{'fraction_non_alphanumeric': 0.03436540771386627, 'fraction_numerical': 0.011410649939943947, 'mean_word_length': 5.223837209302325, 'pattern_counts': {'":': 0, '<': 6, '<?xml version=': 0, '>': 3, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Risk factors for mortality in patients undergoing peritoneal dialysis: a systematic review and meta-analysis

Abstract Aim Inconsistent investigations of the risk factors for all-cause mortality in patients undergoing peritoneal dialysis (PD) were reported. The present meta-analysis aimed to assess the impact of some clinical characteristics on the risk of mortality in PD patients. Methods PubMed and Embase were systematically searched for studies evaluating the risk factors for all-cause mortality in PD patients. Hazard ratio (HR) and 95% confidence interval (CI) were derived using a random-effect or fixed-effect model considering the heterogeneity across studies. Result A total of 26 studies were included in this meta-analysis in accordance with the inclusion and exclusion criteria. Age, primary cardiovascular diseases, diabetes mellitus, and high level of alkaline phosphatase showed significant positive associations with elevated risk of all-cause and cardiovascular mortality in PD patients, while hemoglobin acted as a benefit factor. Furthermore, early onset of peritonitis, high peritoneal transport status, elevated body mass index and high-sensitivity C-reactive protein could also considerably increase the risk of all-cause mortality. The absolute serum level of magnesium, potassium, and uric acid required to improve survival in PD patients should be verified further. Conclusions Multiple factors could affect the risk of mortality in PD patients.


Introduction
Peritoneal dialysis (PD) is one of the major renal replacement therapies for patients with end-stage kidney disease (ESKD) [1]. The number of PD patients has been increasing in numerous developing countries. However, the long-term survival rate of PD patients remains low [2]. Additionally, cardiovascular disease (CVD) and death are highly prevalent in patients with ESKD [3,4]. These findings may be attributed to chronic inflammation, disturbed mineral metabolism, primary CVD, and other physical conditions. For instance, commonly accepted nutritional markers, such as serum albumin (ALB) level, serum creatinine (Cr) level, hemoglobin (Hb) level, and body mass index (BMI), might be used to assess prognosis of patients with chronic kidney disease (CKD) [5,6]. However, other studies reported a poor predictive value of serum ALB, serum Cr, and other characteristics of PD patients for all-cause mortality or cardiovascular outcomes [7,8]. Furthermore, the prognostic values of various physiological ions have not been well determined [9][10][11][12]. This meta-analysis aimed to identify the risk factors for mortality in PD patients to improve prognosis.
'hemoglobin') AND Clinical Trial[ptyp]) as the search terms. Moreover, the references of all the relevant original articles were manually reviewed to identify additional eligible studies.

Selection criteria
Respective study was assessed by two independent reviewers, and any disagreements between the two reviewers were resolved by another independent reviewer. The inclusion criteria were as follows: (1) studies including patients undergoing PD; (2) studies mentioning at least one of the risk factors, namely, age, Hb level, serum ALB level, BMI, diabetes mellitus (DM), serum potassium level, serum magnesium level, peritonitis, peritoneal transport characteristics, alkaline phosphatase (ALP) level, high-sensitivity C-reactive protein (hs-CRP) level, and uric acid (UA) level; (3) studies evaluating all-cause mortality; (4) studies reporting statistical data including hazard ratio (HR) and 95% confidence interval (CI). Studies without adjustment for specific potential confounders and non-English studies were excluded. Finally, a total of 26 studies were included.

Statistical analysis
All statistical analyses were conducted in Review Manager 5.3 software. HR adjusted for confounding variables and 95% CI were extracted from included studies. Each HR was transformed into a log HR, and the standard error was calculated based on the corresponding 95% CI. Statistical heterogeneity among studies was evaluated using the I 2 index [14]. A random-effect model was adopted if the I 2 index was >50%, demonstrating substantial heterogeneity; otherwise, a fixedeffect model was employed. A p value <0.05 was considered statistically significant. Furthermore, Egger's tests were performed to assess potential publication bias, and a sensitivity analysis was conducted to determine the robustness of the conclusion by excluding each article from the meta-analysis.

