Louise Oni

Precision Dosing in Children

ABSTRACT Unlike adult medicine, there are fewer choices of medicines per condition in children, and for existing medications, supporting data on pharmacokinetics, pharmacodynamics, or pharmacogenomics is often incomplete. Many pediatric doses are calculated using body weight to produce a dose for the individual child, but this is not true personalisation as the dose suggested (usually in mg/kg) is the same for a large age range of children. The challenge for implementation of precision medicine in pediatrics is therefore to develop an appropriate evidence base (particularly for unlicensed and off label medications), then add onto it the relevant genotype, environmental and lifestyle data to guide both medication selection (where choices exist) and the dose required. This review will consider where consideration of dose is crucial in pediatrics, including the developmental changes across childhood, pediatric obesity, and old and new medicines where data on dosing are scarce and/or inadequately extrapolated from adults.

Increased concentration of plasma TNFR1 and TNFR2 in paediatric lupus nephritis

Background Juvenile-onset systemic lupus erythematous (JSLE) is a debilitating condition that frequently involves the kidneys (lupus nephritis; LN). Tumour necrosis factor alpha (TNF-α), an important pro-inflammatory cytokine, is expressed locally in the kidney and correlates with LN disease activity. The aim of this study was to ascertain whether soluble receptors for TNF-α (sTNFR1/sTNFR2) are significantly increased in children with LN. Methods Plasma samples were collected from JSLE patients at routine review. Concentrations of sTNFR1 and sTNFR2 were measured (median; interquartile range, IQR) using enzyme-linked immunosorbent assay (ELISA) in 25 JSLE patients (seven LN) and 20 healthy controls (HCs). Results sTNFR2 concentration was significantly increased in JSLE (5149 pg/dl, 3413–8561) compared to HCs (3858 pg/dl, 2254–5165; p = 0.049). sTNFR1 concentration was significantly increased in active LN (n = 7, 1765 pg/dl, IQR 1133–4167) compared to inactive LN (n = 18, 1104 pg/dl, 886–1272; p = 0.018). There was a non-significant increase in sTNFR2 concentration in active LN (9829 pg/dl, 3298–21271) compared to inactive LN (4595 pg/dl, 3345–6993; p = 0.146). sTNFR1 concentration correlated moderately with sTNFR2 (r = 0.66, p < 0.001). sTNFR2 demonstrated strong positive correlations with ESR (r = 0.941, p < 0.01) and anti-dsDNA antibodies (r = 0.998, p = 0.041). Both receptors also positively correlated with creatinine (TNFR1 r = 0.81, p < 0.001; TNFR2 r = 0.50, p = 0.015) and urinary albumin creatinine ratio (TNFR1 r = 0.64, p < 0.01; TNFR2 r = 0.63, p < 0.01). Conclusions These data indicate that sTNFR1 and sTNFR2 concentrations are elevated in LN and may reflect renal activity. These results provide basis for further investigation into the pathological pathways underlying LN.

Optimising the use of medicines to reduce acute kidney injury in children and babies

&NA; The majority of medications in children are administered in an unlicensed or off‐label manner. Paediatricians are obliged to prescribe using the limited evidence available. The 2007 EU regulation on the use of paediatric drugs means pharmaceutical companies are now obliged to (and receive incentives for) contributing to paediatric drug data and carrying out paediatric clinical trials. This is important, as the efficacy and adverse effect profiles of medicines vary across childhood. Additionally, there are significant age‐related changes in the pharmacodynamic and pharmacokinetic activity of many drugs. This may be related to physiological (differential expressions of cytochrome P450 enzymes or variable glomerular filtration rates at different ages for example) and psychological (increasing autonomy and risk perception in teenage years) changes. Increasing numbers of children are surviving life‐threatening childhood conditions due to medical advances. This means there is an increasing population who are at risk of the consequences of the long‐term, early exposure to nephrotoxic agents. The kidney is an organ that is particularly vulnerable to damage as a consequence of drugs. Drug‐induced acute kidney injury (AKI) episodes in children and babies are principally due to non‐steroidal anti‐inflammatory drugs, antibiotics or chemotherapeutic agents. The renal tubules are vulnerable to injury because of their concentrating ability and high‐energy hypoxic environment. This review focuses on drug‐induced AKI and the methods to minimise its effect, including general management plus the role of child‐specific pharmacokinetic data, the use of pharmacogenomics and early detection of AKI using urinary biomarkers and electronic triggers.

