Derivation of a prediction model for emergency department acute kidney injury.

BACKGROUND AND OBJECTIVE: Quality management of Acute Kidney Injury (AKI) is dependent on early detection, which is currently deemed to be suboptimal. The aim of this study was to identify combinations of variables associated with AKI and to derive a prediction tool for detecting patients attending the emergency department (ED) or hospital with AKI (ED-AKI). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: This retrospective observational study was conducted in the ED of a tertiary university hospital in Wales. Between April and August 2016 20,421 adult patients attended the ED of a University Hospital in Wales and had a serum creatinine measurement. Using an electronic AKI reporting system, 548 incident adult ED-AKI patients were identified and compared to a randomly selected cohort of adult non-AKI ED patients (n = 571). A prediction model for AKI was derived and subsequently internally validated using bootstrapping. The primary outcome measure was the number of patients with ED-AKI. RESULTS: In 1119 subjects, 27 variables were evaluated. Four ED-AKI models were generated with C-statistics ranging from 0.800 to 0.765. The simplest and most practical multivariate model (model 3) included eight variables that could all be assessed at ED arrival. A 31-point score was derived where 0 is minimal risk of ED-AKI. The model discrimination was adequate (C-statistic 0.793) and calibration was good (Hosmer & Lomeshow test 27.4). ED-AKI could be ruled out with a score of <2.5 (sensitivity 95%). Internal validation using bootstrapping yielded an optimal Youden index of 0.49 with sensitivity of 80% and specificity of 68%. CONCLUSION: A risk-stratification model for ED-AKI has been derived and internally validated. The discrimination of this model is objective and adequate. It requires refinement and external validation in more generalisable settings.

Epidemiology of emergency department acute kidney injury.

AIM: The epidemiology of acute kidney injury (AKI) diagnosed in the emergency department (ED) is poorly described. This study describes the incidence, demographics and outcomes of patients diagnosed with AKI in the ED (ED-AKI). METHODS: A prospective cohort study was completed in a University Teaching Hospital, (UK) between April and August 2016. In total, 20 421 adult patients attended the ED and had a serum creatinine measurement. The incident ED-AKI patient episodes were compared with a randomly selected cohort of non-AKI ED patients. RESULTS: A total of 572 patients had confirmed eAlert ED-AKI (548 incident cases), incidence 2.8% (of all ED attendances). ED-AKI was associated with a 24.4% in-patient mortality (non-AKI 3.2%, P < .001) of which 22.3% of deaths occurred within 24 hours and 58% within 7 days. Progression of the admission AKI stage to a higher AKI stage was associated with a 38.8% mortality compared with a 21.4% mortality in those who did not progress (P < .001). In multivariate analysis, ED-AKI was an independent risk for mortality (hazard ratio, 6.293; 95% confidence interval, 1.887-20.790, P = .003). For those discharged from hospital, 20.4% of ED-AKI patients re-attend for acute assessment within 30-days post-discharge (non-AKI 7.6%, P < .001). At 90-days post-discharge, 10.0% of ED-AKI patients died (non-AKI 1.4%, P < .001). Twelve months post-discharge 17.8% of ED-AKI patients developed CKD progression or de-novo CKD (non-AKI 6.0%). CONCLUSION: The ED-AKI is an independent predictor of death. Mortality is predominantly in the early stages of hospital admission, but for those who survive to discharge have significant long-term morbidity and mortality.

Functional characterization of novel ABCB6 mutations and their clinical implications in familial pseudohyperkalemia.

Isolated familial pseudohyperkalemia is a dominant red cell trait characterized by cold-induced 'passive leak' of red cell potassium ions into plasma. The causative gene of this condition is ABCB6, which encodes an erythrocyte membrane ABC transporter protein bearing the Langereis blood group antigen system. In this study analyzing three new families, we report the first functional characterization of ABCB6 mutants, including the homozygous mutation V454A, heterozygous mutation R276W, and compound heterozygous mutations R276W and R723Q (in trans). All these mutations are annotated in public databases, suggesting that familial pseudohyperkalemia could be common in the general population. Indeed, we identified variant R276W in one of 327 random blood donors (0.3%). Four weeks' storage of heterozygous R276W blood cells resulted in massive loss of potassium compared to that from healthy control red blood cells. Moreover, measurement of cation flux demonstrated greater loss of potassium or rubidium ions from HEK-293 cells expressing ABCB6 mutants than from cells expressing wild-type ABCB6. The R276W/R723Q mutations elicited greater cellular potassium ion efflux than did the other mutants tested. In conclusion, ABCB6 missense mutations in red blood cells from subjects with familial pseudohyperkalemia show elevated potassium ion efflux. The prevalence of such individuals in the blood donor population is moderate. The fact that storage of blood from these subjects leads to significantly increased levels of potassium in the plasma could have serious clinical implications for neonates and infants receiving large-volume transfusions of whole blood. Genetic tests for familial pseudohyperkalemia could be added to blood donor pre-screening. Further study of ABCB6 function and trafficking could be informative for the study of other pathologies of red blood cell hydration.

