Association between conversion to in-center nocturnal hemodialysis and right ventricular remodeling

Association between conversion to in-center nocturnal hemodialysis and right ventricular remodeling ABSTRACT Background In-center nocturnal hemodialysis (INHD) is associated with favorable left ventricular (LV) remodeling. Although right ventricular (RV) structure and function carry prognostic significance, the impact of dialysis intensification on RV is unknown. Our objectives were to evaluate changes in RV mass index (MI), end-diastolic volume index (EDVI), end-systolic volume index (ESVI) and ejection fraction (EF) after conversion to INHD and their relationship with LV remodeling. Methods Of 67 conventional hemodialysis (CHD, 4 h/session, three times/week) patients, 30 continued on CHD and 37 converted to INHD (7–8 h/session, three times/week). Cardiac magnetic resonance imaging was performed at baseline and 1 year using a standardized protocol; an experienced and blinded reader performed RV measurements. Results At 1 year there were significant reductions in RVMI {−2.1 g/m2 [95% confidence interval (CI) −3.8 to − 0.4], P = 0.017}, RVEDVI [−9.5 mL/m2 (95% CI − 16.3 to − 2.6), P = 0.008] and RVESVI [−6.2 mL/m2 (95% CI − 10.9 to − 1.6), P = 0.011] in the INHD group; no significant changes were observed in the CHD group. Between-group comparisons showed significantly greater reduction of RVESVI [−7.9 mL/m2 (95% CI − 14.9 to − 0.9), P = 0.03] in the INHD group, a nonsignificant trend toward greater reduction in RVEDVI and no significant difference in RVMI and RVEF changes. There was significant correlation between LV and RV in terms of changes in mass index (MI) (r = 0.46), EDVI (r = 0.73), ESVI (r = 0.7) and EF (r = 0.38) over 1 year (all P < 0.01). Conclusions Conversion to INHD was associated with a significant reduction of RVESVI. Temporal changes in RV mass, volume and function paralleled those of LV. Our findings support the need for larger, longer-term studies to confirm favorable RV remodeling and determine its impact on clinical outcomes. cardiac magnetic resonance imaging, hemodialysis, right ventricle Conventional hemodialysis (CHD) is the dominant form of renal replacement therapy for end-stage renal disease (ESRD) and is routinely administered in 4-h sessions, three times per week [1]. Despite advances in medical care, patients on chronic dialysis continue to have unacceptable cardiovascular mortality rates as high as 15–20% annually [2]. There has been growing interest in dialysis intensification to improve cardiovascular outcomes. Left ventricular (LV) hypertrophy is common in the dialysis population [3] and the change in left ventricular mass (LVM) has been used as a surrogate endpoint in major randomized controlled trials of dialysis intensification [4, 5] In-center nocturnal hemodialysis (INHD) administered over 7–8 h sessions, three times per week is associated with improved mineral metabolism and quality of life [6]. Significant LVM regression has been demonstrated in patients who converted to INHD compared with those who remained on CHD [7]. Hypertension, inflammation, anemia and the toxic milieu of ESRD, which have been implicated in LV remodeling and cardiomyopathy, may injure the right ventricle (RV) as well [8]. Dialysis recipients are also susceptible to numerous stresses that target the RV. RV dysfunction may be a direct consequence of pulmonary hypertension, which is common in dialysis recipients. The physiology and clinical importance of the RV have been described by Dell’Italia [8]. Pathophysiologic mechanisms for pulmonary hypertension include arteriovenous fistula (AVF)-induced increased cardiac output, endothelial dysfunction, dysregulation of vascular tone due to an imbalance in vasoactive substances (nitric oxide) and local and systemic inflammation. Despite this, there are only limited data on RV structure and function in the dialysis population. A few studies have utilized echocardiography, which is suboptimal for RV assessment [9–12]. Cardiac magnetic resonance (CMR) imaging is considered the reference standard for RV assessment due to excellent delineation of the endocardial borders, relatively high spatial and temporal resolution and true volumetric measurements without any geometric assumptions [13]. Despite the known prognostic significance of RV dysfunction in various disease states [14–17], there are no published studies that have used CMR for RV assessment in the dialysis population. Furthermore, the impact of INHD, or any form of intensified dialysis, on RV structure and function has not been studied. Our primary objective was to evaluate changes in the RV mass index (RVMI), RV end-diastolic volume index (RVEDVI), RV end-systolic volume index (RVESVI) and RV ejection fraction (RVEF) after conversion to INHD. We also examined the relationship between RV remodeling in relation to concurrent structural changes in the LV. MATERIALS AND METHODS Participants In a two-center prospective cohort study of patients with ESRD, we previously demonstrated significant LVM regression in patients who converted to INHD compared with those who remained on CHD [7]. In the present study we examine the changes in RV volume and EF in this cohort of patients. Details of the study design have been previously published [7]. Briefly, this prospective observational study was conducted with 67 patients who had been on CHD for at least 90 days at two university-affiliated tertiary care centers in Canada, St Michael’s Hospital (Toronto) and St Paul’s Hospital (Vancouver). CHD was administered for 3–4 h per session and INHD for 7–8 h per session, both three times a week. The decision to convert to INHD was jointly made by the treating nephrologist and the patient. The exclusion criteria were the same for both the INHD and CHD groups and included serious comorbidities with life expectancy <1 year, planned renal transplant from a live donor in the coming year, contraindications to CMR and confirmed pregnancy. Thirty-seven patients converted to INHD and 30 individuals who chose to remain on CHD were recruited as the control group. All patients in the CHD arm continued on their previous dialysis prescription. All fundamental aspects of hemodialysis care conformed to prevailing guidelines during the study period and did not differ between the two groups. Approval of the Research Ethics Boards of each site and written consent from all participants were sought. Follow-up Planned follow-up for all patients was 52 weeks. This was preceded by a 12-week baseline period during which all patients were on CHD. During this time, baseline CMR scans were performed. We collected clinical and biochemical data including blood pressure, intradialytic weight gain, concentration of serum phosphate, high-sensitivity troponin I, N-terminal B-type natriuretic peptide (NT-BNP) and fibroblast growth factor 23 (FGF-23). At the conclusion of the 52-week follow-up, a 12-week end-of-study (EOS) period commenced during which the subjects continued on the same dialysis schedule and the same array of investigations was conducted and similar data were collected. CMR acquisition and post-processing All CMR examinations (except for one patient who could not fit into the 1.5 T scanner, thus a 3 T scanner was used) were performed using a 1.5 T MRI scanner with a phased-array cardiac coil, retrospective vector-cardiographic gating and a standardized protocol [18]. All CMR post-processing was performed using cvi42 software (Circle Cardiovascular Imaging, Calgary, Alberta, Canada). LV measurements were performed by an experienced blinded cardiologist (A.T.Y.) [7]. RV measurements were performed offline separately by a cardiac radiologist (G.R.K.) who was blinded to the treatment group, order of exam and LV and other clinical data. RV endocardial and epicardial contours were manually drawn using standard techniques on the short-axis SSFP images, which did not include trabeculation or papillary muscle mass for volumetric and mass calculation [19]. RV hypertrophy (RVH) was defined as RVMI >29 g/m2 in men and >28 g/m2 in women [20]. To ensure accuracy and reliability, 10 months after the initial image analysis, 20 cases were randomly selected and the blinded cardiac radiologist repeated the post-processing without knowledge of the previous calculations or order of the study. Intra-observer agreement was excellent, with intraclass correlation coefficients of 0.99 [95% confidence interval (CI) 0.98–1] for RVEDVI, 0.98 (95% CI 0.95–1) for RVESVI and 0.96 (95% CI 0.89–0.98) for RVMI. Statistical analysis Means (± standard deviation) or medians (interquartile range) were used to describe continuous variables. Intergroup comparisons were made using the t-test or Mann–Whitney U-test, as appropriate. Within each group, baseline and EOS comparisons were made by the paired t-test. For the primary analysis, we compared the differences in 1-year