The aetiology of hypophosphatemia in children recovering from Kwashiorkor

Thesis (MMed)--Stellenbosch University, 2015ENGLISH ABSTRACT : Abstract Background The aetiology of hypophosphatemia in children recovering from kwashiorkor is poorly understood. Current theory of the pathophysiology of hypophosphatemia due to refeeding syndrome in adults describes intracellular phosphate trapping, mediated by a metabolic shift from lipid-based catabolism to carbohydrate metabolism. Treatment of hypophosphatemia associated with severe acute malnutrition (SAM) presents a challenge to the control of serum phosphate levels. Hypothesis This study explores the hypothesis that hypophosphatemia is caused by impaired renal tubular phosphate reabsorption in children recovering from oedematous malnutrition. Study Design A prospective pilot study was based at the Tygerberg Children’s Hospital Gastroenterology Unit, a tertiary referral unit in Cape Town, South Africa. Written informed consent was obtained from the legal guardian and ethical approval was obtained from Stellenbosch University’s Human Research Ethics Committee. Ten children between the ages 6-59 months admitted to the Gastroenterology Unit and classified as having kwashiorkor or marasmic kwashiorkor were included. Children were excluded if they were known with pre-existing renal or endocrine disease involving phosphate, magnesium or calcium metabolism. Additionally patients transferred from referring hospitals who had already initiated a refeeding and treatment regimen, any patient with a haemoglobin of ≤6g/dl on admission or any child known to be HIV positive were also excluded from the study. Methods Biochemical and anthropometric variables were monitored during the course of treatment and refeeding. Management of the patients was standardised as per the Tygerberg Children’s Hospitals protocol for refeeding in severe acute malnutrition, which is in accordance with the WHO 10 step protocol. Treatment of hypophosphatemia included oral administration of 75-100 mg/kg/day of 0.8g Na2HPO4 + 0.2g KH2PO4 + 10 ml H2O providing a solution of 100 mg PO4/ml (7.8 mmol of phosphate per 10 mls solution). If patients were unable to tolerate oral feeds intravenous KPO4 was administered at 1 mmol/kg/day of phosphate. Results On admission 70% of children were assessed as severely underweight for age (median WAZ: -2.77, IQR: -5.07; -1.10) and 60% as stunted (median HAZ: -2.52, IQR: -5.23; -1.14) based on the WHO Z-score classification. All children were oedematous. Serum phosphate levels fell within the reference range for age (median: 1.3 mmol/l, IQR: 0.9; 1.4) and decreased to a nadir on day 7 (median: 1.15 mmol/l, IQR: 0.82; 1.5) despite routine phosphate supplementation. Low serum ionised calcium concentration at baseline (median: 1.8, IQR: 1.6; 1.88) reached a nadir at day 3 of treatment (median: 1.71, IQR: 1.53; 1.98), associated with a peak in PTH secretion on day 7 (median: 11.35, IQR: 9.1; 13.6), and an increased urinary phosphate (median: 3.85 IQR: 0.9; 37.85) on day 14. Renal threshold for phosphate reabsorption remained low throughout the course of refeeding and none of the patients developed biochemical evidence of refeeding syndrome. A significant positive correlation between ionised calcium and phosphate (p=0.004) was determined when calculating the Spearman Rank co-efficient; indicating that low serum ionised calcium concentration contributed to hypophosphatemia. This finding was confirmed by appropriate physiologic response to ionised serum hypocalcaemia by the parathyroid hormone axis. Although a positive correlation between urinary and serum phosphate; and a negative correlation between urinary phosphate and serum calcium were observed as expected; these were not found to be statistically significant, possibly due to the limited sample size and missing variables. However, a significant negative correlation (p=0.0012) was demonstrated between ionised calcium levels and PCT; this finding is previously undescribed in the setting of SAM. Conclusion This study demonstrated that in children recovering from SAM, low serum ionised calcium levels are a potential driver for phosphaturia in the face of hypophosphatemia. This is mediated via