Effect of Nocturnal Hemodialysis versus Conventional Hemodialysis on End-Stage Renal Disease: A Meta-Analysis and Systematic Review

Objectives The purpose of this study is to assess the efficacy and safety of nocturnal hemodialysis on end-stage renal disease (ESRD) patients. Methods We searched Medline, EmBase, and the Cochrance Central Register of Controlled Trials for studies up to January 2016. Analysis was done to compare variant outcomes of different hemodialysis schedules, including mortality, cardiovascular-associated variables, uremia-associated variables, quality of life (QOL), side-effects, and drug usage. Results We collected and analyzed the results of 28 studies involving 22,508 patients in our meta-analysis. The mortality results in this meta-analysis indicated that the nocturnal hemodialysis (NHD) group was not significantly different from conventional hemodialysis (CHD) group (Mortality: OR: 0.75; 95% confidence intervals (CIs): 0.52 to 1.10; p = 0.145), but the CHD group had significantly fewer number of hospitalizations than the NHD group (OR: 1.54; 95%CI: 1.32 to 1.79; p<0.001). NHD was superior to CHD for cardiovascular-associated (left ventricular hypertrophy [LVH]: SMD: -0.39; 95%CI: -0.68 to -0.10; p = 0.009, left ventricular hypertrophy index [LVHI]: SMD: -0.64; 95%CI: -0.83 to -0.46; p<0.001) and uremia-associated intervention results (Serum albumin: SMD: 0.89; 95%CI: 0.41 to 1.36; p<0.001). For the assessment of quality of life, NHD treatment significantly improved the patients’ QOL only for SF36-Physical Components Summary (SMD: 0.43; 95%CI: 0.26 to 0.60; p<0.001). NHD intervention was relatively better than CHD for anti-hypertensive drug usage (SMD: -0.48; 95%CI: -0.91 to -0.05; p = 0.005), and there was no difference between groups in our side-effects assessment. Conclusion NHD and CHD performed similarly in terms of ESRD patients’ mortality and side-effects. NHD was superior to CHD for cardiovascular-associated and uremia-associated results, QOL, and drug usage; for number of hospitalizations, CHD was relatively better than NHD.


Results
We collected and analyzed the results of 28 studies involving 22,508 patients in our metaanalysis. The mortality results in this meta-analysis indicated that the nocturnal hemodialysis (NHD) group was not significantly different from conventional hemodialysis (CHD) group (Mortality: OR: 0.75; 95% confidence intervals (CIs): 0.52 to 1.10; p = 0.145), but the CHD group had significantly fewer number of hospitalizations than the NHD group (OR: 1.54; 95%CI: 1.32 to 1.79; p<0.001). NHD was superior to CHD for cardiovascular-associated

Introduction
End-stage renal disease (ESRD) is a chronic and progressive decline in kidney function, which will eventually lead to uremia and death if it is not treated properly [1]. However, with a progress of technology in past decades, the mortality have not improved significantly and exceeding 20% in chronic hemodialysis patients [2,3]. Cardiovascular events are the main driving force for this high mortality. Therefore, there is a need for new methods to improve ESRD patients' cardiovascular and mortality risk.
There are currently two main methods for treatment of ESRD patients. The first, renal transplantation, is a permanent method to cure ESRD patients, however, that means ESRD patients have an issue of having a proper kidney source, thus it has limited application [4,5]. The second, hemodialysis, is applied worldwide but has a high risk of cardiovascular complications and significantly reduces the quality of life of patients [6,7]. Nocturnal hemodialysis (NHD) is an important branch of hemodialysis [8,9]. The schedule for nocturnal dialysis is 3-7 times per week, 7-8 hours every time. This approach extends the effective duration of dialysis without affecting the patient's daytime activities making it more convenient as a method of treatment. This approach has been widely used in Canada; however, the clinical results still require further examination. Dialysis-related disease is defined as the complications caused by long-term dialysis on ESRD patients; cardiovascular disease is the leading cause of death for ESRD patients [10][11][12][13].
Previously, several systemic reviews analyzed the mortality, blood pressure, and urinaryrelated indexes of NHD for ESRD patients [14][15][16]. However, the qualities of included studies were relatively low and not comprehensive evaluated all relevant clinical outcomes. Our research is up to date with recently published research and analyzes the effects of NHD by mortality, cardiovascular-related variables, uremia-related variables, quality of life, side-effects, and drug usage to provide better insight in clinical choices for dialysis methods.

