Biomedical subjects

John K Leypoldt

Publications and source records attributed to John K Leypoldt.

At least 19 recordsLinked to original sources

PubMed2006

Effects of anaesthesia on fluid and solute transport in a C57BL6 mouse model of peritoneal dialysis.

BACKGROUND: Genetically modified mice show promise as animal models for studying the physiology and pathophysiology of the peritoneum during peritoneal dialysis (PD). Methods for evaluation of the functional characteristics of the mouse peritoneum have not been studied extensively, and the effects of anaesthesia on fluid and solute transport in mouse models of PD are unknown. METHODS: A single exchange of dialysis solution was performed in C57BL6 mice by injecting fluid into the peritoneal cavity using a 27-gauge needle and allowing fluid to dwell for 30, 60 or 120 min. Experiments evaluated the effect of ketamine (plus xylazine) anaesthesia on fluid and solute transport; these effects were examined in separate experiments using glucose and mannitol as the osmotic agent added to the injected dialysis solution. After euthanasia, blood was collected, the remaining dialysis solution was drained and their contents analysed for concentrations of the osmotic solute (glucose or mannitol), urea nitrogen (UN), sodium (Na) and a volume marker (fluorescein-labelled albumin) added to the initial, injected dialysis solution. Determined parameters included final volume of dialysis solution (drained plus residual fluid volume), dialysate concentration (D/D0) of glucose (or D/D0 mannitol), dialysate-to-plasma concentration ratio for (D/P) UN and D/P Na and the apparent dialysis solution volume by indicator dilution. Peritoneal permeability-area (PA) values or mass transfer-area coefficients were also calculated for the osmotic solutes. RESULTS: Final volumes of dialysis solution were higher when mice were anaesthetized with ketamine than in unanaesthetized mice, independent of whether glucose or mannitol was used as the osmotic agent. The increases in final volume were paralleled by higher dialysate concentrations (D/D0 values) and lower calculated PA values for both glucose and mannitol. When using either osmotic agent, anaesthesia also increased plasma glucose concentrations, suggesting that ketamine altered glucose metabolism. CONCLUSIONS: Ketamine anaesthesia in the mouse decreases PA values for glucose and mannitol when used as osmotic agents in PD solutions. The decrease in transperitoneal transport for these osmotic agents increases the final volume of fluid which can be obtained from the peritoneal cavity.

Anesthesia↗

PubMed2006

The association of lipid levels with mortality in patients on chronic peritoneal dialysis.

BACKGROUND: The role of traditional risk factors, including plasma lipids, in the pathogenesis of cardiovascular (CV) disease in chronic dialysis patients is unclear. Previous studies have suggested that lower serum total cholesterol (TC) is associated with higher mortality in patients on chronic haemodialysis (HD). Whether this relationship is specific to the HD population or is common to the uraemic state is unclear. The present study evaluated the association of serum TC and triglycerides with clinical outcomes in chronic peritoneal dialysis (PD) patients. METHODS: Data of 1053 PD patients from the United States Renal Data System (USRDS) prospective Dialysis Morbidity and Mortality Study Wave 2 were examined. Cox regression was used to evaluate the relationship between lipid levels and mortality. RESULTS: Patients with TC levels < or =125 mg/dl (3.24 mmol/l) had a statistically significant increased risk of an all-cause mortality, including those taking or not taking lipid-modifying medications, compared with the reference of 176-225 mg/dl (4.54-5.83 mmol/l). In stratified analysis, this association was demonstrated in patients with serum albumin >3.0 g/dl (30 g/l), but not with albumin < or =3.0 g/dl. Compared with patients with triglyceride levels of 201-300 mg/dl (2.27-3.39 mmol/l), a statistically significant reduction of all-cause, but not CV, mortality was observed in patients with triglyceride levels of 101-200 mg/dl (1.14-2.26 mmol/l), as well as in the subgroup with serum albumin levels <3.0 g/dl (30 g/l) and triglycerides of < or =100 mg/dl (1.13 mmol/l) and 101-200 mg/dl (1.14-2.26 mmol/l). CONCLUSIONS: While confounding factors and causal pathways have not been clearly identified, aggressive lowering of plasma cholesterol in PD patients is not supported by this study, however, treatment of hypertriglyceridaemia may be warranted with triglyceride levels >200 mg/dl (2.26 mmol/l).

Adult↗

PubMed2006

Perivascular tissue pharmacokinetics of dipyridamole.

PURPOSE: The tissue diffusivity (D(g)) and partitioning (K) for dipyridamole were determined and a model was developed to examine the relationship between perivascular dose and local dipyridamole tissue concentrations. METHODS: Experiments were performed using an in vitro perfusion apparatus that recirculated buffer through different graft samples or normal porcine femoral arteries and veins. The grafts or blood vessels were immersed in a compartment containing Krebs-Henseleit (KH) buffer and dipyridamole (30 microg/mL). The recirculating buffer was sampled at multiple time points and dipyridamole was assayed. Estimates of the effective diffusivity (D(g)) and partition coefficient (K) of the drug in the vessel wall were determined and used to simulate dipyridamole tissue concentration after perivascular delivery. RESULTS: Dipyridamole diffusivity within native femoral veins (D(g) = 3.87 +/- 0.93 x 10(-6) cm2/s) was approximately twice that within femoral arteries (D(g) = 2.06 +/- 0.79 x 10(-6) cm2/s, p < 0.01). Explanted grafts showed the lowest diffusivity. Partition coefficients of femoral arteries (K = 4.11 +/- 0.99) were higher than those of femoral veins (K = 2.05 +/- 0.85, p < 0.01) and explanted graft (K = 0.89 +/- 0.56, p < 0.01). DISCUSSION: The results demonstrate that local drug kinetics vary greatly for different types of blood vessels and grafts. The pharmacokinetic parameters and resulting computational simulations are helpful in exploring perivascular drug delivery strategies.

Algorithms↗

PubMed2006

Elevated fibrinogen fragment levels in uremic plasma inhibit platelet function and expression of glycoprotein IIb-IIIa.

Hemostatic dysfunction is frequently noted in uremia, but the mechanisms responsible for it are poorly understood and are assumed to be multifactorial. Preliminary findings from our laboratory suggest that elevated levels of circulating fibrinogen fragments (FF) might contribute to the hemostatic defect in uremic patients. Defibrinated plasma obtained from chronic hemodialysis (HD) patients as well as normal subjects were examined by SDS-PAGE and immunoblotting and quantified by an immunoassay. In addition, endogenous FF isolated from normal and uremic plasma using affinity chromatography were examined by flow cytometry for their effect on glycoprotein (GP) IIb-IIIa receptor expression and tested for their ability to inhibit platelet aggregation. The mean FF concentration in uremic plasma (1.14 +/- 0.85 mg/ml) was noted to be eight times greater than in normal plasma (0.15 +/- 0.01 mg/ml) (P < 0.05). Moreover, the mean FF level decreased by 48.25% following HD (from 1.14 +/- 0.85 mg/ml to 0.59 +/- 0.33 mg/ml; P < 0.05). SDS-PAGE and immunoblotting experiments showed that the decrease was observed in both medium-sized (20-60 kDa) as well as large (>100 kDa) FF. Further, FF isolated from uremic plasma inhibited platelet aggregation by (46.8 +/- 18.1)% (P < 0.05) and the GP IIb-IIIa receptor expression by (28.0 +/- 7.6)% (P < 0.05 vs. control). The results show that (1) FF levels are elevated in uremic plasma, (2) HD results in significant decrease in FF and (3) endogenous FF inhibit platelet function, presumably via competitive binding to the fibrinogen receptor GP IIb-IIIa. The decrease in plasma levels of FF > 100 kDa following HD suggests that adsorption to the dialysis membrane contributes to their removal.

