Hypertension is Not Adequately Controlled in Hemodialysis Patients

Hypertension is Not Adequately Controlled in Hemodialysis Patients Jhoong S. Cheigh, MD, Claudio Milite, MD, John F. Sullivan, MD, Albert L. Rubin, MD, and Kurt H. Stenzel, MD • To examine the adequacy of hypertension control, we monitored the blood pressure (BP) of 53 hemodialysis patients who received treatment for hypertension. BP measurement using an ambulatory BP monitor began 1 hour before dialysis and continued every 30 to 60 minutes for 48 hours until the next dialysis. Diet, medications including antihypertensive drugs, and hemodialysis prescription were not changed during this study. Each patient had a mean of 68 BP measurements during the monitoring period. Mean (±SD) systolic and diastolic BP levels of all patients over 48 hours were 158.6 ± 22.7 mm Hg and 88.7 ± 16.6 mm Hg, respectively, without diurnal variations. In these, BP loads (the percentage of systolic BP exceeding 150 mm Hg and diastolic BP exceeding 90 mm Hg) were 58.4% and 39.4%, respectively, suggesting that hypertension was inadequately controlled for more than half of the study period. Eight patients (15%) maintained BP within normal ranges at all times. All patients lost weight (2.9 ± 0.9 kg) at the end of dialysis by ultrafiltration. However, only 27 patients (51%) had a greater than 5% decrease in mean arterial BP postdialysis, which returned to predialysis levels within 12 to 24 hours. Reduction of BP postdialysis was significantly more common among black patients (72%) than white patients (30%) (P < 0.01). However, there was no difference in age, cause of kidney disease, amount of ultrafiltration, and BP loads between those whose BP decreased and those whose did not. BP monitoring was repeated in eight patients, 2 to 3 months after adjustment of their antihypertensive regimens. In the repeat study, systolic BP loads were 18.4%, compared with 77.1% in the previous study.(P < 0.001). In summary, (1) hypertension is not adequately controlled in the majority of hemodialysis patients despite antihypertensive treatment; (2) only half of hypertension patients have a decrease in BP at the end of dialysis, which returns to predialysis levels between 12 and 24 hours; (3) reduction of BP in response to ultrafiltration is significantly more common in blacks than whites, suggesting a different mechanism is operational in maintaining hypertension among races; (4) circadian rhythm in BP is not preserved; and (5) continuous ambulatory BP monitoring helps improve hypertension control. We conclude that a considerable number of hemodialysis patients who are treated for chronic hypertension do not have adequate control of hypertension. This finding may explain, at least partially, why cardiac and cerebrovascular disease remain the major causes of death in dialysis patients. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Hemodialysis; hypertenSion; ambulatory blood pressure monitoring.

A

RECENT STUDY reported that cardiac and cerebrovascular disease remain the major causes of death in dialysis patients. 1 Since hypertension is one of the most important causes of cardiac and cerebrovascular diseases in this population,2,3 inadequate control of hypertension may contribute to the high incidence of cardiovascular death in dialysis patients. Cardiovascular mortality of hypertensive patients depends not only on the initial severity of hypertension, but also, and to a large extent, on the degree of hypertension controlled by antihypertensive therapy.4-6 Despite a plethora ofliterature on hypertension in dialysis patients, there are few studies that examine how well hypertension is controlled in this population. 7- 10 These studies are based on a few blood pressure (BP) readings taken at specific instances in time and not in the patient's everyday living environment. Since hemodialysis patients have marked variations in extracellular fluid (ECF) volume between dialysis treatments, their BP varies along the dialysis cycles as well. Therefore, multiple measurements of BP along the dialysis cycle are necessary for proper assess-

ment of hypertension and the development of therapeutic strategy. Currently available noninvasive, portable, ambulatory BP monitors allow BP measurements to be made reliably and consistently over a prescribed time period at specific intervals. Whole-day, ambulatory BP recordings document BP more accurately during normal activity, and correlate more closely with target organ damage and long-term prognosis. II - 17 To examine the adequacy of BP control, we monitored the BP of 53 hemodialysis patients with chronic hypertension for a 48-hour dialysis cycle using an ambulatory BP monitor. We found that, From the Rogosin Kidney Center, the Rogosin Institute; and the New York Hospital/Cornell University Medical College, New York, NY. Presented in part at the 23rd meeting of The American Society of Nephrology, December 2-5, 1990, (Washington, DC, and published in abstract form in J Am Soc Nephroll:351, 1990. Address reprint requests to Jhoong S. Cheigh, MD, The New York Hospital, 525 E 68th St, Box 135, New York, NY 10021.

