Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management.

Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empirical measures which neglect the fact that the majority of IV-iron reactions are not IgE-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV-iron reactions represent complement activation-related pseudo-allergy (CARPA), at least in part. The review compares the features of IV-iron reactions to those of immune and non-immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV-iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV-iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high-risk IV-iron patients.

The new FDA label for erythropoietin treatment: how does it affect hemoglobin target?

The erythropoietin analogs have been an important advance for the treatment of the anemia of kidney disease, resulting in reduced need for blood transfusion and improved quality of life. Recent studies, however, have indicated risks associated with targeting higher levels of hemoglobin (Hb). As a result, in March 2007, the US Food and Drug Administration (FDA) substantially changed prescribing information for these drugs to alert clinicians to these risks. In this review, we consider the recent literature, the change in FDA warnings, and new National Kidney Foundation Anemia Guidelines. Suggestions for new Hb targets during erythropoiesis-stimulating agent treatment are presented.

Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

INTRODUCTION: Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. METHODS: HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of < or = 33% were enrolled. Subjects were divided as follows: Group 1: target SFer of 200 ng/ml, Group 2: target SFer of 400 ng/ml. Each subject below the target level received IVFe in up to 10 divided doses during consecutive dialysis sessions as needed to reach the target. HCT was maintained between 32.5% and 36% by adjusting rHuEPO dosage. RESULTS: Mean SFer concentration at the study conclusion in Group 1: 261 ng/ml; Group 2: 387 ng/ml. The mean decrease in rHuEPO dose for Group 1 was 31 U/kg body weight/week (250 - 219 U/kg bw/wk) while in Group 2 it was 154 U/kg body weight/week (312 - 158 U/kg bw/wk) (p < 0.001). There was no difference in HCT between groups. Our results suggest that higher target serum ferritin concentrations can be well tolerated and lower rHuEPO requirements.

A randomized trial of iron deficiency testing strategies in hemodialysis patients.

BACKGROUND: Diagnosis of iron deficiency in hemodialysis patients is limited by the inaccuracy of commonly used tests. Reticulocyte hemoglobin content (CHr) is a test that has shown promise for improved diagnosis in preliminary studies. The purpose of this study was to compare iron management guided by serum ferritin and transferrin saturation to management guided by CHr. METHODS: A total of 157 hemodialysis patients from three centers were randomized to iron management based on (group 1) serum ferritin and transferrin saturation, or (group 2) CHr. Patients were followed for six months. Treatment with intravenous iron dextran, 100 mg for 10 consecutive treatments was initiated if (group 1) serum ferritin <100 ng/mL or transferrin saturation <20%, or (group 2) CHr <29 pg. RESULTS: There was no significant difference between groups in the final mean hematocrit or epoetin dose. The mean weekly dose of iron dextran was 47.7 +/- 35.5 mg in group 1 compared to 22.9 +/- 20.5 mg in group 2 (P = 0.02). The final mean serum ferritin was 399.5 +/- 247.6 ng/mL in group 1 compared to 304.7 +/- 290.6 ng/mL in group 2 (P < 0.05). There was no significant difference in final TSAT or CHr. Coefficient of variation was significantly lower for CHr than serum ferritin and transferrin saturation (3.4% vs. 43.6% and 39.5%, respectively). CONCLUSIONS: CHr is a markedly more stable analyte than serum ferritin or transferrin saturation, and iron management based on CHr results in similar hematocrit and epoetin dosing while significantly reducing IV iron exposure.

Prostaglandin D(2) synthase induces apoptosis in pig kidney LLC-PK1 cells.

BACKGROUND: Prostaglandin D(2) synthase (PGD(2)S), a unique member of the lipocalin family, is found at elevated levels in the serum of patients with renal impairment and has recently been implicated as a new biochemical marker of renal insufficiency. The aim of this study was to investigate the apoptotic effects of PGD2S on a pig kidney epithelial cell line (LLC-PK1) and to investigate the effects of prostaglandins and growth factors on this process. METHODS: Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL), annexin V staining, and electron microscopy. RESULTS: A four- to fivefold increase in apoptosis was observed in PGD(2)S-treated cells as compared with controls and the apoptosis appeared to act via caspase-3. A cyclooxygenase-2 inhibitor, anti-PGD(2)S antibody, and selenium all significantly inhibited the apoptosis induced by PGD(2)S; however, none had any effect on the apoptosis induced by the known apoptotic inducer camptothecin. Furthermore, prostaglandins E(1) and E(2), known to induce mitogen-activated protein (MAP) kinase phosphorylation and exhibit cytoprotective effects, both inhibited PGD(2)S-induced apoptosis, while prostaglandin H(2) had no significant effect. Growth factors such as insulin, insulin-like growth factor-1, and platelet-derived growth factor also decreased PGD(2)S-induced apoptosis. In addition, PGD(2)S isolated from human serum seemed slightly more effective at inducing apoptosis than recombinantly expressed protein. CONCLUSIONS: We report on the induction of apoptosis by PGD(2)S in LLC-PK1 pig kidney epithelial cells, and speculate that the accumulation of PGD(2)S in the serum of kidney failure patients may further exacerbate renal problems and is most likely regulated by other prostaglandins and growth factors.

