Abstract
Introduction
Cardiovascular disease remains the leading cause of mortality in maintenance hemodialysis (MHD) patients. While both pulmonary hypertension (PH) and heart valve calcification (HVC) are established independent risk factors for adverse outcomes in this population, the synergistic effect of these two echocardiographic parameters on cardiovascular prognosis has not been well investigated.
Methods
In this prospective study, we analyzed clinical and echocardiographic data from 302 MHD patients over a two-year follow-up period. Patients were stratified into three groups based on the presence of risk factors: group 1 (no risk factors), group 2 (either PH or HVC), and group 3 (both PH and HVC). Survival analysis was performed using Kaplan-Meier curves, and Cox regression models were employed to evaluate the impact on all-cause mortality, cardiovascular mortality, and new-onset cardiovascular events (CV events).
Results
During follow-up, 63 patients (20.9%) died from all causes, with 36 deaths (57.1%) attributed to CV events. Cardiovascular mortality was significantly higher in groups 2 (13.2%) and 3 (30.2%) compared to group 1 (5.1%; p < 0.001). New-onset CV events occurred in 33.1% of patients, with rates of 20.3%, 35.5%, and 67.4% in groups 1, 2 and 3, respectively (p < 0.001). The presence of both PH and HVC was associated with a higher risk of all-cause mortality, cardiovascular mortality, and new-onset CV events compared to either PH or HVC alone. After adjusting for confounders, the combination of PH and HVC remained a significant predictor, demonstrating a higher risk than having a single risk factor (hazard ratio [HR] for all-cause mortality: 3.76 [95% CI: 1.83–7.73] vs. 1.90 [95% CI: 1.03–3.52]; HR for cardiovascular mortality: 9.23 [95% CI: 3.42–24.95] vs. 3.11 [95% CI: 1.23–7.84]; HR for new-onset CV events: 4.21 [95% CI: 2.39–7.21] vs. 1.68 [95% CI: 1.01–2.76]).
Conclusion
The coexistence of PH and HVC significantly increases cardiovascular risk compared to either condition alone in MHD patients. Echocardiography is a valuable tool for screening and risk stratification in this high-risk population by identifying both PH and HVC.
Keywords: Echocardiography, Pulmonary hypertension, Heart valve calcification, Hemodialysis, Cardiovascular outcomes
Plain Language Summary
Cardiovascular disease is the leading cause of death for patients undergoing maintenance hemodialysis (MHD), a treatment for kidney failure. Two conditions, pulmonary hypertension (PH) and heart valve calcification (HVC), have been linked to higher risks of heart problems and death in these patients. However, the combined impact of both conditions on health outcomes in MHD patients has not been well studied. In this study, we followed 302 MHD patients for two years to understand how having PH and/or HVC affects their health. We divided the patients into three groups: those with neither condition, those with one condition, and those with both PH and HVC. We found that patients with both PH and HVC had a much higher risk of dying from heart-related causes and experiencing new heart problems compared to those with just one condition or neither condition. This study shows that PH and HVC together are strong indicators of poor health outcomes in MHD patients. By using cardiac ultrasound to check for these conditions, doctors can better predict which patients are at higher risk and provide more effective care.
Introduction
Maintenance hemodialysis (MHD) patients face a significantly high risk of mortality, primarily driven by cardiovascular disease, with cardiovascular mortality (CV mortality) rates 10–30 times higher than in the general population [1–3]. These patients often present with multiple cardiovascular comorbidities, contributing to their elevated risk of adverse outcomes. The complex interplay of cardiovascular comorbidities including anemia, hyperphosphatemia, and secondary hyperparathyroidism further exacerbates this risk [3], creating an urgent need for effective risk stratification tools to guide personalized treatment strategies.
Heart valve calcification (HVC) and pulmonary hypertension (PH) are highly prevalent in end-stage renal disease (ESRD). HVC affects over 50% of incident dialysis patients and becomes nearly universal with advancing age and prolonged dialysis [3–5]. As a robust independent predictor of mortality, HVC severity correlates with accelerated atherosclerosis, left ventricular dysfunction, and sudden cardiac death risk. PH is increasingly recognized in MHD populations, classified as WHO group V reflecting its multifactorial etiology [6, 7]. A meta-analysis estimated 33% PH prevalence among ESRD patients receiving dialysis [8], with both our previous work and other studies demonstrating PH’s association with elevated cardiovascular mortality and new-onset cardiovascular events in MHD patients [8–10].
