Hypertension is a leading problem; it affects around thirty million adult Egyptians, according to the last national registry. The exact prevalence of resistant hypertension (RH) in Egypt wasn’t spotted before. The purpose of this study was to determine the prevalence, predictors, and impact on adverse cardiovascular outcomes among adult Egyptians with RH.The present study examined a cohort of 990 hypertensive patients who were divided into two groups based on their blood pressure control; group I (n = 842) patients who achieved blood pressure control and group II (n = 148) patients who met the RH definition criteria. All patients underwent a close follow-up for one year to evaluate the major cardiovascular events.2, and NSAID use. After one year of follow-up, the RH group displayed noticeably higher rates of major cardiovascular events, including new-onset atrial fibrillation , cerebral stroke , myocardial infarction , and acute heart failure .The prevalence of RH was 14.9%. The main predictors impacting the cardiovascular outcomes of RH were advanced age (≥65 years), the presence of chronic kidney diseases, a BMI ≥ 30 kg/mThe prevalence of RH in Egypt is moderately high. Patients with RH have a far higher risk of cardiovascular events than those whose blood pressure is within control. Hypertension (HTN) is a major reversible clinical obstacle leading to increased morbidity and mortality globally. It affects approximately 1.3 billion people and is responsible for 7.5 million deaths a year . Accordi5Resistant hypertension (RH) is a subtype of hypertension characterized by the difficulty of achieving BP goals below 140/90 mmHg despite the maximal dose of three anti-hypertensive medications, including diuretics, or achieving BP goals on four anti-hypertensive medications . The cliUncontrolled BP is associated with a higher increase in all cardiovascular morbidity and mortality . Each 10The current study was conducted on patients who visited the cardiology outpatient clinic at Tanta university hospital with a confirmed diagnosis of hypertension between May 2020 and September 2021. The diagnosis of HTN was established either by the previous history of diagnosis and treatment of HTN or by blood pressure ≥ 140/90 mmHg on 2 to 3 office visits two weeks apart, besides their home BP >130/80 mmHg or a single BP measurement of ≥180/110 mmHg. The sample size was calculated using the EPI 7 ™ info program  [According to the control of blood pressure, the patients were divided into two groups: group I (controlled hypertension) included 842 patients who achieved blood pressure measurements < 140/90 on two different visits, and group II (resistant hypertension) included 148 patients whose BP was ≥140/90 mmHg, despite being adherent to medications and taking 3 antihypertensive drugs on the optimal dose, including the diuretic, or taking four or more drugs, nevertheless they weren’t controlled. All patients who enrolled in the study signed informed consent. The study was accepted by the Ethical Committee of Tanta Medical Faculty and agreed with the principles of the Declaration of Helsinki II.At baseline, a detailed history was taken for risk factors evaluation, including age, sex, smoking, diabetes, dyslipidemia, physical activity, excess use of salt diet >5 g sodium per day, previous history of cardiovascular, cerebrovascular, chronic kidney, and peripheral arterial diseases, obstructive sleep apnea, family history of hypertension, and history of their medications, which include antiplatelets, statins, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) if taken more than three times per week, antidepressants, and corticosteroid drugs. In addition, the dose of antihypertensive drugs, and their adherence to prescribed medication were assessed by a questionnaire with every single visit. Moreover, the patients’ level of education, income category, place of residence, and presence of health insurance were assessed. Consequently, occupational and marital status were asked.A physical examination was done for all patients, including an assessment of their weight, height, body mass index (BMI), heart rate, blood pressure, and ankle-brachial index. Blood pressure measurements at baseline were average for the second and third visits after the established diagnosis of HTN. All patients underwent laboratory investigations, an electrocardiogram (ECG) was done for all patients at baseline, at the end of 12 months, and at any cardiovascular events. Transthoracic echocardiography was carried out for all patients using the Vivid E9 ultrasound system  equipped with an M5S phased array transducer (2.5–5.0 MHz) according to the guidelines of the American Society of Echocardiography . Two-dimSecondary causes of hypertension were excluded, including renal artery stenosis, coarctation of the aorta, and endocrine abnormalities, before patients› enrolment. the compliance to prescribed medication and its doses was checked during the first visit and the scheduled follow-ups at the 2nd and 4th weeks from the first visit then after 3, 6, 9, and 12 months using a questionnaire at every single visit. Patients with non-compliance or non-adherence to medication were excluded from the study. Patients who were absent during follow-ups, experienced an acute systemic illness, such as COVID-19 were also excluded from the study. We used both home and office BP monitoring to rule out the white-coat effect and patients with white coat hypertension were excluded from the study. At each visit, blood pressure and heart rate were measured, along with clinical evaluations for recording and assessing the occurrence of any major cardiovascular events. The primary endpoint of the study was the occurrence of mortality or major adverse cardiovascular events (MACE), including cardiac events , cerebral events , resuscitation after cardiac arrest, and acute peripheral vascular ischemia.2) test was used to assess two qualitative parameters. A two-sided P value > 0.05 was considered statistically significant. Multivariate regression analysis was done to identify the independent predictors of RH.Statistical analysis was performed using SPSS 23, IBM, Armonk, NY, USA. Quantitative data were expressed as mean ± standard deviation. Qualitative data were expressed as frequency and percentage. The student’s t-test was used to test the significance between the two groups in the quantitative data. A chi-square (XThe current study included 990 patients with hypertension divided into two groups: 842 patients (85.1%) had a controlled BP <140/90 mmHg (group I), and 148 patients (14.9%) had RH (group II). Baseline characteristics, risk factors, and socioeconomic factors of all patients in both groups were summarized in 2) than the other group (26.72 ± 4.45 kg/m2). The RH group had significantly elevated systolic and diastolic blood pressure values . However, the discrepancies in glycemic and lipid profiles between the two groups were negligible. Raised serum creatinine was substantially greater in the RH group, with a decrease in e-GFR in relation to the controlled BP group  and , respectively. Microalbuminuria, serum potassium, uric acid, ankle-brachial index, and carotid IMT levels did not differ significantly between the two groups as shown in As regarding the clinical, laboratory, and echocardiographic data for both groups. The RH group had a higher BMI .Concerning echocardiographic findings, E/E’ was significantly higher in the RH group , and LAVI was noticeably higher P = 0.016. Furthermore, the percentage of patients with LVH was raised in the RH group in comparison to the controlled BP group  with a higher LVMI , and NSAIDs use , as illustrated in The major cardiovascular events that occurred in all participants were demonstrated in Resistant hypertension is a challenge in controlling the BP and management of hypertension-related complications, resulting in a remarkable increase in cardiovascular diseases, end organ damage, and premature death. Hereditary genes, aberrant sympathetic and renin-angiotensin-aldosterone system activation, endothelial dysfunction, decreased arterial compliance, and increased systemic vascular resistance all contribute to the pathogenesis of resistant hypertension 16. SubseThe prevalence of RH was 14.9% in the current study. The incidence of RH differed around the world and was estimated at around 10–20% . In-deptComparable to the age of the patients in the present study, patients with RH were significantly older than the controlled BP group . In agreement, many studies demonstrated a significant increase in RH incidence with aging 89, which wThe current study revealed that the number of patients suffering from CKD was higher in the RH group. In correspond with these results, a meta-analysis demonstrated the high prevalence of RH in CKD 29%) and renal transplantation patients (56%) . In para82728% and ren2 doubled the possibility of RH; moreover, visceral obesity was attached to a high aldosterone level with a final result of uncontrolled BP. In the present study, RH was linked to obstructive sleep apnea (P = 0.043). Supporting this result, several studies, including a large cohort study in the USA, demonstrated an increase in the intensity risk of RH with obstructive sleep apnea by 60% [33The prevalence of obesity and BMI was significantly higher in patients with RH in the current study. These results came in agreement with Gijón-Conde et al. , Naseem a by 60% 3334. By by 60% 33 and Buhnby 60% 33 remarkedby 60% 33.Concerning echocardiographic findings, there was a noticeable increase in the incidence of LVH and LVMI in patients with RH. In concordance with the present results, Dobrowolski et al.  revealedThe RH group had a poorer outcome after one year of follow-up, and MACE rates were significantly higher in this group of patients. The RH group had a considerably greater incidence of new-onset atrial fibrillation (6.8%) than the controlled group (2.5%). It is the consequence of high E/E’ and LAVI, resulting in left atrial remodeling and an increase in its filling pressure. Additionally, acute heart failure incidence was higher in the RH group (4.7% vs. 1.8%). Heart failure with preserved ejection fraction was previously known to be the predominant type in RH, which may be explained by the current results of an increase in LA filling pressure and a reduction of diastolic function .Additionally, cerebral stroke was (4.1%) in the RH group and (1.2%) in the controlled BP group. Likewise, the myocardial infarction rate was significantly elevated in the RH group. Nevertheless, no significant difference in mortality could be detected owing to the short follow-up period. Similar to the previous results, Chun et al.  after 4.2, and the use of NSAIDs. In the ALLHAT Trial, old age, BMI ≥ 30 kg/m2, and serum creatinine above 1.5 mg/dl were linked to failure to reach BP goals, a high incidence of atherosclerosis, and stiffness in the vessels [2) was an independent factor associated with a high risk of RH, and patients with CKD were at a higher risk of increased cardiovascular events, especially heart failure. Also, the use of NSAIDs was combined with an increase in the prevalence of RH, especially in the elderly and CKD patients, due to deterioration of kidney function, renal ischemia, and activation of the renin-angiotensin systems [Concerning the independent predictors influencing the cardiovascular outcomes in the present study, a multivariate regression analysis was done, showing the following predictors: age ≥ 65 years, CKD, BMI ≥ 30 kg/m vessels . Therefo vessels  studied  systems .The present study was a one-center study with only one-year follow-up, and a quietly small number of populations, to a certain extent, reflected the prevalence of RH in Egypt. As a result, multicenter studies on RH are needed to identify the prevalence of RH in other geographical areas in Egypt, such as Upper Egypt, and to augment awareness of the disease’s hazardous complications as well as the importance of lifestyle adjustments, and regular follow-ups.Resistant hypertension is a heading socioeconomic burden on global health, especially in growing countries like Egypt. Its prevalence is rising and differs according to the demographic characterization of the populations. It was an adjunct to the significant risk of MACE. So, early identification of the affected patients and establishing a proper modifiable plan of management are crucial, along with reliable follow-up. Furthermore, a special interest in geriatric, obese, NSAIDS users, and CKD patients is prudent to reduce the progress of end-organ damage and MACE.


