A total of 757 eligible CAPD patients with a mean follow-up time of 54.7 (standard deviation (SD), 33) months were included in the study (Fig. 1). The median age of our cohort was 49 (interquartile range (IQR), 38–60) years, and the proportion of men was 55.1%. A total of 91 (12%) patients experienced stroke during a median follow-up time of 15 months and with a median occurrence age of 61.5 years, and the counts of ischemic stroke and hemorrhagic stroke were 74 (83.1%) cases and 23 (25.8%) cases, with median ages of 64.5 and 55 years, respectively. The median incidence of stroke among our CAPD patients was 18.9 (IQR, 15.7–22.1) per 1000 person-years. An obvious phenomenon was noticed in which patients at the initiation and 5 years and 10 years after CAPD had a high incidence of stroke (Supplemental Fig. 1). A total of 153 (20%) patients in our cohort experienced composite endpoints, and the proportion of composite endpoint events increased significantly in the stroke group compared to that of the nonstroke group (39.6% vs 17.6%, respectively; p value < 0.001).
A few significant differences at the initiation of CAPD were observed between the stroke and nonstroke groups in our cohort. The median age in the stroke group was significantly older (62 vs 48 years; p value < 0.001), and the stroke group had lower levels of serum albumin (33.6 vs 35.7 g/l, p value = 0.002), serum phosphorus (1.6 vs 1.7 mmol/l, p value = 0.001), iPTH (167.7 vs 269.0 pg/ml, p value = 0.001) and DBP (76.6 vs 84.6 mmHg, p value < 0.001). Furthermore, the prevalence of chronic heart disease (97.8% vs 25.8%, p value < 0.001) and diabetes (53.8% vs 24.3%, p value < 0.001) was significantly higher in the stroke group. Interestingly, the prevalence of vitamin D supplementation was significantly lower in the stroke group than in the nonstroke group (53.8% vs 70.9%, respectively; p value = 0.002). The results of the comparison between the stroke and nonstroke groups are shown in Table 1.
Table 1
Comparing the clinical characteristics and laboratory measurements of the included CAPD patients with and without stroke.
Characteristics | Nonstroke | Stroke | p |
Patients (n) | 666 | 91 | |
Male (n, %) | 368 (55.3) | 49 (53.8) | 0.9 |
Age (years, median [IQR]) | 48.0 [37.0, 58.0] | 62.0 [52.5, 68.5] | < 0.001 |
Serum albumin (g/l, median [IQR]) | 35.7 [32.0, 39.1] | 33.6 [31.2, 37.1] | 0.002 |
Hemoglobin (g/l, median [IQR]) | 81.3 (18.7) | 80.0 (19.2) | 0.5 |
Serum creatinine (µmol/l, median [IQR]) | 748.0 [571.0, 946.2] | 583.7 [470.0, 790.5] | < 0.001 |
Serum calcium (mmol/l, median [IQR]) | 2.1 [1.9, 2.2] | 2.1 [1.9, 2.2] | 0.7 |
Serum phosphorus (mmol/l, median [IQR]) | 1.7 [1.5, 2.0] | 1.6 [1.3, 1.9] | 0.001 |
iPTH (pg/ml, median [IQR]) | 269.0 [154.7, 422.0] | 167.7 [87.7, 346.2] | 0.001 |
SBP (mmHg, mean (SD)) | 140.7 (25.1) | 143.6 (26.6) | 0.3 |
DBP (mmHg, mean (SD)) | 84.6 (14.9) | 76.6 (16.4) | < 0.001 |
MAP (mmHg, mean (SD)) | 103.3 (16.7) | 99.0 (17.6) | 0.02 |
Follow-up time (month, mean (SD)) | 54.6 (32.7) | 55.5 (35.4) | 0.8 |