an appropriate PTH response. Further investigation of calcium supplementation and the contribution of vitamin D to phosphate homeostasis in SAM should be undertaken.AFRIKAANSE OPSOMMING : Agtergrond Die etiologie van hipofosfatemie in kinders met kwasjiorkor is onbekend. Die huidige teorie vir die patofisiologie van hipofosfatemie in volwassenes met hervoedingsindroom is dat fosfaat intrasellulêr vasgevang word weens die verskuiwing van ‘n oorheersend lipied afhanklike energie metabolisme na een wat koolhidraat oorheersend is. Die behandeling van hipofosfatemie en in die wangevoed kind is uitdagend. Hipothese Die studie ondersoek die etiologie van hipofosfatemie in kinders wat van kwasjiorkor herstel met spesifieke verwysing na kalsiumhomeostase, tendense in urinêre fosfaat verliese en merkers van voedings rehabilitasie. Studie-Ontwerp Die studie het plaas gevind in die gastroënterologie eenheid van Tygerberg Kinder Hospitaal, 'n tersiêre verwysing eenheid in Kaapstad, Suid-Afrika. Tien kinders tussen die ouderdomme van 6-59 maande met kwasjiorkor of marasmiese kwasjiorkor is in die gastroënterologie eenheid opgeneem. Toestemming is van die wettige ouer verkry. Etiese goedkeuring vir die studie is verkry van die Navorsingsetiekkomitee van die Universiteit van Stellenbosch. Kinders bekend met bestaande nier of endokriene siektes wat fosfaat, magnesium of kalsium metabolism kon beinvloed was uitgesluit. Pasiënte wat reeds in ander hospitale behandel is, of enige pasiënt met 'n hemoglobien van ≤6g / dl met toelating; of enige kind bekend met MIV infeksie is nie ingesluit nie. Methode Biochemiese en antropometriese veranderlikes is tydens toelating aangeteken. Die kinders is behandel volgens die Tygerberg Kinder Hospitaal protokol vir die behandeling van ernstige wanvoeding, hierdie protokol stem ooreen met die WGO riglyne. Behandeling van hipofosfatemie sluit die orale toediening van 75-100 mg / kg / dag van 0.8g Na2HPO4 + 0.2g KH2PO4 + 10 ml H2O in deur ‘n oplossing van 100mg PO4 / ml (7.8 mmol fosfaat per 10ml oplossing). Indien pasiënte nie die orale oplossing kon inneem nie is binneaarse KPO4 (1mmol / kg / dag) toegedien. Resultate Met opname was 70% van die kinders ernstig ondergewig (mediaan WAZ: -2.77, IKR: -5.07; -1.10) en 60% as groeivertraag (mediaan HAZ: -2.52, IKR: -5.23; -1.14) gebaseer op die WGO klassifikasie. Serum fosfaat vlakke het binne die normale verwysing waardes vir ouderdom geval (mediaan: 1.3 mmol/l, IKR: 0.9; 1.4 mmol / l) en het verminder tot ‘n laagte punt op dag 7 (mediaan: 1.15mmol / l, IKR: 0.82; 1.5) ten spyte van roetine fosfaat supplementasie. Die serum geïoniseer kalsiumkonsentrasie was laag met toelating (mediaan: 1.8, IKR: 1.6; 1.88) en het verder gedaal tot 'n laagtepunt op dag 3 van behandeling (mediaan: 1.71, IKR: 1.53; 1.98). Na dag 3, het die PTH konsentrasie gestyg tot ‘n hoogtepunt op dag 7 (mediaan: 11.35, IKR: 9.1; 13.6). Urinêre fosfaat het ‘n hoogtepunt bereik op dag 14 (mediaan: 3.85, IKR: 0.9; 37.85). Nie een van die pasiënte het enige biochemieise tekens van hervoedingsindroom ontwikkel nie. Die Spearman Rang koëffisiënt het aangedui dat daar 'n hoogs beduidende positiewe korrelasie tussen geïoniseerde kalsium en fosfaat (p= 0.004) is. Hierdie bevinding bevestig dat lae serum geïoniseerde kalsiumkonsentrasie die behandeling van hipofosfatemie mag beinvloed. Hierdie bevinding is bevestig deur die toepaslike fisiologiese reaksie op die lae geïoniseerd kalsium deur paratiroïed hormoon. Daar was nie 'n beduidende positiewe korrelasie tussen urinêre en serum fosfaat, of 'n beduidende negatiewe korrelasie tussen urinêre fosfaat en serum kalsium nie. Die belang van hierdie bevindinge is onseker aangesien die datastel nie volledig was nie. 'n Hoogs beduidende negatiewe korrelasie (p= 0.0012) is gevind tussen die geïoniseerd kalsium vlak en PKT, hierdie bevinding is nie voorheen beskryf in kinders met wanvoeding nie. Gevolgtrekking Fosfaaturie in die teenwoordigheid van hipofosfatemie tydens die behandeling van wangevoede kinders is waarskynlik gedryf deur 'n lae geïoniseerde serum kalsium vlak met ‘n toepaslike fisiologiese PTH reaksie. Kalsium aanvullings en die bydrae van vitamiene D in fosfaat homeostase moet verder ondersoek word