In this multicenter retrospective study, we found that even after adjustment for baseline variables, higher plasma CK levels were incrementally associated with a higher risk of all-cause mortality in PD patients, especially in those male and non-diabetes PD patients.
Plasma CK tightly binds to ATP-utilizing enzymes, including Ca2+-ATPase, myosin ATPase, and Na+/K+-ATPase, to rapidly regenerate ATP from ADP, H+, and phosphocreatine . Usually, the release of CK from tissues is proportional to the intracellular CK concentration, a physiological process that occurs without tissue damage, as summarized by Brewster . Therefore, the plasma CK of healthy people at rest reflects the tissue CK concentration [3, 4, 13]. However, as lymphatic flow increases with exercise, CK from the interstitial space may enter the circulation rather abruptly and be cleared by the liver in approximately three days . An elevation of plasma CK levels is seen following acute myocardial infarction, rhabdomyolysis, intramuscular injections, and strenuous physical activity. A high tissue CK level is thought to result in a phenotype with greater vasoconstriction and enhanced sodium retention by greater ATP-buffering capacity of ATPases involved in ion transport and contractile responses [2, 3, 12, 14].
Previous studies found that relatively high CK is thought to enhance ATP-demanding processes, including resistance to arterial contractility and sodium retention, and to reduce ADP-dependent function in the general population [12, 15][12, 15]. Subsequently, in a randomized sample of a multiethnic population in Amsterdam, the Netherlands, CK proved to be an important independent predictor of BP levels and the failure of antihypertensive treatment . This study found that after adjusting for age, gender, BMI, and ethnicity, CK was independently associated with BP and with systolic and diastolic BP, increasing by 8.0 and 4.7 mmHg/log CK, respectively. Since then, several other studies have reported that plasma CK levels are associated with the failure of antihypertensive drug treatment [4, 15][4, 15]. In addition, plasma CK has been associated with decreased inflammation in obesity, while inflammation is associated with obesity-related CVD . Notably, plasma CK along with lean body mass is inversely and independently associated with hs-CRP in overweight and obese individuals, supporting the anti-inflammatory effects of CK. Thus, these findings suggest that CK may also have beneficial and detrimental effects on the prognosis of patients. Therefore, it is difficult to speculate on the association between CK and death in PD patients. To date, little is known about the association between plasma CK levels and all-cause mortality in PD patients. Our study showed that high plasma CK Quartiles were associated with higher risk of all-cause mortality in PD patients, independent of confounding factors, such as age, sex, CCI, CCB use, ACEIs/ARBs use, β-blocker use and diuretic use. Meanwhile, we found that the results from the competing risk model were consistent with the Cox regression models. Additionally, similar results were also observed in the male and those without diabetes. These findings suggested that monitoring plasma CK levels may be beneficial for improving the prognosis of PD patients, especially in the male and those without diabetes.
A possible explanation for the described association between total plasma CK levels and mortality was that plasma CK was associated with the failure of antihypertensive therapy, which has been linked to higher mortality . There is increasing evidence that high plasma CK levels are thought to enhance ATP-demanding processes, including resistance to arterial contractility and sodium retention. In our study, higher plasma CK levels were associated with a higher risk of all-cause death. Our results showed that there was a significantly positive relationship between the levels of plasma CK and BP. It is well known that high BP is associated with high all-cause mortality [16, 17]. Although the lowest Quartile of CK (<60 U/L) was associated with a lower risk of all-cause death, the mean hemoglobin and albumin levels in the Quartile 1 were significantly lower than those in the Quartile 4. It is well known that lower hemoglobin and albumin, as markers of malnutrition, are associated with a higher risk of all-cause mortality . Additionally, lower plasma CK may be considered a marker of malnutrition and relatively low muscle mass, which has been linked to a higher risk of all-cause mortality [17, 19]. Thus, these findings suggested that the adverse effect of the failure of antihypertensive treatment of higher CK levels on all-cause mortality may be stronger than the protective effect of anti-inflammatory of higher CK levels on all-cause mortality, which may lead to increased all-cause mortality in the present study. Therefore, mechanisms of the effect of plasma CK on mortality should be investigated in future studies, and the management of plasma CK may improve the clinical prognosis of PD patients.
The strengths of this study are the multicenter nature of the study, a large number of patients, the ability to adjust for significant risk factors for all-cause mortality, and sensitive analysis of competing risk model. There are some limitations in the present study. First, due to the multicenter design of the cohort, there were some variations in the ascertainment and validation of the endpoint. However, it was a multicenter study; therefore, center-specific effects may be excluded. Second, the retrospective nature of the study allows us to establish associations but not causal relationships. As with all retrospective studies, a potential limitation is that the associations may be influenced by confounding by other risk factors. Because of the restriction of sample size, we did not adjust for all factors associated with higher mortality. Therefore, the effect of residual confounding cannot be eliminated completely. Due to the retrospective data, we are not capable of getting precise home BP data because of patient’s bias. We will prospectively observe the longitudinal association between plasma CK levels and BP of these patients. Third, guidelines of dialysis do not regularly recommend lipid-regulating treatment of hyperlipidemia and CVD events in PD patients. Thus, even though PD patients developed CVD events, we usually do not prescribe statins for these patients. This was why patients with statins accounted for < 10% of total PD patients. Nonetheless, the findings are mainly applicable in statin naïve subjects. Future study should focus on the relationship between CK levels and statins in PD patients. Fourth, whether plasma CK can be cleared via PD remains unknown. Thus, whether the patients with higher CK had greater clearance needs that were not met by the CAPD remains unknown. We will further observe the association between dialysis dose and plasma CK levels. Lastly, the changes in variables and treatments overtime during the follow-up were not included.