ESPE2021 Free Communications Diabetes (6 abstracts)
Aldosterone and pro-atrial natriuretic peptide kinetics in response to rehydration in children with diabetic ketoacidosis
Marie-Anne Burckhardt 1,2 , Marije Otto 3 , Verena Gotta 3 , Svetlana Beglinger 4 , Sara Bachmann 1 , Melanie Hess 1 , Katharina Rentsch 5 , Gilbert Koch 3 , Elizabeth Davis 2 , Urs Zumsteg 1 , Tim Jones 2 , Marc Pfister 3 & Gabor Szinnai 1
1Pediatric Endocrinology and Diabetology, University Children’s Hospital Basel UKBB, and Department of Clinical Research, University of Basel, Basel, Switzerland.;2Children’s Diabetes Centre, Telethon Kids Institute, University of Western Australia of, Perth, Australia and Perth Children’s Hospital, Perth, Australia.;3Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel UKBB, University of Basel, Basel, Switzerland.;4Pediatric Emergency Department, University Children’s Hospital Basel UKBB, University of Basel, Basel, Switzerland.;5Department of Laboratory Medicine, University Hospital, Basel, and University of Basel, Basel, Switzerland
Background: Diabetic ketoacidosis (DKA), a frequent complication of type 1 diabetes (T1D), is characterized by hyperosmolar hypovolemia. The response of water-regulating hormones to DKA treatment in children is not well known. While arginine vasopressin (AVP) is thought to respond to changes in osmolality, aldosterone and atrial natriuretic peptide (ANP) are expected to respond to volume changes (dehydration and overhydration, respectively). The objective of this analysis was to describe the change of aldosterone and pro-ANP during rehydration therapy in children with DKA.
Methods: An observational multi-centre study was conducted in 2015-2019, including paediatric T1D patients treated for DKA according to ISPAD guidelines. Aldosterone and pro-ANP concentrations were measured at 0-4-8-12-24-72h after start of hydration therapy. Data were log-transformed to calculate the mean (95%CI) and coefficient of variation [CV] for each time point. Assumed dehydration and correction was calculated based on protocol fluid infusion rates, weight and DKA severity [mild (pH<7.2-7.3): 5%, moderate (pH 7.1-7.2): 6%, severe (pH<7.1): 8.5%]. A semi-mechanistic modelling approach was further applied to describe aldosterone kinetics as a function of a volume-dependent secretion rate (non-linear mixed effects regression).
Results: 95 pro-ANP and 92 aldosterone samples were obtained from 20 (male: 14) children (median age: 12 years [IQR: 9.8-14]) with mild (n = 1), moderate (n = 9) or severe (n = 10) DKA. Pro-ANP levels were normal and did not change significantly during the study. Mean aldosterone concentration at start of rehydration was increased (4672 pmol/l, 95%CI: 2561-8524, CV: 106%), remained elevated up to 8h (5135 pmol/l, 95%CI: 3595-7335, CV: 94%) and reached 748 pmol/l (95%CI: 514-1088, CV: 67%) at 72h. Mean time to correction of dehydration was calculated to 14.1h (mild), 16.5h (moderate) and 22.7h (severe DKA). Under the assumption of fast aldosterone degradation (expected turnover half-life <1h), semi-mechanistic modelling showed a delayed aldosterone response to rehydration (turn-over half-life in the order of 10-20h).
Conclusion: Stable pro-ANP levels suggest that the treatment protocol did not result in volume overload. While copeptin levels described previously declined immediately after start of treatment, the decrease in aldosterone levels was delayed. Compared to reported paediatric reference intervals, aldosterone levels were still elevated at 72h, whilst dehydration had already been restored. One possible explanation for this delayed adaptation of aldosterone levels could be chronic upregulation of aldosterone synthase (CYP11B2) expression caused by prolonged exposure to angiotensin II and potassium in response to longstanding polyuria during DKA development.
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