Nicholas J. A. Webb

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.

A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard‐dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 ± 0.32 with TAC/MMF/DAC and 0.03 ± 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04–0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05–0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy‐proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Unilateral multicystic dysplastic kidney: the case for nephrectomy

Management of unilateral multicystic dysplastic kidneys (MCDK) presents physicians and surgeons with a significant dilemma. Recent studies have indicated that the incidence of short term complications of MCDK is low and many authors have recommended conservative non-operative treatment. Surgery has been proposed by some because of the potential complications of hypertension, infection, and malignant change. Three children with hypertension secondary to MCDK seen at this institution in the past four years, one of whom had been discharged from follow up as a result of ‘disappearance’ of the cystic kidney on ultrasound examination, are reported. We believe that the risks of hypertension secondary to MCDK have been understated, and that based on the conclusions of these studies, many children may be receiving suboptimal follow up. We currently favour elective nephrectomy as the treatment of choice for this lesion.

Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Immunisation against varicella in end stage and pre-end stage renal failure

OBJECTIVES To investigate the seroconversion rate and duration of persistence of protective antibody titres after varicella immunisation in children with renal failure. DESIGN 32 children (25 end stage and 7 pre-end stage renal failure) were immunised using 2 × 2000 plaque forming unit doses of varicella vaccine 3 months apart. Varicella antibody titres were measured by enzyme linked immunosorbent assay. RESULTS All children initially seroconverted after immunisation. At a mean follow up of 20.3 months, 23 of 28 had protective antibody titres, 4 children having died of unrelated causes. Two children required a third booster dose. 11 children underwent renal transplantation; 10 had protective titres at the time of transplantation and, at a mean of 23.4 months after immunisation, 6 currently have protective titres. Minor side effects occurred after 11 vaccine doses in 9 children. No child developed varicella, despite 10 clear episodes of exposure to the wild-type virus. CONCLUSIONS Varicella immunisation in children with end stage and pre-end stage renal failure results in a high rate of seroconversion and persistence of protective antibody titres. More widespread use of the vaccine before renal transplantation is recommended.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6‐month, multicenter, randomized, controlled, open‐label, parallel‐group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus‐based regimen in pediatric renal transplant recipients. Patients <18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10–20 ng/mL between days 0–21 and 5–15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients <40 kg) or 20 mg (patients ≥40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy‐proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid‐resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 μmol/L in the TAS and 91 μmol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus‐based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Building consensus on transition of transplant patients from paediatric to adult healthcare

Objective Despite improvements in recent years at many centres, there remains an overall lack of consistency in the healthcare and support services provided to young people during their transition from paediatric to adult transplant units. Concerns that such deficiencies may be causally related to subsequent graft loss through patient non-concordance have prompted calls for the delivery of a more patient-centred service. To address these issues, representatives from major transplantation centres in the UK (cardiac, hepatic, renal) and across all disciplines were brought together to produce a series of consensus statements specifying key actions needed to improve the quality and consistency of transition healthcare. Design Participants at the meeting included transplant physicians and surgeons from both adult and paediatric centres, allied health professionals (nurse specialists, psychologists, psychosocial support workers, transplant coordinators, youth workers), as well as young or adolescent transplant patients, their parents/carers and representatives of various support groups concerned with the young transitioning patient. The meeting consisted of presentations, group discussions (plenary and breakout) and a final discussion led by the seven participants who comprised the consensus panel. Results Seven consensus statements emerged from the meeting, which are strongly representative of the current opinion of families and the UK transplant community. Conclusions The actions they specify may therefore be seen as recommendations for timely and wide adoption, and as guidelines for best practice.

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.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Vitamin D deficiency in children with renal disease

Aims: The purpose of this study was to assess the vitamin D status of children with renal disease attending the outpatient clinics of our tertiary nephrology centre, allowing us to determine the prevalence of vitamin D deficiency and study its relationship with glomerular filtration rate (GFR) and serum parathyroid hormone (PTH) concentration. Methods: 90 boys and 53 girls (99 white Caucasians, 38 of South Asian origin and six from other ethnic groups) were enrolled into the study. 18 were on dialysis (15 peritoneal dialysis and three haemodialysis), 61 had a functioning renal transplant (19 with reduced GFR), 18 had chronic renal failure and 46 had a variety of renal disorders with normal renal function. Serum/plasma concentrations of 25(OH)D, 1,25(OH)2D, PTH, creatinine, calcium, phosphate and alkaline phosphatase were measured. Patients with serum 25(OH)D concentrations of less than 25 nmol/l were considered to be deficient and those with levels of 25–50 nmol/l considered insufficient. Results: 26% of all patients were 25(OH)D deficient and a further 32% were insufficient. The prevalence in South Asians was higher (87% deficient/insufficient) than in white Caucasians (46% deficient/insufficient, p<0.001). In children with reduced GFR who were not on dialysis, 25(OH)D levels of less than 50 nmol/l were associated with a high PTH in 90% of cases compared to only 50% of those with normal vitamin D concentrations (p = 0.013). Conclusion: A high proportion of renal patients were vitamin D deficient/insufficient, particularly children of South Asian origin. High PTH values in the setting of reduced GFR might be due to vitamin D deficiency and should lead to estimation of serum 25(OH)D concentration.