Accuracy of Peridialytic, Intradialytic, and Scheduled Interdialytic Recordings in Detecting Elevated Ambulatory Blood Pressure in Hemodialysis Patients.

RATIONALE & OBJECTIVE: Current recommendations suggest the use of ambulatory blood pressure monitoring (ABPM) as the gold standard for hypertension diagnosis and management in hemodialysis patients. This study assesses the accuracy of peridialytic, intradialytic, and scheduled interdialytic recordings in detecting abnormally elevated 44-hour interdialytic blood pressure (BP). STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: 242 Greek hemodialysis patients who successfully underwent ABPM. TESTS COMPARED: Ambulatory BP was used as the reference method to evaluate the accuracy of the following BP metrics: predialysis and postdialysis BP, intradialytic BP, intradialytic plus pre/postdialysis BP, and scheduled interdialytic BP (on an off-dialysis day at 8:00 am, 8:00 pm, and their average). OUTCOME: 44-hour ambulatory systolic BP/diastolic BP (SBP/DBP) ≥ 130/80 mm Hg. RESULTS: The 44-hour SBP/DBP levels differed significantly from predialysis and postdialysis BP but showed no or minor differences compared with the other BP metrics. Bland-Altman plots showed an absence of systematic bias for all metrics but large between-method difference and wider 95% limits of agreement for predialysis and postdialysis BP compared with intradialytic, intradialytic plus pre/postdialysis, and averaged scheduled interdialytic BP. The sensitivity/specificity and κ-statistic for diagnosing 44-hour SBP ≥ 130 mm Hg were low for predialysis (86.5%/38.6%, κ-statistic = 0.27) and postdialysis BP (63.1%/73.3%, κ-statistic = 0.35), but better for intradialytic BP (77.3%/76.2%, κ-statistic = 0.53), intradialytic plus pre/postdialysis BP (76.6%/72.3%, κ-statistic = 0.49), and scheduled interdialytic BP (87.9%/77.2%, κ-statistic = 0.66). In receiver operating characteristic (ROC) analyses, the areas under the curve (AUC) of predialysis SBP (AUC = 0.723) and postdialysis SBP (AUC = 0.746) were significantly lower than that of intradialytic SBP (AUC = 0.850), intradialytic plus pre/postdialysis SBP (AUC = 0.850), and scheduled interdialytic SBP (AUC = 0.917) (z test, P < 0.001 for all pairwise comparisons). Similar observations were made for DBP. LIMITATIONS: Typical home BP data were not obtained, and no assessment was obtained of the reproducibility of the examined metrics over time. CONCLUSIONS: Intradialytic, intradialytic plus pre/postdialysis, and scheduled interdialytic BP measurements were more accurate in detecting elevated 44-hour BP than predialysis and postdialysis BP. Averaged intradialytic BP recordings or scheduled readings at the off-dialysis day appear to be promising approaches to the diagnosis of elevated BP in hemodialysis.

The association of interdialytic blood pressure variability with cardiovascular events and all-cause mortality in haemodialysis patients.

BACKGROUND: Long-term pre-dialysis blood pressure variability (BPV) in haemodialysis patients is associated with increased cardiovascular risk. The association of the main haemodynamic culprit in dialysis, that is, short-term BPV, with outcomes has not been investigated. We examine the prognostic role of short-term BPV for mortality and cardiovascular events in this population. METHODS: A total of 227 haemodialysis patients underwent 44-h ambulatory monitoring during a standard interval and were followed-up for 30.17 ± 17.70 months. We calculated SD, weighted SD (wSD), coefficient of variation (CV) and average real variability (ARV) of BP with validated formulas. The primary endpoint was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary endpoints were: (i) all-cause mortality, (ii) cardiovascular mortality and (iii) a combination of cardiovascular events. RESULTS: Cumulative freedom from the primary endpoint was similar for quartiles of pre-dialysis and 44-h systolic BP (SBP), but was progressively longer for increasing quartiles of 44-h SBP-SD (P = 0.014), wSD (P = 0.007), CV (P = 0.031) and ARV (83.9, 71.9, 70.2 and 43.9% for quartiles 1-4; P < 0.001). Higher quartiles of 44-h SBP-ARV were associated with higher risk of all studied outcomes. Among diastolic BPV indices, 44-h diastolic BP (DBP)-CV and 44-h DBP-ARV were associated with increased risk for the composite cardiovascular outcome. In Cox regression analysis, SBP-BPV was related to the primary endpoint, independently of SBP levels and interdialytic weight gain [ARV: hazard ratio (HR) 1.115, 95% confidence interval (95% CI) 1.048-1.185]. This association become insignificant after adjustment for pulse wave velocity (PWV; HR 1.061, 95% CI 0.989-1.137), and further attenuated after additional adjustment for age, dialysis vintage, gender, comorbidities and prevalent cardiovascular disease (HR 1.031, 95% CI 0.946-1.122). CONCLUSIONS: Increased BPV during the interdialytic interval is associated with higher risk of death and cardiovascular events, whereas ambulatory BP levels are not. This association was not independent after adjustment for PWV, other risk factors and prevalent cardiovascular disease. Short-term BPV could be a mediator promoting the adverse cardiovascular profile of haemodialysis patients.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function.

BACKGROUND: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. METHODS: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45-70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. RESULTS: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. CONCLUSIONS: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Serum Fas Ligand, Serum Myostatin and Urine TGF-ß1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function.

