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Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.
Kourek, C, Briasoulis, A, Papamichail, A, Xanthopoulos, A, Tsougos, E, Farmakis, D, Paraskevaidis, I
International journal of molecular sciences. 2024;(6)
Abstract
Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include β-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.
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Urea for Chronic Hyponatremia.
Rondon-Berrios, H
Blood purification. 2020;(1-2):212-218
Abstract
BACKGROUND Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous. Recent evidence suggests that even milder forms of hyponatremia are associated with increased morbidity and mortality. Despite this, currently available treatments for chronic hyponatremia lack data on efficacy and/or have important limitations related to patient nonadherence, adverse side effects, and/or significant costs. Consequently, there is a clear need for investigation of alternative treatments for this common condition. SUMMARY Small case series conducted in Europe since the early 1980s suggest that urea, an oral osmotic diuretic that increases urinary water excretion, is safe and effective for the treatment of chronic hyponatremia. In 2016, a novel formulation of urea became available in the United States. Our group recently reported the first and only study describing the efficacy and safety of this American formulation of oral urea among hospitalized patients with hyponatremia. Key Messages: Oral urea appears to be an effective, safe, and well-tolerated therapeutic strategy in the management of chronic hyponatremia.
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Non-invasive diagnostic tests for Helicobacter pylori infection.
Best, LM, Takwoingi, Y, Siddique, S, Selladurai, A, Gandhi, A, Low, B, Yaghoobi, M, Gurusamy, KS
The Cochrane database of systematic reviews. 2018;(3):CD012080
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Abstract
BACKGROUND Helicobacter pylori (H pylori) infection has been implicated in a number of malignancies and non-malignant conditions including peptic ulcers, non-ulcer dyspepsia, recurrent peptic ulcer bleeding, unexplained iron deficiency anaemia, idiopathic thrombocytopaenia purpura, and colorectal adenomas. The confirmatory diagnosis of H pylori is by endoscopic biopsy, followed by histopathological examination using haemotoxylin and eosin (H & E) stain or special stains such as Giemsa stain and Warthin-Starry stain. Special stains are more accurate than H & E stain. There is significant uncertainty about the diagnostic accuracy of non-invasive tests for diagnosis of H pylori. OBJECTIVES To compare the diagnostic accuracy of urea breath test, serology, and stool antigen test, used alone or in combination, for diagnosis of H pylori infection in symptomatic and asymptomatic people, so that eradication therapy for H pylori can be started. SEARCH METHODS We searched MEDLINE, Embase, the Science Citation Index and the National Institute for Health Research Health Technology Assessment Database on 4 March 2016. We screened references in the included studies to identify additional studies. We also conducted citation searches of relevant studies, most recently on 4 December 2016. We did not restrict studies by language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA We included diagnostic accuracy studies that evaluated at least one of the index tests (urea breath test using isotopes such as 13C or 14C, serology and stool antigen test) against the reference standard (histopathological examination using H & E stain, special stains or immunohistochemical stain) in people suspected of having H pylori infection. DATA COLLECTION AND ANALYSIS Two review authors independently screened the references to identify relevant studies and independently extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We performed meta-analysis by using the hierarchical summary receiver operating characteristic (HSROC) model to estimate and compare SROC curves. Where appropriate, we used bivariate or univariate logistic regression models to estimate summary sensitivities and specificities. MAIN RESULTS We included 101 studies involving 11,003 participants, of which 5839 participants (53.1%) had H pylori infection. The prevalence of H pylori infection in the studies ranged from 15.2% to 94.7%, with a median prevalence of 53.7% (interquartile range 42.0% to 66.5%). Most of the studies (57%) included participants with dyspepsia and 53 studies excluded participants who recently had proton pump inhibitors or antibiotics.There was at least an unclear risk of bias or unclear applicability concern for each study.Of the 101 studies, 15 compared the accuracy of two index tests and two studies compared the accuracy of three index tests. Thirty-four studies (4242 participants) evaluated serology; 29 studies (2988 participants) evaluated stool antigen test; 34 studies (3139 participants) evaluated urea breath test-13C; 21 studies (1810 participants) evaluated urea breath test-14C; and two studies (127 participants) evaluated urea breath test but did not report the isotope used. The thresholds used to define test positivity and the staining techniques used for histopathological examination (reference standard) varied between studies. Due to sparse data for each threshold reported, it was not possible to identify the best threshold for each test.Using data from 99 studies in an indirect test comparison, there was statistical evidence of a difference in diagnostic accuracy between urea breath