Four hemodynamic patterns emerged from Key words: ESRD, sympathetic nervous system, volume expansion, reninangiotensin system, vasodilation, blood pressure. © 1998 by the International Society of Nephrology Kidney International, Vol. 54, Suppl. 68 (1998), pp. S-67–S-72 S-67 this study (Fig. 3). In two patients blood pressure did not rise. In two patients in whom blood pressure increased, only cardiac output rose without changes in total peripheral resistance. In five patients total peripheral resistance rose without alterations in cardiac output. In one anephric patient, an initial rise in cardiac output without changes in peripheral resistance was followed by a decrease in cardiac output with marked elevation of peripheral resistance. Since the level of expansion was identical in all patients, these varied responses indicate different mechanisms of response in different patients. Thus, as suggested in Figure 1, mechanisms other than whole body autoregulation, including alterations in vasoactive substances or abnormal ion channel function, play a role in the development of hypertension in ESRD. Evidence for the participation of multiple factors in the genesis of ESRD hypertension may be gleaned from a recent hemodialysis record study of 434 patients [20]. Equal numbers of dialysis patients were receiving antihypertensive therapy after one year of intense treatment, moreover, hypertension persisted irrespective of whether interdialytic weight fell, rose or stayed the same. In addition, the nature of the underlying renal disease, a previous diagnosis of hypertension, sex, or race, did not modify persistence of hypertension and the need for treatment. These results also point to the possibility that long-standing hypertension and/or volume expansion may lead to damage of the vasculature that makes it unresponsive to treatment. This could result from either reduced production of vasodilator substances or increased production of vasoconstrictor agents. Despite some of the controversial results it should be clear that volume overload is to be avoided in the ESRD patient, since it is clear that either directly or indirectly a surfeit of sodium and water is deleterious. SYMPATHETIC SYSTEM Sympathetic overactivity has been demonstrated in essential hypertension and renal diseases, including the nephrotic syndrome [21]. Overactivity of this system augments cardiac output and total peripheral resistance. This may result from direct actions on cardiac and vascular receptors, Fig. 1. Factors that may alter cardiac output and total peripheral resistance in end-stage renal disease, and thus raise blood pressure. The role of abnormal channel function is hypothetical, but it might contribute to either an increase in peripheral resistance or an increase in cardiac output (detailed in the text and Fig. 3). Fig. 2. Sequential response to volume expansion in anephric patients and those with renal disease: the theory of whole-body autoregulation [18]. S-68 Martinez-Maldonado: Pathophysiology of hypertension in ESRD or by the influence on the release of renin and sodium retention by the kidney. Plasma norepinephrine (NE) and plasma renin activity (PRA, vide infra) are increased in hypertensives with mild renal insufficiency as compared to similarly renal-impaired normotensives or to normals [22]. Although the value of NE plasma levels to assess sympathetic activity has been questioned, Converse and his collaborators demonstrated that bilateral nephrectomy abolishes increased sympathetic discharge, lowers calf vascular resistance and reduces blood pressure in ESRD [23]. Of interest is the demonstration of a reduced threshold for the pressor response to NE in both normotensive and hypertensive patients with mild renal insufficiency [24]. Moreover, administration of debrisoquin, a post-ganglionic sympathetic blocker, significantly reduced blood pressure in hypertensive dialysis patients, but not in controls or normotensive dialysis patients [25]. RENIN-ANGIOTENSIN SYSTEM Patients with mild to moderate renal insufficiency exhibit elevated PRA and plasma angiotensin II concentrations that correlate with blood pressure [1]. Administration of saralasin to hypertensive patients with early renal disease results in a significant drop in blood pressure that is proportional to basal PRA activity [26]. Angiotensin I converting enzyme inhibitors (ACEI) and beta blockers can also lower renal renin secretion, and have similar antihypertensive effects in patients with mild to moderate renal insufficiency as a result of various non-diabetic chronic nephropathies [27]. The majority of hypertensive patients with ESRD attain normotension or exhibit reduced blood pressure in response to dry weight attainment with dialysis. In these subjects plasma renin and angiotensin II levels are within normal limits, but these are inappropriately elevated in relation to exchangeable sodium [28]. By contrast, a group of ESRD patients who do not respond to sodium removal have high renin and angiotensin II levels that correlate with the hypertension [29]. Blood pressure in this group of patients is reduced or normalized in response to saralasin or ACEI [30]. The strong relationship between PRA, angiotensin II and blood pressure in many ESRD patients lends support to an important role of the renin-angiotensin system (RAS) in the genesis of hypertension. A relatively unexplored but