BACKGROUND/AIMS: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-ß1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. METHODS: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-ß1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. RESULTS: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-ß1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-ß1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-ß1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). CONCLUSIONS: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-ß1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

Ambulatory aortic blood pressure, wave reflections and pulse wave velocity are elevated during the third in comparison to the second interdialytic day of the long interval in chronic haemodialysis patients.

BACKGROUND: Increased arterial stiffness and aortic blood pressure (BP) are independent predictors of cardiovascular outcomes in end-stage renal disease. The 3-day interdialytic interval is associated with elevated risk of cardiovascular morbidity and mortality in haemodialysis. This study investigated differences in ambulatory aortic BP and arterial stiffness between the second and third day of the long interdialytic interval. METHODS: Ambulatory BP monitoring with Mobil-O-Graph monitor (IEM, Stolberg, Germany) was performed in 55 haemodialysis patients during a 3-day interval. Mobil-O-Graph records oscillometric brachial BP and pulse waves and calculates aortic BP and augmentation index (AIx) as measure of wave reflections, and pulse wave velocity (PWV) as measure of arterial stiffness. RESULTS: Ambulatory aortic systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher during the third versus second interdialytic day (123.6 ± 17.0 versus 118.5 ± 17.1 mmHg, P < 0.001; 81.5 ± 11.8 versus 78 ± 11.9 mmHg, P < 0.001, respectively). Similar differences were noted for brachial BP. Ambulatory AIx and PWV were also significantly increased during the third versus second day (30.5 ± 9.9 versus 28.8 ± 9.9%, P < 0.05; 9.6 ± 2.3 versus 9.4 ± 2.3 m/s, P < 0.001, respectively). Differences between Days 2 and 3 remained significant when day-time and night-time periods were compared separately. Aortic SBP and DBP, AIx and PWV showed gradual increases from the end of dialysis session onwards. Interdialytic weight gain was a strong determinant of the increase in the above parameters. CONCLUSIONS: This study showed significantly higher ambulatory aortic BP, AIx and PWV levels during the third compared with the second interdialytic day. These findings support a novel pathway for increased cardiovascular risk during the third interdialytic day in haemodialysis.

Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. METHODS: We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73 m(2)), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73 m(2)), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. RESULTS: Group A and B had significantly higher ADMA levels as compared to controls (1.68 ± 0.7 vs 0.51 ± 0.2 µmol/l, P<0.001 and 1.26 ± 0.7 vs 0.51 ± 0.2 µmol/l, P<0.001, respectively). 15-F2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8 ± 185.0 vs 383.1 ± 86.0 pgr/ml, P<0.001 and 11.4 ± 6.6 vs 6.4 ± 2.6 EU/ml, P<0.05 respectively) and were further elevated in Group A. In correlation analysis, ADMA levels exhibited strong associations with levels of 15-F2t-Isoprostane (r=0.811, P<0.001) and oxidized-LDL (r=0.788, P<0.001), whereas an inverse correlation was evident between ADMA and eGFR (r=-0.460, P<0.001). CONCLUSION: This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD. © 2014 S. Karger AG, Basel.

Nebivolol reduces short-term blood pressure variability more potently than irbesartan in patients with intradialytic hypertension.

Increased blood pressure (BP) variability (BPV) is associated with high cardiovascular risk in hemodialysis. Studies on the effects of antihypertensive drugs on BPV in hemodialysis are scarce. This study examines the effects of nebivolol and irbesartan on short-term BPV in patients with intradialytic hypertension. This randomized-cross-over study included 38 patients (age: 60.4 ± 11.1 years, male: 65.8%) with intradialytic hypertension (intradialytic-SBP increase ≥ 10 mmHg at ≥4 over 6 consecutive sessions). After the baseline evaluation, participants were randomized to nebivolol 5 mg and subsequently irbesartan 150 mg, or vice versa, with a two-week wash-out period before initiation of the second drug. Patients underwent three respective 24 h-ABPM sessions starting before a midweek-session. We calculated the standard deviation (SD), weighted SD (wSD), coefficient of variation (CV), and average real variability (ARV) of BP with validated formulas. The post-hemodialysis and 24 h-SBP and DBP levels were significantly lower after treatment with both drugs. The systolic-BPV indices were marginally lower after nebivolol but not after irbesartan compared to baseline (SD: baseline 15.70 ± 4.69; nebivolol 14.45 ± 3.37, p = 0.090; irbesartan 15.39 ± 3.85, p = 0.706; wSD: 14.62 ± 4.36 vs 13.40 ± 3.07, p = 0.053 vs 14.36 ± 3.47, p = 0.805, respectively). The diastolic-BPV indices decreased with nebivolol and increased with irbesartan, resulting in significant differences between the two drugs (SD: baseline 10.56 ± 2.50; nebivolol 9.75 ± 2.12; irbesartan 10.84 ± 1.98, between-drug p = 0.014; wSD: baseline 9.86 ± 2.12; nebivolol 9.34 ± 2.01; irbesartan 10.25 ± 2.01, between-drug p = 0.029). The diastolic-BPV during intradialytic and day-time periods was marginally lower with nebivolol than with irbesartan. During nighttime, the BPV indices were unchanged with either drug. The short-term BPV was reduced after nebivolol but not after irbesartan treatment in patients with intradialytic hypertension. These findings suggest that sympathetic-overdrive may be a major factor that affects BPV in intradialytic hypertension patients.