New Perspectives on Blood Pressure Variability in Hemodialysis Patients

Abstract

Related Article, p. 409 Related Article, p. 409 Patients with chronic kidney disease treated by hemodialysis have a significantly increased risk for cardiovascular morbidity and mortality compared with the general population. Nephrologists are aware of this risk and have been searching for nontraditional and potentially modifiable risk factors to explain this phenomenon. Blood pressure variability is proposed to be a possible risk factor. In an observational cohort study appearing in this issue of the American Journal of Kidney Diseases, Flythe et al address these important questions by proposing an optimal metric and factors associated with intradialytic blood pressure variability.1Flythe J.E. Kunaparaju S. Dinesh K. Cape K. Feldman H.I. Brunelli S.M. Factors associated with intradialytic systolic blood pressure variability.Am J Kidney Dis. 2012; 59: 409-418Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Blood pressure variability in the general population is believed to pose a significant risk for cardiovascular disease. Increased systolic blood pressure variability, independent of absolute blood pressure, is a risk factor for stroke, regardless of prior cerebrovascular disease.2Rothwell P. Howard S. Dolan E. et al.Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.Lancet. 2010; 375: 895-905Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar Increased systolic blood pressure variability is also associated with increased risk for heart failure, angina, or myocardial infarction.2Rothwell P. Howard S. Dolan E. et al.Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.Lancet. 2010; 375: 895-905Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar The exact mechanisms behind these findings are not understood, but there has been prior evidence of associations between increased blood pressure variability and end-organ damage. In a study of patients admitted to the hospital for neurologic disease, systolic blood pressure variability was a stronger predictor of common carotid artery intima media thickness, a surrogate for atherosclerotic disease, than other traditional risk factors.3Sander D. Klingelhofer J. Diurnal systolic blood pressure variability is the strongest predictor of early carotid atherosclerosis.Neurology. 1996; 47: 500-507Crossref PubMed Scopus (57) Google Scholar The correlation between blood pressure variability and intima media thickness existed regardless of the presence or absence of hypertension. In that study,3Sander D. Klingelhofer J. Diurnal systolic blood pressure variability is the strongest predictor of early carotid atherosclerosis.Neurology. 1996; 47: 500-507Crossref PubMed Scopus (57) Google Scholar variability was defined as the standard deviation of all blood pressure measurements obtained during a 24-hour time period. However, other definitions have yielded similar findings. Increased daytime blood pressure variability has also been associated with increased left ventricular mass and microalbuminuria in hypertensive individuals.4Tatasciore A. Renda G. Zimarino M. et al.Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.Hypertension. 2007; 50: 325-332Crossref PubMed Scopus (218) Google Scholar Baseline daytime blood pressure variability has also been shown to predict progression of intima media thickness over a 3-year follow-up period.5Sander D. Kukla C. Klingelhofer J. Winbeck K. Conrad B. Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: a 3 year follow-up study.Circulation. 2000; 102: 1536-1541Crossref PubMed Scopus (346) Google Scholar These studies cumulatively demonstrate the robust association of blood pressure variability with end-organ damage and clinical outcomes in hypertensive individuals. Despite these findings in hypertensive individuals, it is difficult to make similar conclusions regarding hemodialysis patients because of the unique blood pressure patterns that occur in this patient population. Most hemodialysis patients experience a decrease in blood pressure from pre- to postdialysis and a gradual increase in blood pressure in the interdialytic period.6Kelley K. Light R. Agarwal R. Trended cosinor change model for analyzing hemodynamic rhythm pattern in hemodialysis patients.Hypertension. 2007; 50: 143-150Crossref PubMed Scopus (41) Google Scholar Additionally, many hemodialysis patients are “nondippers.” Thus, there are numerous time periods in which to explore the definition and significance of blood pressure variability in these patients. In a cohort study of 144 Japanese hemodialysis patients, increased blood pressure variability (defined by coefficient of variation in visit to visit blood pressure) was determined to be an independent predictor for all-cause, but not cardiovascular, mortality.7Tozawa M. Iseki K. Yoshi S. Fukiyama K. Blood pressure variability as an adverse prognostic risk factor in end-stage renal disease.Nephrol Dial Transplant. 