Target haematocrit during erythropoietin therapy.
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Cardiovascular System↗
Biomedical subjects
A Besarab
Publications and source records attributed to A Besarab.
Measuring the adequacy of hemodialysis access.
Vascular access morbidity is still an important problem. The risk of thrombosis increases in prosthetic grafts as the access flow decreases below 600 ml/min, whereas native arteriovenous accesses can maintain patency at much lower flows, in some cases flows below those needed to deliver adequate dialysis. Intra-access pressures are also dissipated differently in the two access types. These differences between native and prosthetic grafts determine the utility of the monitoring techniques that are useful for detecting stenosis and assessing function in the two access types. Modern non-urea methods for measuring access recirculation are therefore useful in native but not in graft hemoaccesses. Direct or indirect intra-access pressure measurements and direct flow measurements are most useful in grafts to detect and then correct lesion before thrombosis.
Arteriovenous Shunt, Surgical↗
Utility of intra-access pressure monitoring in detecting and correcting venous outlet stenoses prior to thrombosis.
Vascular access thrombosis is a major problem for hemodialysis patients. Over 7.75 years, we performed intra-access venous pressure monitoring at zero dialyzer blood flow (VP0), correlated VP0 with access anatomy angiographically, and examined the effect of two levels of stenosis, 50% and > 65% luminal diameter reduction (% D) as selection criteria for referral and elective angioplasty or surgical revision upon access outcomes. Summary receiver outcome curves for absolute intra-access pressure (VP0) and intra-access pressure normalized for systemic pressure (VP0/systolic BP) were constructed to evaluate sensitivity and specificity and compared to recirculation and duplex color-flow Doppler. Access outcomes included thrombosis, revision, replacement, and angioplasty rates that were normalized per 100 patient years (100 pt-yrs). During the 7.75 year long study period totaling 832 patient-access years of risk, the percentage of prosthetic bridge grafts increased from 65% to 80%. SROC showed better sensitivity for normalized (VP0/systolic BP) than absolute intra-access pressure (VP0) in grafts. Recirculation had poor predictive power in prosthetic bridge grafts compared to VP0. Predictive power of recirculation was superior to VP0 in native arteriovenous fistulae. The angioplasty rate correlated inversely with the degree of luminal reduction used as selection criterion for referral for angioplasty or surgical revision. A strong inverse relationship between thrombosis rate and the angioplasty rate (R2 = 0.99) but not between thrombosis rate and the number of angiograms performed (R2 = 0.39) was noted. A consistent, yet evolving, intensive graft maintenance protocol produced a 70% decrease in the thrombosis rate, a 79% decrease in the access replacement rate, and an increase in the average age of patent usable vascular accesses from 1.97 to 2.98 years that was associated with a 13-fold increase in the angioplasty rate. We conclude that vascular access monitoring with VP0/systolic BP provides excellent selection criteria for angiographic referral. Intervention for stenotic lesions > 50% D using angioplasty or surgical revision markedly reduces thrombosis and access replacement rates.
Angiography↗
The use of recombinant human erythropoietin in predialysis patients.
Recombinant human erythropoietin is increasingly used to treat anemia in predialysis patients. Approximately 33-40% of patients ultimately receiving dialysis or a transplant may be eligible for treatment, thus increasing the costs. Clinical trials demonstrate no significant alteration in the progression of renal disease, secondary to changes in systemic hemodynamics or blood volume, provided that blood pressure is controlled. Hypertension results from changes in viscosity and erythrocyte fluidity, loss of hypoxic vasodilatation, and changes in blood volume. The predialysis patient treated with recombinant human erythropoietin is likely to need aggressive antihypertensive therapy and vigorous diuresis. Cardiac output remains unchanged in the absence of blood volume expansion. The effects on left ventricular hypertrophy, left ventricular volume, or exercise-induced ischemic electrocardiographic changes in predialysis have not been studied systematically. Doses of recombinant human erythropoietin in predialysis patients tend to be lower when administered subcutaneously rather than intravenously, but the comparative cost-effectiveness of different dosing strategies is currently unknown. The dosing frequency can vary from three times a week to twice a month. The effect of anemia correction on the 'rehabilitation' of predialysis patients remains to be addressed.
Anemia↗
The rate and control of baseline red cell production in hematologically stable patients with uremia.
It is generally accepted that the anemia of uremia is caused by decreased production of erythropoietin. Nevertheless, the erythropoietin titers are not lower than but equal to or higher than in normal non-anemic individuals. To examine this discrepancy, erythrokinetic studies were made of 22 hematologically stable dialysis patients without clinical or laboratory evidence of extrarenal inflammation, infection, or neoplastic disorders. The red cell life span was normal in 14, and because of stable hematocrits, their daily rate of red cell production had to equal their daily rate of red cell destruction, which could be determined by dividing the red cell mass by red cell life span. These rates were about one half the rates of normal stable individuals, despite the same or higher erythropoietin titers. This suggests that the anemia of uremia is caused in part by a decreased bone marrow response to endogenous erythropoietin.
