•Medical treatment for 12 weeks reduced serum PFOS by 60 % in a randomized cross-over study in a highly exposed population.•Serum concentrations of all measured PFAS decreased significantly in the ...treatment period.•Findings may offer a potential treatment to especially vulnerable, highly exposed populations.
Per- and polyfluoroalkyl substances (PFAS) are heat and stain resisting chemicals. They are persistent, bioaccumulating and spread ubiquitously. Many hotspots where humans are exposed to high levels of PFAS have been reported. A few small observational studies in humans suggest that treatment with an Anion Exchange Resin (AER) decreases serum PFAS. This first clinical controlled crossover study aimed to assess whether AER decreases perfluorooctanesulfonic acid (PFOS) in highly exposed adults.
An open label 1:1 randomized treatment sequence crossover study with allocation to oral AER (cholestyramine 4 g three times daily) or observation for 12 weeks was conducted among citizens from a PFAS hotspot. Main inclusion criteria was serum PFOS > 21 ng/mL. Primary endpoint was change in serum PFOS levels between treatment and observational period.
In total, 45 participants were included with a mean age of 50 years (SD 13). Serum PFOS baseline median was 191 ng/mL (IQR: 129–229) and decreased with a mean of 115 ng/mL (95 % CI: 89–140) on treatment, and 4.3 ng/mL in observation period corresponding to a decrease of 60 % (95 % CI: 53–67; p < 0.0001). PFHxS, PFOA, PFNA and PFDA decreased during treatment between 15 and 44 %. No serious adverse events were reported.
Oral treatment with AER significantly lowered serum PFOS concentrations suggesting a possible treatment for enhancing elimination of PFOS in highly exposed adults.
Enhancing early help-seeking is important for early intervention in psychosis. However, knowledge is limited about those help-seekers who are not initially found to have psychotic symptoms when ...assessed in services aiming at psychosis detection and, thus, deemed ineligible for early intervention of psychosis programs. We aimed to examine clinical diagnostic and socioeconomic pathways of help-seekers accessing an early detection of psychosis service with referral-free access. Specific focus was on the help-seekers initially assessed not to have psychotic symptoms, considered the non-cases, and to examine potential differences and similarities between non-cases and cases (i.e., those initially assessed to have psychotic symptoms).
We followed 450 help-seekers assessed by a free-of-referral early detection of psychosis team in national registers for up to 4 years. We examined clinical diagnoses and status of not in education, employment, or training (NEET) before and after contact with the team.
Of the non-cases, 46% were referred to mental health services by the early detection of psychosis team for evaluation of other mental disorders, and 15% of these were subsequently diagnosed with a non-affective psychotic disorder during follow-up of 12-52 months. Prior to current help-seeking, 39% (
= 174) of the help-seekers had had contact with other mental health services. Nearly a quarter of help-seekers were NEETs at the time of assessment; the number increased during follow-up, both for cases and non-cases. Of the cases, 58% were subsequently clinically diagnosed by mental health services. Those seeking help who had no previous contact with mental health services were more frequently diagnosed with a non-affective psychotic disorder during follow-up (
= 0.05).
Referral-free services to promote early detection of psychosis seem a valuable add-on to established pathways, allowing early intervention in psychosis. Our results point to an unmet mental health service need among non-cases; overall, in our sample, independent of case status, social functioning was markedly affected. Our results have implications for future focus in early detection of psychosis. Offering intervention to non-cases within the service has the potential to be cost effective, e.g., if a timely and targeted intervention reduces repeated contacts in other mental health services and social services.
Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many ...patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease.
We conducted a meta-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators. We included randomised controlled trials, and the first period of randomised cross over trials lasting ≥4 weeks in adults.
Nineteen trials (21 study groups, 1 646 patients) were included. In random effects meta-analysis, addition of mineralocorticoid receptor antagonists to renin angiotensin system inhibition resulted in a reduction from baseline in systolic blood pressure (-5.7 -9.0, -2.3 mmHg), diastolic blood pressure (-1.7 -3.4, -0.1 mmHg) and glomerular filtration rate (-3.2 -5.4, -1.0 mL/min/1.73 m(2)). Mineralocorticoid receptor antagonism reduced weighted mean protein/albumin excretion by 38.7 % but with a threefold higher relative risk of withdrawing from the trial due to hyperkalaemia (3.21, 1.19, 8.71). Death, cardiovascular events and hard renal end points were not reported in sufficient numbers to analyse.
