A Copeptin-Based Classification of the Osmoregulatory Defects in the Syndrome of Inappropriate Antidiuresis

Abstract

Hyponatremia, the most frequent electrolyte disorder, is caused predominantly by the syndrome of inappropriate antidiuresis (SIAD). A comprehensive characterization of SIAD subtypes, defined by type of osmotic dysregulation, is lacking, but may aid in predicting therapeutic success. Here, we analyzed serial measurements of serum osmolality and serum sodium, plasma arginine vasopressin (AVP), and plasma copeptin concentrations from 50 patients with hyponatremia who underwent hypertonic saline infusion. A close correlation between copeptin concentrations and serum osmolality existed in 68 healthy controls, with a mean osmotic threshold6SD of 28264 mOsM/kg H 2 O. Furthermore, saline-induced changes in copeptin concentrations correlated with changes in AVP concentrations in controls and patients. With use of copeptin concentration as a surrogate measure of AVP concentration, patients with SIAD could be grouped according to osmoregulatory defect: Ten percent of patients had grossly elevated copeptin concentrations independent of serum osmolality (type A); 14% had copeptin concentrations that increased linearly with rising serum osmolality but had abnormally low osmotic thresholds (type B); 44% had normal copeptin concentrations independent of osmolality (type C), and 12% had suppressed copeptin concentrations independent of osmolality (type D). A novel SIAD subtype discovered in 20% of patients was characterized by a linear decrease in copeptin concentrations with increasing serum osmolality (type E or "barostat reset"). In conclusion, a partial or complete loss of AVP osmoregulation occurs in patients with SIAD. Although the mechanisms underlying osmoregulatory defects in individual patients are presumably diverse, we hypothesize that treatment responses and patient outcomes will vary according to SIAD subtype.

Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: ‘The Co-MED Study'

“…who found copeptin levels alone to have only limited diagnostic utility for hypoosmolar hyponatraemia, especially for SIAD. Furthermore, recently published data described a wide range of copeptin levels in patients with SIAD most probably reflecting different patterns of copeptin secretion …”

Hyponatraemia in older patients: a clinical and practical approach

“…We believe that urea therapy should be attempted in patients that do not respond to tolvaptan, presumably due to type D SIADH, 85 although resistance to vaptans in the latter subtype has recently been called into question. 86 Since urea is not considered to be a medication, no randomized clinical trials have been undertaken to ascertain side-effects. However, we know that 37% of ICU patients with marked hyponatraemia have 'overcorrected' on urea therapy 84 and initial studies indicated that i.v.…”

Copeptin Is Associated with Kidney Length, Renal Function, and Prevalence of Simple Cysts in a Population-Based Study

“…Finally, the positive association of copeptin with urinary osmolality is similar to that reported for AVP. Although the physiologic regulation of copeptin release seems to be similar than that of AVP, 26 we cannot exclude that other regulatory factors are involved. In addition, it is unknown whether copeptin acts on the same receptors as AVP.…”

“…17 Copeptin is strongly correlated to AVP over a large range of plasma levels and has the same kinetics in response to changes in plasma osmolality or during hemorrhagic shock. 18,[22][23][24][25][26] Furthermore, copeptin has a longer t 1/2 than AVP, is stable at room temperature, and does not need extraction nor special sample handling procedures. For these reasons, copeptin is now considered as a robust surrogate for AVP, overcoming the technical problems related to AVP dosage.…”