In patients with right heart failure (RHF) and pulmonary hypertension (PH), classical teaching often advises cautious diuresis in the setting of ‘preload dependence’ to avoid renal injury and hemodynamic compromise. However, while this physiology may hold true in some clinical settings, such as acute ischemia with right ventricular infarction, it cannot necessarily be extended to PH-related RHF. Rather, in patients with precapillary PH and decompensated RHF, diuresis aimed to decongest the right heart and systemic venous system may be directly beneficial. This study aimed to evaluate the effects of diuresis on renal function and blood pressure in patients with severe precapillary PH. A retrospective chart review was conducted on 62 patients with severe precapillary PH admitted for decompensated RHF. The hemodynamic phenotype of these patients was characterized by invasive hemodynamics and echocardiographic data. Laboratory and hemodynamic data were collected at both admission and discharge. After large-volume diuresis in this patient population, there was an improvement in both glomerular filtration rate and creatinine. While there was a decline in blood pressure after diuresis, this was not clinically significant, given the blood pressure remained in a normal range with improvement in renal function. In conclusion, this study demonstrated that despite concern for preload dependence, significant diuresis in patients with acute decompensated RHF from precapillary PH is not only safe but beneficial. Patients with right heart failure (RHF) and pulmonary hypertension (PH) have typically been considered to be ‘preload dependent’ . This anOn the contrary, in patients with significant precapillary PH who present with acute decompensated heart failure and volume overload, the etiology of RV dysfunction is increased RV afterload rather than impaired intrinsic RV contractility. In this setting, decongestion with diuresis may be immediately beneficial through the reduction in right heart filling pressures, RV dimension, and the degree of TR with ultimate hemodynamic improvement ,6. In reThe study aimed to examine the safety and effects of significant diuresis on both renal function and hemodynamics in patients presenting with acute decompensated heart failure secondary to precapillary PH.We performed a retrospective study on an electronic chart review of 62 patients with severe PH-related decompensated RHF with signs and symptoms of volume overload. The patients were admitted to a specialized advanced heart failure and PH service and treated with intravenous diuresis tailored to the clinical needs of each patient. Prior to the start of our study, the Temple Institutional Review Board (IRB) evaluated and approved our protocol and methods. The Temple IRB determined that all the criteria for a waiver of Health Insurance Portability and Accountability (HIPAA) authorization were met.Consecutive patients on inpatient Advanced Heart Failure and Pulmonary Hypertension Service at Temple University Hospital were reviewed from 2013 to 2021. Weekly sign-out documents were reviewed by a single investigator and screened for search terms, including heart failure, volume overload, intravenous diuresis, and pulmonary hypertension. We included patients with severe precapillary PH. All patients meeting each of the following criteria were included in the analysis: (1) age 18 years or older, (2) PH categorized as World Health Organization (WHO) group 1 or 3 PH and defined as mean pulmonary arterial (PA) pressure ≥ 20 mm Hg on cardiac catheterization and pulmonary vascular resistance (PVR) greater than 4 Woods Units (WU), and (3) admission for acute decompensated heart failure and intravenous diuresis. Patients were excluded if they had PH that was predominantly related to left-sided heart disease as evidenced by (1) a left ventricular ejection fraction (EF) < 40%, (2) significant mitral or aortic valve disease, (3) a PVR less than 4 WU, or (4) if the pulmonary capillary wedge pressure (PCWP) was >15 mmHg on cardiac catheterization. Patients were also excluded if they were not diuresed during the inpatient admission or if their admission was non-heart-failure related .Data regarding baseline demographic characteristics, including age, gender, height, weight, and body mass index, were collected through chart review for each patient. Clinical data, including pertinent co-morbidities, functional class, past surgical history, PH-targeted medical therapy, other medication regimens, and social history, were collected. Echocardiograms closest in temporal proximity to admission were reviewed. The time between the echocardiograms and the admission dates ranged from 0 days to 4.3 months, with a median of 7.5 days. The following qualitative and quantitative data points were collected: date of the study, right atrial size, left atrial size, septal contour, RV outflow tract systolic notching, RV size, RV function, tricuspid annular planar systolic excursion (TAPSE), left ventricular EF, and all regurgitant or stenotic lesions of the tricuspid, pulmonic, mitral, and aortic valves. An echocardiographic assessment was performed by an independent and blinded observer who was a board-certified echocardiographer with extensive experience in echocardiographic quantitation of the right heart and pulmonary hypertension. The echocardiographer was provided with a visual scorecard with illustrations of mild, moderate, and severe septal flattening. The coding of the degree of septal flattening was made by comparing the reference illustration card to the reference echocardiographic image of the individual patient. Right heart catheterizations (RHC) closest in temporal proximity to admission were reviewed. The time between RHC and the admission date ranged from 0 days to 23.4 months, with a median of 20 days. The following data points were collected: date of the study, heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and hemodynamic pressure measurements, including right atrial, RV systolic, RV diastolic, PA systolic, PA diastolic, mean PA, and PCWP. Additionally, CO, cardiac index (CI), PVR, and systemic vascular resistance (SVR) were examined for each RHC.2O) were collected from the initial history and physical note and from the clinical note on the day of discharge. While exams documented by attending physicians were prioritized, if these were not available, JVP exams documented by resident or fellow physicians were included, as they were obtained under the direct guidance of attending physicians within the Heart Failure and Pulmonary Hypertension departments. In order to quantify the amount of diuresis performed throughout the duration of the hospitalization, data were collected on net fluid balance, weight loss, and maximum daily diuretic dose. The diuretic dose was reported in milligrams of intravenous (IV) furosemide or furosemide equivalents for patients receiving either Bumetanide or Torsemide. Other data points collected included length of stay, 30 day readmission rates, and death during admission.Laboratory data were collected on the day of admission and the day of discharge, including sodium, glomerular filtration rate (GFR), and creatinine. The initial documented systolic, diastolic, and mean blood pressure values were collected from the admission day and from the discharge day. Jugular venous pressure (JVP) exam values . Descriptive data for continuous variables are presented as means ± SEM or as medians (25% and 75%) when appropriate. Categorical data was compared using Fisher’s exact test. Comparisons between groups for continuous variables were performed using unpaired two-sample n = 44, 71%), inhaled, oral, or parenteral Prostacyclins , endothelin receptor antagonists (ERA) , and soluble guanlylate cyclase (sGC) stimulators . There were two patients (3.2%) who remained on no PH medical therapy at the time of discharge, and both of these patients were Group 3 PH. Other pertinent medications taken concurrently included either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB) (12.9%), mineralocorticoid receptor antagonists (27.4%), calcium channel blockers (6.5%), beta-blockers (33.9%), statins (41.9%), and immunosuppressants (8.1%). Of note, 12 patients (19.4%) had coronary artery disease, and 12 patients had a history of atrial arrhythmias (19.4%).2), and SVR (1736 ± 824 Dynes-5).The patients had severe PH by right heart catheterization, with a mean pulmonary artery pressure of 49.9 ± 10.9 mmHg and a mean PVR of 11.7 ± 5.7 WU. The mean PCWP was 10 ± 4 mmHg. Additionally, the mean right atrial pressure (RA) was 12 ± 6 mmHg, and the RA:PCWP ratio was elevated at 1.3 ± 0.7 . Thus, mn = 8). Patients received relatively high dose diuretics, with a mean maximum daily diuretic dose of 552 ± 752 mg in oral Furosemide equivalents. Diuretic choices included Furosemide (25 patients), Bumetanide (41 patients), and Torsemide (2 patients). Patients experienced a mean net diuresis of 13.3 ± 7.6 L, with a mean weight loss of 7.0 ± 6.7 kg. Five patients (8%) received an additional diuretic, either metolazone or intravenous chlorothiazide. Fourteen patients (22.5%) had a new diagnosis of PH on admission. These patients were either directly admitted from a clinic after an initial outpatient visit or transferred from another institution in the context of a new diagnosis of PH.p < 0.05). Similarly, there was a significant improvement in GFR from 47.3 ± 12.1 mL/min/1.73 m2 on admission to 50.3 ± 11.1 mL/min/1.73 m2 on discharge, post diuresis (p < 0.05). There was no significant change in serum sodium on admission (137.3 ± 5.2 mmol/L) when compared to discharge (137 ± 3.9 mmol/L). In terms of hemodynamics, a decline in the mean arterial pressure from 85.6 ± 14.5 mmHg on admission to 78.5 ± 10.9 mmHg on discharge following large-volume diuresis (p < 0.05) was statistically significant. Jugular venous pressure examination significantly decreased from admission to discharge (15.8 ± 3.8 on admission to 8.7 ± 1.8 cm H2O on discharge)  on admission to 1.2 ± 0.4 mg/dL (106.8 ± 35.4 µmol/L) on discharge (scharge) .This study demonstrated that