test-13C, urea breath test-14C, serology and stool antigen test (P = 0.024). The diagnostic odds ratios for urea breath test-13C, urea breath test-14C, serology, and stool antigen test were 153 (95% confidence interval (CI) 73.7 to 316), 105 (95% CI 74.0 to 150), 47.4 (95% CI 25.5 to 88.1) and 45.1 (95% CI 24.2 to 84.1). The sensitivity (95% CI) estimated at a fixed specificity of 0.90 (median from studies across the four tests), was 0.94 (95% CI 0.89 to 0.97) for urea breath test-13C, 0.92 (95% CI 0.89 to 0.94) for urea breath test-14C, 0.84 (95% CI 0.74 to 0.91) for serology, and 0.83 (95% CI 0.73 to 0.90) for stool antigen test. This implies that on average, given a specificity of 0.90 and prevalence of 53.7% (median specificity and prevalence in the studies), out of 1000 people tested for H pylori infection, there will be 46 false positives (people without H pylori infection who will be diagnosed as having H pylori infection). In this hypothetical cohort, urea breath test-13C, urea breath test-14C, serology, and stool antigen test will give 30 (95% CI 15 to 58), 42 (95% CI 30 to 58), 86 (95% CI 50 to 140), and 89 (95% CI 52 to 146) false negatives respectively (people with H pylori infection for whom the diagnosis of H pylori will be missed).Direct comparisons were based on few head-to-head studies. The ratios of diagnostic odds ratios (DORs) were 0.68 (95% CI 0.12 to 3.70; P = 0.56) for urea breath test-13C versus serology (seven studies), and 0.88 (95% CI 0.14 to 5.56; P = 0.84) for urea breath test-13C versus stool antigen test (seven studies). The 95% CIs of these estimates overlap with those of the ratios of DORs from the indirect comparison. Data were limited or unavailable for meta-analysis of other direct comparisons. AUTHORS' CONCLUSIONS In people without a history of gastrectomy and those who have not recently had antibiotics or proton ,pump inhibitors, urea breath tests had high diagnostic accuracy while serology and stool antigen tests were less accurate for diagnosis of Helicobacter pylori infection.This is based on an indirect test comparison (with potential for bias due to confounding), as evidence from direct comparisons was limited or unavailable. The thresholds used for these tests were highly variable and we were unable to identify specific thresholds that might be useful in clinical practice.We need further comparative studies of high methodological quality to obtain more reliable evidence of relative accuracy between the tests. Such studies should be conducted prospectively in a representative spectrum of participants and clearly reported to ensure low risk of bias. Most importantly, studies should prespecify and clearly report thresholds used, and should avoid inappropriate exclusions.
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Molecular and physiological interactions of urea and nitrate uptake in plants.
Pinton, R, Tomasi, N, Zanin, L
Plant signaling & behavior. 2016;(1):e1076603
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Abstract
While nitrate acquisition has been extensively studied, less information is available on transport systems of urea. Furthermore, the reciprocal influence of the two sources has not been clarified, so far. In this review, we will discuss recent developments on plant response to urea and nitrate nutrition. Experimental evidence suggests that, when urea and nitrate are available in the external solution, the induction of the uptake systems of each nitrogen (N) source is limited, while plant growth and N utilization is promoted. This physiological behavior might reflect cooperation among acquisition processes, where the activation of different N assimilatory pathways (cytosolic and plastidic pathways), allow a better control on the nutrient uptake. Based on physiological and molecular evidence, plants might increase (N) metabolism promoting a more efficient assimilation of taken-up nitrogen. The beneficial effect of urea and nitrate nutrition might contribute to develop new agronomical approaches to increase the (N) use efficiency in crops.
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Kt/V (and especially its modifications) remains a useful measure of hemodialysis dose.
Daugirdas, JT
Kidney international. 2015;(3):466-73
Abstract
Removal of small molecular weight solutes shows a strong relationship to hemodialysis outcomes. In contrast, survival with high-flux dialysis or hemodiafiltration is only slightly better than with low-flux hemodialysis. Despite laboratory evidence regarding toxicity of protein-bound uremic solutes, few data exist showing that increased removal of this class of molecules impacts outcomes. In the FHN trials, there was no effect of frequent dialysis, including frequent and long dialysis, on nutrition or control of anemia, outcomes expected to be sensitive to uremic toxin removal; the main benefit appeared to be better volume control. Scaling of hemodialysis dose to total body water may not be optimal. Kt/V scaling to body surface area and use of a continuous measure such as standard Kt/V reduces the likelihood of underdialysis of small patients, including children, and women. Minimum hemodialysis time may best be considered in respect to ultrafiltration rate, and a maximum target ultrafiltration rate unscaled to body size may be optimal. Intensive, extended dialysis may cause adverse effects to residual kidney function, and more information needs to be collected to better understand how urine volume modifies dose requirements, and how to maximize the chances of preserving residual kidney function.
