Sustained hypotension (SH), defined by a systolic blood pressure (SBP) lower than 100 mmHg in the interdialytic period, affects 5%-10% of hemodialysis (HD) patients, and is more prevalent among elderly patients on chronic HD. Epidemiologic and retrospective studies have shown that low blood pressure (BP) at pre-HD was correlated with high mortality.1-3 Although several clinical factors, such as autonomic dysfunction, reduced pressor response to vasopressor agents and cardiac dysfunction, have been shown to be responsible for the occurrence of SH,1 the pathophysiology of chronic hypotension in dialysis patients has yet to be fully clarified.
Adrenomedullin (AM) is a novel vasodilator peptide that has recently been isolated from human pheochromocytoma.4 Plasma AM level is associated with the fall of BP during HD.5 Furthermore, AM could not be removed by dialysis treatment using a low-flux dialyzer, as the molecular weight of AM is considered to be about 5.7 kD. However, AM could be removed during HD by the use of a high-flux dialyzer.6 In the present study, we investigated whether removal of AM by HD treatment using a high-flux dialyzer can improve the level of BP in elderly HD patients with SH.
Forty-eight patients (22 men and 26 women) undergoing regular HD at the Kidney Center of the Chinese People's Liberation Army General Hospital were enrolled in this study. The mean age of the patients was (74.1±4.6) years and the mean duration of HD was (59.9±28.6) months. HD was performed three times per week in all patients. The study population was restricted to patients whose urine volumes less than 100 ml between HD sessions with almost no residual renal function. Patients were excluded if they had one of the following conditions: hemoglobin (Hb) <90 g/L, albumin (Alb) <30 g/L, solitary kidney, after kidney transplantation or nephrectomy, myocardial infarction, cardiac insufficiency, tumor, rheumatism and autoimmune diseases, active inflammation, chronic obstructive pulmonary disease, severe liver function failure, diabetes mellitus. The underlying renal diseases were as follows: chronic glomerulonephritis in 38 patients, drug-induced renal injury in 4 patients, polycystic kidney disease in 3 patients, and other diseases in 3 patients. Supine blood pressure was measured with electronic sphygmomanometer (OMRON HEM-7112, Japan) in the arm of each patient at least 3 times every day. SH was defined as SBP less than 100 mmHg at predialysis in at least 80% of BP measurements in the previous three months.1 Normotensive (NT) was defined as SBP less than 145 mmHg but more than 100 mmHg and DBP less than 90 mmHg but more than 60 mmHg at predialysis in at least 80% of BP measurements in the previous three months.1
All patients were treated with 4008S HD machine (Fresenius, German), ultrapure dialysate fluid with double filtration (Diasafe Plus; Fresenius). Vascular access for HD was arteriovenous fistula. Blood flow was usually 250-300 ml/min with a dialysate flow rate of 500 ml/min at 35°C. SH patients were randomly divided into two groups: low-flux group (n=14) with F-7HPS dialyzer (polysulfone membrane; Fresenius) and high-flux group (n=14) with FX-60 dialyzers (polysulfone membrane; Fresenius). All the patients underwent HD for 3 months. All the drugs that raise BP were stopped at least one week prior to the study. Other medicines were taken as usual.
All samples were transferred to chilled tubes containing ethylene diamine tetraacetic acid (EDTA) (final concentration, 1 mg/ml) and aprotinin (final concentration, 1000 U/ml), immediately placed on ice, and centrifuged within 30 minutes. Plasma was separated and stored at -70°C until analysis. Plasma AM (mature form) concentrations were measured using a commercial kit (AM RIA-Shionogi; Shionogi, Osaka, Japan). Blood sampling was performed at pre-HD to measure AM, hematocrit (Hct), Alb, calcium (Ca), cholesterol (CH), triglyceride (TG). BP was measured with electronic sphygmomanometer (OMRON HEM-7112, Japan) in the arm of each patient at the time of blood sampling to calculate mean arterial pressure (MAP). All the measurements were performed 3 months after therapy in SH patients.