Aged↗

PubMed2005

Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study.

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.

Adult↗

PubMed2005

A crossover study of short daily haemodialysis.

BACKGROUND: The benefits of daily haemodialysis (DHD) compared to conventional three times per week haemodialysis (CHD) have been described in a number of observational studies. Most of these previous studies however have not been performed with rigorous controls. METHODS: We performed a crossover study following an A-B-A design: phase A was 4 weeks of thrice weekly dialysis, 3-4 h per treatment (CHD); phase B was 8 weeks of six times/week dialysis, each session being one-half of the usual time (DHD) and phase A with 4 weeks of thrice weekly dialysis (CHD) was repeated. Patients characteristics: n=12, six males; age 52+/-18 years, six diabetics. RESULTS: Weekly single-pool Kt/V, equilibrated Kt/V and standard Kt/V of urea, and beta-2-microglobulin clearance values were greater during DHD. Eight of 12 patients who completed the study reported symptomatic benefits from DHD that partially or completely disappeared during the second period of CHD. Quality of life of patients improved during DHD. Three patients had problems with arteriovenous access during DHD. Average blood pressure was lower during DHD (systolic 139.5+/-22.7 mmHg) compared to the initial (147.7+/-21.4 mmHg, P<0.001) and last (146.4+/-20.0 mmHg, P<0.005) CHD periods. No significant changes in predialysis haemoglobin and the serum concentration of albumin, phosphate, beta-2-microglobulin or B-type natriuretic peptides (BNP) were observed, although BNP trended downward during DHD and returned to baseline level during the second period of CHD. The dose of erythropoietin did not change significantly. Patient compliance with the dialysis schedule was lower during DHD. Dialysis staff perceived an increased workload but felt that the patients benefited medically from DHD. CONCLUSIONS: The results of this cross-over study suggest symptomatic benefits and decrease in blood pressure, but there are potential problems with compliance and vascular access during DHD.

Adult↗

PubMed2005

The association between BP and mortality in patients on chronic peritoneal dialysis.

BACKGROUND: The relationship between blood pressure (BP) and mortality in haemodialysis patients is unconventional. It is not clear if this is the consequence of uraemia or related to the dialysis type. The goal of this project was to identify the relationship between BP and mortality in patients on chronic peritoneal dialysis (PD). METHODS: Patients on PD (n = 1053) from the USRDS prospective DMMS Wave 2 study were analysed. Primary outcomes were all-cause and cardiovascular mortality and duration of hospitalization. RESULTS: Low systolic BP categories, <100 mmHg [hazard ratio (HR), 2.71, P<0.001; and HR 3.83, P<0.001, respectively] and 101-110 mmHg (HR 1.85, P<0.05; and HR 2.92, P<0.005, respectively), but not high systolic BP, increased the risk of all-cause and cardiovascular mortality, with systolic BP 111-120 mmHg as the reference. Pulse BP, but not diastolic BP, followed a similar trend. In subgroup analysis, this association was demonstrated only in patients with a history of heart failure, in patients with diabetes and in those treated with antihypertensive medications. CONCLUSION: Systolic BP <111 mmHg in PD patients is associated with higher mortality risk, while systolic BP >120 mmHg is associated with fewer hospital days. Aggressive treatment of hypertension in the PD population should be cautioned.

Blood Pressure↗

PubMed2005

Dialyzer membranes as determinants of the adequacy of dialysis.

Hemodialysis membranes have undergone a gradual but substantial evolution over the past few decades. Classification of modern dialyzer membranes by chemical composition bears little relationship to their functional characteristics. The fundamental properties that determine the capacity of the membrane to remove solutes and fluids are its surface area, thickness, pore size, pore density, and potential to adsorb proteins. Dialyzer membrane performance is characterized clinically by its efficiency, defined as the potential to remove urea and presented as the mass-transfer area coefficient (KoA) and ultrafiltration coefficient (K(uf) ),defined as the potential to remove water adjusted for the transmembrane pressure. The parameter K(uf) usually, but not invariably, correlates with the membrane permeability, defined as the potential to remove middle molecules, with beta2-microglobulin being the currently popular marker. The sieving coefficient reflects the membrane potential to transport solutes by convection and is particularly useful for hemofiltration. Enhancing solute clearance is accomplished clinically by increasing blood and dialysate flow rates, strategies that also are applicable to middle molecules for highly permeable membranes. Novel designs of dialyzers include the optimization of fluid flow path geometry and increasing the membrane pore selectivity for solutes by using nanotechnology.

