Current guidelines recommend that disease-modifying pharmacological therapies may be considered for patients who have heart failure with mildly reduced ejection fraction (HFmrEF). We aimed to describe the characteristics, outcomes, provision of pharmacological therapies and dose-related associations with mortality risk in HFmrEF.p = 0.040) and in HFpEF (HR 0.61 (95% CI 0.52–0.71); p < 0.001) compared to HFrEF. Adjusted all-cause mortality risk was lower in patients with HFrEF and HFmrEF who received the highest doses of beta-blockers or renin-angiotensin inhibitors. These associations were not evident in HFpEF. Once adjusted for relevant confounders, each mg equivalent of bisoprolol  and ramipril  was associated with incremental reductions in mortality risk in patients with HFmrEF.We explored data from two prospective observational studies, which permitted the examination of the effects of pharmacological therapies across a broad spectrum of left ventricular ejection fraction (LVEF). The combined dataset consisted of 2388 unique patients, with a mean age of 73.7 ± 13.2 years of whom 1525 (63.9%) were male. LVEF ranged from 5 to 71% (mean 37.2 ± 12.8%) and 1504 (63.0%) were categorised as having reduced ejection fraction (HFrEF), 421 (17.6%) as HFmrEF and 463 (19.4%) as preserved ejection fraction (HFpEF). Patients with HFmrEF more closely resembled HFrEF than HFpEF. Adjusted all-cause mortality risk was lower in HFmrEF ; Pharmacological therapies were associated with lower mortality risk in HFmrEF, supporting guideline recommendations which extend the indications of these agents to all patients with LVEF < 50%.HFmrEF more closely resembles HFrEF in terms of clinical characteristics and outcomes. Pharmacological therapies are associated with lower mortality risk in HFmrEF and HFrEF, but not in HFpEF. The benefits of disease-modifying pharmacological therapies for heart failure with reduced ejection fraction (HFrEF) are clear. Four classes of medications targeting the neurohormonal maladaptations of the syndrome are proven to reduce hospitalisations and improve survival . EligibiWe explored data from two prospective observational studies, which permitted the examination of the effects of pharmacological therapies across a broad spectrum of LVEF. Our aims were firstly, to report prevalence of HFrEF, HFmrEF and heart failure with preserved ejection fraction (HFpEF) amongst a real-world population referred to secondary care with symptoms of chronic heart failure (CHF). Secondly, to describe the clinical characteristics and outcomes of patients with HFmrEF compared to HFrEF and HFpEF, and thirdly, to report the provision of pharmacological therapies and explore dose-related associations with outcomes across heart failure classifications.The United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-HEART-2) and the Prospective evaluation of the diagnostic efficacy of the 2010 United Kingdom National Institute for Clinical Excellence guidelines on Chronic Heart Failure (NICE-CHF) are two prospective, observational studies conducted within the same region in the UK. UK-HEART-2 represents a prevalent population of ambulatory patients under the care of four specialist heart failure outpatient clinics. Consecutive patients were approached to participate between July 2006 and December 2014. Inclusion required stable symptoms ± signs of CHF for at least 3 months and LVEF ≤ 45%. NICE-CHF represents a population of consecutive people newly referred to a specialist heart failure outpatient clinic, from a primary care catchment of over 750,000 people. We required patients to have symptoms ± signs of CHF and elevated natriuretic peptides . All patients attending between May 2012 and May 2013 were included, regardless of LVEF.Upon arrival at the outpatient heart failure clinic, demographic details, medical history, blood pressure, and for the UK-HEART-2 cohort functional capacity according to the New York Heart Association classification were recorded. A venous blood sample was taken at enrolment and tested for full blood count, creatinine, and albumin. For patients included in NICE-CHF, NT-proBNP was measured from samples taken in primary care using the Immulite 2000 assay  in the biochemistry laboratory at the Leeds Teaching Hospitals NHS Trust. The inter-batch coefficient of variation was 8.9% at 350 pg/mL and 5.9 at 4100 pg/mL. Standard 12-lead electrocardiograms were recorded at 25 mm/s and analysed by a senior cardiologist  blinded to patient characteristics. Two-dimensional transthoracic echocardiography was performed by senior cardiac sonographers , blinded to measurements of NT-proBNP. LV dimensions, LVEF, left atrial volumes and LV Doppler measurements were calculated according to the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines [Prescription of beta-blocker, angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and loop diuretic were expressed as equivalent doses, relative to the maximum licensed dosages of bisoprolol, ramipril and furosemide as previously published . For thePatients were categorised according to the Universal Definition and Classification of Heart Failure as having HFrEF, HFmrEF, HFpEF or not having CHF . HFrEF aχ2 for categorical variables. Kaplan–Meier analysis was used to plot survival and groups compared using log-rank test. Age-sex adjusted and multivariable analyses used Cox proportional hazards regression. In all analyses, statistical significance was defined as p < 0.05.All statistical analyses were performed using IBM SPSS Statistics version 26 . Normality of distribution was explored visually by distribution plots and confirmed using skewness tests. Continuous variables are presented as mean ± standard deviation if normally distributed, as median (interquartile range) if non-normally distributed and discrete variables are presented as number (percentage). Groups were compared using two-sided t tests or one-way analysis of covariance for normally distributed continuous data, Mann–Whitey or Kruskal–Wallis H tests for non-normally distributed data, and two-sided Pearson The Health Research Authority provided ethical approval for the studies /2013) which were conducted in accordance with the principles outlined in the Declaration of Helsinki. Participants enrolled in UK-HEART-2 provided informed written consent for inclusion. Ethical approval for NICE-CHF was achieved through a Sect. 251 application reviewed by the Confidential Advisory Group which allows individual patient data to be used for health service improvement without the need for individual patient consent.UK-HEART-2 recruited a total of 1802 participants, 47 had insufficient endocardial definition to measure LVEF and five had missing medication doses, leaving 1750 patients, of whom 1423 (81.3%) were classified as having HFrEF and 327 (18.7%) as having HFmrEF. NICE-CHF included 982 patients, of these 22 had insufficient endocardial definition to measure LVEF, 182 did not have CHF and 2 had missing medication doses, leaving 776 patients, 190 (24.5%) of whom had HFrEF, 123 (15.9%) had HFmrEF and 463 (59.7%) had HFpEF. Following the exclusion of 138 duplicate entries for patients enrolled in both studies , the combined dataset consisted of 2388 unique patients, who had a mean age of 73.7 ± 13.3 years and 1525 (63.9%) were male. Within the entire study cohort, LVEF ranged from 5 to 71% (mean 37.2 ± 12.8%)  with higher mean dosing of loop diuretic in those with lower LVEF (p < 0.001 in the combined dataset).Descriptive data contrasting patients according to heart failure classification are displayed in Table Within the combined dataset, 1875 (78.5%) were prescribed a beta-blocker, 1977 (82.8%) an ACEi/ARB and 728 (30.5%) a mineralocorticoid receptor antagonist (MRA) (Table p = 0.98). However, in age-sex adjusted analysis, all-cause mortality risk was lower in HFmrEF ; p = 0.040) and in HFpEF (HR 0.61 (95% CI 0.52–0.71); p < 0.001) than HFrEF  or HFmrEF (p = 0.74) but was associated with a worse prognosis in the small proportion of patients with HFpEF who received these agents (p = 0.001).During a mean follow-up of 4.8 ± 2.1 years, a total of 1331 (55.7%) patients died. Unadjusted survival was not different between classifications of CHF  and those prescribed high doses  of beta-blockers and ACEi/ARB. Higher dosing of beta-blockers and ACEi/ARBs was associated with lower all-cause mortality risk in patients with HFrEF and HFmrEF, but this was not the case in HFpEF Fig.  and 3.Fip = 0.83) or ACEi/ARB (p = 0.91) in patients with LVEF < 50%. Regression models including factors associated with dosing of beta-blockers and ACEi/ARB were used to determine the association of dosing of these agents with all-cause mortality risk. In a model including age, sex, diabetes mellitus, chronic obstructive pulmonary disease, heart rate, LVEF, serum haemoglobin, and albumin , each mg equivalent dose of bisoprolol was associated with incremental reductions in all-cause mortality risk in HFmrEF (HR 0.95 (95% CI 0.91–1.00); p = 0.047). Similarly, when adjusted for age, sex, systolic and diastolic blood pressure, heart rate, serum haemoglobin, creatinine and albumin  each mg equivalent of ramipril was associated with a similar magnitude of reduction in all-cause mortality risk (HR 0.95 (95% CI 0.90–1.0); p = 0.044).We then used Cox regression to further define the association between dosing of beta-blockers and ACEi/ARB and all-cause mortality risk in HFrEF and HFmrEF. Interaction analyses suggested that LVEF (as a continuous variable) was not a significant modifier of the effect of the dosing of beta-blockers  HFmrEF is highly prevalent amongst patients presenting to secondary care with symptoms of CHF and elevated natriuretic peptides; (2) clinical characteristics and outcomes varied according to LVEF, but patients with HFmrEF more closely resembled HFrEF, than HFpEF; and (3) higher dosing of beta-blockers and ACEi/ARB was associated with better survival in HFrEF and HFmrEF, but not in HFpEF. Taken together, our findings support guideline recommendations extending the indications of pharmacological therapies to all patients with CHF and LV systolic dysfunction.Although the combined dataset included patients enrolled in UK-HEART-2 which excluded people with LVEF > 45%, by separately reporting data from the NICE-CHF study, we were able to show that in an unselected cohort referred to secondary care with symptoms ± signs of CHF and elevated natriuretic peptides , ~ 75% hWe observed differences in the baseline characteristics of patients with HFmrEF compared to HFrEF. However, although these differences were statistically significant, the numerical differences between groups were relatively small, and the distribution of co-morbidities was similar. Overall, the clinical characteristics of patients with HFmrEF more closely resembled those of HFrEF. The baseline characteristics of patients with HFpEF were more distinct. HFpEF patients were more likely to be older, to be female and had biomarker evidence of less severe clinical heart failure, for example, lower natriuretic peptides, higher blood pressure and better renal function.Prior registry and interventional studies have reached conflicting conclusions as to whether patients with HFmrEF more closely resemble HFrEF, HFpEF or are a group with distinct clinical characteristics and outcomes. Earlier studies, for example the GWTG-HF registry, suggest that these patients were more similar to those with HFpEF, and furthermore, showed no difference in adjusted survival rates across the heart failure classifications . In compConsistent with other reports , unadjusFor the first time, guidelines recommend that pharmacological therapies approved for HFrEF may be considered for those with LVEF 41–49% , supportp = 0.02) [There are no cardiovascular outcomes trials specifically designed to evaluate the efficacy of pharmacological therapies in HFmrEF . Further = 0.02) . Similar = 0.02) . Finally = 0.02) , patient = 0.02) .For all patients with HFrEF, guidelines recommend four classes of medications proven to reduce hospitalisations and cardiovascular mortality . AdherenRecent observational studies also lend support to the notion that pharmacological therapies may improve outcomes in HFmrEF. In the Swedish Heart Failure Registry, the provision of an ACEi/ARB was associated with lower all-cause mortality. However, the association for beta-blockers was only evident in those with coronary artery disease . The CHAOur analysis included patients from two prospective studies representative of real-world populations of patients with CHF, encompassing a broad spectrum of LVEF and categorised according to guideline recommendations . Some liPatients classified as having HFmrEF according to the Universal Definition and Classification of Heart Failure seem to derive dose-dependent benefits from pharmacological therapies on a par with patients with HFrEF. These findings lend support to guideline recommendations which extend the indications of pharmacological therapies to all patients with symptoms of CHF and LV systolic dysfunction.


