Clinical trial NCT06910475: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Kidney Disease, Chronic
Kidney Failure Chronic
Keywords: Exerkines
uremic toxins
physical training
physical exercise
indoxyl sulfate
p-Cresyl sulfate
hippuric acid
trimethylamine N-oxide
asymmetric dimethylarginine
redox balance
inflammation
tumor necrosis factor alpha
interleukin
leptin
irisin
BNDF
ancestry
telomere
Lead sponsor: Catholic University of Brasília
Sponsor class: OTHER
First posted: 2025-04-04
Enrollment: 1600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: The intervention of the study will consist of physical exercise, including aerobic exercise, resistance training, and concurrent training (a combination of both). These interventions will follow a structured and supervised training protocol to assess their effects on the selected outcomes.
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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).

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.

Primary outcomes:
measure: Concentrations of uremic toxins - Indoxyl sulfate
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Concentrations of uremic toxins - p-Cresyl sulfate
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Concentrations of uremic toxins - hippuric acid
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Concentrations of uremic toxins - trimethylamine N-oxide
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Concentrations of uremic toxins - screening
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Serum albumin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Creatinine
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Cystatin C levels
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Estimation of renal function in patients undergoing conservative treatment
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Secondary outcomes:
measure: Anthropometric measures - weight
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Cardiopulmonary capacity - Graded Incremental Test and Metalyzer 3B
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Cardiovascular Autonomic Regulation during Deep Breathing
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Nutritional profile - dietary recall
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Telomere length
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Exerkinas - serum levels of irisin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Glycemic profile - fasting glucose
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Patient's quality of life
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Gut microbiota profile
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Inflammatory profile - TNF-α, IL-6, IL-10, IL-11, IL-18 e FGF-23
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Ancestry Assessment
timeFrame: 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.
measure: Muscle strength - 1-repetition maximum
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Anthropometric measures - height
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Anthropometric measures - Body mass index
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Body composition - DEXA
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Body composition - 7 Skinfold
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Psychosocial aspects of patients
timeFrame: Every two months, over a follow-up period of at least 6 months and up to up to 10 years.
measure: Cardiopulmonary capacity - Fitcheck
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Cardiopulmonary capacity - Respiratory Muscle Strength
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Valsalva Maneuver
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Handgrip Exercise
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Post-Exercise Ischemia
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Cold pressure test
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - handgrip strenght
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - respiratory rate
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Heart rate
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Arterial Oxygen Saturation
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - blood pressure
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Femoral Artery Measurements
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Heart Rate Variability (HRV)
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Spontaneous Baroreflex Sensitivity (SBS)
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Instantaneous Cerebral Electrical Activity
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Nutritional profile - Food Frequency Questionnaire
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Exerkinas - adiponectin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Exerkinas - α-Klotho and sirtuin-1 (SIRT-1)
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Exerkinas - Sestrin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Exerkines - screening
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Glicemic profile - glycated hemoglobin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Glycemic profile - insulin
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Glycemic profile - HOMA-IR
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Glycemic profile - HOMA-B
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Lipid profile
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Inflammatory profile - CRP
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Inflammatory profile - MPO, Leptin, GDF-15
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Inflammatory profile - ADMA
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Redox profile - TBARS e NOx
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Redox balance - paraoxonase-1 and catalase
timeFrame: 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.
measure: Redox profile - TROLOX
timeFrame: : Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Redox balance - SOD
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Telomerase Activity Measurement
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Muscle strength - handgrip
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Muscle strength - isokinetic dynamometry
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Muscle strength - e-lastic
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Stroke Volume
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Cardiac Output
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
measure: Autonomic function - Blood Pressure Variability (BPV)
timeFrame: Every two months, over a follow-up period of at least 6 months and up to 10 years.
Other outcomes:
Locations:
city: Taguatinga
country: Brazil
facility: Catholic University of Brasília
state: Distrito Federal
Study officials:
affiliation: Catholic University of Brasília
name: Thiago S Rosa, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Catholic University of Brasília
name: Hugo L Correa, MSc
role: STUDY_CHAIR
References: