Evidence for shrunken pore syndrome in children.

The link between cystatin C and mortality independent of glomerular filtration rate (GFR) in adults has prompted the "Shrunken Pore Syndrome" (SPS) hypothesis, where high serum cystatin C with normal creatinine is explained by smaller glomerular pores, through which creatinine can pass freely, while the larger cystatin C, beta-trace protein (BTP) and pro-inflammatory molecules are retained. This study set out to apply the definition of SPS to children. In 294 children who underwent inulin clearance (Cin) test, serum creatinine, cystatin C and BTP were measured. For all three markers eGFRx was calculated using the full age spectrum equations. The ratio eGFRcys/eGFRcrea was plotted against the error of eGFRBTP(%) (i.e. eGFRBTP-Cin)/Cin*100%). Patients with and without SPS according to different cut-off points of eGFRcys/eGFRcrea and eGFRcys/Cin (i.e. ≤0.6,0.7,0.8) were compared in terms of eGFRx, Cin, error of eGFRx(%) and eGFRBTP/eGFRcrea-ratio. The ratio eGFRcys/eGFRcrea and error of eGFRBTP(%) were positively correlated. The prevalence of SPS by eGFRcys/eGFRcrea with a cut-off of 0.6 was 4.8%. Patients with SPS had a more negative error of eGFRcys(%) and eGFRBTP(%) and higher Cin regardless of the definition. Overestimation of eGFRcrea in patients with SPS was only present when using the eGFRcys/eGFRcrea rather than the eGFRcys/Cin definition. Cystatin C and BTP are related independent of creatinine, suggesting glomerular pore size as a common denominator. The prevalence of SPS in children is comparable to adults. For research in SPS, a definition based on eGFRcys/exogenous clearance study may be useful to study the effect of SPS on creatinine metabolism.

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

BACKGROUND: Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. OBJECTIVES: To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. SELECTION CRITERIA: All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. MAIN RESULTS: We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. AUTHORS' CONCLUSIONS: We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

BACKGROUND: Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. The exact occurrence and duration of HPA axis suppression after glucocorticoid therapy for childhood ALL are unclear. OBJECTIVES: To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (in The Cochrane Library, issue 3, 2010), MEDLINE/PubMed (from 1945 to July 2010) and EMBASE/Ovid (from 1980 to July 2010). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA: All study designs, except case reports and patient series with fewer than 10 patients, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which was checked by another review author. MAIN RESULTS: We identified seven studies (total number of participants = 189), including one randomised controlled trial (RCT), which assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, results could not be pooled. All studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all patients in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of patients recovered within a few weeks, but a small amount of patients had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCT, the occurrence and duration of adrenal insufficiency did not differ between the prednisolone and dexamethasone arms. In one study included in the review it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. AUTHORS' CONCLUSIONS: Based on the available evidence, we conclude that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL, to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.

The association of birth weight and infant growth with childhood autonomic nervous system activity and its mediating effects on energy-balance-related behaviours-the ABCD study.

BACKGROUND: The purpose of this study was to examine the association of birth weight and infant growth with childhood autonomic nervous system (ANS) activity and to assess whether ANS activity mediates the associations of birth weight and infant growth with energy-balance-related behaviours, including energy intake, satiety response, physical activity and screen time. METHODS: In 2089 children, we prospectively collected birth weight, infant growth defined as conditional weight and height gain between birth and 12 months and-at 5 years-indices of cardiac ANS activity and parent-reported energy-balance-related behaviours. A mediation analysis was conducted, based on MacKinnon's multivariate extension of the product-of-coefficients strategy. RESULTS: Birth weight and infant height gain were inversely associated with sympathetic, but not parasympathetic, activity at age 5. Infant weight gain was not associated with childhood ANS activity. Infant weight gain was predictive of increased childhood screen time and infant height gain of diminished childhood energy intake, but sympathetic activity did not mediate these associations. CONCLUSIONS: Low-birth-weight children have higher sympathetic activity, which is considered a risk factor for cardiovascular disease. Height gain in infancy seems to be beneficial for childhood sympathetic activity. However, sympathetic activity was no mediator of the associations of infant growth with childhood energy-balance-related behaviours. As individual differences in ANS activity predict increased risk of cardiovascular disease, these differences may offer insight into the early-life origins of chronic diseases and provide further basis for public health strategies to optimize birth weight and infant growth.