Physicochemical properties of ferumoxytol, a new intravenous iron preparation.

BACKGROUND: Intravenous iron is a critical component of anaemia management. However, currently available preparations have been associated with the release of free iron, a promoter of bacterial growth and oxidative stress. MATERIALS AND METHODS: We determined the molecular weight, dialysability and capacity for free iron release of ferumoxytol, a semi-synthetic carbohydrate-coated superparamagnetic iron oxide nanoparticle. Ferumoxytol was compared with three intravenous iron preparations in clinical use: iron dextran (low molecular weight), sodium ferric gluconate and iron sucrose. Intravenous iron preparations were also incubated in rat, and pooled human sera (at concentrations of 600 microM and 42 microg mL(-1) respectively) from healthy subjects. RESULTS: The molecular weight of ferumoxytol was 731 kDa. The relative order of molecular weight was as follows: ferumoxytol > iron dextran > iron sucrose > sodium ferric gluconate. The least ultrafilterable iron was observed with ferumoxytol and the most with ferric gluconate. The least dialysable free iron was observed with ferumoxytol and the most with ferric gluconate. Incubation of intravenous iron preparations in rat or pooled human sera demonstrated minimal free iron release with ferumoxytol. The order of catalytic iron release as detected by the bleomycin detectable iron assay was as follows: ferumoxytol < iron dextran < iron sucrose < ferric gluconate. A similar trend was observed for the in vivo serum concentration of free iron in rats. CONCLUSIONS: In vitro observations from these experiments suggest that ferumoxytol has a favourable profile in terms of tendency to release free iron, in comparison with currently available intravenous iron preparations.

Anemia: an early complication of chronic renal insufficiency.

The strong association between anemia and cardiovascular complications among patients with end-stage renal disease suggests that anemia during chronic renal insufficiency (CRI) may also have important consequences. We performed a retrospective cohort study to identify factors associated with severe anemia (hematocrit [Hct] < 30%) and examine anemia management practices in CRI. The CRI cohort was composed of 604 adult patients with elevated serum creatinine levels. There was a direct correlation between predicted glomerular filtration rate and Hct (r = 0.49) and an inverse correlation between serum creatinine level and Hct (r = -0.37). Anemia was noted early in CRI; 45% of patients with serum creatinine levels of 2 mg/dL or less had an Hct less than 36%, and 8% had an Hct less than 30%. During the course of the study, mean Hct decreased from 35.1% +/- 5.6% to 31.8% +/- 5.6%. Iron studies were obtained in only 19% of patients, and among these, the prevalence of iron deficiency (transferrin saturation < 20%) was 54%. Only 30% and 26% of patients were administered recombinant human erythropoietin (rHuEPO) and iron, respectively. Multivariate analyses showed that diabetes as the cause of renal disease, greater serum creatinine level, and having a single nephrology visit were associated with greater odds for the presence of anemia. A lower Hct and having a single nephrology visit were associated with greater odds for rHuEPO use. These results show that anemia begins early in the course of CRI, and management of anemia is suboptimal, even among patients under the care of nephrologists. Educational programs to optimize anemia management among patients with CRI are needed.

Intraperitoneal administration of recombinant human growth hormone in children with end-stage renal disease.

Recombinant human growth hormone (GH) therapy has been shown to be effective in the treatment of growth failure related to growth hormone resistance among children with chronic renal failure. The traditional route of administration is subcutaneous injection. This study was designed to evaluate the effectiveness and tolerability of intraperitoneal (i.p.) administration of GH in prepubertal peritoneal dialysis patients. Nine subjects were enrolled. Eight completed 24 months of therapy with GH. Baseline height standard deviation scores (SDS) and growth velocity for the prior year were used for comparison. Peak serum GH was achieved 4 h after administration and serum half-life was 4.6 h. Mean height SDS was -3.1 at baseline, -2.5 at 1 year, and -2.3 at 2 years (NS) of GH therapy. Mean height velocity increased from a baseline of 4.6 cm/yr to 8.5 cm/yr in year 1 (P < 0.05) and 6.1 cm/yr in year 2 (NS) of i.p. GH therapy. Peritonitis infection rates were not increased from overall center rates. This research suggests that the intraperitoneal route of administration of GH can be utilized in the treatment of short stature among children requiring maintenance peritoneal dialysis therapy.

Anemia management in patients with chronic renal insufficiency.