Although guidelines provide excellent expert guidance for managing patients with septic shock, they leave room for personalization according to patients’ condition. Hemodynamic monitoring depends on the evolution phase: salvage, optimization, stabilization, and de-escalation. Initially during the salvage phase, monitoring to identify shock etiology and severity should include arterial pressure and lactate measurements together with clinical examination, particularly skin mottling and capillary refill time. Low diastolic blood pressure may trigger vasopressor initiation. At this stage, echocardiography may be useful to identify significant cardiac dysfunction. During the optimization phase, echocardiographic monitoring should be pursued and completed by the assessment of tissue perfusion through central or mixed-venous oxygen saturation, lactate, and carbon dioxide veno-arterial gradient. Transpulmonary thermodilution and the pulmonary artery catheter should be considered in the most severe patients. Fluid therapy also depends on shock phases. While administered liberally during the resuscitation phase, fluid responsiveness should be assessed during the optimization phase. During stabilization, fluid infusion should be minimized. In the de-escalation phase, safe fluid withdrawal could be achieved by ensuring tissue perfusion is preserved. Norepinephrine is recommended as first-line vasopressor therapy, while vasopressin may be preferred in some patients. Essential questions remain regarding optimal vasopressor selection, combination therapy, and the most effective and safest escalation. Serum renin and the angiotensin I/II ratio may identify patients who benefit most from angiotensin II. The optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. In all cases, vasopressor therapy should be individualized, based on clinical evaluation and blood flow measurements to avoid excessive vasoconstriction. Inotropes should be considered in patients with decreased cardiac contractility associated with impaired tissue perfusion. Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support. Shock is a life-threatening condition characterized by inadequate delivery of oxygen to tissues . Septic Personalization of hemodynamic monitoring implies considering the different SOSD phases . At each stage, the available techniques and targets for resuscitation vary Fig. .Fig. 1SuAt the time of shock recognition and identification, the initial treatment aims to provide tissue perfusion levels compatible with life. In this phase, hemodynamic monitoring is often very basic and therapeutic options limited to fluids and vasopressors.Clinical evaluation is crucial to identify tissue hypoperfusion. Blood pressure measurement, skin mottling, and capillary refill time (CRT) inform on the progress of resuscitation. Alterations in CRT and mottling scores can be used for basic monitoring as they correlate with outcome , 7 and rIf medical history suggests that cardiac function may be impaired or if the patient fails to respond to fluids, rapid echocardiographic evaluation is useful to refine the hemodynamic evaluation . BedsideDuring salvage, inotropes may be indicated when a relevant cardiogenic component (related to septic cardiomyopathy or patient comorbidities) contributes to the shock process , 10. ThiBasic clinical monitoring has a role in identifying patients who may respond to fluids and assessing their response . In part2 saturation (ScvO2) and the gradient of carbon dioxide partial pressure (pCO2) between central venous and arterial blood (Pv-aCO2) may be useful to guide resuscitation.Measuring blood lactate levels is useful to identify impairment in tissue perfusion. In addition, when a central venous catheter is in place, central venous OWhile some patients may respond to fluid therapy alone, others need vasopressor support. The SSC guidelines recommend maintaining mean arterial pressure (MAP) ≥ 65 mmHg but do not indicate timing or provide guidance on prioritization of fluids versus vasopressors. Some patients with severe hypotension may require starting vasopressors early, i.e., without waiting for the fluid effects, in order to accelerate the restoration of arterial pressure. Indeed, delaying the correction of hypotension is associated with poor outcome . MoreoveThe decision to start vasopressors early, along with fluid therapy, seems logical in cases of profound hypotension, although no precise cutoff of MAP can be given. Diastolic pressure (DAP) may also guide the decision. DAP is determined by vascular tone and the decay time of aortic blood volume. In sepsis, a low DAP often reflects severe vasodilation and is associated with increased mortality . Then, iAt this stage, the goal of resuscitation is to optimize tissue perfusion through optimization of perfusion pressure and CO. Ideally, this should also include optimization of regional blood flow distribution and microcirculatory perfusion. While alterations in the distribution of regional blood flow  and micr2, Pv-aCO2, and lactate concentrations. Importantly, even if some correlation between the different indices exists at baseline, some variables normalize more rapidly than others [. It seems logical to combine several variables and to stop resuscitation when most are normalized, without pursuing normalization of the variables like lactate concentrations that have a longer lag time [The most frequent indices of tissue hypoperfusion used at the bedside include arterial pressure, urine output, skin perfusion, CRT, ScvOn others . ScvO2 sn others . It seemlag time . When tiCRT is a marker of skin hypoperfusion that dynamically responds to vasoactive substances. The extent to which CRT reflects central tissue perfusion remains unknown. While one study concluded that CRT reflected central circulation , other tDetermining the systemic blood pressure target necessary to achieve adequate tissue perfusion remains difficult. In principle, organ blood flow depends on perfusion pressure  and resistance. However, preservation of systemic arterial pressure is not sufficient to ensure the adequacy of microcirculatory flow. Importantly, perfusion pressures differ across vascular beds Table , and thoMost organs have the endogenous ability to preserve the microcirculation within a certain range of perfusion pressures. For instance, heart and brain can maintain a constant blood flow despite large changes in perfusion pressure. In case the pressure falls below the organ-specific autoregulation zone, organ blood flow becomes dependent on inflow pressure, hence the focus on reversing hypotension during the salvage state.The heterogeneity of patients, distinct organ-specific microcirculatory regulation, variable receptor density, and the impact of pharmacological interactions make a uniform approach to septic shock challenging . The SSCCVP is a complex variable, reflecting right ventricular preload and function when elevated, and affected by intrathoracic pressures . AlthougCO is a key determinant of tissue perfusion. However, there is no fixed value of optimal CO in shock and CO should be optimized according to tissue perfusion indices listed below and organ function. Importantly, microvascular alterations may persist even when a low CO is corrected, impairing tissue perfusion , 35. In 2 or SvO2 is not even quoted in the new SSC guidelines [2 indicates impaired or inadequate O2 delivery, explained by an inadequate CO if hemoglobin and arterial O2 saturation are within normal ranges. In sepsis, SvO2 and ScvO2 are expected to be normal or elevated even when tissue perfusion is impaired [2 or ScvO2 values in all patients has been challenged [2 or ScvO2 may identify patients who should benefit from further resuscitation efforts. This may consist in increasing CO with fluids or an inotropic agent, or sometimes Hb by transfusing blood in anemic patients. In patients with high ScvO2, other indices of impaired perfusion should be carefully checked.Although ScvOidelines , they arimpaired . While tallenged , finding2 depends on the total carbon dioxide (CO2) production, CO and microvascular perfusion, and the complex relationship between CO2 partial pressures and CO2 blood contents. According to the modified Fick equation, Pv-aCO2 is inversely related to CO (curvilinear relationship). Under stable conditions of both oxygen consumption (VO2) and CO2 production (VCO2), Pv-aCO2 progressively increases in response to reductions in CO due to the CO2-stagnation phenomenon in microvessels. Progressive increases in Pv-aCO2 reflect decreased microcirculatory perfusion in the early stages of septic shock [2 may identify septic patients who are inadequately resuscitated [2 values [2 in response to therapy are both associated with outcome [2 may be particularly helpful in patients with normal values of