不同种类透析膜对血浆补体终末复合物浓度的影响

目的：了解不同种类透析膜对补体系统激活的影响。方法：用酶联免疫吸附法（ELISA）测定维持性血液透析患者用不同种类透析膜透析膜透析过程中不同时间血浆SC5b-9（补体终末复合物）浓度,并进行比较。结果：用CU膜（cuprophane membrane,铜仿膜）透析,透析过程中血浆SC5b-9浓度变化最大;其次是用PMMA膜（polymethyl methacrylate,聚甲基丙烯酸甲酯膜）、HE膜（hemophane membrane,血仿膜）、PSN膜（polysynthane hemodialyser,仿生膜）透析;HE膜用过氧乙酸和福尔马林消毒第4次复用,血浆SC5b-9浓度变化幅度较首次使用明显降低（P＜0.05）。结论：不同种类透析膜激活补体的能力不同,依次为：CU＞PMMA＞HE＞PSN;HE膜用过氧乙酸和福尔马林消毒复用可在一定程度降低其激活补体的能力。     

奥美沙坦酯对慢性心力衰竭小鼠肾脏氧化应激的作用

目的 探讨奥美沙坦酯对慢性心力衰竭小鼠肾脏氧化应激的作用。 方法 健康C57小鼠分为假手术组（SHAM组）、慢性心力衰竭组（CHF组）和奥美沙坦酯治疗组（OLM组）。以冠状动脉左前降支结扎法建立慢性心力衰竭小鼠模型，其中奥美沙坦酯治疗组以10 mg/kg剂量每日胃饲，12周时观察各组小鼠心率、血压、心功能状况、Scr、BUN、血浆和肾脏血管紧张素（Ang）Ⅱ水平。实时PCR法检测肾脏gp91phox、p22phox和NOX4的表达。AZAN染色和二氢乙啶（DHE）染色观察肾组织病理变化。 结果 与SHAM组比较，CHF组和OLM组左室舒张末期内径（LVDd）和左室收缩末期内径（LVDs）显著增加（P ＜ 0.05）；短轴缩短率（FS）和射血分数（EF）显著降低（P ＜ 0.05）；CHF组收缩压、Scr和BUN显著增高，而OLM组以上指标较CHF组均显著降低（P ＜ 0.05）。与SHAM组比较，CHF组血浆和肾脏AngⅡ水平增高，gp91phox、p22phox和NOX4表达增高（P ＜ 0.05）；OLM组肾脏AngⅡ水平、gp91phox、p22phox和NOX4表达较CHF组均显著降低（P ＜ 0.05）。与SHAM组比较，CHF组肾脏AZAN染色和DHE染色阳性增强（P ＜ 0.05），而OLM组较CHF组显著降低（P ＜ 0.05）。 结论 慢性心力衰竭可使肾内NADPH氧化酶激活并导致肾小球间质纤维化，奥美沙坦酯通过抑制AngⅡ引起的氧化应激反应起到肾脏保护作用。     

Gentamicin Pharmacokinetics and Pharmacodynamics during Short-Daily Hemodialysis

Background/Aims: Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl(dial)) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. Methods: Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl(dial) and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl(s)) and central volume of distribution (V(c)) and influence of urea removal estimates on Cl(dial) were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. Results: A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl(s) and Cl(dial) were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl(s) and V(c). Predialysis every-other-day regimens were as effective (C(max) ≥8 mg/l and AUC(48 h) ≥140 mg·h/l) and less toxic (C(min) <2 mg/l and AUC(48 h) <240 mg·h/l) than postdialysis regimens. Conclusions: Estimated gentamicin Cl(dial) is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.     