The introduction of recombinant human erythropoietin (rHuEPO) more than a decade ago provided the first effective treatment for the anemia of chronic renal insufficiency (CRI). The use of rHuEPO in the treatment of anemia has been associated with partial regression of left ventricular hypertrophy among both dialysis and nondialysis patients, and has been shown to reduce the frequency of cardiac complications such as congestive heart failure and number of days of hospitalization among dialysis patients. Despite this evidence, the anemia of CRI remains highly prevalent, underrecognized, and undertreated. A number of considerations arise regarding the management of anemia among patients with CRI. In this article, we review the rationale for treatment of anemia, current management practices, proposed treatment strategies, and the economic implications of improved anemia treatment.

Level of renal function at the initiation of dialysis in the U.S. end-stage renal disease population.

UNLABELLED: Level of renal function at the initiation of dialysis in the U.S. end-stage renal disease population. BACKGROUND: More than 285,000 individuals in the United States suffer from end-stage renal disease (ESRD) and are treated predominantly by dialysis. Despite the high cost and poor outcomes of dialysis treatment for ESRD, there are few data about the level of renal function at the onset of ESRD and no established medical criteria for the initiation of dialysis. METHODS: We report the level of serum creatinine and glomerular filtration rate (GFR) in 90,897 patients who began dialysis in the U. S. between April 1995 through September 1997. Data were obtained from the U.S. Renal Data System. GFR was predicted by an equation developed from the Modification of Diet in Renal Disease Study. RESULTS: The mean (SD) serum creatinine was 8.5 (3.8) mg/dl. The mean (SD) predicted GFR was 7.1 (3.1) ml/min/1.73 m2, with a range from 1 to 42 ml/min/1.73 m2. The proportion of patients with predicted GFR of > 10, 5 to 10, and <5 ml/min/1.73 m2 was 14, 63, and 23%, respectively. The mean predicted GFR was significantly lower among younger patients, women, African Americans, patients with a higher body weight, patients with ESRD because of diseases other than diabetes, uninsured patients, patients who were employed, homemakers or students, and patients selecting hemodialysis. CONCLUSIONS: There is wide variation in renal function at the initiation of dialysis in the U.S. ESRD population, and a substantial fraction of patients start dialysis at very low levels of predicted GFR. Further analyses are needed to examine the factors associated with late initiation of dialysis and its impact on the cost and outcomes of ESRD.

Acute renal failure after cardiopulmonary bypass in related to decreased serum ferritin levels.

Acute renal failure (ARF) requiring dialysis occurs in up to 4% of patients after cardiopulmonary bypass (CPB). CPB leads to the generation of intravascular free hemoglobin, resulting in increased endothelial and renal tubular cell free iron, which is associated with renal injury. Conversely, renoprotection is conferred by processes that upregulate heme and iron sequestration pathways, such as ferritin. This study evaluates the influence of free hemoglobin generation during CPB and the capacity to sequester free iron on the occurrence of post-CPB renal insufficiency. Thirty consecutive patients undergoing CPB were enrolled in the study. Serum creatinine, free hemoglobin, and ferritin were measured preoperatively, at the end of bypass, and 24 and 48 h after surgery. Renal injury, as determined by an increase in the serum creatinine of > or =25% (ARF) by 48 h after surgery, occurred in 40% (12 of 30) of patients, and dialysis was necessary in 6.6% (2 of 30). Free hemoglobin levels increased in all patients but did not correlate with postoperative ARF. However, patients with preoperative serum ferritin levels < or =130 microg/L, the median value for the group, had a sixfold greater likelihood of developing ARF compared to patients with levels above this value (P = 0.03). Lower serum ferritin levels appear to be associated with the development of ARF. Serum ferritin levels may signify intravascular as well as endothelial and renal epithelial cell ability to bind free iron generated during CPB-induced hemolysis, and thus may help provide information regarding the risk for ARF.

Intraperitoneal erythropoietin in children on peritoneal dialysis: A study of pharmacokinetics and efficacy.