in patients with severe precapillary PH presenting with acute decompensated RHF, significant intravenous diuresis had no significant adverse effect on renal function but rather led to the improvement of both creatinine and GFR. Additionally, there was no clinically significant adverse effect on hemodynamics when examining blood pressure before and after diuresis. These results mirror what has been anecdotally known by clinicians treating PH-related right heart failure, but this is the first objective evidence to support diuresis in the correct clinical context of precapillary PH patients.Patients with RV dysfunction are often considered ‘preload dependent’, thus raising concern for hemodynamic and renal function compromise following extracellular volume removal ,14,15. TIn addition, unlike acute RV ischemia and infarction, the patients in our cohort presented with chronic PH-related right heart dysfunction and decompensated heart failure with clinical evidence of significant extracellular volume expansion. As such, in our cohort, intravenous diuresis was undertaken in the context of volume overload with the goal of restoring euvolemia and avoiding hypovolemia through careful serial assessment of right-sided filling pressures via JVP evaluation. Effective and appropriately administered diuresis in this context often has the opposite and, therefore, the beneficial effect of reduction in right heart filling pressure, RV dimension, and TR with ultimate hemodynamic improvement.As management of RHF varies depending on its mechanism, we aimed to examine a group of patients with a robust precapillary PH phenotype, as evidenced by both echocardiographic data and hemodynamics from RHC. Precapillary PH has been defined as a mean PA pressure of >20 mmHg, along with a PVR of ≥3 WU, and a PCWP of ≤15 mmHg ,10. Our The severity of the precapillary PH phenotype is supported by the invasive hemodynamic data of the cohort, with a mean pulmonary artery pressure of 50 mmHg, PVR of nearly 12 WU, and a PCWP of only 10 mmHg . There wIn this context, significant intravenous diuresis with an attendant volume and weight loss of 13 L and 7 kg, respectively, had no adverse effects on blood pressure or renal function. In contrast, there was a significant decrease in creatinine, a significant increase in GFR, and no significant change in serum sodium levels. Therefore, right heart decongestion with intravenous diuresis in this setting was not only safe but was directly beneficial to renal function. Improved renal function in this context is likely related to the direct relationship between right atrial pressure and renal venous pressure. Right heart decongestion and improved RA pressure translate to decreased renal venous pressure, subsequently leading to an improved renal arterial venous perfusion gradient. Diuresis was guided by daily assessment of right-sided filling pressures through JVP evaluation by experienced physicians within both the Heart Failure and PH departments and accomplished with relatively high doses of IV diuretics  decreased by 46%. Recognizing that right atrial pressure is a close approximate to renal venous pressure, these findings lend toward a net increase in renal perfusion pressure, which likely in part explains the improved creatinine and GFR as in our cohort .It is important to emphasize that this was a cohort of acutely decompensated patients, many of whom were presenting to our practice for the first time at the outset of initiation of their PH medical therapy. While a significant minority of patients were either on no PH medical therapy (22%) or PH monotherapy (19.3%) upon admission, this does not reflect their long-term PH therapy regimens. Changes were made to PH therapy regimens both during hospitalization and during short-term follow-up in the outpatient setting under the guidance of experienced PH experts. Notably, only two patients remained off all PH medical therapy at discharge, both limited by severe hypoxia in the context of Group 3 PH. While changes in the PH regimen were not the focus of our study, our observations of a lack of acquired azotemia and systemic hypotension in the context of often newly initiated PH medical therapy may strengthen our observations further. Specifically, it is notable that even in the context of severe precapillary PH presenting to us without a high incidence of dual or triple therapy, a relatively large volume IV diuresis was still not associated with clinically significant hypotension or azotemia.OR in the presence of an intensified PH regimen. Lastly, our observations should be interpreted with the understanding that the patients in our cohort were medically managed and diuresed at a major PH center under the care of experienced PH specialists.A potential limitation of the current study was the retrospective nature of the review, although the straightforward nature of our observations would not likely yield a different result if studied prospectively. Additionally, echocardiographic and hemodynamic data were not systemically repeated at the time of admission. However, echocardiographic and hemodynamic data were typically obtained in relatively close temporal proximity to admission. This, combined with the chronic nature of the condition, leads to the reported echocardiographic and hemodynamic data being representative of the patients’ physiologies at the time of admission. It is also important to note that the majority of patients with severe PH in this cohort either presented on PH medical therapy or were started on PH medical therapy during hospitalization. Although clinically appropriate and commensurate with the severe nature of their PH, our observations may have differed if the diuresis had been undertaken in the absence of PH therapy In spite of anecdotal concern for preload dependence and hesitancy to diurese patients with PH and right heart dysfunction, this study demonstrated that significant intravenous diuresis in patients with severe precapillary PH and right heart dysfunction and clinical HF is not only safe but beneficial.


Tubular dysfunction, assessed by β2-microglobulin excretion rate normalized to Ccr(Eβ2M/Ccr) was associated with both diabetes and Cd exposure. Doubling of Cd body burden, hypertension and a reduced estimated GFR (eGFR) increased the risks for a severe tubular dysfunction by 1.3-fold, 2.6-fold, and 84-fold, respectively. Albuminuria did not show a significant association with ECd/Ccr, but hypertension and eGFR did. Hypertension and a reduced eGFR were associated with a 3-fold and 4-fold increases in risk of albuminuria. These findings suggest that even low levels of Cd exposure exacerbate progression of kidney disease in diabetics.Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline in glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney disease (DKD) is marked by albuminuria and a declining GFR and both may eventually lead to kidney failure. The progression to kidney disease in diabetics exposed to Cd has rarely been reported. Herein, we assessed Cd exposure and the severity of tubular proteinuria and albuminuria in 88 diabetics and 88 controls, matched by age, gender and locality. The overall mean blood and Cd excretion normalized to creatinine clearance (C Cadmium (Cd) is a toxic metal pollutant of global public health concern because even low environmental exposure to this metal promotes high prevalence of diseases, such as chronic kidney disease (CKD) and type 2 diabetes . Prediab2), which requires dialysis or kidney transplantation for survival. In cross-sectional and prospective cohort studies of 231 diabetic patients in the Netherlands, both Cd and active smoking were associated with a progressive decline in eGFR b, log2[(ECd/Ccr) × 105], smoking, gender, hypertension, and diabetes , Alb excretion rate (p = 0.001) and reduction in eGFR (p = 0.001). The excretion rate of β2M as log[(Eβ2M/Ccr) × 103] was associated with age (β = 0.164), urine Cd (β = 0.244) and diabetes (β = 0.432). The other 5 independent variables did not show a significant association with the β2M excretion. The excretion rate of Alb as log [(EAlb/Ccr) × 104] was associated with hypertension (β = 0.259), and diabetes (β = 0.286). In contrast, eGFR was inversely associated with age (β = −0.357) only.Eight independent variables together accounted for 33%, 17.1% and 14.1% of the variation in the β2M, microalbuminuria, and a reduced eGFR, indicated by (Eβ2M/Ccr) × 100 ≥ 300 µg/L, (EAlb/Ccr) × 100 ≥ 20 mg/L, and eGFR ≤ 60 mL/min/1.73 m2, respectively  for three adverse kidney outcomes associated with Cd and duration of diabetes. The adverse outcomes of kidney function assessed were a defective tubular re-absorption of βectively .2[(ECd/Ccr) × 105] and ≥10-y DM duration were associated with increased risk of tubular dysfunction. Per a 1-year increase in age and doubling urine Cd, the POR for tubular dysfunction rose by 6% (p = 0.029), and 26% (p = 0.044) respectively. Compared to controls, the POR for tubular dysfunction was increased by 4-fold in the ≥10-yr DM group (p = 0.036). The POR for microalbuminuria was associated only with DM duration, where there was a 6.142  in those who had DM ≥10 years, compared to controls. The POR for a reduced eGFR was increased by 14.7% (p = 0.029) per a 1-year increase in age (p = 0.001). There was a 6.9-fold (p = 0.009) increase in POR for reduced eGFR in the ≥10 yr-DM group (p = 0.009).Age, log2 were associated with increases in the POR for a severe tubular proteinuria by 14-fold and 84-fold, compared with eGFR ≥ 90 mL/min/1.73 m2  × 103] showed a moderate positive association with Cd body burden measured as log [(ECd/Ccr) × 105] in controls (R2 = 0.151) and diabetics (R2 = 0.110)  a. Data fM groups b. After Equivalent covariance analysis of Alb excretion rate and eGFR indicate that the associations of these two parameters with Cd body burden were insignificant.2. Among eight independent variables, only hypertension and eGFR levels were associated with the increment of POR for microalbuminuria.An overall effect of GFR on microalbuminuria was assessed by a logistic regression