FHD: an index to evaluate drug elimination by hemodialysis

BACKGROUND: In hemodialyzed patients, physicians have to (1) adjust drug dosage for a creatinine clearance lower than 10-15 ml/min and (2) know whether or not the drug will be removed by the dialysis session to decide whether it may be administered before or after the session on dialysis days. However, of several indices being used to evaluate drug removal by dialysis none is appropriate and we suggest a novel index named F(HD), which reflects the role of hemodialysis clearance of a drug in its overall clearance during the session. METHODS: Pharmacokinetic simulations were performed to test the influence of dialysis on the pharmacokinetics of some drugs, whether F(HD) was considered or not, to determine when to administer the drug. F(HD) was then calculated for several drugs and its value compared with other indices. Five hemodialysis patients from our department for whom the time of drug administration was determined according to F(HD) were included in a small study and their drugs' trough concentrations were monitored. RESULTS: F(HD) emphasized that considering hemodialysis clearance alone may lead to false interpretations of the potential dialyzability of some drugs. In our patients, who received their treatment according to the 'F(HD) rule', monitoring of trough levels gave satisfactory results. CONCLUSION: The use of the 'F(HD) rule' should be tested on a long-term administration basis to confirm our conclusion. F(HD )could be the index of choice to determine when to administer a drug, before or after the session, in hemodialysis patients.     

The perioperative management for the patients to undergo open heart surgery with chronic renal failure

From January, 1996 to December, 1999, eight patients with chronic renal failure received open heart surgery. They consists of six males and two females aged between 45 and 72 with a mean of 59.6. The duration of hemodialysis was 4.0 years in a mean. Seven of them had isolated coronary artery bypass grafting (CABG), one of them had CABG and aortic valve replacement. All patients were dialysed dialy two days before operation. Intraoperative hemodialysis (HD) was used in all patients. In recent six patients extracorporeal ultrafiltration methods (ECUM) were also performed intraoperatively in addition to HD. In postoperatively continuous hemodiafiltration (CHDF) has been preferred to HD in all patients, and nafamostat mesilate is a useful anticoagulation agent to prevent postoperative bleeding complications. The duration of CHDF was 3.2 days in a mean (the shortest for one day and the longest for eight days). When the circulatory situation were stable, HD was performed on early postoperative day. One patients died of low output syndrome and multiple organ failure. We reported problems in perioperative management of patients with chronic renal failure and our protocol.     

Hemodynamic effects of endothelin-1 and big endothelin-1 in chronic hemodialysis patients

Increased plasma concentrations of endothelin-1 (ET-1) and big endothelin-1 (big ET-1) have been reported in patients with end-stage renal failure (ESRD). In the present study, which included hemodialysis (HD) patients with (n = 21) and without (n = 32) ischemic heart disease, the putative association between plasma levels of ET-1 and big ET-1 and ischemic heart disease and the influence of the dialysis procedure on ET concentrations was investigated. This study also examined in an additional five HD patients without cardiac disease whether intravenously infused ET-1 and big ET-1 (0.2, 1, and 4 pmol/kg per min, each dose for 20 min) preserve their vasoactive potency and whether exogenous big ET-1, which in healthy humans is converted in the kidney, is still converted to ET-1 in ESRD. HD patients with ischemic heart disease demonstrated higher plasma levels of ET-1 and big ET-1 than HD patients without this disorder, and HD reduced plasma ET-1 and big ET-1 concentrations. In HD patients, the big ET-1 infusion, resulting in a 1.5-fold increase in plasma ET-1, caused a more marked and prolonged rise in mean arterial BP than ET-1 (20% versus 13%, P = 0.0001) and a slightly smaller but more prolonged decrease in estimated splanchnic blood flow than ET-1 (37% versus 44%, P = 0.02). Furthermore, big ET-1 lowered heart rate by 9% (P = 0.01) but ET-1 did not. Plasma half-lives of ET-1 and big ET-1 were longer in HD patients than in healthy humans. Thus, ET-1 and big ET-1 preserve their vasoactive potency, and circulating big ET-1 is still converted to active ET-1 in ESRD. Consequently, the increased plasma levels of ET-1 and big ET-1 noted in HD patients, especially in patients with ischemic heart disease, might play a role in the development of uremic cardiovascular complications.     