Prostaglandin D2 synthase induces apoptosis in PC12 neuronal cells.

Apoptosis of neuronal cells is a proposed cause of certain neurological disorders. Here, we report on a 5- to 6-fold increase in apoptosis by exposure to prostaglandin D2 synthase (PGD2S) in PC12 neuronal cells. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and appears to be mediated via caspase-3 activation. Neutralization with anti-PGD2S antibody or pre-treatment with selenium, which inhibits PGD2S enzymatic activity, both significantly inhibited the PGD2S-induced apoptosis, however, neither had any effect on the apoptosis induced by the known neuronal apoptotic inducer, glutamate. In addition, prostaglandins E1, E2, and F2alpha all inhibited the PGD2S-induced apoptosis while prostaglandin H2 had no significant effect. Furthermore, PGD2S isolated from human serum was more effective at inducing apoptosis then recombinantly expressed protein, presumably due to glycosylation. This novel role of PGD2S, as an inducer of apoptosis, may have implications in PC12 differentiation and possibly some neurological disorders.

Self-assessed quality of life in peritoneal dialysis patients.

BACKGROUND/AIMS: Studies comparing quality of life (QOL) between peritoneal and hemodialysis patients have yielded inconsistent results. Physical (PCS) and mental component summary (MCS) scales of Short Form 36 (SF-36) health survey are highly validated measures of self-assessed QOL. We sought to evaluate these indices in PD patients: (1) as measures of QOL, (2) predictors of QOL, (3) to study change in QOL over time, and (4) to compare QOL in PD vs. hemodialysis patients. METHODS: SF-36 questionnaires were administered every 3 months to patients over a 2-year period and PCS and MCS were calculated. Mean follow-up was 15.3 +/- 6.6 months for PD and 14.5 +/- 5.7 months for HD. RESULTS: Average PCS in PD (31.8 +/- 7.8) was lower than HD (36.9 +/- 9.8) (p < 0.02), while MCS was similar in the groups (p = NS). The prevalence of depression was 26.1% in PD and 25.4% in HD patients (p = NS). Serum albumin was the only significant predictor of PCS among PD patients and explained much of the decrease in PCS in them. The number of hospitalizations and in-hospital days were significantly lower for PD compared to HD patients (p < 0.05). PCS as well as MCS remained stable in both groups throughout the observation period. CONCLUSION: Self-assessed physical function is diminished, while mental function is similar in PD compared to HD patients. When corrected for serum albumin, this difference is eliminated. Over time, QOL in patients treated with PD remained stable.

Self-assessed physical and mental function of haemodialysis patients.

BACKGROUND: Physical (PCS) and mental (MCS) component summary scales of the Short Form 36 (SF-36) health survey are validated measures of quality of life (QOL) and functional status. We sought to evaluate the PCS and MCS in haemodialyis patients as compared to the general population and other chronic diseases. METHODS: A cohort of 134 haemodialysis patients (mean age 60.9+/-14.3 years, males 63.4%, Caucasians 66.4%) was followed from January 1996 to December 1998 (mean follow up 14.5+/-5.7 months). SF-36 questionnaires were administered every 3 months and PCS and MCS were calculated. Results were compared to the general population and other chronic diseases. Correlators of PCS and MCS, change in QOL over time, and the correlators of this change were determined. RESULTS: Mean PCS was 36.9+/-8.8 and mean MCS was 47+/-10.7. Compared to the general US population, these represent a decline of 8.7+/-0.8 for PCS (P<0.0001) and 2.7+/-0.8 for MCS (P<0.001). PCS and MCS in end-stage renal disease (ESRD) were lower than in most other chronic diseases studied. Univariate correlators of PCS in haemodialysis patients included age, male sex, haematocrit, serum albumin, and severity of comorbid cardiac and pulmonary illnesses. Multivariate analysis demonstrated independent correlators of PCS to be male sex, serum albumin and severity of comorbid cardiac and pulmonary diseases. Univariate as well as multivariate correlators of MCS included: serum albumin, KT/V(urea), and status living alone. A trend analysis revealed that both PCS and MCS tended to decline in the initial months of dialysis but stabilized over time. Status living alone was a significant predictor of improvement in MCS by univariate as well as multivariate analysis. CONCLUSIONS: Self assessed physical and mental health of haemodialysis patients is markedly diminished compared to the general population and other chronic diseases.

