The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

Prophylactic Ureteric Stents in Renal Transplant Recipients: A Multicenter Randomized Controlled Trial of Early Versus Late Removal.

Prophylactic ureteric stenting in renal transplantation reduces major urological complications; however, morbidity is related to the indwelling duration of a stent. We aimed to determine the optimal duration for stents in this clinical setting. Patients (aged 2-75 years) from six UK hospitals who were undergoing renal transplantation were recruited and randomly assigned to either early stent removal at 5 days (without cystoscopy) or late removal at 6 weeks after transplantation (with cystoscopy). The primary outcome was a composite of stent-related complications defined as pain, visible hematuria, migration, fragmentation, and urinary tract infections (UTIs) within 3 mo of transplantation. Between May 2010 and Nov 2013, we randomly assigned 227 participants, with 205 included in the final analysis of the primary outcome. Stent-related complications were significantly higher in the late versus early stent removal groups (36 of 126 [28.6%] vs. 6 of 79 [7.6%]; p < 0.001). The majority of stent complications consisted of UTIs, with an incidence of 31 of 126 (24.6%) in the late group compared with 6 of 79 (7.6%) in the early group (p = 0.004). We found early stent removal on day 5 significantly reduced stent-related complications and improved quality of life in the first 3 mo after transplantation (ISRCTN09184595).

Iron metabolism, hepcidin, and anemia in orthotopic heart transplantation recipients treated with mammalian target of rapamycin.

PURPOSE: Functional iron deficiency is characterized by the presence of adequate stores as defined by conventional criteria, but with the inability to sufficiently mobilize iron for erythropoiesis. Hepcidin, produced by hepatocytes in response to anemia, hypoxia, or inflammation, is a key regulator of iron homeostasis. Anemia is relatively common among patients treated with mammalian target of rapamycin (mTOR) antagonists. We tested hypothesis that hepcidin was related to the functional iron deficiency, defined as a ferritin value above 200 ng/mL with transform saturation (TSAT) below 20% among orthotopic heart transplant recipients (OHT) treated (n = 35) versus not treated (n = 134) with mTOR. METHODS AND MATERIALS: Using standard laboratory methods we assessed iron status: serum iron, total iron binding capacity, ferritin, TSAT, complete blood count and creatinine. Soluble transferrin receptor (sTFR), high sensitivity C-reactive protein (hSCRP), interleukin-6 (IL-6) hepcidin, and cystatin C were measured using commercially available kits. RESULTS: According to the World Health Organization definition, the prevalence of anemia was 51% among mTOR treated whereas in the rest of the OHT the prevalence of anemia 30% among the other OHT patients. Functional iron deficiency was present in 80% of mTOR-treated patients. Serum hepcidin, IL-6, hsCRP, serum creatinine, cystatin C, NT-proBNP were significantly higher among mTOR treated patients; whereas sTFR, estimated glomerular filtration rate, hemoglobin, and erythrocyte count were significantly lower. CONCLUSIONS: Functional iron deficiency which is common among OHT patients treated with mTOR, was associated with high hepcidin levels and inflammatory markers. This form of anemia in mTOR-treated OHT resembles the disorder of chronic disease, suggesting that OHT patients show low-grade inflammation, which should be investigated for underlying, potentially reversible causes. Iron treatment should also be considered.

Hemojuvelin and iron metabolism in kidney and heart allograft recipients.

INTRODUCTION: Hemojuvelin plays an essential role in the regulation of hepcidin expression, specifically in the iron-sensing pathway. Dietary iron sensing and inflammatory pathways converge in the regulation of the key regulator hepcidin. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. We studied correlations of hemojuvelin with markers of iron status and of inflammation among 61 prevalent kidney allograft recipients and 136 prevalent heart transplant recipients. METHODS: Complete blood count, urea, serum lipids, fasting glucose, and creatinine were measured using standard laboratory methods in the central laboratory of the hospital. Hepcidin, soluble transferin receptor (sTFR), interleukin-6 (IL-6) and hemojuvelin were assayed by enzyme immunosorbent assay using commercially available kits. RESULTS: Among heart transplant recipients hemojuvelin correlated strongly with kidney function, transferrin saturation and white blood cell count; moderately with red blood cell count, hepcidin, IL-6, high-sensitivity C-reactive protein (hsCRP) and weakly with sTfR. Multiple regression analysis revealed the predictors of hemojuvelin to be kidney function and TSAT, explaining 79% of the variations among hemojuvelin values in heart transplant recipients. Among kidney transplant recipients hemojuvelin correlated with kidney function, TSAT, hepcidin and hsCRP, and tended to correlate with IL-6. Predictors of hemojuvelin on multiple regression analysis were TSAT and creatinine. CONCLUSIONS: Elevated hemojuvelin as well as hepcidin levels in kidney or heart transplant recipients may be due to the impaired kidney function and disturbed iron status frequently encountered among this population.

Intercurrent events and comorbid conditions influence hemoglobin level variability in dialysis patients.

