1,720,983 research outputs found
Bilineal inheritance of PKD1 abnormalities mimicking autosomal recessive polycystic disease
No full textBACKGROUND: Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent.CASE-DIAGNOSIS/TREATMENT: We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1.CONCLUSIONS: Biallelic inheritance of abnormalities of PKD1 may cause extremely severe disease resembling autosomal dominant polycystic kidney disease (ADPKD) which can result in diagnostic confusion. Accurate diagnosis is essential for genetic counseling
Hemizygous loss of function mutations in CLCN5 causing end-stage kidney disease without Dent disease phenotype
No full textDent disease type 1 is suspected in the presence of a complete phenotype of low molecular weight (LMW) proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, nephrolithiasis, haematuria, hypophosphatemia or chronic kidney disease (CKD). We present two brothers who presented with CKD alone. In the absence of typical clinical features, further assessment of LMW proteinuria and hypercalciuria was not undertaken. Whole-genome sequencing revealed hemizygous loss of function mutations in chloride voltage-gated channel 5 (CLCN5) consistent with Dent disease. Dent disease should, therefore, be considered in patients with an incomplete phenotype, including unexplained CKD alone
Thrombotic microangiopathy following haematopoietic stem cell transplant
No full textThrombotic 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.</p
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease
No full textWe sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10
–4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10
–8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10
–5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
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Exome analysis resolves differential diagnosis of familial kidney disease and uncovers a potential confounding variant
Get PDFEstimating 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?
No full textObjective: 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
AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis
No full textBackground: 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.<br/
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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