Short-term effects of parathyroidectomy on plasma biochemistry in chronic uremia

Parathyroidectomy (PTx) is indicated in hemodialysis (HD) patients who have severe osteitis fibrosa unresponsive to vitamin D therapy or in whom the latter treatment is contraindicated. Immediately after PTx, plasma immunoreactive parathyroid hormone, calcium and phosphorus concentrations decline abruptly. However, little is known in such patients about the short-term effects of PTx on plasma alkaline phosphatase (AP) activity and plasma aluminum (Al) levels. The present, preliminary study was performed to determine such parameters in 37 HD patients, and to correlate them with data of bone histology. Mean plasma AP activity started to increase after PTx from day 4 onwards. Thus, AP values significantly higher than pre-PTx values were observed at day 7 and 14 (415 +/- 54 vs. 619 +/- 77 and 749 +/- 83 IU/liter, means +/- SEM; N = 37; P less than 0.05 and 0.001, respectively). This increase, in the absence of changes in liver function, was mainly due to the bone-specific iso-AP. Moreover, the degree of increase in plasma AP activity was higher in the subgroup with negative (group I, 21 patients) than in that with positive bone Al staining (group II, 16 patients). However, plasma osteocalcin (BGP) did not change after PTx (N = 8). Basal plasma Al levels were significantly higher in group II both before and two weeks after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentration of human atrial natriuretic polypeptide in patients with impaired renal function

Using direct radioimmunoassay, the plasma concentration of human atrial natriuretic polypeptide (hANP) was measured in patients with impaired renal function. Patients on maintenance hemodialysis (HD) and those still on medical management (non-HD) were examined. In 13 non-HD patients with serum creatinine values from 2.0 to 8.3 mg/dl, mean plasma hANP (+/- SE) was 404 +/- 23 pg/ml, while it was 236 +/- 11 pg/ml in the normal control group (n = 15) and the difference was significant (p less than 0.001). In all patients as a whole, there was a positive correlation between plasma hANP and mean blood pressure (r = 0.56, p less than 0.05) but no correlation was present between plasma hANP and renal function. Fifty-six HD patients were divided into 2 groups depending on blood pressure level. Plasma levels of hANP in the hypertensive (BP greater than or equal to 150/90 mmHg, n = 21) and in the normotensive (BP less than 150/90 mmHg, n = 35) HD group were 588 +/- 58 pg/ml and 364 +/- 29 pg/ml, respectively, with plasma hANP in both HD groups significantly higher than in the controls (p less than 0.001). There was also a significant difference of plasma hANP between hypertensive and normotensive HD patients (p less than 0.01). However, when the normotensive HD group without cardiomegaly (cardiothoracic ratio less than 50%, n = 17) was compared with the control, the value of plasma hANP was not statistically different from that of the control group. These results suggest that plasma hANP in patients with impaired renal function is influenced by blood pressure and/or cardiac condition.     

The alteration of QT dispersion in hemodialysis subjects

OBJECTIVE: We attempted to observe the alterations in QTd and QTcd in chronic renal failure (CRF) patients before and after hemodialysis (HD) to determine the relevant determinants of QTc duration in HD. METHODS: The HD was carried out 2 or 3 times/week in a standard setting for 4-4.5 h. No drug therapy was applied during HD, except for isotonic NaCl infusions and sodium heparin. Maintenance drug therapy, including digitalis, antihypertensive, anti-anginal, and beta-blocking agents, was not changed. In the study, we investigated the alterations in QTd and QTcd in 68 CRF patients before and after HD with 12-lead ECG. Plasma Na(+), K(+), ionized Ca, creatinine, urea nitrogen, and hemoglobin were also controlled before and after HD. RESULTS: In our study QTd and QTcd significantly increased at the end of HD (p < 0.01). Plasma Na(+) and K(+) decreased, and ionized Ca increased after HD (p < 0.05, 0.01). Plasma Na(+), K(+), ionized Ca levels, ultrafiltration volume and myocardial ischemia appear to be the main determinants of QTc duration in HD, not hypertension, gender, patient age, or duration of chronic HD. CONCLUSION: Changes in plasma Na(+), K(+) and ionized Ca, the ultrafiltration volume and presence of ischemic heart disease in HD have significant effects on QTcd. ECG data demonstrate that the risk of arrhythmia could be higher with decreased plasma Na(+) and K(+), increased ionized Ca, the presence of ischemic heart disease and an increased ultrafiltration rate during HD. These results might provide some valuable references for proper HD programs.     

