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Disorders of Plasma Sodium

Article in New England Journal of Medicine March 2015
Impact Factor: 55.87 DOI: 10.1056/NEJMc1501342#SA3 Source: PubMed

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2 authors:
Michael L Moritz

Juan Carlos Ayus

University of Pittsburgh

renal consultas of houston

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correspondence

through a central-nervous-system mechanism in

animal models. On the basis of this new information, weight loss in patients with congenital
leptin deficiency who are receiving leptin treatment may result not only from an improvement
in hyperphagia2 but also from increased energy
expenditure owing to leptin-induced browning
of white adipose tissue.
We have now been able to analyze stromal
vascular cells isolated from subcutaneous white
adipose tissue obtained from three patients with
congenital leptin deficiency caused by a c.389delG
mutation3 in the leptin gene. Subjecting all three
samples to adipogenic differentiation ex vivo in
the presence of leptin led to an increase in messenger RNA (mRNA) expression of the gene encoding uncoupling protein 1 (UCP1) (Fig. 1A).
This protein is produced mainly in brown adipose tissue and is involved in the generation of
heat by nonshivering thermogenesis, thereby
regulating energy expenditure. Preliminary data
also hinted at an increase in mRNA expression
of UCP1 after leptin treatment in SimpsonGolabiBehmel syndrome adipocytes (Fig. 1B).4,5
Our data suggest that leptin-induced browning

of white adipose tissue might be mediated not

only by the central nervous system but also by a
direct peripheral effect of leptin on adipocytes.
Pamela Fischer-Posovszky, Ph.D.
Jan-Bernd Funcke, M.Sc.
Martin Wabitsch, M.D., Ph.D.
University of Ulm
Ulm, Germany
pamela.fischer@uniklinik-ulm.de
Since publication of their article, the authors report no further potential conflict of interest.
1. Dodd GT, Decherf S, Loh K, et al. Leptin and insulin act on

POMC neurons to promote the browning of white fat. Cell 2015;

160:88-104.
2. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.
N Engl J Med 1999;341:879-84.
3. Funcke J-B, von Schnurbein J, Lennerz B, et al. Monogenic
forms of childhood obesity due to mutations in the leptin gene.
Mol Cell Pediatr 2014;1:3.
4. Wabitsch M, Brenner RE, Melzner I, et al. Characterization
of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord 2001;25:
8-15.
5. Fischer-Posovszky P, Newell FS, Wabitsch M, Tornqvist HE.
Human SGBS cells a unique tool for studies of human fat cell
biology. Obes Facts 2008;1:184-9.
DOI: 10.1056/NEJMc1501146

Disorders of Plasma Sodium

To the Editor: The review by Sterns (Jan. 1
issue)1 on disorders of plasma sodium concentration, which are among the most frequently
encountered (and mismanaged) problems in
medicine, was enhanced by the use of illustrative
cases (which appear in the Supplementary Appendix, available with the full text of the article
at NEJM.org). After the second patient had a subarachnoid hemorrhage, plasma hyponatremia
associated with excessive urinary sodium loss
developed. Did this patient really have the syndrome of inappropriate antidiuretic hormone secretion (SIADH), or did he have cerebral salt
wasting, which is also seen in the clinical situation described? Information on the water balance
(hypovolemic, euvolemic, or hypervolemic) would
be helpful here, because cerebral salt wasting is
associated with hypovolemia. The differential diagnosis of SIADH versus cerebral salt wasting is
clinically relevant because the treatments are diametrically opposed.2

Axel Petzold M.D., Ph.D.

UCL Institute of Neurology
London, United Kingdom
a.petzold@ion.ucl.ac.uk
No potential conflict of interest relevant to this letter was reported.
1. Sterns RH. Disorders of plasma sodium causes, conse-

quences, and correction. N Engl J Med 2015;372:55-65.

