been labeled as pseudohyponatremia rather than true hyponatremia. Pseudohyponatremia is the method-dependent artifactual reduction of serum sodium attributed to measurement error caused by hyperlipidemia, which results in displacement of a portion of plasma water by increased lipid concentration. Currently, direct potentiometry is the method of choice for measuring blood electrolytes. With this method, undiluted serum samples are used to measure transmembrane potentials resulting from electrolyte gradients by using an ion-selective electrode. Thus, the water content of the sample does not affect measurement of serum sodium, and pseudohyponatremia is rarely seen.¹ True hyponatremia in patients with INS is included in the category of diseases with extracellular fluid volume expansion, as in congestive heart failure (CHF), and cirrhosis. In CHF and cirrhosis there is plasma-volume expansion but effective circulatory volume depletion secondary to primary reduction in cardiac output or vascular resistance. However in INS, hypoalbuminemia leads to plasma-volume contraction. Edema is secondary to compensatory retention of sodium and water by the kidney because of effective circulatory volume depletion in CHF/cirrhosis and plasma-volume contraction in INS.² Studies have reported increased serum osmolality and osmolal gap (defined as the difference between the measured and the calculated 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 with INS who presented with hyponatremia and severe edema.

METHODS

Known patients with INS who were admitted to inpatient service (from November 2004 to January 2006) with generalized edema were considered for the study. Investigations performed included obtaining serum urea nitrogen (SUN), serum creatinine, electrolyte, and albumin levels, serum osmolality, hemoglobin and hematocrit levels, urinalysis, and urine protein/creatinine ratio. All investigations were performed at the time of admission before starting treatment with dietary salt restriction (<2 mEq/kg per day) and intravenous albumin and diuretics. Patients with fever, vomiting, or diarrhea or those who were already on diuretics, steroids, or immunosuppression for treatment of INS were excluded from the study. Serum sodium was measured in undiluted samples by using the principle of direct potentiometry by ion-selective electrodes (Vitrios 250 Chemistry System; Ortho-Clinical Diagnostics, Rochester, NY). Serum sodium was also measured in undiluted capillary blood samples by using a blood-gas analyzer by the same principle of direct potentiometry (ABL800 FLEX; Radiometer, Westlake, OH). Serum osmolality was measured by freezing-point depression in milliosmole-per-kilogram water. Additional tests that were performed to exclude secondary causes of nephrotic syndrome included hepatitis B and hepatitis C serology, serum complements C3 and C4, antinuclear antibody, and HIV antibody. Calculated serum osmolality was estimated by the following formula: 2 x Na_p + glucose/18 + SUN/2.8. An osmolal gap (difference between measured and calculated osmolality) of 0 to 10 mOsm/kg water was accepted as being within normal limits.^2,6,7

RESULTS

Twenty patients with INS with severe hypoproteinemia and generalized edema were admitted to our service over a period of 15 months. Of these patients, 7 (35%) were found to have low serum sodium levels as measured by direct potentiometry during routine laboratory tests. One of these patients, who had increased SUN and serum creatinine levels, was excluded from the study. The remaining 6 patients were included in the study. 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).

View this table: [in this window] [in a new window]   TABLE 1 Laboratory Results of the Patients at Time of Admission

 
As shown in Table 1, the measured serum osmolality was low in patients 1, 3, and 5 (reference range: 285–295 mOsm/kg water), borderline in patient 2, and within the reference range in patients 4 and 6. The calculated serum osmolality was low in all patients, and the osmolal gap was high in all patients.

DISCUSSION

Pseudohyponatremia was originally described⁸ when flame photometry was used for serum-electrolyte determination. Using this technique, serum samples were diluted before the actual measurement of serum electrolytes, which resulted in an artificially low serum sodium level in conditions such as hyperlipidemia, wherein the aqueous phase of plasma is reduced. However, biochemical analyzers, such as direct potentiometry, that are currently in use assay sodium concentration in the aqueous phase only and result in accurate determination of serum sodium levels.⁹ Given this fact, it has been suggested that the term "pseudohyponatremia" no longer be used.¹ This argument is supported by recent reports on the presence of true hyponatremia in patients with multiple myeloma¹⁰ and in those who had received intravenous immunoglobulin infusions,¹¹ conditions that previously were associated with pseudohyponatremia.

The exact incidence of hyponatremia in patients with INS and severe edema is not known. It is reported that serum sodium concentration is usually within the reference range in patients with INS unless it is influenced by vigorous diuretic measures or during acute water load.^12–14 Of the 20 such patients admitted to our service, 7 (35%) had low serum sodium concentrations as measured by direct potentiometry and confirmed by blood-gas analysis.