Chronic kidney disease (CKD) is a progressive and incurable disease that impairs kidney function. Its prevalence is estimated to affect up to 800 million individuals within the general population, and patients with diabetes and hypertension are particularly at risk. This disorder disrupts the physiological mechanisms of the body, including water and electrolyte balance, blood pressure regulation, the excretion of toxins, and vitamin D metabolism. Consequently, patients are exposed to risks such as hyperkalemia, hyperphosphatemia, metabolic acidosis, and blood pressure abnormalities. These risks can be reduced by implementing appropriate diagnostic methods, followed by non-pharmacological  and pharmacological strategies after diagnosis. Selecting the appropriate diet and suitable pharmacological treatment is imperative in maintaining kidney function as long as possible. Drugs such as finerenone, canakinumab, and pentoxifylline hold promise for improved outcomes among CKD patients. When these interventions prove insufficient, renal replacement therapy becomes essential. This is particularly critical in preserving residual renal function while awaiting renal transplantation or for patients deemed ineligible for such a procedure. The aim of this study is to present the current state of knowledge and recent advances, providing novel insights into the treatment of chronic kidney disease. AccordiAs for the classification of chronic kidney disease, there are grades from I-V related to the value of GFR . A more The causes of chronic kidney disease are various, and the most important ones are indicated in The purpose of this paper is to present the diagnosis, the latest therapy, both pharmacological and non-pharmacological, looking at dialysis and transplantation.2 or albuminuria 30 mg per 24 h) for more than 3 months. Diabetes and hypertension are the most frequent causes of CKD in affluent nations. The interplay between hypertension and CKD is complicated, increasing the risk of poor cardiovascular and cerebrovascular consequences. This is especially important in the case of resistant hypertension, which is frequent in CKD patients. The pathophysiology of CKD-related hypertension is complex, with several pathways contributing to hypertension. These pathogenic processes include sodium dysregulation, increased sympathetic nervous system activity, and changes in the function of the renin–angiotensin–aldosterone system [+ and water homeostasis. Even little increases in water and salt intake can help to reduce arginine vasopressin (AVP) and blood pressure rises. Preventive education for the general public is both cost-effective and helpful [CKD is usually discovered as a result of routine screening with a blood chemical profile and urine tests, or as an incidental finding . Patiente system ,10. The  helpful  when it  helpful . Staging helpful .Treatment is very broad and involves many different ways to prevent, treat, and slow CKD. The most important goals are slowing the progression of CKD; treating pathology-related complications such as anemia, mineral and bone disorder, hydroelectrolytic disorders, metabolic acidosis, and cardiovascular disease; preparing the patient for kidney replacement therapy (KRT), and establishing an immunization routine, particularly for hepatitis B. It is critical to emphasize that a multidisciplinary team, notably of nutrition, nursing, psychiatry, and social aid, is required at all levels of therapy .There are a few non-pharmacological methods that can be implemented in the CKD patient group, in order to decelerate kidney function decline, that at the same time can lead to postponement in time, or complete avoidance of dialysis therapy in future. To achieve these goals, methods like raising the amount of physical activity (PA), abstaining from smoking, specific diets including sodium-restricted diet, and losing excess weight are being implemented . One of Another, but also significant non-pharmacological method of CKD therapy is incorporation of proper diet . The fact that conventional dietary guidelines for patients suffering from CKD focus mainly on the amount of consumed nutrients may result in a reduced consumption of vegetables and fruits. This can lead to the loss of the benefits derived from consumption of higher amounts of fiber which are, among others, shifting the gut microbiota to reduce production of uremic toxins; it also implies lower intake of plant fats, like olive oil which shows anti-atherogenic properties or plant anions, that could alleviate metabolic acidosis and decelerate CKD development . DespiteLast but not least, a way to improve health in CKD is avoiding usage of substances such as alcohol and cigarettes, especially in higher amounts. Both significant alcohol abuse and smoking by itself are linked with elevated risk of declining kidney function .The mainstay for the management of CKD patients comprises pharmacological and nutritional therapies. There is a growing body of evidence of the role of diet in the treatment of kidney diseases and their ensuing complications . Proper 2, a separate analysis revealed a statistically significant increase in eGFR from 76.32 to 82.21 mL/min/1.73 m2 [2. The study focused on a plant-centered KD and observed positive outcomes, such as a mean reduction of 5.6% in body weight, a 16.5% decrease in fasting blood glucose levels, and an average eGFR increase of 8.6% [Ketogenic diets (KD) are a popular and frequently used diet for weight loss. A ketogenic diet is a high-fat, low-carbohydrate dietary approach that shifts the body into a state of ketosis, where it primarily relies on fats and ketones for energy, instead of carbohydrates . It is s/1.73 m2 . In addi of 8.6% . Neverth of 8.6% ,37. Furt of 8.6% ,39. What of 8.6% ,41.Limited clinical trials have been conducted on the effects of intermittent fasting (IF) on CKD. However, Malik et al. investigated the effects of IF on patients with CKD during Ramadan. Nevertheless, these studies have found either an improvement, a decline, or no alteration in kidney function . RestricAnother dietary pattern reviewed for patients with kidney diseases is plant-based diet (PBD). It prioritizes the intake of plant-derived foods and may incorporate limited quantities of meat, fish, seafood, eggs, and dairy products, depending on individual preferences and choices . This tyThe Mediterranean diet appears to be associated with the maintenance of kidney function, improved cardiometabolic profile and lowered risk of mortality in individuals diagnosed with CKD ,50. A meThe dietary and lifestyle changes should be viewed as complementary to current medical interventions. Each diet has individual benefits and disadvantages. The consumption of minimally processed, whole, plant-based foods is a feature of these healthy diets that is supported by a growing body of studies that highlight potential benefits for people with CKD. In order to improve their health as much as possible, patients should be given the knowledge and resources they need to adopt the diet that is most applicable to their circumstances and stage of CKD . HoweverMineralocorticoid Receptor Antagonists (MRAs) are a group of drugs, the best-known representatives of which are spironolactone and eplerenone—classic steroid antagonists. Among the non-steroidal MRAs we can distinguish, for example, finerenone, exaserenone, and apararenone . For exaThe FIDELIO-DKD trial involved patients with T2DM and more advanced CKD whereas FIGARO-DKD involved patients with T2DM in earlier stages of CKD but at high risk of CVD. Randomized patients were administered once a day oral treatment with finerenone or the placebo. In total, these trials included 13,026 patients, among whom 5935 had a history of Atherosclerotic Cardiovascular Disease (ASCVD). The results showed that the drug significantly reduced the risk of cardiovascular and renal disease in patients with T2DM, independently of the presence of ASCVD. The safety profile of finerenone did not differ between