changes (EOS minus baseline) between the two groups with respect to RV parameters and reported 95% CIs. Multivariable linear regression was performed to adjust for baseline differences in the INHD and CHD recipients, where the change in the RV parameter (mass, volume or EF) was the dependent variable and dialysis modality (INHD versus CHD), age, number of months on dialysis, diabetes mellitus and vascular access type were the independent variables. Pearson’s correlation was used to examine the relationships between RV and LV parameters and Spearman’s (nonparametric) correlation was used for relationships with biomarkers. A two-sided P-value <0.05 was considered statistically significant. All analyses were conducted with SPSS version 22 (IBM, Armonk, NY, USA). RESULTS Thirty-seven patients converted to INHD from CHD while 30 patients eligible for INHD remained on CHD and served as controls. Patients who converted to INHD were older, more likely to have diabetes, less likely to have glomerulonephritis and had a shorter dialysis history compared with the control group. Cardiovascular and selected laboratory parameters at baseline are shown in Table 1. At baseline, a total of only seven patients had RVH. At 1 year, 10 patients did not undergo follow-up CMR due to receipt of a renal transplant (n = 2), serious morbidity or death (n = 8); 1 patient had an incomplete follow-up CMR and was excluded from this analysis. Table 1 Baseline characteristics of the study population Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Continuous variables displayed as mean ± SD or median (interquartile range). Table 1 Baseline characteristics of the study population Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Continuous variables displayed as mean ± SD or median (interquartile range). RV mass, volumes and EF In the control group, baseline to EOS comparisons using the paired t-test did not show significant changes over 1 year in RVMI [−0.4 g/m2 (95% CI −2.1–1.4), P = 0.65], RVEDVI [−2.2 mL/m2 (95% CI −8.7–4.3), P = 0.49], RVESVI [1.2 mL/m2 (95% CI −2.4–4.8), P = 0.50] or RVEF [−2.3% (95% CI −5.6–1), P = 0.16]. In contrast, patients who converted to INHD had a significant reduction in RVMI [−2.1 g/m2 (95% CI −3.8 to −0.4), P = 0.017], RVEDVI [−9.5 mL/m2 (95% CI −16.3 to −2.6), P = 0.008] and RVESVI [−6.2 mL/m2 (95% CI −10.9 to −1.6), P = 0.011]. The increase in RVEF was not significant [2.2% (95% CI −1.3–5.7), P = 0.21]. Despite the larger reduction in RVMI in the INHD group, the difference in 1-year changes between the two groups was not significant [−1.9 g/m2 (95% CI −4.6–0.8), P = 0.16] (Figure 1). Similarly, the differences in 1-year changes in RVEDVI [−9.4 mL/m2 (95% CI −20.3–1.4), P = 0.09] and RVEF [3.6% (95% CI −1.9–9.1), P = 0.19] were also not significant (Figures 2 and 3). However, the difference in 1-year change in RVESVI was significant [−7.9 mL/m2 (95% CI −14.9 to −0.9), P = 0.03] (Figure 4). The results were similar in multivariable regression analysis (Table 2). Table 2 Between-group temporal changes in RV parameters following conversion to INHD at 1 yeara RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  a CHD was the referent group. b Adjusted for age, number of months on dialysis, diabetes mellitus and vascular access type. Table 2 Between-group temporal changes in RV parameters following conversion to INHD at 1 yeara RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  a CHD was the referent group. b Adjusted for age, number of months on dialysis, diabetes mellitus and vascular access type. FIGURE 1 View largeDownload slide Mean changes in RV mass index over 1 year in the INHD versus CHD (control) group. FIGURE 1 View largeDownload slide Mean changes in RV mass index over 1 year in the INHD versus CHD (control) group. FIGURE 2 View largeDownload slide Mean changes in the RVEDVI over 1 year in the INHD versus CHD (control) group. FIGURE 2 View largeDownload slide Mean changes in the RVEDVI over 1 year in the INHD versus CHD (control) group. FIGURE 3 View largeDownload slide Mean change in the RVEF over 1 year in the INHD versus CHD (control) group. FIGURE 3 View largeDownload slide Mean change in the RVEF over 1 year in the INHD versus CHD (control) group. FIGURE 4 View largeDownload slide Mean change in the RVESVI over 1 year in the INHD versus CHD (control) group. FIGURE 4 View largeDownload slide Mean change in the RVESVI over 1 year in the INHD versus CHD (control) group. Relationship between RV and LV remodeling The changes in RV parameters paralleled those in LV, with positive and moderate to strong correlations (Table 3). Table 3 Relationships between RV and LV remodeling over 1 year Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Table 3 Relationships between RV and LV remodeling over 1 year Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Vascular access and biomarkers Of the 67 patients at baseline, 39 patients had an AVF/graft and 28 patients had a central venous catheter (CVC) for vascular access. Of the 28 patients with a CVC, 5 converted to an AVF/graft, 1 patient had a catheter change and the remainder continued with a CVC; 1 of 39 patients with an AVF/graft switched to a CVC due to graft failure. There was no association between access type and RV parameters at baseline or over 1 year. Among biomarkers, significant correlation existed only between the change in RVESVI and NT-BNP (r = 0.3, P = 0.04) (Table 4). There was no significant correlation between NT-BNP, troponin I and RV mass and volume indices or EF. RV parameters also did not show any significant correlation with interdialytic weight gain and systolic blood pressure (Table 4). Table 4 Spearman’s correlations between 1-year changes in RV parameters and volume overload, systolic blood pressure and biomarkers   RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39    RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39  Table 4 Spearman’s correlations between 1-year changes in RV parameters and volume overload, systolic blood pressure and biomarkers   RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39    RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39  DISCUSSION We found that conversion to INHD was associated with a significant reduction in RV mass and volume indices at 1 year. Compared with the control group, the INHD group showed significantly greater reduction in the RVESVI, while the reductions in the RVMI, RVEDVI and increase in RVEF were not significant. The temporal changes in RV volume and function paralleled those observed in the LV. The pathophysiology of cardiac remodeling in dialysis patients is complex and likely mediated by myriad mechanical and biochemical factors. These include persistent volume overload, fluctuating volume status, coexisting hypertension, accumulation of uremic toxins, inflammation, anemia and endocrine axis derangements [21]. We postulate that these same factors leading to adverse LV remodeling would also contribute to RV remodeling. Furthermore, AVFs/grafts in chronic dialysis patients increase the preload on the right heart and might impact its performance [22]. There is a high prevalence of pulmonary hypertension in dialysis patients, ranging between 17% and 49.5%, depending on the mode of dialysis and other cardiovascular comorbidities [23]. Impairment of pulmonary circulation along with chronic volume overload and high levels of fibrosis promoting cytokines and growth factors, namely platelet-derived growth factor, FGF and transforming growth factor-β, likely contribute to pulmonary hypertension [21]. Endothelial dysfunction, lower activity of nitric oxide synthase and increased levels of serum endothelin promote extensive growth of endothelial cells, leading to complete obliteration of pulmonary vessels [22]. Vasoconstriction and vascular sclerosis triggered by microbubbles escaping from the dialysis circuit have also been implicated [24]. Furthermore, hemostatic mechanisms have been described linking ESRD and dialysis with increased risk of pulmonary venous thromboembolism [25], which could impair right heart function. Multiple mechanisms have been proposed for the cardiovascular benefits of INHD. Due to improved blood pressure control, patients who convert to INHD require fewer antihypertensive medications [7, 26, 27]. LV hypertrophy is strongly associated with hypertension and thus improved blood pressure control likely contributes to LV mass regression in INHD patients [28]. Extracellular volume expansion is the main pathophysiological determinant of hypertension in dialysis patients [29]. INHD has shown improved control of extracellular volume excess by reducing the time-averaged fluid load [30]. INHD may also more closely approximate the capacity of a native or transplanted kidney to regulate extracellular volume and solute composition [30–32]. Improved mineral metabolism with lower serum phosphate and calcium–phosphate products has been