2. Tisdall M, Crocker M, Watkiss J, Smith M. Disturbances of
sodium in critically ill adult neurologic patients: a clinical review. J Neurosurg Anesthesiol 2006;18:57-63.
DOI: 10.1056/NEJMc1501342

To the Editor: The third case reviewed by Sterns

is one in which a 30-year-old woman with symptomatic, desmopressin-associated hyponatremia
has sodium overcorrection and neurologic injury
after the discontinuation of desmopressin and is
given a 3% saline infusion. There is no mention
of how to treat this condition properly.
My colleagues and I recently published a series
of 15 cases of desmopressin-associated hypo-

n engl j med 372;13nejm.orgmarch 26, 2015

The New England Journal of Medicine

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The

n e w e ng l a n d j o u r na l

natremia.1 In 13 patients, neurologic injury and

death resulted because of overcorrection of serum sodium concentrations consequent to the
discontinuation of desmopressin and concurrent
use of hypertonic saline. In 2 patients, desmopressin was continued and hypertonic saline was
administered, and both survived, with no neurologic sequelae.
Desmopressin-associated hyponatremia has
the potential to become a common disorder as
the use of desmopressin expands to include the
treatment of enuresis in children and elderly
patients.2 When treating this condition, it is important to recognize the development of severe,
symptomatic hyponatremia in response to desmopressin and to continue to administer the drug
along with hypertonic saline.
Steven G. Achinger, M.D.
Watson Clinic
Lakeland, FL
steven.achinger@gmail.com
No potential conflict of interest relevant to this letter was reported.
1. Achinger SG, Arieff AI, Kalantar-Zadeh K, Ayus JC. Desmo-

pressin acetate (DDAVP)-associated hyponatremia and brain

damage: a case series. Nephrol Dial Transplant 2014;29:2310-5.
2. Vande Walle J, Stockner M, Raes A, Nrgaard JP. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007;
2:232-8.

m e dic i n e

treatment of hyponatremic encephalopathy in

the emergency department. This treatment was
safe and effective and without systemic or neurologic complications.5 As much as 500 ml of 3%
saline can be given safely in non-ICU settings.
Michael L. Moritz, M.D.
Childrens Hospital of Pittsburgh of UPMC
Pittsburgh, PA
michael.moritz@chp.edu

Juan C. Ayus, M.D.

Renal Consultants of Houston
Houston, TX
No potential conflict of interest relevant to this letter was reported.
1. Kerns E, Patel S, Cohen DM. Hourly oral sodium chloride

for the rapid and predictable treatment of hyponatremia. Clin

Nephrol 2014;82:397-401.
2. Ayus JC, Arieff A, Moritz ML. Hyponatremia in marathon
runners. N Engl J Med 2005;353:427-8.
3. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus
Development Conference, New Zealand, 2007. Clin J Sport Med
2008;18:111-21.
4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice
guideline on diagnosis and treatment of hyponatraemia.
Nephrol Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol
Dial Transplant 2014;40:924.]
5. Ayus JC, Caputo D, Bazerque F, Heguilen R, Gonzalez CD,
Moritz ML. Treatment of hyponatremic encephalopathy with a
3% sodium chloride protocol: a case series. Am J Kidney Dis
2014 November 25 (Epub ahead of print).
DOI: 10.1056/NEJMc1501342

DOI: 10.1056/NEJMc1501342

To the Editor: Sterns endorses the use of 100-ml

bolus infusions of 3% saline for the treatment of
symptomatic hyponatremia. However, the appropriate route and setting for administration are
not mentioned. A potential barrier to the use of
3% saline is the perception that it must be administered through a central catheter in an intensive
care unit (ICU).1 We recommended peripheral intravenous administration of 100-ml infusions of
3% saline for the management of exercise-associated hyponatremia in medical tents.2 This approach is now the standard treatment for this
condition3 and is recommended in the European
Clinical Practice Guideline for the treatment of
symptomatic hyponatremia of any cause.4 No information exists on how much 3% saline can be
safely administered through a peripheral intravenous catheter. We recently reported the administration of 500 ml of 3% saline through a peripheral intravenous catheter over 6 hours for the

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of

To the Editor: We were surprised that Sterns

did not refer to the recently published European
hyponatremia guidelines1, which specifically do
not recommend the use of vasopressin antagonists for any indication. Furthermore, Sternss
statement that to reduce symptoms and improve
potential outcomes, chronic hyponatremia should
be corrected gradually with the use of . . . vasopressin antagonists is potentially dangerous and
misleading. The focus should always be to treat
the cause first. Vasopressin antagonists have never
been shown to improve symptoms or outcomes,
and the recommendation of their use is not consistent with labeling from the Food and Drug
Administration or, to our knowledge, with the
primary end point of any published paper. The
authors opinion on the use of vasopressin antagonists is not shared by the European Society of Intensive Care Medicine, the European Society of
Endocrinology, or the European Renal Association
European Dialysis and Transplant Association.

n engl j med 372;13nejm.orgmarch 26, 2015

The New England Journal of Medicine

Downloaded from nejm.org by MICHAEL MORITZ on April 14, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.

correspondence

Harry Peled, M.D.

