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1.  Shorter delivered dialysis times associate with a higher and more difficult to treat blood pressure 
Nephrology Dialysis Transplantation  2013;28(6):1562-1568.
Background
Shorter delivered dialysis times are associated with increased all-cause mortality. Whether shorter delivered dialysis times also associate with an increase in blood pressure (BP) and reduce the ability of probing dry weight to lower BP is unclear.
Methods
Among patients participating in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) trial, interdialytic ambulatory BP was recorded at baseline, 4 weeks and 8 weeks. Median intradialytic BP was also calculated at each dialysis treatment and associated with the delivered daily dialysis time.
Results
The median time on dialysis at baseline was 3.6 h per treatment (range 2.5–4.5 h). At baseline, modeled median intradialytic systolic BPs were higher among those who received fewer hours of dialysis. Among subjects who did not have their dry weight probed (control group), the median intradialytic systolic BP continued to be elevated. Probing dry weight (ultrafiltration group) provoked a drop in median intradialytic systolic BP regardless of the delivered dialysis time. However, the reduction in BP was achieved after fewer sessions of dialysis when delivered dialysis was longer in duration. The pattern of change was confirmed using interdialytic ambulatory BP monitoring.
Conclusions
Fewer hours of delivered dialysis are associated with a higher systolic BP. Upon probing dry weight, compared with shorter dialysis treatment times, 4 h of delivered dialysis per session provokes reductions in systolic BP over fewer dialysis treatment sessions. Reduction of BP may lag dry-weight reduction when shorter dialysis is delivered.
doi:10.1093/ndt/gfs597
PMCID: PMC3685306  PMID: 23348881
hemodialysis; hypertension
2.  KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD 
In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.
doi:10.1053/j.ajkd.2013.03.018
PMCID: PMC3929429  PMID: 23684145
Kidney Disease: Improving Global Outcomes (KDIGO); guideline; blood pressure
3.  Chemometric Analysis for Identification of Botanical Raw Materials for Pharmaceutical Use: A Case Study Using Panax notoginseng 
PLoS ONE  2014;9(1):e87462.
The overall control of the quality of botanical drugs starts from the botanical raw material, continues through preparation of the botanical drug substance and culminates with the botanical drug product. Chromatographic and spectroscopic fingerprinting has been widely used as a tool for the quality control of herbal/botanical medicines. However, discussions are still on-going on whether a single technique provides adequate information to control the quality of botanical drugs. In this study, high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC), capillary electrophoresis (CE) and near infrared spectroscopy (NIR) were used to generate fingerprints of different plant parts of Panax notoginseng. The power of these chromatographic and spectroscopic techniques to evaluate the identity of botanical raw materials were further compared and investigated in light of the capability to distinguishing different parts of Panax notoginseng. Principal component analysis (PCA) and clustering results showed that samples were classified better when UPLC- and HPLC-based fingerprints were employed, which suggested that UPLC- and HPLC-based fingerprinting are superior to CE- and NIR-based fingerprinting. The UPLC- and HPLC- based fingerprinting with PCA were able to correctly distinguish between samples sourced from rhizomes and main root. Using chemometrics and its ability to distinguish between different plant parts could be a powerful tool to help assure the identity and quality of the botanical raw materials and to support the safety and efficacy of the botanical drug products.
doi:10.1371/journal.pone.0087462
PMCID: PMC3909187  PMID: 24498109
4.  Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients 
Nephrology Dialysis Transplantation  2012;27(10):3908-3914.
The staggering cardiovascular risk of kidney failure and the disappointing results of very recent and older trials are a sounding board that nephrologists should multiply efforts at identifying modifiable risk factors, to improve the dim health perspectives of dialysis patients. Moving PH from the limbo category (WHO V) where it stands now, to categories of known aetiology, may perhaps be a significant step towards this tantalizing goal.
