Hypertension and Cardiac Death in Dialysis Patients-.Should Target Blood Pressure Be Lowered?

Eberhard Ritz Department of Internal Medicine, Rupert0 Carola-University, Heidelberg, Germany

Excess cardiovascular, and specifically cardiac, mortality in dialysis patients has been well docu- mented in several large studies. Of particular inter- est is the fact that uremia increases the risk of car- diac death by 5-20-fold in populations with widely varying baseline rates of cardiac death, e.g., in males or females, in Northern or Southern coun- tries of Europe, etc. (1). We (2) and others showed that sudden death is at least as common as myocar- dial infarction in the dialysis population. It is of particular note that left ventricular hypertrophy (a risk factor for death from cardiac arrhythmia in pa- tients with primary hypertension) is common in di- alysis patients and is a predictor of cardiac death in this population as well (3). If such excess cardiac death is to be prevented, an assessment of the role of hypertension is of overriding importance. In this context, then, it is pertinent to ask: What is the relationship between blood pressure and cardiac death in dialysis patients?

Reports in the literature that analyze the relation- ship between cardiac death and blood pressure in dialysis patients are, at first sight, rather confusing. Rostand et al. (4) found that diastolic blood pres- sure at the beginning of renal replacement therapy was related to the appearance of subsequent isch- emic heart disease (IHD). The relationship of blood pressure to IHD was significant by multivariant analysis but it explained only a minor proportion of the total variance. Diastolic blood pressure in those who failed to develop IHD was 99.5 k 20.2 mmHg while in those who developed IHD it was 114 k 27.8 mmHg. Vincenti et al. (5 ) looked at biopsy speci- mens of the hypogastric artery at the time of renal transplantation. Patients with more advanced ath- erosclerosis were more frequently hypertensive prior to dialysis (93%) than those without lesions (63%), but they were also older (42.8 k 2.8 years versus 28.3 k 1.7 years).

Neff et al. (6) found that patients who survived 10 years of hemodialysis were less likely to have dia- stolic blood pressures above 110 mmHg on admis- sion (41%) than non-survivors (50%), a difference that is certainly not impressive. In a retrospective analysis of 200 diabetic and non-diabetic dialysis patients, we found (2) that the duration of hyper-

Address correspondence to: Prof. Eberhard R i b Klinikum der Uni- versitat Heidelberg, Sektion Nephrologie, Bergheimer Strasse 56a, 6900 Heidelberg 1, Germany. Seminars in Dialysis-Vol 6, No 4 [Jul-Aug) 1993 pp 227-228

tension and the presence of hypertension on admis- sion to dialysis predicted the relative risk of cardio- vascular death. This risk increased in diabetic pa- tients by a factor of 2.3 when a history of hypertension of five or more years was present and increased by a factor of 2.5 when a systolic blood pressure >160 mmHg was present on admission.

One intuitively associates hypertension with an even higher risk of left ventricular hypertrophy and of coronary and non-coronary cardiac death than that which has been observed. Why is it that hyper- tension is such a poor predictor of survival in dial- ysis patients? Several possibilities must be consid- ered. First, it is possible that high blood pressure as well as very low blood pressure decreases survival so that an overall correlation is difficult to demon- strate.

Second, most of the above studies comprised small cohorts. It is of note that Degoulet et al. (7), in the French Diaphane study, followed a total of 1,435 patients and found a significant correlation between cardiovascular death and high blood pres- sure. The ratio of expected to observed deaths from all causes as well as from cardiovascular causes (but not of non-cardiovascular causes) was signifi- cantly (p 0.01) higher for patients in the highest ter- tile of diastolic blood pressure compared with the lowest (ratio 1.57 versus 0.65 for cardiovascular death).

A third possibility relates to definition of what is hypertension. We feel that in most studies blood pressures were far above what may be optimal lev- els for dialysis patients. It is conceivable that the threshold for blood pressure that divides patients with good from those with adverse cardiac progno- sis is relatively low.