Study on the assay of uremic protein-binding inhibitors: furan compound and hippuric acid]

Plasma levels of 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (FA) and hippuric acid (HA) were studied in healthy subjects, uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Analysis of FA and HA in the plasma were performed by gas chromatography with capillary column. The mean value of FA in HD patients (16.7 +/- 6.1 micrograms/ml) was significantly higher than these in healthy subjects (3.6 +/- 1.0 micrograms/ml) and in patients on CAPD (4.1 +/- 3.7 micrograms/ml) (p less than 0.01). HA levels in CAPD and HD groups were higher than those in healthy controls (2.4 +/- 0.8 micrograms/ml). In addition, the values in HD patients (46.7 +/- 53.5 micrograms/ml) were more increased than those in CAPD (18.5 +/- 16.5 micrograms/ml) (p less than 0.05). Approximately 95% of total FA and 25% of HA were bound to the plasma protein. However, the plasma level of HA was significantly reduced by HD therapy, whereas that of FA was not altered. In the previous study, it was described that no effect of HD on the percent of the binding of acid drugs to the plasma protein in the uremic plasma was observed. Therefore it is supposed that FA is more involved in the binding of drugs to the plasma protein in comparison with HA. The peritoneal losses of FA and HA in CAPD were 2.3 +/- 1.3 mg/day and 276 +/- 40 mg/day, respectively. As the duration of HD became longer, plasma concentrations of FA in HD patients were more increased. In general, they were maintained to be comparatively low in patients on CAPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of an in vitro dialysis system to predict drug removal.

BACKGROUND: Variation in the extent of drug removal under different dialysis conditions presents a challenge for prediction of drug elimination and dosage regimen adjustment during haemodialysis (HD). Dependence on clinical pharmacokinetic studies in HD patients for dosing guidelines is problematic given the increasing number of dialysers with variable rates of drug removal. Thus, the purpose of this study was to characterize drug removal using an in vitro system and to evaluate its reliability to predict in vivo elimination by HD using vancomycin (VANC) as a model drug. METHODS: In vitro dialysis was performed for 2 h (volume 4.0 l normal saline, initial VANC concentration 30 mg/l, flow rate 300 ml/min, dialysate flow 800 ml/min) using four different dialysers: polymethylmethacrylate (BK-2.1 U), polysulfone (F-80), AN69 (Filtral-20) and hemophan (COBE 700HE). The in vitro dialysis clearance for VANC (CL(D)) for the polysulfone dialyser was compared with values determined in eight HD patients. In vitro VANC CL(D) for all dialysers was compared with the clearance and KoA for B12 reported for each dialyser. RESULTS: In vitro VANC CL(D) values were 93+/-11 ml/min for the polymethylmethacrylate BK-2.1, 136+/-7 ml/min for the AN69, 65+/-9 ml/min for the hemophan COBE 700HE and 143+/-10 ml/min for the polysulfone F80. The CL(D) for the polysulfone F80 was not statistically different from the in vivo CL(D) of 135+/-18 ml/min (P = 0.48). In vitro VANC CL(D) correlated with the B12 CL(D) (r(2) = 0.77) and the B12 KoA (r(2) = 0.63) reported for each dialyser. CONCLUSION: VANC CL(D) in HD patients for the polysulfone dialyser was correctly predicted using the in vitro dialysis system. Use of this system may be superior to estimations of drug CL(D) based on dialyser information provided by the manufacturer for compounds of similar molecular weight.     