analysis, where eGFR was categorized into three levels; ≥90, 61−89, ≤60 mL/min/1.73 m2  × 103] showed a moderate inverse association with eGFR in controls (R2 = 0.216), while showing a strong inverse association with eGFR in diabetics (R2 = 0.461)  a. A covaM groups b. After Alb/Ccr) × 104] was inversely associated with eGFR only in the DM group (R2 = 0.197) in bivariate analysis  × 104] were higher the <10-y and the ≥10-y DM groups, compared to controls (Alb/Ccr) × 104] was higher in ≥10-y DM with hypertension than the hypertensive only control group.The mean values of logp) were measured to ascertain diabetes diagnosis and diabetes free stage of controls. The assay of plasma concentration of glucose was based on colorimetry. Assays of creatinine in urine and plasma  were based on the Jaffe reaction. Urine concentration of albumin ([Alb]u) was determined using an immunoturbidimetric method. The Beta-2 microglobulin matched ELISA antibody pair set, human  was employed to determine urine concentration of β2M ([β2M]u) with the low detection limit of 3.13 pg/mL.Participants were requested to fast overnight, and the collection of blood and urine samples was carried out at a local health center of Pakpoon Municipality in the morning of the following day. For glucose assay, blood samples were collected in tubes containing fluoride as an inhibitor of glycolysis. Blood samples for Cd analysis were collected in separate tubes containing ethylene diamine tetra-acetic acid (EDTA) as an anticoagulant. The blood and urine samples were kept on ice and transported within 1 h to the laboratory of Walailak University, where plasma samples were prepared. Aliquots of urine, whole blood and plasma samples were stored at −80 °C for later analysis. Fasting plasma glucose concentrations  was determined with the GBC System 5000 Graphite Furnace Atomic Absorption Spectrophotometer . Multielement standards were used to calibrate metal analysis . Reference urine and whole blood metal control levels 1, 2, and 3  were used for quality control, analytical accuracy, and precision assurance. The analytical accuracy of metal detection was checked by an external quality assessment every 3 years. All test tubes, bottles, and pipettes used in metal analysis were acid-washed and rinsed thoroughly with deionized water. When a [Cd]b level was less than its detection limits, the concentration assign was the detection limit divided by the square root of 2 u = urine creatinine concentration (mg/dL). The ratio [x]u/[cr]u was expressed in μg/g of creatinine.Ex was normalized to Ccr as Ex/Ccr = [x]u[cr]p/[cr]u, where x = Cd; β2M or Alb; [x]u = urine concentration of x (mass/volume); [cr]p = plasma creatinine concentration (mg/dL); and [cr]u = urine creatinine concentration (mg/dL). Ex/Ccr was expressed as the excretion of x per volume of filtrate p ≤ 0.9 mg/dL, and Y = −1.209 if [cr]p > 0.9 mg/dL. Female eGFR = 144 × [plasma creatinine/0.7]Y × 0.993age, where Y = −0.329 if [cr]p ≤ 0.7 mg/dL, and Y = −1.209 if [cr]p > 0.7 mg/dL. For dichotomous comparisons, CKD was defined as eGFR ≤ 60 mL/min/1.73 m2. CKD stages 1, 2, 3a, 3b, 4, and 5 corresponded to eGFR of 90–119, 60–89, 45–59, 30–44, 15–29, and <15 mL/min/1.73 m2, respectively.Male eGFR = 141 × [plasma creatinine/0.9]2. Reduced eGFR was assigned when eGFR ≤ 60 mL/min/1.73 m2.Data were analyzed with IBM SPSS Statistics 21 . The Kruskal–Wallis test was used to assess differences in means among three groups, and the Pearson chi-squared test was used to assess differences in percentages. The one-sample Kolmogorov–Smirnov test was used to identify departures of continuous variables from a normal distribution, and logarithmic transformation was applied to variables that showed rightward skewing before they were subjected to parametric statistical analysis. The multivariable logistic regression analysis was used to determine the Prevalence Odds Ratio (POR) for categorical outcomes. Obesity was designated when BMI > 30 kg/mcr-normalized data, kidney tubular dysfunction was defined as (Eβ2M/Ccr) × 100 ≥ 300 µg/L of filtrate [Alb/Ccr) × 100 ≥ 20 and 200 mg/L of filtrate, respectively. For Ecr-normalized data, tubular proteinuria was defined as Eβ2M/Ecr ≥ 300 µg/g creatinine [Alb/Ecr ≥ 20 and ≥30 mg/g creatinine in men and women, respectively. Macroalbuminuria was assigned, when EAlb/Ecr > 300 mg/g creatinine. The mean β2M excretion rate and mean Alb excretion rate adjusted for age, BMI, and interaction in groups of subjects were obtained by univariate/covariance analysis with Bonferroni correction in multiple comparisons. For all tests, p-values ≤ 0.05 were considered to indicate statistical significance.For Cfiltrate . Microaleatinine ,27. MicrThe present study shows that environmental exposure to Cd is one of the contributing factors to tubular proteinuria in people with and without diabetes. Chronic exposure to even low levels of environmental Cd contributes, at least in part to diabetic macroalbuminuria. The tubular proteinuria in people with diabetes who are also exposed to Cd is a manifestation of defective kidney tubular protein reabsorption and nephron loss.


Previous studies have suggested the clinical value of metrics related to respiratory gas collected during recovery from peak exercise, particularly recovery time to 50% (T1/2) of peak VO2. The current study explores these metrics in detail during recovery from peak exercise in CHF.Cardiopulmonary Exercise Testing (CPX) is essential for the assessment of exercise capacity for patients with Chronic Heart Failure (CHF). Respiratory gas and hemodynamic parameters such as Ventilatory Efficiency (VE/VCO2/VO2), ventilatory equivalent for oxygen (VE/VO2), end-tidal partial pressure of oxygen (PETO2), and T1/2 of peak VO2 and VCO2.Patients with CHF who were referred for CPX and healthy individuals without formal diagnoses were assessed for inclusion. All subjects performed CPX on cycle ergometers to volitional exhaustion and were monitored for at least five minutes of recovery. CPX data were analyzed for overshoot of respiratory exchange ratio . Mean Left Ventricular Ejection Fraction (LVEF) was 35.9 ± 9.8% for patients with CHF compared to 61.1 ± 8.2% in the control group. The T1/2 of VO2, VCO2 and VE was significantly higher in patients  than in controls  while the overshoot of PETO2, VE/VO2 and RER was significantly lower in patients  than in controls . Most of the recovery metrics were significantly correlated with peak VO2 in CHF patients, but not with LVEF.Thirty-two patients with CHF and 30 controls were included. Peak VO2, VCO2, VE, PETO2, RER and VE/VO2, reflecting a greater energy required to return to baseline. Abnormal respiratory gas kinetics in CHF was negatively correlated with peak VO2 but not baseline LVEF.Patients with CHF have a significantly blunted recovery from peak exercise. This is reflected in delays of VO Cardiopulmonary Exercise Testing (CPX) provides substantial information on cardiopulmonary function and cardiorespiratory fitness through the evaluation of respiratory gases, ventilation, electrocardiographic and blood pressure adaptations, and symptoms during exercise. It is recommended in the diagnostic and prognostic work-up for several cardiac and pulmonary conditions as well as for clinical exercise prescription.32), ventilatory efficiency (VE/VCO2 slope), and the pattern of end-tidal partial pressure of CO2 (PETCO2), which all have demonstrated strong independent diagnostic and prognostic value in patients with CHF.The most established clinical CPX metrics collected during exercise are peak oxygen uptake , ventilatory equivalent for oxygen (VE/VO2), and the end-tidal partial pressure of oxygen (PETO2). The increase (“overshoot”) of these parameters during recovery has been observed to be reduced in patients with CHF compared to healthy subjects, and furthermore to be correlated with other common markers of CRF.,Additional studies have observed that a marked delay in respiratory gas exchange kinetics post-exercise is correlated with worse clinical outcomes.The aim of the present study was to comprehensively investigate the behavior of respiratory gas exchange kinetics during recovery from peak exercise in a population of patients with documented CHF compared to healthy controls.This study included patients with CHF and subjects with no history of the disease. All adult individuals who performed CPX in the Division of Cardiovascular Medicine of Stanford University Hospital between 2018‒2019 were eligible for the study. Patients were included in the experimental group if they had documented CHF, were between 18 and 75 years old, had no documented pulmonary or other relevant comorbidities, and performed successful CPX with at least five minutes of recovery. Healthy controls were recruited prospectively from the local community and were included if they did not have documented or reasonable suspicion of cardiovascular or pulmonary disease.Exclusion criteria for exercise testing were: (i) Acute myocardial infarction; (ii) Unstable angina; (iii) Uncontrolled arrhythmia with hemodynamic compromise; (iv) Active/acute endocarditis, myocarditis, pericarditis; (v) Symptomatic severe aortic stenosis; (vi) Decompensated heart failure; (vii) Acute pulmonary injury or deep vein thrombosis; (viii) Acute aortic dissection; (ix) Any disability/comorbidity which precluded safe exercise testing; and (x) Inability to understand instructions and/or give informed consent.2 was defined as the highest value attained in a 20‒30 second interval during the last phase of exercise per recommendations.2/PETCO2. The VE/VCO2 slope was calculated as the coefficient of linear regression obtained by plotting the VE and VCO2 data for the entire exercise phase. Hemodynamic and ventilatory parameters from CPX were visually inspected by two of the investigators, with disagreements being resolved by a third .Maximal exercise testing was performed on a cycle-ergometer  with respiratory gas collection using a metabolic cart . The metabolic gas analyzers and turbines were calibrated before every exercise test. Respiratory gases were collected