• diabetes mellitus
• end stage renal disease
• entropy
• hemodialysis

• Humans
• Entropy
• Glucose
• Renal Dialysis/adverse effects
• Hemodynamics/physiology
• Blood Pressure
• Kidney Failure, Chronic/therapy

• 403 Military Institute of Medicine

Background: Heart rate variability (HRV), reflecting circadian rhythm of heart rate, is reported to be associated with clinical outcomes in stage 5 chronic kidney disease (CKD5) patients. Whether CKD related factors combined with HRV can improve the predictive ability for their death remains uncertain. Here we evaluated the prognosis value of nomogram model based on HRV and clinical risk factors for all-cause mortality in CKD5 patients.

Methods: CKD5 patients were enrolled from multicenter between 2011 and 2019 in China. HRV parameters based on 24-h Holter and clinical risk factors associated with all-cause mortality were analyzed by multivariate Cox regression. The relationships between HRV and all-cause mortality were displayed by restricted cubic spline graphs. The predictive ability of nomogram model based on clinical risk factors and HRV were evaluated for survival rate.

Results: CKD5 patients included survival subgroup (n = 155) and all-cause mortality subgroup (n = 45), with the median follow-up time of 48 months. Logarithm of standard deviation of all sinus R-R intervals (lnSDNN) (4.40 ± 0.39 vs. 4.32 ± 0.42; p = 0.007) and logarithm of standard deviation of average NN intervals for each 5 min (lnSDANN) (4.27 ± 0.41 vs. 4.17 ± 0.41; p = 0.008) were significantly higher in survival subgroup than all-cause mortality subgroup. On the basis of multivariate Cox regression analysis, the lnSDNN (HR = 0.35, 95%CI: 0.17–0.73, p = 0.01) and lnSDANN (HR = 0.36, 95% CI: 0.17–0.77, p = 0.01) were associated with all-cause mortality, their relationships were negative linear. Spearman’s correlation analysis showed that lnSDNN and lnSDANN were highly correlated, so we chose lnSDNN, sex, age, BMI, diabetic mellitus (DM), β-receptor blocker, blood glucose, phosphorus and ln intact parathyroid hormone (iPTH) levels to build the nomogram model. The area under the curve (AUC) values based on lnSDNN nomogram model for predicting 3-year and 5-year survival rates were 79.44% and 81.27%, respectively.

Conclusion: In CKD5 patients decreased SDNN and SDANN measured by HRV were related with their all-cause mortality, meanwhile, SDNN and SDANN were highly correlated. Nomogram model integrated SDNN and clinical risk factors are promising for evaluating their prognosis.

• all-cause mortality
• chronic kidney disease
• circadian rhythm
• heart rate
• heart rate variability
• nomogram model

• Chronic kidney disease
• Death
• Dialysis
• End stage kidney disease
• End stage renal disease
• Mortality
• Predictors

Inflammation and autonomic dysfunction are common findings in chronic and end-stage kidney disease and contribute to a markedly increased risk of mortality in this patient population. The cholinergic anti-inflammatory pathway (CAP) is a vagal neuro-immune circuit that upholds the homoeostatic balance of inflammatory activity in response to cell injury and pathogens. CAP models have been examined in preclinical studies to investigate its significance in a range of clinical inflammatory conditions and diseases. More recently, cervical vagus nerve stimulation (VNS) implants have been shown to be of potential benefit for patients with chronic autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. We have previously shown that dialysis patients have a functional CAP ex vivo. Here we review the field and the potential role of the CAP in acute kidney injury and chronic kidney disease (CKD) as well as in hypertension. We also present a VNS pilot study in haemodialysis patients. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for improved treatment, outcome, prognosis and quality of life for patients with CKD.

• acute kidney injury
• cholinergic anti-inflammatory pathway
• chronic kidney disease
• dialysis
• inflammation
• vagus nerve stimulation

Monitoring the cardiovascular system plays an important role in this treatment to detect cardiovascular repercussions in dogs with chronic kidney disease (CKD) treated with intermittent haemodialysis (IHD). This study aimed to describe the time-domain and frequency-domain heart rate variability indexes, P and QT dispersions and electrocardiographic alterations observed in dogs with Stage IV CKD undergoing IHD. Animals were divided into three groups, control (10 healthy dogs), clinical treatment (10 dogs with CKD IV submitted to clinical treatment) and IHD (10 dogs with CKD IV submitted to clinical treatment and to dialysis treatment). Clinical, laboratory, HRV indexes and electrocardiographic parameters, as well as QT and P-wave dispersions, were assessed in both CKD groups, prior to and after the end of each clinical treatment/IHD session during the first three sessions. Dogs with CKD IV undergoing IHD had clinically important electrolyte imbalances, electrocardiographic findings, such as the occurrence of arrhythmias and increases in possible predictive parameters for arrhythmias. HRV indexes were better in IHD group, and haemodialysis was more effective at reducing levels of creatinine, urea and phosphorus when compared to intravenous fluid therapy treatment.