lactate or ScvO2, identifying those at risk of poor outcome despite apparent adequate resuscitation [2 target based on observational trials. The ratio of Pv-aCO2 over the arteriovenous difference in oxygen content is an estimate of the respiratory quotient and, as such, may be a direct indicator of anaerobic metabolism, with faster changes than lactate [Pv-aCOic shock . Thus, ascitated . Admissi2 values  and chan outcome . Measuricitation –42. It i lactate .Lactate levels have a strong prognostic value and can thus be used for triage. The assessment of serial lactate levels is useful, as these usually decrease in patients who improve and often remain elevated or even increase when septic shock is poorly controlled. Resuscitation strategies targeting decreases in lactate level were associated with decreased hospital mortality . Thus, iHowever, elevated lactate levels can also originate from other causes than tissue hypoxia . In patients with shock, hyperlactatemia is predominantly of hypoxic origin in the first few hours after admission, while non-hypoxic causes predominate at later stages . DecreasPerforming echocardiography should be considered as both left and right ventricular function may have been affected by the initial resuscitation procedures: left ventricular dysfunction may occur due to afterload increase following correction of severe hypotension; dynamic obstruction may have been caused by inotropic or vasopressor agents; and, finally, right ventricular dysfunction may be due to mechanical ventilation. In addition, sepsis-induced cardiopathy may impair the left and right ventricular function. Echocardiography may be used to evaluate volume status .In sepsis, different phenotypes can be identified by a combination of echocardiographic indices . This alDifferent tools can be used to measure CO reliably, but the choice of technique should be guided by other variables of interest, depending on patient conditions Fig. . In a pa(EVLW) and vascular permeability. This comprehensive hemodynamic evaluation is particularly helpful in fluid management, as it provides a dynamic evaluation of fluid responsiveness coupled with an assessment of the risks associated with volume administration [Transpulmonary thermodilution (TPTD) combines a calibrated measurement of CO, a beat-by-beat and precise estimation of SV that is useful for predicting fluid responsiveness, static volumetric preload indicators, indices of cardiac function, extravascular lung water stration .2, the use of PAC provides an assessment of the adequacy of CO and its determinants. While it does not predict fluid responsiveness, PAC is excellent for assessing fluid effectiveness and tolerance through the fluid challenge. The simultaneous measurement of CVP and pulmonary artery pressure makes PAC ideal for monitoring patients with right heart dysfunction.Through the combined measurements of CO, pulmonary pressures and SvOEventually, the choice of monitoring technique should be based on the patient condition, local experience and availability, and anticipated response to therapy. A stepwise approach for the patient in septic shock is suggested Fig. .During stabilization and de-escalation, the tools and targets should be adapted. During these phases, the purpose of hemodynamic support changes from optimization of tissue perfusion to prevention of complications while providing organ support. It includes evacuation of accumulated fluids and weaning of vasoactive support while preserving tissue perfusion.During the stabilization phase, cardiac dysfunction and resuscitation-induced volume overload are common, and the already implemented hemodynamic tools often continue to be used. Lung ultrasound and the assessment of hepatic, renal, and portal venous flow patterns by ultrasound can identify signs of venous congestion which may indicate the need for volume removal and/or administration of inotropes . A combiA frequent complication is the development of right ventricular dysfunction that may develop in 20% of patients with acute respiratory distress syndrome (ARDS) subjected to lung protective ventilatory strategies . AccordiDuring the de-escalation phase, the situation is even more complex. Patients are usually minimally monitored, and indices of tolerance are not well defined. Should we still target the same values as in the optimization phase? Probably not, but it remains unknown how to determine the level of abnormality that may be tolerated. It sounds logical not to go back to shock (hence the term “de-resuscitation” is inappropriate). However, some degree of decrease in blood pressure and blood flow can be tolerated provided tissue oxygenation and function are preserved. Obviously, de-escalation should be stopped before hypoperfusion occurs. As an example, excessive fluid removal with ultrafiltration has been shown to be associated with increased mortality . MonitorPersonalization of fluids, vasopressors, and inotropes should be tailored to tissue perfusion indices and cardiovascular state, taking into account the response to therapy.Fluid management is essential in septic shock. During the salvage phase, fluids can be liberally administered as the benefits largely outweigh the risks. During optimization, the situation is more complex. The proportion of patients responding to fluids progressively decreases  while thThe personalized way of fluid administration comprises several steps. First, there should be a clear indication for fluids, i.e., a perfusion impairment that is expected to respond to fluids. Second, the patient should be predicted to respond to fluids. Prediction of fluid responsiveness is better achieved with dynamic tests  over staDuring stabilization, resuscitation fluids, maintenance and dilution fluids should be minimized . In the While guidelines suggest balanced crystalloids , individVasopressors are initiated, titrated, and weaned according to MAP, measures of perfusion and organ function, as mentioned above. They differ in their pharmacology, effects on capillary perfusion, organ function, and safety profiles Table .Table 3VNorepinephrine is recommended as the first-line vasopressor in septic shock based on a large RCT comparing norepinephrine versus dopamine and several meta-analyses , 60. In Angiotensin II has emerged as a novel pressor in the treatment of vasodilatory shock. It is effective at raising blood pressure and has a catecholamine-sparing effect compared to placebo . A post Essential questions remain regarding optimal vasopressor selection, the role of combination therapy, and the most effective and safest method of escalation in different patient cohorts . More toSeveral genetic polymorphisms are associated with different responses to vasopressor agents , 74 but Finally, the evidence regarding the optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. The α1 receptors, like any other vasopressor receptor, may be saturated and/or hypo-responsive in refractory shock. It makes sense to consider alternative vasopressors that act on different receptors (vasopressin derivatives or angiotensin II) rather than using an agent from the same class.Similarly, the indications for adjunctive therapies vary and predictive tools are necessary. Identification of patients responding to corticosteroids may be helped by the analysis of selected cytokines  or identThere are no data to support the systematic use of inotropic agents. The indiscriminate use of levosimendan in such patients was unsuccessful . Even atDiscussion on the type of agent is more complex. No agent has proven to be superior to another in patients in shock. Of note, most trials comparing inotropic agents were performed in patients with heart failure and excluded patients in cardiogenic shock. Accordingly, meta-analyses of these trials should be considered cautiously.Based on pharmacologic properties, we suggest the following stepwise approach: First, test a limited dose of dobutamine (2.5 to 5 mcg/kg/min) and evaluate efficacy and tolerance. In cases of severe contractility impairment, higher doses (up to 20 mcg/kg/min) may be considered. Second, substitute or add enoximone or milrinone and evaluate efficacy and tolerance (beware of the risk of hypotension). Third, substitute or add levosimendan in cases of severe impairment. At each step, efficacy  and tolerance  should be evaluated. For each of the agents, the lowest dose associated with the desired effect should be administered. As soon as the situation improves, weaning of inotropes should be attempted.Even though some general rules apply for septic shock management, a personalized approach should be considered for hemodynamic monitoring and support. Importantly, monitoring and support should be adapted to the four stages of shock and the impact of the interventions should be continuously evaluated.


