Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.

Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.

INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.

Estimating Total Energy Expenditure to Determine Energy Requirements in Free-Living Children With Stage 3 Chronic Kidney Disease: Can a Structured Approach Help Improve Clinical Care?

OBJECTIVE: Malnutrition and obesity are complex burdensome challenges in pediatric chronic kidney disease (CKD) management that can adversely affect growth, disease progression, wellbeing, and response to treatment. Total energy expenditure (TEE) and energy requirements in children are essential for growth outcomes but are poorly defined, leaving clinical practice varied and insecure. The aims of this study were to explore a practical approach to guide prescribed nutritional interventions, using measurements of TEE, physical activity energy expenditure (PAEE), and their relationship to kidney function. DESIGN AND METHODS: In a cross-sectional prospective age-matched and sex-matched controlled study, 18 children with CKD (6-17 years, mean stage 3) and 20 healthy, age-matched, and gender-matched controls were studied. TEE and PAEE were measured using basal metabolic rate (BMR), activity diaries and doubly labeled water (healthy subjects). Results were related to estimated glomerular filtration rate (eGFR). The main outcome measure was TEE measured by different methods (factorial, doubly labeled water, and a novel device). RESULTS: Total energy expenditure and PAEE with or without adjustments for age, gender, weight, and height did not differ between the groups and was not related to eGFR. TEE ranged from 1927 ± 91 to 2330 ± 73 kcal/d; 95 ± 5 to 109 ± 5% estimated average requirement (EAR), physical activity level (PAL) 1.52 ± 0.01 to 1.71 ± 0.17, and PAEE 24 to 34% EAR. Comparisons between DLW and alternative methods in healthy children did not differ significantly, except for 2 (factorial methods and a fixed PAL; and the novel device). CONCLUSION: In clinical practice, structured approaches using supportive evidence (weight, height, BMI sds), predictive BMR or TEE values and simple questions on activity, are sufficient for most children with CKD as a starting energy prescription.

Fifteen-minute consultation: Empowering children, young people and families through shared decision-making: a practical guide.

Shared decision-making (SDM) is a collaborative approach to healthcare decision-making that involves patients and healthcare professionals working together to make decisions that are informed by the best available medical evidence, as well as the patient's values, preferences and goals. The importance of SDM and the intricate interplay among parents, children and young people (CYP), and healthcare professionals are increasingly acknowledged as the crucial aspects of delivering high-quality paediatric care. While there is a substantial evidence base for SDM improving knowledge and reducing decisional conflict, the evidence for long-term measures such as improved health outcomes is limited and mainly inconclusive. To support healthcare teams in implementing SDM, the authors offer a practical guide to enhance decision-making processes and empower CYP and their families.

Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/-) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6.

A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease.

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.

Association of nutritional status and health-related quality of life in children with chronic kidney disease.

PURPOSE: Health-related quality of life (HRQoL) is an important, patient-centred measure. Although nutritional status is altered in children with CKD, the impact of nutritional status on HRQoL in this population has not been explored. The aims of this study are to report the HRQoL scores as assessed by the validated PedsQL™ questionnaire and to explore the relationship of HRQoL scores to markers of nutritional status. It will also examine the concordance between the scores of the child and their parent/carer. METHODS: A single-centre, cross-sectional, observational study was performed exploring the markers of nutritional status (anthropometry-including presence of obesity, micronutrient status and appetite) and HRQoL and assessed by the PedsQL™ questionnaire in children aged 3-18 years with pre-dialysis, conservatively managed CKD. RESULTS: A total of 46 children were recruited, with a mean age of 10.5 years. HRQoL scores were lower than in healthy controls throughout all domains. Lower scores were associated with short stature and poor appetite. Markers of obesity or micronutrient status were not associated with HRQoL scores. DISCUSSION: Nutritional status impacts upon HRQoL. Further study is needed to evaluate how changing nutritional status may affect HRQoL in children with CKD, and this may be used to facilitate the development of patient-centred treatment goals and plans.

Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial.

This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure • There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: • A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD • This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.

Vitamin B6 in Pediatric Renal Transplant Recipients.

OBJECTIVES: Our aim was to assess the vitamin B6 intake and biochemical status in a sample of children who have undergone renal transplantation. METHODS: A prospective observational study was performed in 10 pediatric renal transplant recipients to determine their vitamin B6 status through dietary assessment and serum Pyridoxal 5'-phosphate (PLP) measurement. RESULTS: Ten children (mean age of 11.9 years) had median serum PLP concentrations of 62.45 nmol/L (interquartile range ±83.40). Two children (20%) had values above the reference range, and none below. Mean vitamin B6 intake was 138.7% of reference nutrient intake (standard deviation ±35.2%). No children were in receipt of vitamin B6 supplementation. CONCLUSION: There is no previous literature on vitamin B6 status in children who have undergone renal transplantation. In adult transplant recipients, elevated serum PLP concentrations have been described and ascribed to possible excessive intakes. In this sample, no children appeared biochemically deficient, but 20% had elevated concentrations. Dietary intakes were not excessive, and no children reported oral Vitamin B6 supplementation. Exploration of vitamin B6 metabolism in this population is required.

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.