Oxidative status and prevalent cardiovascular disease in patients with chronic renal failure treated by hemodialysis

BACKGROUND: Hemodialysis (HD) patients are exposed to oxidative stress which contributes to cardiovascular disease (CVD). The purpose of this study was to investigate the oxidative and antioxidative status in HD patients with (CVD+, n = 38) and without (CVD-, n = 67) prevalent CVD. PATIENTS AND METHODS: A total of 105 HD patients and 21 healthy controls were assessed for lipid peroxidation indices (plasma malondialdehyde (MDA)), oxidizability of apolipoprotein B-containing lipoproteins (apo B-deltaMDA) and red blood cells (RBC-MDA) together with various components of the antioxidant system in plasma (paraoxonase/arylesterase activities, total carotenoids, vitamins C and E) and RBC (superoxide dismutase and glutathione peroxidase activities). RESULTS: Plasma MDA and RBC-MDA were significantly higher, vitamin C and total carotenoid levels were significantly lower in both CVD+ and CVD- HD groups than in the control group. Plasma MDA levels were significantly higher and serum paraoxonase activity, uric acid and albumin levels were significantly lower in patients with CVD+ HD patients compared to those of the CVD- patients. CONCLUSION: This study suggests that the elevated level of plasma MDA and the lower activity of paraoxonase could contribute to the increased incidence of cardiovascular disease in hemodialysis patients.     

Increased endothelin: nitric oxide ratio is associated with erythropoietin-induced hypertension in hemodialysis patients

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.     

Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients

The objective of this study was to quantitate the improvement in exercise capacity produced in anemic chronic hemodialysis (HD) patients after correction of their anemia with recombinant human erythropoietin (rHuEPO). The maximal exercise capacity and quadriceps strength of 19 anemic HD patients was tested before and after correction of the anemia with rHuEPO. A progressive work exercise protocol (PWET) on a cycle ergometer was used to compare measurements of maximal oxygen uptake (VO2max), maximal heart rate, and subjective assessment of fatigue during the test. Measurements of quadriceps strength were performed before the cycle ergometer studies. At baseline, all patients had reduced VO2max (15.3 +/- 5.4 mL/kg/min) and maximal exercise heart rates (138.5 +/- 23.9 beats/min). rHuEPO increased the mean hematocrit from 21.2% to 35%, and this was associated with a 17% increase (P less than 0.0005) in the VO2max. At any specified work load, rHuEPO treatment decreased heart rate, minute ventilation, and the subjective perception of fatigue. Both isometric and isokinetic measurements of quadriceps strength were improved following administration of rHuEPO. The maximal exercise heart rate was decreased in comparison to the baseline measurements (P less than 0.04), suggesting that in contrast to normal subjects, HD patients stop exercise before oxygen transport limitations are reached. In this unselected group of chronic HD patients, rHuEPO produced clinically significant improvements in both aerobic exercise capacity and isometric and isokinetic quadriceps strength. The improvement in aerobic capacity was substantially less than would have been expected from the correction of a comparable degree of anemia in non-HD patients. None of the 19 treated patients attained the exercise performance level predicted for a sedentary normal subject.     

Pharmacokinetics of netilmicin in hypertonic hemodiafiltration and standard hemodialysis

Recently, we developed a peculiar model of hemodiafiltration (HDF), in which a conventional acetate hemodialysis (HD) is combined with a high flux dialyzer, a high ultrafiltration flow rate and a postdilution hypertonic reinfusion (H HDF). The pharmacokinetics of netilmicin (N), a relatively new aminoglycoside, were evaluated during 5 sessions of H HDF of 180 min and 2 sessions of HD of 270 min in the same 8 patients with a comparable blood (approximately 400 ml/min) and dialysate flow rate (approximately 520 ml/min). Additional studies were performed in 7 out of the 8 patients after 2 sessions of H HDF and one session of HD. N clearance, calculated both as plasma water and total body clearance, was so exceedingly higher during H HDF than during HD, that the amount of drug removed by H HDF in 180 min was still significantly higher than that removed by HD in 270 min. Consequently, the N half-life during HD was about 5 h, whereas during H HDF it was less than 2.5 h, approaching that reported in normal subjects. N half-life out of dialysis treatments was about 55 h. In conclusion, N pharmacokinetics are strikingly different between H HDF and HD, with N clearance during H HDF about the double of that during HD. The implications of this study are: a different dosage adjustment of aminoglycosides is needed for patients routinely treated by HDF; HDF may be a very effective treatment for the overdose of many drugs.     