Emerging evidence reveals pathophysiological connections between PH and vascular calcification, though mechanistic understanding remains incomplete in chronic kidney disease (CKD) populations. While RUNX2-mediated osteogenic transdifferentiation drives vascular calcification in primary pulmonary arterial hypertension [11–13], clinical observations in dialysis patients show that severe vascular calcifications independently predict PH occurrence and major adverse cardiovascular events [14]. The pathophysiological continuum in MHD patients appears driven by synergistic effects of uremic toxin accumulation, chronic inflammation, oxidative stress, and disordered mineral metabolism [15, 16], collectively promoting both PH and HVC through shared pathways.
Echocardiography’s unique capacity for simultaneous noninvasive assessment of both conditions enables clinical translation of these findings. We hypothesize that MHD patients with both PH and HVC face greater cardiovascular risk than those with either condition alone. To date, no studies have systematically evaluated their combined impact on cardiovascular outcomes in MHD patients. This study therefore aimed to examine the independent and synergistic effects of PH and HVC on cardiovascular prognosis in this high-risk population.
Methods
Study Population
This prospective observational study was conducted at the Hemodialysis Center of Guangdong Provincial People’s Hospital. The inclusion criteria were as follows: (1) patients who had undergone regular MHD (≥3 months, 3 times per week) before April 2009; (2) individuals aged ≥18 years; (3) patients who provided consent for echocardiographic evaluation and routine hematological assessments. Exclusion criteria included PH attributable to chronic obstructive pulmonary disease, connective tissue disease, pulmonary metabolic disorders, interstitial pulmonary fibrosis, rheumatic heart disease, congenital heart disease, acute heart failure, or portal hypertension [17]. Data were collected from January 2009 to April 2010, followed by a two-year follow-up period.
Detection of PH and HVC
M-mode, two-dimensional, and tissue Doppler echocardiography were performed on all participants using an Acuson Sequoia C256 Echocardiographic Imaging System (Acuson, Mountain View, CA, USA) with a 2.0–3.5 MHz transducer. To minimize the impact of intravascular volume shifts on cardiac hemodynamics, all examinations were conducted within 2–4 h after hemodialysis sessions [18].
PH was evaluated according to the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension [19]. Tricuspid regurgitation velocity (TRV) was measured as the primary parameter, with systolic pulmonary artery pressure (SPAP) estimated using the simplified Bernoulli equation: SPAP = 4 × (TRV)2 + right atrial pressure, where right atrial pressure was assumed to be 10 mm Hg in the absence of inferior vena cava collapse [19, 20]. PH was defined as SPAP ≥35 mm Hg [21], a threshold widely validated in clinical and epidemiological studies. While right heart catheterization (RHC) remains the gold standard for PH confirmation, echocardiography is the recommended first-line screening tool – particularly in high-risk populations such as MHD patients – due to its noninvasive nature, accessibility, and prognostic utility [19]. This approach is consistent with prior studies in hemodialysis cohorts [8, 22, 23], where RHC is often impractical.
Clinical and Laboratory Data Collection
The following details were recorded: smoking history; presence of diabetes, hypertension, or coronary artery disease; body mass index; systolic and diastolic blood pressure; pre-dialysis heart rate; CKD etiology; and other comorbidities (e.g., peptic ulcer, liver cirrhosis, chronic obstructive pulmonary disease). Pre-dialysis blood pressure was calculated as the average of three consecutive pre-dialysis measurements.
The Charlson Comorbidity Index was used to quantify overall comorbidity burden: 1 point for history of heart failure, cardiac infarction, peripheral disease, cerebrovascular disease, dementia, chronic lung disease, connective tissue disease, peptic ulcer, mild liver disease, diabetes mellitus without target-organ damage; 2 points for hemiplegia, diabetes mellitus with target-organ damage, tumors without metastases, lymphomas, leukemia, and myeloma; 3 points for moderately severe liver disease; and 6 points for tumors with metastases or HIV.
Laboratory parameters measured included serum albumin, calcium, phosphorus, calcium-phosphorus product, parathyroid hormone, C-reactive protein, uric acid, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The initial laboratory data collected at enrollment served as the basis for statistics.
Definition of New-Onset CV Events and Follow-Up
New-onset CV events included acute heart failure, angina, acute myocardial infarction, sudden cardiac arrest (or sudden death), arrhythmia necessitating hospitalization, transient ischemic attack, thromboembolic or hemorrhagic stroke, and peripheral vascular disorders. The observation period spanned from April 2009 to April 2011. New-onset CV events and mortality were the follow-up objectives.