demonstrated in several studies [6, 26, 27, 33]. Studies have also suggested that nocturnal hemodialysis is associated with improved vascular risk in patients with ESRD by playing a role in restoration of abnormal smooth muscle cell biology [34]. Studies suggest that these mechanisms may promote favorable RV remodeling as well [35]. Our findings suggest that these mechanisms may promote favorable RV remodeling as well. The INHD group demonstrated improvements in the RVEDVI and RVEF, even though these differences were not statistically significant compared with the control group. Interestingly, conversion to INHD was associated with a significant reduction in the RVESVI. We found that the temporal changes in RV volume and function paralleled those of the LV and were in a similar direction with moderate to strong association. This further supports the notion that the beneficial effects of INHD on the LV also impact the RV. The significance of reduction of the RVESVI in the hemodialysis population remains to be studied. RV dysfunction is prognostically important in various disease states, such as coronary artery disease, where depiction of RV wall motion abnormalities on stress echocardiography has independent and incremental prognostic value even over LV wall motion abnormalities [14]. In tetralogy of Fallot patients, the RVESVI has been identified as a more sensitive marker of reverse remodeling after pulmonary valve replacement [15]. In nonischemic dilated cardiomyopathy, RV systolic dysfunction has been shown to be a powerful independent predictor of cardiac transplant–free survival and adverse heart failure outcomes [16]. Furthermore, reevaluation of the RVEF during follow-up conferred additive long-term prognostic value [17]. Therefore, our findings raise the interesting hypothesis that favorable RV structural and functional changes might also lead to improved clinical outcomes in the setting of ESRD. Despite evidence linking RV dysfunction with chronic dialysis and demonstration of RV function as an independent prognosticator in other conditions, there exists a significant knowledge gap. LV mass is a well-established, powerful, independent prognosticator that has been used in multiple randomized controlled trials evaluating newer dialysis modalities [3–5]. While CMR has shown favorable LV changes in INHD patients, CMR assessment of the RV has not been systematically performed in patients on conventional or intensified hemodialysis. Only a few studies have attempted to assess the RV in hemodialysis patients using echocardiography [9–11]. These were cross-sectional studies with a small number of patients that only assessed acute hemodynamic effects of dialysis using echocardiography with no long-term follow-up. There are no published studies that have assessed RV mass, volume and systolic function using the reference standard CMR in a longitudinal fashion, in INHD or in any form of intensified dialysis. Echocardiographic assessment of the RV is known to be inaccurate due to its complex geometry, predominant contribution of longitudinal motion to systolic function, difficult visualization due to anterior location and near-field artifact [36, 37]. Furthermore, based on the anatomy, structure and function, the RV is divided into the inflow and outflow tracts and therefore is not amenable to simple geometric assumptions [38, 39]. The RV is thin-walled (2–4 mm) with a muscle mass approximately one-sixth that of the LV. Therefore, even with the excellent spatial resolution (∼1.5–2 mm) and signal:noise ratio in CMR, we may not be able to detect small changes in RV mass, in contrast to relatively small changes in LV mass. Nevertheless, CMR remains the best available technique for the assessment of RV structure and function that does not require geometric assumptions. Our study therefore provides novel insights into the pathophysiology of RV remodeling in INHD patients. It also highlights the need for larger and longer-term follow-up studies to detect significant RV changes. CVC use was relatively high in our patients, comprising 41.8% of the overall cohort and 56.8% of the INHD patients. There are several reasons for this phenomenon. A greater proportion of INHD patients had diabetes and tend to have vasculature that is less amenable to creation of a permanent vascular access. The INHD patients received dialysis for a shorter period of time compared with the control group at recruitment, and therefore they were more likely to remain on hemodialysis with a CVC. Only a minority of patients switched vascular access during the follow-up period. Studies using echocardiography have shown that RV abnormalities and hypertrophy are more frequent in patients on hemodialysis compared with peritoneal dialysis, particularly those with an AVF as opposed to a CVC, likely related to development of pulmonary hypertension [40–42]. In contrast to these studies, we observed no significant difference in RV structure and function at baseline or changes over 1 year with respect to the vascular access. The small number of participants in our study might have limited the power to detect differences. Our study showed a borderline significant correlation between change in the RVESVI and NT-proBNP. While this correlation may represent a chance finding, an elevated BNP level might reflect increased filling pressure in both ventricles. However, we did not find any significant relationship between RV measurements and interdialytic weight gain as a measure of volume overload and systolic blood pressure. It is possible that the relative importance of these factors is different in LV and RV remodeling. We also did not observe any relationship between biomarkers of cardiomyocyte injury and myocardial fibrosis (high-sensitivity troponin I and FGF23, respectively) and RV remodeling. Further studies to elucidate mechanisms of LV and RV remodeling in ESRD are needed. To our knowledge, this is the first prospective longitudinal study that performed rigorous RV assessment in the intensified dialysis population using the reference imaging standard CMR. All RV measurements were independently performed by a single experienced reader who was blinded not only to the order of examination and other clinical data, but also the LV measurements. However, our study had several limitations, including a small sample size, which might have limited our power to demonstrate subtle changes in RV structure and function. Despite our efforts to minimize bias due to observed baseline differences, there probably existed unmeasured confounders in this nonrandomized study. The small sample size of our study also likely limited the power to demonstrate any relationship between vascular access and RV remodeling. Larger and longer-term prospective studies using CMR are required to elucidate this in the future. Finally, as we did not assess RV remodeling beyond 1 year, our study might not detect more gradual remodeling of RV. In conclusion, compared with continuation of CHD, conversion to INHD was associated with a significant reduction of RVESVI, along with a trend toward improvements in RVMI, the RVEDVI and RVEF. The parallel changes in LV and RV structure and function suggest that similar salutary mechanisms might mediate favorable remodeling in both ventricles. Our findings support future larger prospective studies with longer-term follow-up to elucidate the impact of dialysis intensification on the RV. AUTHORS’ CONTRIBUTIONS G.R.-K.: study conception and design, data analysis and interpretation, drafting and revision of the manuscript. R.W.: study conception and design, data analysis and interpretation, manuscript revision. M.B.G.: data analysis and interpretation, manuscript revision. R.W.: data analysis and interpretation, manuscript revision. L.J.-J.: data analysis and interpretation, manuscript revision. M.K.: data analysis and interpretation, manuscript revision. J.L.: data analysis and interpretation, manuscript revision. A.K.: data analysis and interpretation, manuscript revision. O.B.: data analysis and interpretation, manuscript revision. A.B.: data analysis and interpretation, manuscript revision. M.-Y.N.: data analysis and interpretation, manuscript revision. D.P.D.: data analysis and interpretation, manuscript revision. A.T.Y.: study conception and design, data analysis and interpretation, manuscript revision. FUNDING This study was supported by an operating grant from the Canadian Institutes of Health Research (MOP-89982) and a grant-in-aid from the Heart and Stroke Foundation (project number G-14-0005856). The study sponsors had no role in the study design, data collection or analysis, interpretation of the findings, writing the manuscript or the decision to submit the manuscript for publication (ClinicalTrials.gov identifier NCT00718848). CONFLICT OF INTEREST None declared. This manuscript has not been previously published and is not being considered for publication elsewhere in whole or in part in any language except Nephrology Dialysis Transplantation. REFERENCES 1 Go AS, Chertow GM, Fan D et al.  . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med  2004; 351: 1296– 1305 Google Scholar CrossRef Search ADS PubMed  2 Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2003 to 2012. Ottawa, ON: CIHI; 2014. 3 Culleton BF, Walsh M, Klarenbach SW et al.  . Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA  2007; 298: 1291– 1299 Google Scholar CrossRef Search ADS PubMed  4 Chertow GM, Levin NW, Beck GJ et al.  . In-center hemodialysis six times per week versus three times per week. N Engl J Med  2010; 363: 2287– 2300 Google Scholar CrossRef Search ADS PubMed  5 Rocco MV, Lockridge RSJr, Beck GJ et al.  . The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int  2011; 80: 1080– 1091 Google Scholar CrossRef Search ADS PubMed  6 Bugeja A, Dacouris N, Thomas A et al.  . In-center nocturnal hemodialysis: another option in the management of chronic kidney disease. Clin J Am Soc Nephrol  2009; 4: 778– 783 Google Scholar CrossRef Search ADS PubMed  7 Wald R, Goldstein MB, Perl J et al.  . The association between conversion to in-centre nocturnal hemodialysis and left ventricular mass regression in patients with end-stage renal disease. Can J Cardiol  2016; 32: 369– 377 Google Scholar CrossRef Search ADS PubMed  8 Dell’Italia LJ. The right ventricle: anatomy, physiology, and clinical importance. Curr Probl Cardiol  1991; 16: 653– 720 Google Scholar PubMed  9 Rudhani ID, Bajraktari G, Kryziu E et al.  . Left and right ventricular diastolic function in hemodialysis patients. Saudi J Kidney Dis Transpl  2010; 21: 1053– 1057 Google Scholar PubMed  10 Sadler DB, Brown J, Nurse H et al.  . Impact of hemodialysis on left and right ventricular Doppler diastolic filling indices. Am J Med Sci  1992; 304: 83– 90 Google Scholar CrossRef Search ADS PubMed  11 Akkaya M, Erdogan E, Saq S et al.  . The effect of hemodialysis on right ventricular functions in patients with end-stage renal failure. Anadolu Kardiyol Derg  2012; 12: 5– 10 Google Scholar PubMed  12 Ho SY, Nihoyannopoulos P. Anatomy, echocardiography, and normal right ventricular dimensions. Heart  2006; 92(Suppl 1): i2– i13 Google Scholar CrossRef Search ADS PubMed  13 Geva T. MRI is the preferred method for evaluation right ventricular size and function in patients with congenital heart disease. Circ Cardiovasc Imaging  2014; 7: 190– 197 Google Scholar CrossRef Search ADS PubMed  14 Wever-Pinzon O, Silva Enciso J, Romero J et al.  . Right ventricular function is a strong prognosticator in patients with HIV referred for stress echocardiography. Circulation  2010; 122(Suppl 21): A13232 15 Oosterhof T, van Straten A, Vliegen HW et al.  . Preoperative thresholds for pulmonary valve replacement in patients with corrected tetralogy of Fallot using cardiovascular magnetic resonance. Circulation  2007; 116: 545– 551 Google Scholar CrossRef Search ADS PubMed  16 Gulati A, Ismail TF, Jabbour A et al.  . The prevalence and prognostic significance of right ventricular systolic dysfunction in nonischemic dilated cardiomyopathy. Circulation  2013; 128: 1623– 1633 Google Scholar CrossRef Search ADS PubMed  17 Merlo M, Gobbo M, Stolfo D et al.  . The prognostic impact of the evolution of RV function in idiopathic DCM. JACC Cardiovasc Imaging  2016; 9: 1034– 1042 Google Scholar CrossRef Search ADS PubMed  18 Jakubovic BD, Wald R, Goldstein MB et al.  . Comparative assessment of 2-dimensional echocardiography vs cardiac magnetic resonance imaging in measuring left ventricular mass in patients with and without end-stage renal disease. Can J Cardiol  2013; 29: 384– 390 Google Scholar CrossRef Search ADS PubMed  19 Prakken NH, Velthuis BK, Vonken EJJ et al.  . Cardiac MRI: standardized right and left ventricular quantification by briefly coaching inexperienced personnel. Open Magn Reson J  2008; 1: 104– 111 Google Scholar CrossRef Search ADS   20 Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER et al.  . Normal values for cardiovascular magnetic resonance in adults and children. J Cardiovasc Magn Reson  2015; 17: 29 Google Scholar CrossRef Search ADS PubMed  21 Curtis BM, Parfrey PS. Congestive heart failure in chronic kidney disease: disease-specific mechanisms of systolic and diastolic heart failure and management. Cardiol Clin  2005; 23: 275– 284 Google Scholar CrossRef Search ADS PubMed  22 Di Lullo L, Floccari F, Polito P. Right ventricular diastolic function in dialysis patients could be affected by vascular access. Nephron Clin Pract  2011; 118: 257– 261 Google Scholar CrossRef Search ADS   23 Kosmadakis G, Aquilera D, Carceles O et al.  . Pulmonary hypertension in dialysis patients. Ren Fail  2013; 35: 514– 520 Google Scholar CrossRef Search ADS PubMed  24 Nakhoul F, Yigla M, Gilman R et al.  . The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access. Nephrol Dial Transplant  2005; 20: 1686– 1692 Google Scholar CrossRef Search ADS PubMed  25 Wattanakit K, Cushman M, Stehman-Breen C et al.  . Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol  2008; 19: 135– 140 Google Scholar CrossRef Search ADS PubMed  26 Ok E, Duman S, Asci G et al.  . Comparison of 4- and 8-h dialysis sessions in thrice-weekly in-centre haemodialysis: a prospective, case-controlled study. Nephrol Dial Transplant  2011; 26: 1287– 1296 Google Scholar CrossRef Search ADS PubMed  27 Jin X, Rong S, Mei C et al.  . Effects of thrice-weekly in-center nocturnal vs. conventional hemodialysis on integrated backscatter of myocardial tissue. Hemodial Int  2011; 15: 200– 210 Google Scholar CrossRef Search ADS PubMed  28 Wald R, Goldstein MB, Wald RM et al.  . Correlates of left ventricular mass in chronic hemodialysis recipients. Int J Cardiovasc Imaging  2014; 30: 349– 356 Google Scholar CrossRef Search ADS PubMed  29 D’Amico M, Locatelli F. Hypertension in dialysis: pathophysiology and treatment. J Nephrol  2010; 15: 438– 445 30 Wald R, Yan AT, Perl J et al.  . Regression of left ventricular mass following conversion from conventional hemodialysis to thrice weekly in-centre nocturnal hemodialysis. BMC Nephrol  2012; 13: 3 Google Scholar CrossRef Search ADS PubMed  31 Troidle L, Finkelstein F, Hotchkiss M et al.  . Enhanced solute removal with intermittent, in-center, 8-hour nocturnal hemodialysis. Hemodial Int  2009; 13: 487– 491 Google Scholar CrossRef Search ADS PubMed  32 Cravedi P, Ruggenenti P, Mingardi G et al.  . Thrice-weekly in-center nocturnal hemodialysis: an effective strategy to optimize chronic dialysis therapy. Int J Artif Organs  2009; 32: 12– 19 Google Scholar CrossRef Search ADS PubMed  33 Lacson EJr, Xu J, Suri RS et al.  . Survival with three-times weekly in-center nocturnal versus conventional hemodialysis. J Am Soc Nephrol  2012; 23: 687– 695 Google Scholar CrossRef Search ADS PubMed  34 Chan CT, Lovren F, Pan Y et al.  . Nocturnal haemodialysis is associated with improved vascular smooth muscle cell biology. Nephrol Dial Transplant  2009; 24: 3867– 3871 Google Scholar CrossRef Search ADS PubMed  35 Chan CT, Greene T, Chertow GM et al.  . Effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling. Clin J Am Soc Nephrol  2013; 8: 2106– 2116 Google Scholar CrossRef Search ADS PubMed  36 Srinivasan C, Sachdeva R, Morrow WR et al.  . Limitations of standard echocardiographic methods for quantification of right ventricular size and function in children and young adults. J Ultrasound Med  2011; 30: 487– 493 Google Scholar CrossRef Search ADS PubMed  37 Lindqvist P, Calcutteea A, Henein M. Echocardiography in the assessment of right heart function. Eur J Echocardiogr  2008; 9: 225– 234 Google Scholar PubMed  38 Haddad F, Hunt SA, Rosenthal DN et al.  . Right ventricular function in cardiovascular disease, part I. Circulation  2008; 117: 1436– 1448 Google Scholar CrossRef Search ADS PubMed  39 Haddad F, Doyle R, Murphy DJ et al.  . Right ventricular function in cardiovascular disease, part II. Circulation  2008; 117: 1717– 1731 Google Scholar CrossRef Search ADS PubMed  40 Momtaz M, Al Fishawy H, Aljarhi UM et al.  . Right ventricular dysfunction in patients with end-stage renal disease on regular hemodialysis. Egypt J Intern Med  2013; 25: 127– 132 41 Huang S, Zhao L. Effect of different dialysis modalities on right ventricular dysfunction in patients with end-stage renal disease. Nephrol Dialysis Transplant  2015; 30(Suppl 3): iii556– iii569 42 Paneni F, Gregori M, Ciavarella GM et al.  . Right ventricular dysfunction in patients with end-stage renal disease. Am J Nephrol  2010; 32: 432– 438 Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Association between conversion to in-center nocturnal hemodialysis and right ventricular remodeling

Loading next page...
 
/lp/ou_press/association-between-conversion-to-in-center-nocturnal-hemodialysis-and-Hp5qua6zrO
Publisher
Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
D.O.I.
