The association of peritoneal dialysis and hemodialysis on mitral and aortic valve calcification associated mortality: a meta-analysis

Cardiac valve calcification (CVC), characterized by the accumulation of calcium in the heart valves, is highly prevalent among patients undergoing dialysis. This meta-analysis aimed to provide an updated summary of recent studies on the prognostic value of CVC in patients undergoing dialysis. We conducted a search of PubMed, Embase, and Web of Science to identify observational studies investigating cardiovascular or all-cause mortality associated with CVC in dialysis patients until March 2023. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated for the meta-analysis, and the strength and significance of the associations between CVC and mortality outcomes in dialysis patients were assessed. From 6218 initially identified studies, we included 10 critical studies with a total of 3376 dialysis patients in a further meta-analysis. Pooled analyses demonstrated a significant association between CVC and an elevated risk of all-cause and cardiovascular mortality in dialysis patients. In our study, we discovered HRs of 1.592 (95% CI 1.410–1.797) for all-cause mortality and 2.444 (95% CI 1.632–3.659) for cardiovascular mortality. Furthermore, subgroup analysis revealed elevated all-cause mortality among patients with mitral valve calcification (HR 1.572; 95% CI 1.200–2.060) compared to those with aortic valve calcification (HR 1.456; 95% CI 1.105–1.917). Similarly, patients undergoing peritoneal dialysis faced a greater risk for all-cause mortality (HR 2.094; 95% CI 1.374–3.191) than those on hemodialysis (HR 1.553; 95% CI 1.369–1.763). This highlights the possibility of CVC being an independent risk factor for dialysis patients, particularly in relation to mitral valve calcification or peritoneal dialysis.


Search strategy
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.A systematic search of PubMed, EMBASE, and Web of Science was performed using the following keywords and synonyms: renal dialysis, kidney failure, renal replacement therapy, heart OR cardiac OR valve OR valvular, and calcification OR calcified.The search strategy included Boolean searches and medical subject heading (MeSH) terms.Details of the electronic search strategy are provided in Supplementary Table 1.The last search was performed in March 2023.

Study selection
Studies that met the following criteria were included: (1) observational cohort studies, including prospective, retrospective, and bidimensional studies; (2) studies limited to human subjects; and (3) those reporting adjusted hazard ratios and corresponding 95% confidence intervals (CIs) of CV or all-cause mortality due to CVC in dialysis patients.Letters, comments, protocols, case reports, case series, reviews, and animal studies were excluded from analysis.Studies with insufficient data were excluded from analysis.

Data extraction
Two authors independently analyzed each article and performed data extraction.In cases of disagreement, a third investigator was consulted to reach consensus.The following data were extracted from each study: article name, first author, publication year, study design, country of origin, sample size, dialysis vintage and type, sex, age, detection methods and prevalence of CVC, follow-up time endpoint, and covariate adjustments.

Quality assessment
Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) for observational studies, which comprises three domains (selection, comparability, and outcome) with a maximum score of 9 points.Risk of bias was categorized into three groups: good, fair, and poor.The results were described in Table 1.Two reviewers independently assessed the quality of each study.

Statistical analysis
Comprehensive meta-analysis software (version 3.0) was used for statistical analysis.Risk estimates were calculated using adjusted hazard ratios (HRs) and 95% CI.Cochran's Q test was performed, and Q and p values were used to evaluate the heterogeneity among the studies.Statistical significance was set at p value < 0.05.Pooled effects were calculated, and a two-sided p value < 0.05 was considered significant.Subgroup analysis was also performed to further assess the association between CVC and the risk of mortality according to clinical characteristics.Sensitivity analysis was performed by excluding one study at a time to test the robustness of the pooled results.Publication bias was assessed using the Egger's test.Statistical significance was set at p value < 0.05.In addition, we used a funnel plot test to assess publication bias.

Search results
In total, 6218 studies were identified in the database search.After the initial screening of titles and abstracts, 23 full-text reports were included and assessed for eligibility.Of these, 10 (3376 patients) were included in the quantitative analysis.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the study selection process is shown in Fig. 1.Quality assessment using the NOS for observational studies is described in Table 1.Four studies were classified as good quality, six as fair quality, and none as poor quality.

