Association of MLR With Risk of Death and Cardiovascular Events in PD Patients

Study Overview
=================
Brief Summary
-----------------
The current incidence of chronic kidney disease (CKD) in China is approximately 10.8%, with approximately 119 million patients. Among them, patients with end-stage renal disease (ESRD) are about 200-250 cases per million population. At present, the main renal replacement therapy is: hemodialysis (HD) or peritoneal dialysis (PD). Compared with HD, PD is easy to operate, better preserves residual renal function, has early survival advantages, and is more cost-effective. Despite this, the prognosis of PD patients is still not ideal, and cardiovascular disease (CVD) remains the leading cause of death in PD patients. Persistent inflammatory states are critical in the pathogenesis of CVD such as atherosclerosis and vascular calcification, and lead to protein energy expenditure and premature death outcomes in patients with CKD. Therefore, screening for markers that predict the risk of CVD in dialysis patients is essential. Some novel inflammatory markers have been shown to have diagnostic and prognostic value in ESRD patients in terms of inflammation, malnutrition, cardiovascular calcification, all-cause, and risk of CVD death. Among them, blood cell related parameters such as neutrophil / lymphocyte ratio (NLR) and monocyte / lymphocyte ratio (MLR)can reflect both inflammation and immune deficiency. NLR, MLR has been proposed as a new inflammatory biomarker and a potential predictor of cardiovascular risk. Studies have reported that MLR is associated with cardiovascular death and all-cause death risk in hemodialysis patients, and is superior to NLR. However, the relationship between MLR and the prognosis of patients with peritoneal dialysis is rarely reported. Therefore, in this study, we aimed to evaluate the association of MLR with risk of death and cardiovascular events in PD patients.