10.1093/ndt/gfx232
Publisher site
See Article on Publisher Site

Abstract

ABSTRACT Background In-center nocturnal hemodialysis (INHD) is associated with favorable left ventricular (LV) remodeling. Although right ventricular (RV) structure and function carry prognostic significance, the impact of dialysis intensification on RV is unknown. Our objectives were to evaluate changes in RV mass index (MI), end-diastolic volume index (EDVI), end-systolic volume index (ESVI) and ejection fraction (EF) after conversion to INHD and their relationship with LV remodeling. Methods Of 67 conventional hemodialysis (CHD, 4 h/session, three times/week) patients, 30 continued on CHD and 37 converted to INHD (7–8 h/session, three times/week). Cardiac magnetic resonance imaging was performed at baseline and 1 year using a standardized protocol; an experienced and blinded reader performed RV measurements. Results At 1 year there were significant reductions in RVMI {−2.1 g/m2 [95% confidence interval (CI) −3.8 to − 0.4], P = 0.017}, RVEDVI [−9.5 mL/m2 (95% CI − 16.3 to − 2.6), P = 0.008] and RVESVI [−6.2 mL/m2 (95% CI − 10.9 to − 1.6), P = 0.011] in the INHD group; no significant changes were observed in the CHD group. Between-group comparisons showed significantly greater reduction of RVESVI [−7.9 mL/m2 (95% CI − 14.9 to − 0.9), P = 0.03] in the INHD group, a nonsignificant trend toward greater reduction in RVEDVI and no significant difference in RVMI and RVEF changes. There was significant correlation between LV and RV in terms of changes in mass index (MI) (r = 0.46), EDVI (r = 0.73), ESVI (r = 0.7) and EF (r = 0.38) over 1 year (all P < 0.01). Conclusions Conversion to INHD was associated with a significant reduction of RVESVI. Temporal changes in RV mass, volume and function paralleled those of LV. Our findings support the need for larger, longer-term studies to confirm favorable RV remodeling and determine its impact on clinical outcomes. cardiac magnetic resonance imaging, hemodialysis, right ventricle Conventional hemodialysis (CHD) is the dominant form of renal replacement therapy for end-stage renal disease (ESRD) and is routinely administered in 4-h sessions, three times per week [1]. Despite advances in medical care, patients on chronic dialysis continue to have unacceptable cardiovascular mortality rates as high as 15–20% annually [2]. There has been growing interest in dialysis intensification to improve cardiovascular outcomes. Left ventricular (LV) hypertrophy is common in the dialysis population [3] and the change in left ventricular mass (LVM) has been used as a surrogate endpoint in major randomized controlled trials of dialysis intensification [4, 5] In-center nocturnal hemodialysis (INHD) administered over 7–8 h sessions, three times per week is associated with improved mineral metabolism and quality of life [6]. Significant LVM regression has been demonstrated in patients who converted to INHD compared with those who remained on CHD [7]. Hypertension, inflammation, anemia and the toxic milieu of ESRD, which have been implicated in LV remodeling and cardiomyopathy, may injure the right ventricle (RV) as well [8]. Dialysis recipients are also susceptible to numerous stresses that target the RV. RV dysfunction may be a direct consequence of pulmonary hypertension, which is common in dialysis recipients. The physiology and clinical importance of the RV have been described by Dell’Italia [8]. Pathophysiologic mechanisms for pulmonary hypertension include arteriovenous fistula (AVF)-induced increased cardiac output, endothelial dysfunction, dysregulation of vascular tone due to an imbalance in vasoactive substances (nitric oxide) and local and systemic inflammation. Despite this, there are only limited data on RV structure and function in the dialysis population. A few studies have utilized echocardiography, which is suboptimal for RV assessment [9–12]. Cardiac magnetic resonance (CMR) imaging is considered the reference standard for RV assessment due to excellent delineation of the endocardial borders, relatively high spatial and temporal resolution and true volumetric measurements without any geometric assumptions [13]. Despite the known prognostic significance of RV dysfunction in various disease states [14–17], there are no published studies that have used CMR for RV assessment in the dialysis population. Furthermore, the impact of INHD, or any form of intensified dialysis, on RV structure and function has not been studied. Our primary objective was to evaluate changes in the RV mass index (RVMI), RV end-diastolic volume index (RVEDVI), RV end-systolic volume index (RVESVI) and RV ejection fraction (RVEF) after conversion to INHD. We also examined the relationship between RV remodeling in relation to concurrent structural changes in the LV. MATERIALS AND METHODS Participants In a two-center prospective cohort study of patients with ESRD, we previously demonstrated significant LVM regression in patients who converted to INHD compared with those who remained on CHD [7]. In the present study we examine the changes in RV volume and EF in this cohort of patients. Details of the study design have been previously published [7]. Briefly, this prospective observational study was conducted with 67 patients who had been on CHD for at least 90 days at two university-affiliated tertiary care centers in Canada, St Michael’s Hospital (Toronto) and St Paul’s Hospital (Vancouver). CHD was administered for 3–4 h per session and INHD for 7–8 h per session, both three times a week. The decision to convert to INHD was jointly made by the treating nephrologist and the patient. The exclusion criteria were the same for both the INHD and CHD groups and included serious comorbidities with life expectancy <1 year, planned renal transplant from a live donor in the coming year, contraindications to CMR and confirmed pregnancy. Thirty-seven patients converted to INHD and 30 individuals who chose to remain on CHD were recruited as the control group. All patients in the CHD arm continued on their previous dialysis prescription. All fundamental aspects of hemodialysis care conformed to prevailing guidelines during the study period and did not differ between the two groups. Approval of the Research Ethics Boards of each site and written consent from all participants were sought. Follow-up Planned follow-up for all patients was 52 weeks. This was preceded by a 12-week baseline period during which all patients were on CHD. During this time, baseline CMR scans were performed. We collected clinical and biochemical data including blood pressure, intradialytic weight gain, concentration of serum phosphate, high-sensitivity troponin I, N-terminal B-type natriuretic peptide (NT-BNP) and fibroblast growth factor 23 (FGF-23). At the conclusion of the 52-week follow-up, a 12-week end-of-study (EOS) period commenced during which the subjects continued on the same dialysis schedule and the same array of investigations was conducted and similar data were collected. CMR acquisition and post-processing All CMR examinations (except for one patient who could not fit into the 1.5 T scanner, thus a 3 T scanner was used) were performed using a 1.5 T MRI scanner with a phased-array cardiac coil, retrospective vector-cardiographic gating and a standardized protocol [18]. All CMR post-processing was performed using cvi42 software (Circle Cardiovascular Imaging, Calgary, Alberta, Canada). LV measurements were performed by an experienced blinded cardiologist (A.T.Y.) [7]. RV measurements were performed offline separately by a cardiac radiologist (G.R.K.) who was blinded to the treatment group, order of exam and LV and other clinical data. RV endocardial and epicardial contours were manually drawn using standard techniques on the short-axis SSFP images, which did not include trabeculation or papillary muscle mass for volumetric and mass calculation [19]. RV hypertrophy (RVH) was defined as RVMI >29 g/m2 in men and >28 g/m2 in women [20]. To ensure accuracy and reliability, 10 months after the initial image analysis, 20 cases were randomly selected and the blinded cardiac radiologist repeated the post-processing without knowledge of the previous calculations or order of the study. Intra-observer agreement was excellent, with intraclass correlation coefficients of 0.99 [95% confidence interval (CI) 0.98–1] for RVEDVI, 0.98 (95% CI 0.95–1) for RVESVI and 0.96 (95% CI 0.89–0.98) for RVMI. Statistical analysis Means (± standard deviation) or medians (interquartile range) were used to describe continuous variables. Intergroup comparisons were made using the t-test or Mann–Whitney U-test, as appropriate. Within each group, baseline and EOS comparisons were made by the paired t-test. For the primary analysis, we compared the differences in 1-year changes (EOS minus baseline) between the two groups with respect to RV parameters and reported 95% CIs. Multivariable linear regression was performed to adjust for baseline differences in the INHD and CHD recipients, where the change in the RV parameter (mass, volume or EF) was the dependent variable and dialysis modality (INHD versus CHD), age, number of months on dialysis, diabetes mellitus and vascular access type were the independent variables. Pearson’s correlation was used to examine the relationships between RV and LV parameters and Spearman’s (nonparametric) correlation was used for relationships with biomarkers. A two-sided P-value <0.05 