Humans↗

PubMed2005

Different responses by cultured aortic and venous smooth muscle cells to gamma radiation.

BACKGROUND: Stenosis of hemodialysis arteriovenous grafts is usually focal and caused by the proliferation of vascular smooth muscle cells (SMCs). External radiation of the graft is a potential strategy to prevent stenosis; however, the relative responsiveness of arterial and venous SMCs to radiation is unknown. METHODS: Human aortic and saphenous vein SMCs were cultured in a medium containing growth factors and serum and treated with 0 to 50 Gy in a gamma irradiator. At 2 to 20 days post-irradiation, cell counting, methylthiazoletetrazolium dye reduction, [(3)H]-thymidine uptake, and bromodeoxyuridine (BrdU) incorporation assays were performed. RESULTS: All assays showed that 1 to 50 Gy inhibited the proliferation of both aortic and venous SMCs in a dose-dependent manner. Importantly, venous cells were less susceptible to radiation in all assays, compared to aortic cells. At day 10, 1 to 50 Gy of radiation inhibited the increase in the number of aortic cells by 24% to 66% and venous cells by 8% to 25% (P < 0.01) (aortic vs. venous). The differences between aortic and venous cells varied among different assays and were most pronounced in the BrdU assay. CONCLUSION: Inasmuch as myointimal hyperplasia occurs at both arterial and venous anastomoses, future strategies using radiation to prevent hemodialysis vascular access stenosis should take these differences into consideration.

Antimetabolites↗

PubMed2004

Daily hemofiltration for end-stage renal disease: a feasibility and efficacy trial.

BACKGROUND: Although conventional hemodialysis (CHD) is currently provided primarily on an intermittent basis for patients with end-stage renal diseases (ESRD), the value of daily dialysis is well documented. Daily hemofiltration (DHF) is a convective therapy that has received little attention as an alternative to CHD. The aim of this feasibility study was to validate and assess the efficacy of DHF (6 times/week) as an alternative to CHD (3 times/week) in patients with ESRD. METHODS: In this prospective single-arm open-labeled study, DHF was administered over 4 weeks after a 1-week run-in phase period of CHD. Blood samples were drawn at baseline and on a weekly basis during the trial, and ultrafiltrate samples were collected weekly during the DHF period. The primary endpoint was to achieve a daily spKt/V of 0.40 (equivalent to a weekly stdKt/V of approximately 2.0). To achieve this goal, the DHF prescription consisted of an exchange volume of 40% of total body water. Secondary endpoints were the evaluation of blood pressure and anemia parameters, nutritional and mineral metabolism markers and health-related quality of life measures. RESULTS: Twelve patients completed the study. Mean age was 54 years, two-thirds were men, and 83% had arteriovenous fistulae. DHF delivered a mean (+/-SD) spKt/V of 0.44 +/- 0.06. This goal was reached by delivering an exchange volume of 13-14 liters, consisting of a replacement fluid volume of 11.7 +/- 1.9 l/session and net fluid loss of 1.4 +/- 0.1 l/session. Conversion from CHD to DHF resulted in marked reduction in treatment time (3.8 vs. 2 h/session, p < 0.001) and net fluid loss (2.6 vs. 1.4 l/session, p < 0.001). Calculated weekly standard Kt/V during the last week of DHF was 1.9 +/- 0.2. DHF achieved a median beta2-microglobulin (beta2-M) removal of 170 mg/session, resulting in a decrease of mid-week pre-therapy beta2-M levels (48 +/- 34 vs. 36 +/- 25 mg/l, p = 0.07). Compared with CHD, DHF resulted in lower systolic (143 +/- 19 vs. 133 +/- 16 mm Hg, p = 0.002) and diastolic (79 +/- 11 vs. 72 +/- 12 mm Hg, p = 0.002) blood pressure, reduction in antihypertensive medications (2.1 +/- 0.7 vs. 1.1 +/- 0.8, p = 0.002), higher caloric intake (1,778 +/- 441 vs. 2,044 +/- 564 kcal/day, p = 0.01), higher normalized protein catabolic rate (0.88 +/- 0.17 vs. 1.00 +/- 0.35 g/kg/day, p = 0.05), higher pre-albumin levels (330 +/- 50 vs. 378 +/- 84 g/dl, p = 0.06), higher vitality (p = 0.02), improved cognitive function (p = 0.04) and less symptoms/problems (p = 0.03). Serum albumin and potassium levels remained unchanged but the serum bicarbonate level dropped during the 1-month period of DHF. CONCLUSIONS: DHF (6 times/week) over a 1-month period achieved a weekly stdKt/V of approximately 2.0, which is similar to that recommended for 3 times weekly CHD, reduced beta2-M levels, lowered blood pressure, and had some beneficial effect on nutritional parameters, and health-related quality of life measures.