Baseline characteristics
Baseline patient characteristics are shown in Table 2 Six studies were prospective cohort studies and four were retrospective cohort studies.Two studies focused on peritoneal dialysis (PD), while others investigated patients undergoing hemodialysis (HD).The percentage of males ranged from 49.3 to 69.9%.Eight studies have investigated Asian patients.The average age of the patients ranged from 55.4 to 68.6 ± 12.6 years.Three studies focused on incident dialysis patients, and the dialysis duration of the other ranged from 2.5 to 8.12 ± 7.62 years.Most studies have defined cardiac calcification as bright echoes of > 1 mm on one or more cusps of the aortic valve, mitral valve, or mitral annulus.The prevalence of CVC ranged from 23.3 to 80.3%, with a mean prevalence of 47.87%.The median follow-up duration ranged from 1.5 to 6.3 years.Three studies only mentioned all-cause mortality as the primary outcome, whereas the other studies reported both all-cause and CV mortalities.Potential confounding factors influencing mortality were adjusted in each study.

Association between cardiac valve calcification and all-cause mortality
Ten studies reported the all-cause mortality rates of MVC or AVC without significant heterogeneity (p = 0.478, I-square = 0%).Pooled results in a fixed-effects model showed an association between CVC and mortality (Fig. 2, HR 1.592; 95% CI 1.410-1.797;p < 0.001).

Association between cardiac valve calcification and cardiovascular mortality
Seven studies reported CV mortality rates of MVC or AVC with heterogeneity (p ≤ 0.001, I-square = 75.68%).Pooled results in a random-effects model showed an association between CVC and CV mortality (Fig. 3, HR 2.444; 95% CI 1.632-3.659;p < 0.001).

Publication bias
Funnel plots and Egger's test showed no publication bias in the meta-analysis of all-cause mortality (Fig. 4; Egger's test, p = 0.527).In addition, Egger's test showed no publication bias in the meta-analysis of CV mortality (p = 0.897) or subgroup analysis of CVC and MVC (p = 0.315).More information was described in Supplementary Table 2.

Sensitivity analysis
We performed sensitivity analyses by excluding the articles with the largest weights and repeating the primary analyses.The results were consistent across different analyses, indicating the robustness of the observed outcomes.

Discussion
This meta-analysis demonstrated the prognostic value of CVC in all-cause mortality and CV mortality in patients undergoing dialysis, particularly in those with MVC or those undergoing PD.Moreover, and increased number of calcified valves is associated with a higher mortality risk.CVC is highly prevalent owing to the dysregulation of bone mineral metabolism in dialysis patients.The clinical presentation of CVC encompasses a wide range of manifestations and often overlaps with symptoms of heart failure and anemia, which are also common in dialysis patients 4,9,26 .Therefore, it is challenging to precisely calculate the prevalence of CVC.The current diagnostic gold standard for CVC is transthoracic echocardiography, which is consistent with the findings of most studies included in the analysis.The reported prevalence of valvular calcification ranges from 23 to 59%, with an increasing prevalence as renal function declines 7,14 .The prevalence in the included studies ranged from 23.5 to 80.3%.Although the upper limit is higher than that reported in previous studies, if we exclude this outlier, the prevalence ranges from 23.5 to 57.6%, which is consistent with the results of previous studies.Severe CVC often progresses to valvular heart disease and worsens hemodynamic profile.However, the prognostic value of CVC  www.nature.com/scientificreports/remains controversial.Our primary outcomes showed that CVC was associated with higher rates of all-cause mortality and CV mortality among patients undergoing dialysis, with HRs of 1.592 (95% CI 1.410-1.797)and 2.444 (95% CI 1.632-3.659),respectively.Besides, dual CVC presents a higher risk compared to single CVC.These findings are consistent with those of a previous study by Wang et al. 14 , which included relatively recently published retrospective and prospective studies.The HRs for all-cause and CV mortality were slightly lower than those reported in previous studies (1.592 and 1.73, respectively, and 2.444 and 2.81, respectively).Cochrane's Q test showed higher heterogeneity in the results of CV mortality, which may be due to the limited number of studies included in this analysis.Subgroup analyses revealed that patients with MVC had a higher risk than those with AVC did.This finding was not reported in a previous meta-analysis of dialysis patients 14 .Renal failure is associated with left-sided valvular disease, especially aortic stenosis and mitral regurgitation, resulting in a poor prognosis.Therefore, we focused on the association between progressive calcification and left valvular disease.Several meta-analyses have indicated an association between AVC and MVC and worse outcomes in the general population with or without CVD [27][28][29][30] .While AVC and MVC share similar contributing factors, such as aging, abnormal calcium and phosphate metabolism, and systemic atherosclerosis 31 , previous studies have reported differences in the underlying mechanisms.Hensen et al. reported that although AVC was more prevalent than MVC in both dialysis patients and the general population, MVC was independently associated with more advanced CKD stages and higher allcause mortality, whereas AVC did not show such associations.The authors suggested that this difference may be due to delayed diagnosis and lower rates of valve intervention therapy owing to the subtle symptoms of MVC 32 .Furthermore, an association has been observed between MVC and elevated levels of serum β2-microglobulin (β2M) 33 , a substance mainly eliminated by the kidneys that tends to accumulate in the myocardium, aortic and mitral valves, and other cardiac tissues in patients undergoing HD 34 .In addition to being an indicator of the clearance of middle molecules by HD, serum β2M is considered a marker of inflammation and is related to an increased risk of all-cause mortality, long-term HD, dyslipidemia, and malnutrition, all of which have unfavorable effects on CV outcomes 33 .In addition, studies of patients undergoing PD have implied a similar result of higher C-reactive protein levels in MVC-positive patients 35 , and that diabetes mellitus can serve as a risk factor for MVC 36 .Another risk factor for MVC is increased mitral stress, which accelerates the calcification process and is associated with hypertension, aortic stenosis, hypertrophic cardiomyopathy, and other diseases that increase the left ventricular systolic pressure.Finally, MVC is associated with valvular diseases and other CV complications including atrial fibrillation 37,38 , arrhythmia due to mitral annulus conduction abnormalities 39 , and endocarditis 40 .
In summary, aspects related to the diagnosis, pathophysiology, and occurrence of CV complications may contribute to the association between AVC and MVC incidence and mortality.A recent meta-analysis evaluated the correlation between CVC and prognosis of patients with CKD.The results showed that both MVC and AVC had  Table 3. Subgroup analyses of all-cause mortality.AVC aortic valve calcification, MVC mitral valve calcification.

