Impaired Cardiopulmonary Fitness in Youth with CKD

CKD in childhood is associated with tenfold to 30-fold higher mortality rates than the general pediatric population, with cardiovascular disease as the leading cause of death in children and adults with CKD.¹ Traditional risk factors for cardiovascular disease like hypertension, dyslipidemia, impaired glucose tolerance, and obesity begin to accumulate early in CKD, along with declining levels of physical activity as CKD progresses. Although the 2024 Kidney Disease: Improving Global Outcomes clinical practice guideline for CKD recommends daily physical activity in children up to a level compatible with their cardiovascular tolerance, most children with CKD do not achieve this goal.² Impaired exercise tolerance is a critical barrier to physical activity for children with CKD. Several small studies of youth with CKD have found reduced aerobic exercise capacity primarily in those with end-stage kidney disease; however, detailed phenotyping of cardiopulmonary fitness in youth across the stages of CKD using modern pediatric reference values has not been available until this issue of CJASN.³

Werner et al. have conducted a prospective, cross-sectional analysis of 88 youth aged 6–17 years with CKD stages 2–5 who underwent cardiopulmonary exercise testing and spirometry between 2022 and 2024 in three French pediatric nephrology centers. Patients performed spirometry at rest and then completed cardiopulmonary exercise testing on a cycle ergometer (stationary exercise bicycle) for a target duration of 8–12 minutes. The primary outcome was VO_2max, or maximal oxygen uptake, which represents the cardiovascular system's ability to use oxygen during peak exercise and is a significant predictor of health-related quality of life in children with chronic diseases and mortality in adults. Importantly, VO_2max was expressed as a Z score using updated pediatric reference equations that account for the abnormal body composition in youth with CKD better than traditional weight-based reference equations.

Of the 88 patients who attempted cardiopulmonary exercise testing, including 18 patients on dialysis, 77 patients achieved valid results. There was a stepwise decline in mean VO_2max Z-score with advancing CKD, ranging from −0.6 (±1.7) in stage 2 to −3.6 (±3.1) in stage 5. Impaired cardiopulmonary fitness, defined as a VO_2max Z score <−1.64, was already present in 24% of youth with stage 2 and 56% with stage 3, increasing to 79% and 87% in stages 4 and 5, respectively. Although there was no healthy control group for comparison, the mean VO_2max of 33.5 ml/kg per minutes in this study population represents an approximately 10 ml/kg per minutes reduction in VO_2max compared with age- and sex-based norms. Werner et al. note that this degree of impairment is greater than the 4–6 ml/kg per minutes reduction observed in other pediatric chronic diseases like cystic fibrosis, congenital heart disease, asthma, and cancer. The more pronounced reduction in VO_2max with CKD is particularly concerning given that a reduction of only 3.5 ml/kg per minutes (i.e., one metabolic equivalent) is associated with an 11% increase in all-cause mortality in adult studies.⁴

Several modifiable factors mediated the association between CKD and impaired cardiopulmonary fitness. Nearly 80% of the variance in VO_2max was explained by a multivariable model that included the potential therapeutic targets of hemoglobin concentration, hypertension status, forced expiratory volume in one second, ventilatory anaerobic threshold (an effort-independent marker of aerobic fitness that measures the volume of oxygen uptake when aerobic metabolism switches to anaerobic metabolism during exercise), and V_E/V_CO2 slope (a marker of ventilatory efficiency that measures the ventilatory response needed to expire a given volume of CO₂). Clinicians may address these risk factors for impaired cardiopulmonary fitness by optimizing three core tenets of guideline-recommended CKD care: anemia management, hypertension control, and exercise promotion. Other modifiable clinical variables that were not measured in the study, like acidosis, nutritional status, sarcopenia and growth retardation, may help explain the remaining 20% of the variance in VO_2max.

Strengths of the study include the prospective multicenter design; balanced distribution of patients across CKD stages 2–5; high-quality cardiopulmonary exercise testing; VO_2max Z scores adjusted for age, sex, and body mass index based on contemporary pediatric reference values; assessment of biochemical markers of mineral and bone disorder; and echocardiogram and spirometry data to complement cardiopulmonary exercise testing results. Limitations include the absence of healthy controls, use of self-reported physical activity instead of objective monitoring, no evaluation of health-related quality of life, and lack of information about potential contributors to cardiopulmonary fitness like muscle strength, nutrition, inflammation, and social determinants of health. In addition, the cross-sectional design limits causal inferences on what may be a bidirectional relationship between CKD progression and cardiopulmonary fitness. Nevertheless, Werner et al. have accomplished a critical step toward promoting cardiopulmonary fitness in youth with CKD by phenotyping aerobic exercise capacity across the stages of CKD.