on a breath-by-breath basis and analysis was performed after applying a rolling average filter every 10 seconds averaged over the previous 30 seconds . Heart rate was collected continuously with an integrated 12-lead ECG. Blood pressure was measured at rest, every two minutes during exercise, at peak intensity, and every two minutes during recovery. Peak VO2. The recovery of respiratory gases was analyzed as a percentage change from the peak and as a time to 50% (T1/2) of peak VO2 after exercise over a duration of five minutes. The percentage change from peak values of the metrics displaying an overshoot during recovery  was calculated as the magnitude of the overshoot .2, VCO2 and VE) was defined as the time required to reach 50% of peak.Recovery was defined as the period beginning when the workload was removed until participants returned to within 10% of resting HR and VOt-test for normally distributed variables and a Mann-Whitney U test for non-normally distributed variables. Correlations were evaluated with Pearson's correlation index if normally distributed and Spearman's correlation index if non-normally distributed. Statistical analysis was performed using IBM SPSS Statistics software version 25.The normality of the data was assessed using a visual inspection of frequencies and the Shapiro-Wilk test. Data are expressed as mean ± SD. Categorical variables are expressed as numbers and percentages. The difference between groups was assessed with a 2, p < 0.01). Patients with CHF exercised for a shorter duration and to a lower peak load compared to controls . Peak VO2, VE and the VE/VCO2 slope were significantly different between groups. Four patients and one control had significantly less than five minutes of recovery upon analyses . The mean time of recorded recovery was 249 ± 40s for patients and 264 ± 29s for healthy subjects (p < 0.01).2, VCO2 and VE were significantly longer in patients with CHF than in controls; similarly, the magnitude of the overshoot of VE/VO2, RER and PETO2 was lower in CHF. One patient (peak VO2 7.8 mL/Kg/min−1) did not show an overshoot nor a recovery T½, one (peak VO2 7.5 mL/Kg/min−1) did not show a recovery T½, and one (peak VO2 9.7 mL/Kg/min−1) did not display an overshoot of PETO2. Three other patients did not show a recovery T½ of VE . T1/2 for both VO2. EF was not significantly correlated with the other variables in patients, while it was correlated with the PETO2 overshoot  in controls. The main correlations between the recovery metrics and CPX parameters are represented in Recovery metrics showed statistically significant correlations with peak VO2 were the metrics more strongly correlated with peak VO2 . Conversely, as shown in 2 was weak in healthy subjects.The magnitude of the RER overshoot and the T½ of VO2 in CHF compared to controls.Despite the growing use of CPX in clinical practice, there is limited data on the value of assessing respiratory gas kinetics during the recovery phase after exercise. This is the first controlled study to provide a comprehensive assessment of relevant CPX metrics during recovery from peak exercise in a cohort of patients with CHF. The recovery of respiratory gases was found to be slower in patients with CHF than in healthy subjects, and this was correlated with a lower peak VO2 in patients with CHF as T½, showing that it was correlated with peak VO2, being reproducible and largely unaffected by exercise intensity .2, VCO2 and VE increased with the worsening of CHF. The T½ of ratio of inorganic phosphate to creatine phosphate has been observed to be correlated with T½ VO2, reflecting an inability to replace peripheral energy stores.2 deficits has been associated with reduced VO2/Work Rate slopes in patients compared to healthy subjects, suggesting lower aerobic efficiency.2 in patients with CHF correlated strongly with established indices of exercise capacity.2 and cardiac output in patients with CHF has also been described by others.,,Cohen-Solal et al. described the recovery of VO2 kinetics during recovery is the hypothesis that the repayment of the oxygen debt is prolonged in patients with CHF.2 seem to be correlated with indices of CRF but not with resting Left Ventricular Ejection Fraction (LVEF).,,,The main rationale underlying the potential usefulness of analyzing the VO2 on-kinetics during exercise has been proposed as an important marker for CPX evaluation in different chronic diseases,2 is more reproducible than the VO2 on-kinetics.2 on-kinetics.Although the response of VO2 and VE/VO2) during recovery, which commonly displays an “overshoot” and seems to be reduced in magnitude among patients with CHF. A good correlation was found between the magnitude of the overshoot and common indices of CRF. However, no correlation was found with LVEF at rest, suggesting at best a weak relationship with resting cardiac function.More recently, the knowledge around this topic has been implemented describing the pattern of other CPX metrics  supports the observations of previous studies. In particular, Takayanagi et al. found the presence of a recovery overshoot of the aforementioned metrics in 100% of their cardiac patients.2 while one patient did not display an overshoot of RER or VE/VO2. These subjects were among those with the most severe disease.In the present study, the behavior of recovery variables that display an “overshoot”  with novel markers , demonstrating that the magnitude of the overshoot of the RER is the variable with the strongest correlation with peak VO2, particularly T½ VO2 and the overshoot of RER. Conversely, there was a weak correlation between these metrics in controls.Among patients with CHF, the recovery variables assessed in the present study showed generally a good correlation with peak VO2 but rather reflect other physiologic mechanisms (such as the capacity to resynthesize PCr). This might be associated with a deficit in the replenishing of oxygen accumulated during exercise due to impaired cardiac output or local circulatory dysfunction.,,2/WR slopes, exertional dyspnea, and resulting in slower recovery kinetics. These considerations are further supported by the lack of strong correlations between resting ventricular function and the recovery parameters in both patients and controls. Studies that investigate muscle metabolism during and after exercise in these patients would help to answer some of these questions.The current data support the hypothesis that recovery metrics are not sole derivatives of peak VO2, the correlation between the recovery metrics and VE/VCO2 appeared to be weaker. This finding was unexpected since previous studies showed significant correlations of recovery metrics with VE/VCO2 slope.2, which could result in large differences between the studies.Compared to the correlation between the recovery variables and peak VO2 in patients with CHF, showing that it was significantly associated with prognosis.,2 recovery as a stronger predictor of death, heart transplantation, and mechanical heart implantation than well-established prognostic markers such as peak VO2 and Heart Failure Survival Score (HFSS).2 permanently fell below peak VO2, demonstrating an association with worse transplant-free survival.Although assessing the prognostic significance of these recovery metrics was not the purpose of this study, their prognostic utility may be inferred based on previous literature. In fact, De Groote et al. found that in patients with dilated cardiomyopathy and moderate exercise intolerance, the ratio between total oxygen consumption during exercise and during recovery was an independent predictor of survival together with left ventricular ejection fraction.Cardiac rehabilitation programs are currently recommended by major scientific societies and guidelines for the management of CHF, with different modalities and types of exercise training.This was a retrospective study based on CPX evaluations performed for clinical purposes compared to health controls. Although the main objective of the study was to comprehensively describe CPX parameters during recovery in a population of patients with CHF, definitive conclusions on the prognostic significance of these recovery markers cannot be drawn from the present data. Future integration of the parameters studied with prognostic data will permit a better understanding of the impact of impaired recovery on disease progression as well as on survival and/or hospitalizations.2 deficit and thus to the “anaerobic burden” during exercise, the lack of data on lactic acid accumulation limits the understanding of how and to what extent the recovery parameters reflect the relative aerobic and anaerobic contributions in patients with CHF.Moreover, since the pathophysiology behind the recovery delay is thought to be closely connected to the O2, p=0.002). This difference could affect exercise tolerance in cycle ergometry and have some influence on the interpretation of the results and conclusions of the current trial.Finally, although most participants fall into the ‘overweight’ category based on BMI, the CHF group had a significantly higher average BMI than the control group  and VE together with data on the recovery of those parameters that tend to show an overshoot after exercise , showing good reproducibility of this kind of analysis in a clinical setting. The results strengthen previous evidence that reported a slower recovery of VO2, VCO2 and VE after exercise in patients with CHF, and a reduced magnitude of the recovery overshoot of RER, PETO2 and VE/VO2. A good correlation between recovery parameters and peak VO2 was observed in patients with CHF but not in controls, suggesting a greater role of aerobic capacity in determining the recovery kinetics of subjects belonging to lower classes of cardiorespiratory fitness. A more standardized evaluation of this phase could provide important additional information on patient's functional capacity and help tailor their exercise prescription for cardiac rehabilitation programs.The present study strengthens the evidence on the blunted recovery of VOThe authors declare no conflicts of interest.