Search strategy and selection criteria
This review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement [17] issued in 2009. Any studies that examined NHD versus conventional hemodialysis (CHD) on ESRD patients were eligible for inclusion in our study with no restrictions placed on language or publication status (published, or in press). We searched the Medline, EmBase, and Cochrane Library electronic databases for articles published through January 2016 and used "nocturnal", "dialysis", "hemodialysis", and "controlled trials" as the search keywords. We also conducted manual searches of reference lists from all relevant original articles and reviews to identify additional eligible studies.
A literature search was undertaken independently by 2 authors and any inconsistencies were settled via group discussion. A study was eligible for inclusion if the following criteria were met: (1) the trial investigated nocturnal hemodialysis NHD versus conventional hemodialysis CHD; (2) all of patients included with ESRD; and (3) the outcomes variable included one of the following: mortality, cardiovascular-associated variables, uremia-associated variables, quality of life, side-effect, and drug usage. Case series, reviews, and editorials were excluded.

Data collection and quality assessment
Two reviewers independently extracted all data with disagreements resolved in consultation with third-party investigators. The following items were extracted from the included articles: first author, publication year, country, location or data source, study design, sample size, disease status, mean age, gender proportion, mean duration of dialysis, Dialysis session, and reported outcomes. The outcome assessments included: mortality, cardiovascular-associated variables, uremia-associated variables, quality of life, side-effects, and drug usage. In analysis, the numerical changes between, before, and after dialysis of statistical indicators had priority to be adopted, if not, the dialysis numerical indicators after dialysis was adopted. In addition, the numerical units were adjusted for consistency, such as g/L and g/dL. Two reviewers independently assessed the quality of included studies according to the Cochrane risk of bias tool in the following six domains: selection, performance, detection, attrition, reporting and other bias [18].

Statistical analysis
For our meta-analysis, we used the inverse variance method to pool continuous data and the Mantel-Haenszel method for dichotomous data; the results are presented as standardized mean difference (SMD) with 95% confidence intervals (CIs) and odds ratio (OR) with 95% CIs. The I 2 statistic was calculated to evaluate the extent of variability attributable to statistical heterogeneity between trials. In the absence of statistical heterogeneity (I 2 50%), we used a fixed-effect model, otherwise we used a random-effect model for traditional meta-analysis [19]. To investigate the sources of heterogeneity, predefined subgroup analysis were performed: dialysis schedule and design bias. We assessed for publication bias using the Begg-Mazumdar [20] and Egger's test [21]. A non-parametric "Trim and Fill" method of assessing publication bias was applied if needed [22]. All tests were two tailed, and a p value of less than 0.05 was deemed statistically significant. We analyzed the data using Review Manager (Version 5.3) and STATA (Version 12.0).
A total number of 22,508 ESRD patients were examined. The average reported age of patients was between 40-60 years while two studies did not mention the patients' ages [31,32]. The number of men was slightly greater than the number of women. The follow-up time duration was 6 months to 36 months. The schedule for NHD was 3 nights/week or 6-7 nights/ week, and 3 times/week for CHD. The summary graph of risk of bias for each study is shown in Fig 2. In our meta-analysis, mortality results were not significantly different between the NHD group and the CHD group (OR: 0.75; 95%CI: 0.52 to 1.10; p = 0.145). For number of hospitalizations, the CHD group had significantly fewer than NHD group (OR: 1.54; 95%CI: 1.32 to 1.79; p<0.001); in addition, there was no significant difference between the two groups in the number of infection hospitalizations (OR: 1.60; 95%CI: 0.48 to 5.35; p = 0.445).
There was publication bias was found in systolic blood pressure results (Table 3, Begg'test, p = 0.592; Egger's test, p = 0.001). However, no other publication bias was found. After correction of the results with "Trim and Fill" method the conclusion was not changed.