If a lower blood pressure threshold for increased cardiac mortality is present in dialysis patients, it may no longer be possible to find a difference in survival between patients with poor blood pressure control and those in whom it is abysmal. There is one convincing piece of evidence that points in this direction. Charra et al. (8) noted that in patients whose mean arterial pressure (MAP) on dialysis was above 99 mmHg, survival was markedly infe- rior compared with those whose MAP was below 99 mmHg. Five-, 10- and 15-year survival in patients with MAP of <99 mmHg was 93%, 85%, and 67%, respectively, versus 81%, 65%, and 43% in patients with MAP >99 mmHg. The excess mortality was accounted for by cardiovascular causes: 9.7 versus 17.7 per 1,000 patient years in patients with MAP

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below and above 99 mmHg, respectively. It follows that blood pressures currently considered accept- able may indeed be unacceptably high.

The hypothesis that ideal blood pressure in the dialysis patient should be lower than is convention- ally accepted is in line with recent observations. In patients with diabetic nephropathy , a mean arterial pressure of around 90 mmHg is the point at which the decrease in GFR and rise in albuminuria is low- est (9). Further, a diastolic blood pressure below 70 mmHg is no longer considered to confer an in- creased risk of vascular complications in the dia- betic patient. The question of whether blood pres- sure below 140/90 mmHg should be sought during antihypertensive treatment in patients with primary hypertension is currently the subject of a large mul- tinational European trial (HOT, hypertension opti- mal treatment). It would be curious if these obser- vations did not also apply to the high risk dialysis patient population.

The benefits from lower blood pressure in the interdialytic interval must be balanced against the risk of hypotension from aggressive ultrafiltration when lower blood pressure is sought by volume control (10). Charra et al. (8) achieved low blood pressures in their patients by dialyzing longer (cur- rently three times 8 hr per week) than is conven- tionally done in Europe. They attributed the effi- cacy of their approach in controlling blood pressure to better volume control. This is certainly one com- ponent but I wonder whether the recent observation of Vallance et al. (11) does not provide another, or complementary, explanation. These investigators found NG,NG-dimethylarginine (asymmetric dime- thylarginine, ADMA) to be nine times higher in the blood of nine men with ESRD compared with six normal controls. This compound, normally ex-

creted in the urine, is a potent inhibitor of nitric oxide synthase, which generates nitric oxide, i.e., endothelium derived relaxing factor (EDRF) from L-arginine. ADMA, a low molecular weight com- pound, is probably dialyzable and may account for poor control of blood pressure with short hemodi- alysis sessions and superior control with longer treatments.

From the above considerations it is clear that: (1) in dialysis patients a lower target blood pressure than is currently thought acceptable may be appro- priate, and (2) controlled trials to prove the efficacy of such an approach are needed.

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References Combined report on regular dialysis and transplantation in Europe, XXII, 1991 Ritz E, Strumpf C, Katz F, et al.: Hypertension and cardiovascular risk factors in hemodialyzed diabetic patients. Hypertension 7(Suppl 1I):II-I 18-11-124, 1985 Silberberg JS, Barre PE, Prichard SS, et al.: Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 36: 286-290, 1989 Rostand ST, Kirk KA, Rutsky EA: Relationship of coronary risk factors to hemodialysis-associated ischemic heart disease. Kidney Int 22:304-308, 1982 Vincenti F, Amend WJ, Abene J, et al.: The role of hypertension in hemodialysis-associated atherosclerosis. Am J Med 68:363-369, 1980 Neff MS, Esier AR, Slitkin RF, et al.: Patients surviving LO years of hemodialysis. Am J Med 74:9961004, 1983 Degoulet P, Legrain M, R6ach I, et al.: Mortality risk factors in pa- tients treated by chronic hemodialysis. Nephron 31: 103-1 10, 1982 Charra B, Calemard E, Ruffet M, et al.: Survival as an index of adequacy of dialysis. Kidney Int 41:12861291, 1992 Mogensen CE: Risk factors and optimal blood pressure levels for insulin-dependent diabetic patients, in International Yearbook of Ne- dzrolopv 1992. edited bv Andreucci VE. Fine LG. London. Snrineer- . - Verlai'l992, p. 141 I

Ritz E, Ruffmann K, Rambausek M, et al.: Dialysis hypotension-Is it related to diastolic left ventricular malfunction? Nephrol Dial Transplant 2:293-297, 1987 Vallance P, Leone A, Calver A, Collier J, Moncada S: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339572-575, 1992