Renal resistive indices (RRI) have been shown to predict the progression of kidney disease. This study aims to evaluate the association of RRI with mortality and dialysis initiation after adjustment to therapeutic and life style interventions.This is a retrospective study that included all chronic kidney disease patients followed for at least two years in three nephrology clinics between 2006 and 2019 and who had a RRI level in their files. Kaplan Meier and log rank test compared the survival of patients with normal versus high RRI. Cox regression analysis evaluated the association between RRI and death or dialysis initiation after adjustment to treatments and life style modifications.p < 0.001; Spearman correlation coefficient = -0.521). The survival was significantly better in patients with RRI < 0.7 with a Log Rank test < 0.001. The univariate cox regression analysis showed a significant association between RRI and mortality  that remained significant after adjustment to cardiovascular risk factors and interventions such as salt reduction, blood pressure control, statins and RAAS inhibitors . Cox regression analysis showed a significant association between RRI and dialysis initiation .A total of 192 patients were analyzed: 68 had RRI < 0.7 and 124 had RRI ≥ 0.7. Their mean age was 66.5 ± 13.1 years at first visit, 78.1% were males. There was a negative correlation between baseline eGFR and RRI (Our study revealed that patients with an elevated RRI ≥ 0.7 are at a higher risk of mortality after adjustment to medications and lifestyle modifications. RRI can, according to this study, be considered as an independent prognostic factor in CKD patients.The online version contains supplementary material available at 10.1186/s12882-023-03398-6. Chronic kidney disease (CKD) is defined as an alteration of the kidney function and structure during more than three months , 2. The Kidney ultrasound (US) is the gold standard imaging to rule out urinary tract obstruction, to assess kidneys' size and corticomedullary differentiation . When kiRRI has been demonstrated by several researchers as a renal and cardiovascular prognostic marker –18. In hTherefore, this study aims to evaluate the association of high RRI with renal outcome and mortality in CKD patients and to assess whether this association persists after adjustment to therapeutic and life style modifications.This is a multi-center retrospective study that included CKD patients who consulted at three Lebanese nephrology clinics for the first time between February 2006 and December 2019. Nephrologists following these patients are affiliated to the Faculty of Medicine of the Saint-Joseph University of Beirut.Patients were included if they were older than 18 years, if they had a renal Doppler US with a RRI level in their file and if they were followed for at least two years. Single (solitary) kidney patients, kidney transplant recipients, patients diagnosed with polycystic kidney disease or renal artery stenosis were excluded.Data collection was conducted between April and September 2022. Baseline data collected from patients' medical files included demographics, date of first visit, number of visits, cardiovascular (CV) risk factors such as hypertension, diabetes, smoking, dyslipidemia, obesity, history of coronary artery disease (CAD), heart failure and/or strokes, laboratory values at the first visit (T1) such as serum creatinine, glomerular filtration rate (GFR) estimated by the 2012 CKD-EPI equation, urine albumin over creatinine ratio (ACR), HbA1c level. RRI levels were collected once from reports of Doppler US at T1 or between the first and second visit. If RRI levels of the two kidneys were different, we recorded the average of both levels.Follow-up data included the number of visits, date of last visit, laboratory values of serum creatinine, eGFR, ACR and HbA1c at last visit (T2), chronic medications namely statin, proton pump inhibitor (PPI), calcium channel blocker (CCB), renin–angiotensin–aldosterone system (RAAS) inhibitor (Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker), beta-blocker, thiazide diuretic and occurrence of any new cardiovascular event such as coronary event, heart failure, or stroke.CKD is defined in this study based on the KDIGO classification taking into consideration GFR categories and urine albumin to creatinine ratio (ACR) . GFR catWe collected whether blood pressure was controlled, defined as < 140/90 at the last visit (T2), whether HbA1c was reduced between first and last visit. Other recorded life style modifications were smoking cessation, weight loss and compliance with a low sodium diet. Weight loss was defined as any weight loss above 2 Kgs between T1 and T2. Patients were considered as compliant to low salt diet based on their statement, and/or their caregiver's confirmation and/or low 24-h urinary salt less than 5 g per day when available. The compliance to medications was assessed by the count of boxes that the patients bring to the clinic in order to renew the unified prescription and to get reimbursed by the national social security fund or the military funds of the country, that constitute 80% of all patients' coverage. For the remaining 20%, we assessed patients' compliance by the renewed prescriptions.Two outcomes were recorded: death and initiation of dialysis. The time before death and/or dialysis has been determined, as well as the cause of mortality. Another outcome assessed was the three-point major cardiovascular event (3P-MACE) including non-fatal myocardial infarction, non-fatal stroke or cardiovascular death.Radiologists affiliated to the three clinics were well-trained at performing RRI measurement using Doppler US. RRI is defined as the maximum blood flow velocity in systole minus the minimum blood flow velocity at the end of diastole over peak systolic velocity.The laboratory biological parameters including creatinine level, ACR and HbA1c were measured using standard techniques in the three hospitals’ labs.P-value < 0.05 was considered as statistically significant.Statistical analyses were performed using the Statistical Package for the Social Sciences, Version 24.0 . Continuous data were reported as mean and standard deviation (SD) if normally distributed and as median and interquartile (IQR) if skewed. Categorical data were reported as numbers and percentages. Missing data was estimated at 7.8% for compliance to salt reduction, 6% for smoking cessation, 11.5% for weight loss and 49.5% for ACR (T2). ACR at T2 was removed from the analysis. Little's MCAR test showed that compliance to salt reduction, smoking cessation and weight loss were missing completely at random. We performed a multiple imputation regression model to replace the missing values. The imputed data was used to analyze the multivariable cox regression model and the results were similar to the original model. Mann Whitney test, independent t-test, Chi Square test were used to compare two groups of RRI levels. Spearman rho correlation evaluated the correlation between two continuous variables. The receiver operating curve (ROC) analysis was used to assess the predictive value of RRI for dialysis and death. Kaplan Meier survival analysis and log rank test evaluated the difference in survival between patients with normal and high RRIs. Cox regression analysis assessed the factors associated with death and the association between RRI and dialysis. A Cox proportional hazards regression analysis was performed to assess factors associated with death, dialysis and 3P-MACE; the first model included all cardiovascular risk factors, the second, third and fourth models added to Model 1 renal factors, therapeutic and preventive interventions. Among the 1600 medical files reviewed in three different clinics, 289 patients responded to the inclusion criteria . Were excluded: 23 kidney transplants, 36 solitary kidneys and 38 polycystic kidney disease patients. Finally, a total of 192 CKD patients responded to inclusion and exclusion criteria    Table . Age, CA1) Table .Table 6After adjusting to cardiovascular risk factors, renal factors, treatments and lifestyle modifications, RRI remained an independent risk factor associated with death Table .Table 7P = 0.001), that remained significant after adjustment to CV risk factors . This association was not statistically significant after adding eGFR and albuminuria to demographics and CV risk factors  and after further adding of treatment and lifestyle modifications .Logistic regression analysis showed a significant association between RRI and 3P-MACE . Table S2. Cox regression analysis of factors associated with death .


The TGlittre time was significantly different between the PALs considered “sedentary”, “irregularly active”, and “active” (p = 0.038). There were no significant correlations between TGlittre time and the SF-36 dimensions. Patients with NDD-CKD had a reduced functional capacity to exercise with difficulties performing squatting and manual tasks. There was a relationship between TGlittre time and both HGS and PAL. Thus, the incorporation of the TGlittre in the evaluation of these patients may improve the risk stratification and individualization of therapeutic care.This study evaluated the functional capacity measured by the Glittre-ADL test (TGlittre) in patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and analyzed the test’s associations with muscle strength, physical activity level (PAL), and quality of life. Methods: Thirty patients with NDD-CKD underwent the following evaluations: the TGlittre; the International Physical Activity Questionnaire (IPAQ); the Short Form-36 (SF-36); and handgrip strength (HGS). The absolute value and percentage of the theoretical TGlittre time were 4.3 (3.3–5.2) min and 143.3 ± 32.7%, respectively. The main difficulties in completing the TGlittre were squatting to perform shelving and manual tasks, which were reported by 20% and 16.7% of participants, respectively. The TGlittre time correlated negatively with HGS ( Chronic kidney disease (CKD) consists of renal injury with progressive loss of kidney function, including glomerular, tubular, and endocrine functions . CKD oriIt has already been widely discussed in the literature that patients with CKD commonly present loss of muscle mass, muscle weakness, and deterioration of physical function . An impoPatients with NDD-CKD may benefit from a detailed evaluation of physical capacity if a more functional approach is also taken into account. Functional tests may be even more advantageous if they are able to reflect the functional performance represented by ADLs. In recent years, the Glittre-ADL test (TGlittre) has emerged as an instrument for assessing functional capacity to exercise by the performance of multiple ADLs incorporating the muscle activity of the upper and lower limbs. The TGlittre is a reliable and valid instrument for functional evaluation in different populations and has even been used among patients undergoing hemodialysis . Since a2 or albuminuria >30 mg/dL in an isolated sample or 24-h urine [Between January and June 2022, a cross-sectional and quasi-experimental study was conducted among 30 (of 33 eligible) patients with NDD-CKD who were followed up as outpatients at the Vila Esperança Specialty Center, São Luís, MA, Brazil. The patients were aged ≥18 years with proven NDD-CKD for a period >3 months by an estimated glomerular filtration rate (eGFR) ≤60 mL/min per 1.73 m-h urine . The folThe protocol was approved by the Research Ethics Committee of the Augusto Motta University Centre, Rio de Janeiro, Brazil, under number 52697821.5.0000.5235. This study was conducted according to the principles of the Declaration of Helsinki. All patients signed an informed consent form.According to the “Kidney Disease: Improving Global Outcomes (KDIGO) 2012” guidelines . ThroughPAL in daily life was evaluated by the short form of the International Physical Activity Questionnaire (IPAQ) . The IPAThe Short Form-36 (SF-36) was used to evaluate HRQoL. This is a multidimensional and self-administered tool composed of 36 items grouped into 8 dimensions: physical functioning, physical role limitations, bodily pain, general health perceptions, vitality, social functioning, emotional role limitations, and mental health . The resFor the evaluation of handgrip strength (HGS), a digital handheld dynamometer  was used. Participants were instructed to perform a maximum contraction for 3 s in each test. Three measurements with an interval of 30 s were performed. The participants were comfortably seated in an armless chair with their feet on the floor and their hips and knees positioned at approximately 90 degrees of flexion. The shoulder of the tested limb was adducted and in neutral rotation, the elbow was flexed at 90 degrees, the forearm was in a neutral position, and the wrist was between 0 and 30 degrees of extension and between 0 and 15 degrees of adduction. The hand of the nontested limb rested on the thigh on the same side. The highest value was considered for analysis . For comThe TGlittre was performed as previously proposed  Figure . In the r) or Spearman’s (sr) correlation coefficients for numerical variables and by Student’s t test for independent samples or one-way analysis of variance (ANOVA) for categorical variables. Additionally, Tukey’s multiple comparison test was used to identify the subgroups that differed significantly from each other. For comparison purposes, participants were grouped into low/moderate, high, or very high risk according to the KDIGO 2012 guidelines [p < 0.05. Data analysis was performed using the statistical software SPSS version 26.0 for Windows.The normality of the distribution of the