Manish D. Sinha

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome

BACKGROUND AND OBJECTIVES Up to 95% of children presenting with steroid-resistant nephrotic syndrome in early life will have a pathogenic single-gene mutation in 1 of 24 genes currently associated with this disease. Others may be affected by polymorphic variants. There is currently no accepted diagnostic algorithm for clinical genetic testing. The hypothesis was that the increasing reliability of next generation sequencing allows comprehensive one-step genetic investigation of this group and similar patient groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study used next generation sequencing to screen 446 genes, including the 24 genes known to be associated with hereditary steroid-resistant nephrotic syndrome. The first 36 pediatric patients collected through a national United Kingdom Renal Registry were chosen with comprehensive phenotypic detail. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing. RESULTS Analysis revealed known and novel disease-associated variations in expected genes such as NPHS1, NPHS2, and PLCe1 in 19% of patients. Phenotypically unexpected mutations were also detected in COQ2 and COL4A4 in two patients with isolated nephropathy and associated sensorineural deafness, respectively. The presence of an additional heterozygous polymorphism in WT1 in a patient with NPHS1 mutation was associated with earlier-onset disease, supporting modification of phenotype through genetic epistasis. CONCLUSIONS This study shows that next generation sequencing analysis of pediatric steroid-resistant nephrotic syndrome patients is accurate and revealing. This analysis should be considered part of the routine genetic workup of diseases such as childhood steroid-resistant nephrotic syndrome, where the chance of genetic mutation is high but requires sequencing of multiple genes.

Disease activity, severity, and damage in the UK juvenile-onset systemic lupus erythematosus cohort

OBJECTIVE The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort. METHODS Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n=198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE. RESULTS Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4-14.5 years). Male patients were younger than female patients (P<0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P<0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1. CONCLUSION The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Genomic and clinical profiling of a national Nephrotic Syndrome cohort advocates a precision medicine approach to disease management

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

Blood Pressure Control and Left Ventricular Mass in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Heart disease is a major cause of death in young adults with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) is common and is associated with hypertension. The aims of this study were to evaluate whether there is a relationship between LVH and BP in children with CKD and whether current targets for BP control are appropriate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this single-center cross-sectional study, 49 nonhypertensive children, (12.6 ± 3.0 years, mean GFR 26.1 ± 12.9 ml/min per 1.73 m²) underwent echocardiographic evaluation and clinic and 24-hour ambulatory BP monitoring. LVH was defined using age-specific reference intervals for left ventricular mass index (LVMI). Biochemical data and clinic BP for 18 months preceding study entry were also analyzed. RESULTS The mean LVMI was 37.8 ± 9.1 g/m²·⁷, with 24 children (49%) exhibiting LVH. Clinic BP values were stable over the 18 months preceding echocardiography. Patients with LVH had consistently higher BP values than those without, although none were overtly hypertensive (> 95th percentile). Multiple linear regression demonstrated a strong relationship between systolic BP and LVMI. Clinic systolic BP showed a stronger relationship than ambulatory measures. Of the confounders evaluated, only elemental calcium intake yielded a consistent, positive relationship with LVMI. CONCLUSIONS LVMI was associated with systolic BP in the absence of overt hypertension, suggesting that current targets for BP control should be re-evaluated. The association of LVMI with elemental calcium intake questions the appropriateness of calcium-based phosphate binders in this population.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.

Incidence of left ventricular hypertrophy in children with kidney disease: impact of method of indexation of left ventricular mass