New-onset CV events and causes of mortality were noted during follow-up and the individuals converting to peritoneal dialysis or receiving a kidney transplant were excluded from analysis. Family members of patients who passed away outside of a hospital were contacted via phone to inquire about potential causes of death. When patients experienced multiple CV events, the time of the first event was considered for survival analysis.
Statistical Analysis
Count data were summarized as frequencies and percentages. Differences across groups were analyzed using the chi-square test. Measurement data were presented as mean, standard deviation, median and quartiles, with differences assessed using the t test (for normally distributed variables) or the Mann-Whitney U test (for non-normally distributed variables). The cumulative incidence of all-cause death, cardiovascular mortality, and new-onset CV events for the 3 groups were calculated using the Kaplan-Meier method. Cox regression was employed to assess the risk and influencing factors of all-cause death, cardiovascular mortality, and new-onset CV events in patients. Hazard ratios (HRs) were calculated in an unadjusted model (model 1); after adjustment for age, sex [24] (model 2); and after adjustment for additional potential confounders including body mass index (calculated as weight in kilograms divided by height in meters squared), clinical (hypertension, previous history of CVD), CKD-specific factors (age of initial dialysis) [24], and traditional cardiometabolic risk factors (diabetes, dyslipidemia [low-density lipoprotein cholesterol, total cholesterol, triglyceride]) due to their direct pathophysiological links to cardiovascular outcomes [25] (model 3). Differences were deemed statistically significant at p < 0.05 level. All analyses were conducted utilizing SPSS version 22.0 (SPSS, Chicago, IL, USA) and GraphPad Prism 9.
Results
Patient Enrollment and Baseline Characteristics
A total of 302 patients were eligible for enrollment. PH and HVC were identified as risk determinants. Patients were classified into three groups based on echocardiography results: group 1 (no PH or HVC, n = 138), group 2 (PH only, n = 65; HVC only, n = 56), and group 3 (both PH and HVC, n = 43). Among the 302 patients, 162 (53.6%) were male, with a mean age at the commencement of dialysis of 58.2 ± 15.0 years and a median dialysis duration of 23.1 months (range: 9.6–53.0 months). Baseline characteristics of patients in each group are presented in Tables 1 and 2.
Table 1.
General data of 302 patients on MHD
| Characteristic | Without PH and HVC (n = 138) | With PH or HVC (n = 121) | With PH and HVC (n = 43) |
|---|---|---|---|
| Age, years | 66 (56.0, 75.0) | 60 (49.5, 71.0)a | 57 (45.0, 71.0)a |
| Male/female ratio | 75/63 | 62/59 | 25/18 |
| Age of initial dialysis, years | 57.3 (43.5, 69.3) | 62.0 (50.5, 71.2) | 62.7 (55.3, 71.3) |
| Systolic BP, mm Hg | 148±22 | 149±25 | 157±27a |
| Diastolic BP, mm Hg | 77±15 | 75±18 | 74±16 |
| Body mass index, kg/m2 | 21.5±3.0 | 21.3±3.1 | 20.9±3.0 |
| Diabetes, n (%) | 40 (29.0) | 44 (36.4) | 18 (41.9) |
| Hypertension, n (%) | 130 (94.2) | 109 (90.1) | 40 (90.3) |