Wang et al¹⁵ reported significantly decreased serum sodium concentrations in 5.8% of their patients with INS who presented with hypovolemic shock and in 12.5% of their patients with INS who presented with symptomatic hypovolemic episodes without hypotension. Our patients were not on diuretics, and they were clinically stable with no clinical evidence of cardiovascular decompensation.

Despite true hyponatremia in all 6 of our patients, the measured serum osmolality was low in only 3 patients (patients 1, 3, and 5); the remaining 3 patients had serum osmolality that was either borderline (patient 2) or within the reference range (patients 4 and 6). The calculated osmolality was low in all patients, and all had an increased osmolal gap. Under normal circumstances, in otherwise healthy individuals, low serum sodium concentration (true hyponatremia) is associated with low measured and calculated serum osmolality and a normal osmolal gap. The presence of an increased osmolal gap in all of our patients and normal measured serum osmolality in 2 of our patients (patients 4 and 6) is intriguing.

The most common settings in which low serum sodium concentration is not associated with a decrease in serum osmolality occurs when there are additional osmolytes in the extracellular fluid such as ethanol, methanol, or ethylene glycol.^2,12 The coexistence of hyponatremia with an increased osmolal gap, as noted in our patients, has implications in understanding the pathophysiology and management of severe edema in patients with INS. We believe that the increase in the osmolal gap in patients with INS is caused by the presence of unidentified non-Na⁺ and non-K⁺ osmoles that try to maintain the intravascular volume in patients with volume contraction, as indicated in most of our patients by increased hematocrit levels and urine osmolality at the time of admission (Table 1). An increase in the osmolal gap ranging from 30 to 100 mOsm/kg water has been reported in clinical and experimental models of shock,^3–5 although a detailed identification of these endogenous osmoles is lacking.¹⁶ The increase in osmolal gaps in our patients (range: 10–20 mosm/kg water) is lower than that reported in patients with shock. However, hypovolemic shock is a known complication of INS,¹⁷ and the increased osmolal gap in our patients could be indicative of intravascular volume depletion with a preshock state. Thus, patients with INS who are admitted with severe edema and hyponatremia would initially need slow volume expansion. Initial fluid restriction and diuresis in such patients could further exacerbate their volume contraction and increase the risk of pre–renal failure or ischemic acute tubular necrosis.

Our observations assume relevance when viewed in the context of recent work by Nguyen and Kurtz,^18,19 who have highlighted the role of physiologic parameters, besides Na_e + K_e/TBW (Na_e = total exchangeable sodium, K_e = total exchangeable potassium, and TBW = total body water),²⁰ that play a role in modulating serum sodium and in the generation of dysnatremias. These factors include osmotic coefficient of sodium salts, Gibbs-Donnan equilibrium, osmotic equilibrium, osmotically inactive Na_e and K_e, and osmotically active non-Na⁺ and non-K⁺ osmoles.^18,19 The effect of these additional parameters in the setting of hypoalbuminemia and severe edema in patients with INS needs to be studied in detail. However, on the basis of the Nguyen-Kurtz formula, it has been shown that Gibbs-Donnan equilibrium has an incremental effect on serum sodium, and the presence of osmotically active non-Na⁺ and non-K⁺ osmoles in the plasma has a depressive effect on serum sodium, which may explain the presence of a relatively low serum sodium concentration and measured osmolality with the higher osmolal gap in our patients. Hypoalbuminemia in patients with INS could cause a decrease in the Gibbs-Donnan effect in these patients, contributing to hyponatremia.¹⁹

CONCLUSIONS

Our results show that in children with INS and severe edema, the measurement of serum sodium by current methods indicates true hyponatremia, not pseudohyponatremia. Identification of true hyponatremia is important, because the additional presence of an increased serum osmolal gap in these patients is indicative of volume contraction. These patients need slow plasma-volume expansion, because fluid restriction would increase their risk of pre–renal failure. Additional studies are needed to elucidate in detail the role of additional physiologic parameters in the generation of dysnatremias in such patients.

FOOTNOTES

Accepted Nov 29, 2006.

Address correspondence to Tej K. Mattoo, MD, FRCP, Pediatric Nephrology, Division of Nephrology 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{at}med.wayne.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kapur, G. Articles by Mattoo, T. K. Search for Related Content PubMed PubMed Citation Articles by Kapur, G. Articles by Mattoo, T. K. Related Collections Genitourinary Tract Social Bookmarking                         What's this?