Mineralocorticoid receptor antagonism reduces blood pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit.
The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients ...with microalbuminuria (MA) is unknown.
Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years.
CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank Mantel-Cox p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model.
A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionPatients receiving haemodialysis are at increased risk of arrhythmias and sudden cardiac death, but data on arrhythmia burden and the pathophysiology remain limited. Among potential risk ...factors, hypoglycaemia is proposed as a possible trigger of lethal arrhythmias. The development of implantable loop recorders (ILR) and continuous glucose monitoring (CGM) enables long-term continuous ECG and glycaemic monitoring. The current article presents the protocol of a study aiming to increase the understanding of arrhythmias and risk factors in patients receiving haemodialysis. The findings will provide a detailed exploration of the burden and nature of arrhythmias in these patients including the potential association between hypoglycaemia and arrhythmias.Methods and analysisThe study is an investigator-initiated, prospective, multicentre cohort study recruiting 70 patients receiving haemodialysis: 35 with diabetes and 35 without diabetes. Participants are monitored with ILRs and CGM for 18 months follow-up. Data collection further includes a monthly collection of predialysis blood samples and dialysis parameters. The primary outcome is the presence of clinically significant arrhythmias defined as a composite of bradycardia, ventricular tachycardia, or ventricular fibrillation. Secondary outcomes include the characterisation of clinically significant arrhythmias and other arrhythmias, glycaemic characteristics, and mortality. The data analyses include an assessment of the association between arrhythmias and hypoglycaemia and hyperglycaemia, baseline clinical variables, and parameters related to kidney failure and the haemodialysis procedure.Ethics and disseminationThe study has been approved by the Ethics Committee of the Capital Region of Denmark (H-20069767). The findings will be presented at national and international congresses as well as in international peer-reviewed scientific journals.Trial registration numberNCT04841304.
CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration ...rate (eGFR) to <60 ml/min per 1.73 m
.
In analyses of 2087 individuals from 6 cohorts (46.4% women; 73.5% with diabetes; mean age, 46.1 years; eGFR ≥ 60 ml/min per 1.73 m
, 100%; urinary albumin excretion rate UAE ≥20 μg/min, 6.2%), we accounted for cohort, sex, age, mean arterial pressure, diabetes, and eGFR at baseline and expressed associations per 1-SD increment in urinary biomarkers.
Over 5 (median) follow-up visits, eGFR decreased more with higher baseline CKD273 than UAE (1.64 vs. 0.82 ml/min per 1.73 m
;
< 0.0001). Over 4.6 years (median), 390 participants experienced a first renal endpoint (eGFR decrease by ≥10 to <60 ml/min per 1.73 m
), and 172 experienced an endpoint sustained over follow-up. The risk of a first and sustained renal endpoint increased with UAE (hazard ratio ≥ 1.23;
≤ 0.043) and CKD273 (≥ 1.20;
≤ 0.031). UAE (≥20 μg/min) and CKD273 (≥0.154) thresholds yielded sensitivities of 30% and 33% and specificities of 82% and 83% (
≤ 0.0001 for difference between UAE and CKD273 in proportion of correctly classified individuals). As continuous markers, CKD273 (
= 0.039), but not UAE (
= 0.065), increased the integrated discrimination improvement, while both UAE and CKD273 improved the net reclassification index (
≤ 0.0003), except for UAE per threshold (
= 0.086).
In conclusion, while accounting for baseline eGFR, albuminuria, and covariables, CKD273 adds to the prediction of stage 3 chronic kidney disease, at which point intervention remains an achievable therapeutic target.