Background
The prevalence, determinants and prognosis of pulmonary hypertension among long-term hemodialysis patients in the USA are poorly understood.
Methods
A cross-sectional survey of prevalence and determinants of pulmonary hypertension was performed, followed by longitudinal follow-up for all-cause mortality. Pulmonary hypertension was defined as an estimated systolic pulmonary artery pressure of >35 mmHg using echocardiograms performed within an hour after the end of dialysis.
Results
Prevalent in 110/288 patients (38%), the independent determinants of pulmonary hypertension were the following: left atrial diameter (odds ratio 10.1 per cm/m2, P < 0.0001), urea reduction ratio (odds ratio 0.94 per %, P < 0.01) and vitamin D receptor activator use (odds ratio 0.41 for users, P < 0.01). Over a median follow-up of 2.15 years, 97 (34%) patients died yielding a crude mortality rate (CMR) of 114.2 per 1000 patient-years. Of these, 58 deaths occurred among 110 patients with pulmonary hypertension (53%, CMR 168.9/1000 patient-years) and 39 among 178 without pulmonary hypertension (22%, CMR 52.5/1000 patient-years) [unadjusted hazard ratio (HR) for death 2.12 (95% confidence interval 1.41–3.19), P < 0.001]. After multivariate adjustment, pulmonary hypertension remained an independent predictor for all-cause mortality [HR 2.17 (95% confidence interval 1.31–3.61), P < 0.01].
Conclusions
Among hemodialysis patients, pulmonary hypertension is common and is strongly associated with an enlarged left atrium and poor long-term survival. Reducing left atrial size such as through volume control may be an attractive target to improve pulmonary hypertension. Improving pulmonary hypertension in this group of patients may improve the dismal outcomes.
doi:10.1093/ndt/gfr661
PMCID: PMC3484729  PMID: 22290987
epidemiology; hemodialysis; pulmonary hypertension; risk factors; survival
5.  The controversies of diagnosing and treating hypertension among hemodialysis patients 
Seminars in Dialysis  2012;25(4):370-376.
This review discusses ten current controversies regarding the dialysis patient with hypertension. The clinician is faced with a dilemma at the bedside on how to evaluate blood pressure and treat this condition in a patient on long-term hemodialysis. The evidence base to give firm recommendations is thin, but the epidemiological evidence tells us to do nothing. This appears to be the incorrect strategy, at least based on what we know today. Evaluating home BP in every dialysis patient, evaluating volume status on a regular basis, and treating hypertension predominantly with non-pharmacological strategies are worthwhile.
doi:10.1111/j.1525-139X.2012.01092.x
PMCID: PMC3400711  PMID: 22686564
6.  Unfavourable results with distraction in craniofacial skeleton 
Distraction osteogenesis has revolutionised the management of craniofacial abnormalities. The technique however requires precise planning, patient selection, execution and follow-up to achieve consistent and positive results and to avoid unfavourable results. The unfavourable results with craniofacial distraction stem from many factors ranging from improper patient selection, planning and use of inappropriate distraction device and vector. The present study analyses the current standards and techniques of distraction and details in depth the various errors and complications that may occur due to this technique. The commonly observed complications of distraction have been detailed along with measures and suggestions to avoid them in clinical practice.
doi:10.4103/0970-0358.118594
PMCID: PMC3901900  PMID: 24501455
Complications; distraction osteogenesis; unfavourable results
7.  Neither Proteinuria Nor Albuminuria Is Associated With Endothelial Dysfunction in HIV-Infected Patients Without Diabetes or Hypertension 
The Journal of Infectious Diseases  2011;204(12):1946-1950.