Despite the benefits of exercise on cardiovascular health, bone metabolism, academic achievement, psychosocial well-being, and quality of life, there are multiple barriers to increasing physical activity in youth with CKD. In the current study population, 65% of all youth with CKD reported exercising more than once per week, including 94% with stage 2 but only 36% with stage 5.³ The study does not describe patients' exercise habits in detail, but previous literature from the Chronic Kidney Disease in Children cohort has shown that only 13% of youth with predialysis CKD met the guideline-recommended 60 minutes of daily physical activity while 98% exceeded the 2-hour limit on daily screen time.²

Youth with CKD report avoiding physical activity for several reasons, including pain, weakness, fatigue, concern about the negative effects of exercise on their health, and fear of injury because of their short stature.⁵ About one in three adolescents with autosomal dominant polycystic kidney disease state that they avoid sports based on the advice of their doctor or parent.⁵ Practice patterns on exercise restrictions vary among pediatric nephrologists, particularly for youth on dialysis, as there is no evidence to guide providers' recommendations on sports participation. Even after kidney transplant, more youth receive counseling on limiting physical activity than counseling encouraging physical activity.⁵ In addition to patient- and provider-level attitudes that may limit participation, youth with CKD encounter structural barriers to exercise, including lack of nearby facilities or programs, cost, bullying, neighborhood safety, transportation insecurity, long waiting lists for adaptive programs, and lack of skilled instructors.

Future research is needed to explore the effect of psychosocial factors on physical activity and cardiopulmonary fitness in youth with CKD. Perceived self-efficacy has been associated with aerobic capacity on cardiopulmonary exercise testing in youth with congenital heart disease,⁶ which aligns with qualitative data in youth with CKD noting limited self-confidence and motivation around exercise.⁵ Pediatric nephrologists can do their part by prioritizing exercise promotion in clinic with a clear prescription for exercise tailored to each patient.⁷ A single small trial in 20 youth patients after kidney transplant found that providers actively emphasizing daily exercise at follow-up visits combined with an office-based physical therapy program was associated with improved cardiopulmonary fitness, quality of life, and mental health.⁸ Other intervention studies on exercise promotion in pediatric CKD using pedometers, community exercise programs, video games, or mobile apps have shown null to modest effects on cardiopulmonary fitness and have been limited by significant nonadherence, dropout, and poor motivation.⁵

Although high-quality evidence is lacking on exercise programs in pediatric CKD, the recent QUALIREHAB trial in French youth with congenital heart disease offers a pragmatic model that may be adaptable to youth with CKD.⁹ The trial randomized adolescents and young adults with congenital heart disease and impaired VO_2max to a 12-week hybrid center- and home-based rehabilitation program versus usual care. The intervention was associated with improved quality of life, body mass index, and self-reported physical activity at 12-month follow-up and an increase in VO_2max by 3.0 ml/kg per minutes at the end of the 12-week program. Semistructured interviews with patients from the intervention arm found that continuous psychological support, personalized guidance, and improved confidence were key strengths of the exercise program.

Although it may not be feasible to implement cardiopulmonary exercise testing in routine CKD care, the high prevalence of impaired exercise tolerance observed by Werner et al. in 57% of youth with CKD stages 2–5 suggests a need for structured exercise training programs in this population.³ Given the multilevel barriers and negative patient perceptions toward exercise, future research is needed to develop multidisciplinary exercise interventions or adapt proven-effective rehabilitation programs to increase physical activity in youth with CKD. In the meantime, pediatric nephrologists can empower their patients to meet guideline-recommended exercise goals by encouraging participation with adaptations as needed, instead of focusing on restrictions.¹⁰

Werner et al. have shown that impaired exercise tolerance begins in early CKD and accelerates as kidney function declines.³ The extent to which exercise can delay progression of CKD in youth remains unknown. However, the implications of the current study for pediatric clinicians are clear. Owing to the high prevalence of impaired aerobic capacity in early CKD and the consistent association between cardiopulmonary fitness and quality of life throughout the pediatric literature, clinicians should provide exercise counseling and tailor exercise training programs starting at the time of CKD diagnosis.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at https://links.lww.com/CJN/C829.

Author Contributions

Conceptualization: James T. Nugent.

Writing – original draft: James T. Nugent.

Writing – review & editing: James T. Nugent.

Funding

J.T. Nugent: American Heart Association (Career Development Award 24CDA1051185), National Heart, Lung, and Blood Institute (K23HL177261).