Anemia↗
Optimizing epoetin therapy in end-stage renal disease: the case for subcutaneous administration.
The effectiveness of various recombinant human erythropoietin (epoetin) administration routes and dosage schedules in patients on dialysis was studied. The mean dose required to achieve and maintain a hematocrit level between 33% and 40% is 225 U/kg/wk when administered intravenously (i.v.) in three divided doses. A once-weekly i.v. schedule requires a dose of 429 U/kg/wk to maintain the same target hematocrit. In contrast, the required epoetin dose is reduced by an average of 25% to 50% when administered via the subcutaneous (SC) route. Analysis of data from 25 dialysis centers shows that SC epoetin administration resulted in higher normalized responses than i.v. administration. The hematocrit response in patients at these centers was proportional to the weekly dose, with a greater slope in those centers using predominantly SC as compared with i.v. dosing. Cost analysis indicates that the use of SC dosing two or three times weekly at an average total weekly dose of 120 U/kg is effective for the treatment of anemia in most patients on dialysis.
Anemia↗
Hemodynamics of failing dialysis grafts.
Pressures were measured in the graft and the central vein during 104 consecutive angiographic examinations of failing hemodialysis grafts. Stenosis severity greater than 40% led to a statistically significant rise in graft pressure. In grafts in which all stenoses were of 40% or less severity, the systolic pressures in the venous and arterial limbs of the grafts were 31% +/- 16 and 45% +/- 17, respectively, of systemic systolic pressure. In grafts in which the highest grade of stenosis was greater than 40%, pressures in the venous and arterial limbs of the grafts were 53% +/- 25 and 75% +/- 24, respectively, of systemic systolic pressure. Graft thrombosis tended to occur at a higher degree of lumen reduction (but at similar pressures) with central vein stenoses compared with venous anastomotic stenoses. Dialysis graft pressures can help determine the hemodynamic importance of stenoses and the need for intervention. Percutaneous intervention should achieve arterial and venous limb pressures of less than 50% and 33% of systemic pressure, respectively.
Angiography, Digital Subtraction↗
The beneficial effects of isradipine on renal hemodynamics in cyclosporine-treated renal transplant recipients.
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Adult↗
The relationship between dialysis graft pressure and stenosis.
RATIONALE AND OBJECTIVES: Pressure measurements during dialysis have been used to screen for venous outlet stenosis, but the relationship between the degree of stenosis and pressure has not been defined. METHODS: To determine this relationship, failing or failed dialysis grafts (n = 34) were studied with angiography and pressure measurements from the segment of the graft near the arterial anastomosis. RESULTS: By linear regression, the relationship between the highest grade stenosis in or central to the graft and pressure was as follows: percent stenosis = 55 systolic graft pressure/systolic blood pressure+13 (r = 0.75). CONCLUSIONS: There is a positive correlation between the severity of stenosis and graft pressure, confirming the use of this measurement in screening for stenosis. It is hypothesized that this relationship is the result of progressive elimination of the normal pressure drop between the artery and arterial limb of the graft as the degree of stenosis increases.
Angiography↗
Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration.
The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoetin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 +/- 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 +/- 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 +/- 10 U/kg. The other 16 patients required 137 +/- 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t1/2 of 6.8 +/- 0.3 h). Single i.v. doses greater than 150 U/kg were required to increase basal erythropoietin by 30 mU/mL at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that i.v. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of 110 to 120 U/kg is effective treatment of anemia in most dialysis patients.
Adolescent↗
Elevated plasma histamine in chronic uremia. Effects of ketotifen on pruritus.
A role for histamine in the pathogenesis of uremic pruritus was investigated in maintenance hemodialysis patients. Venous plasma histamine levels, as determined by radioenzymatic assay, were significantly higher (p less than 0.05) in hemodialysis patients with pruritus (368 +/- 103 pg/ml [mean +/- SEM], n = 6) than in those without pruritus (146 +/- 22 pg/ml, n = 5) and in normal controls (142 +/- 16, n = 5). Arteriovenous fistula histamine levels (202 +/- 52 pg/ml, n = 6) were significantly lower (p less than 0.05) than simultaneously drawn venous samples. Markedly elevated histamine-degrading enzyme (histaminase) activities were found in both hemodialysis patients with (2.95 +/- 0.18 pg histamine degraded/minute) and without (2.44 +/- 0.28) pruritus, but was undetectable in normal controls. Histaminase activities did not significantly differ in simultaneously drawn venous and fistula samples. With hemodialysis, histaminase activities fell significantly (p less than 0.01), whereas plasma histamine did not change. We further examined the effects of ketotifen, a putative mast cell stabilizer, on severe uremic pruritus. Five of five patients had significant (p less than 0.01) reductions in pruritus, as judged on a six-point pruritus index, after 8 weeks of drug (x = 2.3), as compared to conventional therapy (x = 5.9). Despite these improvements, no significant differences were noted in pre- versus post-drug plasma histamine levels, histaminase activities, or the histamine content per gram of skin biopsy specimen. These data support prior hypotheses that mast cell activation contributes to the pruritus of uremia.