It is unknown whether systemic endothelial dysfunction underlies the association between nephropathy and cardiovascular disease (CVD) in persons infected with human immunodeficiency virus (HIV). Spot urine protein to creatinine ratio, spot urine albumin to creatinine ratio, creatinine clearance, estimated glomerular filtration rate, and flow-mediated dilation (FMD) of the brachial artery were evaluated in 123 study participants infected with HIV (58 receiving antiretroviral therapy [ART] and 65 not receiving ART) with no history of diabetes or hypertension. None of the renal markers, modeled as either continuous or categorical variables, correlated with FMD. Contrary to expectations, endothelial dysfunction may not be the link between nephropathy and CVD in HIV.
doi:10.1093/infdis/jir668
PMCID: PMC3209818  PMID: 22013226
8.  Body mass index-mortality paradox in hemodialysis: can it be explained by blood pressure? 
Hypertension  2011;58(6):1014-1020.
Unlike the general population, among hemodialysis patients body-mass index(BMI)is inversely related to blood pressure (BP) and mortality. To explore the reasons for this risk-factor paradox the cross-sectional association of obesity with the following factors was examined: the prevalence of hypertension, its control and echocardiographic left ventricular mass index (LVMI). Longitudinal follow-up explored the relationship of BMI with all-cause mortality. Further it explored whether poorer survival in leaner individuals was related to either high BP or greater LVMI. Among 368 hemodialysis patients both the prevalence of hypertension and its poor control were inversely related to BMI. BMI was also inversely associated with evidence of excess extracellular fluid volume but adjustment for this variable did not completely remove the inverse relationship between BP and BMI. Over 1122 patient-years of cumulative follow up (median 2.7 years) 119 (32%) patients died. In the first two years of follow up, the mortality hazard for the lowest BMI group was increased; thereafter, the survival curves were similar. Adjusting for several risk factors including BP and LVMI did not remove the inverse relationship of BMI with mortality. In conclusion, leaner patients on dialysis have a higher prevalence of hypertension, poorer control of hypertension, more LVMI, and greater evidence of extracellular fluid volume excess. However, volume only partially explains the greater prevalence or poorer control of hypertension. Leaner patients have an accelerated mortality rate in the first two years; this is not completely explained by BP, LVMI or other cardiovascular or dialysis-specific risk factors.
doi:10.1161/HYPERTENSIONAHA.111.180091
PMCID: PMC3241970  PMID: 22042814
Body mass index; epidemiology; hemodialysis; ambulatory blood pressure; left ventricular hypertrophy; survival
10.  Epidemiology of Interdialytic Ambulatory Hypertension and the Role of Volume Excess 
American Journal of Nephrology  2011;34(4):381-390.
Background
The epidemiology of hypertension among hemodialysis (HD) patients is difficult to describe accurately because of difficulties in the assessment of blood pressure (BP).
Methods
Using 44-hour interdialytic ambulatory BP measurements, we describe the epidemiology of hypertension in a cohort of 369 patients. To seek correlates of hypertension control, antihypertensive agents were withdrawn among patients with controlled hypertension and ambulatory BP monitoring was repeated.
Results
Hypertension (defined as an average ambulatory systolic BP ≥135 mm Hg or diastolic BP ≥85 mm Hg, or the use of antihypertensive medications) was prevalent in 82% of the patients and independently associated with epoetin use, lower body mass index and fewer years on dialysis. Although 89% of the patients were being treated, hypertension was controlled adequately in only 38%. Poor control was independently associated with greater antihypertensive drug use. Inferior vena cava (IVC) diameter in expiration was associated with increased risk of poorly controlled hypertension both in cross-sectional analysis and after withdrawal of antihypertensive drugs.
Conclusions
Interdialytic hypertension is highly prevalent and difficult to control among HD patients. End-expiration IVC diameter is associated with poor control of hypertension in cross-sectional analyses as well as after washout of antihypertensive drugs. Among HD patients, an attractive target for improving hypertension control appears to be the reduction of extracellular fluid volume.
doi:10.1159/000331067
PMCID: PMC3182044  PMID: 21893975
Ambulatory blood pressure monitoring; Epidemiology; Epoetin; Hemodialysis; Hypertension; Vitamin D receptor activators
11.  Home Blood Pressure Monitoring: How Good a Predictor of Long-Term Risk? 
Current hypertension reports  2011;13(3):192-199.