This study was designed to evaluate the synergism of two couples of antihypertensive drugs (amlodipine + telmisartan and amlodipine + candesartan) on blood pressure reduction in vivo by both SynergyFinder 3.0 and probability sum test. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine , telmisartan , candesartan , nine combinations for amlodipine and telmisartan, and nine combinations for amlodipine and candesartan. The control rats were treated by 0.5% carboxymethylcellulose sodium. Blood pressure was recorded continuously up to 6 h after administration. Both SynergyFinder 3.0 and the probability sum test were used to evaluate the synergistic action. The synergisms calculated by SynergyFinder 3.0 are consistent with the probability sum test both in two different combinations. There is an obviously synergistic interaction between amlodipine and telmisartan or candesartan. The combinations of amlodipine and telmisartan (2 + 4 and 1 + 4 mg/kg) and amlodipine and candesartan (0.5 + 4 and 2 + 1 mg/kg) might exert an optimum synergism against hypertension. Compared with the probability sum test, SynergyFinder 3.0 is more stable and reliable to analyze the synergism.  BRAIDBivariate Response to Additive Interacting DosesCMCcarboxymethylcellulose sodiumDBPdiastolic blood pressureMBPmean blood pressureMuSyCMultidimensional Synergy of CombinationsSBPsystolic blood pressureSDstandard deviationSHRsspontaneously hypertensive rats1Drug combinations have become a standard therapy for many complex diseases, including cancers and cardiovascular diseases.SynergyFinder, a web‐application, was put forward in 2017 and has been widely used for the discovery of novel synergistic drug combinations.q test) has been suggested to evaluate the synergism.For the combination of different antihypertensive drugs, the probability sum test  and the probability sum test were performed to analyze the synergism on blood pressure reduction in vivo. Two couples of antihypertensive drugs (amlodipine + telmisartan and amlodipine + candesartan) were used in spontaneously hypertensive rats (SHRs). We mainly focused in the difference between the probability sum test and SynergyFinder 3.0 for the evaluation of synergism on blood pressure reduction.22.1Male SHRs (aged 3 months) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The rats were housed with controlled temperature (23–25°C) and lighting  and with free access to food and tap water. All the animals used in this experiment received humanitarian concern. All animal experiments were approved by the Committee on ethics of biomedicine of Naval Medical University and were conducted according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.2.2The operation and measurement were conducted as described previously in detail.Experiment 1 protocol: The effect of a single dose or different combinations of amlodipine and telmisartan on blood pressure reduction in SHRs.n = 10 per group) and administered by the following drugs: amlodipine , telmisartan , and the combinations .Male SHRs were divided into 15 groups (The drugs were dissolved in the 0.5% carboxymethylcellulose sodium (CMC) and were given into the stomach through a catheter. The blood pressure was recorded according aforementioned method. The blood pressure values an hour before administration and mean values 6 h after administration were recorded to analyze.Experiment 2 protocol: The effect of a single dose or different combinations of amlodipine and candesartan on blood pressure reduction in SHRs.n = 10 per group) and administered by the following drugs: amlodipine (0.5 mg/kg), candesartan  and the combinations . The drugs were dissolved in the 0.5% CMC and were given into the stomach through a catheter. The blood pressure was recorded according aforementioned method. Blood pressure data of other 2 amlodipine alone groups (1 and 2 mg/kg) were got from experiment 1.Male SHRs were divided into 13 groups (Another 10 SHRs were treated by vehicle (0.5% CMC) with the same volume as a control group. The blood pressure was recorded accordingly. The blood pressure values 1 h before administration and mean values 6 h after administration were recorded to analyze.2.3An excel was set up. There are several lines, including “Pair Index”, “Drug 1”, “Drug 2”, “dose 1”, “dose 2”, “Response” and “Dose Unit”. “Pair Index” represents how many pairs of drugs. “Drug 1” and “Drug 2” are the name of drugs in a dose‐response, while “dose 1” and “dose 2” are the doses of the drugs in combination. “Response” means the effect of drug combinations at the doses input by “dose 1” or “dose 2”. It is the reduction percentage of blood pressure. The range of the “Response” is expected from 0 to 100. The “Dose Unit” means the unit of drugs' dose.https://synergyfinder.fimm.fi).The inhibition ratio of blood pressure reduction was used for SynergyFinder 3.0 system. Inhibition ratio = (blood pressure after administration − blood pressure before administration) × 3.33/blood pressure before administration × 100%. Unlike tumor cells, blood pressure cannot be reduced or inhibited by 100%. About 30% reduction in blood pressure is most appropriate in clinical.Briefly, the mean percentage of blood pressure reduction of a pair of antihypertensive drugs, and their combinations at different doses were input respectively. According to the software recommendation, highest single agent (HSA) reference model was selected in this study. This model states the expected combination effect is the maximum of the single drug responses at corresponding concentrations. Finally, the comprehensive synergy score and synergy maps of drug combination were obtained automatically by the software using HSA model. The synergy score was used to evaluate the efficacy of the combination. According to the user guide in the website, synergy score was evaluated as follows: scores <−10: the interaction between two drugs was likely to be antagonistic; from −10 to 10: the interaction between two drugs was likely to be additive; and > 10: the interaction between two drugs was likely to be synergistic.The synergy scoring can be visualized as either a two‐dimensional or a three‐dimensional interaction surface over the dose matrix. The depth of the color reveals the degree of percentage of blood pressure reduction in the two‐dimensional image and the height of the 3D drug interaction landscape is standardizing as the percentage of blood pressure reduction to show the comparison of the degrees of interaction among drug combinations.2.4q value as follows: q = PA+B/(PA + PB − PA × PB). A and B represent drug A and drug B. P is the percentage of responders in each group. PA+B is the responders' real percentage and (PA + PB − PA × PB) is the expected response ratio. (PA + PB) is the sum of the probabilities when drug A and drug B are used alone. PA × PB is the probability of ratios responding to both drugs when they were used alone. We considered that the combination was synergistic when q was >1.15 and the combination was antagonistic when q was <0.85. When q was between 0.85 and 1.15, the combination was additive.The probability sum test was used to evaluate the synergism of the combination according to the references.2.5t‐test (two‐tailed paired t‐test) was used for comparisons between before and after drug administration. p < .05 was considered statistically significant.The investigators were blinded to the animal groups when they assessed the blood pressure and analyzed the synergistic score using SynergyFinder 3.0 or the probability sum test. The animals were randomly assigned by using the random permutations table. Continuous variables were expressed as mean ± standard deviation (SD). Student's 33.1t‐test, p < .05). DBP values were significantly reduced by 5, 8, and 14 mmHg, respectively. MBP values were reduced by 6, 10, and 16 mmHg, respectively. In telmisartan treatment groups , SBP values showed significant reduction by approximately 6, 10, and 16 mmHg, respectively. DBP was reduced by 16, 10, and 16 mmHg, and MBP was reduced by 6, 10, and 16 mmHg, respectively. Blood pressure values were also significantly reduced by the different combinations .The effects of a single dose of amlodipine and telmisartan alone or in their combinations on SBP, DBP, and MBP are shown in Figure In combination groups with amlodipine 1 mg/kg, adding telmisartan  significantly reduced SBP by 15, 12, and 14 mmHg, respectively. In combination groups with amlodipine 2 mg/kg, adding telmisartan  significantly reduced SBP by 21, 14, and 17 mmHg, respectively. In combination groups with amlodipine 4 mg/kg, adding telmisartan  significantly reduced SBP by 17, 19, and 21 mmHg, respectively. The similar results were also got from DBP and MBP.No significant change in blood pressure was observed in control rats compared with the blood pressure before administration.3.2p = .08). DBP and MBP values were both reduced by 4 mmHg . In candesartan treatment groups , SBP values showed reduction by approximately 4, 4, and 8 mmHg, respectively. DBP was significantly reduced by 7, 10, and 11 mmHg, and MBP was significantly reduced by 5, 7, and 10 mmHg, respectively. Blood pressure values were significantly reduced by the different combinations  except for one combination group (amlodipine 0.5 mg/kg + candesartan 2 mg/kg).The effects of amlodipine and candesartan alone or in their combinations on SBP, DBP, and MBP are shown in Figure In combination groups with amlodipine 0.5 mg/kg, adding candesartan  reduced SBP by 8, 3, and 9 mmHg, respectively. In combination groups with amlodipine 1 mg/kg, adding candesartan  significantly reduced SBP by 7, 14, and 11 mmHg, respectively. In combination groups with amlodipine 2 mg/kg, adding candesartan  significantly reduced SBP by 20, 13, and 20 mmHg, respectively. The significant reduction was also got from DBP and MBP.3.3The mean dose‐response of SBP, DBP, and MBP in rats administrated with amlodipine and telmisartan or their combinations are shown in Table 3.4The mean dose‐response of SBP, DBP, and MBP in rats administrated with amlodipine and candesartan or their combinations are shown in Table 3.5q values only in two combination groups  are <1.15 (1.05 and 0.90). These data indicate that all the other combination groups might have a synergistic effect on SBP. For DBP, the q values only in one group (1 + 8 mg/kg) are <1.15 (0.97). All q values of MBP are larger than 1.15. In the combination group (2 + 4 mg/kg), the q values (6 for SBP and 6.25 for MBP) are larger than any other groups. These data indicate that this combination (2 + 4 mg/kg) might exert an optimum synergistic effect.Table 3.6q values only in two combination groups  are <1.15 (1.13 and 1.11). All the other q values of combination groups are larger than 1.15. These groups might have a synergistic effect on SBP. For DBP and MBP, the q values only in one group (0.5 + 2 mg/kg) are <1.15 . All the other q values are larger than 1.15. For SBP and MBP, the q values in two combination groups (2 + 1 and 0.5 + 4 mg/kg) are larger than any other group. All these data indicates that these two combinations (2 + 1 and 0.5 + 4 mg/kg) might exert an optimum synergistic effect.Table 4Amlodipine is a calcium channel blocker (CCB).It's difficult to determine the synergistic interaction in practice for antihypertensive drugs, especially in vivo. For anti‐cancer drugs, there are some new methods to evaluate the synergism of drugs combination.SynergyFinder 3.0 might be an answer. SynergyFinder was designed to calculate the synergism between anti‐cancer medicines firstly. It has been widely used for the discovery of novel synergistic drug combinations and updated to version 3.0.q values in two doses groups (2 + 4 and 1 + 4 mg/kg) are larger than any other group. The synergy scores by SynergyFinder 3.0 are also highest in these two groups. The two combinations groups of amlodipine and candesartan (0.5 + 4 and 2 + 1 mg/kg) also get the similar results.In this study, we selected two different couples of antihypertensive drugs (amlodipine plus telmisartan or amlodipine plus candesartan) as an example, and calculated the synergistic effect on blood pressure reduction by SynergyFinder 3.0 in vivo. The inhibition ratio of blood pressure reduction was used for SynergyFinder 3.0 system. For hypertensive patients, a 30% reduction in blood pressure is most appropriate in clinical. So we defined a 30% reduction in blood pressure as 100% inhibition. The results output by SynergyFinder 3.0 are more credible. The results are consistent with the probability sum test both in the combination of amlodipine and telmisartan or amlodipine and candesartan (effective reduction of blood pressure defined as ≥15 mmHg). In the combination groups of amlodipine and telmisartan, the q value (PA+B/(PA + PB − PA × PB)). However, there are some disadvantages for this method compared with SynergyFinder 3.0. First, the definition of responders for blood pressure reduction. We usually define a decrease in blood pressure >15 or 20 mmHg as responders.P is the percentage of responders in each group. When the reduction percentage is equal to zero, it will have a great impact on the q values, which might cause a big difference between different responders. Second, the elimination of some data might affect the accuracy of q values. In this experiment, a reduction in blood pressure >15 mmHg is defined as responders. A decrease <12 mmHg (80% of 15 mmHg) is defined as non‐responders and data ranging from 12 to 15 mmHg are discarded, which might affect the synergistic conclusion.The probability sum test also has been widely used to analyze the synergism of the combinations of two antihypertensive drugs.In SynergyFinder 3.0, all the data are input to the system and are reflected in synergy pictures and scores. SynergyFinder 3.0 combines multiple synergy scoring models and obtains a novel consensus synergy score. During the data processing, the false positive results will be removed with an improved outlier detection functionality.In conclusion, SynergyFinder 3.0 is more stable and reliable to analyze the synergism on blood pressure reduction in vivo than the probability sum test. There is an obviously synergistic interaction between amlodipine & telmisartan or candesartan. The combinations of amlodipine & telmisartan (2 + 4 and 1 + 4 mg/kg) and amlodipine & candesartan (0.5 + 4 and 2 + 1 mg/kg) might exert an optimum synergistic effect against hypertension.Conceived the idea: Ai‐Jun Liu. Designed the experiments: Ai‐Jun Liu and Yan‐Qiong Cheng. Performed the experiments: Tian Xia, Lu‐Lu Xu, and Wan‐Ting Shi. Analyzed the data: Tian Xia, Lu‐Lu Xu, Yan‐Qiong Cheng, and Ai‐Jun Liu. Wrote the paper: Ai‐Jun Liu and Tian Xia.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.All experiments were approved by the Committee on ethics of biomedicine of Naval Medical University and were conducted according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.Table S1–S6Click here for additional data file.