Adolescent↗

PubMed2004

Arterial and venous smooth-muscle cells differ in their responses to antiproliferative drugs.

Arteriovenous polytetrafluoroethylene (PTFE) grafts used for hemodialysis often fail as the result of myointimal hyperplasia with vascular smooth-muscle-cell (SMC) proliferation. The stenotic lesions occur primarily at the graft-vein anastomosis and less frequently at the graft-artery anastomosis. To explore the potentials of pharmacologic agents in preventing hemodialysis-graft stenosis, we first examined the susceptibility of venous and aortic SMCs to 3 antiproliferative drugs. Human aortic and saphenous-vein SMCs were cultured in a medium containing insulin, epidermal growth factor, fibroblast growth factor, and fetal bovine serum. Various concentrations of dipyridamole (0-100 microg/mL), paclitaxel (0-100 microg/mL), and tranilast (0-300 microg/mL) were added. After 72 hours, we subjected the cells to a mitochondrial enzymatic (methylthiazoletetrazolium; MTT) assay and a bromodeoxyuridine (BrdU)-incorporation assay as a means of assessing their proliferation. Dipyridamole, paclitaxel, and tranilast each inhibited the proliferation of aortic and venous SMCs in a dose-dependent manner ( P <.0001). Approximately 90% inhibition was achieved at dipyridamole concentrations of 75 microg/mL and greater in both MTT and BrdU assays; paclitaxel and tranilast were less effective. The venous SMCs were substantially more susceptible to inhibition by all 3 drugs than were the aortic SMCs in the MTT assay. The concentrations required to produce 50% inhibition (IC 50 ) in the venous cells were 5.8 microg/mL (11.5 micromol/L), 9.1 microg/mL (10.7 micromol/L), and 37.4 microg/mL (114.3 micromol/L), respectively, for dipyridamole, paclitaxel, and tranilast. These concentrations were approximately 4.2, 5.3, and 3.0 times lower, respectively, than the corresponding IC 50 values for the aortic cells. The differences in IC 50 between the aortic and venous cells for the 3 drugs were less pronounced in the BrdU assay. The results of this study suggest that strategies for the prevention of stenosis should take into account the fact that lesions at venous anastomoses of arteriovenous grafts may respond differently to drugs than do those at arterial anastomoses.

Arteries↗

PubMed2004

Kinetics of urea and beta-microglobulin during and after short hemodialysis treatments.