was considered statistically significant. All analyses were conducted with SPSS version 22 (IBM, Armonk, NY, USA). RESULTS Thirty-seven patients converted to INHD from CHD while 30 patients eligible for INHD remained on CHD and served as controls. Patients who converted to INHD were older, more likely to have diabetes, less likely to have glomerulonephritis and had a shorter dialysis history compared with the control group. Cardiovascular and selected laboratory parameters at baseline are shown in Table 1. At baseline, a total of only seven patients had RVH. At 1 year, 10 patients did not undergo follow-up CMR due to receipt of a renal transplant (n = 2), serious morbidity or death (n = 8); 1 patient had an incomplete follow-up CMR and was excluded from this analysis. Table 1 Baseline characteristics of the study population Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Continuous variables displayed as mean ± SD or median (interquartile range). Table 1 Baseline characteristics of the study population Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Characteristic  CHD (n = 30)  INHD (n = 37)  P-value  Age (years)  50.2 ± 12.2  56.8 ± 11.6  0.03  Male (sex)  17 ± 56.7  20 ± 54.1  0.83  Weight (kg)  72.5 ± 18.9  80.4 ± 21.2  0.12  Months since starting dialysis  50 (22–79)  20 (8–49)  0.02  Ethnicity, n (%)   Caucasian  5 (16.7)  14 (37.8)  0.36   African Canadian  8 (26.7)  9 (24.3)     Pacific Islander  5 (16.7)  5 (13.5)     East Indian  4 (13.3)  4 (10.8)     Asian  5 (16.7)  5 (13.5)     Latin American  1 (3.3)  0 (0)     Other  2 (6.7)  0 (0)    Cause of ESRD, n (%)   Diabetes mellitus  6 (20)  17 (46.0)  0.18   Hypertension  2 (6.7)  2 (5.4)     Glomerulonephritis  17 (56.7)  12 (32.4)     Polycystic kidney disease  1 (3.3)  1 (2.7)     Other  4 (13.3)  5 (13.5)    Vascular access, n (%)   Arteriovenous fistula  19 (63.3)  15 (40.5)  0.01   Arteriovenous graft  4 (13.3)  1 (2.7)     Tunneled central venous catheter  7 (23.3)  21 (56.8)    Interhemodialysis weight gain (kg)  2.5 ± 0.9  2.7 ± 1  0.58  Systolic blood pressure (mmHg)  140.1 ± 11.8  146 ± 17.8  0.09  High-sensitivity troponin I (ng/mL)  0.013 (<0.006–0.02)  0.025 (0.01–0.04)  <0.01  NT-BNP (pg/mL)  1619 (935–2484)  2430 (1402–7246)  0.03  FGF23 (RU/mL)  2038 (721–6955)  1705 (753–4481)  0.95  RVMI (g/m2)  20.7 ± 4.8  21 ± 5.7  0.89  RVEDVI (mL/m2)  81.8 ± 21.1  86.5 ± 27.4  0.68  RVESVI (mL/m2)  39.6 ± 8.9  46 ± 17.3  0.24  RVEF (%)  51 ± 6.0  47 ± 9.0  0.12  LVMI (g/m2)  66.3 ± 15.4  72.1 ± 15.2  0.13  LVEDVI (mL/m2)  83.4 ± 23.9  85.1 ± 21.6  0.73  LVESVI (mL/m2)  32.2 ± 10.8  38.5 ± 19.8  0.28  LVEF (%)  61.5 ± 5.2  56.2 ± 12.6  0.09  Continuous variables displayed as mean ± SD or median (interquartile range). RV mass, volumes and EF In the control group, baseline to EOS comparisons using the paired t-test did not show significant changes over 1 year in RVMI [−0.4 g/m2 (95% CI −2.1–1.4), P = 0.65], RVEDVI [−2.2 mL/m2 (95% CI −8.7–4.3), P = 0.49], RVESVI [1.2 mL/m2 (95% CI −2.4–4.8), P = 0.50] or RVEF [−2.3% (95% CI −5.6–1), P = 0.16]. In contrast, patients who converted to INHD had a significant reduction in RVMI [−2.1 g/m2 (95% CI −3.8 to −0.4), P = 0.017], RVEDVI [−9.5 mL/m2 (95% CI −16.3 to −2.6), P = 0.008] and RVESVI [−6.2 mL/m2 (95% CI −10.9 to −1.6), P = 0.011]. The increase in RVEF was not significant [2.2% (95% CI −1.3–5.7), P = 0.21]. Despite the larger reduction in RVMI in the INHD group, the difference in 1-year changes between the two groups was not significant [−1.9 g/m2 (95% CI −4.6–0.8), P = 0.16] (Figure 1). Similarly, the differences in 1-year changes in RVEDVI [−9.4 mL/m2 (95% CI −20.3–1.4), P = 0.09] and RVEF [3.6% (95% CI −1.9–9.1), P = 0.19] were also not significant (Figures 2 and 3). However, the difference in 1-year change in RVESVI was significant [−7.9 mL/m2 (95% CI −14.9 to −0.9), P = 0.03] (Figure 4). The results were similar in multivariable regression analysis (Table 2). Table 2 Between-group temporal changes in RV parameters following conversion to INHD at 1 yeara RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  a CHD was the referent group. b Adjusted for age, number of months on dialysis, diabetes mellitus and vascular access type. Table 2 Between-group temporal changes in RV parameters following conversion to INHD at 1 yeara RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  RV parameter  Unadjusted  Adjustedb  (95% CI)  (95% CI)  RVMI (g/m2)  −1.7 (−0.8–4.1)  −1.9 (−4.6–0.8)  P = 0.17  P = 0.16  RVEDVI (mL/m2)  −7.3 (−2.4–16.9)  −9.4 (−20.3–1.4)  P = 0.14  P = 0.09  RVESVI (mL/m2)  −7.7 (1.2–13.6)  −7.9 (−14.9 to − 0.9)  P = 0.02  P = 0.03  RVEF (%)  4.5 (−9.4–0.4)  3.6 (−1.9–9.1)  P = 0.07  P = 0.19  a CHD was the referent group. b Adjusted for age, number of months on dialysis, diabetes mellitus and vascular access type. FIGURE 1 View largeDownload slide Mean changes in RV mass index over 1 year in the INHD versus CHD (control) group. FIGURE 1 View largeDownload slide Mean changes in RV mass index over 1 year in the INHD versus CHD (control) group. FIGURE 2 View largeDownload slide Mean changes in the RVEDVI over 1 year in the INHD versus CHD (control) group. FIGURE 2 View largeDownload slide Mean changes in the RVEDVI over 1 year in the INHD versus CHD (control) group. FIGURE 3 View largeDownload slide Mean change in the RVEF over 1 year in the INHD versus CHD (control) group. FIGURE 3 View largeDownload slide Mean change in the RVEF over 1 year in the INHD versus CHD (control) group. FIGURE 4 View largeDownload slide Mean change in the RVESVI over 1 year in the INHD versus CHD (control) group. FIGURE 4 View largeDownload slide Mean change in the RVESVI over 1 year in the INHD versus CHD (control) group. Relationship between RV and LV remodeling The changes in RV parameters paralleled those in LV, with positive and moderate to strong correlations (Table 3). Table 3 Relationships between RV and LV remodeling over 1 year Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Table 3 Relationships between RV and LV remodeling over 1 year Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Parameter  Pearson’s correlation (r)  P-value  (n = 56)  Mass index  0.46  <0.001  End-diastolic volume index  0.73  <0.001  End-systolic volume index  0.70  <0.001  Ejection fraction  0.38  0.004  Vascular access and biomarkers Of the 67 patients at baseline, 39 patients had an AVF/graft and 28 patients had a central venous catheter (CVC) for vascular access. Of the 28 patients with a CVC, 5 converted to an AVF/graft, 1 patient had a catheter change and the remainder continued with a CVC; 1 of 39 patients with an AVF/graft switched to a CVC due to graft failure. There was no association between access type and RV parameters at baseline or over 1 year. Among biomarkers, significant correlation existed only between the change in RVESVI and NT-BNP (r = 0.3, P = 0.04) (Table 4). There was no significant correlation between NT-BNP, troponin I and RV mass and volume indices or EF. RV parameters also did not show any significant correlation with interdialytic weight gain and systolic blood pressure (Table 4). Table 4 Spearman’s correlations between 1-year changes in RV parameters and volume overload, systolic blood pressure and biomarkers   RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39    RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39  Table 4 Spearman’s correlations between 1-year changes in RV parameters and volume overload, systolic blood pressure and biomarkers   RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39    RVEDVI  RVESVI  RVMI  RVEF  Interdialytic weight gain  r  −0.17  −0.20  0.05  −0.02  P  0.23  0.16  0.72  0.86  Systolic blood pressure  r  0.11  0.13  0.07  −0.03  P  0.42  0.34  0.60  0.83  High-sensitivity troponin I  r  −0.19  0.03  0.11  −0.21  P  0.20  0.86  0.47  0.14  NT-BNP  r  0.24  0.30  0.002  −0.14  P  0.10  0.04  0.99  0.33  FGF23  r  0.15  −0.08  0.09  0.13  P  0.30  0.60  0.52  0.39  DISCUSSION We found that conversion to INHD was associated with a significant reduction in RV mass and volume indices at 1 year. Compared with the control group, the INHD group showed significantly greater reduction in the RVESVI, while the reductions in the RVMI, RVEDVI and increase in RVEF were not significant. The temporal changes in RV volume and function paralleled those observed in the LV. The pathophysiology of cardiac remodeling in dialysis patients is complex and likely mediated by myriad mechanical and biochemical factors. These include persistent volume overload, fluctuating volume status, coexisting hypertension, accumulation of uremic toxins, inflammation, anemia and endocrine axis derangements [21]. We postulate that these same factors leading to adverse LV remodeling would also contribute to RV remodeling. Furthermore, AVFs/grafts in chronic dialysis patients increase the preload on the right heart and might impact its performance [22]. There is a high prevalence of pulmonary hypertension in dialysis patients, ranging between 17% and 49.5%, depending on the mode of dialysis and other cardiovascular comorbidities [23]. Impairment of pulmonary circulation along with chronic volume overload and high levels of fibrosis promoting cytokines and growth factors, namely platelet-derived growth factor, FGF and transforming growth factor-β, likely contribute to pulmonary hypertension [21]. Endothelial dysfunction, lower activity of nitric oxide synthase and increased levels of serum