Current concepts of anemia management in chronic renal failure: impact of NKF-DOQI.

Since the introduction of recombinant human erythropoietin (rHuEPO) into clinical nephrology practice 10 years ago, there has been a slow increase in hemoglobin (Hgb) levels, but most patients with the anemia of chronic renal failure are still moderately anemic and have not achieved the target Hgb (11 to 12 g/dL) recommended by the NKF-DOQI anemia guidelines. Functional iron deficiency, insufficient rHuEPO doses and comorbid factors such as inflammation/infection have been the major reasons for not achieving this target. By optimizing iron stores with regular infusions of intravenous iron in the hemodialysis patient (who has significant blood [iron] losses related to the hemodialysis procedure), and giving adequate amounts of rHuEPO, preferably subcutaneously instead of intravenously, the NKF-DOQI recommended target Hb can be achieved in the majority of patients so treated.

Methods used to evaluate the quality of evidence underlying the National Kidney Foundation-Dialysis Outcomes Quality Initiative Clinical Practice Guidelines: description, findings, and implications.

This report describes the approach the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) used to assess the strength of published evidence pertinent to individual NKF-DOQI Clinical Practice Guidelines, as well as the relationship between that approach and methods used by the US Preventive Services Task Force, the Cochrane Collaboration, and the Agency for Health Care Policy and Research to rate the quality and/or strength of evidence. We also present the results of an analysis of the strength of evidence underlying the NKF-DOQI Guidelines showing that one cannot infer the quality of evidence reported in a study (rated either on a 0-to-1 scale or categorically as excellent, very good, good, fair, or poor) simply by knowing the type of study design used (randomized trial, nonrandomized trial, natural experiment, cohort study, cross-sectional study, case-control study, case report). Issues related to assessment of the strength of evidence underlying a practice guideline opposed to that reported in an individual study are highlighted.

Iron overload in renal failure patients: changes since the introduction of erythropoietin therapy.

Iron overload was a common complication in patients with chronic renal failure treated with dialysis prior to the availability of recombinant human erythropoietin (rHuEPO) therapy. Iron overload was the result of hypoproliferative erythroid marrow function coupled with the need for frequent red blood cell transfusions to manage symptomatic anemia. The repetitive use of intravenous iron with or without the use of red blood cell transfusions also contributed to iron loading and was associated with iron deposition in liver parenchymal and reticuloendothelial cells; however, there were no abnormal liver function tests or evidence of cirrhosis unless viral hepatitis resulted from the transfusions. With rHuEPO therapy, the excess iron stores were shifted back into circulating red blood cells as the anemia was partially corrected, and red blood cells were lost from circulation by the hemodialysis procedure. After several years of rHuEPO therapy, most hemodialysis patients required iron supplements to replace the continuing blood losses related to hemodialysis. The potential complications of iron overload (parenchymal iron deposition, permanent organ damage, increased risk of bacterial infections, and increased free radical generation) are reviewed in the context of this setting.

Implementation of the Anemia Guidelines.

Implementation of the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Guidelines for the treatment of the anemia of chronic renal failure is a great challenge to all concerned with the improvement in the quality of life and survival of patients with chronic renal failure. These include physicians, nurses, technicians, dietitians, social workers, administrators, and private and public (Health Care Financing Administration) payers of the care. The principles of the process of implementation are reviewed and the barriers that can prevent implementation are discussed, showing how most of these can be overcome. Several of the more controversial Guidelines are discussed in detail, showing that with protocols that address the means for implementation, the goals of these Guidelines can be achieved.

Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients.

Much progress has been made in recent years in the management of anemia associated with chronic and renal failure with recombinant human erythropoietin (r-Hu EPO). However, there remains much debate surrounding the diagnosis and treatment of iron deficiency. To ensure that full benefit from erythropoietin therapy is received, most patients require iron supplement during treatment. There are, however, few guidelines for the use of iron therapy. Iron deficiency results in an inadequate response to r-Hu EPO and is the main cause of resistance to this treatment. Oral iron therapy is of limited value in patients receiving r-Hu EPO. Thus, intravenous iron supplementation should be administered only in patients who do not tolerate available intravenous iron preparations or who are on continuous ambulatory peritoneal dialysis with no evidence of functional iron deficiency. This article provides guidelines for the diagnosis of absolute or functional iron deficiency in patients with renal anemia and suggests treatment schedules for intravenous iron supplementation. We hope that all dialysis patients will be able on this basis to achieve a satisfactory iron status and benefit fully from r-Hu EPO therapy.