| Causes of CKD, n (%) | |||
| Primary glomerular diseases | 52 (37.7) | 29 (24.0) | 9 (20.9) |
| Hypertensive nephrosclerosis | 35 (25.4) | 34 (28.1) | 12 (27.9) |
| Diabetes nephropathy | 28 (20.3) | 34 (28.1) | 15 (34.9) |
| Obstructive nephropathy | 6 (4.3) | 15 (12.4) | 5 (11.6) |
| Others | 17 (12.3) | 9 (7.4) | 2 (4.7) |
| Previous history of CVD, n (%) | 42 (30.4) | 33 (27.3) | 16 (37.2) |
| Angina pectoris | 15 (10.9) | 10 (8.3) | 6 (14.0) |
| Acute myocardial infarction | 3 (2.2) | 2 (1.7) | 2 (4.7) |
| Cerebral infarction | 19 (13.8) | 10 (8.3) | 9 (20.9) |
| Cerebral hemorrhage | 5 (3.6) | 1 (0.8) | 2 (4.7) |
| Sudden death | 2 (1.4) | 1 (1.8) | 0 |
| Acute heart failure | 10 (7.2) | 12 (9.9) | 4 (9.3) |
| Severe arrhythmia | 4 (2.9) | 5 (4.1) | 3 (7.0) |
| Transient ischemic attack | 2 (1.4) | 3 (2.4) | 1 (2.3) |
| Charlson rating (≥1), n (%) | 41 (29.7) | 44 (36.4) | 19 (44.2) |
| 1 | 28 (20.2) | 23 (19.0) | 14 (32.6) |
| 2 | 9 (6.5) | 12 (9.9) | 5 (11.6) |
| ≥3 | 4 (2.9) | 9 (7.4) | 0 |
| Valve reg. mod-severe, n (%) | 13 (9.4) | 48 (40.0)a | 25 (58.1)a,b |
| LVEF, % | 65±7 | 61±13a | 62.1±13 |
| Vascular access for AVF, n (%) | 105 (76.1) | 110 (90.9)a | 39 (90.7)a |
| UFR, mL/kg/h | 10.9±4.9 | 11.1±4.4 | 11.2±3.9 |
| Antihypertensive drug use, n (%) | |||
| Calcium antagonists | 88 (63.8) | 82 (67.8) | 31 (72.1) |
| ACEI or ARB | 59 (42.8) | 62 (51.2) | 22 (51.2) |
| ACEI and ARB | 13 (9.4) | 7 (5.8) | 4 (9.3) |
| Beta-blocker | 77 (55.8) | 62 (51.2) | 23 (53.5) |
| Alpha receptor blocker | 46 (33.3) | 48 (40.0) | 23 (53.5) |
BP, blood pressure; valve reg. mod-severe, moderate-to-severe valvular regurgitation; LVEF, left ventricular ejection fraction; AVF, arteriovenous fistula; UFR, ultrafiltration rate; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
a p < 0.05 compared to 0-risk factor group.
b p < 0.05 compared to 1-risk factor group.
Table 2.
Laboratory data of 302 patients on MHD
| Characteristic | Without PH or HVC (n = 138) | With PH or HVC (n = 121) | With PH and HVC (n = 43) |
|---|---|---|---|
| URR, % | 71.7±8.7 | 69.4±8.1a | 68.1±8.0a |
| Kt/V | 1.7±0.3 | 1.6±0.3a | 1.5±0.3a |
| Albumin, g/L | 30.5±4.2 | 30.2±3.5 | 31.6±3.5 |
| Hemoglobin, g/L | 95.7±22.3 | 101.1±20.8 | 98.7±23.0 |
| Ferritin, ng/mL | 239.1 (88.0–579.7) | 285.8 (83.8–617.3) | 425.3 (145.5–746.0) |
| TSAT, % | 28.9±17.6 | 27.1±17.5 | 27.7±21.1 |
| Ca, mmol/L | 2.4±0.2 | 2.4±0.2 | 2.5±0.2 |
| Phosphorus, mmol/L | 2.1±0.7 | 2.1±0.9 | 2.2±0.9 |
| Calcium-phosphorus product, mg2/dL2 | 59.4±22.0 | 61.8±23.2 | 64.8±24.5 |
| PTH, pg/mL | 193.6 (86.7–406.4) | 231.4 (109.5–576.2) | 278.2 (69.1–499.0) |
| ALP, U/L | 60.0 (50.0–80.5) | 79.0 (56.1–97.5) | 61.5 (55.5–97.5) |
| β2-MG, mg/L | 36.7±13.9 | 40.7±15.2 | 38.3±11.5 |
| CRP, mg/L | 3.2 (1.5–7.0) | 5.8 (2.3–11.9) | 7.4 (1.7–13.6) |
| Uric acid, mmol/L | 431.3±113.3 | 438.4±96.2 | 414.5±88.6 |
| Cholesterol, mmol/L | 4.3±1.1 | 4.2±1.1 | 3.9±1.0 |
| Triglyceride, mmol/L | 1.5±1.2 | 1.4±1.2 | 1.2±0.7 |
| HDL-C, mmol/L | 1.1±0.4 | 1.1±0.4 | 1.0±0.3 |
| LDL-C, mmol/L | 2.2±0.9 | 2.2±0.8 | 2.1±0.8 |
Data are given as mean ± SD, medians (25th to 75th percentiles), or numbers and percentages as appropriate.