AIMS Patients with chronic kidney disease are at high risk of cardiovascular morbidity and mortality. Increased left ventricular mass (LVM) has been shown to be an adverse prognostic factor. LVM may be indexed for body size by different methods related to height, weight, or body surface area (BSA). Our Null hypothesis was that different methods of indexation would not influence categorization as to whether LVM was within normal limits or increased. METHODS AND RESULTS Prospective study in children with renal disease. M-mode echocardiography assessed by single investigator blinded to medical therapy. Three different partition values and two different published z-scores were used: Method 1: indexation of LVM to the allometric height in metres raised to the power of 2.7 (m(2.7)), value of 38.6 g/m(2.7) denotes 95th percentile. Method 2: indexation of LVM by body weight, ratio of LVM in gm/kg of >3.0 indicating LVH. Method 3: indexation by BSA, 88.9 g/m(2) represents 95th percentile. Z-score based methods from recent studies with z-score >1.65 denoting LVH, Method 4: z-score indexed either for BSA or Method 5, z-score indexed for height(2.7). One hundred and twenty-three echocardiograms were performed in 80 patients with a mean +/- SD age of 13.1 +/- 3.1 years, height 147.2 +/- 15.3 cm, weight 46.4 +/- 15.8 kg, and body mass index 20.8 +/- 4.1 kg/m(2). Method 1, LVH was observed in 68 (55.3%) studies. Method 2, 32 (26%) studies had LVM/kg >3.0. Method 3, 51 studies (41.5%) demonstrated LVH. Method 4, 22 (17.9%) studies demonstrated LVH and Method 5, 25 studies (20%) demonstrated LVH (chi(2) test, P < 0.001). CONCLUSION Different methods of indexation have a profound influence on the categorization of children with respect to LVH. This will have a major impact on the number of patients who are treated as per current guidelines especially in high-risk groups.

Evaluation of blood pressure in children.

Purpose of reviewThis review briefly highlights origins of hypertension with emphasis on the influences of gestation, birth weight, salt intake, and adiposity. We focus on the role of ambulatory blood pressure monitoring, and the assessment of comorbidity and target organ change in hypertensive children and adolescents. Recent findingsLow birth weight, prematurity and uric acid levels are associated with hypertension early in childhood and in young adult life, not just in later adult life. Reduction of dietary salt intake leads to significant reductions in blood pressure in infants and young children. Newly applied techniques for assessment of target organ damage in children include arterial studies using retinal photography, ultrasound assessment of arterial intima-media thickness, and applanation tonometry. SummaryOverweight and obesity are increasingly common, and are major determinants of high blood pressure in children, in both the developed and developing world. Initial evaluation of the hypertensive child must include carefully confirming if they are hypertensive using published reference data for blood pressure in children, and increasingly through ambulatory blood pressure monitoring. Left ventricular hypertrophy based on echocardiography remains the most widely used indirect marker of hypertensive end organ change. New techniques for assessing target organ damage are being developed.

Measles-Associated Encephalopathy in Children with Renal Transplants

Two children, boys of 8 and 13 years, presented with measles‐associated encephalopathy several years after kidney transplantation for congenital nephrotic syndrome. In the absence of prior clinical measles, the neurological symptoms initially eluded diagnosis, but retrospective analysis of stored samples facilitated the diagnosis of measles‐associated encephalopathy without recourse to biopsy of deep cerebral lesions. Each had received a single dose of measles mumps and rubella vaccine before 12 months of age. Prior vaccination, reduction of immunosuppression and treatment with intravenous immunoglobulin and ribavirin may have contributed to their survival. Persistent measles virus RNA shedding, present in one child, was not controlled by treatment with i.v. ribavirin. Two years later, both patients continue to have functioning allografts with only minimal immunosuppression. These cases illustrate the difficulty in diagnosing measles‐associated encephalopathy in the immunocompromised host, even in the era of molecular diagnostics, and highlight the renewed threat of neurological disease in communities with incomplete herd immunity.

Postauricular fascial flap and suture otoplasty: A prospective outcome study of 227 patients

The anterior scoring technique is criticised for a higher risk of haematoma related complications while the suture techniques for suture-extrusion and recurrence. Horlock et. al. described a suture otoplasty with addition of a postauricular fascial flap to reduce suture extrusion and noted recurrence rates of 8%. We report the senior authors experience with this technique in 227 consecutive cases. All cases were done by or under supervision of the senior author and the data collected prospectively. Complications, recurrence, revision rate and results as recorded were analysed. A total of 10 (7 early 3 late) complications were recorded (4.4%). Suture extrusion (n = 6, 2.64%), Keloids (n = 3, 1.32%), Infection, anterior skin necrosis (n = 1 each, 0.44%). A total of 6 unilateral and 5 bilateral cases had a recurrence (3.67% total ears) and 97% of recorded outcomes were reported as good or excellent results. The low complication rate seems to support the hypothesis that the fascial flap prevents suture extrusion and reduces risk of recurrence. Lack of Anterior dissection avoids risks of bleeding and haematoma.