Most management decisions for the diagnosis and treatment of hypertension are made using blood pressure (BP) measurements made in the clinic. However, home BP recordings may be of superior prognostic value. In this review, we show that home BP recordings are generally superior to clinic BP measurements in predicting long-term prognosis. Home BP has been shown to significantly predict important end points including all-cause mortality, progression of chronic kidney disease, and functional decline in the elderly. In addition, home BP recordings significantly and strongly predict cardiovascular events. These findings are robust, as they concur despite having been studied in disparate populations, using heterogeneous methods of clinic and home BP measurement, and with varied methods of statistical analysis. The advantages of home BP recordings are not due solely to a larger number of measurements, and they extend to the elderly, patients with chronic kidney disease, and those on hemodialysis. Because home BP recordings combine improved accuracy with the advantages of low cost and easy implementation, most patients with known or suspected hypertension should have their BP assessed and managed by means of home BP recordings.
doi:10.1007/s11906-011-0193-z
PMCID: PMC3124655  PMID: 21327567
BP measurement; Home BP; Clinic BP; Comparative study; Prognosis; Chronic kidney disease; Hemodialysis
12.  Probing Dry-Weight Improves Left Ventricular Mass Index 
American Journal of Nephrology  2011;33(4):373-380.
Background
Although probing dry-weight improves blood pressure control, its effect on echocardiographic left ventricular mass index (LVMI) is unknown.
Methods
Shortly following dialysis, 292 echocardiograms in 150 patients participating in the DRIP trial were obtained at baseline and longitudinally every 4 weeks on 2 occasions.
Results
At baseline, LVMI was 136.3 g/m2 in the control group and 138.7 g/m2 in the ultrafiltration group (p > 0.2 for difference). The change from baseline in LVMI in the control group was +3.5 g/m2 at 4 weeks and +0.3 g/m2 at 8 weeks (p > 0.2 for both changes). The change from baseline in LVMI in the ultrafiltration group was −7.4 g/m2 at 4 weeks (p = 0.005) and −6.3 g/m2 at 8 weeks (p = 0.045). With ultrafiltration, the change in LVMI diameter was −10.9 g/m2 more compared to the control group at 4 weeks (p = 0.012) and −6.6 g/m2 more compared to the control group at 8 weeks (p = 0.21). The reduction in interdialytic ambulatory blood pressure was also greater in response to probing dry-weight in those in the top half of LVMI at baseline (p = 0.02 for interaction effect at week 8).
Conclusion
LVMI, an important determinant of prognosis among long-term dialysis patients, is responsive to probing dry-weight.
doi:10.1159/000326235
PMCID: PMC3078237  PMID: 21447945
Hemodialysis; Hypertension; Ultrafiltration; Ambulatory blood pressure; Volume overload; Echocardiogram; Left ventricular hypertrophy; Left ventricular systolic function
13.  Interdialytic hypertension—an update 
The reference standard for making a diagnosis of hypertension among hemodialysis patients is 44-hour interdialytic ambulatory BP monitoring. However, a more practical way to diagnose and manage hypertension is to perform home BP monitoring that spans the interdialytic interval. In contrast to pre- and postdialysis BP recordings, measurements of BP made outside the dialysis unit correlate with the presence of left ventricular hypertrophy and directly and strongly with all-cause mortality. Hypervolemia that is not clinically obvious is the most common treatable cause of difficult to control hypertension; volume control should be the initial therapy to treat hypertension in most hemodialysis patients. To diagnose hypervolemia, continuous blood volume monitoring is emerging as an effective and simple technique. Reducing dietary and dialysate sodium is an often overlooked strategy to improve BP control. Although definitive randomized trials that demonstrate cardiovascular benefits of BP lowering among hypertensive hemodialysis have not been performed, emerging evidence suggests that lowering BP may reduce cardiovascular events. Since predialysis and post-dialysis BP are quite variable and agree poorly with measurements obtained outside the dialysis unit, treatment should be guided by BP obtained outside the dialysis unit. While the appropriate level to which BP should be lowered remains elusive, current data suggests that interdialytic ambulatory systolic BP should be lowered to <130 mmHg and averaged home systolic BP to <140 mmHg. Antihypertensive drugs will be required by most patients receiving 4 hour thrice weekly dialysis. Beta blockers, dihydropyridine calcium blockers and agents that block the renin-angiotensin system appear to be effective in lowering BP in these patients.