© 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1905-0010$3.00/0

American Journal of Kidney Diseases, Vol XIX. No 5 (May). 1992: pp 453-459

453

CHEIGH ET AL

454

despite antihypertensive treatment, hypertension was not adequately controlled in many of these patients. This finding may explain, at least partially, why cardiac and cerebrovascular diseases remain the major causes of death in the dialysis population. PATIENTS AND METHODS

Patients During the study period, 108 of 244 chronic hemodialysis patients (44.3%) in our Out-Patient Hemodialysis Unit were receiving one to three antihypertensive regimens regularly to control hypertension. Minors, patients with organic brain syndrome, those who had been on hemodialysis for less than I year, and those who started dialysis on either the early morning shift (5:00 to 6:00 AM) or evening shift (7:00 to 8:00 PM) were excluded from the study (a total of 48 patients). Seven patients who agreed to participate, but who did not wear the ambulatory BP monitor for a 48-hour dialysis cycle, were also excluded. The remaining 53 patients who met the selection criteria and completed continuous BP monitoring for a 48-hour dialysis cycle were the subjects of this study. They were all adult, ambulatory, chronic hemodialysis patients who had hypertension requiring antihypertensive regimens. There were 31 men and 22 women, aged 24 to 73 years (mean ± SD, 53 ± 13). Twenty-five patients were black, 20 white, and eight Hispanic or Oriental. They had been on hemodialysis treatmept for 12 to 142 months (40.0 ± 35.6). The causes of end-stage renal disease (ESRD) were diabetic nephropathy (16 patients; 30%), hypertensive nephropathy (15 patients; 28%), chronic glomerulonephritis (10 patients: 20%), and other miscellaneous causes (12 patients; 22%). Patients received hemodialysis treatment three times a week, 3.5 to 4 hours each session, with a dialysate containing calcium (3.0 to 3.5 mEqj L), bicarbonate (35 mEqjL), and high sodium concentration (140 mEqjL). During hemodialysis, all patients were ultrafiltrated to maintain their hydration status to dry weight as defined by Heyka and Paganini. 18 Twenty-four patients began hemodialysis between 8:00 and 9:30 AM, and the remainder began dialysis between 2:00 and 3:30 PM. Their diet consisted of 2.0 to 3.0 g sodium, 2.0 to 3.0 g potassium, and 1.0 to 1.3 gjkg· d protein. At the time of this study, only 10 subjects had been receiving epoetin-alfa, 2,000 U intravenously per hemodialysis. The mean hematocrit of the patients receiving epoetin was 27% ± 7 %.

hour dialysis cycle. For the purpose of this study, systolic and diastolic BP loads were defined as the percentage of ambulatory systolic and diastolic BP readings exceeding 150 mm Hg and 90 mm Hg, respectively.14 A decrease of greater than 5% in mean arterial BP postdialysis, the criterion reported by Sullivan et al as the hemodynamic characteristic of sodium-sensitive human subjects,19 was defined as "dialysis-responsive hypertension." Unless otherwise stated, all data are reported as the mean (±SD). The data were statistically evaluated by Student's t test or chi-square test where applicable. P values of less than 0.05 were considered statistically significant.