The burden of both acute kidney injury and chronic kidney disease is on the rise globally. In sierra Leone, there has been no data on renal patients or admissions. This study intends to close this gap in knowledge and give preliminary data on the burden of renal disease in this country.The study was a retrospective review of the case notes of patients admitted at Connaught Hospital, Freetown over a 2 year period. Data extraction was done using a well- structured proforma.A 2.7% renal admission burden was obtained; mean duration of hospital stay was 15.1 ± 14.7; mean age of patients was 47.2 ± 17.5 with a female preponderance. The common risk factors for chronic kidney disease were systemic hypertension (43%) and diabetes mellitus (24%). The common risk factors for acute kidney injury were sepsis (77%) and hypovolemia (15%). The in- hospital mortality rate was 47% and 73% were non-compliant with haemodialysis probably due to financial reasons.There is a significant burden of kidney disease in our environment, affecting mainly our young and middle-aged population. A rational approach is to embark on kidney disease prevention programs. The impact of chronic kidney disease (CKD) on global health is escalating in terms of morbidity and mortality. An estimated global prevalence of chronic kidney disease was 9.1% in 2017, accounting for 697·5 million cases of all-stage CKD, with approximately 1·2 million persons dying from the disease . HoweverPrior to December 2016, Sierra Leone had no facility for renal replacement therapy in the form of haemodialysis. This means that all patients with end-stage renal disease or severe acute kidney injury requiring dialysis lost their lives. This describes the poor state of renal care in Sierra Leone and there is no previous data on hospitalized renal cases in Sierra Leone. This study aims to close this gap in knowledge and give preliminary data on admitted renal cases in Sierra Leone. This information might be useful for planning and improving renal care services in Sierra Leone.The study was conducted at the Connaught Hospital, University of Sierra Leone Teaching Hospitals Complex (USLTHC) situated in Freetown, the capital city of Sierra Leone with about 312 bed capacity. The hospital departments include surgery, internal medicine, pharmacy, nursing, radiology, laboratory, ophthalmology, oral health and ear, nose and throat.The study was a retrospective review of case notes of patients with renal impairment (acute or chronic) admitted at the cardio-renal ward, intensive care unit and other medical wards between November 2018 and October 2020.The study included all patients with renal disease  who were ≥18 years old and who were admitted at the Connaught Hospital during the study period and whose case notes were retrievable. All patients below 18 years old as well as non- renal admissions were excluded.2, presence of proteinuria or sonographic features like shrunken kidneys or loss of corticomedullary differentiation [e calculated their estimated GFR (Glomerular filtration rate) using the Chronic kidney disease epidemiology equation (CKD-EPI) based on their serum Creatinine. Patients were classified as acute kidney injury when the symptoms of kidney disease were < 4 weeks and at least one of the following: serum creatinine is > 2 mg/dl or urine output ≤0.3 ml/kg/hour [Data collection was done using a structured proforma from the case notes of patients admitted at the cardio-renal ward, intensive care unit and other medical wards. The data collected included socio demographic characteristics, risk factors for chronic kidney disease, risk factors for acute kidney injury, common presenting symptoms of renal disease, examination findings, laboratory findings, duration of hospital stay and outcomes of renal admisisions. We defined renal admissions as any patient admitted with a serum Creatinine of ≥2 mg/dl or those admitted with a diagnosis of chronic kidney disease or acute kidney injury. Patients were classified as having chronic kidney disease based on the presence of symptoms of kidney disease lasting ≥3 months and 2 or more of the following: estimated GFR < 60 ml/min/1.73mntiation . We calc/kg/hour . We alsoP-value of < 0.05 was considered statistically significant. Data was presented using tables and figures.All data collected were cross-checked and entered into a Microsoft Excel spreadsheet, and exported to statistical package for social sciences (SPSS) statistical software for analysis. Descriptive statistics, including frequencies, percentages, mean and standard deviations (SD) was used to summarize study variables/ Binary logistic regression was used to analyze the association between patients who had dialysis while on admission and their related mortality using odds ratio (OR) at 95% confidence level. A A total of 3741 admissions were made into the medical wards including the cardio renal ward and intensive care unit. Out of this, 100 were renal admissions(as stated in the methods section). This gives a 2.7% burden of renal admissions. The mean duration of hospital stay (days) for these patients was 15.1 ± 14.7; 51% were unemployed, 73% had no formal education, 4% were HIV positive and 73% were non–compliant with haemodialysis. The outcomes of renal admissions were as follows: 45% were discharged home, 47% died on admission, 2% were discharged against medical advice, 6% were re-admitted.2 using CKD-EPI equation; 3% had EGFR 15-29mls/min/1.73m2; 5% had eGFR 30-44 ml/min/1.73m2; 8% had eGFR 45-59 ml/min/1.73m2;7% had eGFR 60-89 ml/min/1.73m2 and 6% had eGFR ≥90 ml/min/1.73m2.Majority of these patients (71%) were admitted with estimated GFR (eGFR) less than 15 mls/min/1.73mTable Table Table Table The summary of findings from this study reveals a 2.7% admission burden, young age of patients affected with kidney disease, female preponderance, high level of unemployment among patients with kidney disease and the relationship between dialysis and mortality. The findings also highlighted systemic hypertension, diabetes mellitus as the commonest underlying risk factor for chronic kidney disease with sepsis and hypovolemia as the commonest risk factors for acute kidney injury.A 2.7% admission burden might be an understatement as many people with kidney disease are asymptomatic or are residing in hard to reach areas. Also, the lack of a formidable referral system and facilities for conducting renal function tests in many primary and secondary health facilities are other contributory factors. In addition, this was a single center hospital-based study and so data collected might just be the tip of the iceberg. In another study, reasons cited for understating the actual burden of chronic kidney disease were patients remaining undiagnosed or finding solace in spiritual or traditional healing . Studies2 (stage IV and V). This suggests a relatively advanced renal failure and some may require renal replacement therapy in the form of dialysis. In addition, they are often anaemic and may require blood transfusion. This tends to delay the commencement of haemodialysis and extend their stay in hospital. The mean hospital stay for these patients is about 2 weeks. A summary of their laboratory values also suggest a mean occurrence of hypocalcaemia and hyperphosphatemia suggesting evidence of mineral bone disease. Urinalysis findings revealed a frequent occurrence of proteinuria (nephrotic and sub-nephrotic) and haematuria suggesting ongoing renal insults. The most frequent abdominopelvic ultrasound findings were renal parenchymal changes described as increased parenchymal echogenicity, loss of corticomedullary differentiation and shrunken kidneys suggesting longstanding renal injury. The commonest symptoms at presentation for the renal patients are bilateral leg swelling, reduction in urine output and exertional dyspnoea. These are well known symptoms of advanced renal failure. This late presentation leads to many unplanned dialysis sessions. Such patients will commence dialysis without adequate time for education on kidney disease and other options of renal replacement therapy as well as fashioning of an arteriovenous fistula. Late presentation is a major contributor to early mortality among haemodialysis patients [Many of our patients present with an estimated glomerular filtration rate less than 30mls/min/1.73mpatients , 17. Higpatients .The mean age of patients was less than 50 years old. A vast majority of the patients were less than 60 years old. There is a slight female preponderance as well as a high rate of unemployment among our patients. The young age at presentation of many of our patients may be due to a high rate of infections  in our environment which might affect the kidneys resulting in post-infectious glomerulonephritis and subsequently chronic kidney disease. The high rate of unemployment among our patients would suggest that many of them cannot afford to pay for their haemodialysis treatment or to buy drugs like erythropoietin, parenteral iron, phosphate binders or calcitriol. This often results in high morbidity and mortality among our patients. The major risk factors for chronic kidney disease were systemic hypertension and diabetes mellitus. The lack of data on chronic glomerulonephritis might have been due to documentation bias. However, we can say that the burden attributable to systemic hypertension will also include those with chronic glomerulonephritis as many of our patients are in the young age group.Prior to 2021, the unavailability of kidney biopsy needles and other factors relating to human resource made kidney biopsy a remote possibility. Even with the use of kidney biopsy and the presence of Pathologists, making a tissue diagnosis of kidney disease is still limited by lack of special stains and absence of immunofluorescence and electron microscopy. Nevertheless, inferences are made from the Haematoxylin & Eosin stained specimen, clinical history and laboratory results so that some patients can be started on immunosuppresives or steroids. Some of the common histopathology seen so far are suggestive but not conclusive of minimal change disease, focal segmental glomerulosclerosis, focal mesangial proliferation and interstitial nephritis.Sociodemographic factors may impact the effect of established risk factors on the development of kidney disease . These fThe major risk factors for acute kidney injury (AKI) were sepsis and hypovolemia. The high rate of both bacterial and parasitic infections in our locality, the poor health- seeking behavior of our patients which include late presentation to hospitals, use of alternative medicine might be contributory. In addition, the probable high rate of medical malpractice, antimicrobial resistance, increased incidence of water-borne diseases and many people living in unsanitary conditions may play a role. A single-center study done in Sudan also highlighted similar risk factors for acute kidney injury . GloballIt was difficult to apply the serum creatinine-based Kidney Disease Improving global outcomes (KDIGO) definition for