Intravenous versus subcutaneous dosing of epoetin alfa in hemodialysis patients.

Hemodialysis patients were studied to determine whether the dose of recombinant human erythropoietin (Epoetin alfa; Amgen Inc, Thousand Oaks, CA) required to maintain a therapeutic hematocrit level changed when the route of administration was switched from intravenously (IV) three times per week to subcutaneously (SC) three times per week. Thirteen to 16 weeks after patients were changed from IV three times per week to SC three times per week treatment, the Epoetin alfa requirement was reduced by 18.5% +/- 3.8% (P < 0.001; n = 72), and after 21 to 24 weeks of SC treatment the mean dosage had decreased from the IV dose by 26.5% +/- 4.2% (P < 0.001; n = 41). Sixty-one percent (44 of 72) of patients experienced maintenance-dose reductions over 13 to 16 weeks of treatment and 80% (33 of 41) were maintained on lower weekly doses after 21 to 24 weeks of treatment than at baseline (IV). There was interpatient variability, however: 26% of the patients required greater doses SC than IV following 13 to 16 weeks of SC treatment, and 15% required greater doses SC than IV following 21 to 24 weeks. On completing the initial SC three-times-per-week stage of the study, patients were randomized to one of three SC dosing strategies for an additional 12 weeks: (1) once per week, (2) three times per week Epoetin alfa diluted 1:2 with bacteriostatic saline to mitigate stinging at the injection site, or (3) continued three times per week with undiluted Epoetin alfa. Patients who were switched to administration of SC once per week undiluted Epoetin alfa (n = 20) had their total weekly dose lowered by 18.0% +/- 9.4% (P > 0.05), but the mean hematocrit for this cohort also decreased, from 34.3% +/- 3.0% to 32.4% +/- 3.9% (P > 0.05), rendering dose comparison between the two schedules ambiguous. The maintenance dose for patients who received Epoetin alfa diluted 1:2 with bacteriostatic saline (n = 23) did not differ from the undiluted three times per week dose at the end of stage 1. The third cohort of patients (n = 24), who continued to receive undiluted Epoetin alfa on the same SC three-times-per-week schedule, did not require a significant change in dosage over the ensuing 12 weeks. Comparison of SC three times per week mean dosage after an average of 32 weeks following the switch from IV three times per week for this latter cohort revealed a decrease of 23.5% +/- 6.5% (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

The future of r-HuEPO.

Since the introduction of recombinant human erythropoietin (r-HuEPO) 9 years ago, there have been tremendous physiological improvements in patients with various anaemias due to absolute and relative erythropoietin (Epo) deficiencies. However, not all patients that could benefit from r-HuEPO are being treated, not all are responding who should be responding, and most dialysis patients (who comprise the single largest group of treatment recipients) are being inadequately treated. The future of r-HuEPO will depend upon whether clinicians can optimize the use of r-HuEPO and determine what should be the optimal haematocrit. These issues will, in turn, depend upon whether three interdependent variables are addressed: the need for more scientific studies to evaluate various aspects of the use and effectiveness of r-HuEPO; the need for physician education to better understand the role of r-HuEPO in optimizing health in patients with anaemia in chronic renal failure and in the anaemia of chronic disease; and the need for less costly r-HuEPO therapy so that more patients can be treated and receive optimal therapy. Better use of r-HuEPO could result in significantly improved morbidity and perhaps improved survival of patients with Epo-deficient anemias.

Effects of erythropoietin on strength and functional status of patients on hemodialysis.

The strength, endurance, and functional status of 15 anemic (HCT 21.2 +/- 4.6) hemodialysis patients was quantified prior to the administration of erythropoietin (epoetin) and after the anemia was partially corrected (HCT 35.4 +/- 2.3). Subjects showed significant increases in strength, measured isometrically (p < .01) and isokinetically (p < .01 at four of five speeds). They also demonstrated improved endurance and rated their functional ability higher. Anemia contributes to significant debilitation in hemodialysis patients and, when reversed with epoetin therapy, results in significantly improved muscle function and endurance.

A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects.

The erythropoietic response to graded doses of recombinant human erythropoietin (epoetin alfa) was assessed in 24 hemodialysis patients by quantitative ferrokinetic studies, and measurement of the reticulocyte count and plasma levels of transferrin receptor protein. These responses were compared to those of 22 normal subjects. Epoetin alfa was given intravenously at 15, 50 or 150 U/kg every other day for four injections. Three patients with chronic renal failure were restudied after renal function was restored following renal transplantation. The results of these three different measurements of erythroid function showed that the acute response to recombinant human erythropoietin was similar in normal subjects and patients with renal failure. We conclude that chronic uremia does not alter the responsiveness to erythropoietin in vivo.

