Exerkidney: A Tracking of Uremic Toxins, Exerkines, Genetic Aspects, Physical Fitness, Body Composition, and The Effects of Physical Training in People With Chronic Kidney Disease at Different Stages
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 1,600
- 试验地点
- 1
- 主要终点
- Concentrations of uremic toxins - Indoxyl sulfate
研究概览
简要总结
The accumulation of uremic toxins is detrimental to physiological systems and induces premature biological aging. Renal function assessment methods, such as predictive formulas, may be influenced by ancestry in Brazilians, given the country's ethnic diversity, resulting in inaccurate estimates. On the other hand, physical exercise is an important ally in treating chronic kidney disease (CKD) as it induces metabolic changes that help slow the disease's progression. Additionally, the anti-aging effect conferred on those who engage in physical exercise is widely recognized. However, investigations into the impact of physical exercise on the concentration of uremic toxins and biological aging in patients with chronic kidney disease and their relationship with ancestry are still in the early stages and inconclusive. The investigators aim to track uremic toxins, exerkines, genetic aspects, nutritional profile, physical fitness, body composition, and the effects of different types of physical training (periodized and progressive) in people with chronic kidney disease at various stages. Additionally, to verify associations between these factors and their effects on different physiological systems. This is a triple-blind randomized clinical trial, with a 10-year follow-up of patients. The sampling will be non-probabilistic in terms of accessibility or convenience. Adult volunteers of both biological sexes aged 18 or older, with chronic kidney disease in conservative treatment (stages 2, 3, 4, and 5, n~400), patients undergoing renal replacement therapy (hemodialysis or peritoneal dialysis, n~800), and transplant recipients (n~400) will be recruited from different hemodialysis centers. After being grouped by disease stage, patients will be randomized according to pre-training variables and then allocated to the following groups: control group (CTL; at least n~100), strength training (ST; at least n~100), aerobic training (AT; at least n~100), and combined training (CT; at least n~100). The patients will undergo evaluations of body composition, cardiorespiratory capacity, muscle strength, autonomic nervous system function, and nutritional, psychological, and biomolecular assessments. The training protocols will be adjusted according to the patient's physical capacity, always considering periodization and progression.
详细描述
This study is a randomized, triple-blind clinical trial with a 10-year follow-up. Sampling is non-probabilistic by accessibility or convenience. Recruitment: Recruitment will be widely promoted via mass media (social media, TV) to invite individuals with chronic kidney disease. Additionally, the investigators will receive referrals from partner physicians and public-private partnerships. Participants will be recruited from dialysis clinics, outpatient clinics, and hospitals in Brasília, DF, respecting privacy and confidentiality. The investigators aim to recruit a minimum of 1,600 adult patients (both sexes), aged 18+, divided into those with CKD in conservative treatment (stages 2, 3, 4, 5, n~400), renal replacement therapy (hemodialysis and peritoneal dialysis, n~800), and kidney transplant patients (n~400). Participants will receive all pertinent information about the study and potential risks and benefits. Those who agree will sign an informed consent form. Following consent, each patient will undergo a comprehensive history assessment, including exercise, medical, and nutritional histories, along with an analysis of their medical records. Monthly evaluations will cover all procedures and interventions outlined for their allocated group. Patient Randomization: Participants will be stratified by CKD stage (conservative treatment, hemodialysis, peritoneal dialysis, and post-transplant) and further randomized by pre-training variables (biological sex, body weight, BMI, and body composition), using an online application. Patients will then be allocated to one of four groups: control (CTL; n~100), strength training (ST; n~100), aerobic training (AT; n~100), and combined training (CT; n~100). Assessments: Body Composition: BMI, DEXA, 7-Skinfold (Jackson and Pollock protocol); Cardiopulmonary Capacity: Anaerobic threshold, Fitcheck, respiratory muscle strength, spirometry; Muscle Strength: 1RM, handgrip, isokinetic force and power, E-lastic portable dynamometer; Autonomic Nervous System: Cardiovascular regulation during deep breathing, Valsalva maneuver with handgrip exercise, post-exercise ischemia, cold-water hand immersion, perceived exertion, respiratory rate, heart rate, arterial oxygen saturation, HRV, BPV, spontaneous baroreflex sensitivity, EEG, cognitive assessment; Nutritional Assessment: 24-hour dietary recall, food frequency questionnaire; Psychological Assessment: Quality of life (KDQOL-SF36), sleep quality, Beck Depression Inventory; Biochemical and biomolecular Assessments: Biological sample collection (urine, feces, saliva, blood) for measurements of creatinine, cystatin-C, leptin, GDF-15, TGF-β, insulin, albumin, SIRT-1, C-reactive protein, irisin, intact FGF23, C-terminal FGF23, ADMA, soluble α-Klotho, glycated hemoglobin (HbA1c), total cholesterol, LDL-c, HDL-c, triglycerides, myeloperoxidase, lipoperoxidation assay, paraoxonase-1, total antioxidant capacity, nitric oxide, lactate, creatine kinase, uremic toxins (KIM-1, NGAL, indoxyl sulfate, p-cresyl sulfate, TMAO, TNF-α, IL-6, ADMA, exercise-related proteins, BDNF, DNA and RNA isolation (salting out method), telomere length and telomerase activity, microRNA expression analysis, HPLC quantification, and identification of compounds by MALDI TOF/TOF mass spectrometry); Ancestry Analysis: Ancestry genome-wide association stratification; Training Protocols: Physical training protocols will include strength, aerobic, and combined training; Statistical Analysis: Sample size is calculated for 99% power (1-β = 0.99) with an alpha of 5% (α = 0.05) and effect size of 0.1, resulting in 400 patients. Descriptive analysis will be presented in tables and charts. Normality and homogeneity of data will be tested by Shapiro-Wilk and Levene's tests. For normally distributed data, group comparisons will be conducted by two-way ANOVA with Tukey's post-hoc test for significant differences. Non-normally distributed data will be analyzed by Kruskal-Wallis with Dunn's post-test, with results expressed as medians and interquartile ranges. Significance will be set at p < 0.05, with effect size calculated by Cohen's d. Associations between variables will be evaluated by Spearman's correlation. To minimize type II error, the investigators will calculate variations before and after training as Δ = post-training - pre-training. Principal Component Analysis (PCA) and individual variability analysis will use delta results to identify key variables affecting estimated glomerular filtration rate. This analysis will use the Past software (v4.09). Typical error and smallest worthwhile change (SWC) will be calculated per Swinton et al. (2018). Effect size will follow Hopkins' scale: <0.2 (trivial), 0.2-0.6 (small), 0.6-1.2 (moderate), 1.2-2.0 (large), 2.0-4.0 (very large), >4.0 (extremely large). Additionally, K-means cluster analysis, an unsupervised machine learning method, will identify patterns based on numerical distance between variables. Statistical analyses will use Microsoft Excel® 2010, GraphPad Prism 6.0, R and RStudio (v4.1.3), and SPSS (v.21.0).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Supportive Care
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •those diagnosed with chronic kidney disease and presenting persistent albuminuria (>300mg/g) following KDIGO guidelines;
- •metabolic syndrome {i.e., type 2 diabetes mellitus, arterial hypertension (blood pressure >180/100mmHg), overweight or obesity, and dyslipidemia};
- •no complications arising from pre-existing clinical metabolic diseases (i.e., diabetic coma, ketoacidosis, hyperosmolarity, and/or uncontrolled diabetes), as evaluated by a nephrologist;
- •absence of neurodegenerative, musculoskeletal, lupus erythematosus, or congenital kidney disease;
- •no apparent cardiovascular complications, such as heart failure, severe arrhythmia, angina, or cerebrovascular disease;
- •no comorbidities that limit performance in physical tests or training;
- •not engaged in exercise programs for at least six months prior to the start of the experimental protocol;
- •no smoking or alcohol consumption behavior;
- •D-dimer values within normal range (220-500 ng/mL FEU)
排除标准
- •regularly engage in physical exercise,
- •have suffered a stroke in the last 6 months and/or present autoimmune diseases,
- •have unstable cardiac dysfunctions, such as: uncontrolled coronary artery disease, aneurysm at risk of rupture, uncontrolled arrhythmia, uncontrolled hypertension (SBP > 190 mmHg and/or DBP > 100 mmHg), heart attack in the last 3 months;
- •infectious conditions, Hb < 8 in the last routine monthly hemodialysis exam;
- •musculoskeletal pain;
- •resting SpO2 lower than 94%;
- •restriction by the clinical team.
研究组 & 干预措施
Conservative CKD
Patients with CKD under conservative treatment.
干预措施: Resistance training (Other)
Conservative CKD
Patients with CKD under conservative treatment.
干预措施: Endurance training (Other)
Conservative CKD
Patients with CKD under conservative treatment.
干预措施: Concurrent training (Other)
Hemodialysis
Patients with CKD under hemodialysis treatment.
干预措施: Resistance training (Other)
Hemodialysis
Patients with CKD under hemodialysis treatment.
干预措施: Endurance training (Other)
Hemodialysis
Patients with CKD under hemodialysis treatment.
干预措施: Concurrent training (Other)
Peritonial dialysis
Patients with CKD under peritonial dialysis.
干预措施: Resistance training (Other)
Peritonial dialysis
Patients with CKD under peritonial dialysis.
干预措施: Endurance training (Other)
Peritonial dialysis
Patients with CKD under peritonial dialysis.