Intermittent haemodialysis (IHD) is used in dogs with chronic kidney disease (CKD) to reduce azotaemia. Monitoring the cardiovascular system plays an important role in this treatment to detect cardiovascular repercussions. Heart rate variability (HRV) and dispersions of the QT interval and P wave are important markers for mortality risk in humans. This study aimed to describe the time-domain and frequency-domain heart rate variability indexes, P and QT dispersions and electrocardiographic alterations observed in dogs with Stage IV CKD undergoing IHD. Thirty dogs of both sexes, of varying ages and breeds, and weighing between 15 and 30 kg were used. Animals were divided into three groups, control (10 healthy dogs), clinical treatment (10 dogs with CKD IV submitted to clinical treatment twice a week) and IHD (10 dogs with CKD IV submitted to clinical treatment and to dialysis treatment with intermittent haemodialysis twice a week). Clinical, laboratory, HRV indexes and electrocardiographic parameters, as well as QT and P-wave dispersions, were assessed in both CKD groups, prior to and after the end of each clinical treatment/IHD session during the first three sessions. Dogs with CKD IV undergoing IHD had clinically important electrolyte imbalances, primarily hypokalaemia, and pertinent electrocardiographic findings, such as the occurrence of supraventricular arrhythmias and increases in possible predictive parameters for arrhythmias. In spite of these observations, HRV indexes were better in animals undergoing haemodialysis and, in addition, IHD was more effective at reducing levels of creatinine, urea and phosphorus compared to intravenous fluid therapy treatment.

• canine
• cardiology
• electrocardiogram
• nephrology

• Intradialytic exercise
• fluid overload
• hemodialysis
• hemodynamic stability

• Blood Pressure/physiology
• Cross-Over Studies
• Exercise/physiology
• Female
• Hemodynamics/physiology
• Humans
• Kidney Failure, Chronic/complications
• Male
• Middle Aged
• Renal Dialysis/methods

• T32 AR007581 NIAMS NIH HHS

• cardiovascular and all-cause mortality
• cardiovascular autonomic neuropathy
• end-stage renal disease
• risk assessment

• Adult
• Aged
• Body Mass Index
• Case-Control Studies
• Diabetes Mellitus, Type 2/epidemiology
• Diabetes Mellitus, Type 2/physiopathology
• Female
• Heart Rate
• Humans
• Male
• Middle Aged
• Regression Analysis
• Risk Factors

• Baroreflex sensitivity
• blood pressure variability
• chronic kidney disease
• heart rate variability
• predialysis
• pulse wave velocity

• all-cause mortality
• cardiac autonomic neuropathy
• left ventricular function
• renal failure

• ambulatory blood pressure
• autonomic neuropathy
• chronic kidney disease
• glomerular filtration rate
• heart rate variability

Alterations in autonomic nervous function are common in hemodialysis (HD) patients. Sympathetic as well as parasympathetic activation may be associated with immune and inflammatory responses. We intended to confirm a role of autonomous dysregulation for inflammation in HD patients.

30 HD patients (including 15 diabetics) and 15 healthy controls were studied for heart rate variability (HRV) using 5 min ECG recordings. Heart rate variability was estimated by time-domain parameters (the standard deviation of the RR intervals (SDNN) and the percentage of pairs of adjacent RR intervals differing by >50 ms (pNN50)) and frequency-domain-analysis (high- and low-frequency variation of RR intervals, HF and LF). Inflammation was detected as serum C-reactive Protein (CRP), IL-6 and circulating monocyte subpopulation numbers. Immune cells were characterized by ACh receptor expression.

Patients differed from controls in terms of age (68.0 [14.8] yrs vs. 58.0 [13.0] yrs, p < 0.001; Median [IQR]) and sex. However, HRV parameters were different in controls and HD patients (SDNN controls 34.0 [14.0] ms, HD patients 15.5 [14.8] ms, p < 0.01). This finding was not restricted to patients with diabetes mellitus (diab), although diabetes is an important cause of autonomous dysfunction (SDNN, diab 13.0 [14.0] ms, non-diab 18.0 [15.3] ms, p = 0.8). LF and HF were reduced by the same magnitude to 1/3 of those in controls. Patients suffered from chronic inflammation (CRP 9.4 [12.9] mg/l, controls 1.6 [2.4] mg/l, p < 0.001) and expanded proinflammatory monocyte subpopulations (CD14++/CD16+ cells: patients 41 [27]/μl, controls 24 [18]/μl, p < 0.01). ECG parameters did not correlate with inflammation in patients, but monocyte ACh receptor expression was enhanced, indicating potentially elevated responsiveness of this cell type to parasympathetic regulation.