patients with and without ASCVD, and overall it was well tolerated ,66. In JCanakinumab is a human monoclonal antibody directed against interleukin IL-1β ,69. IL-1Pentoxifylline (PTF) methylxanthine derivative is a non-specific phosphodiesterase inhibitor ,79. The 2. Moreover, another analysis from these two studies showed that patients assigned to treatment with these drugs were more likely to achieve a 30% reduction in UACR compared to the placebo, regardless of baseline UACR [Glucagon-like peptide-1 (GLP-1) receptor agonists are a new but already widely used group of antidiabetic drugs. By affecting the GLP-1 receptor, they influence the action of incretin GLP-1, a protein produced by cells in the small intestine. This leads to lower HbA1c levels by stimulating glucose-dependent insulin secretion and reducing glucagon secretion, gastric emptying, and food intake. In CKD terms, GLP-1 receptor agonists help reduce risk factors by: lowering insulin levels, lowering glucose levels, lowering blood pressure, and causing weight loss ,85. Moreine UACR ,89. The ine UACR .2 at the start of treatment, -DM2-uACR is 22.6 mg/mmol or higher [SGLT2—sodium–glucose cotransporter-2—inhibitors are one of a group of hypoglycemic drugs that have also recently found use in treating heart failure and limiting the progression of renal complications often referred to as cardiac-renal complications ,92. The r higher .Sacubitril/Valsartan, an angiotensin receptor and neprilysin inhibitor, is a first-in-class ARNI that reduces the risk of death from cardiovascular causes or alleviates symptoms of heart failure and reduces hospitalizations for it ,96. ThesWhen pharmacotherapy proves insufficient and KRT is unavoidable, several factors must be considered before commencing treatment, as well as all associated advantages and disadvantages. KRT encompasses in-center hemodialysis, home hemodialysis, and peritoneal dialysis (PD) . In addiThe decision to initiate the dialysis should be founded upon a comprehensive assessment of the patient’s symptoms, laboratory results, and GFR level, in conjunction with the patient’s unique preferences and quality of life considerations. According to the KDIGO guidelines, an eGFR of <20 mL/min per 1.73 m² signifies an appropriate moment to contemplate KRT implementation. Additionally, the presence of at least one of four specific factors warrants consideration for dialysis initiation: manifestation of symptoms or signs directly attributable to renal failure , inability to effectively control volume status or blood pressure, progressive decline in nutritional status despite dietary intervention, or cognitive impairment . Other cThe initiation of dialysis therapy should be implemented at the right time. Gradual transition to dialysis and to sustain residual renal function as long as possible is suggested . A study2 [Before deciding on dialysis, the presence of comorbidities should also be taken into account. Due to the fact that each dialyzed patient has individual clinical and biochemical issues, the same dialysis procedure may not be able to meet the needs of every patient on chronic dialysis. Dialysis patients afflicted with congestive heart failure (HF) or pulmonary edema exhibit a diminished survival rate . Convers2 .Due to the diverse advantages and disadvantages associated with each dialysis method, personalization of dialysis therapies is essential before implementing KRT.Despite the continuous improvement of dialysis, mortality rates for dialysis patients are still high. A study by Chandrashekar A et al.  showed tOne of the primary causes of sudden cardiac death (SCD) in ESKD patients are electrolyte imbalances, frequently present in patients on HD. These abnormalities can explain arrhythmic phenomena. However, due to the elevated incidence of SCD in peritoneal dialysis patients, it is crucial to consider other risk factors related to cardiac comorbidities and uremia that may also contribute to sudden mortality . IncreasUpon determining a specific method of KRT and in the absence of medical contraindications, appropriate preparations should be initiated. These encompass preparation of an arteriovenous fistula for hemodialysis, patient training in PD, implantation of a Tenckhoff catheter, and conducting serological tests for hepatitis B and C, and human immunodeficiency virus (HIV) . A critiPatient preferences regarding the choice of medical management should be carefully discussed and respected. The implementation of appropriate procedures aimed at improving the quality of life of dialysis patients holds significant importance. There are many studies on the beneficial effect of physical activity on outcomes in patients undergoing hemodialysis ,117,118 2 [When it comes down to the management of ESRD, there are two methods of treatment, which are dialysis therapy or kidney transplantation. The second one, namely kidney transplantation, appears to be a preferred approach. It not only shows reduced mortality risk in every age group in comparison to patients on dialysis, who were on waiting lists, but also enables a better quality of life. However, in the case of the elderly patient group, the most significant threat is the elevated mortality in the postoperative period of time ,121. The2 . The tra2 .The kidney can be transplanted in two ways, namely by open kidney transplantation (OKT) or by robot-assisted kidney transplantation (RAKT). Despite the fact that OKT is the dominant method in most centers, the RAKT shows a number of benefits due to use of minimally invasive surgery. These advantages are decreased risk of operating field contamination, reduced postoperative pain, shortening the length of hospital stay, and smaller incision size compared to the OKT method. Moreover, there are no differences in graft or patient survival, as well as no difference in renal functioning at all .Unfortunately, despite its benefits, RAKT is not the most commonly used method for kidney transplantation, mainly due to the significantly higher cost of performing such a procedure compared to OKT . NeverthAnyway, regardless of the transplant method, every transplanted kidney’s function should be regularly assessed, starting with a frequency of twice a week in the first month, gradually reducing this frequency during the first year to at least every 3 months for an indefinite period. There are also situations in which it is important to check serum creatinine concentration, especially during widespread immune response due to, for instance, viral infection. If values exceed 20–25% of the baseline level, this should be a warning sign, because general immune response can be the cause of graft rejection . The aboCKD is a common and progressive condition. Nevertheless, a variety of factors could have an impact on this process, leading to an increased rate of morbidity and mortality. Early detection and classification are pivotal to implementing interventions that can effectively slow down disease progression and minimize associated complications. Further, maintaining kidney function can improve outcomes and can be accomplished through pharmacological interventions, as well as non-pharmacological strategies (such as dietary and lifestyle changes).In this review, we focused on the important aspects of CKD. Proper diagnosis and its influence on the management of CKD were considered to be of interest. We paid attention to the role of non-pharmacological strategies, such as physical activity and various dietary patterns and their influence on the development of this disease. Moreover, we discussed novel therapies for CKD: finerenone, canakinumab, and pentoxifylline, together with renal replacement therapy. Furthermore, the role of transplantation was concluded.These findings might shed new light on CKD and prospective targets for prevention and treatment in the future. However, the significant scientific achievements of recent years and the many new discoveries and mechanisms still require careful attention and additional studies.


