Correspondence

Nephrogenic Syndrome of Inappropriate Antidiuresis

N Engl J Med 2005; 353:529-530August 4, 2005

Article

To the Editor:

The elegant work presented by Feldman et al. (May 5 issue)1 shows that point mutations in codon 137 of the V2 vasopressin receptor (V2R) can result in either a loss-of-function mutation (R137H, which is associated with congenital nephrogenic diabetes insipidus) or a gain-of-function mutation (R137C or R137L, which is associated with the congenital nephrogenic syndrome of inappropriate antidiuresis). In the Discussion section of the article, the authors mention the possibility of an activating mutation in aquaporin-2. Because the clinical data were also consistent with this differential diagnosis, how was this possibility ruled out so as to arrive at the initial hypothesis that these infants had hyperactive V2Rs?

The authors also state that arginine vasopressin (AVP) antagonists “would probably be ineffective, given the ligand-independent nature of the lesion.” However, subtle conformational changes can take place when a ligand binds to a receptor. Therefore, is it not plausible that some of these conformations could effectively down-regulate activity?

Finally, the acronym “NSIAD” (nephrogenic syndrome of inappropriate antidiuresis) might easily be mistaken for the much more familiar “NSAID” (nonsteroidal antiinflammatory drug). Perhaps renaming the syndrome “congenital pseudo-SIADH” (where SIADH denotes the syndrome of inappropriate antidiuretic hormone secretion) could be considered.

Alan Segal, M.D.
University of Vermont College of Medicine, Burlington, VT 05401
alan.segal@uvm.edu

1 References

1
Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005;352:1884-1890
Full Text | Web of Science | Medline

To the Editor:

Feldman et al. state that since the AVP assay is not optimized to identify low values, sequencing the V2R gene (AVPR2) before NSIAD is diagnosed is recommended. They also suggest that there may be additional defects in the V2R signaling cascade in patients who have an NSIAD phenotype but not a V2R mutation. However, the plasma AVP level is low in many acquired diseases in the absence of a V2R gene mutation or defects in the signaling cascade. Thus, such conclusions seem unwarranted.

AVP secretion is almost totally suppressed when the plasma osmolality falls below 275 to 280 mOsm per kilogram, so the plasma osmolality should be measured simultaneously with the plasma AVP level.1 Moreover, the plasma AVP level is low and the plasma osmolality is normal in patients with the type D secretion pattern of SIADH.2 Increased sensitivity to AVP or other antidiuretic substances, such as chlorpropamide or the antidiuretic substance produced in prolactinoma, may be present in such patients.3,4 The authors might recommend sequencing the V2R gene after ruling out these clinical conditions.

Chao-Fu Chang, M.D.
Taipei Veterans General Hospital, Taipei 112, Taiwan

Wu-Chang Yang, M.D.
National Yang-Ming University, Taipei 112, Taiwan

Chih-Ching Lin, M.D.
Taipei Veterans General Hospital, Taipei 112, Taiwan
lincc2@vghtpe.gov.tw

4 References

1
Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med 1982;72:339-353
CrossRef | Web of Science | Medline

2
Hypoosmolal states — hyponatremia. In: Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. 5th ed. New York: McGraw-Hill, 2001:696-745.

3
Moses AM, Fenner R, Schroeder ET, Coulson R. Further studies on the mechanism by which chlorpropamide alters the action of vasopressin. Endocrinology 1982;111:2025-2030
CrossRef | Web of Science | Medline

4
Kern PA, Robbins RJ, Bichet D, Berl T, Verbalis JG. Syndrome of inappropriate antidiuresis in the absence of arginine vasopressin. J Clin Endocrinol Metab 1986;62:148-152
CrossRef | Web of Science | Medline

Author/Editor Response

In response to Dr. Segal: evaluation of the first patient with NSIAD (Patient 2 in our article) included concurrent sequencing of the genes encoding V2R (AVPR2) and aquaporin-2. This patient was found to have a gain-of-function mutation in V2R (R137L) and no mutation in aquaporin-2. Subsequent AVPR2 sequence analysis in the second patient (Patient 1) also demonstrated a missense mutation in V2R (R137C). The gene encoding aquaporin-2 has not yet been sequenced in this patient. Regarding AVP antagonists, Dr. Segal notes that “subtle conformational changes can take place when a ligand binds to a receptor” and might “effectively down-regulate activity.” As discussed in a review by Seifert and Wenzel-Seifert,1 a ligand that stabilizes a constitutively active receptor in an inactive state would be considered an “inverse agonist” rather than an antagonist. It has been reported, however, that a nonpeptide V2R antagonist also has inverse-agonist properties,2 which may lead to the down-regulation of V2R activity in the naturally occurring constitutively active mutants. Finally, with respect to the naming of this syndrome, we had considered the term “pseudo-SIADH” but agreed with the editors and reviewers of the article, who encouraged the use of the term that was ultimately chosen for the reasons we outlined therein. To avoid confusion with “NSAID,” one might want to refer to this condition as “nephrogenic SIAD.”

As emphasized in our article and as suggested by Dr. Chang and colleagues, proper evaluation of patients with hyponatremia requires careful consideration of a broad differential diagnosis. The algorithm for laboratory testing during such an evaluation needs to be tailored to the specific patient and to the frequencies of the possible causes of hyponatremia. The causes discussed by Chang et al. are rarely encountered in children. Currently, it is not clear how frequently NSIAD occurs in the general population, and therefore physicians must rely on their index of suspicion for this newly identified disease. Although many conditions may be associated with hyponatremia and low plasma levels of AVP, such a presentation in a male infant with a persistent state of inappropriate antidiuresis strongly suggests the presence of NSIAD. As more epidemiologic information is acquired, the importance of sequencing the V2R gene will become increasingly apparent.

Stephen E. Gitelman, M.D.
Brian J. Feldman, M.D., Ph.D.
Stephen M. Rosenthal, M.D.
University of California at San Francisco, San Francisco, CA 94143
sgitelma@peds.ucsf.edu

2 References

1
Seifert R, Wenzel-Seifert K. Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol 2002;366:381-416
CrossRef | Web of Science | Medline

2
Morin D, Cotte N, Balestre MN, et al. The D136A mutation of the V2 vasopressin receptor induces a constitutive activity which permits discrimination between antagonists with partial agonist and inverse agonist activities. FEBS Lett 1998;441:470-475
CrossRef | Web of Science | Medline

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