Subgroup Studies HR (95% CI) p value Heterogenicity (p value)
Total 10 Patients HD 8 Cheng et al. 16 , Bai et al. 17 , Liao et al. 23 , Zhu (2020), Chen et al. 24 , Takahashi et al. 20 , Raggi et al. 25  www.nature.com/scientificreports/predictive value and that MVC had a higher risk, which is also consistent with our findings 41 .Further evaluation is necessary to determine the underlying mechanisms.
The prevalence of CVC varies among patients undergoing different dialysis modalities, ranging from 19 to 84% in those undergoing HD patients to 32-47% in those undergoing PD 42 .Our results showed that the average prevalence of CVC was lower in PD patients than in HD patients (26.9% and 51.5%, respectively), this finding corresponds with another study 43 .However, in the subgroup analysis, the HR is higher in PD patients than in HD patients.A previous meta-analysis showed the same trend 14 , and a cohort study reported that PD was associated with a higher risk of myocardial infarction and CV mortality than HD 44 and that this effect persisted beyond the first year of treatment 45 .However, another study found no significant differences in the risk of mortality, de novo CV disease, or ischemic heart disease between patients undergoing HD and PD.Nevertheless, HD is associated with a high risk of congestive heart failure 46,47 .Recently, a meta-analysis demonstrated comparable mortality rates and adverse CV events between PD and HD 48 .Conversely, another recent meta-analysis found that PD patients had lower rates of CV events, such as congestive heart failure, atrial fibrillation, and peripheral arterial disease, but higher mortality rates than HD patients 49 .Several hypotheses have been proposed to explain the conflicting results.Infusion of dialysis solution into the peritoneal cavity increases intraperitoneal pressure and systolic blood pressure, which may be associated with fluid overload and hemodynamic changes that increase CV risk 50 .On the other hand, the rapid removal and exchange of body fluid during HD contribute to hemodynamic instability 51 , and the arteriovenous fistula used in HD patients increases cardiac preload and leads to congestive heart failure 49 .Therefore, the variable mortality between HD and PD may related to patient-specific factors and selection bias.Although CVC is a marker of higher mortality and cardiovascular mortality in this population, the effect is not independent of other traditional CV risk factors 21 , such as age, diabetes, hypercalcemia and hyperphosphatemia 52,53 .Previous study also suggest higher glucose levels in PD patients can lead to insulin resistance, and also alterations in glycation products may increase CV damage 54 .Inconsistent definitions of cardiac mortality may also have influenced the statistical results of different studies 55 .In addition, the small number of patients from only two studies included in our analysis is a limitation.In summary, the association between dialysis modality and CV mortality remains controversial and is affected by CVC and other factors 56 .Our results showed CVC is less frequent in peritoneal dialysis than in HD, but its presence still indicates a greater prognostic value.Additional studies are required to confirm the association between CVC and dialysis modality.
Owing to the potential risks to the CV system, the CVC should be appropriately controlled in dialysis patients.However, methods for reversing the impact of calcified valves are limited.The aim of the current medical treatment of CVC emphasizes the control and prevention of CKD-MBD, namely, the stabilization of the serum levels of calcium, phosphate, and PTH 42,57 .Calcimimetics, calcitriol, and vitamin D analogs are used to treat secondary hyperparathyroidism in dialysis patients 58 .Although vitamin D analogs decrease serum PTH levels, they also induce calcification by elevating serum calcium and phosphate levels 59 .Therefore, calcimimetics such as cinacalcet activate receptors on the parathyroid gland and thus lower the levels of PTH, serum calcium, and phosphate have been introduced.However, a randomized controlled trial and meta-analysis did not find significant reductions in all-cause mortality, CV mortality, or major adverse CV events in dialysis patients receiving cinacalcet therapy 60,61 .Calcium-based and non-calcium-based phosphate binders are widely used 62 .Non-calcium-based phosphate binders, such as sevelamer, were found to be associated with lower all-cause mortality than calciumbased phosphate binders in one study 63 , whereas another study found no significant benefit on CV mortality 64 .Owing to the failure of traditional therapies, novel treatments have emerged to control CVC in patients with CKD or on dialysis.For example, serum alkaline phosphate levels have been correlated with CVC in HD patients 65 , and serum albumin levels have been shown to be predictors of CVC severity in dialysis patients 66 .In addition, a novel calcification inhibitor, SNF472, has entered clinical trials 67 .www.nature.com/scientificreports/This study had several limitations.First, because of the relatively strict inclusion criteria and the limited number of previous studies, the analysis included only 10 studies, and the majority of patients included in the studies were from Asia, which may have led to publication bias and restricted the applicability of this metaanalysis to different populations.Second, the adjustments for covariates between the studies were different, and the heterogeneity in the comparisons of CV mortality may have influenced the robustness of the results.Third, the relatively short median dialysis time may have prevented the detection of certain CV diseases, which typically require a long period of development.