Later stage chronic kidney disease (CKD) is associated with poorer self-perceived health-related quality of life (HRQOL), a major consideration for many patients. Psychological factors such as depression and anxiety have been linked with poorer HRQOL. We aimed to determine if anxiety or depressive symptoms are significantly associated with self-perceived health-related quality of life, in patients with CKD Stage 5. The secondary aim was to determine which patient-associated factors are associated with HRQOL in patients with CKD Stage 5.This retrospective cross-sectional study included patients that attended the St George Hospital Kidney Supportive Care (KSC) clinic between 1 and 2015 and 30 June 2022 with CKD Stage 5 . Patients completed surveys of their functional ‘domains’ and quality of life (EQ-5D-5L) and symptom surveys  at their first visit. We performed multivariable linear regression analysis with the outcome of interest being HRQOL, measured using the EQ-VAS, a continuous 100-point scale, for patients undergoing conservative management or dialysis. Pre-specified variables included age, sex, eGFR (for those conservatively-managed), “feeling depressed” , “feeling anxious”  and “anxiety/depression” (EQ-5D-5L).We included 339 patients. 216 patients received conservative kidney management (CKM) and 123 patients received dialysis. Patients receiving CKM were significantly older than those on dialysis, . For conservatively-managed patients, variables independently associated with poorer EQ-VAS were difficulty performing usual activities (EQ-5D-5L), drowsiness  and shortness of breath . For patients receiving dialysis, variables that were independently associated with poorer EQ-VAS were reduced ability to perform self-care (EQ-5D-5L) and lack of energy . Anxiety and depressive symptoms were not significantly associated with poorer EQ-VAS for either group of patients.Symptoms associated with reduced HRQOL include shortness of breath, drowsiness and impaired functional ability. Optimization of multidisciplinary teams focusing on these issues are likely to be of benefit.The online version contains supplementary material available at 10.1186/s12882-023-03355-3. Chronic kidney disease (CKD) affects over 10% of the general population worldwide, with a higher incidence in older populations . As patiRegardless of whether patients proceed down the dialysis or CKM pathway, late-stage CKD is associated with poorer self-perceived health-related quality of life HRQOL , 15). In. In15]).Many patients with kidney failure, whether they are managed with CKM or with dialysis, have a high symptom burden and poorer HRQOL , 31. PatThe primary aim of this study was to determine if anxiety or depressive symptoms are significantly associated with self-perceived health-related quality of life, in patients with kidney failure  The primary hypothesis is that self-reported anxiety and/or depressive symptoms are significantly associated with self-perceived health-related quality of life in patients with kidney failure.The secondary aim was to determine which patient-associated factors  are associated with HRQOL in patients with kidney failure .This study is designed as a retrospective cross-sectional study.Patients who attend the St George Hospital Kidney Supportive Care (KSC) clinic complete surveys using a validated tools of their functional ‘domains’ and quality of life , functional assessment  clinic between 1 and 2015 and 30 June 2022 were asked to complete the EQ-5D-5L and IPOS-Renal survey at their first KSC visit, Patients with CKD Stage 5 managed with either CKM or dialysis were included in the study. Patients were excluded if they did not have CKD Stage 5 or if they had a kidney transplant.Primary outcome is the patients’ self-perceived health-related quality of life score, which will now be referred to as the EQ-VAS, on a continuous 100-point scale (collected on the EQ-5D-5L survey).Data to be analysed was from participants’ first clinic visit.Potential variables analysed included demographic data, functional assessment (Karnofsky score), eGFR , Charlson comorbidity score and co-morbidities and biochemical data  and ‘anxiety or depression’ (as a domain on the EQ-5D-5L).Descriptive data was reported separately based on pathway . Continuous variables were summarised with means ± SD for normally distributed variables and medians  for non-normally distributed variables. Unpaired t-tests were performed to compare differences in normally-distributed continuous variables between the two pathways. Mann-Whitney U tests were performed to compare differences in non-normally distributed continuous variables between the two pathways. Chi-squared tests were performed to compare differences in categorical variables between the two pathways.Multivariable analyses were performed separately based on pathway . For each pathway, univariable analyses were first performed for each dependent variable for the outcome of interest (EQ-VAS). Only variables with a p < 0.20 on univariable analysis were included in the multivariable model. Multivariable linear regression analysis was performed with pre-specified variables including age, sex, eGFR (for those on CKM), “Feeling depressed,”  “Feeling anxious”  and “Anxiety/depression” (EQ-5D-5L). Missing variable data was excluded from analysis. Statistical analyses were performed with IBM SPSS Statistics V26.0. p-values of < 0.05 were regarded as significant. The reporting of this study adheres to the STROBE checklist. This data has not been previously published.A total of 339 patients  were included in the study. The majority of patients on dialysis were receiving haemodialysis (85%). Patients receiving CKM were significantly older than those on dialysis . Overall, proportions of men and women were similar between the CKM and dialysis groups. In the dialysis group, a significantly higher proportion of patients had kidney failure caused by diabetes mellitus or glomerulonephritides. In the CKM group, a significantly higher proportion of patients had kidney failure caused by ischemic nephrosclerosis. Median eGFR for patients on the CKM pathway was 14 mL/min, with a median creatinine at first clinic visit of 310 umol/L. The CKM group also had a higher proportion of comorbidities including congestive cardiac failure, dementia, a previous cerebrovascular accident and those who had smoked within the last 5 years , Karnofsky score (p = 0.008), pain  (p = 0.005), shortness of breath  (p = 0.006), lack of energy  (p = 0.003), mouth problems  p = 0.013), drowsiness  (p < 0.001), poor mobility  (p < 0.001), feeling anxious  (p = 0.015), feeling depressed  (p = 0.004), reduced mobility (EQ-5D-5L) (p < 0.001), reduced ability to perform self-care (EQ-5D-5L) (p < 0.001), reduced ability to perform usual activities (EQ-5D-5L) (p < 0.001), pain or discomfort (EQ-5D-5L) (p = 0.002) and anxiety or depression (EQ-5D-5L) (p = 0.005). Full results of the univariable analyses are attached in the Supplemental Material 3, drowsiOn multivariable analysis, variables that were independently associated with poorer EQ-VAS were difficulty performing usual activities (EQ-5D-5L), drowsiness  and shortness of breath  Fig. .For the patients receiving dialysis, variables significantly associated with poorer EQ-VAS on univariable analysis were lower Karnofsky score (p = 0.007), lack of energy  p = 0.01), nausea  (p = 0.008), poor appetite  (p = 0.04), poor mobility  (p = 0.015), poor mobility (EQ-5D-5L) (p < 0.001), ability to perform self-care (EQ-5D-5L) (p < 0.001), ability to perform usual activities (EQ-5D-5L) (p < 0.001), pain or discomfort (EQ-5D-5L) (p = 0.043) and anxiety or depression (EQ-5D-5L) (p = 0.007). Full results of the univariable analyses are attached in the Supplemental Material , nausea On multivariable analysis, variables that were independently associated with poorer EQ-VAS were reduced ability to perform self-care (EQ-5D-5L) and lack of energy  Fig. .Our findings suggest that for patients with CKD Stage 5 not receiving dialysis, independent predictors of poorer self-perceived health-related QOL (measured through the EQ-VAS) include reduced ability to perform their usual activities (work or leisure activities), higher severity of self-rated shortness of breath and higher severity of self-rated drowsiness. Interestingly, despite being significant on univariable analysis, anxiety and depressive symptoms  were not independently associated with poorer EQ-VAS. For patients with CKD Stage 5 receiving dialysis, independent predictors of poorer EQ-VAS include inability to perform self-care  and lack of energy. Again, despite being significant on univariable analysis, anxiety and depressive symptoms were not independently associated with poorer EQ-VAS.These findings contrast with the majority of the literature in the non-dialysis, CKD population which broadly suggests that anxiety and depressive symptoms are associated with poorer HRQOL. However, many of the studies reporting this association –23 in noIn the dialysis population, our findings that anxiety and depressive symptoms were not significantly associated with EQ-VAS is also in contrast to the current literature –29. HoweThe most significant impact on self-perceived QOL in both groups was patients’ functional capacity, rather than physical symptoms (pain/discomfort) or psychological symptoms (anxiety/depression). Functional aspects are not routinely assessed in nephrology services, and it may be important to direct resources towards interventions aimed at maintaining functional capacity for patients with kidney failure.Our study was limited by its retrospective cross-sectional nature, as we were only able to use data that was already collected. There may also be other variables that we did not collect, which may have confounded our conclusions, though the validated tools we used are fairly extensive. Although a strength of our study was its relatively large numbers compared to most of the published studies, our dialysis population was limited by only having a very small number of patients on peritoneal dialysis and by being a selected group who were referred to the KSC clinic for additional care. Further research will need to be conducted for patients of other cultural and logistical settings.For patients with kidney failure managed without dialysis, factors that are significantly associated with poor HRQOL (measured by EQ-VAS) include shortness of breath and drowsiness, which have not been described in the literature before. Reduced functional ability is associated with reduced HRQOL in patients with CKD Stage 5 managed with or without dialysis, and optimization of multidisciplinary teams within KSC units are likely to be of benefit. Further research is needed to validate these findings and to determine whether allied heath interventions can improve HRQOL in these patients.Below is the link to the electronic supplementary material.Supplementary Material 1