BACKGROUND: Daily short hemodialysis (HD) is often prescribed by simply doubling treatment frequency and halving treatment time; however, the effect of this prescription approach on the equilibrated HD dose (urea eKt/V) and whole body clearance for beta(2)-microglobulin has not been established. METHODS: We compared urea and beta(2)-microglobulin kinetics during and 60 minutes after a short HD treatment and a conventional HD treatment in a crossover study on 22 maintenance HD patients: 16 male and 6 female, 61 +/- 18 (mean +/- standard deviation) years of age. One patient in each treatment modality was excluded from certain analyses because of missing data. Short and conventional HD treatments were essentially identical, except for treatment times, which were 116 +/- 14 and 241 +/- 27 minutes, respectively. Blood samples were collected at regular intervals during and after treatments, and additional blood and dialysate samples were collected at 60 minutes of treatment to evaluate dialyzer clearances. RESULTS: Plasma water urea clearances measured directly across the dialyzer during short and conventional HD treatments were not different (255 +/- 23 mL/min and 255 +/- 28 mL/min, respectively). The 60-minute postdialysis blood urea nitrogen concentration rebounded more (P < 0.01) after short HD than conventional HD (5.9 +/- 3.1 vs. 4.0 +/- 1.5 mg/dL, respectively). Calculated urea eKt/V values using the Daugirdas-Schneditz rate equation were not different from those measured during conventional HD using the 60-minute postdialysis concentration but significantly overestimated measured urea eKt/V values during short HD. Postdialysis rebound of beta(2)-microglobulin concentrations was variable but similar after short and conventional HD treatments (0.1 +/- 3.4 vs. 0.7 +/- 1.8 mg/L, respectively). Whole body clearances of beta(2)-microglobulin calculated from predialysis and immediate (10-second) postdialysis serum concentrations during short and conventional HD treatments were not different from each other (42.9 +/- 24.1 vs. 41.9 +/- 22.4 mL/min, respectively). CONCLUSION: These observations show that the Daugirdas-Schneditz rate equation is accurate in predicting urea eKt/V during conventional, but not during short, HD. In contrast, whole body clearances of beta(2)-microglobulin during short and conventional HD treatments were similar. We conclude that calculation of accurate estimates of urea eKt/V, but not clearances of beta(2)-microglobulin, differ during short and conventional HD treatments.

Blood Urea Nitrogen↗

PubMed2004

Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel.

BACKGROUND: Neointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibility of local drug delivery to inhibit neointimal hyperplasia at dialysis grafts in a canine model. METHODS: Bilateral polytetrafluoroethylene loop grafts (10-cm length and 6-mm internal diameter) were placed between the femoral artery and ipsilateral femoral vein of five mongrel dogs. At the time of surgery or 1 to 5 weeks later, 2 mL of a thermosensitive biodegradable copolymer (ReGel) mixed with 0.26 mg or 0.65 mg paclitaxel were applied to the external surface of one graft around the anastomoses to provide a depot for sustained release of the drug. ReGel alone without paclitaxel was applied to the contralateral graft as a control. The grafts and the connecting vessels were explanted at eight or nine weeks, and the cross-sections were examined histologically. The degree of hyperplasia at the anastomoses was graded by five blinded independent reviewers, with scores ranging from 0 to 5. RESULTS: The median (25th-75th percentile) hyperplasia score of both arterial and venous anastomoses was 1.80 (0.90-3.05) in the grafts treated with ReGel alone, and 0.95 (0.70-1.50) in the grafts treated with ReGel/paclitaxel (N= 8; P < 0.05 by Wilcoxon signed rank test). There were no noticeable localized or systemic complications attributed to the treatments in these animals. Paclitaxel levels in the plasma obtained from forelimb veins were undetectable (<10 ng/mL). CONCLUSION: These results suggest that the local delivery of antiproliferative agents using a thermosensitive, injectable biodegradable copolymer (ReGel) for sustained delivery is a promising strategy to inhibit neointimal hyperplasia of arteriovenous hemodialysis grafts.