variables was assessed by the Shapiro-Wilk test. The correlations of TGlittre time with anthropometric data, HRQoL, muscle strength, comorbidities, risk of disease progression, and PAL were analyzed with Pearson’s  months. The main causes of CKD were hypertension, diabetes, and chronic and idiopathic glomerulopathy, which occurred in 23 (76.7%), 12 (40%), 5 (16.7%), and 3 (10%) participants, respectively. Almost half of the participants  had a very high risk of disease progression. Regarding the SF-36, the dimensions with the worst scores were physical role limitations and general health perceptions, with median scores of 50 (19–100) and 60 (42–67), respectively. Anthropometric data, comorbidities, renal function, risk of disease progression, and HRQoL are shown in Regarding PAL, almost half of the participants  were considered “sedentary” by the IPAQ. Regarding the evaluation of peripheral muscle strength, the median absolute value of HGS was 29 (26–41) kgf, while the median absolute value in relation to the theoretical value for the Brazilian population in the study by Neves et al.  was 78 . We did not observe significant correlations between TGlittre time and the dimensions of the SF-36. The associations between TGlittre time and the data related to sex, comorbidities, risk of disease progression, and PAL are shown in p = 0.038). The TGlittre time was significantly different between the participants who reported no difficulty and those who reported any difficulty in performing the TGlittre tasks . Notably, the TGlittre time was not significantly different between the participants in relation to the risk of disease progression according to KDIGO 2012 .The associations between TGlittre time and anthropometric data, HRQoL, and muscle function data are shown in p = 0.004) and the IPAQ classification “active” (p = 0.014) were the only significant independent variables that explained TGlittre time; the other variables showed no independent contribution at the 5% level, including the risk of disease progression according to KDIGO 2012 and comorbidities.Functional tests seek to represent ADLs as accurately as possible to improve the evaluation and make it more reliable in the clinical environment. In this sense, the TGlittre is quite accurate in portraying ADLs because, in addition to simulating walking activities, it includes walking up and down steps, sitting and standing, and trunk and upper limb movements with load . The maiIn our study, we observed that the median TGlittre time was approximately 43% longer than predicted for the Brazilian population. The underlying mechanisms for the reduction in functional capacity to exercise in these patients are multifactorial and may be associated with impaired renal function leading to anemia, uremic neuropathy, myopathy, and cardiovascular abnormalities . This heCKD has recently been defined as a “model of accelerated ageing”, influencing the human body in a way that is patently comparable to ageing . In our Functional disability in patients with CKD is multifactorial and is associated with cardiovascular disease, muscle weakness, reduced eGFR, and sedentary behavior . In factThe general population has a better HRQoL than patients with CKD of all stages, although patients with NDD-CKD or kidney transplant patients have a better HRQoL than patients on dialysis . There aSome limitations of our study should be mentioned. First, the small sample size and nonrandomized nature of this study may limit the possibility of generalizing our findings. Accordingly, our study did not include a control group of healthy individuals, although the discrepancies are possibly enormous in relation to patients with NDD-CKD. Furthermore, as this study used a quasi-experimental design, there was no prediction of comparison with a control group . Third, As evaluated by the TGlittre, patients with NDD-CKD had a reduced functional capacity to exercise with difficulties in performing squatting and manual tasks. In addition, there was a relationship between TGlittre time and both HGS and PAL. Thus, the incorporation of the TGlittre into the routine evaluation of patients with NDD-CKD may improve the risk stratification and individualization of therapeutic care.


Chronic kidney disease (CKD) is a non-reversible and progressive disease affecting the kidneys, significantly impacting global public health. One of the complications of chronic kidney disease is impaired intestinal barrier function, which may allow harmful products such as urea to enter the bloodstream and cause systemic inflammation. This study aimed to investigate whether supplementation with activated charcoal could reduce uremic toxins in patients with end-stage renal disease (ESRD). The study was a randomized clinical trial conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Governorate. Eighty-two patients with ESRD on regular hemodialysis were enrolled, with 15 patients receiving oral supplementation with activated charcoal in addition to standard care and 13 patients receiving only standard care. Blood samples were collected at baseline and after eight weeks, and several biomarkers were measured, including estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. The results showed a significant reduction in both serum urea and serum phosphorus levels after eight weeks of oral-activated charcoal treatment. However, the other biomarkers were not affected by the treatment. In conclusion, the use of oral-activated charcoal for eight weeks in Iraqi patients undergoing maintenance hemodialysis improved urea and phosphorus levels. Chronic kidney disease (CKD) is a progressive and irreversible syndrome that results in an inability to maintain metabolic, fluid, and electrolyte balance, thereby causing uremia or azotemia , 2. CKD In CKD, there is a gradual loss of functional nephrons, which can be caused by primary kidney disease or secondary complications arising from systemic disorders, such as hypertension or diabetes mellitus. In addition, acute kidney injury can cause irreversible damage. In CKD, the colon adapts, assuming the role of the primary excretory organ responsible for maintaining bodily homeostasis. However, this adaptation can have severe effects on the gut environment. In individuals with CKD, serum urea accumulates, leading to an increased presence of urea within the intestinal lumen. Urease-producing bacteria then hydrolyze urea into ammonia and ammonium hydroxide, which increases intestinal pH, mucosal irritation, and structural changes to the gut barrier -10. ThesActivated charcoal operates as an adsorbent within the gastrointestinal (GI) tract, effectively trapping various chemicals. These captured substances are then retained within the charcoal matrix, preventing or reducing their absorption into the bloodstream -17. OralActivated charcoal and protein-limited diets are utilized to manage uremic symptoms in patients with diverse stages of renal disease. Through binding with urea and other urine toxins, activated charcoal effectively eliminates them via the feces . FurtherStudies have been carried out to reduce the flow of uremic toxins from the gut to slow the progression of CKD . Activatst, 2022, to Jan 20th, 2023. The study enrolled 42 patients with ESRD who were undergoing regular hemodialysis. Of these, 21 patients were assigned to receive oral supplementation with activated charcoal from AMS company in addition to standard care, while the other 21 patients received only standard care. Blood samples were collected at baseline and after eight weeks to measure parameters such as estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. Data were recorded using a data extraction sheet.A randomized clinical study was conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Government in Iraq from Oct 1The primary objective of the study was to investigate the association between renal function tests and the use of activated charcoal. As a secondary objective, the present study explored whether demographic characteristics impacted the protective effect of activated charcoal. The inclusion criteria for the study were patients aged >18 and <75 years old, undergoing regular hemodialysis for at least one month, of both genders, able to communicate in Arabic language or through their caregiver, and able to provide informed consent. Patients who did not meet these criteria were excluded from the study.The statistical software SPSS version 23 and Microsoft Office Excel 2010 were utilized to perform statistical analysis. Categorical variables were represented as percentages and counts. To determine if quantitative variables exhibited normal distribution, the Kolmogorov-Smirnov test was used. Numeric variables with a normal distribution were expressed as mean and standard deviation, while those without were expressed as median and inter-quartile range. These measures indicate central tendency and dispersion, respectively. The study employed thorough statistical analysis using three tests: (1) Chi-square test to determine the association between categorical variables, but only when expected counts were greater than 5 in 20% of cells or more, (2) Independent sample t-test to compare means between two groups if numeric variables were normally distributed, or Mann-Whitney U test if non-normally distributed, and (3) Paired t-test to compare means before and after treatment. The data was meticulously analyzed using these tests, displaying a rigorous approach to the study.In the study, 100 dialysis patients were initially screened for eligibility, out of which 42 patients met the inclusion criteria, and 28 were eventually enrolled. The remaining 14 patients had different reasons for not completing the study. 2 and 5.27±1.98 ml/minute/1.73m2, respectively (p=0.106). Baseline blood urea was also not significantly different between the control and activated charcoal groups, 131.15±32.85 mg/dl and 144.54±38.67 mg/dl, respectively (p=0.337). However, a significant difference was observed in baseline serum creatinine between the two groups, control and activated charcoal groups, 8.98±1.55 mg/dl and 11.19±2.69 mg/dl, respectively (p=0.015).Furthermore, baseline serum albumin showed no significant difference between the control and activated charcoal groups, 3.46±0.39 g/dl and 3.65±0.36 g/dl, respectively (p=0.193). Additionally, no significant difference was observed in baseline serum phosphorous between the control and activated charcoal groups, 4.82±1.36 mg/dl and 6.10±2.56 mg/dl, respectively (p=0.118). Lastly, there was no significant difference in baseline serum indoxyl sulfate between the control and activated charcoal groups, 519.18±139.17 ng/ml and 435.25±167.96 ng/ml, respectively (p=0.166).This study investigated whether oral activated charcoal could adsorb uremic toxins and improve renal function tests in patients with end-stage renal disease undergoing regular hemodialysis. The process, known as “intestinal dialysis” occurs when urea and other waste products bind to charcoal and are excreted in the feces, creating a concentration gradient for continuous diffusion . The preet al. [et al. [The activated charcoal group showed a significant decrease in serum urea and phosphorus throughout the follow-up period. A study by Al-Shazly et al.  showed s [et al.  supporteIt is well known that the kidneys cannot excrete waste products such as urea and creatinine in end-stage renal disease. Instead, their excretion relies mainly on hemodialysis procedures . As ureaRegarding albumin levels, most end-stage renal disease patients suffer from hypoalbuminemia for several reasons, such as a low protein diet, protein loss through urine, and dialysate, especially with high flux filters. However, the current study found a non-significant decrease in albumin levels. This could be due to the frequent monitoring of albumin levels in both groups and intravenous albumin treatment was administered to patients with hypoalbuminemia. Additionally, the majority of dialysis patients suffer from malnutrition associated with anorexia and poor protein intake.Furthermore, the study revealed an increase in eGFR in the control group and a decrease in the activated charcoal group, but the changes did not reach significant levels in either group. These insignificant changes may be due to the need for longer durations of activated charcoal use to show beneficial effects or a larger sample size .The uremic toxin indoxyl sulfate is difficult to remove through regular hemodialysis, and even hemodiafiltration has limited success in removing it . VariousThe progressive decline of renal function in CKD leads to the accumulation of numerous uremic toxins, including indoxyl sulfate. This representative toxin builds up in the blood and tissues of patients with impaired kidney function , 38. TheThe current study has several limitations. Firstly, the sample size was restricted as only a small number of patients met the inclusion criteria out of 100 patients in the center. Secondly, the study was open-label due to concerns about black discoloration of stool, which may have influenced the tolerability and adverse effects. Thirdly, the study was novel, with few comparable studies or references. Finally, the study was conducted in a single center, and the results cannot be generalized to all centers treating hemodialysis patients in Iraq.In conclusion, oral activated charcoal showed promise in reducing uremic toxins in Iraqi patients on maintenance hemodialysis. However, larger, longer-term studies with multiple centers and a greater number of patients are needed to confirm its nephroprotective effect. Further research is also needed to determine its potential benefits in pre-dialyzed patients.