The abnormal neural control of atria has been considered one of the mechanisms of paroxysmal atrial fibrillation (PAF) pathogenesis. The baroreceptor reflex has an important role in cardiovascular regulation and may serve as an index of autonomic function. This study aimed to analyze the baroreceptor reflex’s role in heart rate regulation during upright tilt (HUT) in patients with lone PAF. The study included 68 patients with lone PAF and 34 healthy individuals who underwent baroreflex assessment. Parameters such as baroreflex sensitivity (BRS), number of systolic blood pressure (BP) ramps, and the baroreflex effectiveness index (BEI) were evaluated. The study found that PAF patients had comparable resting BPs and heart rates (HRs) to healthy individuals. However, unlike healthy individuals, PAF patients showed a sustained increase in BP with an upright posture followed by the delayed activation of the baroreceptor function with a blunted HR response and lower BEI values. This indicates a pronounced baroreflex impairment in PAF patients, even at rest. Our data suggest that together with BRS, BEI could be used as a marker of autonomic dysfunction in PAF patients, making it important to further investigate its relationship with AF recurrence after ablation and its involvement in cardiovascular autonomic remodeling. Atrial fibrillation (AF), a highly prevalent type of cardiac arrhythmia in clinical settings, considerably affects health outcomes. It often correlates with detrimental effects on life span and quality of life, posing a considerable public health concern ,3,4,5,6.Understanding the intricate physiopathology of AF remains a complex and challenging task. One reason is the multitude of mechanisms underpinning its initiation and maintenance. For example, lone AF is associated with a sequence of electrophysiological events that involve the participation of numerous wavelets, which spread and randomly interact across the surface of the atrium. Furthermore, these wavelets may be influenced by focal sources of electrical activity referred to as “triggers”. It has been proposed that these triggers could be affected by combined sympathovagal discharges, further complicating this scenario ,12,13.The autonomic nervous system (ANS) plays a central role in the pathogenesis of AF and influences atrial electrophysiology and function ,15,16,17The baroreceptor reflex, which is crucial for short-term blood pressure regulation, serves as an autonomic index of function . While sIn light of these gaps in understanding, our study aimed to explore the behavior of baroreceptor reflex control in patients with lone PAF, both at rest and during an upright tilt (HUT) through the evaluation of BRS and BEI. This approach could provide valuable insights into the complex interplay between autonomic regulation and atrial fibrillation, paving the way for more targeted therapeutic strategies.In this prospective research study, which focuses on elucidating the role of the baroreceptor reflex in cardiovascular regulation during an HUT in patients diagnosed with lone paroxysmal atrial fibrillation (PAF), and which was conducted at the Arrhythmology Department of Santa Marta Hospital in Lisbon, Portugal, we recruited adult patients of both sexes who had suffered from lone PAF for at least one year. A careful history was taken for each patient, followed by confirmatory tests with electrocardiograms (ECGs) and Holter recordings. All patients were characterized by lone PAF, without clinical or echocardiographic signs of concomitant cardiovascular disease. This strict inclusion criterion was set to exclude potential confounding variables and to ensure the accuracy of the study. Exclusion criteria were clearly defined so that all patients with a history of syncope, myocardial infarction, congestive heart failure, renal failure, diabetes mellitus, hypertension, and sleep apnea were excluded. In addition, patients under the effect of beta-blockers or those who had experienced an episode of AF within the 48 h before the study were excluded. Antiarrhythmic drugs, if present, were discontinued for at least five half-lives before the baroreflex sensitivity (BRS) and effectiveness (BEI) assessment were performed. In addition, the study also included a control group of healthy adults of both sexes who were closely matched for age, gender, and other relevant demographic factors. This meticulous selection process was aimed at ensuring a balanced and rigorous comparison between the two cohorts. Following data protection regulations and policies, all patient data used in this study were collected, stored and analyzed securely and confidentially. Patient data were anonymized and de-identified before analysis to protect privacy. The research report does not contain any identifiable personal information. Ethical approval was obtained from the ethics committee of Centro Hospitalar Universitario Lisboa Central, and informed consent was obtained from all participants. The study strictly adhered to the principles of the Declaration of Helsinki and its subsequent amendments, as well as Portuguese data protection laws and regulations .The participants were instructed not to consume alcohol or tobacco and not to take any medication with anticholinergic properties, at least in the 12 h before the test. HUT was performed in a dedicated lab, in a quiet environment, with controlled temperature and humidity, during the morning period, following four hours of fasting. Briefly, the subjects were placed on a tilt table with a footboard, secured with snug restraints to prevent falling if syncope occurred, and, after a resting period of 15 min in the supine position . After the end of the 5th minute in the orthosthatic position, the subjects were tilted down. All subjects were instructed to breathe normally during the full length of the test. ECG and blood pressure (BP) were continuously monitored using a Task Force Monitor .All signals were acquired using the Taskforce Monitor . The ECG was sampled at 1000 Hz with an accuracy of +/−5 V, synchronized with continuous blood pressure measurements sampled at 100 Hz. The raw data underwent preprocessing to minimize interference. Power line interference was attenuated using a 3rd-order notch filter (49–51 Hz). Baseline wander, typically <0.5 Hz, was reduced using a high-pass second-order Butterworth filter. Muscle noise was addressed using a low-pass filter with a 35 Hz cut-off. A wavelet-based QRS detector followed by an adaptive dual-threshold algorithm was employed for waveform detection. After QRS detection using a Daubechies 12 discrete wavelet transform, the adaptive double threshold algorithm was applied. This ensured robust peak detection and accurate results with a maximum error tolerance of 1–2 ms. A waveform typing algorithm differentiated between QRS complex morphologies, identifying the dominant morphology and distinguishing it from other beats. Ectopic beats or outliers were replaced using cubic spline interpolation.Continuous RR intervals (RRIs) and non-invasive BPs were obtained, and data analysis was performed on three periods: (1) the last 4 min of the supine resting period ; (2) during the first minute of tilt adaptation at 70° (TA1); and (3) in the fifth minute after tilting (TA5). Systolic BPs (sBPs) and RRIs were used for the subsequent analysis of baroreflex function through the sequence method (BRS) as stated elsewhere ,29,30. BFor each period considered for analysis, BEI, which reflects the number of times the arterial baroreflex is in control of the heart rate response to blood pressure fluctuations and is defined as the ratio between the number of BRS sequences detected and the total number of sBP ramps observed, was calculated .p < 0.05 was considered statistically significant. To rigorously assess the potential impact of confounding variables on our primary outcomes of BRS and BEI, a multiple regression analysis was employed to control for age, BMI, baseline BP, and HR as covariates. Each variable was included in the regression model to evaluate its independent effect on the outcomes while adjusting for the other variables. The significance of each variable was tested, and the adjusted effect sizes (beta coefficients) were computed. In addition, a sensitivity analysis was computed to examine the finding’s robustness. For that, each potential confounding variable was sequentially excluded from the regression model, and the resulting effect sizes and p-values were compared to the original model. This sensitivity analysis was carried out for both BRS and BEI to ensure that our findings were not unduly influenced by any single confounding variable. Data was analyzed using GraphPAD Instruments version 3.05 .Continuous variables are expressed as mean ± standard error of the mean (SEM), unless otherwise specified. Categorical variables are given as frequencies and percentages, and the chi-square test was used to determine if there was any association between variables. The normality of the distributions of the continuous variables was analyzed with the