Development and validation of a model for predicting the risk of cardiovascular events in maintenance hemodialysis patients – Scientific Reports

We developed and validated for quantifying the association of cardiovascular events with the risk of 3- and 5-years for patients undergoing MHD. The study included 13 indicators (including age, mode of dialysis, whether or not intradialytic hypotension, waist-to-hip ratio, handgrip strength, extracellular water, lean tissue index, lymphocyte, platelet distribution density, total bilirubin, age on dialysis, and presence of hypertension and/or diabetes mellitus), all of which were evaluated and validated to confirm the reliability and accuracy of the model for predicting the risk of cardiovascular events in patients with MHD, providing a basis for cardioprotection in hemodialysis patients.

Protein-energy wasting (PEW) refers to a state of “malnutrition” in patients with chronic kidney disease in which various nutritional and metabolic abnormalities lead to a decrease in the body’s protein energy reserves6. Studies have confirmed7 that during the development of PEW, a decrease in the rate of muscle protein synthesis and an increase in the rate of catabolism will cause progressive skeletal muscle wasting. Upper arm circumference, triceps skinfold thickness, calf circumference, body weight, and handgrip strength decreased with the progression of PEW, which seriously affected the quality of survival of patients6. This is consistent with our findings that the decrease in waist-to-hip ratio and handgrip strength with disease progression and dialysis treatment will increase the risk of cardiovascular events in patients. Several studies have shown that8,9 LTI correlates with skeletal muscle mass, reflecting the nutritional status of the patient, and that patients with low LTI have a significantly higher mortality rate than those with normal LTI, which is an independent predictor of mortality. Our results show that the loss of LTI is associated with the risk of cardiovascular events, which may be related to the decrease of fat reserve is more obvious than skeletal muscle.

Fluid overload is also one of the major risk factors for all-cause and cardiovascular mortality in MHDs, and we assess patient’s nutritional and fluid loading status through the bioelectrical impedance. A recent study showed that10 patients with PEW and high ECW/ICW ratios were more likely to die from any cause and that the ECW/TBW ratio can be used to predict not only PEW, but also inflammation and volume overload in MHD, and is a strong predictor of mortality in patients with MHD.

The risk of cardiovascular disease-related death is increased approximately 30-fold in patients with end-stage renal disease receiving hemodialysis. Lipid oxidation or oxidative stress plays an important role in the pathogenesis of atherosclerosis. Previous studies have shown that serum bilirubin has potent antioxidant effects that are associated with the prevention of kidney injury and the reduction of cardiovascular events11,12. A large sample cohort study by Su et al. showed13 that higher TB levels were associated with higher mortality in MHDs without liver disease or abnormal liver function, and mildly elevated TB levels were not associated with a protective effect in MHDs. The authors’ explanation may be because total bilirubin is negatively correlated with nutrition and body mass index, and low body mass index is strongly associated with mortality in uremic patients.

Increased platelet activation and release will be presented as an increase in the density of platelet distribution Platelet. The activation and oxidative of platelets play a key role in atherosclerotic plaque instability and plaque rupture with subsequent thrombus formation in patients with ST-segment elevation myocardial infarction14. Platelet activation leading to the release of proinflammatory, pro-mitotic, and pro-apoptotic molecules and cytotoxic substances, as well as interactions with leukocytes and endothelial cells, will trigger the onset and amplification of myocardial ischemia–reperfusion injury15.

Microinflammation is the first step in the “inflammation-dystrophy-atherosclerosis” process in end-stage hemodialysis patients16, which is closely related to cardiovascular events. Our findings showed that lymphocyte counts were positively associated with the risk of cardiovascular events in maintenance hemodialysis patients, which may be related to the activation of the immune system by microinflammatory responses and the release of inflammatory mediators thereby impairing vascular endothelial function, ultimately leading to atherosclerosis and cardiovascular events. A retrospective study by Yanping Zhang et al. demonstrated17 that a high platelet-to-lymphocyte ratio (PLR) independently predicted all-cause mortality in patients with MHD and that a highly expressed PLR was associated with cardiovascular mortality.

Intradialytic hypotension (IDH) is associated with higher ultrafiltration volumes (roughly > 10–13 ml/h/kg in different studies)18,19, reduced cardiac output, and sluggish sympathetic activation. Based on IDH may lead to end-organ damage such as cerebral ischemia, mesenteric ischemia, accelerated loss of residual renal function, and is also associated with thrombosis and cardiac arrhythmias, which are independent risk factors for all-cause mortality20,21,22. Many studies have shown a “U-shaped” or “reverse J-shaped” relationship between blood pressure and mortality, suggesting that mortality is higher for lower systolic blood pressure (< 120 mmHg) pre- and post-dialysis (especially for those < 50 years of age and those with comorbid diabetes mellitus), and that higher systolic blood pressure (> 180 mmHg) is associated with slightly higher risk of death, and that the mortality due to low systolic blood pressure is attributable to cardiovascular complications23.

A prediction model for cardiovascular events in a Japanese hemodialysis population developed by Li et al. indicated24 that age, diabetes status, and frequency of dialysis were associated with the occurrence of cardiovascular events, which is consistent with our study. There is a positive correlation between the age of the patient and the risk of cardiovascular events. The decline in physical function with increasing age may lead to hardening of the blood vessel walls and a decline in cardiac function, resulting in an increased risk of cardiovascular events. However, the age of patients on dialysis was inversely associated with the risk of cardiovascular events. Studies have shown25 that mortality in HD patients ranges from 5.6–8.6% within 90 days of starting hemodialysis and 16.2–24.3% within one year, which may be related to poor renal function at the initial base of the disease, fluctuations in blood volume (alternating between hyper- and hypovolemia), activation of pro-inflammatory cytokines and complement, and nutritional status.

Compared to existing models, our clinical prediction model has many advantages. For example, in the research by Matsubara et al.26, the follow-up period for our model was much longer than theirs. It is critical that we have assessed the external validation of this model. And the sample size of our model is large enough compared to existing models, such as Li et al.27. It is important that the Model is concise, practical, and steady, and the predictors are intuitively derived from clinical work, which has high practicability. Nonetheless, there are limitations to this study, and the model requires external validation in a broader maintenance hemodialysis population.

In conclusion, we developed a model to estimate the cardiovascular events risk for patients undergoing MHD. We found that protein-energy expenditure plays a critical role in disease progression and prognosis in maintenance hemodialysis patients and is an important goal in delaying disease progression. Identifying potential pathophysiologic factors underlying cardiovascular events in maintenance hemodialysis patients is critical to reducing both the incidence of cardiovascular events and mortality in maintenance hemodialysis patients. All of the above relevant factors are associated with the risk of cardiovascular events in maintenance hemodialysis patients and could provide clinicians with appropriate references.