Publications by authors named "Helen Aitkenhead"

8 Publications

  • Page 1 of 1

Free 25-hydroxyvitamin-D concentrations are lower in children with renal transplant compared with chronic kidney disease.

Pediatr Nephrol 2020 06 22;35(6):1069-1079. Epub 2020 Jan 22.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Total serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes.

Methods: We assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2-3, 18 dialysis, and 21 post-transplant).

Results: Total-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, - 0.6, respectively; R = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p < 0.001).

Conclusions: In transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.
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http://dx.doi.org/10.1007/s00467-020-04472-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184055PMC
June 2020

Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study.

J Am Soc Nephrol 2019 04 7;30(4):678-691. Epub 2019 Mar 7.

Nephrology Unit, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce.

Methods: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score.

Results: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher 2-microglobulin. The HDF cohort had lower 2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time.

Conclusions: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.
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http://dx.doi.org/10.1681/ASN.2018100990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442347PMC
April 2019

Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children.

PLoS One 2018 18;13(6):e0198320. Epub 2018 Jun 18.

Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Randomized trials in adults have shown reduced all-cause and cardiovascular mortality on hemodiafiltration (HDF) compared to high-flux hemodialysis (HD), but the mechanisms leading to improved outcomes are not clear. We studied biomarkers of inflammation, oxidative stress, anti-oxidant capacity and endothelial dysfunction in 22 children (13 female, age 8-15 years). All children received HD for at least 3 months, and were then switched to HDF, keeping all dialysis related parameters and dialysis time constant. All the biomarkers of inflammation (ß2-microglobulin, IL-6, IL-10, high sensitive C-reactive protein [hsCRP]), oxidative stress (nitrotyrosine, advanced glycation end-products [AGEs], oxidized low density lipoprotein [ox-LDL] and anti-oxidant capacity) and endothelial dysfunction (asymmetric dimethyl arginine [ADMA], symmetric dimethyl arginine [SDMA]), were comparable between incident and prevalent patients on HD, suggesting that even a short dialysis vintage of 3 months on HD increases inflammation and endothelial stress. After 3 months of HDF therapy there was a significant reduction in ß2-microglobulin (p<0.001), hCRP, ADMA, SDMA, AGEs, ox-LDL (p<0.01 for all) and an increase in total antioxidant capacity (p<0.001) compared to HD. All children were maintained on the same dialyser, dialysis water quality, dialysis time and blood flow speeds suggesting that improved clearances on HDF led to an improved biomarker profile. Even in children with residual renal function there was a significant reduction in ß2 microglobulin, hsCRP, SDMA, ox-LDL and AGEs on HDF compared to HD. Children with a lower blood flow had higher inflammatory status (higher IL-6/IL-10 ratio; p = 0.04, r = -0.43). Children who achieved a higher convective volume (≥median 12.8L/m2) had lower ox-LDL (p = 0.02). In conclusion, we have shown that a significant improvement in inflammation, antioxidant capacity and endothelial risk profile is achieved even within a short time (3 months) on HDF compared to HD treatment.

Trial Registration: ClinicalTrials.gov: NCT02063776.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005477PMC
December 2018

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Nephrol Dial Transplant 2018 12;33(12):2208-2217

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD).

Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated.

Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2.

Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.
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http://dx.doi.org/10.1093/ndt/gfy012DOI Listing
December 2018

Measuring Erythrocyte Thiopurine Methyltransferase Activity in Children-Is It Helpful?

J Pediatr 2016 12 15;179:216-218. Epub 2016 Sep 15.

Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Objective: To assess the profile of thiopurine transmethyltransferase (TPMT) enzyme activities in children and discuss the utility of measuring TPMT levels before commencing azathioprine therapy.

Study Design: Retrospective study in a single pediatric center of all patients who had TPMT enzyme assay measured during a 3-year period before the start of azathioprine therapy. Patients' TPMT enzyme activities were classified as normal (26-50 pmol/h/mgHb), intermediate (10-25 pmol/h/mgHb), and deficient (<10 pmol/h/mgHb). Medical and electronic prescribing records were studied, with records of patients' demographic data, diagnoses, dosages, and adverse drug reactions monitored.