Detailed Description
-----------------
The epidemiological survey of chronic kidney disease in China shows that the current incidence of chronic kidney disease (CKD) in China is about 10.8%, with about 119 million patients. About 2% of patients will enter the stage of end-stage renal disease (ESRD) and require dialysis or kidney transplantation to support life. Currently the main renal replacement therapy is: hemodialysis (HD) or peritoneal dialysis (PD). Among them, PD patients are increasing year by year. As of 2016, more than 900,000 people in Asia are undergoing maintenance dialysis (218 cases per million population). Statistics from the CNRDS system show that as of the end of 2017, the number of PD patients in China has reached 86264. Compared with HD, PD is easy to operate, better preserves residual renal function, has early survival advantages, and is more cost-effective. In spite of this, the prognosis of PD patients is still unsatisfactory. At present, the main causes of death in PD patients are cardiovascular disease, peritoneal dialysis-related peritonitis, gastrointestinal bleeding, and tumors. Among them, cardiovascular disease (CVD) is the most important, accounting for about 50% of the deaths of PD patients. Among all CVD events, coronary heart disease, heart failure, and stroke are the most common. CVD risk factors for dialysis patients can be divided into traditional and non-traditional categories. Traditional Framingham risk factors can only explain some of the CVD risks of PD patients. Non-traditional risk factors, especially persistent inflammatory states, are essential in the pathogenesis of CVD such as atherosclerosis and vascular calcification, and lead to protein energy expenditure and premature death outcomes in patients with CKD. The causes of chronic inflammation in patients with peritoneal dialysis are mainly divided into two aspects. Dialysis-related factors include: catheter-related infections, continuous exposure to biologically incompatible PD solutions, peritonitis, increased adipose tissue, and adipose factor balance disorders; associated with low GFR Factors include decreased clearance of pro-inflammatory factors, accumulation of uremic toxins, endotoxin exposure, oxidative stress, increased volume load, oral or other organ infections, and susceptibility to infections. The causes of inflammation in peritoneal dialysis are interconnected, leading to a persistent state of inflammation that ultimately increases the risk of cardiovascular events. Therefore, it is important to screen for markers that predict the risk of CVD in dialysis patients. At present, various inflammatory mediators, such as c-reactive protein（CRP）, interleukins（IL）and tumor necrosis factor（TNF）, have been studied and proven to independently predict the risk of CVD in dialysis patients. CRP can induce the expression of adhesion molecules in endothelial cells, increase the adhesion of vascular endothelial cells and monocytes; promote the formation of foam cells and atherosclerosis; aggravate vascular endothelial dysfunction; TNF-α can increase the expression and activity of alkaline phosphatase, enhance Isolated vascular wall calcification; aggravates vascular endothelial dysfunction; promotes left ventricular remodeling and aggravates left ventricular dysfunction. IL-6 can stimulate macrophages to secrete monocyte chemotactic protein 1, induce endothelial cell adhesion molecule expression; stimulate vascular smooth muscle cell proliferation and migration; aggravate vascular endothelial dysfunction; and induce cardiac hypertrophy. Although the mechanisms are different, they all increase the risk of CVD death in dialysis patients by aggravating vascular endothelial dysfunction, promoting ventricular remodeling and inducing myocardial hypertrophy. However, such markers are expensive and their detection is not easy to limit their clinical application. This prompted researchers to devote themselves to mining new markers of inflammation. In recent years, experts and scholars have become interested in blood cell parameters. Previous studies have shown that white blood cells and their subgroups (neutrophils, lymphocytes, monocytes) ), Neutrophil / lymphocyte ratio (NLR), monocyte / lymphocyte ratio (MLR), platelet / lymphocyte ratio (PLR) and other indicators have important predictive value for all causes and prognosis of cardiovascular disease in dialysis population . They have the advantages of low cost and easy detection. Among them, MLR has been proven to be an independent predictor of death in cardiovascular diseases such as coronary heart disease and heart failure. Previous research found. Monocytes play a key role in the occurrence and development of atherosclerosis. After the initial injury, endothelial cells are activated and promote monocytes to roll, attach and migrate under the endothelium. Monocytes that migrate to the subendothelium can differentiate into dendritic cells, which are key participants in activating adaptive immunity, or differentiate into macrophages, which secrete pro-inflammatory cytokines, thereby recruiting more immune cells and Promote inflammation. Macrophage phagocytosis of lipoprotein particles can lead to the formation of fatty streaks, the earliest ultrastructural changes in the formation of atherosclerosis. The migration of smooth muscle cells from the medial membrane to the intimal membrane further promotes the atherogenic process. Monocyte-derived cells transform this early lesion into advanced atherosclerotic plaques, which contain lipid-rich and macrophage-rich necrotic cores that eventually cause the plaque to rupture. In addition, previous studies have shown that physiological stress can lead to a significant increase in systemic cortisol production, which has led to a shift in leukocyte differentiation toward a decrease in lymphocytes and an increase in the percentage of granulocytes. Measuring lymphocyte counts can reflect stress levels. In patients with coronary heart disease, studies have shown that a decrease in lymphocyte count is an independent predictor of prognosis in patients with coronary heart disease; there is a phenomenon of lymphocyte apoptosis on the endothelium of atherosclerotic injured blood vessels. Therefore, low lymphocytes can reflect the occurrence and development of atherosclerotic diseases. In patients with end-stage renal disease, there will be changes in the number of immune cells such as increased monocytes and decreased lymphocytes. First, the decline in renal function causes retention of uremic toxins and cytokines, which leads to increased proinflammatory cytokines and oxidative stress. It further stimulates the proliferation of monocytes, and at the same time down-regulates immunity, resulting in a decrease in the number and function of lymphocytes, which in turn promotes inflammation and oxidative stress, and continues a vicious cycle. MLR can integrate pro-inflammatory and anti-inflammatory effects, and simultaneously reflect inflammation and immune deficiency. It may be an important marker of inflammation in patients with end-stage renal disease. In 2017, Xiang F et al. For the first time found in a prospective cohort study of 355 hemodialysis patients that high MLR levels were independent predictors of all-cause and CVD mortality in hemodialysis patients, and exceeded the predictive value of NLR However, there are no reports about MLR and prognosis in patients with peritoneal dialysis at home and abroad. Our previous retrospective analysis showed that the all-cause and cardiovascular disease survival rates of patients in the low MLR group were significantly higher than those in the high MLR group; high MLR levels were associated with all-cause and increased risk of cardiovascular death in patients with peritoneal dialysis. However, because retrospective studies cannot determine causality, there may be problems such as selection bias. Therefore, a prospective, large-sample study is needed to further explore the correlation between MLR and the prognosis of PD patients.