Literature search
A total of 4421 potentially relevant articles were retrieved from PubMed and Embase. After screening titles and abstracts, 112 duplicate studies and 4139 non-relevant studies were excluded. The remaining 170 studies were subjected to full-text assessment, and 144 trials were further removed based on the following criteria: (i) unavailable full-text, (ii) non-inclusion of PD patients, or (iii) unavailable desired outcomes. Finally, 26 papers were included in our systematic review [9][10][11][12]. This meta-analysis had a good interreviewer agreement (j ¼ 0.851). A flowchart summarizing the selection process is presented in Figure 1.

Study characteristics
The baseline characteristics of included studies are shown in Table 1. Each study included 102-10,692 patients, and median follow-up duration ranged from 13.0 months to 52.8 months. Among these studies, 26 trials ascertained all-cause mortality, and 15 studies enrolled the outcomes of cardiovascular mortality. All  Furthermore, the pooled HR suggested a significant association between Hb level (HR: 0.87, 95% CI: 0.83-0.90, p < 0.00001) and a low risk of all-cause mortality in PD patients. Egger's test revealed no significant publication bias for Hb (p ¼ 0.876).
Meanwhile, this study identified no associations between serum ALB, low BMI, high UA level, high magnesium level, low potassium level, and the risk of allcause mortality in PD patients.

Risk factors for cardiovascular mortality in patients undergoing PD
As shown in Figure 3, the pooled HR indicated that age