Inter-observer variability of the histological classification of lupus glomerulonephritis in children.

The gold standard for the classification of lupus nephritis is renal histology but reporting variation exists. The aim of this study was to assess the inter-observer variability of the 2003 International Society of Nephrology/Royal Pathology Society (ISN/RPS) lupus nephritis histological classification criteria in children. Histopathologists from a reference centre and three tertiary paediatric centres independently reviewed digitalized renal histology slides from 55 children with lupus nephritis. Histological ISN/RPS Class was assigned and features scored; lupus nephritis-activity [scored 0–24], lupus nephritis-chronicity [0–12] and tubulointerstitial activity [0–21]. In the cohort (73% females), the age at the time of biopsy was 15.5 ± 0.39 (mean ± standard error) years. Based on the reference centre, 42% (23/55) had ISN/RPS Class IV with lupus nephritis-activity score 4.23 ± 0.50, lupus nephritis-chronicity 1.81 ± 0.18 and tubulointerstitial activity 4.45 ± 0.35. There were 4–54 (mean 16.7) glomeruli per biopsy. Pathologists had fair agreement for ISN/RPS assignment (kappa; 0.26 ± 0.12), lupus nephritis-chronicity (intra-class correlation 0.36 ± 0.09) and tubulointerstitial activity (0.22 ± 0.09) scores. There was good agreement for lupus nephritis-activity scores (intra-class correlation 0.69 ± 0.06). When categorized into proliferative and non-proliferative disease, poor agreement among sites remained (kappa 0.24 ± 0.11). Despite unified criteria for the interpretation of histological features of lupus nephritis, marked reporting variation remains in clinical practice. As proliferative lupus nephritis is managed more intensively, this may influence renal outcomes.

Identifying cisplatin-induced kidney damage in paediatric oncology patients

Cisplatin is one chemotherapeutic agent used to treat childhood cancer in numerous treatment protocols, including as a single agent. It is likely to remain in clinical use over the long term. However, cisplatin-related toxicities, including neurotoxicity and nephrotoxicity, are common, affecting treatment, day-to-day life and survival of such children. With one in 700 young adults having survived childhood cancer, patients who have completed chemotherapy that includes cisplatin can experience long-term morbidity due to treatment-related adverse reactions. A better understanding of these toxicities is essential to facilitate prevention, surveillance and management. This review article discusses the effect of cisplatin-induced nephrotoxicity (Cis-N) in children and considers the underlying mechanisms. We focus on clinical features and identification of Cis-N (e.g. investigations and biomarkers) and the importance of magnesium homeostasis and supplementation.

The dual-tracer stable isotope method to measure calcium absorption in children on dialysis: a new use for an old technique