URR, urea reduction ratio; Kt/V, dialyzer clearance of urea × time/volume; TSAT, transferrin saturation; PTH, transferrin saturation; ALP, alkaline phosphatase; β2-MG, beta-2 macroglobulin; CRP, C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
a p < 0.05 compared to 0-risk factor group.
Survival of Patients with Varying Risk Factors
The average follow-up time was 21.6 months (median, 24 months). At the end of the follow-up period, 5 patients (1.6%) underwent kidney transplantation, and no patients were lost to follow-up or transitioned to peritoneal dialysis. A total of 63 patients (20.9%) died, with mortality rates of 13.0% in group 1, 24.0% in group 2, and 37.2% in group 3. Cardiovascular deaths accounted for 57.1% of all fatalities (n = 36), with 7 (5.1%) in group 1, 16 (13.2%) in group 2, and 13 (30.2%) in group 3 (Table 3). All-cause and cardiovascular mortality rates were significantly higher in patients with 1 or 2 risk factors compared to those with 0 risk factors (p < 0.05). Cardiovascular deaths included 18 sudden deaths, 9 strokes, 7 acute myocardial infarctions, and 2 arrhythmias. Other causes of death included 12 lung infections, 5 cases of severe malnutrition, 3 malignant tumors, and 7 unidentified causes.
Table 3.
Endpoint events in MHD patients with different risk factors
| Characteristic | Without PH or HVC (n = 138) | With PH or HVC (n = 121) | With PH and HVC (n = 43) |
|---|---|---|---|
| All-cause death | 18 (13.0) | 29 (24.0) | 16 (37.2)a |
| Cardiovascular death | 7 (5.1) | 16 (13.2) | 13 (30.2)a |
| New cardiovascular events | 28 (20.3) | 43 (35.5)b | 29 (67.4)a |
| Cardiac event | 20 (14.5) | 36 (29.8)c | 26 (60.5)a,d |
| Angina pectoris | 5 (3.6) | 4 (3.3) | 6 (14.0) |
| Acute myocardial infarction | 2 (1.4) | 6 (5.0) | 6 (14)c |
| Acute heart failure | 7 (5.1) | 20 (16.5)c | 6 (14) |
| Severe arrhythmia | 4 (2.9) | 10 (8.3) | 8 (18.6)c |
| Sudden death | 4 (2.9) | 7 (5.8) | 7 (16.3)b |
| Cerebrovascular event | 9 (6.5) | 11 (9.1) | 8 (18.6) |
| Stroke | 7 (5.1) | 9 (7.4) | 7 (16.3) |
| Transient ischemic attack | 2 (1.4) | 2 (1.7) | 1 (2.3) |
| Peripheral vascular disease | 1 (0.7) | 2 (1.7) | 0 |
a p < 0.001 compared to 0-risk factor group.
b p < 0.05 compared to 0-risk factor group.
c p < 0.01 compared to 0-risk factor group.
d p < 0.001 compared to 1-risk factor group.
New-Onset CV Events in MHD Patients with Varying Risk Factors
New-onset CV events were observed in 100 patients (33.1%), with 43 (35.5%) in the 1-risk factor group and 29 (67.4%) in the 2-risk factors group. The difference in CV event rates between these two groups was statistically significant (p < 0.05, Table 3). Among the new-onset CV events, sudden heart failure was the most prevalent, followed by stroke and severe arrhythmia. Specifically, stroke was more common in the 0-risk factor group, acute heart failure was more frequent in the 1-risk factor group, while the 2-risk factors group exhibited a higher prevalence of severe arrhythmias, followed by sudden death and stroke.
Predictive Value of PH and HVC in MHD Patients
The combination of PH and HVC independently and jointly predicted all-cause mortality, cardiovascular mortality, and new-onset CV events in MHD patients. Figure 1 illustrates the survival curves. Either PH or HVC was associated with elevated all-cause mortality (shown in Fig. 1a), while the combination of both conditions was associated with a higher risk profile. In the unadjusted model, the HRs for all-cause mortality were 1.91 (95% CI: 1.06–3.44) for the 1-risk factor group and 3.28 (95% CI: 1.67–6.44) for the 2-risk factors group compared to the 0-risk factor group. After multivariable adjustment, the HRs for all-cause mortality were 1.90 (95% CI: 1.03–3.52) for the 1-risk factor group and 3.76 (95% CI: 1.83–7.73) for the 2-risk factors group, respectively (Table 4).