Discussion
The present meta-analysis of 26 studies, including a total of 66,735 patients, was considered as the first meta-analysis exploring the risk factors for all-cause and cardiovascular mortality in patients undergoing PD. It covered five prospective studies. Our results indicated that age, primary CVD, DM, and ALP level negatively affected the risk of all-cause and cardiovascular mortality. Furthermore, early onset of peritonitis, obesity, high hs-CRP level, and membrane transport status might elevate the risk of all-cause mortality. Hb level was found to have a beneficial impact on the risk of all-cause mortality, while serum ALB level had a slight beneficial impact. In this meta-analysis, only articles with sufficient data to calculate HR and adjusted ones were included. In the existing study, functional status of patients undergoing PD might predict the risk of mortality, such as employment status and family education [37,38]. The use of medicine, such as angiotensin receptor blockers and oral active vitamin D, could also reduce the risk of major cardiovascular events and total mortality [39]. Notably, the associations between several clinical and laboratory characteristics of PD patients and all-cause mortality were still under debate.
In the present meta-analysis, age, primary CVD, DM, and high level of ALP were found to be the risk factors for both all-cause and cardiovascular mortality in patients undergoing PD. Additionally, patients with high BMI, high peritoneal transport status, high level of hs-CRP, and early onset of peritonitis also had an elevated risk of all-cause mortality. Primary DM and CVD might impair vascular endothelial cells and cause chronic inflammation, primarily leading to arterial stiffness; it might predict the risk of fatal cardiovascular events and all-cause mortality. Furthermore, poor  glycemic control was found to be an independent risk factor for mortality in PD patients [40,41]. A correlation between an increased BMI and improved outcomes in hemodialysis patients has been reported, although such a relationship is so far unknown in PD patients [42]. In this meta-analysis, we found that patients in the highest BMI group experienced poorer survival outcomes compared to those in the normal BMI group. Although a U-shaped relationship between underweight and mortality was observed previously [43], the association was not significant in our analysis. Obesity was shown to be related to a decline of residual renal function (RRF), adversely affecting survival [44]. However, the prognostic value of BMI might depend on race, total cholesterol level, inflammation status, and comorbidities. Mineral metabolism disorders are highly prevalence among patients with CKD, such as abnormal serum calcium, phosphorus, and parathyroid hormone concentrations. Hyperphosphatemia was shown to be correlated with elevated apoptosis and poor immune response, which might increase risk for mortality [45]. Serum ALP level is generally considered to indicate renal bone disease in patients with CKD. Additionally, high level of ALP might be associated with vascular calcification and osteomalacia. In this meta-analysis, high peritoneal membrane transport, assessed by the peritoneal equilibration test, was also found to be a risk factor for mortality. An increased rate of peritoneal membrane solute transport might enhance protein losses through peritoneal membrane leading to a malnutrition status. Guan et al. [35] reported that higher peritoneal transport status was not an independent predictor after adjusting for ALB level, Hb level, and RRF. Large-scale randomized clinical trials are required to verify this relationship. In addition, we showed that early onset of peritonitis and elevated hs-CRP level increased the risk of all-cause mortality significantly although there was significant heterogeneity among studies in terms of hs-CRP level. Two prospective and one retrospective study were included for hs-CRP as a continuous variable, with different sample sizes, country, and primary status of patients, which might account for the heterogeneous. Meanwhile, elevated Hb level was found to be a protective factor for all-cause mortality. Lower Hb level was commonly regarded as malnutrition, demonstrating the absence of intravenous iron or erythropoiesis-stimulating agent therapy. Hypokalemia is common in PD patients, primarily affecting the cardiovascular system. Furthermore, patients with hypokalemia may have more comorbidities. We included three studies exploring the relationship between serum potassium level and mortality, which was presented as a categorical variable. Xu et al. [12] and Lee et al. [25] reported a serum potassium level of <3 mEq/L or <4.5 mmol/L to be an independent risk factor for all-cause mortality in PD patients. However, the baseline values in another study did not show this relationship [11]. The change or fluctuation in serum potassium level during PD might be more reliable to predict death risk in PD patients and should be investigated further. Magnesium, the fourth most abundant cation in the body, plays a key role in various biological processes. Tubular injuries might cause renal magnesium wasting. Serum magnesium level of <1.8 mg/dL was reported to be a risk factor after adjusting for baseline demographic characteristics and comorbidities, but the risk was attenuated after further adjustment for laboratory indices [9]. Furthermore, the beneficial effect of a serum magnesium level of >0.7 mmol/L might be different between male and female individuals [10]. Considering that lower serum magnesium is associated with a poor nutrition status and increased inflammation, the independent relationship between serum magnesium and mortality in PD patients should be evaluated,and an appropriate treatment to maintain the right serum magnesium level needs to be determined. UA is the final product of nucleotide metabolism, and it is primarily excreted from the kidney by glomerular filtration. High level of serum UA could be an endothelial toxin and aggravated endothelial function by activating the inflammatory pathway [46]; it is also associated with RRF loss [47]. However, we did not observe any significant association between hyperuricemia and mortality. Xiang et al. [16] studied the impact of high serum UA level on mortality in PD patients by divided them into five groups according to their serum UA level. Patients with UA > 7.28 mg/dL had a higher all-cause mortality compared to those in the middle group. Furthermore, UA < 6.06 mg/dL was found to be a risk factor only in an unadjusted model. The other two studies divided patients into three groups according to their UA level. However, Lai et al. [19] reported high serum UA level to be a protective factor for mortality. Serum UA level reflects patients' nutrition condition, and a low serum UA level might lead to inflammation. Considering a potential U-shaped association between UA and mortality, a proper range of serum UA and treatments to lower serum UA level should be determined to improve survival. However, these outcomes might not be feasible because there are only few studies reporting such indices. To confirm this association, more studies were required. Importantly, the present meta-analysis is the first one to explore the risk factors for all-cause mortality in PD patients. This study had a large enough sample size and HR adjusted for possible confounders. There was a debate about different risk factors in previous studies, and this meta-analysis might be more reliable to predict all-cause and cardiovascular mortality in PD patients.
This study has several limitations. First, individual studies adjusted for the different potential confounders, which might result in a high heterogeneity. Second, the present meta-analysis might have missed some unpublished articles without conference abstracts in line with the selection criteria. Third, although we observed a significant heterogeneity in the impact of CVD on mortality across studies, we did not perform a subgroup analysis according to race. Moreover, we applied a random-effect model in this meta-analysis. Fourth, this meta-analysis was not registered in PROSPERO, which might lead to a bias. However, importantly, this metaanalysis was conducted in accordance with the standards of systematic review. Furthermore, more data regarding the respective risk factors are recommended.
In conclusion, the present meta-analysis revealed that a considerable number of risk factors displayed significant associations with an elevated risk of all-cause and cardiovascular mortality in PD patients. A proper threshold for serum magnesium, potassium, and UA should be determined to improve the survival in PD patients. Since data on several indices were limited, more studies are required to confirm the findings of this meta-analysis.