acute kidney injury because many of our patients present late and cannot afford to do serum creatinine more than once . A critiP < 0.05). The overall mortality rate among our patients was a little lower than 50%. Major contributors to patients not accessing haemodialysis include prohibitive costs, few dialysis units  and shortage of skilled workers [Many of our patients required renal replacement therapy while on admission. Patients who could not pay for dialysis died while on admission. Dialysis clearly reduces the in-hospital mortality of patients admitted with kidney disease (OR > 2;  workers . The mor workers , 25. ThiThe admission burden of mainly unemployed young patients poses serious issues bordering around affordability of care even though affordability was not directly assessed in this study. The high mortality, especially among the non-dialyzed also suggest the role financial affordability plays in kidney care. Going forward, there is a need for screening programs directed at the major risk factors for CKD and AKI as earlier documented. Such a program should focus on early diagnosis, availability and compliance to drugs, access to care, regular follow-up, meeting treatment targets. Studies have documented that a well-executed prevention program will help to save lives, create major health gains and improving health equity by preventing end stage kidney disease . The IntThere is urgent need for government, private partners and NGOs to provide financial support to patients with kidney disease in order to improve equity to kidney health. There is also a desperate need to improve renal diagnostic facilities in Sierra Leone and also to embark on intensive renal prevention programs.There is a significant burden of kidney disease in our environment, affecting mainly the young and middle-aged population. Therefore, a plausible approach to improving this situation is to embark on prevention programs. The preventive approach is a cheaper option not only for Sierra Leone but also other countries in sub-Saharan Africa.


To the Editor: Epidermolysis bullosa (EB) is a rare, genetic, blistering disease that has no specific treatments. Trials are underway to compare new treatments with supportive care. Despite this, there is a lack of long-term objective data on how lesions change over time. We have used the validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) at each visit of our patients with EB since 2013.Patients had EB simplex, dominant dystrophic epidermolysis bullosa, junctional epidermolysis bullosa (JEB), or recessive dystrophic epidermolysis bullosa (RDEB) . Eighteehttps://doi.org/10.17632/89jt9s77v8.2). Patient Australasian Epidermolysis Bullosa Registry (AEBR) #34 with comorbid atopic dermatitis had both the EBDASI and Eczema Area and Severity Index scores increasing with eczema flares , suggesting that pruritus and scratching worsened his trauma-induced blisters (A). Patient AEBR#213 with dominant dystrophic epidermolysis bullosa (B) had a course of photobiomodulation, which is a low-level laser treatment that is believed to promote tissue healing and regeneration, and adenosine triphosphate, nucleic acid, and collagen synthesis.2; right side using infrared light, 980 nm, 6 J/cm2; gums using red light, 650 nm, 1 J/cm2). The EBDASI activity score reduced from 53 to 37 and the damage score from 42 to 28 . Five patients with JEB showed stable EBDASI scores over 54 visits over 275 months . An improved damage score was recorded for patient AEBR #11-1 with JEB (C) with the use of thalidomide. However, he was lost to follow-up and later died from a JEB-related cardiomyopathy. The use of colchicine and dapsone also show improvement in the EBDASI scores in JEB.,EBDASI scores were generally lower in the 4 patients with EB simplex  had stable EBDASI activity and damage scores over 217 months. In patient AEBR#86 (D), hemodialysis showed the biggest improvement, similar to that seen in patient AEBR#488 with JEB (E). Other interventions such as suprapubic catheter insertion in JEB  and gastroscopy/percutaneous endoscopic gastrostomy feeding in RDEB  resulted in some improvement in the EBDASI scores.Six patients with RDEB  tools. Drs Ho, Gibson, Kazemikhoo, and Murrell have no conflicts of interest to declare.


Patients with severe uncontrolled asthma still experience acute asthma symptoms and exacerbations, particularly those with non-eosinophilic inflammation who take the maximum amount of standard drug therapy. Tezepelumab, a human monoclonal antibody, can improve lung function and enhance control of asthma symptoms in those patients, regardless of the disease’s baseline characteristics. This study aims to investigate the safety and efficacy of using tezepelumab in controlling severe symptoms of uncontrolled asthma. We performed a comprehensive literature search in several databases, including PubMed, Scopus, Web of Science, Cochrane Library, and clinicaltrial.gov, using a well-established search strategy to include all relevant publications. According to our inclusion criteria, we searched for randomized controlled trials comparing tezepelumab versus placebo in patients with severe, uncontrolled asthma. We analyzed the data using The Revman 5.4 program software. The search identified 589 potential articles. After excluding studies inconsistent with selection criteria, four studies were included and analyzed qualitatively and quantitatively. The pooled effect demonstrated the better performance of tezepelumab over the placebo regarding the decrease in annualized asthma exacerbation rate ), asthma control questionnaire-6 (ACQ-6) Score MD = − 0.32, ), blood eosinophil count ), feNO ) and serum total IgE ). All tezepelumab groups had higher pre-bronchodilator forced expiratory volume in 1 s than the placebo group ). Higher efficacy and safety profile was detected for tezepelumab to control the exacerbations of severe uncontrolled adult asthmatics. In adults, the prevalence rate of asthma is estimated to be 4.5%, which translates to nearly 300 million persons with asthma globally. In developed countries, this prevalence reaches 21.5%2.According to the Global Initiative of Asthma (GINA), asthma is a condition that affects the lower parts of the airway, represented by recurrent respiratory manifestations including wheezing, breathlessness, tightness of the chest, and coughing as well as fluctuating airflow restriction1.In most cases, airway restriction and asthmatic clinical manifestations change with the time of day manner. The manifestations frequently get worse at bedtime or in the early hours of the morning. Flares can be produced by both particular stimuli like allergens and general stimuli like exercising, laughing, irritating exposures, cold air, and respiratory tract infections3. Because of the chronic nature of this inflammatory disease, patients may experience restructuring all air passages, including epithelial apoptotic cell death, proliferation and differentiation of smooth muscle cells, and stimulation of fibroblastic cells contributing to matrix formation. These changes are collectively known as “airway remodeling” and, therefore, can contribute to chronic airway obstruction5.Symptoms and exacerbations occur in severe and uncontrolled cases of chronic asthma despite receiving the maximum amount of standard drug therapy. These cases have type 2 (T2), non-T2, or combined mechanisms-induced chronic airway inflammation6. Biological therapy can be used to enhance the response of the patients to moderate- to high-dose ICSs. The biological therapies that are now approved address particular T2 inflammatory mediators, adding therapeutic value for those with particular asthma characteristics 9. Yet, certain people with chronic asthma, especially those with non-allergic or non-eosinophilic types, are ineligible for current biologic therapies11.Inhaled corticosteroids (ICSs) help decrease airway inflammation, which leads to better clinical asthma results13. The epithelium is the source of TSLP, which is released after its exposure to inhaled epithelial pathogens, including allergens, viruses, and bacteria. By upregulating T2 cytokines, TSLP regulates particular elements of neutrophilic inflammation and activates numerous T2 pro-inflammatory cells. These cells include group 2 innate lymphoid, dendritic, and mast cells13. TSLP has also been demonstrated to contribute to airway remodeling. This remodeling is done by fibroblasts and airway smooth muscle proliferation as TSLP increases collagen production14.Thymic stromal lymphopoietin (TSLP), a cytokine released from epithelial cells, is believed to trigger a number of cell groups and inflammatory pathways implicated in the pathophysiology of asthma. The pathogenesis of both T2 and non-T2 mediated asthma is affected by TSLP, which plays a part in the initiation and maintenance of the airway inflammation16. Despite basal values of T2 inflammatory biomarkers, tezepelumab decreased flare-ups dramatically in adults with severe uncontrolled asthma in phase 3 “NAVIGATOR” (NCT03347279) and phase 2b “PATHWAY” (NCT02054130) investigations15. To combine the existing data and assess the efficiency and safety of tezepelumab as a treatment for severe uncontrolled asthma in adults, we conducted this systematic review and meta-analysis.Tezepelumab, a human monoclonal antibody, attaches to TSLP and blocks binding to its heterodimeric receptors17 and Cochrane Handbook of Systematic Reviews of Intervention18. In addition, we used PROSPERO to register the protocol for this meta-analysis (CRD: CRD42021290047).We conducted this study and presented our findings in accordance with the preferred reporting guidelines for systematic reviews and meta-analyses (PRISMA) 2020We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, clinicaltrial.gov, and Scopus for articles from inception to September 25, 2022, with terms related to asthma and tezepelumab. Supplementary file 19.Two independent authors Ramadan Abdelmoez Farahat and Bassant Hassan Shawki, examined the articles to check if they fit our inclusion criteria. We considered randomized controlled studies (RCT) that looked at the clinical efficacy and safety of tezepelumab. In adults with severe, uncontrolled asthma who were either males or females aged ≥ 18. GINA 2012 guidelines define severe uncontrolled asthma despite being treated with long-acting beta-agonists coupled with a medium dose of fluticasone  or high dosage of fluticasone  of inhaled glucocorticoidsExcept for RCTs, we excluded all other study designs. Also, we did not include research whose extracted data were unreliable for analysis. Another third author arbitrated any discrepancies between the two authors.20. The Rob2 tool consists of six domains: (1) the randomization process, (2) missing outcome data, (3) deviations from the intended interventions, (4) selection of the reported result, (5) measure of the outcome and (6) other bias. The response options of the authors were classified as yes, probably yes, probably no, no, and no information. Two authors separately rated