Discomfort related to cuff inflation may bias 24 h ambulatory blood pressure (BP) measurements, especially during night-time. We accessed the impact of cuff inflations by comparing 24 h BP recorded ...with a cuff-less tonometric wrist device and an upper-arm oscillometric cuff device. Fifty-three participants with type 2 diabetes were assigned randomly to four 24-h BP recordings with a cuff (TM2430: visit 1 or 2, and 4) and a tonometric device (BPro: visit 1 or 2, 3, and 4). The mean 24 h systolic BP was significantly higher when measured with the cuff versus the tonometric device (141.6±14.6 vs. 128.3±14.6 mmHg, P≤0.01), as was nocturnal BP (6.7±5.3 vs. 10.3±7.6%, P=0.002). In conclusion, nocturnal BP decline was higher when measured with the cuff device, suggesting that cuff inflations did not increase night-time BP. Further evaluation of the tonometric device using the updated European Society of Hypertension International Protocol revision 2010 is recommended before applying it in daily clinical practice.
Abstract
BACKGROUND AND AIMS
Mineralocorticoid receptor antagonist treatment is kidney protective but not recommended in patients with advanced renal failure due to perceived risk of hyperkalaemia ...and death. The aim of the present study was to examine the impact of mineralocorticoid receptor antagonist treatment in progressive chronic kidney disease on risk of hyperkalaemia and to evaluate subsequent attributable mortality.
METHOD
Based on data from multiple nationwide health care registers, all Danish residents >18 years with more than or equal to one recorded plasma creatinine measurement were identified in Denmark between 2008 and 2021, and followed until either incident hyperkalaemia >6 mmol/L, death or end-of follow-up (5 October 2021). Cases were identified based on incident hyperkalaemia and subsequently matched with four controls without hyperkalaemia. eGFR was computed based on the latest creatinine measurement until 30 days prior to index using the CKD-EPI equation. Patients with no recorded creatinine measurement within 2 years until 30 days prior of index were excluded. Mineralocorticoid receptor antagonist associated susceptibility for hyperkalaemia was computed across strata of estimated glomerular filtration rate (eGFR) (>60, 30–60 and <30 mL/min/1.73 m2) in a conditional logistic regression model comparing rate of hyperkalaemia with stratification of baseline hazard rate by age, gender, diabetes and hypertension. Model fitting was accomplished using a nested case–control design with 1:4 risk-set matching of cases with age-, gender-, diabetes- and hypertension-matched controls. Subsequent risk of 30-day mortality was assessed in a retrospective cohort study including patients with hyperkalemia only. Patients were followed from the date of hyperkalemia until death, 30 days or end of follow-up (5 October 2021) with comparison of MRA-attributable mortality across strata of eGFR based on the Kaplan–Meier estimator and multiple Cox regression models adjusted for age and gender.
RESULTS
From a population of 4 255 962 Danish citizens with recorded plasma creatinine, a total of 51 775 patients with incident hyperkalaemia were identified between 2008 and 2021. Pre-existing plasma creatinine permitting estimation of renal function was available in 34 442 (66.5%) patients. The 34 442 cases with incident hyperkalaemia were matched 1:4 with 131 410 controls. Gender distribution was 57% male, median age was 73.5 (IQR 64.0–82.0) years and median eGFR was 74 (IQR 55–89) mL/min/1.73 m2.
Mineralocorticoid receptor antagonist treatment was associated with increased rates of hyperkalaemia with HRs of 8.32 (95% CI: 7.82–8.85), 4.55 (95% CI: 4.26–4.86) and 2.00 (95% CI: 1.71–2.32) in patients with eGFR > 60 mL/min/1.73 m2 eGFR 30–60 mL/min/1.73 m2 and eGFR < 30 mL/min/1.73 m2 respectively (reference = No mineralocorticoid receptor antagonist treatment).
30-day mortality in patients with hyperkalaemia stratified on mineralocorticoid receptor antagonist treatment is shown in Figures 1 and 2. Overall, mineralocorticoid receptor antagonist treatment was associated with lower subsequent mortality: HR 0.84 (95% CI: 0.78–0.90); P < 0.001, 0.67 (95% CI: 0.62–0.73); P < 0.001 and 0.98 (95% CI: 0.86–1.1); P = 0.77 for eGFR > 60 mL/min/1.73 m2 30–60 mL/min/1.73 m2 and <30 mL/min/1.73 m2 respectively (reference = mineralocorticoid receptor antagonist).