RESULTS

During the monitoring period, each patient had a mean of 68 ± 6 recorded BP measurements while maintaining his/her usual diet, activity, antihypertensive medication, and hemodialysis prescription. The mean systolic and dias~olic BP levels of all patients over a 48-hour dialysis cycle were 158.6 ± 22.7 mm Hg and 88.7 ± 16.6 mm Hg, respectively (Fig 1). Systolic and diastolic BP loads over the same period were 58.4% ± 30.2% and 39.4% ± 24.1%, respectively. These results suggest that hypertension was inadequately controlled for more than half of the study period in the majority of patients. There were only eight patients (15%) who maintained BP within normal ranges at all times. Twenty-four patients began hemodialysis between 8:00 and 9:30 AM, and ended 3.5 to 4 hours later. The changes of BP in these patients during and after dialysis are shown against actual clock time in Fig 2. It can be seen that the circadian rhythm of BP is no longer evident. In addition, neither the mean daytime (6:00 AM to 6:00 PM) BP, BP loads, nor heart rates were different from that of nighttime (6:00

Methods BP monitoring using a noninvasive, ambulatory BP monitor (SpaceLabs, Redmond, W A; model no. 90207) began I hour before hemodialysis and continued every 30 to 60 minutes for 48 hours until the next dialysis. The BP monitor was applied on the upper, non fistula-bearing arm. Recorded BP was retrieved, processed, and reported using a computer software program (SpaceLabs ABP Analysis System; model no. 9020902). The software program printed out the mean systolic, diastolic, and arterial BP, and BP loads as defined below. The program also produced a graphic presentation of hourly mean systolic and diastolic BP and pulse rates observed over a 48-

T·4

0

3

6

12

24

36

42

J

TIME PRE and POST·HEMODIALVSIS (hour)

Fig 1. Mean (±SD) systolic and diastolic BP of 53 patients observed over a 48-hour dialysis cycle. Shaded area represents the period patients received hemodialysis.

455

HYPERTENSION IN HEMODIALYSIS PATIENTS Systolic

study (P < 0.001). Diastolic BP load was also improved from 36.7% to 9.2% (P < 0.05). DISCUSSION

Fig 2. Mean systolic and diastolic BP of 21 patients who began hemodialysis between 8:00 AM and 9:30 AM. BP changes obseNed over a 48-hour dialysis cycle were plotted against actual clock time. Shaded area represents the period patients received hemodialysis.

PM to 6:00 AM) (BP, 160.7/89.5 v 161.0/87.8 mm Hg; systolic BP loads, 56.5% v 57.9%; diastolic BP loads, 43.8% v 40.8%; heart rate, 85.9 v 84.3 per min). At the end of dialysis, all patients lost body weight (2.9 ± 0.9 kg) by ultrafiltration. However, only 27 patients (51 %) had a significant reduction of BP (>5% in mean arterial BP) at the end of dialysis (dialysis-responsive hypertension). Systolic BP also decreased by at least 10 mm Hg (171.9 ± 25.6/92.8 ± 19.2 mm Hg predialysis and 144.7 ± 27.1/87.5 ± 21.6 mm Hg postdialysis). In these patients, BP returned to predialysis levels between 12 to 24 hours after dialysis (Fig 3). The remaining 26 patients (49%) had either no significant decrease in BP or a higher BP at the end of dialysis (155.6 ± 29.7/82.9 ± 16.6 mm Hg predialysis and 163.7 ± 31.9/90.3 ± 18.3 mm Hg postdialysis) (dialysis-unresponsive hypertension). Dialysis-responsive hypertension was significantly more common among black (72%) than white patients (30%) (P < 0.01). However, there was no difference in age, cause of kidney disease, properties of antihypertensive drugs they received, amount of ultrafiltration (3.2 ± 1.3 kg v 2.8 ± 1.2 kg), and systolic and diastolic BP loads (56.5% v 57.4% in systolic, and 38.9% v 38.0% in diastolic BP loads) between patients with dialysis-responsive and dialysis-unresponsive hypertension. In eight patients who were found to have poorly controlled hypertension, BP monitoring was repeated 2 to 3 months after adjustment of antihypertensive regimens was made based on monitoring data. In the repeat study, systolic BP load was 18.4%, compared with 77.1 % in the first