Kolmogorov–Smirnov test. A two-way ANOVA analysis of variance with repeated measures was used to compare data along the test and between groups. A value of The study sample consisted of 68 patients of both sexes, with a mean age of 53 ± 14 years and a documented history of paroxysmal atrial fibrillation (PAF) of at least one year (range 1–5 years), and 34 healthy volunteers matching age and sex served as the control group. All patients were diagnosed with lone PAF, defined as the absence of clinical or echocardiographic evidence of cardiovascular disease. Our study included all participants’ successful completion of the testing protocol, with no recorded symptoms or initiation of AF. Given the matching and exclusion criteria applied, potential confounders were minimized and no further adjustments for confounders were deemed necessary. The evaluation of the baseline characteristics indicated no significant differences between patients with paroxysmal atrial fibrillation (PAF) and healthy individuals (HIs) in terms of age, sex distribution, body mass index, baseline arterial blood pressure (BP), and heart rate .In our study, it was important to consider the possible bias due to the recruitment and selection procedures, which could affect the generalizability of the results to the wider population of patients with lone AF. A detailed analysis of bias was conducted and can be found in the p < 0.05) and 116 ± 7.4 (TA5) mmHg, whereas diastolic blood pressure changed from 76 ± 5.5 to 62 ± 4.2 (TA1) and 77 ± 7.3 (TA5) mmHg; n = 34). In contrast, PAF patients experienced a continuous and progressive increase in BP followed by a decrease and a slow adaptation until the recovery of basal values. sBP varied significantly from baseline values of 121 ± 4.3 to 139 ± 5.5 (TA1) (p < 0.05) and 122 ± 6.4 (TA5) mmHg, whereas diastolic blood pressure (dBP) changed non-significantly from the baseline values of 81 ± 5.5 to 92 ± 6 (TA1) (p < 0.05) and 82 ± 6.2 (TA5) mmHg (n = 68)  ( 68) see . This re 68) see .n = 68) and 72 ± 5.8 at baseline to 89 ± 6 (TA1) (p < 0.05) and 77 ± 6.7 (TA5) (n = 34)). Thus, heart rate responses to HUT were the same in both groups, with no significant difference in the amount of heart rate change between the PAF and control groups throughout the test (During the transition from baseline to the tilt adaptation periods (TA1 and TA5), heart rate increased in both groups from baseline 70 ± 10.1 to 72 ± 7 (TA1) and to 71 ± 5.7 (TA5) bpm to PAF patients (the test .p < 0.05) ( < 0.05) A. In conp < 0.05). It is noteworthy that the PAF patients consistently had lower BRS values than the control group during the TA1 and TA5 phases (11.3 ± 1.6 mmHg/ms vs. 15.1 ± 2 mmHg (TA5), p < 0.05; −1 (control); p < 0.001 and during tilt (at TA1 (68 ± 4 (PAF) vs. 50 ± 3.5 ms−1 control, p < 0.01 and at TA5 (67 ± 3.5 (PAF) vs. 49 ± 3.7 ms−1 (control); p < 0.01). Spontaneous BRS at baseline was comparable between the control and PAF groups. However, when transitioning to an upright position, both groups showed a decrease in BRS slope, with the decrease being statistically significant in the PAF patients (17.8 ± 1.9 mmHg/ms (supine) vs. 12.1 ± 1.8 (TA1), The baroreceptor reflex stands as one of the most crucial physiological systems facilitating short-term or swift cardiovascular autonomic regulation, gaining particular significance during postural adjustments to mitigate BP fluctuations ,30,31,32The spontaneous sequence method applied to continuous RRI and BP signals allows for the evaluation of BP variability, which prompts baroreceptor activation by calculating sBP ramps. It provides information regarding BRS by evaluating the amplitude of the reflex changes in RRIs concerning variations in sBPs ,32. In aOur results illustrate significant differences in BRS, BEI, and BP responses in the first and fifth minute of the adaptation period after orthostatism in PAF patients compared to control subjects. Despite comparable clinical characteristics and no differences in the mean HR and BP between groups under baseline conditions, PAF patients exhibited a diminished capacity to regulate BP in response to tilt, as demonstrated by a sustained and progressive increase in sBP in the first minute and a delayed baroreflex activation, which is indicated by a lower BEI than the control subjects, with no remarkable changes in the number of sBP ramps. Additionally, the PAF group demonstrated a more significant reduction in the BRS slope from the first minute of HUT onwards.Interestingly, the control group demonstrated a significant rise in sBP ramps over the course of the five-minute head-up tilt test. Conversely, patients with PAF patients showed no variations in the count of sBP ramps during the same test. This specific sBP trend might indicate the repeated activation of the arterial baroreflex and could potentially serve as an indicator of BP variability. However, various studies have questioned the relationship between sBP ramps and baroreflex, suggesting that the occurrence of sBP ramps is somewhat unrelated to baroreflex ,32,33,34In our study, BEI, a measure used to quantify the effectiveness of the baroreflex, was also evaluated. PAF patients showed a lower BEI independently of the period of analysis , which, upon postural baroreceptor unloading, elicits adjustments in sympathetic and parasympathetic outflow to the cardiovascular system, increasing both the heart rate and vasoconstriction ,39,40,41Our findings of simultaneously reduced BRS during the adaptation period to upright position and BEI, along the whole period of evaluation including in the supine position, represent a marker of arterial baroreflex dysfunction in patients with PAF. The discrepancy between our data and those obtained in healthy subjects to determine the BRS and BEI during HUT implies a distinct physiological response in patients with PAF. Several studies have reported a reduction in the BRS slope using spontaneous time-domain (sequence) BRS methods ,43,44,45A critical perspective that is often underrepresented in discussions of HUT, particularly when dealing with complicated conditions such as PAF, is the role of the modulation of preload and the resulting impact on venous return and central volume dynamics. In the context of the cardiovascular system, head tilt can be considered a strong modulator of preload. It leads to a dynamic shift of blood out of the central compartments, challenging central volumes, a phenomenon that has profound implications for the venous side of the circulation. When central volumes are challenged—either by HUT or, more intensely, by interventions such as lower body negative pressure (LBNP)—this has a consequential impact on the regulation of arterial resistance. As arterial resistance changes, we observe fluctuations in BP. These fluctuations are crucial because they can activate the baroreflex mechanism, leading to a modulation of heart rate. These findings are not limited to physiological observations. When we look at pathophysiological conditions, especially complex diseases such as atrial fibrillation, the subtleties become even clearer. The mechanisms underlying the influence of modulations of preload on venous return on baroreflex function in patients with lone PAF may be more complex, underscoring the importance of considering these variables when interpreting the data. These claims are supported by model-based work that has looked in depth at the cardiovascular system. For example, in their seminal study, Mukkamala and Cohen  developeOur study design, being a case–control study, primarily identifies associations rather than causality. While we observed associations between PAF and baroreflex dysfunction, it is essential to acknowledge that these findings do not establish a direct causative relationship. To address potential confounders, we advanced statistical methods including multivariable regression analyses adjusting for age, sex, BMI, baseline BP, and HR. Despite these adjustments, the observed differences in baroreflex function between lone PAF patients and controls persisted, strengthening the validity of our findings and supporting the credibility of our conclusions (for further details of this analysis, see Our study had certain limitations. First, our sample size was relatively small and potentially lacked diversity in age, sex, and other demographic or health characteristics, which may have limited the generalizability of our findings. Moreover, we employed the sequence method as the sole technique to determine the baroreflex sensitivity. Although this method is widely accepted, other methodologies may yield additional or differing results. Lastly, our study did not include measurements beyond the 5 min of tilting up, which did not allow a comparison of baroreflex function during active standing, and prolonged HUT could not be performed. However, since the study’s purpose was to evaluate the rapid adaptations to the upright position, it is widely accepted that rapid short-term adjustments in the first two minutes of HUT are mediated by autonomic control .The primary aim of our study was to investigate the behavior of baroreceptor reflex control in patients with lone PAF both at rest and during HUT by evaluating BRS and BEI. Our results indicate a pronounced impairment of baroreflex function in PAF patients compared to healthy subjects. While the healthy subjects consistently showed effective BRS responses to blood pressure changes, the PAF patients exhibited significant baroreflex dysfunction. Notably, the BEI provided a more descriptive measure of this dysfunction than the BRS. These observations suggest that the BEI could serve as a potential marker for predicting the recurrence of AF or assessing the efficacy of ablative interventions. Given the complicated relationship between baroreflex function and PAF episodes, further research is essential. A deeper understanding of the role of ANS in AF could pave the way for more individualized therapeutic strategies and prevention measures.