Fig. 1.
a Survival curves for all-cause mortality of MHD patients in different risk factor subgroups. b Survival curves for cardiovascular mortality of MHD patients in different risk factor subgroups. c Survival curves for new cardiovascular events of MHD patients in different risk factor subgroups. PH, pulmonary hypertension; HVC, heart valve calcification; MHD, maintenance hemodialysis patients.
Table 4.
HRs for all-cause mortality, cardiovascular mortality, and new-onset CV events among participants in the different risk factor groups
| | Risk factor groups, HR (95% CI)a | p value for trend | ||
|---|---|---|---|---|
| 0 risk factor | 1 risk factor | 2 risk factors | ||
| All-cause mortality (n = 63) | ||||
| Model 1 (unadjusted) | 1 (reference) | 1.91 (1.06–3.44) | 3.28 (1.67–6.44) | 0.001 |
| Model 2b | 1 (reference) | 1.92 (1.06–3.49) | 3.28 (1.65–6.52) | 0.001 |
| Model 3c | 1 (reference) | 1.90 (1.03–3.52) | 3.76 (1.83–7.73) | 0.001 |
| Cardiovascular mortality (n = 36) | ||||
| Model 1 (unadjusted) | 1 (reference) | 2.72 (1.12–6.62) | 7.03 (2.80–17.63) | <0.001 |
| Model 2b | 1 (reference) | 2.95 (1.20–7.20) | 7.70 (3.04–19.5) | <0.001 |
| Model 3c | 1 (reference) | 3.11 (1.23–7.84) | 9.23 (3.42–24.95) | <0.001 |
| CVD events (n = 100) | ||||
| Model 1 (unadjusted) | 1 (reference) | 1.90 (1.18–3.05) | 4.24 (2.52–7.13) | <0.001 |
| Model 2b | 1 (reference) | 1.97 (1.22–3.19) | 4.51 (2.65–7.66) | <0.001 |
| Model 3c | 1 (reference) | 1.68 (1.01–2.76) | 4.21 (2.39–7.21) | <0.001 |
HRs, hazard ratios; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol.
aParticipants were categorized as having 0 risk factor (without PH or HVC); 1 risk factor (with PH or HVC); or 2 risk factors (with PH and HVC).
bModel 2 included adjustment for age and sex.
cModel 3 included the variables in Model 2 and clinical and behavioral characteristics when follow-up time started (previous history of CVD, body mass index, age of initial dialysis, hypertension, diabetes, albumin, LDL-C, TC, TG).
Similarly, the presence of PH or HVC was associated with elevated cardiovascular mortality (shown in Fig. 1b) and CV event rates over the follow-up period (shown in Fig. 1c). In the unadjusted model, the 1-risk factor group had a significantly higher risk of cardiovascular mortality compared to the 0-risk factor group (HR, 2.72; 95% CI: 1.12–6.62), and this association remained after multivariable adjustment (HR, 3.11; 95% CI: 1.23–7.84). For the 2-risk factors group, the HRs for cardiovascular mortality were 7.03 (95% CI: 2.80–17.63) before adjustment and 9.23 (95% CI: 3.42–24.95) after adjustment (Table 4).
For new-onset CV events, the unadjusted HRs were 1.90 (95% CI: 1.18–3.05) for the 1-risk factor group and 4.24 (95% CI: 2.52–7.13) for the 2-risk factors group. After multivariable adjustment, the HRs remained significant: 1.68 (95% CI: 1.01–2.76) for the 1-risk factor group and 4.21 (95% CI: 2.39–7.21) for the 2-risk factors group (Table 4).
Discussion
PH is a frequent complication in patients with CKD, occurring at a rate three to six times higher than in the general population [26]. Our prior study identified PH in 18.1% of a cohort comprising 2,351 Chinese patients with CKD [27]. A recent meta-analysis of 16 studies involving 7,112 CKD patients reported an overall prevalence of PH at 23%, ranging from 21% to 27% in non-dialysis CKD patients and 16%–47% in ESRD patients [28]. Similarly, HVC, particularly aortic valve calcification and mitral valve calcification (MVC), is highly prevalent among dialysis patients [29]. These conditions are not merely passive processes but are actively linked to metabolic and inflammatory pathways commonly observed in ESRD patients [30].