1999; 14: 1976-1981Crossref PubMed Scopus (73) Google Scholar More recently, the visit to visit variability in predialysis measurements was explored in incident hemodialysis patients over the course of 3 months.8Brunelli S. Thadhani R. Lynch K. et al.Association between long-term blood pressure variability and mortality among incident hemodialysis patients.Am J Kidney Dis. 2008; 52: 716-726Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The authors examined 4 different metrics of blood pressure variability and identified that the average residual to intercept ratio was the optimal metric based on its independence of blood pressure slope over time and its weak correlation with average blood pressure intercept. In adjusted analyses, systolic blood pressure variability had a significant association with mortality.8Brunelli S. Thadhani R. Lynch K. et al.Association between long-term blood pressure variability and mortality among incident hemodialysis patients.Am J Kidney Dis. 2008; 52: 716-726Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Currently, there are still major gaps in our understanding of blood pressure variability in hemodialysis patients regarding the blood pressure changes during and between hemodialysis treatments, as well as the underlying etiology for increased blood pressure variability. In their AJKD article, Flythe et al reported their analysis of all blood pressure measurements obtained during 2,422 hemodialysis treatments given to 218 prevalent adult hemodialysis patients over a one-month period.1Flythe J.E. Kunaparaju S. Dinesh K. Cape K. Feldman H.I. Brunelli S.M. Factors associated with intradialytic systolic blood pressure variability.Am J Kidney Dis. 2012; 59: 409-418Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The primary dependent variables were 3 different metrics of systolic blood pressure variability: the absolute change in systolic blood pressure from one measurement to the next during a treatment, the overall standard deviation of systolic blood pressure during a treatment, and the absolute spline systolic blood pressure residual. The authors analyzed numerous demographic and clinical variables proposed to influence blood pressure variability. A large percentage of the participants (56%) had congestive heart failure, and most (86%) were African American. The authors found increasing age to be associated with increased blood pressure variability. Compared with participants who had been receiving hemodialysis for fewer than 12 months, those who had been receiving dialysis therapy for 12-24 months or for greater than 48 months had significantly lower blood pressure variability. When participants were separated into groups according to the quartile of either ultrafiltration rate or ultrafiltration volume, those in the fourth quartile (ie, individuals with the greatest ultrafiltration) had significantly increased systolic blood pressure variability compared with those in the first quartile. Blood pressure variability increased significantly with each standard deviation of ultrafiltration volume or ultrafiltration rate when these variables were expressed as a ratio of total body water. The authors furthermore identified that the spline residual metric provided the best combination of consistency and ability to distinguish nonsystematic blood pressure variability from systematic blood pressure change. The major strengths of this article lie in both its design and statistical analysis of the available data. A large number of individuals were sampled across several urban hemodialysis units. Clinically relevant variables were well ascertained, enabling many potentially important confounders to be controlled for. As intradialytic blood pressure variability has never been studied before, this metric offers the field some sort of standard that can be utilized further in outcome studies. Some important limitations of the study are appropriately acknowledged by the authors and mainly pertain to the inherent inability of an observational study to exclude all potential confounders, and the higher than expected proportion of African Americans and participants with congestive heart failure that may limit the overall generalizability. Another limitation is that the effects of antihypertensive medications on blood pressure variability remain poorly determined. It is reported that neither antihypertensive class, number, nor dialyzability affected blood pressure variability. Without complete ascertainment of the dose and timing of the medications in relation to the dialysis session, it is difficult to validly conclude that blood pressure variability is not dependent on these factors. One additional limitation to be noted is the modest association of ultrafiltration volume and ultrafiltration rate with blood pressure variability when treated as ratios of total body water. Each 1–standard deviation increase in these ratios was only associated with a 0.22– to 0.24–mm Hg increase in systolic blood pressure variability. However, this article generates important hypotheses that are relevant to understanding how to measure intradialytic blood pressure variability and paves the way for studies that can investigate both the underlying mechanisms