High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.

Cardiovascular outcomes in patients with chronic kidney disease and COVID-19: a multi-regional data-linkage study.

BACKGROUND: Data describing cardiovascular outcomes in patients with coronavirus disease 2019 (COVID-19) and chronic kidney disease (CKD) are lacking. We compared cardiovascular outcomes of patients with and without COVID-19, stratified by CKD status. METHODS: This retrospective, multi-regional data-linkage study utilised individual patient-level data from two Scottish cohorts. All patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Cohort 1 between 1 February 2020 and 31 March 2021 and in Cohort 2 between 28 February 2020 and 8 February 2021 were included. RESULTS: Overall, 86 964 patients were tested for SARS-CoV-2. There were 36 904 patients (mean±sd age 61±21 years; 58.1% women; 15.9% CKD; 10.1% COVID-19 positive) in Cohort 1 and 50 060 patients (mean±sd age 63±20 years; 62.0% women; 16.4% CKD; 9.1% COVID-19 positive) in Cohort 2. In CKD patients, COVID-19 increased the risk of cardiovascular death by more than two-fold within 30 days (cause-specific hazard ratio (csHR) meta-estimate 2.34, 95% CI 1.83-2.99) and by 57% at the end of study follow-up (csHR meta-estimate 1.57, 95% CI 1.31-1.89). Similarly, the risk of all-cause death in COVID-19 positive versus negative CKD patients was greatest within 30 days (HR 4.53, 95% CI 3.97-5.16). Compared with patients without CKD, those with CKD had a higher risk of testing positive (11.5% versus 9.3%). Following a positive test, CKD patients had higher rates of cardiovascular death (11.1% versus 2.7%), cardiovascular complications and cardiovascular hospitalisations (7.1% versus 3.3%) than those without CKD. CONCLUSIONS: COVID-19 increases the risk of cardiovascular and all-cause death in CKD patients, especially in the short-term. CKD patients with COVID-19 are also at a disproportionate risk of cardiovascular complications than those without CKD.

Utility of interval kidney biopsy in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is a rare autoimmune disorder that commonly involves the kidney. Early identification of kidney involvement, assessing treatment-response and predicting outcome are important clinical challenges. Here, we assessed the potential utility of interval kidney biopsy in AAV. METHODS: In a tertiary referral centre with a dedicated vasculitis service, we identified patients with AAV who had undergone interval kidney biopsy, defined as a repeat kidney biopsy (following an initial biopsy showing active AAV) undertaken to determine the histological response in the kidney following induction immunosuppression. We analysed biochemical, histological and outcome data, including times to kidney failure and death for all patients. RESULTS: We identified 57 patients with AAV who underwent at least one interval kidney biopsy (59 interval biopsies in total; median time to interval biopsy ∼130 days). Of the 59 interval biopsies performed, 24 (41%) patients had clinically suspected active disease at time of biopsy which was confirmed histologically in only 42% of cases; 35 (59%) patients were in clinical disease-remission, and this was correct in 97% of cases. The clinician's impression was incorrect in one in four patients. Hematuria at interval biopsy did not correlate with histological activity. Interval biopsy showed fewer acute lesions and more chronic damage compared with initial biopsy and led to immunosuppressive treatment-change in 75% (44/59) of patients. Clinical risk prediction tools tended to operate better using interval biopsy data. CONCLUSION: Interval kidney biopsy is useful for determining treatment-response and subsequent disease management in AAV. It may provide better prognostic information than initial kidney biopsy and should be considered for inclusion into future clinical trials and treatment protocols for patients with AAV.

Long-term outcomes in elderly patients with ANCA-associated vasculitis.

OBJECTIVE: ANCA-associated vasculitis (AAV) is a small vessel vasculitis that commonly presents in the elderly. However, there are few long-term outcome data for these patients. Here, we assessed long-term outcomes in a single-centre cohort of elderly patients with AAV. Additionally, we tested whether a pre-morbid frailty score could aid prognosis. METHODS: Using a prospectively-compiled dataset, we investigated patients over the age of 65 who presented with AAV between 2005 and 2017 to a regional vasculitis centre. We used a Cox model to determine the factors associated with mortality. We also compared outcomes in pre-specified subgroups stratified by baseline frailty score, ANCA serotype and induction immunosuppression (with cyclophosphamide, rituximab or mycophenolate mofetil used as the main glucocorticoid-sparing agent). RESULTS: 83 patients were included in the study and were followed for a median of 1203 days. Median age was 74 years (range 65-92). Two- and five-year survival in the overall cohort were 83% (95% CI 75, 92%) and 75% (95% CI 65, 86%), respectively. The median cumulative dose of oral prednisolone was 2030 mg during the first three months. Only one patient received intravenous glucocorticoids. Age, frailty score and CRP at presentation were independently associated with mortality; all deaths occurred in patients aged over 75 at presentation. Patients treated with a cyclophosphamide-based induction regimen tended to be younger than those treated with rituximab or mycophenolate mofetil. Survival was better in the cyclophosphamide-treated group. CONCLUSION: In the contemporary era, the overall prognosis of AAV in elderly patients is good. Baseline frailty associates with disease outcomes including mortality. A low-dose glucocorticoid regimen (avoiding intravenous methylprednisolone) can be used to treat AAV effectively in elderly patients.