HD patients have strongly impaired HRV. Chronic inflammation is not related to autonomous dysfunction, although monocytes express the ACh receptor at enhanced density making them potentially more sensitive to parasympathetic effects.

This study was listed with ClinicalTrials.gov (NCT00878033).

The online version of this article (doi:10.1186/s12872-016-0385-1) contains supplementary material, which is available to authorized users.

• Autonomic nerves
• Dialysis
• Heart rate variability
• Inflammation
• Monocytes

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013–March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. Trial Registration: ClinicalTrials.gov, NCT01774812.

• autonomic nervous system
• chronic kidney disease
• heart rate variability
• hemodialysis
• vitamin D

Low heart rate variability (HRV) has been recognized to correlate with adverse cardiovascular (CV) outcomes in hemodialysis (HD) patients. It has been reported that HRV might be improved after HD, but whether the improved HRV after HD predicts a better CV prognosis remains to be determined. This study examined the ability of the change in HRV before and after HD in predicting overall and CV mortality in HD patients. This study enrolled 182 patients under maintenance HD. HRV was examined to assess changes before and after HD. The change in HRV (ΔHRV) was defined as post-HD HRV minus pre-HD HRV. During a median follow-up period of 35.2 months, 29 deaths (15.9%) were recorded. Multivariate analysis showed that decreased ΔLF% was associated with increased overall (hazard ratios [HR], 0.978; 95% confidence interval [CI], 0.961–0.996; p = 0.019) and CV mortality (HR, 0.941; 95% CI, 0.914–0.970; p < 0.001), respectively. Moreover, adding ΔLF% to a clinical model provided an additional benefit in the prediction of overall (p = 0.002) and CV mortality (p < 0.001). HRV change before and after HD (ΔHRV) is an useful clinical marker, and it is stronger than HRV before HD in predicting overall and CV mortality.

• Female
• Heart Rate
• Humans
• Incidence
• Kidney Failure, Chronic/epidemiology
• Kidney Failure, Chronic/mortality
• Kidney Failure, Chronic/physiopathology
• Male
• Middle Aged
• Multivariate Analysis
• Nonlinear Dynamics
• Peritoneal Dialysis
• Prognosis
• Proportional Hazards Models

It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes.

This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors.

In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = −0.243; SDANN5: r = −0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = −0.243; SDANN5: r = −0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (β = −0.279 and −0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters.

Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.

• End-stage renal disease
• diabetes
• heart rate variability
• high peritoneal transport type
• icodextrin

While fluid overload (FO) and alterations in the autonomic nervous system (ANS) such as hypersympathetic activity, are known risk factors for cardiovascular morbidity and mortality in patients on chronic hemodialysis (HD), their relationship has not been thoroughly studied.

In this observational study involving 69 patients on chronic HD, FO was assessed by whole body bioimpedance measurements before the midweek HD session and ANS activity reflected by Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. In total, 13 different HRV indices were analyzed, comprising a mixture of time domain, frequency domain and complexity parameters. A correlation analysis was performed between the HRV indices and hydration status indices. Successively, patients were retrospectively assigned to a high FO (H, FO > 2.5 L) or low FO (L, FO ≤ 2.5 L) group and these were further compared also after stratification by diabetes mellitus. Finally, a small number of patients without diabetes with significant and persistent FO were followed up for 3 months post-study to investigate how normalization of fluid status affects HRV.

SDANN, VLF, LZC and HF% parameters significantly correlate with FO (correlation coefficients were respectively r = –0.40, r = –0.37, r = –0.28 and r = 0.26, p-value < 0.05). Furthermore, LF% and LF/HF were inversely correlated with hydration status (correlation coefficients were respectively r = –0.31 and r = -0.33, p-value < 0.05). These results indicate an association between FO and reduced HRV, higher parasympathetic activation and reduced sympathetic response to the HD session. Indeed, group H tended to have lower values of SDANN, VLF and LZC, and higher values of HF% than patients in the L group. Finally, there was a trend towards lower LF% measured during the last 30 minutes of HD for the H group versus the L group. Reduction in FO achieved over 3 months by implementation of a strict fluid management plan resulted in an increase of HRV.