doi:10.1053/j.ackd.2010.10.001
PMCID: PMC3053021  PMID: 21224025
Hypertension; diagnosis; hemodialysis; home BP monitoring; ambulatory BP monitoring; treatment; pathophysiology
14.  Intradialytic hypertension is a marker of volume excess 
Nephrology Dialysis Transplantation  2010;25(10):3355-3361.
Background. Intradialytic blood pressure (BP) profiles have been associated with all-cause mortality, but its pathophysiology remains unknown. We tested the hypothesis that intradialytic changes in BP reflect excess volume.
Methods. The dry weight reduction in hypertensive haemodialysis patients (DRIP) trial probed dry weight in 100 prevalent haemodialysis patients; 50 patients who did not have their dry weight probed served as time controls. In this post hoc analysis, intradialytic BP was recorded at each of the 30 dialysis treatments during the trial. The slope of intradialytic BP over dialysis was calculated by the log of BP regressed over time. Using a linear mixed model, we compared these slopes between control and ultrafiltration groups at baseline and over time, tested the effect of dry weight reduction on these slopes and finally tested the ability of change in intradialytic slopes to predict change in interdialytic systolic BP.
Results. At baseline, intradialytic systolic and diastolic BP dropped at a rate of ~3%/h (P < 0.0001). Over the course of the trial, compared to the control group, the slopes steepened in the ultrafiltration group for systolic but not diastolic BP. Those who lost the most post-dialysis weight from baseline to 4 weeks and baseline to 8 weeks also experienced the greatest steepening of slopes. Each percent per hour steepening of the intradialytic systolic BP slope was associated with 0.71 mmHg [95% confidence interval (CI) 0.01–1.42, P = 0. 048] reduction in interdialytic ambulatory systolic pressure.
Conclusions. Intradialytic BP changes appear to be associated with change in dry weight among haemodialysis patients. Among long-term haemodialysis patients, intradialytic hypertension may, thus, be a sign of volume overload.
doi:10.1093/ndt/gfq210
PMCID: PMC2948838  PMID: 20400448
ambulatory BP; dry weight; haemodialysis; hypertension; sodium
15.  Hypervolemia is associated with increased mortality among hemodialysis patients 
Hypertension  2010;56(3):512-517.
Among chronic hemodialysis patients, 217 hospitalizations/1000 patient-years are due to congestive heart failure; some are attributable to unrecognized hypervolemia. Hypervolemia can be detected by relative plasma volume (RPV) monitoring. The purpose of this study was to examine among 308 patients on long-term hemodialysis the value of slope of RPV compared to either ultrafiltration volume or ultrafiltration rate index in determining all-cause mortality. RPV slopes were calculated by least-squares regression. These slopes were related to all-cause mortality in unadjusted and adjusted Cox proportional hazards models. Over a median follow up of 30 months (IQR 14 – 54 months) 96 (31%) patients died yielding a crude mortality rate of 113/1000 patient years. We found that 1) RPV slope measurements were of prognostic significance (hazard ratio of flatter slopes (>1.39%/hour) 1.72, p = 0.01); 2) the ultrafiltration volume alone was not prognostically informative (hazard ratio of higher UF volume (>2.7 liter/dialysis) 0.78, p=0.23); 3) the ultrafiltration rate index alone was also not prognostically informative (hazard ratio of higher UF rate index (>8.4 mL/kg/hr) 0.89, p=0.6); and 4) the prognostic relationship of RPV slope to mortality was independent of conventional and unconventional cardiovascular risk factors including the ultrafiltration volume, ultrafiltration rate or ultrafiltration volume/kg post weight. RPV monitoring yields information that is prognostically important and independent of several risk factors including ultrafiltration volume, aggressiveness of ultrafiltration, and interdialytic ambulatory BP. Its use to assess excess volume among chronic hemodialysis patients should be tested in randomized controlled trials.