Dear Editor, In an article on phosphate binder use in chronic kidney disease (CKD), Rees and Shroff stressed the need for studies of calcium balance, in particular in children on dialysis [1]. We would like to draw attention to the potential for the new use of an old technique: the dual-tracer stable isotope method. This is an established technique that has been used to measure fractional calcium absorption in children of all ages (even premature infants) with many different medical conditions [2]. One stable isotope of calcium is given orally and a different one intravenously (IV) 2 h later. Once the absorbed and IV isotopes are equilibrated, their ratio in blood and urine is independent of differences in calcium pool size and turnover rates. The percent absorption of calcium can be calculated from the ratio of the oral tracer dose to the IV tracer dose recovered in a 24 h urine pool post-dosing. In children on dialysis, recovery from dialysate would also be required. Another approach used to estimate fractional calcium absorption is the single timed serum method, which uses a serum sample taken 4 h after the isotope given orally (and 2 h after the isotope given IV) has been given and does not need urine or dialysate collection [3]. Neither method needs complex metabolic balance studies or faecal collection. Neither has been used in CKD as yet. Ethical committee permission was obtained from the National Research Ethics Committee, Bloomsbury, to obtain pilot data and to compare use of a single timed serum method in children on dialysis. Informed consent was taken from carers and assent from the children. Firstly, we looked at the recovery of isotopes in urine and dialysate using typical doses used previously in this age group: 3 mg of Ca orally and 1 mg Ca IV in an 8-year-old child on peritoneal dialysis (PD). Selection of isotopes was based on their fractional abundance (Ca at 2.083 % and Ca at 0.647 %). Isotopic ratios were measured using magnetic sector thermal ionisation mass spectrometry. The full methodology has been previously described and validated [2]. Enrichment of the orally ingested tracer was readily analysed, but the delta percent excess of isotope was lower than anticipated, at 2.42 % and 0.63 % in the urine and 0.50% and 0.24 % in the peritoneal dialysate for Ca and Ca, respectively. For the next three patients, aged 5–11 years, we studied those on haemodialysis (HD) to compare the timed serum method with the standard 24-h urine collection technique. The doses were increased to 6 mg Ca orally and 1.5 mg Ca IV. The mean percent calcium absorption calculated using the 24-h urine method was 15.6 ± 8.5 % (range 5.9–21.9 %) and in the 4-h serum samples 8.3 ± 7.6 % (range 3.0–17.0 %). Absorption values obtained using the ratio of oral to IV isotope in serum were all lower than the results obtained in the 24-h urine pool, on average by 10.6 % (r = 0.73, p = 0.47) between the serum and urine methods. Other studies have extended this serum collection time serum collection point to 6 h [3]. Additional studies are warranted to explore this issue, as possible alterations in peak absorption times may be evident in patients on dialysis. * Lesley Rees l.rees@ucl.ac.uk

THU0373 Demonstration of an “Excellent” Biomarker Panel for Identifying Active Lupus Nephritis in Children

Background Lupus nephritis (LN) is a serious manifestation of Juvenile-onset Systemic Lupus Erythematosus (JSLE), affecting up to 80% of patients [1]. Conventional markers of JSLE disease activity fail to adequately predict impending LN flares. Renal histology is the gold standard for diagnosing and predicting renal prognosis in LN, and is rarely repeated for monitoring purposes due to its invasive nature. Single novel urine biomarkers are good at predicting and detecting LN flares [2], but to date, no individual urine biomarkers have achieved an “excellent” predictive value (area under the curve (AUC) >0.9). Objectives To assess if combining novel and traditional biomarkers can result in an excellent biomarker panel for identifying active LN. Methods Participants of the UK JSLE cohort study were aged less than 16 years at the time of diagnosis. Disease activity data was collected using the paediatric British Isles Lupus Assessment Group (pBILAG2004) score. Patients were cross-sectionally categorised as active LN (pBILAG2004 renal domain score A or B plus previous histological confirmation of LN), in-active LN (pBILAG2004 renal domain score D or E) or healthy controls (HCs). Novel urinary biomarkers; vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), lipocalin like prostaglandin D synthase (LPGDS), transferrin, ceruloplasmin and alpha-1-acid glycoprotein (AGP) were quantified by enzyme-linked immunosorbent assays. Neutrophil gelatinase associated lipocalin (NGAL) was measured using the Abbot Architect assay. Binary logistic regression modeling and receiver-operating curve (ROC curve) analysis assessed combinations of novel and traditional biomarkers. The study had full ethical approval in place. Results 61 JSLE patients and 19 HCs were recruited. 15 (25%) JSLE patients had active LN and 46 (75%) had in-active LN. Urinary AGP, ceruloplasmin, VCAM-1, MCP-1, LPGDS and transferrin levels were significantly increased in active LN (all p≤0.01). Urinary NGAL levels did not differ between patient groups (p=0.245). AGP was the best single biomarker differentiating active and inactive LN (good AUC 0.890, p≤0.001). Combining novel biomarkers improved the identification of active LN (optimal combination; AGP, ceruloplasmin, LPGDS, transferrin, excellent AUC 0.923, p<0.001). Additional improvement was seen with the addition of dsDNA to this combination (excellent AUC 0.933, p≤0.001). Conclusions A combination of novel urinary and traditional biomarkers produces an excellent “biomarker panel” for active LN identification on a cross sectional basis. It is anticipated that biomarker led monitoring will improve long-term renal outcomes in JSLE patients in the future. References Watson L, Leone V, Pilkington C, et al. Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arth Rheum 2012;64(7):2356-65. Watson L, Tullus K, Pilkington C, et al. Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study. Ped Nephrol 2013;29(3):397-405. Disclosure of Interest None declared