Sodium ferric gluconate complex in the treatment of iron deficiency for patients on dialysis.

Intravenous iron has been found to be an important adjunctive therapy in the treatment of anemia for patients on dialysis. In the United States, iron dextran had been the only form available for parenteral use until 1999. This agent has been associated with a concerning number of severe adverse reactions, in some cases resulting in patients' deaths. Recently, a form of iron used for many years in Europe, sodium ferric gluconate complex in sucrose, was approved for intravenous use in the United STATES: Because this agent does not contain the immunogenic dextran component of iron dextran, it is expected that the safety profile of this drug should be superior to that of iron dextran. The purpose of this review is to critically appraise the relevant literature and to synthesize the information into a strategy for clinical use of this drug.

The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate.

Intravenous iron treatment is an important component of anemia therapy for patients on dialysis. Until recently iron dextran was the only parenteral form of iron available in the United States. This drug has been associated with occasional serious adverse reactions, including full-blown anaphylaxis. In 1999 the Food and Drug Administration approved a second form of iron for intravenous administration, sodium ferric gluconate in sucrose. It is expected that by the time of this publication, a third agent, iron saccharate will also be approved. In this review the comparative safety of these three agents is critically evaluated.

Research directions: new clinical frontiers.

One of the greatest remaining challenges facing nephrology research is obtaining data with detail and precision for the three large, yet "forgotten," populations that span the spectrum of kidney disease: patients with chronic renal insufficiency (CRI), peritoneal dialysis patients, and kidney transplant patients. Studies of these populations, particularly the CRI group, are hampered by the relative mobility of these patients, the lack of stringent epidemiologic or clinical definitions, and the tendency to extrapolate data from hemodialysis populations into other clinical settings. This article suggests a two-pronged approach to a research agenda: first, by recognizing the need for better data regarding the natural history of these kidney failure subsets and their comorbidities; and second, by directing greater effort at identifying rational, efficacious, and cost-effective interventions to influence their natural history positively. Specific efforts are suggested in all three populations. For patients with CRI, studies should be directed at (1) identifying high-risk patients; (2) determining methods for making optimal referrals to the nephrologist; (3) identifying and managing CRI, its complications, and its comorbid conditions; and (4) establishing processes for the smooth transition to dialysis. The peritoneal dialysis population will benefit from studies addressing the treatment of anemia and its ability to modify cardiovascular illness and quality of life. Kidney transplant studies should also focus on the identification and management of comorbid conditions, as well as the effects of various interventions on quality of life. Rational evidence-based care of these conditions, which are critically important to patients, their families, and the health care system in general, must await the conduct of well-designed prospective observational and interventional trials.

Review of issues relating to iron and infection.

Use of erythropoietin (EPO) therapy and iron supplementation has improved the management of anemia in patients with end-stage renal disease (ESRD). As more patients receive supplemental iron, however, concerns are being raised about a potential link between iron and infection. There is biologic plausibility for this link, since iron is a growth factor for bacteria and certain host defense mechanisms are iron-sensitive. Animal models show that injection of iron leads to increased susceptibility to bacterial infection. In some studies, patients with high serum ferritin levels have reduced neutrophil function. However, these studies did not determine whether serum ferritin levels were elevated because of increased iron stores or because of infection. If infection is present, it might cause both the elevated serum ferritin levels and the neutrophil dysfunction. Several clinical studies have found an association between high serum ferritin levels and increased infectious risk. In studies that control for important covariates such as use of catheters and previous infections, the infectious risk associated with iron administration or elevated serum ferritin levels is reduced or eliminated. Collectively, these studies suggest that our current understanding of the relationship between iron and infection is incomplete and further studies are needed. There is no reason to alter current iron treatment strategies based on this literature.

Cerebral salt-wasting syndrome: does it exist?