CONCLUSION
Although mineralocorticoid receptor antagonist treatment was associated with increased risk of hyperkalaemia for all strata of kidney impairment, subsequent 30-day mortality was lower compared with patients with corresponding kidney function without mineralocorticoid receptor antagonist treatment.
Background
Diabetic nephropathy (DN) is associated with cardiovascular disease. Microalbuminuria (MA), its traditional hallmark, reflects both renal and generalised vascular damage. We previously ...established a urinary proteomic classifier (CKD273) for early DN prediction that correlates with other biomarkers of renal function. Whether CKD273 only indicates renal damage or also generalised vascular disease remains unclear.
Methods
We recruited 80 patients with type 2 diabetes (age, 62±7 years; blood pressure 138±11/79±8mmHg) free from cardiovascular complications with normal renal function (eGFR (88±15 ml/min/1.73m
2
) and normoalbuminuria (albumin: creatinine ratio (UACR), 5 (2–16) mg/g). Participants underwent measurement of carotid-femoral pulse wave velocity (PWV; SphygmoCor) and carotid intima media thickness (cIMT; ultrasound). Urinary proteomic analysis was performed by capillary electrophoresis coupled to mass spectrometry.
Results
Mean CKD273 score (−0.234±0.376) was well below the pre-established cut-off (0.343) for diagnosis of DN. There was a trend towards higher CKD273 score in patients with UACR above the median (−0.160±0.372
vs
−0.318±0.368;
P
= 0.061). Median time from diabetes diagnosis was 11 (1–30) years; diabetes control was suboptimal (HbA1c, 62 (45–102) mmol/mol); and participants had subclinical vascular damage (PWV, 9.2 (6.4–12.5) m/s; cIMT, 0.850 (0.543–1.292) mm). As expected we saw a significant correlation between PWV and systolic blood pressure (
r
= 0.259;
P =
0.024). The CKD273 classifier did not correlate with PWV (
r
= 0.174;
P
= 0.132) or cIMT (
r
= −0.096;
P
= 0.415).
Conclusion
CKD273 is not a marker of subclinical macrovascular disease in normoalbuminuric type 2 diabetic patients without overt cardiovascular complications. Our data provide further evidence that CKD273 is a specific marker of renal damage.
Mineralocorticoid receptor antagonist (MRA) treatment is kidney protective but not recommended to patients with advanced renal failure due to the risk of hyperkalemia and death. This study aimed to ...examine the impact of MRA treatment in patients with chronic kidney disease on risk of hyperkalemia and subsequent mortality.
Rates of hyperkalemia were compared across strata of estimated glomerular filtration rate (eGFR) and MRA treatment based on cox regression using a nested case-control framework with 1 : 4 matching of patients with hyperkalemia (K + ≥6.0 mmol/l) with controls from the Danish general population on age, sex, diabetes, and hypertension. Risk of subsequent 30-day mortality was assessed in a cohort study with comparisons across strata of eGFR and MRA treatment based on multiple Cox regression.
Thirty-two thousand four hundred twenty-six cases with hyperkalemia were matched with 127 038 controls. MRA treatment was associated with an increased rate of hyperkalemia with hazard ratios 95% confidence interval (95% CI) of 8.28 (7.78-8.81), 5.12 (4.67-5.62), 3.58 (3.23-3.97), and 1.89 (1.60-2.23) in patients with eGFR at least 60, 45-59, 30-44, and less than 30 ml/min/1.73 m 2 , respectively (Reference: No MRA).However, MRA-exposed patients had a lower 30-day mortality risk following hyperkalemia with absolute risks (95% CI) of 29.3% (27.8-31.1), 20.3% (18.7-22.4), 19.5% (17.9-21.7), and 19.7% (17.4-22.5) compared to 39.8% (38.8-40.8), 32.0% (30.7-33.1), 28.8% (27.5-31.2), and 22.5% (21.4-23.4) in patients without MRA exposure in patients with GFR at least 60, 45-59, 30-44, and less than 30 ml/min/1.7 3m 2 , respectively.
MRA treatment was associated with an increased rate of hyperkalemia but decreased risk of subsequent 30-day mortality across all stages of renal impairment.
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