G440 A Snapshot of acute kidney injury in tertiary paediatric centres in the united kingdom

Background The burden of acute kidney injury (AKI) in the paediatric age group is unknown, partly due to the lack of a universally agreed definition in the past. The aim of this study was to assess the point incidence of AKI among hospitalised children on World Kidney Day 2016. Methods Cross-sectional study involving tertiary paediatric centres across the United Kingdom. Centres reported new cases of AKI on a single observation day. Associated clinical features and follow-up data were recorded. AKI was defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) classification. Results On the observation day, there were 1218 inpatients in 8 centres. 31 children (2.5%) met the case definition for AKI. The majority of patients had no pre-existing, known risk factors for AKI (20/31, 65%), while the leading known risk factor was congenital heart disease (5/31, 15%). Most cases of AKI were hospital acquired (21/31, 68%). The leading acute contributory factors were: medications (13/31, 42%), hypotension/shock (10/31, 32%) and dehydration (10/31, 32%). AKI was subdivided according to severity: stage 1 (24/31, 78%), stage 2 (2/31, 6%) and stage 3 (5/31, 16%). All 31 cases had 7 day follow-up data. Renal replacement therapy was required in 2 cases (6%). Recovery from AKI at 7 days was: complete (18/31, 58%), incomplete (9/31, 29%) or unknown (4/31, 13%); 2 patients (6%) died from non-renal causes. Discussion and Conclusion This is the first study looking at the point incidence of AKI in hospitalised paediatric patients in the UK, according to the KDIGO classification. Our point incidence of 2.5% is similar to international reports. The majority of cases were hospital acquired and due to nephrotoxic medications, a significant modifiable factor. Prospective studies are necessary to evaluate the benefit of interventions designed to reduce the incidence of AKI in children.

G261 Prescribing practices of rituximab in children: a 5-year retrospective review

Aims Rituximab, an anti-lymphocyte monoclonal antibody, is not currently licensed for use in children but is used for treatment of a variety of conditions. The purpose of this study was to (i) describe the current clinical indications being treated with rituximab in children (ii) review the doses used and (iii) investigate trends in prescribing practice. Methods A single-centre retrospective review of children who received rituximab during a 5-year period (October 2009–October 2014). Results Eight-eight patients received rituximab with a median of four doses per patient (range 1–11, total 405 doses). Doses were between 375mg/m 2 and 750mg/m 2 with their frequency varying from weekly to fortnightly for up to four weeks, with clinicians deciding whether to give repeated courses at six monthly intervals. Three oncology patients had rituximab timed with their chemotherapy. The total annual dose per patient ranged from 750mg/m 2 to 2250mg/m 2 . Most common clinical indications were: juvenile idiopathic arthritis JIA (n = 27, 30.7%); cancer (n = 12, 13.6%); SLE (n = 11, 12.5%); neuro-inflammatory disease (n = 9, 10.2%). Figure 1 summarises the clinical indications for rituximab. The number of new patients who received rituximab per year did not increase but the total number of patients and doses administered did increase due to repeat courses (total doses n = 51 year 1, n = 98 year 5, p < 0.001). See Figure 1.Abstract G261 Figure 1 Discussion Despite no licensed indications, rituximab prescriptions have shown a significant increase in the 5 years. While generally safe in the short term, rituximab carries the risk of rare but devastating long term adverse effects (such as progressive multifocal leukoencephalopathy) therefore determination of the optimal dose for each condition with regards to risks and benefits is required. These data provide the first characterisation of the conditions in which rituximab is being used in children, and shows the important role it has in a variety of diseases. Pharmacokinetic work is therefore required to inform safe dosing, appropriate for each indication. Conclusion Rituximab use is increasing due to repeat dosing of patients over time, although number of new patients remains static. Efforts to develop licencing indications for rituximab use in children are urgently needed.