Discussions
In this review, we analyzed the effects of NHD versus CHD in the treatment of ESRD. Our analysis included 28 trials with 22,508 patients. Our results demonstrate that NHD and CHD are similar in mortality and side-effects, and that NHD is superior to CHD in cardiovascularassociated and uremia-associated markers and in QOL and drug usage. CHD is relatively better than NHD for number of hospitalizations. In general, NHD has more advantages in clinical applications for ESRD patients.
In previously published meta-analyses, the results assessment was not comprehensive. Hui MJ et al. studied the effects of long-time dialysis in daytime or nighttime on survival rate compared to that of conventional hemodialysis [16]. Results showed that the survival rate of patients using prolonged hemodialysis was significant higher than those using conventional hemodialysis; however, residual confounders, which include the patients' age, sex, presence of diabetes, and catheter use, interferes with the results in observational studies. This study included literatures with lower design quality while not having a comprehensive assessment index. Our research included more high quality design articles to find that nocturnal dialysis does not significant improve the mortality of patients; however, subgroup analysis of treatment 3times/ week showed reduced mortality rates. This may be due to the fact that the study used patients with relatively mild uremic symptoms while further study is needed to draw conclusions for the  [15]. That study found that intensified hemodialysis could significantly improve the patients' blood pressure, uremia-associated variables, and psychosocial variables, and could reduce the usage of antihypertensive and phosphate binders. However, there was no assessment of patients' mortality and QOL. Our research supports the evidence that intensified hemodialysis could improve cardiovascularrelated and uremia-related indicators; we also defined that nocturnal dialysis could improve the patients' QOL. Paweena Susantitaphong et al. assessed the effects of frequent nocturnal hemodialysis on ESRD patients using the indicators of left ventricular mass and cardiovascular mortality in 2012 [14]. Unfortunately, this research had a paucity of randomized controlled trials. The results supported that frequent or extend hemodialysis could improve cardiac morphology and function; however the outcome of long-term clinical application was limited. Our study includes a longer follow-up period of up to 36 months and RCTs. Our results support the above conclusion and consider long-time nocturnal hemodialysis as beneficial for cardiovascular and uremia-related indicators. It is very common for cardiovascular complications to occur in long-term hemodialysis patients, including hypertension, coronary heart disease, arrhythmia, and heart failure. Cardiac vascular disease events like cerebrovascular accident, ischemic heart disease, congestive cardiac failure, peripheral vascular disease are also much more prevalent in the chronic kidney disease population. Furthermore, cardiovascular complications are the most common causes of death in ESRD patients and the mortality rate for dialysis patients is up to 10-30 times higher than the matched population [51]. The high mortality indicates the effect of drugs to reduce the incident of cardiovascular disease is not ideal. Therefore, researchers presume the incidence of cardiovascular disease in dialysis patients may have a special pathophysiological process.
There are two parallel factors which may contribute to cardiovascular disease in ESRD patients. The first is a change of cardiac morphological including LVH and left ventricular (LV) dysfunction caused by mechanical or hemodynamic overload and the second being the change of vasculature including atherosclerosis and vascular calcification. These two factors can eventually result in cardiomyopathy and arterial thrombosis [52]. Uremia-related hyperphosphatemia, high calcium and phosphorus deposition, and hyperparathyroidism may be the direct reason for vascular calcification in ESRD patients. Currently it is popular to assess the patient's dialysis schedule with cardiovascular-related symptoms, in which left ventricular hypertrophy is an important predictor of cardiovascular side effects. Thus, many RCTs use left ventricular mass (LVM) as the primary outcome [23,28]. Our results show nocturnal dialysis have positive effects on the prevention of cardiovascular disease, which can enhance blood pressure control and reduce serum phosphate, hence reducing the risk of cardiovascular disease.
Although our study shows nocturnal dialysis has a great positive effect on ESRD patients, this approach also has a higher failure rate. For example, a 12 month follow-up period study pointed out that the technique's survival rate is 79.2% [45]; a 24 months follow-up period study showed the technique's survival rate by then was only 24.93% [47], meaning about 3/4 of ESRD patients were unable to continue nocturnal hemodialysis treatment. These studies found that the reasons of technique failure included infection, catheter dysfunction, and psychosocial problems in the early stage and ultrafiltration -failure and catheter-related infection in later stages. Therefore further research is needed to look into ways of increasing the technique's survival rate on patients with high frequency nocturnal dialysis by improving technology and reducing complications.
We comprehensively evaluated the outcome measurements of nocturnal dialysis for ESRD, but still our study had several limitations. First, we did not have specific individual data for all the trials and thus our statistical approach was done at a study level. Second, the quality of included trials was relatively low, although this review included many outcome measures, single measure conclusions were considered from small sample studies of low quality. Third, there was heterogeneity in several outcomes among included trials. Finally, we were not able to use subgroup analysis or meta-regression to reduce the heterogeneity because there was a lack of trials using a single medicine.
Nocturnal hemodialysis and conventional hemodialysis perform similarly in ESRD patients' mortality and side-effects. In cardiovascular-associated and uremia-associated results NHD is superior to CHD; and in QOL and drug usage NHD intervention is relatively better than CHD. For number of hospitalizations, CHD was relatively better than NHD. In general, NHD has more advantages in clinical application for ESRD patients.