The Effects of a Polyacrylonitrile Membrane and a Membrane Made of Regenerated Cellulose on the Plasma Concentrations of Erythropoietin During Hemodialysis

In vitro studies have shown that some dialysis membranes significantly adsorb erythropoietin (EPO), a fact that might have an effect on anemia in long-term hemodialysis (HD) patients and on anemia treatment with recombinant human EPO. The purpose of the study was to determine whether the ability of adsorption demonstrated in vitro also has an effect on EPO concentrations in vivo. In a crossover study, the plasma concentrations of EPO were examined in 11 patients on chronic HD during HD using a polyacrylonitrile (AN69) membrane (high in vitro adsorption) plus EPO administered subcutaneously after the HD session, HD using a Cuprophan membrane (low in vitro adsorption) plus EPO administered subcutaneously after the HD session, HD using an AN69 membrane plus EPO administered subcutaneously after the HD session plus EPO administered intravenously immediately before HD, or HD using a Cuprophan membrane plus EPO administered subcutaneously after the HD session plus EPO intravenously immediately before HD. The intradialysis plasma concentrations of EPO (not detectable in the dialysate) determined at the dialyzer inlet and outlet at Minutes 5 and 240 of the procedure did not differ significantly after its subcutaneous administration from its predialysis concentrations with either the Cuprophan or AN69 membrane. A comparison of EPO concentrations between AN69 and Cuprophan did not reveal marked differences either. The course of concentrations after additional EPO intravenous administration was similar with no statistically demonstrable difference between the 2 membranes. In conclusion, under clinical conditions, AN69 and Cuprophan membranes do not differ in their effects on plasma EPO concentrations. The differences in EPO adsorption between AN69 and Cuprophan, demonstrated in vitro, do not seem to be of clinical importance.     

Plasma atrial natriuretic factor (alpha ANF) during hemodialysis (HD) and hemofiltration (HF).

Plasma concentrations of immunoreactive alpha ANF were measured before, during, and after 3 hours of hemodialysis (HD) and hemofiltration (HF). In seven healthy subjects plasma alpha ANF concentrations were measured to serve as controls. Highly elevated pre-treatment alpha ANF levels were obtained in the HD group (286 +/- 52 pg/ml, mean +/- SE), and in the HF group (275 +/- 48 pg/ml) as compared with the controls (40 +/- 3 pg/ml). The effect of both HD and HF on the alpha ANF concentration was not significant after the first hour of treatment. However, a significant decrease was obtained after the second (HD = 244 +/- 49, HF = 140 +/- 17) and third hours (HD = 244 +/- 48, HF = 135 +/- 15) (p less than 0.05) in both treatments. A steeper decline in the alpha ANF concentration was notable during HF compared with HD. There was a significant difference (p less than 0.05) when both modalities were compared at the end of treatment. A correlation (r2 = 0.98, p less than 0.001) was noted between changes in the alpha ANF levels and the ultrafiltration (UF) volumes only during HF. Plasma alpha ANF concentrations at the filter outlet were lower than at the inlet in both groups. It is concluded that the plasma alpha ANF concentrations are highly elevated in chronic renal failure patients. Despite the decrease in these concentrations during HD and HF it did not reach the normal plasma level. Monitoring of plasma alpha ANF may be a useful indicator for the extracellular volume status during HD and HF treatments.     

Increased Endothelin: Nitric Oxide Ratio Is Associated with Erythropoietin-Induced Hypertension in Hemodialysis Patients

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB₂), prostacyclin (6-keto-PGF1α), and cyclic guanosine 3′,5′-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB₂, and 6-keto-PGF1α were measured by radioimmunoassay. Plasma NOx was measured by highperformance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB₂, 6-keto-PGF1α, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.     