endothelin promote extensive growth of endothelial cells, leading to complete obliteration of pulmonary vessels [22]. Vasoconstriction and vascular sclerosis triggered by microbubbles escaping from the dialysis circuit have also been implicated [24]. Furthermore, hemostatic mechanisms have been described linking ESRD and dialysis with increased risk of pulmonary venous thromboembolism [25], which could impair right heart function. Multiple mechanisms have been proposed for the cardiovascular benefits of INHD. Due to improved blood pressure control, patients who convert to INHD require fewer antihypertensive medications [7, 26, 27]. LV hypertrophy is strongly associated with hypertension and thus improved blood pressure control likely contributes to LV mass regression in INHD patients [28]. Extracellular volume expansion is the main pathophysiological determinant of hypertension in dialysis patients [29]. INHD has shown improved control of extracellular volume excess by reducing the time-averaged fluid load [30]. INHD may also more closely approximate the capacity of a native or transplanted kidney to regulate extracellular volume and solute composition [30–32]. Improved mineral metabolism with lower serum phosphate and calcium–phosphate products has been demonstrated in several studies [6, 26, 27, 33]. Studies have also suggested that nocturnal hemodialysis is associated with improved vascular risk in patients with ESRD by playing a role in restoration of abnormal smooth muscle cell biology [34]. Studies suggest that these mechanisms may promote favorable RV remodeling as well [35]. Our findings suggest that these mechanisms may promote favorable RV remodeling as well. The INHD group demonstrated improvements in the RVEDVI and RVEF, even though these differences were not statistically significant compared with the control group. Interestingly, conversion to INHD was associated with a significant reduction in the RVESVI. We found that the temporal changes in RV volume and function paralleled those of the LV and were in a similar direction with moderate to strong association. This further supports the notion that the beneficial effects of INHD on the LV also impact the RV. The significance of reduction of the RVESVI in the hemodialysis population remains to be studied. RV dysfunction is prognostically important in various disease states, such as coronary artery disease, where depiction of RV wall motion abnormalities on stress echocardiography has independent and incremental prognostic value even over LV wall motion abnormalities [14]. In tetralogy of Fallot patients, the RVESVI has been identified as a more sensitive marker of reverse remodeling after pulmonary valve replacement [15]. In nonischemic dilated cardiomyopathy, RV systolic dysfunction has been shown to be a powerful independent predictor of cardiac transplant–free survival and adverse heart failure outcomes [16]. Furthermore, reevaluation of the RVEF during follow-up conferred additive long-term prognostic value [17]. Therefore, our findings raise the interesting hypothesis that favorable RV structural and functional changes might also lead to improved clinical outcomes in the setting of ESRD. Despite evidence linking RV dysfunction with chronic dialysis and demonstration of RV function as an independent prognosticator in other conditions, there exists a significant knowledge gap. LV mass is a well-established, powerful, independent prognosticator that has been used in multiple randomized controlled trials evaluating newer dialysis modalities [3–5]. While CMR has shown favorable LV changes in INHD patients, CMR assessment of the RV has not been systematically performed in patients on conventional or intensified hemodialysis. Only a few studies have attempted to assess the RV in hemodialysis patients using echocardiography [9–11]. These were cross-sectional studies with a small number of patients that only assessed acute hemodynamic effects of dialysis using echocardiography with no long-term follow-up. There are no published studies that have assessed RV mass, volume and systolic function using the reference standard CMR in a longitudinal fashion, in INHD or in any form of intensified dialysis. Echocardiographic assessment of the RV is known to be inaccurate due to its complex geometry, predominant contribution of longitudinal motion to systolic function, difficult visualization due to anterior location and near-field artifact [36, 37]. Furthermore, based on the anatomy, structure and function, the RV is divided into the inflow and outflow tracts and therefore is not amenable to simple geometric assumptions [38, 39]. The RV is thin-walled (2–4 mm) with a muscle mass approximately one-sixth that of the LV. Therefore, even with the excellent spatial resolution (∼1.5–2 mm) and signal:noise ratio in CMR, we may not be able to detect small changes in RV mass, in contrast to relatively small changes in LV mass. Nevertheless, CMR remains the best available technique for the assessment of RV structure and function that does not require geometric assumptions. Our study therefore provides novel insights into the pathophysiology of RV remodeling in INHD patients. It also highlights the need for larger and longer-term follow-up studies to detect significant RV changes. CVC use was relatively high in our patients, comprising 41.8% of the overall cohort and 56.8% of the INHD patients. There are several reasons for this phenomenon. A greater proportion of INHD patients had diabetes and tend to have vasculature that is less amenable to creation of a permanent vascular access. The INHD patients received dialysis for a shorter period of time compared with the control group at recruitment, and therefore they were more likely to remain on hemodialysis with a CVC. Only a minority of patients switched vascular access during the follow-up period. Studies using echocardiography have shown that RV abnormalities and hypertrophy are more frequent in patients on hemodialysis compared with peritoneal dialysis, particularly those with an AVF as opposed to a CVC, likely related to development of pulmonary hypertension [40–42]. In contrast to these studies, we observed no significant difference in RV structure and function at baseline or changes over 1 year with respect to the vascular access. The small number of participants in our study might have limited the power to detect differences. Our study showed a borderline significant correlation between change in the RVESVI and NT-proBNP. While this correlation may represent a chance finding, an elevated BNP level might reflect increased filling pressure in both ventricles. However, we did not find any significant relationship between RV measurements and interdialytic weight gain as a measure of volume overload and systolic blood pressure. It is possible that the relative importance of these factors is different in LV and RV remodeling. We also did not observe any relationship between biomarkers of cardiomyocyte injury and myocardial fibrosis (high-sensitivity troponin I and FGF23, respectively) and RV remodeling. Further studies to elucidate mechanisms of LV and RV remodeling in ESRD are needed. To our knowledge, this is the first prospective longitudinal study that performed rigorous RV assessment in the intensified dialysis population using the reference imaging standard CMR. All RV measurements were independently performed by a single experienced reader who was blinded not only to the order of examination and other clinical data, but also the LV measurements. However, our study had several limitations, including a small sample size, which might have limited our power to demonstrate subtle changes in RV structure and function. Despite our efforts to minimize bias due to observed baseline differences, there probably existed unmeasured confounders in this nonrandomized study. The small sample size of our study also likely limited the power to demonstrate any relationship between vascular access and RV remodeling. Larger and longer-term prospective studies using CMR are required to elucidate this in the future. Finally, as we did not assess RV remodeling beyond 1 year, our study might not detect more gradual remodeling of RV. In conclusion, compared with continuation of CHD, conversion to INHD was associated with a significant reduction of RVESVI, along with a trend toward improvements in RVMI, the RVEDVI and RVEF. The parallel changes in LV and RV structure and function suggest that similar salutary mechanisms might mediate favorable remodeling in both ventricles. Our findings support future larger prospective studies with longer-term follow-up to elucidate the impact of dialysis intensification on the RV. AUTHORS’ CONTRIBUTIONS G.R.-K.: study conception and design, data analysis and interpretation, drafting and revision of the manuscript. R.W.: study conception and design, data analysis and interpretation, manuscript revision. M.B.G.: data analysis and interpretation, manuscript revision. R.W.: data analysis and interpretation, manuscript revision. L.J.-J.: data analysis and interpretation, manuscript revision. M.K.: data analysis and interpretation, manuscript revision. J.L.: data analysis and interpretation, manuscript revision. A.K.: data analysis and interpretation, manuscript revision. O.B.: data analysis and interpretation, manuscript revision. A.B.: data analysis and interpretation, manuscript revision. M.