Both PH and HVC have been identified as significant predictors of mortality and CV events in dialysis patients. Numerous studies have demonstrated that PH is associated with higher rates of all-cause and cardiovascular mortality. Our group previously reported that PH was associated with higher rates of all-cause and cardiovascular mortality in MHD patients, with HR of 1.85 (95% CI: 1.03–3.34) and 2.36 (95% CI: 1.05–5.31), respectively [9]. These findings are further supported by other studies. Reque et al. [31] followed 211 hemodialysis patients, of whom 43.9% had PH. The mortality rate was significantly higher in the PH group (58.5%) compared to those without PH (29.5%), with PH emerging as an independent predictor of mortality in multivariate analysis. Xu et al. [23] also demonstrated that PH increased the risk of all-cause and cardiovascular mortality in peritoneal dialysis patients, with HRs of 2.10 (95% CI: 1.35–3.27) and 2.60 (95% CI: 1.48–4.56) after adjustment. Collectively, these studies highlight the significant impact of PH on mortality and CV events in patients with ESRD.
Similarly, HVC, particularly MVC, is associated with increased cardiovascular and all-cause mortality in dialysis patients. In a prospective multicenter cohort study of 1,489 dialysis patients (78.4% on hemodialysis and 21.6% on peritoneal dialysis), the prevalence of HVC was 45.8% [2]. A meta-analysis incorporating 10 observational studies involving 3,376 dialysis patients demonstrates that patients with HVC exhibited a 59.2% increased risk of all-cause mortality (HR = 1.592, 95% CI: 1.410–1.797). And HVC was associated with a 144.4% increase in cardiovascular mortality risk (HR = 2.444, 95% CI: 1.632–3.659) [32]. In dialysis patients, factors such as hyperphosphatemia, elevated parathyroid hormone, uremic toxins and oxidative stress promote valve calcification, which may worsen after dialysis initiation [33, 34]. HVC increases cardiac afterload, leading to left ventricular hypertrophy and CV events such as heart failure and atrial fibrillation, thereby elevating cardiovascular mortality risk.
When PH and HVC coexist, their combined effects may synergistically increase the risk of adverse outcomes. Our findings reveal a striking dose-response relationship between risk factor accumulation and adverse outcomes. After full multivariate adjustment, patients with either PH or HVC alone exhibited a 1.90-fold increased all-cause mortality risk (95% CI: 1.03–3.52), while those with both conditions faced a 3.76-fold hazard (95% CI: 1.83–7.73). This nonlinear escalation was even more pronounced for cardiovascular-specific outcomes – the adjusted cardiovascular mortality HR jumped from 3.11 (95% CI: 1.23–7.84) with single risk factor to 9.23 (95% CI: 3.42–24.95) with dual risk factors. Similarly, new-onset CV event risk progressed from 1.68 (95% CI: 1.01–2.76) to 4.21 (95% CI: 2.39–7.21). These multiplicative rather than additive effects suggest pathophysiological synergism between PH and HVC that transcends their individual contributions.
The observed synergistic risk amplification likely stems from interconnected biological pathways operating at multiple levels. Hemodynamically, HVC increases left ventricular afterload through valvular obstruction and ventricular-arterial uncoupling [35], while PH imposes right ventricular pressure overload [36], creating a detrimental “double-hit” scenario. This biventricular strain manifests through three key mechanisms: (1) left-sided dysfunction elevates pulmonary venous pressures, further exacerbating PH; (2) right ventricular failure impairs left ventricular filling via ventricular interdependence; and (3) the combined effect culminates in end-organ hypoperfusion and enhanced arrhythmogenesis. At the molecular level, the uremic milieu activates shared pathological cascades, including FGF23-Klotho axis disruption where elevated FGF23 promotes both left ventricular hypertrophy and pulmonary vascular remodeling through FGFR4 activation [15, 37]. Simultaneously, uremic toxins like indoxyl sulfate accumulate in valvular and pulmonary tissues, inducing osteogenic differentiation via RUNX2 upregulation while causing endothelial dysfunction through reactive oxygen species-nitric oxide imbalance [38, 39]. The inflammatory-osteogenic coupling is further mediated by cytokines (IL-6, TNF-α) that concurrently accelerate valve calcification via Wnt/β-catenin signaling and promote pulmonary vascular remodeling through NF-κB activation [40]. These systemic effects are compounded by coronary microvascular dysfunction – already prevalent in ESRD – which is exacerbated by both PH-induced right ventricular oxygen supply-demand mismatch and HVC-related left ventricular hypertrophy with diastolic impairment. This creates a self-perpetuating cycle of myocardial ischemia and fibrotic remodeling that ultimately drives the dramatically increased cardiovascular risk observed in patients with combined PH and HVC.