O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n–3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines , and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1- Asthma is a chronic airway disease with various particular clinical phenotypes and complex pathophysiological mechanisms ,2. NowadRecent evidence suggests that plasmalogens  obtained from marine organisms  [1-s (DAGE) . On the s (DAGE) . On the s (DAGE) ,35,36,37s (DAGE) ,38,39. Is (DAGE) . In addis (DAGE) ,37.O-alkyl-glycerols for individuals with asthma exacerbated by obesity. It is therefore essential to assess the efficacy of AGs in this particular group. Therefore, given the compelling evidence from animal studies, and the paucity of human data on the benefits of AGs in the immune system and lipid metabolism, further exploration of AGs from new marine sources in relation to pulmonary risk factors and lipidomic profiles is warranted.Currently, there is a lack of research on the potential benefits of 1-O-alkyl-glycerols from the digestive gland of squid Berryteuthis magister on the immune system and lipid metabolism in obese asthma patients has been tested. We examined the influence of AGs on the pulmonary system function, plasma fatty acid and plasmalogen modification, and cytokine and adipokine levels in obese asthma patients.In the present study, the effect of 1-O-alkyl-glycerols. The investigation involved studying a group of healthy individuals  in order to compare baseline parameters in patients with asthma. The baseline clinical, biochemical, and immune characteristics of patients with asthma and obesity are summarized in 2, respectively  were subjected to clinical, biochemical, and immunological examinations to evaluate their baseline parameters before beginning the supplementation by 1-ectively . Our finWe have found that obese asthma patients had high levels of saturated and monoenoic acids such as myristic (14:0), palmitoleic (16:1n−7), hypogeic (16:1n−9), and stearic (18:0) acids in plasma versus the healthy group . Plasma The level of total plasmalogens in the blood plasma was evaluated by measuring the content of plasmalogen derivatives, dimethyl acetals (DMA), by gas chromatography–mass spectrometry (GC-MS), and their ratio to fatty acid methyl esters (FAME), which correspond in terms of the number of carbon atoms. The 16:0DMA/16:0FAME ratio was used to indicate the relative content of DMA16:0 to the total content of palmitic acid (16:0) in blood plasma. The 18:0DMA/18:0FAME ratio was used to calculate the content of DMA18:0 to the total content of stearic acid (18:0) in the test sample. Our study has shown that in patients with asthma and obesity, there was a deficiency of plasmalogens in blood plasma compared to a healthy group . This deBased on the data presented, it seems that the standard asthma treatment does not completely alleviate chronic inflammation and cannot address the plasmalogen deficiency. It is crucial to discover a treatment approach that targets all aspects of asthma pathogenesis linked to obesity, including chronic inflammation and imbalances in the composition of fatty acids and plasmalogens. O-alkyl-glycerol treatment. For instance, forced vital capacity in the first second (FEV1) increased during treatment and remained unchanged for a more prolonged AG intake. Patients with asthma associated with obesity showed an increase in the ratio of forced vital capacity in the first second to vital lung capacity (FEV1/VC) after consuming AGs for one to three months. This positive trend in pulmonary function improvement indicates that natural ether lipids, such as AGs, can affect the function of the lungs.The Asthma Control Questionnaire (ACQ) is a simple questionnaire to assess a patient’s level of asthma control and monitor any changes over time. Higher ACQ scores indicate worse asthma control, and lower ACQ scores correspond with better asthma control . The ACQIn the present study, the mean ACQ of asthma patients with obesity was 1.34 A. After Body mass index (BMI) did not change during the treatment B. It is As mentioned above, obese asthma patients had lower levels of plasmalogens in plasma compared to the healthy group. This lack is identified by a reduction in the levels of 16:0DMA, 18:0DMA, and 18:1DMA, as well as a decrease in the ratios of 16:0DMA/16:0FAME and 18:0DMA/18:0FAME. It has been shown that after 1 month of treatment with AGs, levels of 16:0DMA and 18:1DMA increased in obese asthma patients A,C. The These findings demonstrated that the consumption of AGs through diet can serve as a reliable source of plasmalogen synthesis, thereby correcting its deficiency in asthma and obesity. Plasma fatty acid modification allows us to assess not only the intensity of lipid metabolism, but also the activity of immune processes and the ability of cells to synthesize inflammatory, anti-inflammatory, and pro-resolving lipid mediators. It has been known that obesity has a great impact on lipid metabolism, thereby impairing the activity of immune cells and the synthesis of inflammatory lipid mediators such as oxylipins . Indeed,There were slight differences seen in the levels of saturated fatty acids with AG supplementation for one month and for three months . The amoA decrease in the proportion of saturated fatty acids circulating in the blood in people with asthma and obesity after AG treatment may suggest an improvement of metabolic processes in the liver and a shift in the priority of synthesis from saturated to unsaturated fatty acids. It has been shown that intake of AGs reduced LTB4 and TXB2 generation by immune cells. Obese asthma patients had a lower level of LTB4 A and TXBAdiponectin and leptin are among the vast variety of adipokines produced by adipose tissue and have opposite effects. Leptin resistance and hyperleptinemia in obesity enhance inflammation and a wide range of pathogenic mechanisms. In contrast, adiponectin has an anti-inflammatory effect, and in obesity the level of adiponectin usually decreases .Our findings suggest that obese asthma patients had elevated levels of leptin in their blood plasma, indicating systemic chronic inflammation and an inflammatory response of the adipose tissue . SupplemThe baseline level of adiponectin in obese asthma patients was reduced , which iThese findings demonstrate that the intake of AGs can modify leptin/adiponectin production by adipose tissue, improving the balance between pro-inflammatory and anti-inflammatory adipokines.It has been known that the obese asthma phenotype has a Th2 low profile with the predominant neutrophil type of inflammation. This type of chronic inflammation is characterized by a high generation of inflammatory cytokines such as IL-6, TNF-α, IL-17, IL-1β, and IFN-γ. Higher serum IL-6 levels in adults with asthma have been found to correlate with increased body weight, decreased lung function, and an elevated risk of exacerbations ,7,10,45.O-alkyl-glycerol supplementation for one and three months has had a positive effect on immune system activity. After one month of AG treatment, levels of TNF-α, IL-4, and IL-17a were decreased  from marine organisms [O-alkyl-glycerols exhibit diverse biological activities, including anti-inflammatory, antioxidant, and antitumor effects [Berryteuthis magister on immune cell and adipocyte activities, as well as fatty acid and plasmalogen metabolism in patients with asthma and obesity.Over several decades, there has been an increased interest in studying the pharmacological properties of 1-rganisms ,46,47,48 effects ,46,47,48 effects ,32. The  effects ,36,37,49This open-label investigational study evaluated the clinical and immunological effects of AGs (0.4 g/day) in asthma-obese patients. The selection of the dosage was established based on previous clinical studies ,39,46. EOur investigation demonstrated that consuming AGs on a daily basis for a period of one to three months resulted in an improvement in pulmonary function, as evidenced by increased forced expiratory volume in the first second (FEV1) and FEV1 to vital capacity ratio (FEV1/VC). These results of pulmonary function improvement associated with AG treatment suggest that natural ether lipids can have a positive impact on lung function. The Asthma Control Questionnaire score (ACQ) reduction observed in asthmatic and obese patients who received AGs also provides evidence of the beneficial effect of these marine lipids on the lung function and overall health of participants, despite the lack of weight loss. Although weight loss has been shown to improve clinical and immunological parameters in asthma , persuadThe statistically and clinically significant improvement in asthma control measured by the ACQ, found in our study, presumably is the result of the influence of AG consumption on plasmalogen and fatty acid metabolism. Herein, using lipidomics we have revealed an increase in 16:0 dimethyl acetals (DMA) and 18:1DMA concentration in plasma in obese asthma patients under AG treatment. After AG supplementation, we also observed an increase 16:0DMA/16:0 fatty acid methyl esters (FAME) and 18:0DMA/18:0FAME ratio, indicating the rise of lipids with alkyl linkages relative to acyl lipids. Moreover, the results of the study of alkyl lipids in blood plasma showed that the long-term intake of AGs had a greater impact on the elevation of the plasma plasmalogen level of asthmatic patients. Plasmalogens (Pls) are an important component of lung surfactant, and their modification may be impact lung function . The datFurthermore, we have shown the beneficial influence of AGs on the plasma fatty acid composition in individuals with obesity-related asthma. The levels of 14:0 and 18:0 gradually decreased from one to three months of AG consumption. Conversely, the concentrations of n−3 PUFAs  significantly increased following AG supplementation. The three-month treatment period was more effective in modifying n-3 PUFA levels.Plasmalogens play a vital role in liver fatty acid metabolism, regulating the key biochemical pathways of lipid synthesis ,26. The Taking the above-mentioned investigations together with our