The long-term effects of recombinant human erythropoietin on the cardiovascular system.

Fifty-five hemodialysis patients (pts) received rHuEpo for 3-5 years (51 +/- 11 months, hematocrit 32.5 +/- 3.7). BP medication was required in 42% of pts prior to rHuEpo (Hct 20.8 +/- 3.5) and 69% (38 patients) now require such therapy. BP was controlled with single therapy in 16 pts and only 8 required 3 or more different BP drugs. Vascular access clotting episodes were rare in pts with autologous fistula (17 of 24 pts had no clotting), whereas access clotting episodes were 10 times more common in pts with AV grafts, yet 20% had no clotting after 3-5 years of rHuEpo. Heart size decreased in most who initially had cardiomegaly. Cardiovascular related and other deaths were decreased in this selected group when compared to other dialysis pts matched for age, race and type of renal disease.

Erythropoietin 1991--an overview.

Recombinant human erythropoietin (epoetin) is a remarkably safe and effective biological product. Many dialysis patients are benefiting from the use of this drug when administered intravenously (IV) or subcutaneously (SC) three times a week. However, many patients are not receiving optimal therapy. Optimal therapy requires an understanding of the principles of effective usage and a definition of an optimal hematocrit (Hct) level. These therapeutic principles include (1) the erythroid response to epoetin is dose-dependent, but variable within a given dose; (2) the SC route of injection is as effective, if not more so, than IV injections; (3) the frequency of administration is route-dependent; (4) adequate iron stores are necessary for optimal response; (5) blood pressure may increase as the Hct increases, but may improve with time due to hemodynamic adjustments; (6) the anemia is primarily a hormone-deficiency state and not due to uremia; and (7) infections and traumatic (ie, surgical) inflammation may blunt the response to epoetin. Many patients with the anemia of renal failure have yet to benefit from treatment. These include patients with progressive renal failure or chronic transplant rejection, and dialysis patients who have had incomplete correction of their anemia.

Hypertension following erythropoietin therapy in anemic hemodialysis patients.

Recombinant human erythropoietin (rHuEpo) corrects the anemia of end-stage renal disease. However, hypertension has been observed as an adverse effect of increasing red cell mass. In our study, 44 of 63 patients (70%) treated with rHuEpo had an increase in mean arterial pressure greater than 10 mm Hg or required new or additional hypertensive medications. Retrospective analysis disclosed that increasing blood pressure was associated with pretreatment hematocrit level less than or equal to 0.20 (P = .05) and dependency on red cell transfusions (P less than .01). Factors not associated with hypertension included the rate of rise of the hematocrit, the net rise in hematocrit, age, sex, the number of years on dialysis, the presence or absence of kidneys, smoking, or the presence of pretreatment hypertension. Noninvasive hemodynamic studies in eight normotensive patients before and after improvement of the anemia demonstrated a normalization of the decreased peripheral vascular resistance and a reduction toward normal in the elevated cardiac output. In three of these patients, clinical hypertension subsequently evolved. Follow-up hemodynamic studies in nine other patients receiving new or additional antihypertensive medications were difficult to interpret. Although the hypertension can be controlled with routine medication, hypertensive encephalopathy may occur if the blood pressure increases rapidly when the hematocrit increases with rHuEpo therapy.

Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect.

Transdermal administration of peptides has been limited by the barrier properties of the skin. We compared the acute luteinizing hormone (LH) response to subcutaneous and transdermal administration of an LH-releasing hormone agonist (leuprolide). Eighteen volunteers received 5 mg leuprolide added to electrically powered patches delivering a current of 0.22 microA (transdermally). One week later, they received a 5 mg subcutaneous dose. LH response was measured. The area under the curve for LH response, maximum LH response, and time to maximum LH response were similar. Time to first response was shorter (147 +/- 108 minutes [transdermally] and 73 +/- 74 minutes [subcutaneously]; p less than 0.05), and the area under the curve for the first 150 minutes was greater (3655 +/- 2246 mIU.min/ml [transdermally] and 8666 +/- 4067 mIU.min/ml [subcutaneously]; p less than 0.05) for subcutaneous delivery. No major adverse effects were seen. This electrically powered transdermal technique merits further study.

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.