The goal of treating patients with hypertension is to prevent cardiovascular morbidity and mortality attributable to high BP. Morbidity and mortality associated with hypertension depend not only on the initial severity of hypertension, but also, and to a large extent, on the degree of hypertension controlled by antihypertensive therapy.4.6 Data from patients with essential hypertension demonstrated that those who survived had, on the average, lower systolic and diastolic BP. 20 The inference may be that the lower the BP of treated patients consistent with safety and tolerance, the better the prognosis. However, the target BP to be achieved by treatment is debatable.2 1-23 In this study, we set our target BP arbitrarily at 150/90 mm Hg, and any BP above that level was defined as inadequately controlled hypertension. 23 This study shows that the mean BP for a 48hour dialysis cycle was 158/88 mm Hg. Systolic and diastolic BP loads were 58% and 39%, respectively, for the same period. Only 15% of patients studied maintained their BP below 150/90 mm Hg at all times. These results, therefore, indicate that most hypertensive patients had suboptimally controlled hypertension. Systolic BP

Systolic

Diastolic

......... Dialysis-responsive hypertension (n=27) 0--0 Dialysis-unresponsive hypertension (n=26)

50

o

3

12

50

J

42

TIME PRE and POST·HEMODIALYSIS (hour)

Fig 3. Mean (±SD) systolic and diastolic BP of patients with dialysis-responsive hypertension (n = 27) and those with dialysis-unresponsive hypertension (n = 26) over a 48-hour dialYSis cycle. Dialysis-responsive hypertension is defined by decreasing mean arterial pressure more than 5.0 mm Hg at the end of dialysis than predialysis. Shaded area represents the period patients received hemodialysis.

456

control was even worse than diastolic BP control. Since the risk of cardiovascular complications is more closely related to systolic BP,24,25 sustained systolic hypertension observed in this study could be an important contributor to cardiovascular morbidity and mortality. The number of episodes of uncontrolled hypertension in this study is considerably higher than has been reported. 8,9,26 However, characteristics of this study, such as inclusion of only those with severe hypertension requiring antihypertensive drugs, a large number of patients with diabetic nephropathy or hypertensive nephropathy, and a continuous ambulatory monitoring of BP for a 48-hour dialysis cycle, instead of casual BP, make it difficult to compare with other studies. However, these results are consistent with the report of Ritz et al,27 who found 87% of diabetic patients and 65% of nondiabetic patients on dialysis had inadequate control of hypertension. Ang et al 28 also found, by continuous ambulatory BP monitoring, a high incidence of uncontrolled hypertension among hemodialysis patients who had chronic hypertension requiring antihypertensive agents. There are two major reasons for inadequate control of hypertension. First is the practice of withholding antihypertensive medications hours before hemodialysis to avoid hypotension during dialysis. 18,29 This common practice, coupled with the peak of expanded ECF volume before hemodialysis, may allow BP to run out of control for a considerable period of time. In this study, 85% of patients with dialysis-responsive hypertension and 54% with dialysis-unresponsive hypertension were withheld antihypertensive regimens for up to 12 hours before dialysis. This may explain why the former group had a higher predialysis BP, albeit statistically not significant, than that of the latter group. Since half of the patients' BP remained stable or paradoxically increased through dialysis, the practice of withholding antihypertensive regimens for hours before hemodialysis should be reevaluated. For those who develop hypotensive episodes, other measures,30 such as bicarbonate or high sodium dialysate, should be tried first before withholding antihypertensive agents. In selected patients who have hypertension and hypertrophic cardiomyopathy, treatment with verapamil may help prevent a hypotensive episode, rather than worsening it. 31 Ju-