the quality, and all the debates were dealt with and resolved.The Cochrane risk-of-bias tool for randomized trials (RoB 2) was applied to evaluate the quality of included Randomized clinical trialsTwo authors, Ahmed K. Awad and Eman Reda Gad, worked independently to extract data from a pre-defined excel spreadsheet, including the following data: a brief of the clinical trials’ essential characteristics, descriptions of the patients included in the clinical trials, and tezepelumab outcomes related to safety and efficacy. A discussion between the authors solved discrepancies.Treatment efficacy was assessed by annualized asthma exacerbation rate (AERR), change from baseline in pre-dose/pre-bronchodilator (pre-BD) forced expiratory volume in 1 s (FEV1), weekly mean daily. In addition to asthma symptom diary score, ACQ-6 Score, standardized asthma quality of life questionnaire for 12 years and older (AQLQ(S) + 12) total score, European quality of life-5 dimensions 5 level version (EQ-5D-5L) health state evaluation at Week 52, blood eosinophil count, FeNO, and serum total IgE.Treatment-emergent adverse events (TEAEs) and Treatment-emergent serious adverse events (TESAEs) assessed the occurrence of the adverse events.21.For statistical analyses, we used Revman software Version 5.4.1. For dichotomous data, pooled risk ratio (RR) was used, while for continuous data, the mean difference was used with 95% confidence intervals (CI). We used the random-effect model for the analysis. We considered p-value < 0.05 as a significant point. For heterogeneity, I-square and p-value were used. If the p-value was < 0.05 or I-square was > 60%, the analysis was considered heterogeneous. A leave-one-out test or subgrouping analysis was adopted to solve the heterogeneityWe obtained 1196 studies from clinical trial.gov, PubMed, Web of Science, and Cochrane library, Scopus. 194 of them were duplicates. After removing the duplicates and the title and abstract screening, 963 articles were excluded as they did not follow our inclusion criteria, while 39 full-text articles were evaluated for eligibility. Finally, the meta-analysis included four RCTs  as rescue medicine, and all participants in the study groups continued to receive inhaled glucocorticoids along with rescue medications that may or may not include oral glucocorticoids without alteration.A comprehensive overview of the included trials is provided in Table Tables ROB 2 tool evaluated the bias risk of the included trials from low to high risk. Figures Randomization process bias: We evaluated all the included trials as low risk for the randomization process.Intended interventions bias: In terms of deviations from the intended interventions, the majority of the included trials showed a low risk of bias except for Diver S. et al. 2021, which were judged as high risk. This is because the statistical analysis that was done to calculate the impact of assignments was as treated analysis, and there was a loss during the follow-up exceeding 5% of the population.Missing outcome data bias: Due to the use of the intention to treat analysis, most included trials had a low risk of bias in the missing outcome data, except Diver S et al. 2021. which had a high risk of bias because the authors used an as-treated analysis with 8% withdrawal in the intervention group, and they did not mention the reasons for exclusion in the intervention group.Measurement outcome bias: Because all outcome assessors were blinded and used appropriate outcome measurement methods, we judged the bias risk in the measurement of the outcome as low in the majority of the included trials. Hence, due to the lack of information about blinding the outcome assessor, we judged Wechsler 2022 as having some concerns.Selection of the reported results bias: We judged the risk of bias owing to the selection of the reported results of Wechsler 2022 as raised some concerns, but the other trials were rated low risk because all outcomes established in the results were in the protocols.Other Bias: There is no other bias.22.We couldn’t use Egger’s test for funnel plot asymmetry in this study to detect publication bias as we have only four studies, and for less than ten pooled studies, publication bias assessment is unreliable2 = 85%) but we could not perform leave one out test as we have only three studies in the analysis.  includes three studies with a total of 739 patients in the tezepelumab arms and 745 patients in placebo arms, revealed a significant decrease in AERR favoring tezepelumab with MD -0.74 . High heterogeneity was observed  . Low heterogeneity was found  . Heterogeneity evidence was found  . Heterogeneity evidence was found  Fig. .Figure 72 = 0%) . Heterogeneity evidence was found , which was solved by sensitivity analysis excluding Corren et al. 2021  . High heterogeneity was observed  . Low heterogeneity was found  Fig. .Figure 1Tezepelumab significantly lowers the risk of any serious adverse effects than placebo, with RR 0.71 , as opposed to the analysis of any adverse effects showing no significant risk reduction between tezepelumab and placebo with RR 0.92 . Figs. , 12.FiguThis study revealed significant improvements in asthma management, lung functional status, well-being, and quality of life with tezepelumab treatment compared to placebo. Tezepelumab significantly decreased the occurrence of asthma exacerbations in adults with chronic uncontrolled asthma, including those with reduced blood eosinophil levels, compared to placebo. In addition, tezepelumab showed significant improvements in ACQ-6, AQLQ(S) + 12 scores, and FEV1, decreasing hospitalization or emergency room visits. However, the tezepelumab and placebo groups did not differ significantly regarding the frequency and kinds of adverse incidents.23. The observed decrease in serum total IgE levels could be related to lower levels of interleukin-4 and interleukin-13, which would result in a gradual reduction in B-cell shifting from IgM to IgE isotype production. These findings support the theory that TSLP inhibition has a more considerable physiological impact than just targeting individual T2 cytokines24.Tezepelumab concurrently decreased blood eosinophil count, FENO, and serum total IgE levels, indicating that the drug inhibits numerous inflammatory pathways. Tezepelumab influence on these biomarker levels could be linked to the lower levels of interleukin-5 and interleukin-1326.In response to stimulation , the function of TSLP as an early mediator between cells of immunity and epithelial cells of the airways indicates that tezepelumab may normalize local inflammation through allergic and non-allergic mechanisms, regardless of blood eosinophil count. It is anticipated that TSLP inhibition will reduce the T2 cytokine produced by T-memory cells, mast cells, and innate lymphocyte type 2 cells across the spectrum of inflammation. The roles of TSLP in triggering responsiveness via dendritic cells and interactions between mast cells and smooth muscle cells of the air passages are pathways that could be important to inflammation in low-eosinophil populations27. Another worldwide study on adolescents and adults showed that tezepelumab reduced the annual occurrence of asthma symptoms significantly in adults and adolescents with severe uncontrolled asthma, even in individuals who have blood eosinophil counts as low as 300 cells per microliter at baseline28. Furthermore, another trial, “The PATHWAY” (NCT03347279), showed more reduction in the asthma symptoms yearly incidence than “The NAVIGATOR” trial (NCT02054130).According to a previous systematic review, omalizumab, tezepelumab, and dupilumab may modulate airway hyperresponsiveness by direct action on smooth muscle cells in the airway, in addition to indirect effects on parasympathetic activity and eosinophilic inflammation29.Tezepelumab, as compared to placebo, decreased exacerbations in patients who have or who do not have perennial allergy in a 52-week trial. Furthermore, lung function was enhanced, and blood eosinophil counts and FENO levels decreased regardless of allergy status. In this study, no significant differences were found in the majority of asthma severity assessments between individuals who have and who do not have allergies at baseline. However, there were some differences in the biological indicators of the inflammatory process: patients who have allergic reactions had greater serum total IgE and high FENO at baseline, without discernible change in plasma eosinophil count. Rhinitis and atopic dermatitis were also more prevalent in allergy patients than in non-allergy patients and younger ones30. The percentage of placebo patients whose ACQ-6 and AQLQ(S) + 12 scores increased by clinically significant levels was between 61–78% and 70%, respectively. This finding is consistent with evidence from studies investigating other biologic therapies in asthma34. The high number of placebo group responders in these studies might be attributed to greater adherence to standard-of-care medicines while participating in these clinical trials. Furthermore, several trials have demonstrated that a patient’s impression of the benefits of clinical trial participation may result in a positive response to placebo therapy36.Patients who took tezepelumab instead of a placebo had a more significant percentage of responders as evaluated by the AQLQ(S) + 12 and ACQ-637. Also, Corren et al. found that tezepelumab was safe, the number of patients was modest, and treatment was administered every 2 or 4 weeks for a total duration of 1 year15.Tezepelumab did not decrease submucosal neutrophil cells or lymphocyte cells of the airways, which is reassuring from a safety standpoint. Eosinophil-depleting medications do not cause clinically significant immunosuppressive response, as evidenced by the fact that there was no increased incidence of infectious events in the tezepelumab compared to placebo groups in the previous trialTezepelumab efficacy and safety in patients with severe uncontrolled asthma were summarized in this systematic review and meta-analysis. The study includes four RCTs, yielding a high level of evidence. The studies included ranged in quality from poor to excellent. The study limitations were due to the inherent research: RCTs have often been conducted in small, carefully selected groups of asthmatic patients. Furthermore, the majority of the identified heterogeneity was not resolved. Moreover, due to the small number of papers included, publication bias could not be examined. In addition, we could not get data of Wechsler 2022 from its full text, so we got its data from the protocol.Tezepelumab provided considerable ability to control the exacerbations of severe uncontrolled adult asthmatics. However, minimal is known regarding the actual clinical impact of monoclonal antibodies like tezepelumab in the treatment of asthma. Further research involving large, ethnically varied samples of individuals with uncontrolled asthma is critical to address this clinical challenge for long-term illness care.Supplementary Information.