Animals↗

PubMed2004

In vitro pharmacological inhibition of human vascular smooth muscle cell proliferation for the prevention of hemodialysis vascular access stenosis.

BACKGROUND: Vascular access for chronic hemodialysis often fails as a result of stenosis caused primarily by the proliferation of vascular smooth muscle cells (VSMC). Various drugs have been shown to inhibit the proliferation of VSMC under different conditions. METHODS: In this study, we compared the inhibitory effect of ten drugs on the proliferation of human aortic smooth muscle cells (SMC) in culture. Quiescent cells were cultured in the presence of growth factors, fetal bovine serum and incremental concentrations of the test drug. Cell proliferation was assessed by the MTT reduction assay. RESULTS: Aspirin, enalaprilat, heparin, hydroxyurea, indomethacin and tirofiban were ineffective. While dipyridamole, paclitaxel, tranilast and verapamil inhibited cell proliferation, the concentrations required were significantly higher than the clinical plasma levels achieved after systemic administration. CONCLUSION: Local delivery of these drugs to the target site may therefore be a more effective and appropriate strategy for the prevention of hemodialysis vascular access stenosis.

Antineoplastic Agents↗

PubMed2003

Kinetics and dosing predictions for daily haemofiltration.

BACKGROUND: Thrice-weekly haemofiltration affords excellent outcome when it is used to treat chronic renal failure patients. Daily haemofiltration (DHF) has recently been proposed as a more intensive therapy option, but the total ultrafiltration or exchange volume (replacement volume plus net ultrafiltration volume) requirements for adequate solute clearances during this novel therapy are unknown. METHODS: We calculated theoretical solute kinetic profiles during six times per week DHF for comparison with those during thrice-weekly haemodialysis using a high-flux dialyser (HFHD) or during continuous ambulatory peritoneal dialysis (CAPD). HFHD and CAPD were chosen for comparison because K/DOQI guidelines have defined adequate treatment doses for these therapies. Steady-state concentrations were calculated using a two-compartment model of an anuric patient with 35 l of total body water for five solutes: urea, creatinine, vitamin B(12), inulin and beta(2)-microglobulin. Solute distribution volumes and generation rates were taken from the literature, and excess fluid (1 l/day) was assumed to accumulate in and be removed from the extracellular fluid compartment. Theoretical predictions of solute clearance were compared for a 15-l exchange volume/session during DHF, urea Kt/V of 3.6/week during HFHD and urea Kt/V of 2.0/week during CAPD as solute-specific values of the equivalent renal clearance (EKR) and standard Kt/V (stdKt/V) recently defined by Gotch. Additional comparisons of solute clearances were performed between DHF and other daily therapies including six times per week short daily haemodialysis (SDHD) and six times per week nocturnal haemodialysis (NHD). RESULTS: The calculated results predict that: (i) urea clearance during DHF with an exchange volume of 90 l/week (6x15 l) is equivalent to those during HFHD and CAPD based on urea stdKt/V; and (ii) middle molecule clearances during DHF exceed those achieved during HFHD and CAPD based on either EKR or stdKt/V. As expected, DHF therapy was inferior regarding the clearance of urea and other small solutes to SDHD and NHD; however, DHF therapy was superior to SDHD regarding the clearance of larger middle molecules, approaching the clearances achieved by NHD. CONCLUSIONS: We predict that an exchange volume of approximately 40% of total body water (15/35 l=43%) per session will provide adequate clearance of small solutes and substantial clearance of middle molecules during six times per week DHF therapy. These theoretical predictions require clinical validation.

Blood Urea Nitrogen↗

PubMed2003

Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study.

Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux arm, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95% CI, 0.60 to 0.91; P = 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.

Female↗

PubMed2002

Relationship between volume status and blood pressure during chronic hemodialysis.