CHEIGH ET AL

dicious use of short-acting antihypertensive agents 4 to 6 hours before hemodialysis might help reduce the incidence of excessive hypertension observed in the predialysis period in selected patients. The second reason may be that underestimation of the severity of hypertension based on casual BP readings, particularly predialysis and postdialysis BP measurements alone, lead to insufficient treatment. In this study, even in those patients whose BP decreased at the end of dialysis, the lowered BP lasted less than 12 to 24 hours. The BP levels for the remaining 24 to 36 hours were within the ranges of predialysis. Therefore, an assumption of adequate BP control based on postdialysis BP may mislead one to underestimate the severity of hypertension and, thus, provide insufficient treatment. Clearly, proper assessment of hypertension in hemodialysis patients requires monitoring ofBP for an extended period, including the interval between dialysis treatments. It appears that the lower incidence of uncontrolled hypertension reported in some studies may be due to an insufficient number ofBP measurements, particularly the lack of BP measurements during the interdialysis period. The mechanism of hypertension in patients with ESRD is multifactorial and complex. 32-35 Resetting of the ECF volume-vasopressors (renin-angiotensin system in particular) feedback mechanism appears to be the most important cause of hypertension. 33 These studies suggest that two major types of hypertension exist in chronic renal failure, "volume-dependent" and "renin-dependent. ,,32 As volume-dependent hypertension is by far the more common condition (80% to 90%), it is assumed that volume expansion is the principal factor determining hypertension. Observations showing improved BP control with enhanced ultrafiltration during dialysis support this notion. 8,9 In this study, patients lost a mean of 2.9 kg of body fluid by ultrafiltration, but only 51 % of patients had BP decrease or normalize at the end of dialysis. In the other patients, BP was unchanged or even increased at the end of dialysis, despite the loss of a comparable amount of fluid with ultrafiltration. The lack of declining BP response to ultrafiltration suggests that fluid overload may not play an important role in the maintenance of hypertension in the latter group

HYPERTENSION IN HEMODIALYSIS PATIENTS

of the patients. However, we cannot rule out the possibility that an overestimation of dry weight, and thus insufficient ultrafiltration, might have been a cause of persistent hypertension in some of these patients. An overestimation of dry weight could be more significant in those patients who receive short courses of dialysis treatment and rapid ultrafiltration with high-flux or high-efficiency dialyzers. Since hemodynamic response to ultrafiltration is closely related to intravascular fluid volume,36,37 which is related to the ultrafiltration rate,37,38 a rapid ultrafiltration may result in premature hypotensive episodes before true dry weight is achieved. A low incidence of hypertension in patients receiving long dialysis treatment with Kiil dialyzers supports the notion that slower ultrafiltration helps achieve true dry weight and thus controls BP better. 39,40 It is apparent that we need a more precise means of determining dry weight than the one currently practiced in hemodialysis patients. 18 The existence of refractory hypertension or paradoxically increasing BP in response to ultrafiltration has been recognized. 41 -43 However, the incidence (49%) of dialysis-unresponsive hypertension in this study is considerably higher than previously reported. 8-lo,26.32 Clearly, the characteristics of the study population are partially responsible for the high incidence. In addition, some other factors, such as the use of bicarbonate dialysate with high sodium concentration, may also be responsible for altering the hemodynamic response of hypertensive patients to ultrafiltration. 3o,44-46 In fact, such dialysate prescription has been used to improve hemodynamic tolerance to ultrafiltration and to maintain stable BP throughout dialysis. It appears that characteristics of current patient population and dialysis treatment have appreciably increased the number of those patients who have dialysis-unresponsive hypertension. In this study, dialysis-unresponsive hypertension was significantly more common among white (72%) than black patients (30%). In other words, hypertension in black patients is more responsive to sodium and volume reduction by ultrafiltration than in white patients, suggesting a different mechanism is involved in maintaining hypertension between the two groups. This differential hemodynamic response to ultrafiltration between races has not been recognized before.

