Physical Exercise and Biomolecular Analysis to Reduce Uremic Toxins in Chronic Kidney Disease: An Exploratory Study

Official title

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

Overview

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.

Detailed description

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).

Interventions

• Other Resistance training
  The training program will follow a periodized approach, starting with a low total volume (loads x sets x repetitions), ensuring gradual adaptation, patient safety, and performance progression. Strength training will begin 48 hours after muscle strength tests.Sessions will occur 2 to 4 times per week on non-consecutive days. Each session will include 6-12 exercises, with 1-3 seconds for concentric and eccentric actions, 6-20 repetitions, 1-6 sets, and 1-3 minutes of rest. Intensity will be gauged
• Other Endurance training
  Training sessions will be conducted 2 to 4 times per week on non-consecutive days. Patients will perform aerobic training on different ergometers, namely: bicycle, treadmill, and stair climber. The choice will depend on the patient's needs/abilities and/or equipment availability. The load will be adjusted between 50% and 100% of the ventilatory threshold, according to the patient's cardiorespiratory capacity. The duration of the training will vary between 10 and 60 minutes, always starting with
• Other Concurrent training
  Training sessions will be conducted 2 to 6 times per week, alternating between strength training one day and aerobic training the next, as described above. As patients improve their physical fitness, strength and aerobic training may be performed on the same day.

Primary outcome measures

• Concentrations of uremic toxins - Indoxyl sulfate [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Concentrations of uremic toxins - p-Cresyl sulfate [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Concentrations of uremic toxins - hippuric acid [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Concentrations of uremic toxins - trimethylamine N-oxide [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Concentrations of uremic toxins - screening [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Serum albumin [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Creatinine [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Cystatin C levels [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Estimation of renal function in patients undergoing conservative treatment [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]

Secondary outcome measures (12)

• Anthropometric measures - weight [Time frame: 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 [Time frame: 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 [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Nutritional profile - dietary recall [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Telomere length [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Exerkinas - serum levels of irisin [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Glycemic profile - fasting glucose [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Patient's quality of life [Time frame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.]
• Gut microbiota profile [Time frame: 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 [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]
• Ancestry Assessment [Time frame: 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 [Time frame: Every two months, over a follow-up period of at least 6 months and up to 10 years.]

Eligibility criteria

Inclusion criteria

• 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)

Exclusion criteria

• 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;
• fever;
• resting SpO2 lower than 94%;
• restriction by the clinical team.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Triple blind

Primary purpose

Supportive care

Study locations

Brazil · 1 center

• Catholic University of Brasília — Taguatinga

Identifiers

NCT: NCT06910475 · 79266224.1.0000.002979266224.1 · 445068/2023-0

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