At the end of the follow-up, 33.1% of MHD patients experienced new-onset CV events, with the composition of these events varying by the number of risk factors. Patients without either PH or HVC had the highest incidence of stroke (5.1%) and acute heart failure (5.1%). Those with one risk factor were more likely to experience acute heart failure (16.5%), while those with both risk factors had the highest incidence of severe arrhythmias (18.6%), followed by sudden death (16.3%) and stroke (16.3%). Previous studies have shown that MVC is often associated with cardiac rhythm and conduction abnormalities [41], which is consistent with the higher incidence of severe arrhythmias in patients with HVC in our study.
The striking exponential increase in cardiovascular risk associated with the coexistence of PH and HVC in MHD patients necessitates that a comprehensive echocardiographic screening incorporating both PH and HVC assessment should become standard practice in this population, as evaluating either condition in isolation significantly underestimates mortality risk.
Potential interventions may include optimizing dialysis regimens, managing fluid overload, and evaluating the role of targeted therapies for PH and vascular calcification. Further studies are needed to establish evidence-based treatment strategies for this high-risk group.
This study focuses on MHD patients – a population with a significantly elevated cardiovascular disease risk. Our results demonstrate that MHD patients with both PH and HVC exhibit significantly higher risks of all-cause, cardiovascular mortality and new-onset CV events compared to those with either condition alone or neither condition. We utilized echocardiography, a noninvasive, cost-effective, and widely accessible tool, to identify both PH and HVC. To our knowledge, this is the first study to concurrently evaluate the independent and synergistic effects of HVC and PH on mortality and cardiovascular disease risk in MHD patients, providing a novel risk stratification in this vulnerable population.
Limitations
However, several limitations should be acknowledged. The follow-up period was limited to 2 years, which may not fully capture the long-term impact of PH on mortality and cardiovascular events. The absence of serial cardiac reassessment data in the patients limited us to track dynamic PH progression during the 2-year follow-up. Additionally, the diagnosis of PH was based solely on echocardiographic estimates of SPAP, without confirmation via RHC, the gold standard for PH diagnosis. In the sensitivity analysis using alternative definition for PH (applying a stricter threshold (SPAP >40 mm Hg), the results rendered largely similar (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000549112), confirming the robustness of our primary findings. Larger sample size studies are needed to confirm the prognostic impact of PH combined with HVC in the hemodialysis population.
Conclusion
MHD patients with concurrent PH and HVC have an elevated risk of all-cause mortality, cardiovascular mortality, and new-onset CV events compared to those with either PH or HVC alone. Echocardiography effectively identifies both PH and HVC, aiding in risk stratification and potentially enhancing clinical management strategies in this high-risk population.
Acknowledgment
The authors would like to thank all statisticians for participating in this study.
Statement of Ethics
The studies involving human participants were reviewed and approved by the Ethics Committee of Guangdong Provincial People’s Hospital (ethical No. GDREC2016192H). The need for informed consent was waived by the Ethics Committee of Guangdong Provincial People’s Hospital.
Conflict of Interest Statement
The authors report that there are no competing interests to declare.
Funding Sources
This study was supported by Guangdong Provincial Natural Science Foundation (2022A1515010551) and Tibet Autonomous Region Natural Science Foundation [XZ2024ZR-ZY084(Z) and XZ2023ZR-ZY63(Z)].
Author Contributions
Conceptualization: Xinyi Fu, Chenyu Lei, Wenjing Cai, Zhilian Li, and Min Wu; methodology: Xinyi Fu, Chenyu Lei, Wenjing Cai, Li Zhang, and Zhiming Ye; software: Xinyi Fu, Anning Xu, Linlin Yuan, Li Zhang, and Xinling Liang; validation: Chenyu Lei, Wenjing Cai, Anning Xu, and Linlin Yuan; supervision and visualization: Xinyi Fu, Chenyu Lei, Anning Xu, and Linlin Yuan; writing – original draft: Zhilian Li, Min Wu, Xinyi Fu, and Chenyu Lei; writing – review and editing: Zhilian Li, Xinyi Fu, and Chenyu Lei. Each of the authors contributed an important role in drafting the manuscript, accepting accountability, and ensuring the accuracy or completeness of the overall work is properly investigated and resolved.
Funding Statement
This study was supported by Guangdong Provincial Natural Science Foundation (2022A1515010551) and Tibet Autonomous Region Natural Science Foundation [XZ2024ZR-ZY084(Z) and XZ2023ZR-ZY63(Z)].
Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.