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Once upon a time in dialysis: the last days of Kt/V?
Vanholder, R, Glorieux, G, Eloot, S
Kidney international. 2015;(3):460-5
Abstract
After its proposal as a marker of dialysis adequacy in the eighties of last century, Kt/V(urea) helped to improve dialysis efficiency and to standardize the procedure. However, the concept was developed when dialysis was almost uniformly short and was applied thrice weekly with small pore cellulosic dialyzers. Since then dialysis evolved in the direction of many strategic alternatives, such as extended or daily dialysis, large pore high-flux dialysis, and convective strategies. Although still a useful baseline marker, Kt/V(urea) no longer properly covers up for most of these modifications so that urea kinetics are hardly if at all representative for those of other solutes with a deleterious effect on morbidity and mortality of uremic patients. This is corroborated in several clinical studies showing a dissociation between removal of urea and that of other uremic toxins. In addition, randomized controlled trials showed no benefit of increasing Kt/V(urea). Finally, this parameter also hardly is evocative for metabolic or intestinal generation of toxins, for their removal by residual renal function and for the complex interaction of dialysis length with removal pattern and patient outcomes. We conclude that apart from being a baseline parameter of dialysis adequacy, Kt/V(urea) insufficiently represents all novel strategic changes of modern dialysis. Kt/V(urea) is too simple a concept for the complexities of uremia and of today's dialysis.
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Recognising acute kidney injury.
Jones, M
Clinical medicine (London, England). 2012;(3):287-9
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Finding the cause of acute kidney injury: which index of fractional excretion is better?
Gotfried, J, Wiesen, J, Raina, R, Nally, JV
Cleveland Clinic journal of medicine. 2012;(2):121-6
Abstract
The fractional excretion of urea (FEU) is a useful index for differentiating the main categories of causes of acute kidney injury, ie, prerenal causes and intrinsic causes. It may be used in preference to the more widely used fractional excretion of sodium (FENa) in situations in which the validity of the latter is limited, such as in patients taking a diuretic.
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What is the value of routinely testing full blood count, electrolytes and urea, and pulmonary function tests before elective surgery in patients with no apparent clinical indication and in subgroups of patients with common comorbidities: a systematic review of the clinical and cost-effective literature.
Czoski-Murray, C, Lloyd Jones, M, McCabe, C, Claxton, K, Oluboyede, Y, Roberts, J, Nicholl, JP, Rees, A, Reilly, CS, Young, D, et al
Health technology assessment (Winchester, England). 2012;(50):i-xvi, 1-159
Abstract
BACKGROUND The evidence base which supported the National Institute for Health and Clinical Excellence (NICE) published Clinical Guideline 3 was limited and 50% was graded as amber. However, the use of tests as part of pre-operative work-up remains a low-cost but high-volume activity within the NHS, with substantial resource implications. The objective of this study was to identify, evaluate and synthesise the published evidence on the clinical effectiveness and cost-effectiveness of the routine use of three tests, full blood counts (FBCs), urea and electrolytes tests (U&Es) and pulmonary function tests, in the pre-operative work-up of otherwise healthy patients undergoing minor or intermediate surgery in the NHS. OBJECTIVE The aims of this study were to estimate the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in adult patients classified as American Society of Anaesthesiologists (ASA) grades 1 and 2 undergoing elective minor (grade 1) or intermediate (grade 2) surgical procedures; to compare NICE recommendations with current practice; to evaluate the cost-effectiveness of mandating or withdrawing each of these tests in this patient group; and to identify the expected value of information and whether or not it has value to the NHS in commissioning further primary research into the use of these tests in this group of patients. DATA SOURCES The following electronic bibliographic databases were searched: (1) BIOSIS; (2) Cumulative Index to Nursing and Allied Health Literature; (3) Cochrane Database of Systematic Reviews; (4) Cochrane Central Register of Controlled Trials; (5) EMBASE; (6) MEDLINE; (7) MEDLINE In-Process & Other Non-Indexed Citations; (8) NHS Database of Abstracts of Reviews of Effects; (9) NBS Health Technology Assessment Database; and (10) Science Citation Index. To identify grey and unpublished literature, the Cochrane Register of Controlled Trials, National Research Register Archive, National Institute for Health Research Clinical Research Network Portfolio database and the Copernic Meta-search Engine were searched. A large routine data set which recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. REVIEW METHODS A systematic review of the literature was carried out. The searches were undertaken in March to April 2008 and June 2009. Searches were designed to retrieve studies that evaluated the clinical effectiveness and