Chronic Disease↗
Evidence against chronic progressive cyclosporine nephrotoxicity.
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Creatinine↗
Recombinant human erythropoietin: physiology, pathophysiology of anemia in renal failure, and economic aspects related to dosing.
The anemia associated with renal failure has been studied for over 150 years. It results primarily from inadequate production of erythropoietin such that plasma levels in dialysis patients are only 25% of those expected for the degree of anemia. Shortened red call survival, iron and other nutritional deficiencies, and uremic inhibitors have a secondary and minor role. Recombinant human erythropoietin (rHuEPO) is now used to treat this anemia. It is heavily sialated, which permits its circulation long enough to act on the bone marrow where, in concert with other growth factors, it commits progenitor cells to the erythroid cell pathway. Major issues related to clinical use of rHuEPO are dosage, resistance, and cost. Pharmacokinetic studies predict significant weekly dose reductions (and therefore cost savings) using the subcutaneous route compared to the intravenous route permitting more patients to be treated optimally. Biological heterogeneity and not hyperparathyroidism or aluminum overload accounts for most instances in which more than 450 U/kg/wk of rHuEPO is required.
Anemia↗
A comparison of the effects of cyclosporine versus antilymphocyte globulin on delayed graft function in cadaver renal transplant recipients.
There has been concern that cyclosporine's nephrotoxicity increases the incidence of delayed graft function (DGF), prolongs periods of oliguria, and reduces graft survival. In order to further study whether CsA should be used in DGF, we conducted a randomized prospective trial of the effect of CsA versus antilymphocyte globulin on the effects of DGF. Between 12/22/85 and 3/11/88, all patients with DGF after an initial 12-24 hr of CsA were randomized to either daily Minnesota ALG and prednisone or lower-dose CsA (10 mg/kg/day) and prednisone. Resolution of DGF was defined as a lack of dialysis dependency and a 25% fall in the serum creatinine (CR). If DGF was not resolved by 2 weeks, transplant renal biopsies were performed to assess the presence of occult rejection. CsA (10 mg/kg/day) was initiated in the ALG group only after resolution of the DGF. Of the 45 patients who recovered graft function, 19 received ALG and 26 received CsA. CsA significantly prolonged the duration of DGF (ALG 9.74 days, CsA 13.69 days, P = 0.035) but did not result in a prolongation of hospitalization. No difference in CR was found between the two groups at 1 month, 3 months, 6 months, or 12 months. Mean CR at 12 months was 1.98 mg/dl for ALG versus 1.96 mg/dl for CsA. Overall graft survival did not differ in the CsA and ALG groups (P = 0.33). CsA does slightly increase the duration of DGF as compared with ALG but has no effect on one-year serum CR or one-year graft survival. Since there appeared to be no harmful long-term effects of the slight lengthening of DGF, a lower-dose of CsA protocol with biopsy surveillance for occult rejection can be used in patients with DGF.
Antilymphocyte Serum↗
New insights into the mechanisms of post-transplant erythrocytosis.
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Adult↗
"Erythrocytosis" in renal transplantation patients treated with cyclosporine.
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Blood Volume↗
Dynamics of erythropoiesis following renal transplantation.
We examined the temporal dynamics of the correction of anemia following renal transplantation in 65 recipients using a sensitive radioimmunoassay for erythropoietin to determine the effects of modern immunosuppressive agents, delayed graft function, and early acute rejection. Pretransplant mean erythropoietin (25.6 +/- 3.3 mU/ml) was only 25% of the expected value at the mean hematocrit of 27.2 +/- 0.7, and erythropoietin correlated positively with hematocrit (r = 0.37, P less than 0.05). Following onset of graft function, erythropoietin increased to 109 +/- 13 mU/ml and then decreased in a negative feedback fashion over the next several months. Delayed graft function was associated with delay in the assumption of this orderly process irrespective of the immunosuppressive regimen used. Cyclosporine A produced a biphasic response despite delayed graft function in recipients with underlying adult polycystic kidney disease. Correction of anemia required resumption of graft function. Onset of acute graft rejection within the first month posttransplantation (14 episodes in 11 patients) abrogated the hematopoietic response until the rejection was successfully reversed. We conclude that a major cause for the anemia of renal failure is subnormal production of erythropoietin. Following transplantation, anemia corrects in an orderly manner with restoration of the normal biofeedback process between erythropoietin and red cell mass. This process is delayed by failure of graft to function initially and interrupted by acute early rejection, re-commencing following successful reversal.
Adolescent↗