Epidemiology and outcome of community-acquired acute kidney injury.

AIMS: Very little data exist regarding community-acquired acute renal injury (CA-AKI). We have identified and characterized a patient cohort with CA-AKI, and documented its impact on renal function and patient mortality. METHODS: Using the database of the Medical Biochemistry Department of the Cardiff and Vale University Health Board we identified all patients with CA-AKI over a 1 month period in 2009. Follow-up biochemical and clinical data were used to determine short-term (3 months) and long-term (3 years) outcomes. Comparisons were made to a random and an age/sex matched group. RESULTS: Patients with CA-AKI were older than a non-AKI cohort (70.3 vs 57.1 years; P < 0.0001), with a 61% male predominance. 38% had pre-existing chronic kidney disease (CKD) compared with 25% in the age- and sex-matched non-CA-AKI cohort (P = 0.007). 54% of CA-AKI were admitted for inpatient care. Admission was associated with a higher incidence of complete recovery of renal function. Mortality at 3 months was 16.5%, and was related to the severity of AKI. Over the 3 years of follow-up 71% of patients with CA-AKI developed progressive CKD which was more likely following incomplete/no recovery of renal function and in the context of pre-existing CKD. Three year mortality was 45%, which was higher than that of the age/sex matched control cohort (15.7%; P < 0.0001), but was not related to the development of progressive CKD. CONCLUSIONS: CA-AKI carries significant implications in terms of both development of progressive renal disease and high long-term patient mortality.

Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans.

BACKGROUND: Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects. METHODS AND RESULTS: Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; P<0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, -0.36; 95% confidence interval, -0.50 to -0.23; P<0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, -0.37; 95% confidence interval, -0.55 to -0.19; P=0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, -0.52; 95% confidence interval, -0.70 to -0.34; P<0.0001). CONCLUSIONS: Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals.

A rare case of persistent hyperkalaemia.

Hyperkalaemia is a common biochemical finding that can allude to preanalytical or truly pathological causes. Here, we present a case of a 41-year-old female patient who has regularly presented with incidences of isolated hyperkalaemia since 2012, with otherwise normal renal function and no other associated symptoms. Investigations into the patient's family history revealed similar biochemical findings in her brother and eldest son. Familial causes of hyperkalaemia were investigated and an eventual diagnosis of pseudo-hypoaldosteronism type 2C was established. This is a rare congenital renal tubular disorder - also known as Gordon syndrome - that can cause a characteristic triad of symptoms that include hyperkalaemia, metabolic acidosis and hypertension. The presence and severity of each of these symptoms is dependent upon the disease-causing mutation that occurs in WNK4, WNK1, CUL3 or KLHL3 genes. These mutations alter the regulation of sodium/chloride co-transporter (NCC) expression on the luminal membrane of the principal cells of the distal convoluted tubule, disrupting normal homeostatic regulation of electrolyte reabsorption and excretion. The resolution for treating this condition is the administration of a thiazide diuretic, which directly counteracts the effects of NCC co-transporter overexpression and consequently aims to resolve the symptoms that arise as a result of this aberrant signalling. The case described here uniquely presents an extremely rare pathogenic variant in the conserved acidic motif of WNK1 resulting in a clear electrolyte phenotype with no hypertension.

Clinical and laboratory characteristics of clozapine-treated patients with schizophrenia referred to a national immunodeficiency clinic reveals a B-cell signature resembling common variable immunodeficiency (CVID).

AIMS: An association between antibody deficiency and clozapine use in individuals with schizophrenia has recently been reported. We hypothesised that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns. METHODS: Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunological features for individuals with diagnosis of schizophrenia-like illness. RESULTS: 1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizoaffective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI: 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT. CONCLUSIONS: Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency common variable immunodeficiency, however appears reversible on drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group.

Phospholipase D activity is essential for actin localization and actin-based motility in Dictyostelium.