457

However, the finding is consistent with the observations that black patients with essential hypertension have a higher degree of salt sensitivity than white patients. 47-49 Circadian variations ofBP with higher daytime than nighttime readings have long been recognized in both normal subjects and patients with essential hypertension. 14,50,51 In these patients, the circadian rhythm remains unaltered even by antihypertensive therapy. 52 However, patients with chronic renal failure do not have the nocturnal decline in both systolic and diastolic BP. 27 ,53-55 Some may even have a reversal of the usual daynight changes. 56 The absence or reversal of circadian rhythm has been observed uniformly in patients with various stages of kidney disease, including chronic renal failure, dialysis, and transplantation. A possible exception may be those dialysis patients who are spontaneously normotensive. 57 The dominant role of expanded ECF volume and autonomic nerve dysfunction in BP control is thought to be responsible for the mechanism of abnormal circadian rhythm. Our study confirms again that hypertensive dialysis patients do not have a normal circadian rhythm of BP. In this study, the mean daytime BP (systolic/diastolic) and heart rate were identical with that of nighttime. In addition, the mean systolic and diastolic BP loads were identical with that of nighttime. Therefore, the control of hypertension at nighttime is not better than daytime at all. Rather, in those whose circadian rhythm is reversed, a casual lower daytime BP may lead to underestimation of hypertension. Therefore, the loss or reversal of circadian rhythm in hemodialysis patients has a direct relevance to the assessment and management of hypertension. However, the significance of circadian variation to cardiovascular disease in hemodialysis patients remains to be seen. 58 Continuous monitoring of BP helps improve hypertension control by precisely documenting response of BP to daily activities, hemodialysis, and antihypertensive regimens. 59 ,60 In eight patients who were found to have poorly controlled hypertension, BP monitoring was repeated 2 to 3 months after adjustment of antihypertensive regimens based on monitoring data. In the repeat study, systolic BP loads were now only 18%, compared with 77% in the first study. This study clearly documents that ambulatory BP monitor-

458

CHEIGH ET AL

ing for a 48-hour dialysis cycle helps to guide antihypertensive therapy by aiding accurate assessment of hypertension and informed choice of drugs (potency and duration) and time of administration. In addition, when shown a graphic presentation of their BP monitoring data; the patient's perception of the severity of their hypertension greatly improves, thus enhancing their compliance. In summary, we report that a considerable number of hemodialysis patients who have been treated for chronic hypertension do not have adequate control of hypertension. Even in those whose BP control improves with ultrafiltration, it does not last long. Withholding antihyperten-

sive regimens before hemodialysis and underestimation of severity of hypertension based on casual BP, and thus insufficient treatment, appear to be important causes for the inadequate control of hypertension. These findings may explain, at least partially, why cardiac and cerebrovascular disease remain the overwhelming causes of death in dialysis patients. 1 A more systematic study with a larger number of dialysis patients is warranted to determine the severity and extent of inadequate hypertension control. ACKNOWLEDGMENT

The authors thank Drs Hong S. Kim and Duc C. Bui for their help in this study, and Sue Pino for the preparation of the manuscript.

REFERENCES 1. US Renal Data System: USRDS 1990 Annual Data Report. Bethesda, MD, National Institute of Health, National Institutes of Diabetes and Digestive and Kidney Diseases, August 1990 2. Vincenti F, Amend W, Abele J, et al: The role of hypertension in hemodialysis associated atherosclerosis. Am J Med 68:363-369, 1980 3. Goldberg A, Tindira C, Harter H: Coronary risk in patients with end-stage renal disease: Interaction of hypertension with hyperlipidemia. J Cardiovasc Pharmacol 4:S-257-261, 1982 (suppI2) 4. Bulpitt CJ, Beevers 00, Butler A: Treated blood pressure, rather than pretreatment predicts survival in hypertensive patients. A report from the DHSS Hypertension Care Computing Project (DHCCP). J Hypertens 6:627-632, 1988 5. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure including mild hypertension. JAMA 242:2562-2577, 1979 6. Hartford M, Wende1had I, Berglund G, et al: Cardiovascular and renal effects oflong-term antihypertensive treatment. JAMA 259:2553-2557, 1988 7. Ritz E, Strumpf C, Katz F, et al: Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension 7:118-124, 1985 (suppl 3) 8. Sulkova S, Valek A: Role of antihypertensive drugs in the therapy of patients on regular dialysis treatment. Kidney Int 34:S198-S2OO, 1988 (suppl) 9. Jacobs C, Simon N, Patte R, et al: Control of blood pressure in patients treated by maintenance hemodialysis. Contrib NephroI41:128-136, 1984 10. Hull A, Long D, Prati R, et al: The control of hypertension in patients undergoing regular maintenance hemodialysis. Kidney Int 75:S184-S187, 1974 (suppl) 11. Weber M: Automated blood pressure monitoring: A new dimension in diagnosis. Mayo Clin Proc 63: 1151-1153, 1988 12. Zachariah P, Sheps S, Smith R: Clinical use of home and ambulatory blood pressure monitoring. Mayo Clin Proc 64:1436-1446, 1989