This study aimed to investigate the relationship between venous blood parameters and respiratory functions in patients with amyotrophic lateral sclerosis (ALS) and develop a model to predict respiratory impairment for individual patients with ALS. A total of 416 ALS patients were included in the study, and various hematologic and biochemical laboratory parameters as well as demographic and clinical factors were collected and compared. A multivariable logistic regression model was constructed to assess the association between FVC and venous blood biomarkers and clinical factors. The results showed that along with onset age, bulbar-onset, disease duration, BMI, eosinophil count (EO#), basophil count (BASO#), creatinine (CREA), uric acid (URCI) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio were associated with reduced FVC. The area under the ROC curve is 0.735 for the test set and 0.721 for the validation set. The study also developed a relatively acceptable model for predicting respiratory impairment in ALS patients. These findings suggest that EO#, BASO#, CREA, URIC and LDL/HDL ratio can be useful in assessing FVC in ALS and can be easily accessible, accurate, and low-cost parameters. The initial clinical presentation and evolution of ALS is heterogeneous2. First symptoms usually occur in the fifth or sixth decade of life1. Most patients die within 3–5 years after onset, generally due to respiratory failure3. Thus, monitoring respiratory function is of significant importance for ALS patients5.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a variable natural history, which affects 0.6–3.8 per 100,000 person/year worldwide10. EMPOWER study founded a weak longitudinal correlation between vital capacity and plasma creatinine6. Adriano Chiò et. al. suggested that lower albumin and creatinine (CREA), levels were strongly related to forced vital capacity (FVC)7. And cross-sectional study from Japan suggested that FVC was associated with serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL), CREA, and urate8. Study from USA and Poland also showed that plasma CREA correlated with FVC10. These studies suggested that there were some correlations between hematologic and biochemical laboratory parameters and respiratory function. However, the latest study did not confirm a correlation between plasma CREA and FVC11. The contradictory results suggested that further studies of blood biomarkers and FVC are needed.Recently, several biochemical parameters have been demonstrated to be related to respiratory impairmentThe aim of the present study was to analyze a potential utility of readily available, relatively inexpensive, and rapid to determine laboratory parameters in the assessment of respiratory impairment in patients with ALS; and to develop and validate a model of hematologic and biochemical parameters for predicting respiratory impairment for patients with ALS.This study protocol was reviewed and approved by Ethics Committee of West China Hospital, Sichuan University, approval number 2020-842 and 2021-799, and all the participants signed written informed consent. All protocols and procedures of our research were conducted ethically in accordance with the World Medical Association Declaration of Helsinki. All methods were performed in accordance with the relevant guidelines and regulations.13. Patients with other medical or neurological diseases and patients with missing baseline hematologic and biochemical values were excluded. Patients with manifestations of neoplastic disorders or patients who could not perform respiratory function were also excluded.Patients from two cohorts were included in our study. In the retrospective cohort, 319 patients with ALS were enrolled from 1 January 2015 to 30 December 2020. And in the prospective cohort, 97 participants from 1 March 2017 to 30 October 2021 were enrolled. Our medical center was a large, regional referral ALS clinic located in Southwest China. The diagnosis of ALS was made according to the revised-El Escorial criteria for probable or definite ALS14. Weight and height were measured following international guidelines, and body mass index (BMI) was calculated as weight (kg)/height (m)2 at the time of pulmonary function tests. High blood pressure was defined as systolic blood pressure (SBP) above 140 mmHg and/or diastolic blood pressure (DBP) above 90 mmHg in this study.The clinical analysis included age, sex, age at ALS onset, disease duration, onset body region (limb/bulbar), diagnostic level (probable/definite), blood pressure and comorbidities. We extracted data on comorbidities present at diagnosis as listed in medical records. Charlson comorbidity index (CCI) was used to evaluate comorbid conditions15. The spirometry methods produce comparable measurements of forced vital capacity (FVC)16. At least three acceptable manoeuvres were performed. Obstructive physiology was defined as the presence of airflow limitation with FEV1/FVC < 0.7017. For participants without airflow limitation (FEV1/FVC ≥ 0.7), restrictive physiology was operationalized as FVC < 80% predicted17.Venous blood parameters were obtained using an automated hematology analyzer . Hematologic data on platelet count (PLT), white blood count (WBC), neutrophil count (NEUT#), lymphocyte count (LYMPH#), monocyte count (MONO#), eosinophil count (EO#), and basophil count (BASO#) as well as and biochemical parameters on albumin (ALB), glucose (GLU), urea (UREA), creatinine (CREA), uric acid (URIC), triglyceride (TG), cholesterol (CHOL), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and creatine kinase (CK) were obtained. PLR was calculated as the ratio of PLT to LYMPH# and NLR as the ratio of NEUT# to LYMPH#. LDL/HDL was measured as the ratio of LDL to HDL. FVC was measured using a standard volumetric spirometer, with the patient in a standing position. Spirometer was quality controlled using 2005 criteriawww.rproject.org).(1) Correlation analysis: Continuous variables with normal distribution were reported as mean ± standard deviation; non-normal variables were presented as median (interquartile range [IQR]). The linear correlations of these variables and the FVC were calculated by Spearman. For categorical variables, the correlations were performed by the nonparametric test (Wilcoxon rank sum test). For normal distribution data, differences were performed by Independent Samples T-Test. For non-normal distribution, differences were assessed for significance using the Mann–Whitney test or chi-squared tests. (2) The training set and the test set: The retrospective cohort was divided into two independent sets by random sampling: a training set and a test set. The training set included 70% (220/319) of the retrospective cohort. Four participants with missing data were deleted. The test set included 30% (95/319) of the retrospective cohort. Models were developed using the characteristics in the training set. To verify the model, the test set was used to validate the models for internal validation, and the prospective cohort for external validation, respectively. In order to improve the robustness of the model, fivefold cross-validation was used. And down sampling method was used to deal with the class imbalance problem. (3) Logistic regression: Logistic regression was used to construct a model to predict FVC. For factors among each other  with rho > 0.75 in correlation analysis, only one factor was screened out in the next stage of the analysis. For groups of factors  with strong clinical correlation, only BMI, PLR, NLR, LDL/DHL and hypertension were screened out for the next stage of analysis. Correlation analysis between each variable and FVC was carried out to determine factor for logistic regression. Then, a total of 23 variables including gender, disease duration, onset age, site of onset, diagnostic level, CCI, blood pressure category (hypertension or not), BMI, WBC, NLR, PLR, MONO#, EO#, BASO#, ALB, GLU, UREA, CREA, URIC, TG, CHOL, LDL/HDL, and CK were included to construct the model. Based on the results of backward stepwise regression method combined with Akaike information criterion (AIC), the equation of FVC for predicting respiratory impairment in ALS patients were established. Heatmap of FVC was depicted. Receiver operating characteristic (ROC) curves was used to assess the prediction accuracy of the model. All statistical analyses were performed using SPSS 24.0  and R 4.1.0  with FVC < 3.062 and 40 female patients (30.30%) with FVC < 2.266 in the retrospective cohort Table . In the BMI, PLR, TG and HDL when stratified by FVC either in the retrospective cohort or in the prospective cohort  (Table Receiver operating characteristic (ROC) curve with 9 predictive variables revealed that the area under the curve was 73.5% in the test set Table . And the3. It is of significance to find some easily accessible, accurate, and low-cost parameters to assess the respiratory function. We created and validated a multivariable logistic regression model for the association between FVC and the venous blood biomarkers and clinical factors in ALS patients. Our single-site study found that FVC related to hematologic and biochemical laboratory parameters. EO#, BASO#, CREA, LDL /HDL and URIC are easily accessible, accurate, and low-cost parameters useful in assessment of the FVC in ALS.Respiratory failure is the main cause of death in ALS patients18. In our model, onset age, site of onset, disease duration, BMI, CREA, LDL /HDL and URIC were factors previously reported to predict respiratory impairment18. In addition, EO# and BASO# were two new features predicting to FVC in ALS. This prediction model could be useful in clinical settings in which the respiratory function is not available.To the best of our knowledge, there are few studies about models predicting respiratory function in ALS patients19. BMI, onset age and disease duration were factors correlated with ALS prognostication either in retrospective or in prospective studies23. Recently, a large multinational study with participants aged 40 years and over founded that low BMI was one of the most influential risk factors for chronic airflow obstruction24, which implicated a potential reason for low BMI associated with impaired FVC in this study.Older age and