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome.

BACKGROUND: High-sensitivity cardiac troponin testing may improve the risk stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment, and the effectiveness of testing in this group is uncertain. METHODS: In a prospective multicenter study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate <60mL/min/1.73m2). The negative predictive value and sensitivity of troponin concentrations below the risk stratification threshold (5 ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value and specificity at the 99th centile diagnostic threshold (16 ng/L in women, 34 ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year. RESULTS: Of 4726 patients identified, 904 (19%) had renal impairment. Troponin concentrations <5 ng/L at presentation identified 17% of patients with renal impairment as low risk for the primary outcome (negative predictive value, 98.4%; 95% confidence interval [CI], 96.0%-99.7%; sensitivity 98.9%; 95%CI, 97.5%-99.9%), in comparison with 56% without renal impairment (P<0.001) with similar performance (negative predictive value, 99.7%; 95% CI, 99.4%-99.9%; sensitivity 98.4%; 95% CI, 97.2%-99.4%). The positive predictive value and specificity at the 99th centile were lower in patients with renal impairment at 50.0% (95% CI, 45.2%-54.8%) and 70.9% (95% CI, 67.5%-74.2%), respectively, in comparison with 62.4% (95% CI, 58.8%-65.9%) and 92.1% (95% CI, 91.2%-93.0%) in those without. At 1 year, patients with troponin concentrations >99th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% versus 10%; adjusted hazard ratio, 2.19; 95% CI, 1.54-3.11). CONCLUSIONS: In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low risk and more as high risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had a 2-fold greater risk of a major cardiac event than those with normal renal function, and should be considered for further investigation and treatment. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Activation of podocyte Notch mediates early Wt1 glomerulopathy.

The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.

Pulse-wave velocity is associated with cognitive impairment in haemodialysis patients.

Chronic kidney disease (CKD) is common, its prevalence increasing with age. Cognitive impairment is common in the elderly, in CKD and in those on maintenance haemodialysis. As cognitive impairment is the precursor to dementia, the identification of reversible risk factors for cognitive decline is the key to reducing dementia risk. Arterial stiffness is one such potential risk factor. It is independently associated with cardiovascular outcome in dialysis patients. Importantly, the recent demonstration of an independent association between arterial stiffness and cognitive impairment in these patients suggests that vascular stiffness might be potentially causative in the development of cognitive impairment and also be an opportune target for interventions. Whether unstiffening of blood vessels in patients on maintenance haemodialysis can reduce the incidence of cognitive impairment or indeed slow its progression to dementia, remain unanswered questions. In this issue of the Clinical Science, Angermann and colleagues present thought-provoking data related to cognitive impairment in haemodialysis patients.

A systematic literature review on the health-related quality of life and economic burden of Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disease associated with glycolipid accumulation that impacts multiple physiological systems. We conducted a systematic literature review (SLR) to characterize the humanistic (quality of life [QoL]) and economic burden of FD. METHODS: Searches were conducted in the Embase, MEDLINE®, and MEDLINE® In-Process databases from inception to January 19, 2022. Conference abstracts of specified congresses were manually searched. Additional searches were performed in the Cochrane and ProQuest databases for the humanistic SLR and the National Health Service Economic Evaluations Database for the economic SLR. Studies of patients with FD of any sex, race, and age, and published in the English language were included. There was no restriction on intervention or comparator. For the humanistic SLR, studies that reported utility data, database/registry-based studies, questionnaires/surveys, and cohort studies were included. For the economic SLR, studies reporting economic evaluations or assessing the cost of illness and resource use were included. RESULTS: Of the 1363 records identified in the humanistic search, 36 studies were included. The most commonly used QoL assessments were the 36-item Short-Form Health Survey (n = 16), EQ-5D questionnaire descriptive system or visual analog scale (n = 9), and the Brief Pain Inventory (n = 8). Reduced QoL was reported in patients with FD compared with healthy populations across multiple domains, including pain, physical functioning, and depressive symptoms. Multiple variables-including sex, age, disease severity, and treatment status-impacted QoL. Of the 711 records identified in the economic burden search, 18 studies were included. FD was associated with high cost and healthcare resource use. Contributors to the cost burden included enzyme replacement therapy, healthcare, and social care. In the seven studies that reported health utility values, lower utility scores were generally associated with more complications (including cardiac, renal, and cerebrovascular morbidities) and with classical disease in males. CONCLUSION: FD remains associated with a high cost and healthcare resource use burden, and reduced QoL compared with healthy populations. Integrating information from QoL and economic assessments may help to identify interventions that are likely to be of most value to patients with FD.