The pharmacokinetics and efficacy of intraperitoneal (IP) recombinant human erythropoietin (rHuEPO) were investigated in children undergoing chronic peritoneal dialysis. Eight children were administered a single dose of 100 U/kg of rHuEPO IP with 50 mL of dialysate into a dry peritoneal cavity after nighttime peritoneal dialysis. Serum erythropoietin (EPO) levels were measured at 0, 8, 12, and 24 hours. A mean peak EPO level of 187 mU/mL was obtained at 12 hours. The area under the curve was 5,818 mU/h/mL, and relative bioavailability was similar to that found using subcutaneous (SC) dosing. Nine children completed 11 to 12 weeks of IP rHuEPO therapy. The patients maintained a normal hematocrit (34% +/- 2.3%) with a mean final IP rHuEPO dosage that was not significantly greater than the mean previous SC dosage (IP, 290 +/- 194 U/kg/wk; SC, 279 +/- 126 U/kg/wk; P = not significant). There appeared to be a trend for a slightly increased risk for peritonitis compared with historical controls at our center (relative risk = 3.1; 95% confidence interval, 0.92 to 6.3). IP rHuEPO is effective in children undergoing continuous cycling peritoneal dialysis without requiring increased rHuEPO dosages, but the possibility of an increased risk for peritonitis will need to be further explored.

Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients.

Aluminum accumulation in plasma and tissues is a well-described complication among persons undergoing peritoneal dialysis or hemodialysis. Excess bone aluminum is associated with low bone formation rates and increased risk for fractures. Current recommendations for care of patients with end-stage renal disease include screening for aluminum toxicity with plasma aluminum levels; patients with levels below 40 microg/L are considered to be at low risk for aluminum bone disease (ABD). We examined data from the Toronto Renal Osteodystrophy Study to evaluate the performance of plasma aluminum levels in screening for ABD. Two hundred fifty-eight unselected patients undergoing peritoneal dialysis (n = 143) or hemodialysis (n = 115) underwent diagnostic bone biopsy and measurement of plasma aluminum level. Sixty-nine patients (26.7%) were identified as having ABD, defined as low or normal bone formation rates with 25% or more bone surface aluminum staining. Plasma aluminum level was strongly associated with the presence of ABD; the odds ratio was 1.4 for each increase of 10 microg/L (95%CI, 1.2, 1.6). However, only 50.1% of patients with a plasma aluminum level of 40 microg/L or greater had ABD, whereas 14.2% of patients with a level below this threshold also had ABD. Using this cutoff level of 40 microg/L, the sensitivity and specificity were 65.2% and 76.7%, respectively. We conclude that although there is a correlation between high aluminum levels and ABD, a patient's plasma aluminum level does not predict well the presence of ABD in spite of a relatively high prevalence of disease.

Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States.

Despite improvements in dialysis care, the mortality of patients with end-stage renal disease (ESRD) in the United States remains high. Factors that thus far have received scant attention, but could significantly affect morbidity and mortality in dialysis patients, are the timing and quality of care before the initiation of dialysis (pre-ESRD). Data from the new version of the Health Care Financing Administration (HCFA) 2728 Form were used to examine the prevalence of and factors associated with hypoalbuminemia, severe anemia, and erythropoietin (EPO) use among 155,076 incident chronic dialysis patients in the United States between April 1, 1995 and June 30, 1997. At initiation of dialysis, the median serum albumin and hematocrit were 3.3 g/dl and 28%, respectively. Sixty percent of patients had a serum albumin below the lower limit of normal and 51% had a hematocrit <28%. Overall, only 23% had received EPO pre-ESRD. Among patients with hematocrit <28%, only 20% were receiving EPO, compared to 27% among patients with hematocrit > or =28%. In a multivariate analysis that adjusted for diabetes, functional status, and demographic, socioeconomic, and geographic factors, the odds ratios for hypoalbuminemia, hematocrit <28%, and lack of EPO use were higher for African-Americans, patients with non-private insurance or no insurance, and patients who were started on hemodialysis. There were also significant differences in odds ratios for these outcomes between different geographic regions in the United States. The high prevalence of pre-ESRD hypoalbuminemia, hematocrit <28%, and lack of EPO use suggests that the quality of pre-ESRD care in the United States is suboptimal. Improvement in pre-ESRD care could potentially improve outcomes among ESRD patients.

Prevalence, predictors, and consequences of late nephrology referral at a tertiary care center.