Ischemic stroke (n, %) | | 74 (83.1) | |
Hemorrhagic stroke (n, %) | | 23 (25.8) | |
Composite endpoints (n, %) | 117 (17.6) | 36 (39.6) | < 0.001 |
Combined Diseases | | | |
Chronic heart disease (n, %) | 172 (25.8) | 89 (97.8) | < 0.001 |
Hypertension (n, %) | 645 (96.8) | 91 (100.0) | 0.2 |
Diabetes (n, %) | 162 (24.3) | 49 (53.8) | < 0.001 |
Treatments | | | |
Calcium agents (n, %) | 538 (80.8) | 66 (72.5) | 0.09 |
Antiplatelet agents (n, %) | 208 (31.2) | 62 (68.1) | < 0.001 |
Statins (n, %) | 399 (59.9) | 67 (73.6) | 0.02 |
Vitamin D (n, %) | 472 (70.9) | 49 (53.8) | 0.002 |
RAAS blockades (n, %) | 529 (79.4) | 71 (78.0) | 0.9 |
CCBs (n, %) | 597 (89.6) | 88 (96.7) | 0.05 |
iPTH: intact parathyroid hormone; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; Vitamin D: alfacalcidol or calcifediol; RAAS: renin–angiotensin–aldosterone system; CCBs: calcium channel blockers |
Relationship between baseline iPTH and stroke
Our data showed a significantly skewed distribution of baseline serum iPTH, and the probability density distribution was markedly different between the nonstroke group and the stroke group, with a significant left-shift peak in the stroke group, which means that the levels of serum iPTH were significantly lower in the stroke group (Supplemental Fig. 2a). Our nonlinear Cox regression analysis indicated a significant nonlinear correlation between baseline iPTH and hazard of stroke (p value of linear part = 0.2, and nonlinear part = 0.002). The curve of the relative stroke rate by baseline iPTH levels (referred to as 152 pg/ml) was J-shaped, which means that patients with low and markedly high levels of iPTH had a higher risk of stroke (Supplemental Fig. 2b).
A Kaplan-Meier analysis of stroke among patients with different levels of baseline serum iPTH (cases were separated into four groups based on iPTH levels: ≤150, 150–300, 300–600, and > 600 pg/ml) showed a significant difference in cumulative hazard of stroke between the groups (log-rank test, p value < 0.001), and patients with low baseline iPTH levels (≤ 150 pg/ml) had an increased cumulative hazard of stroke. The pairwise comparison between groups showed that there were significant differences between the ≤ 150 group and the 150–300 group and the 300–600 group (p value = 0.002 and < 0.001, respectively), and there were no significant differences between the ≤ 150 group and the > 600 group (p value = 0.1, Fig. 2).
Risk factors for stroke and composite endpoints
Our univariate Cox regression analysis showed that increased age, decreased DBP and iPTH levels combined with chronic heart disease and diabetes, receiving antiplatelet agents and not taking vitamin D supplements are common risk factors for stroke and composite endpoints. However, male sex is a risk factor for composite endpoints but not for stroke, and taking calcium agents is a protective factor for stroke but not for composite endpoints (Table 2).
Table 2
Univariate Cox regression for stroke and composite endpoints.