Our results suggest that depressed HRV is associated with fluid overload and that normalization of hydration status is accompanied by improved HRV.

• arrhythmias
• chronic kidney disease
• heart failure
• implantable cardioverter defibrillator
• sudden death

• Adult
• Aged
• Cardiovascular Diseases/metabolism
• Cohort Studies
• Disease-Free Survival
• Electrocardiography
• Exercise
• Female
• Glomerular Filtration Rate
• Heart Failure
• Heart Rate/physiology
• Hemoglobins/metabolism
• Humans
• Linear Models
• Male
• Middle Aged
• Phosphorus/metabolism
• Renal Insufficiency/physiopathology
• Renal Insufficiency, Chronic/physiopathology
• Risk Factors
• Treatment Outcome
• Young Adult

• K23 DK087919 NIDDK NIH HHS
• UL1 RR024131 NCRR NIH HHS
• U01DK060980 NIDDK NIH HHS
• P30GM103337 NIGMS NIH HHS
• U01DK061028 NIDDK NIH HHS
• K01DK092353 NIDDK NIH HHS
• U01DK060902 NIDDK NIH HHS
• M01 RR-16500 NCRR NIH HHS
• UL1 RR029879 NCRR NIH HHS
• K23DK087919 NIDDK NIH HHS
• U01 DK061028 NIDDK NIH HHS
• UL1 TR000433 NCATS NIH HHS
• R01 DK072231 NIDDK NIH HHS
• U01DK060963 NIDDK NIH HHS
• U01 DK060984 NIDDK NIH HHS
• U01 DK061021 NIDDK NIH HHS
• U01DK061022 NIDDK NIH HHS
• K01 DK092353 NIDDK NIH HHS
• UL1 RR-024131 NCRR NIH HHS
• P30 GM103337 NIGMS NIH HHS
• U01 DK060980 NIDDK NIH HHS
• UL1TR000433 NCATS NIH HHS
• U01 DK060963 NIDDK NIH HHS
• UL1 TR-000424 NCATS NIH HHS
• U01 DK061022 NIDDK NIH HHS
• U01DK061021 NIDDK NIH HHS
• U01DK060984 NIDDK NIH HHS
• UL1RR029879 NCRR NIH HHS
• U01DK060990 NIDDK NIH HHS
• UL1 TR000003 NCATS NIH HHS
• UL1TR000003 NCATS NIH HHS
• UL1 TR000439 NCATS NIH HHS
• UL1 TR000424 NCATS NIH HHS
• M01 RR016500 NCRR NIH HHS
• U01 DK060902 NIDDK NIH HHS
• U01 DK060990 NIDDK NIH HHS
• UL1TR000439 NCATS NIH HHS

The autonomic nervous system plays a central role in the maintenance of hemodynamic stability. Cardiac autonomic dysfunction may result in serious complications, such as sudden cardiac death. Heart rate variability (HRV) is significantly reduced in patients undergoing chronic hemodialysis (HD). The aim of this study was to evaluate the effect of on-line hemodiafiltration (OL-HDF) on the autonomic nervous system in chronic HD patients.

Forty chronic HD patients were prospectively studied. The participants were divided into conventional HD and OL-HDF groups. They received regular high-flux HD or OL-HDF for 4-hour sessions, three times a week. Time-and frequency-domain measures of the 24-hour HRV were analyzed during the interdialytic period prior to postdilution OL-HDF and every 6 months for 24 months. The 7-year survival was also evaluated.

Among the 40 participants, 15 patients in the HD group and 11 patients in the OL-HDF group completed the study. There was no difference in the baseline characteristics. After 24 months of treatment, β₂-microglobulin concentration decreased (from 33.4±15.2 mg/dL to 28.4±6.2 mg/dL, P =0.02) in the OL-HDF group, while there was no change in the HD group. In the HRV analysis, the frequency-domain HRV parameters increased significantly compared with baseline in the OL-HDF group [natural logarithmic high frequency (lnHF), 3.15±3.36 ms² vs. 4.42±3.81 ms²; ln low frequency (LF), 3.56±3.17 ms² vs. 4.78±3.99 ms²; ln very low frequency (VLF), 4.90±4.62 ms² vs. 6.38±5.54 ms²; LF/HF ratio, 1.4±0.4 vs. 2.5±0.1]. The survival rate was similar between the groups.

This study shows that OL-HDF improved autonomic nervous system dysfunction in chronic HD patients.

• Autonomic neuropathy
• Heart rate variability
• Hemodialysis
• On-line hemodiafiltration

• baroreceptor reflex sensitivity
• end-stage renal disease
• heart rate variability