13. Pickering T, James G, Boddie C, et al: How common is white coat hypertension? JAMA 259:225-228, 1988 14. Zachariah P, Sheps S, Iistrup D, et al: Blood pressure load-A better determinant of hypertension. Mayo Clin Proc 63: 1085-1091, 1988 15. Parati G, Pomidossi G, Albini F, et al: Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 5:93-98, 1987 16. Prisant M, Carr A: Ambulatory blood pressure monitoring and echocardiographic left ventricular wall thickness and mass. Am J Hypertens 3:81-89, 1990 17. White W, Schulman P, McCabe E, et al: Average daily blood pressure, not office blood pressure, determines cardiac function in patients with hypertension. JAMA 261:873-877, 1989 18. Heyka R, Paganini E: Blood pressure control in chronic dialysis patients, in Maher JF (ed): Replacement of Renal Function by Dialysis (ed 3). Detroit, MI, KIuwer Academics, 1989, pp 772-787 19. Sullivan J, Prewitt R, Ratts T, et al: Hemodynamic characteristics of sodium sensitive human subjects. Hypertension 9:398-406, 1987 20. Hardy R, Hawkins CM: The impact of selected indices of antihypertensive treatment on all-cause mortality. Am J Epidemiol 117:566-574, 1983 21. Kaplan NM, Alderman MH, F1amenbaum W, et al: Guidelines for the treatment of hypertension. Am J Hypertens 2:75-77, 1989 22. Alderman M, Ooi W, Madhavan S, et al: Treatment induced blood pressure reduction and the risk of myocardial infarction. JAMA 262:920-924, 1989 23. Berglund G: Goals of antihypertensive therapy. Is there a point beyond which blood pressure reduction is dangerous? Am J Hypertens 2:586-593, 1989 24. Fisher C: The ascendancy of diastolic blood pressure over systolic. Lancet 2: 1349-1350, 1985 25. Rutan G, Kuller L, Neaton J, et al: Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention trial. Circulation 77:504-514,1988

HYPERTENSION IN HEMODIALYSIS PATIENTS

26. Wauters JP, Waeber HR, Brunner JP, et al: Uncontrollable hypertension in patients on hemodialysis: Long term treatment with captopril and salt subtraction. Clin Nephrol 16:86-92, 1981 27. Ritz E, Strumpf C, Katz F, et al: Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension 7:11118-124, 1985 (suppI2) 28. Ang KS, Simon P, Cam G: Ambulatory blood pressure during interdialytic period in uremic patients treated by hemodialysis. Kidney Int 35:238, 1989 (abstr) 29. Diamond S, Henrich W: Hypertension in dialysis patients. Int J Artif Organs 9:213-214, 1986 30. Daugirdas J: Dialysis hypotension: A hemodynamic analysis. Kidney Int 39:233-246, 1991 31. Whelton PK, Watson AJ, Kone B, et al: Calcium channel blockade in dialysis patients with left ventricular hypertrophy and well-preserved systolic function. J Cardiovasc PharmacollO:SI85-S186, 1987 (suppl 10) 32. Vertes V, Cangiano J, Berman L, et al: Hypertension in end-stage renal disease. N Eng! J Med 280:978-981, 1969 33. Weidmann P, Piccoli C, Steffen F, et al: Hypertension in terminal renal failure. Kidney Int 9:294-301, 1976 34. Zucchelli P, Zuccala A, Esposti E, et al: Pathophysiology and management of hypertension in hemodialysis patients. Contrib Nephrol 45:209-217, 1987 35. Zuccala A, Santoro A, Ferrari G, et al: Pathogenesis of hypertension in hemodialysis patients: A pharmacological study. Kid Int 34:S190-S191, 1988 (suppl) 36. Lins L, Jacobsson S, Ljungqvist 0: Hypotension during hemodialysis and its relation to body fluid changes. J Am Soc Nephrol 1:366, 1990 (abstr) 37. DeVries P, Kouw P, Olthof C, et al: The influence of dialysate sodium and variable ultrafiltration on fluid balance during hemodialysis. ASAIO Trans 36:821-824, 1990 38. Stiller S, Thommes A, Konigs F, et al: Characteristic profiles of circulating blood volume during dialysis therapy. ASAIO Trans 35:530-532, 1989 39. Charra B, Calamard E, Cuche M, et al: Control ofhypertension and prolonged survival on maintenance hemodialysis. Nephron 33:96-99, 1983 40. Charra B, Calemard E, Chazot C: Survival as an index of adequacy of dialysis. J Am Soc Nephrol1:351, 1990 (abstr) 41. Brown JJ, Curtis JR, Lever AF, et al: Plasma renin concentrations and the control of blood pressure in patients on maintenance hemodialysis. Nephron 6:329-349, 1969 42. Keusch G, SchiffH, Binswanger U: Diazoxide and labetalol in acute hypertension during hemodialysis. Eur J Clin PharmacoI25:523-527, 1983

