Background: The prevalence of Alport syndrome varies from one in 5,000 to one in 53,000. This study estimated the frequencies of predicted pathogenic COL4A3- COL4A5 variants in sequencing databases of populations without known kidney disease. Methods: Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria that considered collagen IV α3-α5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3-COL4A5 variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants. Results:COL4A3-COL4A5 variants resulting in position 1 Gly substitutions were confirmed associated with haematuria (p each <0.0001). Predicted pathogenic COL4A5 variants were found in at least one in 2,320 individuals. p.(Gly624Asp), represented nearly half (16/33, 48%) the variants in Europeans. Most COL4A5 variants (54/59, 92%) had a biochemical feature that potentially mitigated clinical impact. Predicted pathogenic heterozygous COL4A3 and COL4A4 variants affected one in 106 of the population, consistent with the finding of Thin basement membrane nephropathy in normal donor kidney biopsies. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals and digenic variants in at least one in 44,793. Conclusions: The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3-COL4A5 variants but must be adjusted for the disease penetrance of individual variants, as well as the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.
BackgroundAcute kidney injury (AKI) is a significant cause of morbidity and mortality. Early identification may improve the outcome and in 2012 our hospital introduced an automated AKI alert system for early detection and management of AKI.ObjectivesUsing an automated AKI alert system we analysed whether early review and intervention by the Critical Care and Outreach (CCOT) team improved patient outcomes in AKI and whether serum bicarbonate was useful in predicting outcomes in patients with AKI.MethodsIn a retrospective analysis we identified patients who triggered an AKI alert from 20 April 2012 to 20 September 2013 and collected data on mortality, length of stay, need for intensive care admission and renal replacement therapy (RRT).Results994 AKI alerts were generated and analysed. Patients with bicarbonate outside the normal range had significantly higher mortality. Bicarbonate <22 mmol/L was associated with a mortality of 25.7% (49/191) compared with 16.9% (39/231) when 22–29 mmol/L (p=0.047, χ2). Those patients reviewed ≥1 day after AKI alert by CCOT compared with those seen on the day of the alert had a 2.4 times increase in mortality and were 7 times more likely to require RRT acutely.ConclusionsElectronically identified AKI alerts identify patients at high risk of morbidity and mortality. In this group AKI alerts preceded CCOT review by a mean of 2 days. This represents a window for supportive interventions, which may explain improved outcomes in those reviewed earlier. The addition of serum bicarbonate offers a further method of risk stratifying patients at greater risk of death.
We developed a digitally enabled care pathway for acute kidney injury (AKI) management incorporating a mobile detection application, specialist clinical response team and care protocol. Clinical outcome data were collected from adults with AKI on emergency admission before (May 2016 to January 2017) and after (May to September 2017) deployment at the intervention site and another not receiving the intervention. Changes in primary outcome (serum creatinine recovery to ≤120% baseline at hospital discharge) and secondary outcomes (30-day survival, renal replacement therapy, renal or intensive care unit (ICU) admission, worsening AKI stage and length of stay) were measured using interrupted time-series regression. Processes of care data (time to AKI recognition, time to treatment) were extracted from casenotes, and compared over two 9-month periods before and after implementation (January to September 2016 and 2017, respectively) using pre–post analysis. There was no step change in renal recovery or any of the secondary outcomes. Trends for creatinine recovery rates (estimated odds ratio (OR) = 1.04, 95% confidence interval (95% CI): 1.00–1.08, p = 0.038) and renal or ICU admission (OR = 0.95, 95% CI: 0.90–1.00, p = 0.044) improved significantly at the intervention site. However, difference-in-difference analyses between sites for creatinine recovery (estimated OR = 0.95, 95% CI: 0.90–1.00, p = 0.053) and renal or ICU admission (OR = 1.06, 95% CI: 0.98–1.16, p = 0.140) were not significant. Among process measures, time to AKI recognition and treatment of nephrotoxicity improved significantly ( p < 0.001 and 0.047 respectively).
BackgroundPrimary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN.MethodsWe analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource–Rare Diseases Study. We examined copy number, rare, and common variants.ResultsOur analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10−8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10−8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure.ConclusionsWe found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.
Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3–COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
BackgroundThe development of acute kidney injury (AKI) in hospitalized patients is associated with adverse outcomes and increased health care costs. Simple automated e-alerts indicating its presence do not appear to improve outcomes, perhaps because of a lack of explicitly defined integration with a clinical response.ObjectiveWe sought to test this hypothesis by evaluating the impact of a digitally enabled intervention on clinical outcomes and health care costs associated with AKI in hospitalized patients.MethodsWe developed a care pathway comprising automated AKI detection, mobile clinician notification, in-app triage, and a protocolized specialist clinical response. We evaluated its impact by comparing data from pre- and postimplementation phases (May 2016 to January 2017 and May to September 2017, respectively) at the intervention site and another site not receiving the intervention. Clinical outcomes were analyzed using segmented regression analysis. The primary outcome was recovery of renal function to ≤120% of baseline by hospital discharge. Secondary clinical outcomes were mortality within 30 days of alert, progression of AKI stage, transfer to renal/intensive care units, hospital re-admission within 30 days of discharge, dependence on renal replacement therapy 30 days after discharge, and hospital-wide cardiac arrest rate. Time taken for specialist review of AKI alerts was measured. Impact on health care costs as defined by Patient-Level Information and Costing System data was evaluated using difference-in-differences (DID) analysis.ResultsThe median time to AKI alert review by a specialist was 14.0 min (interquartile range 1.0-60.0 min). There was no impact on the primary outcome (estimated odds ratio [OR] 1.00, 95% CI 0.58-1.71; P=.99). Although the hospital-wide cardiac arrest rate fell significantly at the intervention site (OR 0.55, 95% CI 0.38-0.76; P<.001), DID analysis with the comparator site was not significant (OR 1.13, 95% CI 0.63-1.99; P=.69). There was no impact on other secondary clinical outcomes. Mean health care costs per patient were reduced by £2123 (95% CI −£4024 to −£222; P=.03), not including costs of providing the technology.ConclusionsThe digitally enabled clinical intervention to detect and treat AKI in hospitalized patients reduced health care costs and possibly reduced cardiac arrest rates. Its impact on other clinical outcomes and identification of the active components of the pathway requires clarification through evaluation across multiple sites.
There is currently no agreed universal definition for sarcopenia, but the EWGSOP and FNIH advocate HGS cut-offs as part of their definition. The prevalence of muscle weakness varies according to cut-off and whether age-matched and gender-matched normative data are used. In addition, patient characteristics in terms of age and comorbidity determine the prevalence of muscle weakness.
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