BACKGROUND: The relationship between volume status and blood pressure (BP) in chronic hemodialysis (HD) patients remains incompletely understood. Specifically, the effect of interdialytic fluid accumulation (or intradialytic fluid removal) on BP is controversial. METHODS: We determined the association of the intradialytic decrease in body weight (as an indicator of interdialytic fluid gain) and the intradialytic decrease in plasma volume (as an indicator of postdialysis volume status) with predialysis and postdialysis BP in a cross-sectional analysis of a subset of patients (N=468) from the Hemodialysis (HEMO) Study. Fifty-five percent of patients were female, 62% were black, 43% were diabetic and 72% were prescribed antihypertensive medications. Dry weight was defined as the postdialysis body weight below which the patient developed symptomatic hypotension or muscle cramps in the absence of edema. The intradialytic decrease in plasma volume was calculated from predialysis and postdialysis total plasma protein concentrations and was expressed as a percentage of the plasma volume at the beginning of HD. RESULTS: Predialysis systolic and diastolic BP values were 153.1 +/- 24.7 (mean +/- SD) and 81.7 +/- 14.8 mm Hg, respectively; postdialysis systolic and diastolic BP values were 136.6 +/- 22.7 and 73.9 +/- 13.6 mm Hg, respectively. As a result of HD, body weight was reduced by 3.1 +/- 1.3 kg and plasma volume was contracted by 10.1 +/- 9.5%. Multiple linear regression analyses showed that each kg reduction in body weight during HD was associated with a 2.95 mm Hg (P=0.004) and a 1.65 mm Hg (P=NS) higher predialysis and postdialysis systolic BP, respectively. In contrast, each 5% greater contraction of plasma volume during HD was associated with a 1.50 mm Hg (P=0.026) and a 2.56 mm Hg (P < 0.001) lower predialysis and postdialysis systolic BP, respectively. The effects of intradialytic decreases in body weight and plasma volume were greater on systolic BP than on diastolic BP. CONCLUSIONS: HD treatment generally reduces BP, and these reductions in BP are associated with intradialytic decreases in both body weight and plasma volume. The absolute predialysis and postdialysis BP levels are influenced differently by acute intradialytic decreases in body weight and acute intradialytic decreases in plasma volume; these parameters provide different information regarding volume status and may be dissociated from each other. Therefore, evaluation of volume status in chronic HD patients requires, at minimum, assessments of both interdialytic fluid accumulation (or the intradialytic decrease in body weight) and postdialysis volume overload.

Adult↗

PubMed2002

Computer simulation of small-solute and middle-molecule removal during short daily and long thrice-weekly hemodialysis.

BACKGROUND: More intensive hemodialysis (HD) regimens (short daily and long thrice-weekly HD) provide potential opportunities for improved patient outcome. An adequate dialysis dose for these regimens cannot be established from the existing literature. METHODS: Using computer simulation, we compared conventional HD with short daily HD and long thrice-weekly HD using two dose measures of solute clearance: equivalent renal clearance (EKR) and a generalized standard Kt/V (stdKt/V) for urea, creatinine, vitamin B12, inulin, and beta2-microglobulin. Solute kinetics were simulated using a variable-volume two-compartment mathematical model. RESULTS: Calculated EKR values were greater during short daily HD compared with those during conventional HD by 16.9%, 15.5%, 16.1%, 5.2%, and 2.5% for urea, creatinine, vitamin B12, inulin, and beta(2)-microglobulin, respectively. Calculated stdKt/V values predicted more substantial increases in dose for all solutes. Increasing the time of dialysis from 4 to 8 hours three times weekly resulted in substantially greater stdKt/V and EKR values compared with both conventional and short daily HD. Solute clearances during short daily HD could be enhanced to approach those during long HD if treatment time was increased or very high surface area dialyzers were used with very high blood flow rates. CONCLUSION: Dose measures for all molecules larger than urea increase with either increased frequency or, even more so, increased duration of dialysis. Prediction results of these models require confirmation in clinical studies. Furthermore, the relationship between increased dialysis dose and long-term clinical outcome during more intensive HD regimens requires examination in clinical trials.

Computer Simulation↗