Thrombotic microangiopathy following haematopoietic stem cell transplant.

Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.

AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis.

BACKGROUND: Deletions in the Xq22.3-Xq23 region, inclusive of COL4A5, have been associated with a contiguous gene deletion syndrome characterised by Alport syndrome with intellectual disability (Mental retardation), Midface hypoplasia and Elliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula. METHODS: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein. RESULTS: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother. CONCLUSIONS: Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.

Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland.

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange-treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody-targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody-mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.

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.

Tolvaptan treatment for severe neonatal autosomal-dominant polycystic kidney disease.

BACKGROUND: Severe neonatal autosomal-dominant polycystic kidney disease (ADPKD) is rare and easily confused with recessive PKD. Managing such infants is difficult and often unsuccessful. CASE DIAGNOSIS/TREATMENT: A female infant with massive renal enlargement, respiratory compromise and hyponatraemia was treated with the arginine vasopressin receptor 2 antagonist tolvaptan. This resolved hyponatraemia, and there was no further increase in renal size. CONCLUSION: Tolvaptan may be a useful treatment for severe neonatal PKD.

Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

Mutations in PIK3R1 cause SHORT syndrome.

SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.

Positive trends in paediatric renal biopsy service provision in the UK: a national survey and re-audit of paediatric renal biopsy practice.

BACKGROUND: Paediatric renal biopsy standards introduced in the UK in 2010 were intended to reduce variation and improve practice. A concurrent national drive was aimed at building robust paediatric nephrology networks to ensure services cater for the needs of the family and minimise time away from home. We aimed to identify current national practice since these changes on behalf of the British Association for Paediatric Nephrology. METHODS: All UK paediatric nephrology centres were invited to complete a survey of their biopsy practice, including advance preparation. From 1 January to 30 June 2012, a national prospective audit of renal biopsies was undertaken at participating centres comparing practice with the British Association for Paediatric Nephrology (BAPN) standards and audit results from 2005. RESULTS: Survey results from 11 centres demonstrated increased use of pre-procedure information leaflets (63.6 % vs 45.5 %, P = 0.39) and play preparation (90.9 % vs 9.1 %, P = 0.0001). Audit of 331 biopsies showed a move towards day-case procedures (49.5 % vs 32.9 %, P = 0.17) and reduced major complications (4.5 % vs 10.4 %, P = 0.002). Biopsies with 18-gauge needles had significantly higher mean pass rates (3.2 vs 2.3, P = 0.0008) and major complications (15.3 % vs 3.3 %, P = 0.0015) compared with 16-gauge needles. CONCLUSIONS: Percutaneous renal biopsy remains a safe procedure in children, thus improving family-centered service provision in the UK.

Basal metabolic rate in children with chronic kidney disease and healthy control children.

BACKGROUND: Meeting energy requirements of children with chronic kidney disease (CKD) is paramount to optimising growth and clinical outcome, but little information on this subject has been published. In this study, we examined basal metabolic rate (BMR; a component of energy expenditure) with the aim to determine whether it is related to kidney function independently of weight, height and lean body mass (LBM). METHODS: Twenty children with CKD and 20 healthy age- and gender-matched control children were studied on one occasion. BMR was measured by indirect open circuit calorimetry and predicted by the Schofield equation. Estimated glomerular filtration rate (eGFR) was related to BMR and adjusted for weight, height, age and LBM measured by skinfold thickness. RESULTS: The adjusted BMR of children with CKD did not differ significantly from that of healthy subjects (1296 ± 318 vs.1325 ± 178 kcal/day; p = 0.720). Percentage of predicted BMR also did not differ between the two groups (102 ± 12% vs. 99 ± 14%; p = 0.570). Within the CKD group, eGFR (mean 33.7 ± 20.5 mL/min/m(2)) was significantly related to BMR (ß 0.3, r = 0.517, p = 0.019) independently of nutritional status and LBM. CONCLUSIONS: It seems reasonable to use estimated average requirement as the basis of energy prescriptions for children with CKD (mean CKD stage 3 disease). However, those who were sicker had significantly lower metabolic rates.

Eculizumab in atypical haemolytic uraemic syndrome with severe cardiac and neurological involvement.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder usually caused by dysregulation of the alternative complement pathway. Uncontrolled complement activation results in systemic complement-mediated thrombotic microangiopathy (TMA) and subsequent multi-organ damage. The two most common extrarenal complications comprise neurological and cardiovascular involvement. Eculizumab, a humanised anti-C5 monoclonal antibody, has recently been introduced as a therapy for this condition. CASE-DIAGNOSIS/TREATMENT: A 19-month-old child suffering from aHUS with severe neurological involvement, dilated cardiomyopathy and renal impairment requiring dialysis received eculizumab as first-line treatment, initiated within 12 h of admission, resulting in significant improvements in her neurological state and normalisation of cardiac and renal function. These positive outcomes have been sustained with fortnightly eculizumab therapy (at the time of writing, on-going for 1 year). No further complications of TMA have occurred. CONCLUSION: Severe cardiac involvement in a child with aHUS is an important indication for prompt, first-line treatment with eculizumab, resulting in rapid normalisation of cardiac function.