Official Title
-----------------
Association of Monocyte / Lymphocyte Ratio With Risk of Death and Cardiovascular Events in Peritoneal Dialysis Patients

Conditions
-----------------
Inflammation, Peritoneal Dialysis

Intervention / Treatment
-----------------
* Other: monocyte / lymphocyte ratio


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who underwent continuous ambulatory peritoneal dialysis for at least 3 months. Exclusion Criteria: Age <18 years, with acute or chronic infections such as lung infection,peritoneal dialysis-related peritonitis, urinary system infection, etc . With history of malignant tumor or blood disease. With rheumatic immune diseases, such as systemic lupus erythematosus, vasculitis , Sjögren's syndrome, etc . Used immunosuppressants, such as glucocorticoids, calcineurin inhibitors, etc . Women during pregnancy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| high MLR group<br>Divided into high MLR group and low MLR group according to the median of monocyte / lymphocyte ratio(MLR). Patients undergo peritoneal dialysis 3, 4 or 5 times per day, with a daily peritoneal dialysate dose of approximately 6000-10000 ml. The glucose concentration of peritoneal dialysate varies depending on the specific requirements of the individual patient for ultrafiltration volume. Three concentrations of glucose peritoneal dialysis solution are available for peritoneal dialysis patients. The low concentration is 1.5% or 2.5% and the high concentration is 4.25%. In principle, a 1.5% glucose peritoneal dialysis solution is first applied, or a high concentration of 4.25% glucose peritoneal dialysis solution can be appropriately applied according to the actual situation. Other drugs continued to be used in patients with other diseases. | Other: monocyte / lymphocyte ratio<br>* The lymphocyte / monocyte ratio should be tested every 3-6months after the start of the study, and the final value is the average<br>|
| low MLR group<br>Divided into high MLR group and low MLR group according to the median of monocyte / lymphocyte ratio(MLR). Patients undergo peritoneal dialysis 3, 4 or 5 times per day, with a daily peritoneal dialysate dose of approximately 6000-10000 ml. The glucose concentration of peritoneal dialysate varies depending on the specific requirements of the individual patient for ultrafiltration volume. Three concentrations of glucose peritoneal dialysis solution are available for peritoneal dialysis patients. The low concentration is 1.5% or 2.5% and the high concentration is 4.25%. In principle, a 1.5% glucose peritoneal dialysis solution is first applied, or a high concentration of 4.25% glucose peritoneal dialysis solution can be appropriately applied according to the actual situation. Other drugs continued to be used in patients with other diseases. | Other: monocyte / lymphocyte ratio<br>* The lymphocyte / monocyte ratio should be tested every 3-6months after the start of the study, and the final value is the average<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality and cardiovascular mortality | Proportion of all-cause and cardiovascular deaths during follow-up | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence of cardiovascular events | Cardiovascular events during follow-up (including acute heart failure, angina, acute myocardial infarction, arrhythmias requiring treatment, transient ischemic attack (TIA), cerebral infarction or cerebral hemorrhage, peripheral vascular disease) | 12 months | 
| The Incidence of peritoneal dialysis-associated peritonitis | Peritoneal dialysis-related peritonitis refers to the complications of peritonitis such as abdominal pain, fever, or turbid dialysate during peritoneal dialysis. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
monocyte / lymphocyte ratio, peritoneal dialysis, cardiovascular disease, Inflammation, death