responsible for blood pressure variability and its clinical consequences. The most important finding that should be extrapolated from this study for the purpose of identifying the significance of blood pressure variability in hemodialysis patients is the association of increased blood pressure variability with increased ultrafiltration and ultrafiltration rate. In addition to the fact that older age is itself a risk factor for mortality, both age and dialysis vintage are nonmodifiable risk factors. The associations with increased ultrafiltration and increased ultrafiltration rate are extremely important because these variables are modifiable. As specifically stated in the article, blood pressure variability is “not a fixed characteristic of individuals, but is instead sensitive to extrinsic factors.”1Flythe J.E. Kunaparaju S. Dinesh K. Cape K. Feldman H.I. Brunelli S.M. Factors associated with intradialytic systolic blood pressure variability.Am J Kidney Dis. 2012; 59: 409-418Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Future prospective research should investigate how variables that influence ultrafiltration and ultrafiltration rate affect blood pressure variability and ultimately clinical outcomes. Given the high correlation with interdialytic weight gain and ultrafiltration volume,9Inrig J.K. Patel U.D. Gillespie B.S. et al.Relationship between interdialytic weight gain and blood pressure among prevalent hemodialysis patients.Am J Kidney Dis. 2007; 50 (118.e1-4): 108-118Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar it would be expected that higher interdialytic weight gains would be associated with increased blood pressure variability. Strategies to limit interdialytic weight gain, including dietary sodium and fluid restriction as well as modification of dialysate sodium concentrations, would be potential areas to address as we learn more about the consequences of intradialytic blood pressure variability. The association with ultrafiltration rate also provides a potential mechanism regarding the etiology of increased blood pressure variability. Increased ultrafiltration rate has been associated with increased mortality10Flythe J. Kimmel S. Brunelli S. Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality.Kidney Int. 2011; 79: 250-257Crossref PubMed Scopus (316) Google Scholar as well as with myocardial stunning.11Jeffries H. Virk B. Schiller B. Moran J. McIntyre C. Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning).Clin J Am Soc Nephrol. 2011; 6: 1326-1332Crossref PubMed Scopus (175) Google Scholar No study has directly correlated intradialytic blood pressure variability with myocardial stunning or markers of ischemia reperfusion injury such as capillary damage or tissue ischemia. It would be interesting to see how strategies that minimize ultrafiltration rate and myocardial stunning, such as frequent home hemodialysis, would affect blood pressure variability. As there were no associations with comorbid conditions in a population with such a high prevalence of congestive heart failure, future studies will also need to address how blood pressure variability influences a more heterogeneous group of hemodialysis patients. In summary, this article demonstrates an association between increased intradialytic blood pressure variability with older age, shorter dialysis vintage, increased ultrafiltration rate, and greater ultrafiltration volume. Moreover, this study provides a metric that can be used in further investigations. More studies are clearly required to demonstrate an association between intradialytic blood pressure variability and clinical end points in hemodialysis patients, but this study at least allows for speculation as to how increased variability may be harmful. Studies are also needed to determine the causes and significance of blood pressure variability from ambulatory measurements. However, with accumulating evidence that blood pressure patterns during hemodialysis provide important prognostic information,12Inrig J. Oddone E. Hasselblad V. et al.Association of intradialytic blood pressure changes with hospitalization and mortality rates in prevalent ESRD patients.Kidney Int. 2007; 71: 454-461Crossref PubMed Scopus (138) Google Scholar, 13Inrig J.K. Patel U.D. Toto R.D. Szczech L.A. Association of blood pressure increases during hemodialysis with 2-year mortality in incident hemodialysis patients: a secondary analysis of the Dialysis Morbidity and Mortality Wave 2 Study.Am J Kidney Dis. 2009; 54: 881-890Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar we should take full advantage of readily available measurements to identify those patients at highest risk for mortality. Financial Disclosure: The authors declare that they have no relevant financial interests. Factors Associated With Intradialytic Systolic Blood Pressure VariabilityAmerican Journal of Kidney DiseasesVol. 59Issue 3PreviewAlthough blood pressure lability during hemodialysis has long been recognized, little is known about factors that promote nonsystematic intradialytic blood pressure variability. Full-Text PDF