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation.

BACKGROUND: Hyperhomocysteinaemia, which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lowering total homocysteine (tHcy) plasma concentrations in haemodialysis (HD) patients receiving high-dose folic acid supplementation. METHODS: In order to assess the efficacy on lowering plasma tHcy levels (fasting concentration), 21 HD patients, were randomly assigned and provided folic acid supplementation: 15 mg/day orally (group I, n=7); methylcobalamin 500 mg intravenously after each HD, in addition to folic acid (group II, n=7); or vitamin B(6) (B(6)), 60 mg/day orally, in addition to folic acid and methylcobalamin (group III, n=7). All patients were treated for 3 weeks. A methionine-loading test was conducted before and after supplementation. The following measurements were also made before and after supplementation for each group: serum folic acid, B(6), and vitamin B(12) (B(12)) concentrations (including measurement of proportion of methylcobalamin fraction). Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study. RESULTS: In our randomized HD patients the proportions of methylcobalamin fraction (48.3+/-7.5%) and plasma vitamin B(6) concentration (2.9+/-1.1 ng/ml) were significantly lower than in the normal controls (methylcobalamin 58.7+/-2.2%, P<0.01; B(6) 20.1+/-10.8 ng/ml, P<0.01), while folic acid and vitamin B(12) were not significantly different from the normal controls. Mean percentage reduction in fasting tHcy was 17.3+/-8.4% in group I, 57.4+/-13.3% in group II, 59.9+/-5.6% in group III, and 18.7+/-7.5% in HD controls. The power of the test to detect a reduction of tHcy level was 99.6% in group II and 99.9% in group III when type I error level was set at 0.05. Groups II and III had normal results for the methionine-loading test after treatment. Treatment resulted in normalization of fasting tHcy levels (<12 ng/ml) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6). CONCLUSION: The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable. Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity. This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure.     

Measurements of blood DMSO and DMSO2 in a healthy person and a hemodialysis patient

Background. The aim of the present study was twofold: (1) to confirm gas chromatography/mass spectrometry (GS/MS) as a means of measuring blood and urine concentrations of dimethyl sulfoxide (DMSO) and its metabolite, dimethyl sulfone (DMSO₂), and (2) to measure blood concentrations of DMSO and DMSO₂ in a hemodialysis (HD) patient receiving DMSO. Methods. Measurements were made after deprotenization, using 450 μl of plasma or urine, then using 2 μl of supernatant for GC/MS. DMSO-d ₆ was used as the internal standard. The two subjects were a healthy 43-year-old man, weighing 82 kg, who received a single dose of 5 ml DMSO, and a 48-year-old man, an HD patient, weighing 56 kg, with a 3-year history of HD. The etiology of chronic renal failure was primary amyloidosis. The HD patient had been receiving 5 ml DMSO/day for 3 years and 10 months. Results. A good calibration curve for trace amounts of DMSO and DMSO₂, in the range of 0.25 ng to 50 ng, was obtained from GC/MS. The recovery rate and repeatability from plasma were also good. In the healthy subject, the maximum drug concentration time (Tmax) for DMSO was 2.0 h, the maximum drug concentration (Cmax), 74.92 μg/ml whole blood, and T1/2, 6.8 h. Tmax for DMSO₂ was 24.0 h, Cmax, 58.32 μg/ml whole blood, and T1/2 was greatly extended, to 56.8 h. Blood concentrations of DMSO and DMSO₂ in the HD patient before HD were remarkably high, at 171.32 and 814.22 μg/ml whole blood, respectively. After HD, these values decreased to 66.48 and 405.05 μg/ml whole blood, respectively, but were still higher than the value in the healthy subject. Conclusions. Because the effective drug concentration of DMSO has not been established, the dose level for HD patients must be investigated from the standpoint of therapeutic drug monitoring. Furthermore, as the blood concentration of the metabolite DMSO₂ is higher than that of DMSO, attention must be directed to the pharmacokinetics of DMSO₂. Received: March 1, 2000 / Accepted: May 16, 2001