Results: A total of 228 (45% female) patients ages 1-18 years (median 10 years) were tested for TPMT activity. They were all subsequently commenced on azathioprine. Erythrocyte TPMT activities were 14-76 (median 33.7) pmol/h/mgHb with 88% and 12% of patient having normal and intermediate activity respectively (none were deficient). The initial prescribed dosage of azathioprine was 0.7-3.5 (median 2.0) mg/kg/day. Only 2 patients developed mild neutropenia and required reduction of azathioprine dosage.

Conclusion: This large cohort study demonstrates that the majority of pediatric patients had normal TMPT activities. We would recommend close monitoring of full blood counts after instituting azathioprine therapy but would question the cost-effectiveness of pretreatment TPMT activity in pediatric practice.
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http://dx.doi.org/10.1016/j.jpeds.2016.08.073DOI Listing
December 2016

Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD.

J Am Soc Nephrol 2016 Jan 11;27(1):314-22. Epub 2015 Jun 11.

Center for Pediatric & Adolescent Medicine, University of Heidelberg, Germany.

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and vitamin D-fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median eGFR 51 ml/min per 1.73 m(2)), serum 25-hydroxyvitamin D (25(OH)D), FGF-23, and Klotho levels were measured at baseline and after a median 8 months on ACEi. Children with lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum vitamin D-binding protein were not associated, but 25(OH)D ≤50 nmol/L associated with higher diastolic BP (P=0.004). ACEi therapy also associated with increased Klotho levels (P<0.001). The annualized loss of eGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survival was 75% in patients with baseline 25(OH)D ≥50 nmol/L and 50% in those with lower 25(OH)D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of eGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D ≥50 nmol/L was associated with greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy.
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http://dx.doi.org/10.1681/ASN.2014090947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696567PMC
January 2016

Establishment of paediatric age-related reference intervals for serum prolactin to aid in the diagnosis of neurometabolic conditions affecting dopamine metabolism.

Ann Clin Biochem 2013 Mar 12;50(Pt 2):156-8. Epub 2013 Feb 12.

Department of Chemical Pathology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.

Background: There are a number of inborn errors of dopamine biosynthesis for which prolactin measurement may be a useful screening tool. However, the interpretation of prolactin results is difficult as age-related paediatric reference intervals are scant especially in infancy.

Methods: Serum prolactin reference intervals were calculated from the existing laboratory data using an indirect method, based on patients (n = 2369) attending a tertiary care hospital over a 10-year period. The data were log transformed and partitioned by age and sex.

Results: The prolactin results for all age and sex stratifications show non-gaussian distributions (P < 0.0001). There are apparent age-related differences for prolactin during the first year of life with prolactin declining sharply during the first year of life and continuing to decline until five years of age when the concentrations stabilize. The sex differences are small until 13-17 years of age when prolactin is higher in girls than in boys.

Conclusions: This is the first published study to report age-related prolactin reference intervals spanning all paediatric age groups where the data are age partitioned in infants under one year of age using an 'indirect' approach. It is envisaged that these reference intervals will be used to aid in the selection of patients presenting with features of central dopamine deficiency for lumbar puncture. Also, these reference intervals have the potential for treatment monitoring of patients with diagnoses of inborn errors of dopamine biosynthesis.
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http://dx.doi.org/10.1258/acb.2012.012080DOI Listing
March 2013

Ergocalciferol supplementation in children with CKD delays the onset of secondary hyperparathyroidism: a randomized trial.

Clin J Am Soc Nephrol 2012 Feb 19;7(2):216-23. Epub 2012 Jan 19.

Renal Unit, Ormond Street Hospital for Children NHS Trust and Institute of Child Health, London WC1N 3JH, UK.

Background And Objectives: Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism.

Design, Setting, Participants, & Measurements: A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism.

Results: Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median follow-up was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels >100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D.

Conclusions: Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.
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http://dx.doi.org/10.2215/CJN.04760511DOI Listing
February 2012