-Y.N.: data analysis and interpretation, manuscript revision. D.P.D.: data analysis and interpretation, manuscript revision. A.T.Y.: study conception and design, data analysis and interpretation, manuscript revision. FUNDING This study was supported by an operating grant from the Canadian Institutes of Health Research (MOP-89982) and a grant-in-aid from the Heart and Stroke Foundation (project number G-14-0005856). The study sponsors had no role in the study design, data collection or analysis, interpretation of the findings, writing the manuscript or the decision to submit the manuscript for publication (ClinicalTrials.gov identifier NCT00718848). CONFLICT OF INTEREST None declared. This manuscript has not been previously published and is not being considered for publication elsewhere in whole or in part in any language except Nephrology Dialysis Transplantation. REFERENCES 1 Go AS, Chertow GM, Fan D et al.  . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med  2004; 351: 1296– 1305 Google Scholar CrossRef Search ADS PubMed  2 Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2003 to 2012. Ottawa, ON: CIHI; 2014. 3 Culleton BF, Walsh M, Klarenbach SW et al.  . Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA  2007; 298: 1291– 1299 Google Scholar CrossRef Search ADS PubMed  4 Chertow GM, Levin NW, Beck GJ et al.  . In-center hemodialysis six times per week versus three times per week. N Engl J Med  2010; 363: 2287– 2300 Google Scholar CrossRef Search ADS PubMed  5 Rocco MV, Lockridge RSJr, Beck GJ et al.  . The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int  2011; 80: 1080– 1091 Google Scholar CrossRef Search ADS PubMed  6 Bugeja A, Dacouris N, Thomas A et al.  . In-center nocturnal hemodialysis: another option in the management of chronic kidney disease. Clin J Am Soc Nephrol  2009; 4: 778– 783 Google Scholar CrossRef Search ADS PubMed  7 Wald R, Goldstein MB, Perl J et al.  . The association between conversion to in-centre nocturnal hemodialysis and left ventricular mass regression in patients with end-stage renal disease. Can J Cardiol  2016; 32: 369– 377 Google Scholar CrossRef Search ADS PubMed  8 Dell’Italia LJ. The right ventricle: anatomy, physiology, and clinical importance. Curr Probl Cardiol  1991; 16: 653– 720 Google Scholar PubMed  9 Rudhani ID, Bajraktari G, Kryziu E et al.  . Left and right ventricular diastolic function in hemodialysis patients. Saudi J Kidney Dis Transpl  2010; 21: 1053– 1057 Google Scholar PubMed  10 Sadler DB, Brown J, Nurse H et al.  . Impact of hemodialysis on left and right ventricular Doppler diastolic filling indices. Am J Med Sci  1992; 304: 83– 90 Google Scholar CrossRef Search ADS PubMed  11 Akkaya M, Erdogan E, Saq S et al.  . The effect of hemodialysis on right ventricular functions in patients with end-stage renal failure. Anadolu Kardiyol Derg  2012; 12: 5– 10 Google Scholar PubMed  12 Ho SY, Nihoyannopoulos P. Anatomy, echocardiography, and normal right ventricular dimensions. Heart  2006; 92(Suppl 1): i2– i13 Google Scholar CrossRef Search ADS PubMed  13 Geva T. MRI is the preferred method for evaluation right ventricular size and function in patients with congenital heart disease. Circ Cardiovasc Imaging  2014; 7: 190– 197 Google Scholar CrossRef Search ADS PubMed  14 Wever-Pinzon O, Silva Enciso J, Romero J et al.  . Right ventricular function is a strong prognosticator in patients with HIV referred for stress echocardiography. Circulation  2010; 122(Suppl 21): A13232 15 Oosterhof T, van Straten A, Vliegen HW et al.  . Preoperative thresholds for pulmonary valve replacement in patients with corrected tetralogy of Fallot using cardiovascular magnetic resonance. Circulation  2007; 116: 545– 551 Google Scholar CrossRef Search ADS PubMed  16 Gulati A, Ismail TF, Jabbour A et al.  . The prevalence and prognostic significance of right ventricular systolic dysfunction in nonischemic dilated cardiomyopathy. Circulation  2013; 128: 1623– 1633 Google Scholar CrossRef Search ADS PubMed  17 Merlo M, Gobbo M, Stolfo D et al.  . The prognostic impact of the evolution of RV function in idiopathic DCM. JACC Cardiovasc Imaging  2016; 9: 1034– 1042 Google Scholar CrossRef Search ADS PubMed  18 Jakubovic BD, Wald R, Goldstein MB et al.  . Comparative assessment of 2-dimensional echocardiography vs cardiac magnetic resonance imaging in measuring left ventricular mass in patients with and without end-stage renal disease. Can J Cardiol  2013; 29: 384– 390 Google Scholar CrossRef Search ADS PubMed  19 Prakken NH, Velthuis BK, Vonken EJJ et al.  . Cardiac MRI: standardized right and left ventricular quantification by briefly coaching inexperienced personnel. Open Magn Reson J  2008; 1: 104– 111 Google Scholar CrossRef Search ADS   20 Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER et al.  . Normal values for cardiovascular magnetic resonance in adults and children. J Cardiovasc Magn Reson  2015; 17: 29 Google Scholar CrossRef Search ADS PubMed  21 Curtis BM, Parfrey PS. Congestive heart failure in chronic kidney disease: disease-specific mechanisms of systolic and diastolic heart failure and management. Cardiol Clin  2005; 23: 275– 284 Google Scholar CrossRef Search ADS PubMed  22 Di Lullo L, Floccari F, Polito P. Right ventricular diastolic function in dialysis patients could be affected by vascular access. Nephron Clin Pract  2011; 118: 257– 261 Google Scholar CrossRef Search ADS   23 Kosmadakis G, Aquilera D, Carceles O et al.  . Pulmonary hypertension in dialysis patients. Ren Fail  2013; 35: 514– 520 Google Scholar CrossRef Search ADS PubMed  24 Nakhoul F, Yigla M, Gilman R et al.  . The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access. Nephrol Dial Transplant  2005; 20: 1686– 1692 Google Scholar CrossRef Search ADS PubMed  25 Wattanakit K, Cushman M, Stehman-Breen C et al.  . Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol  2008; 19: 135– 140 Google Scholar CrossRef Search ADS PubMed  26 Ok E, Duman S, Asci G et al.  . Comparison of 4- and 8-h dialysis sessions in thrice-weekly in-centre haemodialysis: a prospective, case-controlled study. Nephrol Dial Transplant  2011; 26: 1287– 1296 Google Scholar CrossRef Search ADS PubMed  27 Jin X, Rong S, Mei C et al.  . Effects of thrice-weekly in-center nocturnal vs. conventional hemodialysis on integrated backscatter of myocardial tissue. Hemodial Int  2011; 15: 200– 210 Google Scholar CrossRef Search ADS PubMed  28 Wald R, Goldstein MB, Wald RM et al.  . Correlates of left ventricular mass in chronic hemodialysis recipients. Int J Cardiovasc Imaging  2014; 30: 349– 356 Google Scholar CrossRef Search ADS PubMed  29 D’Amico M, Locatelli F. Hypertension in dialysis: pathophysiology and treatment. J Nephrol  2010; 15: 438– 445 30 Wald R, Yan AT, Perl J et al.  . Regression of left ventricular mass following conversion from conventional hemodialysis to thrice weekly in-centre nocturnal hemodialysis. BMC Nephrol  2012; 13: 3 Google Scholar CrossRef Search ADS PubMed  31 Troidle L, Finkelstein F, Hotchkiss M et al.  . Enhanced solute removal with intermittent, in-center, 8-hour nocturnal hemodialysis. Hemodial Int  2009; 13: 487– 491 Google Scholar CrossRef Search ADS PubMed  32 Cravedi P, Ruggenenti P, Mingardi G et al.  . Thrice-weekly in-center nocturnal hemodialysis: an effective strategy to optimize chronic dialysis therapy. Int J Artif Organs  2009; 32: 12– 19 Google Scholar CrossRef Search ADS PubMed  33 Lacson EJr, Xu J, Suri RS et al.  . Survival with three-times weekly in-center nocturnal versus conventional hemodialysis. J Am Soc Nephrol  2012; 23: 687– 695 Google Scholar CrossRef Search ADS PubMed  34 Chan CT, Lovren F, Pan Y et al.  . Nocturnal haemodialysis is associated with improved vascular smooth muscle cell biology. Nephrol Dial Transplant  2009; 24: 3867– 3871 Google Scholar CrossRef Search ADS PubMed  35 Chan CT, Greene T, Chertow GM et al.  . Effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling. Clin J Am Soc Nephrol  2013; 8: 2106– 2116 Google Scholar CrossRef Search ADS PubMed  36 Srinivasan C, Sachdeva R, Morrow WR et al.  . Limitations of standard echocardiographic methods for quantification of right ventricular size and function in children and young adults. J Ultrasound Med  2011; 30: 487– 493 Google Scholar CrossRef Search ADS PubMed  37 Lindqvist P, Calcutteea A, Henein M. Echocardiography in the assessment of right heart function. Eur J Echocardiogr  2008; 9: 225– 234 Google Scholar PubMed  38 Haddad F, Hunt SA, Rosenthal DN et al.  . Right ventricular function in cardiovascular disease, part I. Circulation  2008; 117: 1436– 1448 Google Scholar CrossRef Search ADS PubMed  39 Haddad F, Doyle R, Murphy DJ et al.  . Right ventricular function in cardiovascular disease, part II. Circulation  2008; 117: 1717– 1731 Google Scholar CrossRef Search ADS PubMed  40 Momtaz M, Al Fishawy H, Aljarhi UM et al.  . Right ventricular dysfunction in patients with end-stage renal disease on regular hemodialysis. Egypt J Intern Med  2013; 25: 127– 132 41 Huang S, Zhao L. Effect of different dialysis modalities on right ventricular dysfunction in patients with end-stage renal disease. Nephrol Dialysis Transplant  2015; 30(Suppl 3): iii556– iii569 42 Paneni F, Gregori M, Ciavarella GM et al.  . Right ventricular dysfunction in patients with end-stage renal disease. Am J Nephrol  2010; 32: 432– 438 Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Aug 3, 2017

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off