THU0522 Plasma TNFR1 and TNFR2 in Active Paediatric Lupus Nephritis

Background Juvenile systemic lupus erythematous (JSLE) is a debilitating condition that frequently involves the kidneys (lupus nephritis; LN). In LN up to 25% develop end stage renal failure within 10 years.[1] Our group have been investigating the urine biomarker monocyte chemoattractant protein-1 (MCP-1) and the tumour necrosis factor-alpha (TNF-a) pathway is believed to be involved in MCP-1 expression.[2] TNF-a acts via its receptors soluble tumour necrosis factor receptor 1 and 2 (TNFR1 and TNFR2). These are significantly elevated in adult LN.[3] These novel biomarkers have not been investigated in JSLE. Objectives The aim of this study is to ascertain whether sTNFR1 and sTNFR2 are significantly increased in children with LN. Methods Plasma samples were collected from patients recruited to the UK JSLE Cohort Study at routine review. Full ethical approval was attained. Concentrations of sTNFR1 and sTNFR2 were measured using enzyme linked immunosorbent assay (ELISA) in JSLE and healthy controls (HC). Active LN was defined as a renal British Isles Lupus Assessment group (BILAG) score of A/B and previous histological diagnosis. Inactive LN were scores D/E. Statistical analysis used Mann Whitney U and Pearsons correlations. Results Data is represented as median and interquartile ranges. There was a non-significant trend towards increased sTNFR1 in JSLE patients compared to HC (JSLE n=25, 1144pg/dl, 903-1617; HC n=20, 928pg/dl, 838-1143; p=0.071). sTNFR1 was significantly increased in active LN (n=7, 1765pg/dl, 1133-4167) compared to inactive LN (n=18, 1104pg/dl, 886-1272; p=0.018). sTNFR2 was significantly increased in JSLE (5149pg/dl, 3413-8561) compared to HC (3858pg/dl, 2254-5165; p<0.05). There was no difference in sTNFR2 between active LN (9829pg/dl, 3298-21271) and inactive LN (4595pg/dl, 3345-6993; p=0.146). sTNFR1 positively correlated with sTNFR2 (r=0.663, p<0.001). Both receptors positively correlated with creatinine (TNFR1 r=0.811, p<0.001; TNFR2 r=0.50, p=0.015) and urinary albumin creatinine ratio (TNFR1 r=0.639, p<0.01; TNFR2 r=0.627, p<0.01). sTNFR2 positively correlated with ESR (r=0.840, p<0.01). Conclusions This is the first study to investigate sTNFR1 and sTNFR2 in paediatric LN. They appear to have a pathophysiological role as they relate to LN disease activity and correlate with current clinical parameters. The receptors may have an upstream role in inducing MCP-1 production that could be used for early-targeted treatment and this is the focus of current research. Further investigation in a kidney cell line (such as podocytes) is warranted to attain a better understanding of different pathological pathways. References Mok, C. (2006) Therapeutic options for resistant lupus nephritis. Seminars in arthritis and rheumatism. 36, 71-81 Pai, R., Ha, H., Kirschenbaum, M. A and Kamanna, V.S (1996) Role of tumour necrosis factor-alpha on mesangial MCP-1 expression and monocyte migration:mechanisms mediated by signal transduction. joURNAL OF american Society of Nephrology: JASN. 7, 914-923 Mahmoud, R.A., El-Gendi, H. I. and Ahmed, H. H. (2005) Serum neopterin, tumour necrosis factor-alpha and soluble tumour necrosis factor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus. Clinical biochemistry. 38, 134-141 Disclosure of Interest None declared