Statistical analysis was performed using software package SPSS 11.0 for Windows. Data were expressed as mean ± standard deviation (SD). One-way analysis of variable (ANOVA) was used for statistical comparisons between low BP and normal BP groups, 0 month and 3 months. Pearson correlation analysis was performed for correlation between variables. A P value less than 0.05 was accepted as statistically significant.
AM and clinical characteristics in SH and normal NT HD patients
Table 1 summarizes the hemodynamic and laboratory values for the SH and NT HD patients. The average value of plasma AM in SH patients was significantly elevated compared with that in NT patients ((24.92±3.7) ng/L vs. (15.52±6.01) ng/L, P <0.05). SBP and MAP were significantly different between SH and NT patients (P <0.05). There was no significant difference of age, weight gain during HD, Hct, Alb, Ca, CH and TG in SH and NT patients.
The plasma AM levels at pre-HD were inversely correlated with MAP at pre-HD in SH patients (r= -0.5002, P=0.007; Figure).
Effect of high-flux HD on AM in low BP patients
There was no significant difference of SBP, MAP and the average value of plasma AM between the high-flux and low-flux group before the treatment. But after 3 months, SBP and MAP in high-flux group increased ((87.88±7.3) mmHg vs. (102.38±8.85) mmHg; (67.37±4.31) mmHg vs. (74.79±3.59) mmHg, P <0.05, respectively), meanwhile the average value of plasma AM decreased ((24.58±4.36) ng/L vs. (16.18±5.08) ng/L, P <0.05). BP and plasma AM level in low-flux group had no change. SBP recovered over 100 mmHg in 8 patients (57.1%) of high-flux group but not in low-flux group. The dry weight in both groups had no obvious change before and after the treatment (Table 2).
There have been several researches on mechanism of high levels of vasodilator agents in HD patients with hypotension. Imai et al7 conducted a hemodynamic study and reported that while cardiac index, heart rate or stroke volume were similar in hypotensive and normotensive HD patients, total peripheral vascular resistances were lower in the former group. They suggested that increased biosynthesis and/or release of vasodilator agents might be critical in the pathogenesis of hypotension during HD. Plasma atrial natriuretic peptide levels have been reported to be similar in hypotensive and normotensive dialysis patients,8-10 but the possible role of this molecule in chronic hypotension in uremia is controversial.11 In addition to these peptides, AM was reported to be increased in patients with SH.12,13 These studies have shown that the average value of plasma AM in hypotensive HD patients was significantly elevated compared with that in normal BP subjects, and was inversely correlated with MAP. However, there was no correlation between plasma AM levels and MAP in normal BP patients. In the present study, the average value of plasma AM in elderly HD patients with SH was also significantly elevated compared with that in normal BP subjects, and our data were consistent with previous reports. Our data further showed that the BP levels were inversely correlated with the plasma AM levels, indicating that AM is involved in the pathophysiologic mechanisms of hypotension in elderly HD patients.
The exact mechanism of the increased production of vasodilators including AM is still unknown. However, it is likely that the inflammatory state of uremia plays some role.14 The production of both nitric oxide and AM is induced by cytokines, such as hepatocyte growth factor (HGF), which induces endothelial proliferation and nitric oxide-mediated vasodilation, and other studies showed that HGF was increased in hypotensive HD patients. 15 Several studies also suggested the possible roles of microinflammatory state in chronic hypotension of dialysis patients, through the induction of synthesis of several vasodilator substances.16,17
In some previous studies, the treatments of hypotension in HD patients were focused on elevating correction of sodium, using dialysate with hypercalcemia,18 cold dialysis and improving blood volume. Midodrine hydrochloride is also effective to some patients.19,20 Midodrine hydrochloride not only improves hypotension but also leads to a decrease of plasma AM level. But the effect of high-flux dialyzer on hypotension was less studied. AM removal is more effective during HD by the use of a high-flux dialyzer than a low-flux dialyzer. HD removes BP-reducing vasodilator peptides with a high molecular weight, thus contributing to the stability of the BP. In summary, this study shows that high-flux therapy can decreases plasma AM level and improves hypotension; this indicates that plasma AM can modulate BP level. Further studies are necessary to clarify whether other peptides removed by high-flux HD also modulates BP level.
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