Background COVID‐19 is associated with increased risk of acute kidney injury (AKI). Risk factors and biomarkers linked to AKI have now been recognized by national guidelines in the United Kingdom. This analysis aims to validate and expand the comorbidities and biomarkers associated with the presence and severity of AKI in these patients. Methods Data were extracted via structured query language for patients with COVID‐19 at University Hospital Southampton between 1 March and 10 June 2020. Demographics, comorbidities, common biomarkers and AKI stage within 48 hours of admission, peak during admission and the last measurement prior to patient outcome (discharge or death) were collected and statistically analysed. Results Six hundred and thirty‐two COVID‐19 positive patients were admitted during this period; 34.2% had an AKI during their entire admission, 20.3% had AKI stage 1, 8.5% stage 2 and 5.4% stage 3. This was higher when compared with data from the same period in 2019. AKI carried an increased risk of death, 50.0% vs 21.1% (P = <.001). AKI stage was significantly associated with age over 65, diabetes, heart failure, peripheral vascular disease, haematological malignancy, hypertension, respiratory rate, albumin, C‐reactive protein (CRP), d‐dimer, ferritin, high‐sensitivity troponin‐I, neutrophil count, total white cell counts, National Early Warning Score‐2 (NEWS‐2), Charlson comorbidity index and alanine‐aminotransferase. COVID‐19 specific treatment, including dexamethasone, reduced discharge creatinine. Conclusion COVID‐19 increases the risk of AKI and this kidney injury may be responsive to treatment. This analysis identified that AKI is associated with both previously described and new comorbidities and biomarkers.
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The 100,000 Genomes Project (100KGP) diagnosed a quarter of recruited affected participants, but 26% of diagnoses were in genes not on the chosen gene panel(s); with many being de novo variants of high impact. However, assessing biallelic variants without a gene panel is challenging, due to the number of variants requiring scrutiny. We sought to identify potential missed biallelic diagnoses independent of the gene panel applied using GenePy - a whole gene pathogenicity metric. GenePy scores all variants called in a given individual, incorporating allele frequency, zygosity, and a user-defined deleterious metric (CADD v1.6 applied herein). GenePy then combines all variant scores for individual genes, generating an aggregate score per gene, per participant. We calculated GenePy scores for 2862 recessive disease genes in 78,216 individuals in 100KGP. For each gene, we ranked participant GenePy scores for that gene, and scrutinised affected individuals without a diagnosis whose scores ranked amongst the top-5 for each gene. We assessed these participants' phenotypes for overlap with the disease gene associated phenotype for which they were highly ranked. Where phenotypes overlapped, we extracted rare variants in the gene of interest and applied phase, ClinVar and ACMG classification looking for putative causal biallelic variants. 3184 affected individuals without a molecular diagnosis had a top-5 ranked GenePy gene score and 682/3184 (21%) had phenotypes overlapping with one of the top-ranking genes. After removing 13 withdrawn participants, in 122/669 (18%) of the phenotype-matched cases, we identified a putative missed diagnosis in a top-ranked gene supported by phasing, ClinVar and ACMG classification. A further 334/669 (50%) of cases have a possible missed diagnosis but require functional validation. Applying GenePy at scale has identified potential diagnoses for 456/3183 (14%) of undiagnosed participants who had a top-5 ranked GenePy score in a recessive disease gene, whilst adding only 1.2 additional variants (per individual) for assessment.
Background and Aims Hemizygous variants in chloride voltage-gated channel 5 (CLCN5) on chromosome Xp11.22 cause Dent disease type 1, characterised by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. We describe a truncating pathogenic variant in two brothers presenting with end-stage kidney disease (ESKD) and no evidence of nephrolithiasis or nephrocalcinosis. Method Two white British brothers presented to a different regional centre over 20 years ago with ESKD of unknown aetiology. The UK 100,000 Genomes Project provided a unique opportunity to make a molecular diagnosis using whole-genome sequencing linked to clinical records. Results The older brother presented with ESKD aged 23 with bilateral small kidneys and no evidence of nephrolithiasis or nephrocalcinosis on ultrasound. He had various musculoskeletal pains, 'cutaneous ectopic calcification' and secondary hyperparathyroidism, all of which improved post parathyroidectomy. Investigation of his 17-year-old brother for consideration of kidney transplant donation revealed progressive chronic kidney disease (CKD), microscopic haematuria, proteinuria (3g/24hours) and hypokalaemia. There was no nephrocalcinosis or renal calculi on ultrasound or cystoscopy. Renal biopsy showed tubulointerstitial changes with patchy fibrosis and marked chronic inflammatory cell infiltrates. He had a history of enuresis, polydipsia, delayed bone age and general developmental delay. ESKD by the age of 22 was complicated by hypertension and hyperparathyroidism requiring parathyroidectomy. Right knee pain with 'unusual osteochondral abnormality' on MRI resulted in a supracondylar femoral osteotomy. Early serum and urine biochemistry results were not available. A hemizygous nonsense variant p.Arg417Ter in CLCN5 was identified by whole-genome sequencing via the 100,000 Genomes Project. Sanger sequencing at the Wessex Regional Genetics Laboratory confirmed this. This variant was predicted to be protein-truncating, was absent in the genome aggregation database (gnomAD) and equivalent to a variant associated with Dent disease in other patients therefore classified as a class 5 pathogenic variant according to ACMG guidelines. Three male children with Dent disease have previously been reported with the pathogenic variant p.Arg347Ter. A seven and a twelve year old from two different families in Japan had microscopic haematuria, proteinuria, elevated β2-microglobulin and normal renal function. The twelve-year-old had mild hypercalciuria, but neither had a history of nephrolithiasis or nephrocalcinosis. A four-year-old Turkish boy manifested hypophosphataemia, nephrolithiasis and nephrocalcinosis. Unusually for Dent disease, he also had hypokalaemic hypochloraemic metabolic alkalosis and hyper-reninaemic hyperaldosteronism more characteristic of Bartter syndrome, but with elevated β2-microglobulin more typical of Dent disease. None of these cases had CKD but were all reported at a very young age. Conclusion Approximately 15% of patients with ESKD in Europe have an unknown aetiology. Dent disease has a variable phenotype and screening of patients for low molecular weight proteinuria such as β2-microglobulin is not routinely performed. Dent disease type 1 should be considered in patients presenting with unexplained renal failure even without typical clinical features.
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