Despite improvements in dialysis care, mortality of patients with end-stage renal disease (ESRD) remains high. One factor that has thus far received little attention, but might contribute to morbidity and mortality, is the timing of referral to the nephrologist. This study examines the hypothesis that late referral of patients to the nephrologist might lead to suboptimal pre-ESRD care. Clinical and laboratory data were obtained from the patient records and electronic databases of New England Medical Center, its affiliated dialysis unit (Dialysis Clinics, Inc., Boston), and the office records of the outpatient nephrology clinic. Early (ER) and late (LR) referral were defined by the time of first nephrology encounter greater than or less than 4 mo, respectively, before initiation of dialysis. Multivariate models were built to explore factors associated with LR, and whether LR is associated with hypoalbuminemia or late initiation of dialysis. Of the 135 patients, 30 (22%) were referred late. There were no differences in age, gender, race, and cause of ESRD between ER and LR patients. However, there were significant differences in insurance coverage between these two groups. In the multivariate analysis, patients covered by health maintenance organizations were more likely to be referred late (odds ratio = 4.5) than patients covered by Medicare. Compared to ER, LR patients were more likely to have hypoalbuminemia (56% versus 80%), hematocrit <28% (33% versus 55%), and predicted GFR <5 ml/min per 1.73 m2 (17% versus 40%) at the start of dialysis, and less likely to have received erythropoietin (40% versus 17%) or have a functioning permanent vascular access for the first hemodialysis (40% versus 4%). It is concluded that late referral to the nephrologist is common in the United States and is associated with poor pre-ESRD care. Pre-ESRD care of patients treated by nephrologists was also less than ideal. The patient-, physician-, and system-related factors behind this observation are unclear. Meanwhile, pre-ESRD educational efforts need to target patients, generalists, and nephrologists.

Pre-end-stage renal disease care in the United States: a state of disrepair.

Patients with end-stage renal disease (ESRD) experience significant morbidity and mortality. Despite improvements in mortality rates, the life expectancies for dialysis patients are still between 16 and 37% of the age-, gender-, and race-matched U.S. population. One of the factors that thus far has received scant attention, but could significantly contribute to morbidity and mortality among ESRD patients, is the timing and quality of care before initiation of dialysis (pre-ESRD care). Pre-ESRD care involves early detection of progressive renal disease, interventions to retard its progression, prevention of uremic complications, attenuation of comorbid conditions, adequate preparation for renal replacement therapy (RRT), and timely initiation of dialysis. Despite the benefits of pre-ESRD care, recent studies suggest that the quality of pre-ESRD care in the United States is suboptimal. However, indices of quality of pre-ESRD care have been neither clearly defined nor validated. Furthermore, few estimates of the size of the pre-ESRD population are available. This review examines the prevalence of several factors that could reasonably be used to define suboptimal pre-ESRD care, including failure of early detection of renal disease, paucity of interventions to slow its progression, predialysis hypoalbuminemia and severe anemia, suboptimal pre-ESRD education and uninformed choice of modality of RRT, delayed placement of a permanent vascular access, and delayed initiation of RRT. Although the data presented strongly suggest that the quality of pre-ESRD care in the United States is suboptimal, further research is needed for a better definition and validation of indices of quality pre-ESRD care, a more accurate estimate of the size of the pre-ESRD population, examination of the causes of suboptimal pre-ESRD care, and identification of populations at risk for suboptimal pre-ESRD care. This understanding would facilitate development of strategies to improve pre-ESRD care and, eventually, outcomes among patients on RRT.

The hyaluronate-binding site from the plasma membrane is distinct from the binding protein present in brain.

To determine whether the hyaluronate-binding protein from brain is similar or identical to the hyaluronate-binding site from the cell surface, the two molecules were compared with respect to their physical and binding properties. The hyaluronate-binding protein was purified from mouse brains by lectin-affinity chromatography, and then analyzed by molecular-sieve chromatography and rate-zonal centrifugation, which showed that it has a Stokes radius of 6.3 nm, and a sedimentation coefficient of 4.8 S. These values are remarkably close to those obtained previously for the membrane-associated binding site (a = 6.5 nm, s20,w = 4.8 S), indicating that the two molecules have similar shapes and sizes. Binding studies of the semi-purified proteins showed that the dissociation constant for the brain derived binding protein (Kd = 270 ng/0.5 ml) was similar to that of the cell-surface binding site (Kd = 350 ng/0.5 ml). However, when the two molecules were compared with respect to oligosaccharide inhibition of binding, significant differences were observed. The hexasaccharide significantly inhibited the binding of [3H] hyaluronate to the cell-surface binding site but had only a small effect on the binding to the brain derived protein. Differences were also found between the two molecules with respect to the effects of a monoclonal antibody (K-3). This antibody blocked most of the binding activity of the membrane-associated binding site, but had no effect on the protein from brain. Taken together, these results indicate that although the hyaluronate-binding protein derived from brain and the cell-surface binding site are physically similar, they are distinct proteins.