PLD (phospholipase D) activity catalyses the generation of the lipid messenger phosphatidic acid, which has been implicated in a number of cellular processes, particularly the regulation of membrane traffic. In the present study, we report that disruption of PLD signalling causes unexpectedly profound effects on the actin-based motility of Dictyostelium. Cells in which PLD activity is inhibited by butan-1-ol show a complete loss of actin-based structures, accompanied by relocalization of F-actin into small clusters, and eventually the nucleus, without a visible fall in levels of F-actin. Addition of exogenous phosphatidic acid reverses the effects of butan-1-ol, confirming that these effects are caused by inhibition of PLD. Loss of motility correlates with complete inhibition of endocytosis and a reduction in phagocytosis. Inhibition of PLD caused a major decrease in the synthesis of PtdIns(4,5)P2, which could again be reversed by exogenously applied phosphatidic acid. Thus the essential role of PLD signalling in both motility and endocytosis appears to be mediated directly via regulation of PtdIns(4)P kinase activity. This implies that localized PLD-regulated synthesis of PtdIns(4,5)P2 is essential for Dictyostelium actin function.

Does elective parathyroidectomy for primary hyperparathyroidism affect renal function? A prospective cohort study.

INTRODUCTION: Major surgery is associated with acute kidney injury (AKI). This study examines associations between elective parathyroid surgery and post-operative renal impairment. METHODS: Consecutive patients undergoing elective parathyroidectomy were evaluated, and demographic data and relevant blood parameters collected. A renal risk score was calculated for each patient based on locally agreed criteria. RESULTS: 62 patients were evaluated. Mean ± standard deviation creatinine increased between pre-operative and day 1 post-operative (72 ± 19 vs. 76 ± 20 µmol/L; p < 0.010). Mean eGFR reduced between baseline and day 1 (78 ± 15 vs. 75 ± 16; p < 0.010) and baseline and follow-up (78 ± 15 vs. 73 ± 17; p < 0.050). 19 patients (30.7%) had a creatinine increase of ≥10% on day 1 post-operatively and 7 (11.3%) a rise of >20%. At follow-up, 14 (30.4% of 46 patients with follow up creatinine measurements) and 5 (10.9%) patients had a creatinine of >10% and >20% higher than pre-operative or day 1 values respectively. Those with an increase in serum creatinine of ≥10% (at any time point) had a greater renal risk score [median 2 (inter-quartile range, IQR 0-3) vs. 1 (0-2); p = 0.040]. CONCLUSION: A significant minority of patients undergoing elective parathyroid surgery demonstrate worsening renal function post-operatively. A pre-operative risk stratification tool may identify those at risk in the clinical setting.

A comparison of different methods of demand management on requesting activity in a teaching hospital intensive care unit.

BACKGROUND: Laboratory services in the UK have witnessed an annual increase in requesting activity often with no associated increase in budget. This study evaluated the impact of different demand management strategies on biochemistry test requesting activity from a tertiary Intensive Care Unit (ICU) at a UK teaching hospital. METHOD: We conducted an observational longitudinal study in which biochemistry requesting activity from the ICU was gathered over five separate six-month periods between 2009 and 2013. During this time, two different strategies aimed at reducing inappropriate biochemistry requesting were in use and the effects of the two strategies were compared. RESULTS: Implementation of minimum re-testing intervals (MRIs) resulted in an overall 22.7% reduction in total requesting activity in the first year with minor change in clinical workload. In the second year, a 13.3% rise in requesting activity was seen but this was against a background of a 14.6% increase in ICU workload. Removal of the MRIs rules associated with the introduction of an ICU test testing schedule resulted in a 13.4% reduction in total requesting activity in the first year. ICU workload during this year was 1.8% lower than the previous year. In the final year, requesting activity was almost unchanged but ICU workload grew by 6.8%. CONCLUSION: Implementation of MRIs reduced biochemistry test requesting activity on the ICU. Introduction of an agreed test schedule and removal of the MRIs, however, produced a further reduction in ICU requesting activity. Variation in ICU workload does not account for all the observed changes.

The impact of local guidelines on the tumour marker requesting patterns of a General Surgery Department.

BACKGROUND: The inappropriate use of tumour markers (TMs) is a common problem. The aim of this audit was to evaluate the impact of local guidelines on the TM requesting patterns of a General Surgery Department. METHODS: CA 125, CA 19-9, CA15-3, CEA, AFP and HCG requests from all hospital surgical locations were audited over two periods of eight months before and after the implementation of local requesting guidelines. RESULTS: Postintervention, total TM requests decreased by 32% while patient requests decreased by 9.8%. Single TM requesting increased and requests for panels containing four or more TMs decreased from 279 to 60 requests (78% reduction). CONCLUSION: Interdepartmental collaboration and the implementation of local guidelines have resulted in a change in requesting behaviour, most notably a reduction in multiple TM panel requests.