In this study, we demonstrate that both children and adults with cystinosis have impaired muscle strength and that grip strength was only weakly and non-significantly associated with eGFR. Male patients and patients with late initiation of cysteamine therapy had a lower grip strength. Conversely, physical activity was associated with a better grip strength in adults, but we were not able to demonstrate a similar association in children.
Along with a decreased grip strength when compared to age and sex-matched healthy controls, the comparison of our results with previous reports among CKD patients suggest that patients with cystinosis have a decreased grip strength when compared to non-cystinosis CKD patients. Indeed, grip strength reported in adult patients with CKD stage 3 to 5 by Zhou et al. were higher than those found in our adult patients(25). In children, when comparing patients at the same CKD stage, cystinosis patients have a grip strength that is more than one standard deviation lower compared CKD controls, who had a mean grip strength z-score of -0.72(15). These results suggest that the direct effect of cystinosis on muscle strength is additive to the effect of CKD.
There was no significant relationship between eGFR and grip strength in patients with cystinosis. This is similar to a previous study investigating the relationship between grip strength and GFR in children with CKD that did not find a significant effect of CKD stages 2–5 on grip strength, although it did report a significantly higher grip strength in children with CKD stage 1 compared to all other stages. In the study of children with CKD, risk factors for decreased grip strength included longer duration of CKD, pre-pubertal status, delayed puberty, neuropsychiatric comorbidities, need for feeding support, need for alkali therapy, and hemoglobin level(15). We speculate that, similar to non-cystinosis patient with CKD, the effect of CKD stage is less important compared to other factors that affect grip strength in patients with cystinosis.
The two factors associated with poor grip strength in this population were age at cysteamine treatment initiation and male sex. In our study, although statistically significant, the effect of age at treatment initiation was weak with a mean decrease of -0.1SD per year of delay. This is likely due to the fact that the great majority of our patients initiated therapy early. However, our result is consistent with previous studies including patients with delayed treatment initiation and showing a higher incidence of neuromuscular disorders in patients initiating cysteamine therapy after the age of 5 years old (2). In our study, male patients had greater impairment of grip strength compared to females. This may be related to the hypogonadism observed in approximately 70% of male cystinosis patients. Indeed, previous studies have shown that the mean testosterone level in male patients with cystinosis was 50% of control patients(26). Therefore, it can be hypothesized that male patients with cystinosis experience an additional burden with respect to muscle strength due to the hypogonadism induced by cystinosis. This finding deserves further exploration and raises the question of the potential benefit of testosterone supplementation in male cystinosis patients to prevent muscle weakness.
Finally, our study found an association between physical activity and grip strength in adults. Although the design of our study does not allow us to conclude whether a low level of physical activity is a cause or a consequence of impaired muscle strength, it is interesting to note that strength exercises, which are usually thought to be beneficial for increasing or preserving muscle strength, were not associated with better grip strength. However, previous reports demonstrated the ability of resistance training to increase muscle strength. Therefore, the absence of association in our study might suggest that this type of exercise may be recommended to patients with evidence of muscle weakness, creating an indication bias precluding our ability to assess the potential benefit of this type of physical activity. On the contrary, aerobic and flexibility activities were associated with better grip strength and deserve to be investigated in future interventional trials. Indeed, studies in adults with ESKD have demonstrated that an exercise training program improves muscle strength, (27–29) but there are currently no data available in children with CKD or any patients with cystinosis. The absence of association between physical activity and grip strength in children may be explained by the smaller sample size for pediatric patients and by the progressive development of muscle weakness that increases with age.
Preserving muscle strength in patients with cystinosis is important since impaired muscle strength is associated with lower quality of life in both pediatric (15) and adult CKD patients(27). Our study demonstrates the high prevalence of neuro-muscular symptoms in patients with cystinosis. However, it is important to note that only swallowing difficulties were associated with grip strength. The lack of other associations may be related to the relatively small number of patients and the possibility that other factors may cause problems with activities of daily living or sleep disturbances.
This study is one of the larger studies to date assessing muscle strength and its risk factors in cystinosis patients, and it provides novel information regarding the increased impairment in male patients and the association with different types of physical activities. However, this study also has some limitations. The retrospective nature of this study limited the granularity of data available, and we cannot rule out the potential effect of unmeasured confounders on the associations reported in this study. Moreover, more than half of the patients previously received a kidney transplantation. Therefore, although a history of kidney transplantation was not associated with grip strength measurement, we cannot rule out that the association between eGFR and grip strength was confounded by the presence of transplanted patients in our cohort and by the use of eGFR at the time of evaluation that may not capture the real exposure to CKD.