Cerebral salt-wasting syndrome (CSWS) has been regarded as a misnomer of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We take the position that CSWS does exist and might be more common than SIADH. Differentiation between groups has been difficult because of overlapping signs, symptoms, and associated diseases. Euvolemia in SIADH and hypovolemia in CSWS may be the only contrasting variables. However, clinical assessment of extracellular volume is accurate in about 50% of these patients. Determination of serum urate and fractional excretion rates of urate can differentiate one group from the other. In both groups, hyponatremia coexists with hypouricemia and increased fractional excretion of urate. When the hyponatremia is corrected by water restriction, hypouricemia and elevated FEurate correct in SIADH but persist in CSWS. Persistent hypouricemia and elevated FEurate were commonly noted with pulmonary and/or intracranial diseases. The absence of intracranial diseases in some patients suggests that renal salt wasting might be a more appropriate term than CSWS. A review of renal/CSWS reveals three studies involving hyponatremic neurosurgical patients who had decreased blood volume, decreased central venous pressure, and inappropriately high urinary sodium concentrations in the majority of them, suggesting that CSWS was more common than SIADH in neurosurgical patients. Evidence for the presence of a plasma natriuretic factor in CSWS is presented.

Bone histology in patients with nephrotic syndrome and normal renal function.

BACKGROUND: The prevalence of metabolic bone disease in patients with nephrotic syndrome (NS) at normal level of renal function remains uncertain. METHODS: To address this issue, we studied 30 patients (20 men and 10 women, mean age 27.3 +/- 11.7 years) with NS who had normal renal function (mean creatinine clearance 103 +/- 4 ml/min). We evaluated their serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), vitamin D metabolites, urinary calcium, and skeletal survey. The extent of bone mineralization was analyzed by histomorphometric analysis of iliac crest bone biopsy specimens in all patients. The findings on bone histology were correlated with biochemical parameters. RESULTS: The mean duration of NS was 35.5 +/- 26.9 months, with a protein excretion of 7.3 +/- 3.2 g/24 hr and a serum albumin of 2.2 +/- 0.8 g/dl. Total serum calcium was 7.8 +/- 0.8 mg/dl, whereas ionized calcium was 5.7 +/- 0.7 mg/dl, phosphorus 3.2 +/- 1.2 mg/dl, and alkaline phosphatase 149 +/- 48.6 U/liter. Serum iPTH levels were normal in all except two patients. The mean serum 25-hydroxyvitamin D [25(OH)D] level was 3.9 +/- 1.2 ng/ml (normal 15 to 30 ng/ml), whereas 1,25-dihydroxyvitamin D was 24 +/- 4.7 pg/ml (normal 16 to 65). There was an inverse correlation between serum levels of 25(OH)D and the magnitude of proteinuria (r = -0.42, P < 0.05). The mean 24-hour urinary calcium excretion was 82 +/- 21 mg/day. The skeletal survey was normal in all patients. Bone histology was normal in 33.3% of the patients, whereas 56.7% had isolated osteomalacia (OSM), and 10% had an increased bone resorption in association with defective mineralization. The severity of OSM measured by mineralization lag time correlated linearly with the duration (r = 0.94, P < 0.0001) and the amount (r = 0.97, P < 0.0001) of proteinuria. All patients with NS for more than three years had histological changes. Patients with OSM had lower 25(OH)D and serum albumin as compared with those with normal histology (P < 0.005). Bone mineralization had no significant correlation with serum iPTH, divalent ions, or vitamin D levels. CONCLUSIONS: OSM is a frequent finding in adult patients with NS, even at a normal level of renal function. Its severity correlates with the amount and duration of proteinuria.

Partial characterization of apoptotic factor in Alzheimer plasma.

We have previously demonstrated that a plasma natriuretic factor is present in Alzheimer's disease (AD), but not in multi-infarct dementia (MID) or normal controls (C). We postulated that the natriuretic factor might induce the increased cytosolic calcium reported in AD by inhibiting the sodium-calcium antiporter, thereby activating the apoptotic pathway. To test for a factor in AD plasma that induces apoptosis, we exposed nonconfluent cultured LLC-PK1 cells to plasma from AD, MID, and C for 2 h and performed a terminal transferase-dUTP-nick-end labeling (TUNEL) assay. The plasma from AD increased apoptosis nearly fourfold compared with MID and C. The effect was dose dependent and the peak effect was attained after a 2-h exposure. Additionally, apoptotic morphology was detected by electron microscopy, and internucleosomal DNA cleavage was found. We inhibited apoptosis by removing calcium from the medium, inhibiting protein synthesis with cycloheximide, alternately boiling or freezing and thawing the plasma, and digesting a partially purified fraction with trypsin. Heating AD plasma to 56 degrees C did not deactivate the apoptotic factor. These results demonstrate the presence of an apoptotic factor in the plasma of patients with AD.