doi:10.1161/HYPERTENSIONAHA.110.154815
PMCID: PMC2929660  PMID: 20625076
dry-weight; relative plasma volume monitoring; prognosis; end-stage renal disease; hypertension
16.  Managing hypertension using home blood pressure monitoring among haemodialysis patients—a call to action 
Nephrology Dialysis Transplantation  2010;25(6):1766-1771.
doi:10.1093/ndt/gfq171
PMCID: PMC2902892  PMID: 20350928
ambulatory BP; haemodialysis; home BP; hypertension; outcomes
17.  Epidemiology of chronic kidney disease among normotensives—But what is CKD? 
Hypertension  2010;55(5):1097-1099.
doi:10.1161/HYPERTENSIONAHA.110.151811
PMCID: PMC2874423  PMID: 20308606
18.  Blood pressure and mortality among hemodialysis patients 
Hypertension  2010;55(3):762-768.
Blood pressure measured before and after dialysis does not agree well with those recorded outside the dialysis unit. Whether recordings obtained outside the dialysis unit are of greater prognostic value than blood pressure obtained just before and after dialysis remains incompletely understood. Among 326 patients on long-term hemodialysis, blood pressure was self-measured at home for one week, over an interdialytic interval by ambulatory recording and before and after dialysis over two weeks. Over a mean follow up of 32 (SD 20) months, 102 patients died (31%) yielding a crude mortality rate of 118/1000 patient years. Systolic but not diastolic blood pressure was found to be of prognostic importance. Multivariate-adjusted and unadjusted analyses showed increasing quartiles of ambulatory and home systolic blood pressure to be associated with all-cause mortality (adjusted hazard ratios for increasing quartiles of ambulatory: 2.51, 3.43, 2.62 and for home blood pressure: 2.15, 1.7, 1.44). Mortality was lowest when home systolic BP was between 120–130 mm Hg and ambulatory systolic blood pressure was between 110–120 mmHg. Blood pressure recorded before and after dialysis were not statistically significant (p=0.17 for predialysis and p=0.997 for postdialysis) in predicting mortality. Out-of-dialysis unit blood pressure measurement provided superior prognostic information compared to BP within the dialysis unit (likelihood ratio test, p<0.05).
Conclusions
Out-of-dialysis-unit blood pressure among hemodialysis patients is prognostically more informative than that recorded just before and after dialysis. Therefore the management of hypertension among these patients should focus on blood pressure recordings outside the dialysis unit.
doi:10.1161/HYPERTENSIONAHA.109.144899
PMCID: PMC2825286  PMID: 20083728
Home blood pressure; ambulatory blood pressure; prognosis; end-stage renal disease
19.  Relative plasma volume monitoring during hemodialysis aids the assessment of dry-weight 
Hypertension  2009;55(2):305.