cost-effectiveness of routine pre-operative testing of FBC, electrolytes and renal function and pulmonary function in the above group of patients. A postal survey of current practice in testing patients in this group pre-operatively was undertaken in 2008. An exemplar cost-effectiveness model was constructed to demonstrate what form this would have taken had there been sufficient data. A large routine data set that recorded the results of tests was obtained from Leeds Teaching Hospitals Trust. This was linked to individual patient data with surgical outcomes, and regression models were estimated. RESULTS A comprehensive and systematic search of both the clinical effectiveness and cost-effectiveness literature identified a large number of potentially relevant studies. However, when these studies were subjected to detailed review and quality assessment, it became clear that the literature provides no evidence on the clinical effectiveness and cost-effectiveness of these specific tests in the specific patient groups. The postal survey had a 17% response rate. Results reported that in ASA grade 1, patients aged < 40 years with no comorbidities undergoing minor surgery did not have routine tests for FBC, electrolytes and renal function and pulmonary function. The results from the regression model showed that the frequency of test use was not consistent with the hypothesis of their routine use. FBC tests were performed in only 58% of patients in the data set and U&E testing was carried out in only 57%. LIMITATIONS Systematic searches of the clinical effectiveness and cost-effectiveness literature found that there is no evidence on the clinical effectiveness or cost-effectiveness of these tests in this specific clinical context for the NHS. A survey of NHS hospitals found that respondent trusts were implementing current NICE guidance in relation to pre-operative testing generally, and a de novo analysis of routine data on test utilisation and post-operative outcome found that the tests were not be used in routine practice; rather, use was related to an expectation of a more complex clinical case. The paucity of published evidence is a limitation of this study. The studies included relied on non-UK health-care systems data, which may not be transferable. The inclusion of non-randomised studies is associated with an increased risk of bias and confounding. Scoping work to establish the likely mechanism of action by which tests would impact upon outcomes and resource utilisation established that the cause of an abnormal test result is likely to be a pivotal determinant of the cost-effectiveness of a pre-operative test and therefore evaluations would need to consider tests in the context of the underlying risk of specific clinical problems (i.e. risk guided rather than routine use). CONCLUSIONS The time of universal utilisation of pre-operative tests for all surgical patients is likely to have passed. The evidence we have identified, though weak, indicates that tests are increasingly utilised in patients in whom there is a reason to consider an underlying raised risk of a clinical abnormality that should be taken into account in their clinical management. It is likely that this strategy has led to substantial resource savings for the NHS, although there is not a published evidence base to establish that this is the case. The total expenditure on pre-operative tests across the NHS remains significant. Evidence on current practice indicates that clinical practice has changed to such a degree that the original research question is no longer relevant to UK practice. Future research on the value of these tests in pre-operative work-up should be couched in terms of the clinical effectiveness and cost-effectiveness in the identification of specific clinical abnormalities in patients with a known underlying risk. We suggest that undertaking a multicentre study making use of linked, routinely collected data sets would identify the extent and nature of pre-operative testing in this group of patients. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Diagnostic value of urinary sodium, chloride, urea, and flow.
Schrier, RW
Journal of the American Society of Nephrology : JASN. 2011;(9):1610-3
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Abstract
Up to 30% of hospitalized critically ill patients may have a rise in serum creatinine concentration. In addition to history and physical examination, there is diagnostic value in assessing urinary electrolytes, solute excretion, and urine flow in these patients. The correct interpretation of these urinary parameters can avoid unnecessary volume overload and mechanical ventilation, risk factors for increased mortality in patients with rising serum creatinine. The present article also discusses the role of arterial underfilling in causing prerenal azotemia in the presence of an increase in total body sodium and extracellular fluid expansion. As with extracellular fluid volume depletion, arterial underfilling secondary to impaired cardiac function or primary arterial vasodilation can delay or prevent recovery from ischemic or toxic acute tubular necrosis. The present brief review discusses the various aspects of the correct interpretation of urinary electrolytes, solute excretion, and urine flow in the setting of a rising serum creatinine concentration.