bulbar onset are consistently reported to have poorer outcomes9. In these studies, Ken Ikeda et.al found that the annual decline of FVC ≥ 30% was significantly linked to baseline serum levels of CREA8. Serum CREA is a product of nonenzymatic catabolism of creatine phosphate in muscles, and is transported from muscle through the circulation to the kidneys25.Lower level of CREA was related to impaired FVC in ALS in this study, which was consistent with previous studies26 and with BMI in ALS individuals7.A decreased level of plasma CREA in ALS patients is expected because of the variation in muscle mass observed in these patients. Moreover, CREA levels are correlated with lean body mass in healthy individuals18. Whereas in a Dutch study, authors found that mean CHOL and LDL levels were lower in patients with FVC < 70%. Higher serum LDL/HDL ratio was correlated with increased survival27. Study from French reported that serum levels of CHOL and LDL were significantly increased in ALS patients, and the elevation of LDL /HDL ratio was associated with prolonged survival28. Ethical and environmental backgrounds may lead to different lipid levels in patients with ALS. Multicenter, prospective study are needed to elucidate the relationship between lipid and respiratory function.The mean TG level was significantly lower among patients with a lower FVC but not statistical significance at multivariable analysis. We confirmed that decreased LDL/HDL ratio was correlated with decreased FVC, as reported by previous studies8. Interestingly, the level of URIC was not statistically significant between FVC normal group and FVC lower group but independently related to decreased FVC at multivariable analysis in our study. Study from USA found strong hazard ratios relating plasma CREA and ALSFRS-R when using trajectories of all three measures of plasma CREA, plasm URIC, and ALSFRS-R to predict time to death. These studies suggest complex biochemical interactions exist in ALS patients. More studies are warranted to better understand the metabolic mechanisms of disease progression in ALS.Study from Japan showed that the rapid worsening of annual FVC was associated with serum levels of URIC30. For persistent childhood asthma patients, normal lung function and serum EO# at baseline are clinical prognostic indicators of remission by adulthood31. For COPD patients, counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of inhaled corticosteroids withdrawal32. Furthermore, retrospective cohort study also shown that ALS patients concomitant with COPD relates to poor outcome23. One possibility of EO# predicting respiratory in this study is that some ALS patients coexisting with COPD, the other possibility is that ALS patient concomitant with some indirect factors which correlates with EO# and FVC. Further studies are warranted to understand the mechanism underpinning the association of EO# and FVC in ALS.Peripheral EO# is an important clinical biomarker in the management of asthma and chronic obstructive pulmonary disease (COPD)33. Recently, authors found that the number of circulating BASO# was significantly elevated in patients with aspirin-exacerbated respiratory disease34. Except for respiratory disease, Katie Lunnon et al. have found increased numbers of BASO# in people with MCI and AD, Yet the basophil counts are within the normal acceptable range35. More studies are needed to clarify the mechanisms of BASO# and respiratory impairment in ALS and other neurodegenerative disorders.In respiratory disease, BASO# plays a distinct role in the pathogenesis of allergic and nonallergicOur results should be interpreted with caution and a number of limitations should be borne in mind. Firstly, the prediction model derived from the retrospective cohort could not analyze data potentially important to risk of FVC. For example, eosinophils and uric acid values measured at admission may be affected by the other conditions coexisted with ALS, which we did not analyze. Secondly, possible ALS patients were excluded in this study, thus the prediction model is only suitable for probable and definite ALS patients. Thirdly, the model should be tested on multicenter, prospective cohorts to study the validity and predictability.In conclusion, our study indicates that EO#, BASO#, CREA, LDL/HDL and URIC might be important ALS biomarkers and may be used to assess FVC in ALS patients when lung function was not available. This finding needs to be validated in prospective, multi-site studies.


Autophagy protein 5 (ATG5) regulates airway epithelial cell autophagy, immune response, and inflammation, which is involved in asthma progression. This study aimed to evaluate ATG5 levels and its clinical roles in adult asthma patients.Totally, 200 adult asthma patients and 100 healthy controls (HCs) were enrolled in this case-control study. Subsequently, serum ATG5 was measured by enzyme-linked immunosorbent assay.P < 0.001). In asthma patients, ATG5 was positively related to male gender (P = 0.022), a family history of asthma (P = 0.035), eosinophil count (P < 0.001), and immune globulin E (P < 0.001), while it was negatively correlated with forced expiratory volume in 1 s (FEV1)/forced vital capacity (P < 0.001) and FEV1 (Predicted) (P < 0.001). Meanwhile, ATG5 was inversely associated with T helper (Th) 1 cells (P = 0.008), while it was positively linked with Th2 cells (P < 0.001), Th2/Th1 ratio (P < 0.001), interleukin (IL)-4 (P = 0.002), and IL-4/interferon-γ ratio (P = 0.015). Additionally, ATG5 was positively correlated with tumor necrosis factor-α (P < 0.001), IL-1β (P = 0.001), IL-6 (P = 0.003), and IL-17 (P = 0.029). Notably, ATG5 was elevated in asthma patients at exacerbation compared to those at remission [median (interquartile range): 53.6 (37.6–90.0) vs. 35.6 (28.2–51.5) ng/mL] (P < 0.001). It was also noteworthy that ATG5 was positively linked with exacerbation severity in asthma patients (P = 0.005).ATG5 was increased in asthma patients compared with HCs [median (interquartile range): 44.2 (31.7–77.8) vs. 23.2 (16.7–39.2) ng/mL] (Serum ATG5 is related to increased Th2/Th1 ratio, inflammation, exacerbation risk and severity in adult asthma patients, which serves as a candidate marker for the management of asthma. However, further validation is still needed.The online version contains supplementary material available at 10.1186/s13223-023-00821-3. Asthma is characterized by airway obstruction, bronchial hyper-responsiveness, and airway inflammation, resulting in a persistent cough, dyspnea, and chest tightness , 2. Gene+ (CD4+) T helper (Th) cells, airway inflammation, airway hyperresponsiveness, and airway remodeling  and IgE [median (IQR): 151.5 (79.0-287.0) vs. 36.5 (23.3–51.8) IU/mL] were higher in adult asthma patients than those in HCs (both P < 0.001). Furthermore, the mean levels of FEV1/FVC (mean ± SD: 71.8 ± 7.8% vs. 84.1 ± 3.6%) and FEV1 (Predicted) (mean ± SD: 81.9 ± 8.1% vs. 99.5 ± 6.3%) were lower in adult asthma patients than those in HCs (both P < 0.001). Additionally, in adult asthma patients, the median (IQR) values of Th1 cells, Th2 cells, and the Th2/Th1 ratio were 14.0 (11.4–17.2)%, 15.3 (12.6–19.1)%, and 1.2 (0.8–1.5), respectively. More specific clinical characteristics of all participants were described in Table The adult asthma patients included 89 (44.5%) females and 111 (55.5%) males with a mean age of 28.9 ± 8.0 years. Meanwhile, the HCs included 40 (40.0%) females and 60 (60.0%) males with a mean age of 30.1 ± 8.2 years. There was no difference in age (P < 0.001) : 44.2 31.7–77.8) vs. 23.2 (16.7–39.2) ng/mL]           or allergen-specific immunotherapy (P = 0.016) compared to those without during the enrollment. Meanwhile, ATG5 was not different in patients with or without corticosteroids, anti-histamines, and other treatments during the enrollment   Fig. A. Howeve4 Fig. A.rs=-0.238, P = 0.008)             : 53.6 (37.6–90.0) vs. 35.6 28.2–51.5) ng/mL] (.5 ng/mL]1/FVC and FEV1 (Predicted) in adult asthma patients.ATG5, as one of the essential proteins regulating autophagy, is considered to overexpress and mediate immune responses in asthma , 15, 20.+ T cells [Allergen-activated Th2 cells release cytokines, promoting airway eosinophil inflammation, airway hyperresponsiveness, and airway remodeling, which play a central role in the development of asthma , 21. Not T cells , 22, whi T cells –25. SignIt is reported that ATG5 also participates in airway inflammation in asthma patients to a certain extent . TherefoAsthma has a long course, and a potential marker is needed to observe the asthma exacerbation risk and severity to control the progression of asthma . Our stuThere were some limitations in our study: (1) The specific mechanisms of ATG5 regulating Th1 cells, Th2 cells, and inflammatory cytokines in adult asthma patients were required to explore in future studies. (2) Our study did not include an age and sex-matched disease control group. Future research should enroll disease controls to further comprehensively verify the potential of ATG5 as a marker in adult asthma patients. (3) Although the sample size in our study was relatively large, in order to have a clearer conclusion on the clinical significance of ATG5 in adult asthma patients, a larger sample size was needed in further studies. (4) Future studies should consider collecting more direct ATG5 samples  to assess its correlation with clinical indexes in asthma patients. (5) Our study did not evaluate the changes in ATG5 in asthma patients before the exacerbation, and further studies should consider assessing the changes in ATG5 to verify its potential as a candidate marker in asthma patients.In conclusion, serum ATG5 is positively correlated with the Th2/Th1 ratio, proinflammatory cytokines, and exacerbation in adult asthma patients, which may have important clinical significance for the management of asthma.Below is the link to the electronic supplementary material.Supplementary Fig. 1: Changes of ATG5 from M0 to M3 in adult asthma patients after treatment. ATG5 (skewed distributed continuous data) was decreased continually from M0 to M3 in adult asthma patients after treatment (Friedman test)Supplementary Table 1: Comparison of ATG5 in patients with different treatments during the enrollment