St. Jude Medical Center
Fullerton, CA
harry.peled@stjoe.org

Paul E. Marik, M.D.

Eastern Virginia Medical School
Norfolk, VA
No potential conflict of interest relevant to this letter was reported.
1. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice

guideline on diagnosis and treatment of hyponatraemia. Eur J

Endocrinol 2014;170:G1-G47 [Erratum, Eur J Endocrinol 2014;
171:X1.].
DOI: 10.1056/NEJMc1501342

The Author Replies: In response to Petzold:

hyponatremia developed in the second patient
despite the administration of large volumes of
isotonic fluid; his weight increased and his hematocrit fell, suggesting plasma volume expansion. Some may choose to describe his condition
as cerebral salt wasting, whereas others may prefer to call it SIADH with a physiologic natriuresis
caused by iatrogenic hypervolemia. Treatment
with 3% saline will increase the plasma sodium
concentration, regardless of volume status or the
terminology used.1
Achinger observes that a combined infusion
of desmopressin and 3% saline avoids overcorrection of desmopressin-induced hyponatremia.
This strategy is described in the fourth illustrative case in the Supplementary Appendix (available with the full text of the article) and in the
text of the article and should be considered for
patients with severe hyponatremia and a reversible cause of water retention, whether caused by
desmopressin, hypovolemia, adrenal insufficiency, a thiazide diuretic, or drug-induced SIADH.2
Moritz and Ayus correctly observe that 3%
saline can be administered through a peripheral
vein. Unlike hypertonic glucose, 3% saline has
not been reported to cause venous sclerosis or
tissue damage from extravasation when admin-

istered peripherally.2 A standard pharmacy reference recently stopped mandating infusion in a

central vein.3
In response to Peled and Marik: I would point
out that I did refer to the European guidelines in
my article and that the source I referenced4
(number 74 in the article) has the same content
as the article they reference. I also stated that
vasopressin antagonists are one of many therapeutic options (along with fluid restriction, salt,
furosemide, and urea) that can be used to increase the plasma sodium concentration in patients with chronic hyponatremia who have mild
or subtle symptoms. According to expert opinion that has been disputed by others,5 the European guidelines support the use of urea (unavailable in the United States) and discourage the use
of vasopressin antagonists for any purpose.4,5
Experts on both sides of the Atlantic agree that
vasopressin antagonists should not be used as
initial therapy if hyponatremia is causing severe
symptoms or if the plasma sodium concentration is less than 120 mmol per liter (see Table 1
of the article).
Richard H. Sterns, M.D.
University of Rochester School of Medicine and Dentistry
Rochester, NY
richard.sterns@rochestergeneral.org
Since publication of his article, the author reports no further
potential conflict of interest.
1. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH:

what difference? J Am Soc Nephrol 2008;19:194-6.

2. Sood L, Sterns RH, Hix JK, Silver SM, Chen L. Hypertonic

saline and desmopressin: a simple strategy for safe correction of

severe hyponatremia. Am J Kidney Dis 2013;61:571-8.
3. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda,
MD: American Society of Health-System Pharmacists, 2011.
4. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice
guideline on diagnosis and treatment of hyponatraemia. Nephrol
Dial Transplant 2014;29:Suppl 2:i1-i39. [Erratum, Nephrol Dial
Transplant 2014;40:924.]
5. Verbalis JG, Grossman A, Hybye C, Runkle I. Review and
analysis of differing regulatory indications and expert panel
guidelines for the treatment of hyponatremia. Curr Med Res
Opin 2014;30:1201-7.
DOI: 10.1056/NEJMc1501342

Atypical Hyperplasia of the Breast

To the Editor: In their article on the role of
atypical hyperplasia in the assessment of breastcancer risk, Hartmann et al. (Jan. 1 issue)1 state
that the International Breast Cancer Intervention

Study (IBIS) model does not provide accurate risk

estimates for women with atypical hyperplasia.
After the results of the study by Boughey et al.2
were reported in 2010, we noted that our model

n engl j med 372;13nejm.orgmarch 26, 2015

The New England Journal of Medicine

Downloaded from nejm.org by MICHAEL MORITZ on April 14, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.

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