Among hemodialysis patients the assessment of dry-weight remains a matter of clinical judgment because tests to assess dry-weight have not been validated. The objective of this study was to evaluate and validate relative plasma volume monitoring as a marker of dry-weight. We performed relative plasma volume monitoring using the Critline monitor at baseline and 8 weeks in 150 patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial. The intervention group of 100 patients had dry-weight probed whereas 50 patients served as time controls. Relative plasma volume slopes were defined as flat when they were less than the median (1.33%/hour) at the baseline visit. Among predominantly (87%) African-American hemodialysis patients, we found that flat relative plasma volume slopes suggest a volume overloaded state because of the following reasons: 1) probing dry-weight in these patients leads to steeper slopes; 2) those with flatter slopes at baseline had greater weight loss; 3) both baseline relative plasma volume slopes and the intensity of weight loss were found to be important for subsequent change in relative plasma volume slopes; and most importantly 4) relative plasma volume slopes predicted the subsequent reduction in interdialytic ambulatory systolic BP. Those with the flattest slopes had the greatest decline in BP upon probing dry-weight. Both baseline relative plasma volume slopes and the change in relative plasma volume slopes were important for subsequent changes in ambulatory systolic BP. We conclude that relative plasma volume slope monitoring is a valid method to assess dry-weight among hypertensive hemodialysis patients.
doi:10.1161/HYPERTENSIONAHA.109.143974
PMCID: PMC2819307  PMID: 20038754
hypertension; hemodialysis; dry-weight; plasma volume; diagnostic test
20.  Regulation of Circadian Blood Pressure—From Mice to Astronauts 
Purpose of Review
Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of BP has been shown to be associated with greater target organ damage and to be associated with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP
Recent findings
The time-keeper of the mammals resides centrally in the suprachiasmatic nucleus. Besides this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice to the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon 3 major factors: physical activity, autonomic function, and sodium sensitivity.
Summary
The integrated consideration of physical activity, autonomic function, and sodium sensitivity appear to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
doi:10.1097/MNH.0b013e3283336ddb
PMCID: PMC2876349  PMID: 19864947
blood pressure; circadian rhythms; molecular clocks; cosinor modeling; chronic kidney disease; pathophysiology
22.  Chronobiology of Arterial Hypertension in Hemodialysis Patients: Implications for Home Blood Pressure Monitoring 
Background
Hemodialysis patients have a steady increase in blood pressure (BP) over the 44-hour interdialytic interval when ambulatory BP monitoring is used. Home BP recording allows for longer period of monitoring between dialysis and may better define the chronobiology of arterial hypertension. This study sought to determine the optimal time to perform home BP monitoring in hemodialysis patients to improve the strength of prediction of 44-hour interdialytic ambulatory BP.
Study Design
Diagnostic test study
Setting and Participants
This is an ancillary analysis of patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial.
Index test
Home BP measured three times a day for one week using a validated oscillometric monitor on 3 occasions at 4 week intervals after randomization. Home BP measured during the first third, second third and last third of time elapsed after dialysis as well as each third of dialysis was compared to the overall ambulatory BP.
Reference Tests
Interdialytic ambulatory BP measured on 3 occasions at 4 week intervals after randomization.
Results
Over the interdialytic interval, we found an increase in systolic ambulatory BP of 0.30 ± 0.36 mmHg/hr and an increase in systolic home BP of 0.40 ± 0.25 mmHg/hr. This relationship in home BP reached a plateau after approximately 48 hrs. A similar pattern was seen for diastolic home BP. Probing dry-weight steepened the slope of ambulatory BP but did not alter the time-dependent relationship of home BP. Home BP was on average higher (bias) by 14.1 (95% CI 12.0 to 16.2)/5.7 (95% CI 4.6 to 6.9) mmHg. The standard deviation of differences between methods (precision) was 4.6/2.8 mmHg. Measurement of BP during each third of the interdialytic interval gave the best precision as measured by model fit compared to ambulatory BP measurements.
Limitations
Our cohort was overrepresented by African American hemodialysis patients. Whether African American participants have a different pattern of BP response than non-African American participants in the interdialytic period is not known.
