Comments for:

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Hyponatremia in patients on thiazides - SIADH vs. true TIH

Submitter: Anil Pareek | anil.pareek@ipca.com

Authors: Anil Pareek, Ravi T. Mehta, Indranil Purkait, and Anu Grover

Ipca Laboratories Ltd.

Published September 27, 2017

We read the research article with interest and complement the authors for shedding light on the pharmacogenetic aspects of thiazide-induced hyponatraemia (TIH)¹. At the same time, we would like to pose certain queries to the authors so as to enable clinicians gain more insights from this research.

In practise, hyponatremia in patients on thiazides (either alone or with renin-angiotensin-aldosterone system inhibitors), usually occurs in the presence of precipitating events like CNS disorders, infections, etc. which may cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). In such clinical situations, it is important to identify the induced SIADH before classifying it as TIH. Are there any phenotypic characteristics which can help clinicians distinguish hyponatremia due to the SIADH vs. TIH? Can the measurement of urine and plasma osmolality help differentiate the hyponatremia due to these two different etiologies?

The authors mention that hyponatremic patients who had relevant comorbidities were excluded. It will be worthwhile to know how many such patients with a relevant co-morbidity or precipitating event were excluded to get the strictly TIH patients and what were these common events. Further, amongst the patients with TIH included in the study, did the authors observe a dose-effect relationship between dose of thiazide used and the severity of hyponatremia? In a recent systematic review and meta-analysis of TIH, the average duration from thiazide initiation to diagnosis of TIH was 19 days (95% CI 8, 30 days); suggesting that the practice to measure serum biochemistry 1–2 weeks after thiazide initiation may not be appropriate². What was the duration from thiazide initiation to diagnosis of TIH in the current study and whether this duration was different in the half of the TIH cases carrying the SLCO2A1 p.A396T variant?

Finally, the authors have demonstrated a phenotype resembling SIADH in these patients with TIH, but with low or normal ADH levels. If in these same patients, the ADH levels are high; can thiazides be ruled out as the cause of hyponatremia?

References:

1. Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Invest. 2017 Sep 1;127(9):3367-74.

2. Barber J, McKeever TM, McDowell SE, et al. A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol. 2015 Apr;79(4):566-77.

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Response to Pareek and colleagues

Submitter: Mark Glover | Mark.Glover@nottingham.ac.uk

Queen's Medical Centre

Published September 27, 2017

Thank you for your E-letter and your interest in our study. We agree that it is important to consider other causes of hyponatremia in addition to thiazide diuretics and investigate appropriately in all patients who present to hospital with severe hyponatremia, both in research and clinical practise.

We also agree that SIADH remains an important differential diagnosis when considering the cause of hyponatremia in patients who take thiazide diuretics. Although in clinical practise it can be challenging to establish a single cause of hyponatremia, and in some cases hyponatremia may be multi-factorial, for the purposes of our study only patients with a clinical diagnosis of Thiazide-Induced Hyponatremia (TIH) were included. If there was any possibility of another cause for hyponatremia evident to either the clinical care team or researchers then the patient was not invited to participate. The exclusion criteria we used are detailed on supplementary page 3¹. For patients in cohort 2 we were also able to observe that serum sodium recovered to normal following cessation of the thiazide or thiazide-like diuretic.

Our study was not designed to investigate differences between TIH and SIADH in either phenotype or laboratory investigations of blood or urine. The measurement of plasma ADH was undertaken as a research test as part of this study, and is not often measured in routine clinical care in our hospital, and hence we cannot easily answer the question about distinguishing SIADH from TIH by phenotypic differences, although this would make an interesting subject for a future study.

The aetiology of hyponatremia amongst all patients presenting to our hospital has been studied previously ² and in the current study our experience was similar in that many patients had other, multiple or unclear causes of hyponatremia: as discussed above these subjects were excluded from the study.  As the majority of subjects were given the same dose of thiazide, it is unclear if there is a dose response relationship between thiazide dose and risk of TIH. Unfortunately, we do not have precise data on the time from first thiazide dose to hospitalization with severe TIH and so cannot address whether the time course of TIH may differ in those who carry the SLCO2A1 p.A396T variant. A prospective study involving thiazide exposure would be better placed to address these issues.

References:

1. Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Invest. 2017 Sep 1;127(9):3367-74.

2. Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome. QJM. 2006 Aug;99(8):505-11.