干预措施: Concurrent training (Other)
Transplant patient
Transplant patient
干预措施: Resistance training (Other)
Transplant patient
Transplant patient
干预措施: Endurance training (Other)
Transplant patient
Transplant patient
干预措施: Concurrent training (Other)
Control group - conservative
Patients with CKD under conservative treatment.
Control group - Hemodialysis
Pacients under hemodialysis treatment
Control group - peritonial dialysis
Patients under peritonial dialysis
Control group - Transplant patient
Transplant patient
结局指标
主要结局
Concentrations of uremic toxins - Indoxyl sulfate
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Serum concentration of Indoxyl sulfate (µmol/L) will be measured.
Concentrations of uremic toxins - p-Cresyl sulfate
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Serum concentration of p-Cresyl sulfate (µmol/L) will be measured.
Concentrations of uremic toxins - hippuric acid
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Serum concentration of hippuric acid (µmol/L) will be measured.
Concentrations of uremic toxins - trimethylamine N-oxide
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Serum concentration of trimethylamine N-oxide (µmol/L) will be measured.
Concentrations of uremic toxins - screening
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Other uremic toxins may also be identified through miRNA expression, high-performance liquid chromatography (HPLC) and mass spectrometry (MALDI TOF/TOF) identified peptides, with spectra processed via FlexControl and FlexAnalysis.
Serum albumin
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
The serum albumin (mg/dL) will be measured in duplicate using the automated chemical analyzer (COBAS c111 system, Roche Diagnostics, Switzerland).
Creatinine
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Creatinine (mg/dL) will be measured in duplicate using the automated chemical analyzer (COBAS c111 system, Roche Diagnostics, Switzerland).
Cystatin C levels
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Cystatin C levels (mg/dL) will be measured in duplicate using the automated chemical analyzer (COBAS c111 system, Roche Diagnostics, Switzerland).
Estimation of renal function in patients undergoing conservative treatment
时间窗: Every two months, over a follow-up period of at least 6 months and up to 10 years.
The values of creatinine and cystatin C values will be applied to the formula proposed by Inker (2012) to estimate the glomerular filtration rate (eGFR).
次要结局
- Anthropometric measures - weight(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Nutritional profile - dietary recall(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Telomere length(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Exerkinas - serum levels of irisin(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Glycemic profile - fasting glucose(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Cardiopulmonary capacity - Graded Incremental Test and Metalyzer 3B(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Body composition - DEXA(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Body composition - 7 Skinfold(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Psychosocial aspects of patients(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Cardiopulmonary capacity - Fitcheck(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Cardiopulmonary capacity - Respiratory Muscle Strength(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Valsalva Maneuver(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Cold pressure test(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - handgrip strenght(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Heart rate(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Arterial Oxygen Saturation(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - blood pressure(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Femoral Artery Measurements(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Heart Rate Variability (HRV)(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Muscle strength - e-lastic(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Stroke Volume(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Cardiac Output(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Blood Pressure Variability (BPV)(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Handgrip Exercise(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Post-Exercise Ischemia(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Redox profile - TROLOX(: Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Redox balance - SOD(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Telomerase Activity Measurement(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Muscle strength - handgrip(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Muscle strength - isokinetic dynamometry(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Cardiovascular Autonomic Regulation during Deep Breathing(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Patient's quality of life(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Gut microbiota profile(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Inflammatory profile - TNF-α, IL-6, IL-10, IL-11, IL-18 e FGF-23(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Ancestry Assessment(Every two months, over a follow-up period of at least 6 months and up to 10 ye Every two months, over a follow-up period of at least 6 months and up to 10 years.ars.)
- Muscle strength - 1-repetition maximum(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Anthropometric measures - height(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Anthropometric measures - Body mass index(Every two months, over a follow-up period of at least 6 months and up to up to 10 years.)
- Autonomic function - respiratory rate(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Spontaneous Baroreflex Sensitivity (SBS)(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Autonomic function - Instantaneous Cerebral Electrical Activity(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Nutritional profile - Food Frequency Questionnaire(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Exerkinas - adiponectin(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Exerkinas - α-Klotho and sirtuin-1 (SIRT-1)(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Exerkinas - Sestrin(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Exerkines - screening(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Glicemic profile - glycated hemoglobin(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Glycemic profile - insulin(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Glycemic profile - HOMA-IR(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Glycemic profile - HOMA-B(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Lipid profile(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Inflammatory profile - CRP(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Inflammatory profile - MPO, Leptin, GDF-15(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Inflammatory profile - ADMA(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Redox profile - TBARS e NOx(Every two months, over a follow-up period of at least 6 months and up to 10 years.)
- Redox balance - paraoxonase-1 and catalase(Every two months, over a follow-up period of at least 6 months and up to Every two months, over a follow-up period of at least 6 months and up to 10 years.10 years.)
研究者
Lysleine Alves de Deus
Principal Investigator
Catholic University of Brasília