WT1 in disease: shifting the epithelial-mesenchymal balance.

WT1 is a versatile gene that controls transitions between the mesenchymal and epithelial state of cells in a tissue-context dependent manner. As such, WT1 is indispensable for normal development of many organs and tissues. Uncontrolled epithelial to mesenchymal transition (EMT) is a hallmark of a diverse array of pathologies and disturbance of mesenchymal to epithelial transition (MET) has been associated with a number of developmental abnormalities. It is therefore not surprising that WT1 has been linked to many of these. Here we review the role of WT1 in proper control of the mesenchymal-epithelial balance of cells and discuss how far these roles can explain the role of WT1 in a variety of disease states.

Acute kidney injury in the UK: a replication cohort study of the variation across three regional populations.

OBJECTIVES: A rapid growth in the reported rates of acute kidney injury (AKI) has led to calls for greater attention and greater resources for improving care. However, the reported incidence of AKI also varies more than tenfold between previous studies. Some of this variation is likely to stem from methodological heterogeneity. This study explores the extent of cross-population variation in AKI incidence after minimising heterogeneity. DESIGN: Population-based cohort study analysing data from electronic health records from three regions in the UK through shared analysis code and harmonised methodology. SETTING: Three populations from Scotland, Wales and England covering three time periods: Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. PARTICIPANTS: All residents in each region, aged 15 years or older. MAIN OUTCOME MEASURES: Population incidence of AKI and AKI phenotype (severity, recovery, recurrence). Determined using shared biochemistry-based AKI episode code and standardised by age and sex. RESULTS: Respectively, crude AKI rates (per 10 000/year) were 131, 138, 139, 151 and 124 (p=0.095), and after standardisation for age and sex: 147, 151, 146, 146 and 142 (p=0.257) for Grampian 2003, 2007 and 2012; Swansea 2007; and Salford 2012. The pattern of variation in crude rates was robust to any modifications of the AKI definition. Across all populations and time periods, AKI rates increased substantially with age from ~20 to ~550 per 10 000/year among those aged <40 and ≥70 years. CONCLUSION: When harmonised methods are used and age and sex differences are accounted for, a similar high burden of AKI is consistently observed across different populations and time periods (~150 per 10 000/year). There are particularly high rates of AKI among older people. Policy-makers should be careful not draw simplistic assumptions about variation in AKI rates based on comparisons that are not rigorous in methodological terms.

Clinical Aspects of WT1 and the Kidney.

For more than 30 years, WT1 mutations have been associated with complex developmental syndromes involving the kidney. Acting as a transcription factor, WT1 is expressed throughout the nephron and controls the reciprocal interactions and phenotypic changes required for normal renal development. In the adult, WT1 expression remains extremely high in the renal podocyte, and at a lower level in the parietal epithelial cells. Wt1-null mice are unable to form kidneys [1]. Unsurprisingly, WT1 mutations lead to significant abnormalities of the renal and genitourinary tract, causing a number of human diseases including syndromes such as Denys-Drash syndrome, Frasier syndrome, and WAGR syndrome. Recent methodological advances have improved the identification of WT1 mutations, highlighting its importance even in nonsyndromic renal disease, particularly in steroid-resistant nephrotic syndrome. This vast spectrum of WT1-related disease typifies the varied and complex activity of WT1 in development, disease, and tissue maintenance.

A universal vector for high-efficiency multi-fragment recombineering of BACs and knock-in constructs.

There is an increasing need for more efficient generation of transgenic constructs. Here we present a universal multi-site Gateway vector for use in recombineering reactions. Using transgenic mouse models, we show its use for the generation of BAC transgenics and targeting vectors. The modular nature of the vector allows for rapid modification of constructs to generate different versions of the same construct. As such it will help streamline the generation of series of related transgenic models.