Working together to deliver stratified medicine research effectively.

INTRODUCTION OR BACKGROUND: Stratified medicine is an important area of research across all clinical specialties, with far reaching impact in many spheres. Despite recently formulated global policy and research programmes, major challenges for delivering stratified medicine studies persist. Across the globe, clinical research infrastructures have been setup to facilitate high quality clinical research. SOURCES OF DATA: This article reviews the literature and summarizes views collated from a workshop held by the UK Pharmacogenetics and Stratified Medicine Network and the NIHR Clinical Research Network in November 2016. AREAS OF AGREEMENT: Stratified medicine is an important area of clinical research and health policy, benefitting from substantial international, cross-sector investment and has the potential to transform patient care. However there are significant challenges to the delivery of stratified medicine studies. AREAS OF CONTROVERSY: Complex methodology and lack of consistency of definition and agreement on key approaches to the design, regulation and delivery of research contribute to these challenges and would benefit from greater focus. GROWING POINTS: Effective partnership and development of consistent approaches to the key factors relating to stratified medicine research is required to help overcome these challenges. AREAS TIMELY FOR DEVELOPING RESEARCH: This paper examines the critical contribution clinical research networks can make to the delivery of national (and international) initiatives in the field of stratified medicine. Importantly, it examines the position of clinical research in stratified medicine at a time when pressures on the clinical and social services are mounting.

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.

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

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.

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.

Views of patients about sickle cell disease management in primary care: a questionnaire-based pilot study.

OBJECTIVES: To determine how patients with sickle cell disease (SCD) perceive the quality of care that they receive from their primary healthcare providers. DESIGN: A questionnaire-based pilot study was used to elicit the views of patients about the quality of care they have been receiving from their primary healthcare providers and what they thought was the role of primary care in SCD management. SETTING: Sickle Cell Society and Sickle Cell and Thalassaemia Centre, in the London Borough of Brent. PARTICIPANTS: One hundred questionnaires were distributed to potential participants with SCD between November 2010 and July 2011 of which 40 participants responded. MAIN OUTCOME MEASURES: Analysis of 40 patient questionnaires collected over a nine-month period. RESULTS: Most patients are generally not satisfied with the quality of care that they are receiving from their primary healthcare providers for SCD. Most do not make use of general practitioner (GP) services for management of their SCD. Collecting prescriptions was the reason most cited for visiting the GP. CONCLUSION: GPs could help improve the day-to-day management of patients with SCD. This could be facilitated by local quality improvement schemes in areas with high disease prevalence. The results of the survey have been used to help develop a GP education intervention and a local enhanced service to support primary healthcare clinicians with SCD's ongoing management.

Neonatal screening for haemoglobin variants using filter paper-dried blood specimens.

Neonatal screening for haemoglobinopathies utilizing cord blood samples is well established, although it has a high miss rate and has the inherent problem of possible misdiagnosis from maternal contamination of the sample. The use of dried Guthrie card samples which are taken at six days of age avoids these problems and has the advantage of using an established system of sample collection. Controversy exists as to the method of choice for analysis of dried samples, this study of 2406 samples found that Iso-electric focusing (IEF) analysis of dried specimens gives excellent correlation when compared with cellulose acetate/citrate agar electrophoresis of liquid cord blood samples. The IEF results were clear and relatively simple to interpret even when the samples had been stored at room temperature for 4 weeks. The commercial enzyme linked immunosorbent assay (ELISA) screening test JOSHUA reliably determines the presence or absence of haemoglobin S in dried specimens. It could therefore be used as a relatively cheap and simple method for the confirmation of sickle cell trait in neonatal screening programmes based on dried specimens.