The role of spironolactone treatment in hemodialysis patients is debated, but a survival benefit is suggested. Mineralocorticoids and chronic kidney disease have been linked to cardiovascular fibrosis. Therefore, we hypothesized that spironolactone would affect vascular stiffness, cardiac systolic, and diastolic function in hemodialysis patients.This was a randomized crossover study in hemodialysis patients supplemented with an echocardiographic case series. All outcomes reported here were secondary in the trial and were assessed without blinding. Block randomization and allocation determined treatment order. Participants received 50 mg spironolactone daily for 12 weeks and untreated observation for another 12 weeks. Pulse wave velocity (PWV) was measured before and after treatment and observation. Doppler-echocardiography was conducted before and after treatment. Systemic arterial compliance indexed to body surface area (SACi), left ventricular ejection fraction (LVEF), the peak early diastolic mitral inflow velocity (E), the peak late diastolic mitral inflow velocity (A), and the peak early diastolic myocardial lengthening velocity (E’) were measured. E/A and E/E’ were then calculated. Statistical analyses were conducted per protocol. A generalized linear mixed model with random participant effects was used for PWV. The Wilcoxon signed-rank test was used for echocardiographic variables.P = 0.07). There were no significant changes in any of the other variables .Thirty participants were recruited, 18 completed follow-up, and 17 were included in PWV-analyses. Spironolactone treatment showed a tendency toward an increase in PWV of 1.34  m/s, which was not statistically significant (We found no evidence supporting an effect of 12-week administration of spironolactone 50 mg daily on vascular stiffness, cardiac systolic, or diastolic function in hemodialysis patients. In recent years, there have been trials suggesting that mineralocorticoid receptor antagonists, such as spironolactone, reduce the risk of cardiovascular events in patients with end-stage renal disease (ESRD) , 2 and cFibrosis of the cardiovascular system has been associated with mineralocorticoids  and the Mineralocorticoid receptor antagonists reduce vascular stiffness in various populations , 12, 13.We hypothesized that spironolactone would affect vascular stiffness in hemodialysis patients and aimed to describe potential effects on cardiac systolic and diastolic function.This was a randomized crossover trial supplemented with a descriptive case series of Doppler-echocardiography variables. All variables reported here were secondary outcomes of the trial and were collected without blinding. Study design and sample size determination have been described in more detail elsewhere .Participants were recruited from the dialysis units of Örebro University Hospital, Sweden, and Uppsala University Hospital, Sweden, between February 2013 and December 2014. Inclusion criteria were ≥ 18 years of age, hemodialysis sessions ≥ 3 times per week, compliance ≥ 3 months, and adequate cognitive function. Exclusion criteria were cardiac pacemaker, atrial fibrillation (persistent or permanent), plasma potassium > 6.5 mmol/L at any time during the last 2 months, life expectancy < 12 months, pregnancy, or breastfeeding.Randomization was conducted in blocks of six using Clinstat  by a person not involved in the trial. The allocation was concealed by placing randomization results in opaque envelopes that were consecutively numbered and sealed, only to be revealed on the first visit following inclusion.Participants were followed for two periods of 12 weeks separated by a 6-week washout phase. Randomization determined if participants started with treatment  or untreated observation.https://www.medscinet.net/snr/). Laboratory samples were collected, blood pressure was assessed, and pulse wave velocity (PWV) was measured at all visits. Laboratory samples included high-density lipoprotein, low-density lipoprotein, and hemoglobin A1C and were analyzed by the accredited local hospital laboratory. Doppler-echocardiography was conducted before and after the treatment period only.All study visits were scheduled before dialysis treatment on the day of the mid-week dialysis sessions. A total of four visits were planned, before and after both 12-week periods. At the first visit, comorbidities and concomitant medications were recorded from patient history, medical records, and the Swedish Renal Registry .Doppler-echocardiography was conducted by a single operator per study center using GE Vivid 9 with a 3.5 MHz probe . Data were analyzed 2/mmHg), an indicator of vascular stiffness, was determined as described by Mohty et al. from stroke volume, body surface area, and brachial pulse pressure  for continuous variables and number and percentage for categorical variables. PWV and blood pressure data were analyzed using a generalized linear mixed model with fixed effects for treatment, intervention order and baseline measurements, as well as with random effects for participants . We consThe Regional Ethical Review Board in Uppsala, Sweden (reference number 2011/316), and was approved by The Swedish Medical Products Agency. It was registered at The EU Clinical Trials Register before the study started . The Declaration of Helsinki was adhered to, and Good Clinical Practice was applied.This study received ethical approval from A total of 30 participants were recruited, and 29 underwent randomization, of which 18 (60%) completed follow-up . The maiThe majority of participants who conducted at least one study visit were male, 22 (76%), and had a median age of 66 (IQR: 62–70) years . ParticiP = 0.07  m/s and 0.0 (IQR: −1.6 to 1.1) m/s during observation . There wP = 0.07 .A post-hoc power analysis with PWV as the outcome using 17 subjects and the standard deviation of the change during treatment (1.94 m/s) yielded a minimal detectable difference of 1.4 m/s at 80% power.P = 0.12, and diastolic blood pressure by 4.2 (95% CI: −2.2 to 11) mmHg, P = 0.18.Blood pressure did not change during treatment compared to observation; systolic blood pressure by 10 (95% CI: −2.9 to 23) mmHg, P = 0.07.Doppler-echocardiographic variables remained stable during treatment and did not show any statistically significant change . HoweverThis randomized crossover trial was designed to evaluate the effects of spironolactone on the cardiovascular system in hemodialysis patients. Using data from this study and a supplemental case series, we did not find any evidence supporting an effect of spironolactone 50 mg daily for 12 weeks on vascular stiffness, systolic cardiac function, or diastolic cardiac function in the participants.To our knowledge, we are the first to report data on the effect of spironolactone on PWV, the gold standard in assessing vascular stiffness, in hemodialysis. Neither PWV nor SACi, another marker of vascular stiffness, showed any statistically significant change during treatment. These findings contrast previous findings in ESRD , 15 as wDifferences in study design and included populations might explain why our results do not support previous findings. The potential vascular effects of spironolactone might depend on a longer duration of treatment than was the case in this study. Alternatively, the effect might have been mitigated by vascular pathological processes associated with diabetes mellitus, which was highly prevalent in our study, via non-mineralocorticoid pathways, such as advanced glycation end-products . AdditioIn the descriptive analysis of LVEF and markers of diastolic function, we did not see any change during treatment. These findings are in line with recent findings on LVEF , 19, 28 Several limitations of this study must be acknowledged. First, although the number of subjects analyzed was sufficient based on the power analysis for long-term electrocardiographic changes, the sample size was relatively small, and many subjects were lost to follow-up resulting in relatively low power of detecting changes in the variables reported here. Second, the intervention period was relatively short. Nevertheless, studies of spironolactone in congestive heart failure have shown a reduced mortality and rehospitalization rate after 30 days from treatment start , suggestStrengths of this study include its crossover design that provides confounding control per design and requires a smaller number of participants to attain the same power as in parallel-group studies. Also, all measurements were undertaken before the midweek dialysis session, which promotes a similar hydration status between visits, increasing the reliability of measurements and minimizing the risk of confounding.In conclusion, our results did not support any effect of 12 weeks of spironolactone treatment on vascular stiffness, cardiac systolic, or diastolic function in hemodialysis patients. Future studies should consider the possibility of a nonlinear dose-response relationship for spironolactone treatment on vascular stiffness in hemodialysis patients.