Variables | Model 1 | Model 2 |
HR [95% CI] | p value | HR [95% CI] | p value |
Age (years) | 1.07 [1.05, 1.09] | < 0.001 | 1.05 [1.04, 1.06] | < 0.001 |
Male | 0.72 [0.44, 1.18] | 0.2 | 1.67 [1.19, 2.34] | 0.003 |
Serum albumin (g/l) | 0.96 [0.92, 1.00] | 0.06 | 0.96 [0.93, 0.98] | 0.002 |
Serum UA (mg/dl) | 0.97 [0.86, 1.10] | 0.6 | 0.99 [0.91, 1.07] | 0.7 |
Hemoglobin (g/l) | 1.00 [0.99, 1.01] | 0.9 | 1.00 [1.00, 1.01] | 0.3 |
Serum calcium (mmol/l) | 1.44 [0.57, 3.63] | 0.4 | 1.10 [0.61, 1.97] | 0.8 |
Serum phosphorus (mmol/l) | 0.55 [0.30, 1.02] | 0.06 | 0.60 [0.40, 0.90] | 0.01 |
iPTH levels | | | | |
<150 | Ref | - | Ref | - |
150–300 | 0.43 [0.23, 0.81] | 0.01 | 0.86 [0.57, 1.28] | 0.5 |
300–600 | 0.38 [0.20, 0.73] | 0.003 | 0.53 [0.34, 0.82] | 0.004 |
>600 | 0.58 [0.25, 1.33] | 0.2 | 0.69 [0.38, 1.22] | 0.2 |
SBP (mmHg) | 1.00 [0.99, 1.01] | 0.6 | 1.00 [0.99, 1.01] | 1 |
DBP (mmHg) | 0.97 [0.95, 0.98] | < 0.001 | 0.98 [0.97, 0.99] | < 0.001 |
Chronic heart disease | 3.19 [1.95, 5.22] | < 0.001 | 2.96 [2.14, 4.10] | < 0.001 |
Diabetes | 2.81 [1.72, 4.59] | < 0.001 | 2.52 [1.82, 3.49] | < 0.001 |
Calcium agents | 0.53 [0.31, 0.92] | 0.02 | 0.73 [0.50, 1.08] | 0.1 |
Vitamin D | 0.38 [0.23, 0.63] | < 0.001 | 0.47 [0.34, 0.66] | < 0.001 |
Antiplatelet agents | 3.33 [1.99, 5.58] | < 0.001 | 1.75 [1.26, 2.42] | 0.001 |
Statins | 1.38 [0.80, 2.37] | 0.3 | 0.87 [0.62, 1.21] | 0.4 |
HR: hazard ratio; CI: confidence interval; UA: uric acid; SBP: systolic blood pressure; DBP: diastolic blood pressure; Model 1: Univariate model for stroke; Model 2: Univariate model for composite endpoints. |
Our data showed a significant inverse correlation between serum iPTH and age (Kendall's rank correlation coefficient = -0.15, p value < 0.001). We hypothesize that interaction effects may exist between age and iPTH. Thus, an interaction item of serum iPTH and age was constructed in the multivariate Cox models for stroke and composite endpoints. In the stroke model (Table 3, model 1), there was a significant interaction effect between serum iPTH levels and age. Surprisingly, the baseline serum iPTH levels were still significantly associated with stroke, but age was not associated after adjusting for other confounders. In regard to stroke risk, there was no significant interaction effect between serum iPTH and age, and age but not iPTH was significantly associated with composite endpoints (Table 3, model 2). A plot of interaction effects showed that iPTH levels between 150 and 300 pg/ml are appropriate for patients younger than 65 years and between 300 and 600 pg/ml for patients older than 65 years (Supplemental Fig. 3).
Table 3
Multivariate Cox regression of iPTH with interest endpoints.