Conclusion
This article summarizes recent findings regarding the association between CVC and prognosis in dialysis patients and reviews the factors and mechanisms involved in the development of CVC.These results indicate that CVC is associated with higher all-cause and CV mortality in patients undergoing dialysis, whether HD or PD patients.Patients with MVC had a higher all-cause mortality than those with AVC.Further research is required to develop new treatments and to elucidate the mechanisms involved in the development of CVC.
26) Reports not retrieved (n = 3) Identification of studies via databases and registers Identification Screening Reports assessed for eligibility (n = 23) Reports excluded: Irrelevant (n = 10) Non-cohort studies (n = 1) Insufficient data (n = 2) Total studies included in review (n = 10) Included

Figure 1 .
Figure 1.PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 flow diagram of study selection.

Figure 2 .
Figure 2. Forest plot of hazard ratios for the association between cardiac valve calcification and all-cause mortality.

Figure 3 .
Figure 3. Forest plot of hazard ratios for the association between cardiac valve calcification and cardiovascular mortality.

Figure 4 .
Figure 4. Funnel plot by log hazard ratio for all-cause mortality.

Table 1 .
Quality assessment using Newcastle-Ottawa Scale (NOS).(a) The study controls for age (one star).(b) Study controls for other factors (one star).

, years Selection Comparability Outcome Total score Quality Representativeness of Exposed cohort Selection of Non-exposed cohort Ascertainment of exposure Outcome not present at start of study a b Assessment of outcome Follow-up long enough Adequacy of follow-up
Vol:.(1234567890) Scientific Reports | (2024) 14:4748 | https://doi.org/10.1038/s41598-024-55326-9

Table 2 .
Baseline characteristics of the 10 studies included in the final analysis.BMI body mass index, DM diabetes mellitus, CAD coronary artery disease, CVD cardiovascular disease, HTN hypertension, HD hemodialysis, Hb hemoglobin, LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, hsCRP high sensitivity C-reactive protein, iPTH intact parathyroid hormone, eGFR estimated glomerular filtration rate, AKP alkaline phosphatase, 25(OH)D 25-hydroxy Vitamin D, AAC Aortic artery calcification, ALB albumin, Ca calcium, P phosphorus, ADMA plasma asymmetric dimethyl arginine, CVR cardiac valve regurgitation, MS mitral valve stenosis, MR mitral valve regurgitation, AR aortic valve regurgitation, AS aortic valve stenosis, TR tricuspid valve regurgitation, LVEF left ventricular ejection fraction, LVMI left ventricular mass index, LADI left atrial diameter index.