459 43. Batlle D, Riotte A: Delayed hypotensive response to dialysis in hypertensive patients with end-stage renal disease. Am J NephroI6:14-20, 1986 44. Diamond S, Henrich W: Acetate dialysate versus bicarbonate dialysate: A continuing controversy. Am J Kidney Dis 9:3-11, 1987 45. Aguilera D, Diab N, Faivre J: Influence of sodium dialysate variation on hemodynamic stability. Kidney Int 34: SI87-S189, 1988 (suppl) 46. Kramer B, Ress K, Ulshofer T, et al: Hemodynamic and hormonal effects of low or high sodium hemodialysis. Kidney Int 34:S 192-S 195, 1988 (suppl) 47. Weinberger MH, Miller JZ, Luft FC, et al: Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 8:II127 -II134, 1986 48. Eisner GM: Hypertension: Racial differences. Am J Kidney Dis 16:35-40, 1990 49. Falkner B: Differences in blacks and whites with essential hypertension. Biochemistry and endocrine. Hypertension 15:681-686, 1990 50. Millar-Craig M, Bishop CN, Raftery EB: Circadian variation of blood pressure. Lancet 795, 1978 51. Halbert F, Scheving LE, Lucas E, et al: Chronobiology of human blood pressure in the light of static automatic monitoring. Chronobiologia 11:217-247, 1984 52. Raftery EB, Millar-Craig MW, Mann S, et al: Effects of treatment on circadian rhythms of blood pressure. Biote1em Patient Monit 8:113-118, 1981 53. Portaluppi F, Montanari L, Massari M, et al: Loss of nocturnal decline of blood pressure in hypertension due to chronic renal failure. Am J Hypertens 4:20-26, 1991 54. Rosansky S: Nocturnal hypertension in patients receiving chronic hemodialysis. Ann Intern Med 114:96, 1991 (letter to editor) 55. Wadhwa N, Arbeit L: Noninvasive ambulatory blood pressure monitoring in hemodialysis patients. J Am Soc Nephrol1:381, 1990 (abstr) 56. Baumgart P, Walger P, Gemen S, et al: Blood pressure elevation during the night in chronic renal failure, hemodialysis and after renal transplantation. Nephron 57:293-298, 1991 57. DePlaen J: Blood pressure rhythm. Ann Intern Med 114:914, 1991 (letter to editor) 58. Muller JE, Tofler GH: Circadian variation and cardiovascular disease. N Eng! J Med 325: 1038-1039, 1991 59. Weber M, Cheung D, Graettinger W: Characterization of antihypertensive therapy by whole day blood pressure monitoring. JAMA 259:3281-3285, 1988 60. Waeber B, Petrillo A, Nussberger J, et al: Are some hypertensive patients overtreated? Lancet 1:732-734, 1987