Conclusions
Our findings suggest that time elapsed after dialysis must to be considered in interpreting the home BP recordings in hemodialysis patients. Home BP measured in each third of the interdialytic interval is likely to yield the most reliable BP estimate.
doi:10.1053/j.ajkd.2009.03.018
PMCID: PMC2753716  PMID: 19515473
Home BP; ambulatory BP monitoring; hemodialysis; hypertension; chronobiology
23.  Volume-associated ambulatory BP patterns in hemodialysis patients 
Hypertension  2009;54(2):241-247.
Although volume excess causes hypertension whether it also affects circadian patterns of arterial pressures among hemodialysis patients remains unknown. To test the notion whether volume overload is associated with a unique BP “signature” a post-hoc analysis was performed among 145 patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) randomized controlled trial. Using 400 ambulatory BP recordings over 8 weeks comprising 35,302 measurements the trended cosinor model was found to be the best descriptor of BP chronobiology. The trended cosinor model may be described as a pattern of sinusoidal oscillation around a straight line with an upward trend during the interdialytic period and which has an intercept at the postdialysis time. Augmented volume removal therapy (AVRT) reduced the intercept systolic BP and increased the rate of rise in systolic BP over the interdialytic interval but had no effect on the systolic BP fluctuation (amplitude). Thus an elevated intercept and blunted slope pattern characterizes the “volume overload BP pattern” on ambulatory BP monitoring. Similar changes were seen for diastolic BP. AVRT neither restored dipping nor was associated with a lag-phenomenon for either the wake or sleep systolic BP. Lowering of systolic BP was greater than diastolic BP such that pulse pressure was reduced. An observational cohort of 37 patients followed for 6 months confirmed these findings. Randomized trials are now needed to evaluate the clinical impact of AVRT on hard outcomes since reduction of pulse pressure with this simple expedient has the potential to improve survival in hemodialysis patients.
doi:10.1161/HYPERTENSIONAHA.109.136366
PMCID: PMC2745712  PMID: 19528362
hypertension; hemodialysis; ambulatory blood pressure monitoring; blood volume; chronobiology phenomena
24.  Meta-analysis—not proof but call for action 
Hypertension  2009;54(1):e7.
doi:10.1161/HYPERTENSIONAHA.109.133124
PMCID: PMC2905224  PMID: 20640196
25.  Cardiovascular Protection with Antihypertensive Drugs in Dialysis Patients: A Systematic Review and Meta-analysis 
Hypertension  2009;53(5):860-866.
Epidemiological studies demonstrate that a lower blood pressure and decline in blood pressure over months or years are associated with higher mortality in dialysis patients. In contrast, randomized controlled trials lack power to establish benefits of antihypertensive therapy. Patients on long-term dialysis participating in randomized controlled trials and receiving antihypertensive drug therapy were the subject of this meta-analysis. Outcomes assessed were the hazard ratio of cardiovascular events and all-cause mortality in treated group compared to controls. Among 1202 patients we identified in 5 studies, the overall benefit of antihypertensive therapy compared to control or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI 0.56 to 0.84) using a fixed effects model and 0.62 (95% CI 0.44 to 0.88) using a random effects model. In a sensitivity analysis we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI 0.35 to 0.67), but when normotensives were included in the trial lesser cardiovascular protection was seen (pooled hazard ratio of 0.86 (95% CI 0.67 to 1.12)). Test for herterogenity between hypertensive and “normotensive-included” groups was significant (p<0.006). Similar results were seen for risk ratio for death and cardiovascular events. There was evidence of publication bias based on Egger's test and funnel plot. Randomized trials suggest benefit of antihypertensive therapy among hemodialysis patients. Adequately powered randomized trials are required to confirm these observations especially among those with hypertension.
doi:10.1161/HYPERTENSIONAHA.108.128116
PMCID: PMC2728674  PMID: 19273737
Systematic review; cardiovascular events; reverse epidemiology; hypertension; hemodialysis; treatment

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