data, we can conclude that AGs are a beneficial source of endogenous plasmalogens, and their administration can improve fatty acid metabolism as well. Moreover, our study indicated the ability of marine AGs to inhibit the generation of inflammatory oxylipins such as as leukotriene B4 (LTB4), and thromboxane B2 (TXB2). Considering that LTB4 and TXB2 are produced from arachidonic acid via the lipoxygenases (LOX) and cyclooxygenase-1 (COX-1) pathways , the decO-alkyl-glycerols through an additional molecular mechanism.The anti-inflammatory role of lipids with an alkyl bond may be due to the fact that plasmalogens block the activation of nuclear factor (NF)-kB and mitogen-activated protein kinases (MAPKs) such as JNK and p38 MAPK, thereby attenuating the nuclear translocation of the NF-kB subunit and inhibiting inflammatory signaling pathways . A reducIn support of the anti-inflammatory effects of AGs, our study has shown that a dietary intake of AGs was associated with low circulating concentrations of pro-inflammatory cytokines, e.g., interleukin-2 (IL-2), IL-4, Il-17a, and tumor necrosis factor-α (TNF-α), and a decreased level of adipocyte produced leptin. Since the obese asthma phenotype is distinguished by persistent, low-grade inflammation that stems not only from airway inflammation but also from heightened activity in adipose tissue , a high AG diet might provide comprehensive anti-inflammatory properties. Numerous studies have demonstrated that neutrophilic inflammation is a relevant mechanism of the obese asthma phenotype. The abundant neutrophil level is associated with the presence of higher levels of IL-17A, a cytokine involved in neutrophil recruitment of the airways . The obeThus, the consumption of natural AGs derived from marine sources, in combination with basic medication for patients with mild asthma and obesity, can lead to a reduction in chronic inflammation by decreasing the generation of pro-inflammatory cytokines and oxylipins. The observed changes, along with the notable improvements in clinically significant indicators of asthma and inflammation, present a compelling rationale for conducting larger trials to investigate the effects of AG supplementation on lung diseases.To summarize, our study has demonstrated several beneficial effects of supplementing with AGs in individuals with asthma and obesity. These effects include improvements in lung function, fatty acid and plasmalogen metabolism, and immune activity. Dietary supplements containing AGs were observed to modulate plasma plasmalogen levels and effectively reduce chronic inflammation in individuals with asthma associated with obesity. The mechanisms underlying these effects are complex and require further investigation, particularly in the context of pulmonary diseases and the obese asthma phenotype. Considerable effects achieved by the intake of AGs are the elimination of plasmalogen deficiency and improvement in disease control, as indicated by decreased ACQ. Furthermore, the study revealed that these beneficial effects can be observed after one month of alkyl-glycerol supplementation and continue to improve after three months of treatment.O-alkyl-glycerols’ long-term impact and investigate the duration of these active compounds’ anti-inflammatory effect post-discontinuation. In spite of these limitations, the study certainly adds new knowledge about the impact of AGs on lung function, the immune system, and plasmalogen and fatty acid synthesis in obese asthma patients and shows the anti-inflammatory and lipid-metabolism-improving properties of marine AGs. It is important to acknowledge that our study has certain limitations, including the absence of a robust placebo control or cross-over design, as well as a limited number of participants with asthma and obesity. We only focused on results after one and three months of AG supplementation. It is valuable to assess 1-This was a parallel, controlled clinical trial. Participants completed written informed consent before the trial and were allocated into two groups: the AG and control  groups. Patients of the AG group received, alongside the standard prescription treatment, a dietary supplement AGs for 3 months. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, approved by the Ethics Committee of the Institute of Medical Climatology and Rehabilitative Treatment, Vladivostok, Russia . This clinical study included 19 patients of both sexes  with mild asthma associated with obesity, recruited at the Clinical Department of the Institute of Medical Climatology and Rehabilitative Treatment, Russia. Asthma was diagnosed based on the guidance of the Global Strategy for Asthma Management and Prevention [The patients with asthma were selected to participate in the study if their asthma was controlled or partially controlled according to GINA criteria. The study participants continued to follow their usual diet while participating in the study, which means that we did not impose any dietary restrictions or interventions. This helped us to minimize any potential confounding factors and increase the external validity of the study results.The ACQ-5 test (Asthma Control Questionnaire) was used to determine the level of asthma management; the scores ranged 0.75–1.5, which implied the presence of partially controlled asthma. Outcomes included Asthma Control Questionnaire (ACQ) score, the immune state, cytokine and adipokine levels, blood plasma fatty acid and plasmalogen concentrations, and plasma eicosanoid level.The external respiration function was assessed using the Master Screen Body apparatus . The analyzed parameters were vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and FEV1/VC and FEV1/FVC ratio. The reversibility of airway obstruction was evaluated by bronchodilation test with inhaled salbutamol 400 μg). According to current guidelines from the European Respiratory Society (ERS) and the American Thoracic Society (ATS), the absolute and relative changes in FEV1, also known as the bronchodilation ratio, provide a reliable evaluation of the reversibility of airway obstruction. A positive result in the bronchodilation test is achieved when the bronchodilation coefficient is over 12% and the absolute increase in FEV1 is more than 200 mL [0 μg. Acc2) was calculated to diagnose overweight or obesity. Based on the WHO classification, normal body weight was defined as BMI 18.9–24.9 kg/m2, overweight as BMI 25–29.9 kg/m2, obesity Class I was diagnosed as BMI 30–34.9 kg/m2, obesity Class II as BMI 35–39.9 kg/m2, and obesity Class III as BMI ≥ 40 kg/m2.Obesity was established according to the WHO recommendations ,61. BodyO-alkyl-glycerol nutritional supplements, or missing consent. All subjects gave written informed consent prior to the survey. Inclusion criteria for the study included: male and female persons aged 18–60 years old; asthma from mild to moderate severity, controlled and partially controlled course; overweight and obesity of class 1 or 2. Exclusion criteria included: severe asthma, secondary obesity; class 3 obesity, acute illness, chronic diseases , pregnancy and lactation, cancer, intake of n-3 PUFA or 1-Overnight fasting blood samples were obtained early in the morning from healthy volunteers and patients with asthma. All asthma patients were provided with basic therapy with a fixed combination of a low-dose inhaled glucocorticoid (budesonide: 160 micrograms/day) and a long-acting β2-agonist  (steps 1 and 2 of GINA-2019).Berryteuthis magister. «Incodamarine» contains AGs: chimyl alcohol (91.07%) and batyl alcohol (7.38%)  includes natural AGs extracted from the digestive gland lipids of the squid 38%) see . «IncodaPatients, in addition to the standard prescription treatment (described above), received a dietary supplement of AGs for 3 months, 1 capsule 2 times a day after meals, which is equivalent to 0.4 g of pure AGs. The dose selection was determined through previous clinical studies on the use of AGs and the recommended effective doses of AG-containing supplements found in the instructions. The effects of AG supplementation were evaluated in obese asthma patients at one and three months of treatment . ® EDTA tubes with EDTA and samples were centrifuged with 3000 g at 40 C for 10 min. The plasma was collected and stored at −80 C before analysis. The gas chromatography–mass spectrometry GC-MS  method was used to analyze plasma total fatty acids and plasmalogens [Blood from participants was drawn into VACUETTEmalogens ,63,64. Tmalogens . To prepmalogens . A gas cPlasma TXB2 and LTB4 concentrations were determined using enzyme immunoassay kits from Enzo Life Sciences . Columns with reversed-phase C18  for extraction were pre-washed with 10 mL of ethanol >95% and then with 10 mL of deionized water. Then a sample was applied and the column was washed with 10 mL of water, then 10 mL of 15% ethanol and finally 10 mL of hexane. The sample was eluted from the column by adding 10 mL of ethyl acetate and dried on the IKA MPV10 basic (GmbH) rotary evaporator. Then the ELISA method was performed. The 96-well plates were read on an Automatic Immunoassay analyzer . TXB2 and LTB4 concentrations were calculated from a standard curve, according to the kit protocol.The levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A cytokines in the serum were measured using flow cytometry with a BD FACSCantoII cytometer and the “BD Cytometric Bead Array—Human Th1/Th2/Th17 Kit” (USA). The data was processed using “FCAP Array 3.0” software from BD . Commercial ELISAs were used to determine serum concentrations of adiponektine (Human Adiponectin ELISA) and leptin (DRG ELISA) according to manufacturer’s instructions. The plates were read on an Automatic Immunoassay analyzer . p-value less than 0.05 was considered statistically significant. The statistical analysis and graphical illustration of assays were carried out using the GraphPadPrism 9.5.0 software . The data underwent a one-way ANOVA test, followed by a Tukey’s multiple comparison test. The results were presented as the mean ± standard error of the mean (SEM) or as median, and upper and lower quartiles. A