Variables | Model 1 | Model 2 |
HR [95% CI] | p value | HR [95% CI] | p value |
Age (years) | 1.03 [1.00, 1.06] | 0.08 | 1.03 [1.01, 1.06] | 0.009 |
Male | | | 1.61 [1.11, 2.35] | 0.01 |
Serum albumin (g/l) | 0.99 [0.93, 1.04] | 0.6 | 0.98 [0.95, 1.01] | 0.2 |
Serum UA (mg/dl) | 1.07 [0.93, 1.23] | 0.3 | 0.99 [0.91, 1.08] | 0.8 |
Serum calcium (mmol/l) | 0.93 [0.29, 3.03] | 0.9 | 1.29 [0.60, 2.75] | 0.5 |
Serum phosphorus (mmol/l) | 1.12 [0.56, 2.27] | 0.7 | 1.16 [0.72, 1.87] | 0.5 |
iPTH levels | | | | |
<150 | Ref | - | Ref | - |
150–300 | 0.01 [0.00, 0.49] | 0.02 | 0.52 [0.08, 3.59] | 0.5 |
300–600 | 0.16 [0.01, 3.49] | 0.2 | 0.20 [0.03, 1.51] | 0.1 |
>600 | 0.34 [0.01, 19.77] | 0.6 | 0.25 [0.02, 3.48] | 0.3 |
SBP (mmHg) | 1.01 [1.00, 1.02] | 0.09 | 1.00 [0.99, 1.01] | 0.9 |
DBP (mmHg) | 0.99 [0.97, 1.01] | 0.2 | 1.00 [0.99, 1.02] | 0.8 |
Chronic heart disease | 2.03 [1.20, 3.42] | 0.008 | 2.35 [1.64, 3.37] | < 0.001 |
Diabetes | 1.12 [0.64, 1.96] | 0.7 | 1.46 [1.00, 2.13] | 0.05 |
Calcium agents | 0.52 [0.29, 0.93] | 0.03 | | |
Vitamin D | 0.42 [0.24, 0.74] | 0.002 | 0.47 [0.32, 0.68] | < 0.001 |
Antiplatelet agents | 1.71 [0.96, 3.04] | 0.07 | 0.90 [0.62, 1.30] | 0.6 |
Interaction term | | | | |
Age: iPTH < 150 | Ref | - | Ref | - |
Age: iPTH 150–300 | 1.07 [1.01, 1.14] | 0.03 | 1.01 [0.98, 1.05] | 0.5 |
Age: iPTH 300–600 | 1.02 [0.97, 1.08] | 0.4 | 1.02 [0.99, 1.06] | 0.2 |
Age: iPTH > 600 | 1.03 [0.95, 1.10] | 0.5 | 1.04 [0.99, 1.09] | 0.1 |
HR: hazard ratio; CI: confidence interval; SBP: systolic blood pressure; DBP: diastolic blood pressure; Covariables with a p value less than 0.1 in univariate Cox regressions were selected to build the multivariate Cox regression models. Model 1: multivariate model for stroke; Model 2: multivariate model for composite endpoints. |
The difference in iPTH levels during follow-up between the stroke and nonstroke groups
Compared to the nonstroke group, the median values of the original, log-transformed and time-averaged iPTH levels during follow-up decreased significantly in the stroke group (p value = 0.001, < 0.001 and 0.001, respectively). Furthermore, the median absolute difference in serum iPTH levels also decreased significantly in the stroke group (52.9 [34.4, 93.2] vs 66.2 [41.7, 106.5], p value = 0.03), which indicates that serum iPTH was significantly reduced in the stroke group compared with that in the nonstroke group during follow-up (Supplemental Table 1).
The nonlinear regression curves displayed markedly different trends in iPTH levels during follow-up in the stroke group and the nonstroke group; the iPTH levels gradually decreased in the stroke group but increased in the nonstroke group as the number of dialysis months increased (Fig. 3).
Subgroup analysis for vitamin D supplementation
Our multivariate Cox regression analysis indicated that the receiving vitamin D supplementation during follow-up was an independent protective factor both for stroke and the composite endpoints (model 1: HR, 0.42, 95% CI 0.24–0.74, p value = 0.002; model 2: HR, 0.47, 95% CI 0.32–0.68, p value < 0.001; Table 3). To further investigate the effects of vitamin D supplementation among different populations of CAPD patients, a subgroup analysis was performed. Regardless of the levels of serum calcium or phosphate, vitamin D supplementation was a significant protective factor for stroke. Interestingly, vitamin D supplementation was an independent predictive factor for stroke in male patients and older patients (HR 0.38, 95% CI 0.2–0.72, and HR 0.24, 95% CI 0.1–0.58, respectively). Additionally, vitamin D supplementation may decrease the risk of stroke in patients with serum iPTH levels lower than 600 pg/ml (Supplemental Fig. 4).