BACKGROUND: To help identify factors contributing to intra-patient Hb variability, pooled records were analyzed from 5,592 patients undergoing hemodialysis (HD) in European, multicenter, open-label, single-arm Phase 3b trials. PATIENTS AND METHODS: Patients previously treated with recombinant human erythropoietin (rHuEPO) were switched to darbepoietin-alpha administered once a week (QW) or once every 2 weeks (Q2W), maintaining the same dosing schedule and route of ESA administration (intravenous or subcutaneous) up to and through the evaluation period. Patients were treated with darbepoietin-alpha to maintain Hb levels between 10 and 13 g/dl. Intrapatient variability was calculated using the SD model, taking all of an individual patient's Hb values during the evaluation period (Weeks 21 - 24 after conversion) and calculating the SD of these Hb values. Adverse events (AE) of infection or inflammation were recorded. RESULTS: Smaller variability was seen for patients 65 years of age or older compared with younger patients (p = 0.0044) and greater variability for patients less than 40 years of age compared with older patients (p < 0.01). Little difference in variability was seen in relation to sex overall or to the presence or absence of diabetes. Intra-patient Hb variability was greater in the presence of intercurrent conditions, including infection or inflammation (p = 0.0032), blood transfusion (p < 0.0001), hospitalization (p < 0.0001), or hospitalization for cardiovascular (CV) causes (p = 0.0012), than in their absence. Iron status differences had little detectable effect on intra-patient Hb variability. A larger number of changes made to the ESA dose during the evaluation period was also associated with greater Hb variability compared with fewer dose changes, but this association could not be proved as being causative. Although p values were calculated for some comparisons, statistical significance might not indicate clinical significance because of the large sample size. Multivariable analysis to assess the association between AE status and intra-patient Hb variability, adjusting for age, sex, diabetes status, number of dose changes and iron status showed that AE status was significantly associated with Hb variability. CONCLUSION: Additional studies would be needed to further investigate causes and effects of Hb variability and intercurrent events.

ORAMA: a study to investigate EBPG impact on renal anaemia - design and baseline data.

BACKGROUND: It is of paramount importance not only to publish anaemia management guidelines for chronic kidney disease (CKD) but also to verify their implementation in clinical practice. The Optimal Renal Anaemia Management Assessment (ORAMA) is the first European study investigating the impact of adherence to the 2004 revised European Best Practice Guidelines (EBPG) and its impact on patient outcomes. METHODS: Participating centres were randomised into 2 groups: group A with, and group B without, access to an EBPG-based computerised clinical decision support (CDS) system after baseline. Patients with stage 2-5 CKD either anaemic (haemoglobin [Hb] <11 g/dL) or treated with erythropoiesis-stimulating agents (ESAs) and/or iron supplementation were enrolled. Primary end points are based on achievement of anaemia-related guideline targets. Here, baseline data are reported descriptively. RESULTS: Fifty-three centres in 8 countries included 739 patients, 81% of whom have received dialysis. Mean baseline Hb was 11.2 g/dL, and 52% of all patients met the EBPG target of >11 g/dL Hb at baseline. However, only 37% of patients had their Hb values >11 g/dL throughout a 3-month prestudy period. Serum ferritin and transferrin saturation were above the guideline target in circa 80% of patients. The vast majority of patients (96%) received ESA therapy at baseline. CONCLUSIONS: In line with findings from previous studies ORAMA baseline data show that achievement of EBPG is suboptimal across European countries. Final results promise an insight into the impact of guideline-based CDS tools on clinical practice and target attainment.

Acute intermittent porphyria and chronic renal failure.

Despite the little known association between renal damage and the acute porphyrias, limited information is available on the characteristics and pathogenesis of renal disease in this patient group. Previous reports have focused on hypertension as the principal etiological factor. We have studied a series of 9 patients with acute intermittent porphyria (AIP) attending the Porphyria Clinic at King's College Hospital, London, UK, who were referred to the Renal Unit for investigation and treatment of their renal disease. No evidence of a glomerular lesion was found in any of the patients. In contrast, renal histology showed features of a tubulointerstitial disease, and there was evidence of impaired erythropoietin production. Hypertension and nonsteroidal antiinflammatory drug use were present in about a half of the patients. It is postulated that the nephrotoxic effects of porphyrin precursors may contribute to the etiology of this clinical syndrome.

The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study.

AIM: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naive patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. METHODS: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 microg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase > 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. RESULTS: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p < 0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p < 0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses > or = 0.30 microg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 microg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. CONCLUSIONS: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 microg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

Hyporesponsiveness to erythropoietic therapy due to chronic inflammation.

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Erythropoietin response to hypoxia in patients with diabetic autonomic neuropathy and non-diabetic chronic renal failure.

AIMS: An erythropoietin (EPO)-deficient anaemia is recognized in Type 1 diabetic patients with early nephropathy and symptomatic autonomic neuropathy (DN). The aim of this study was to determine whether the EPO response to hypoxia was deficient in order to clarify the mechanisms involved in this process. METHODS: Five Type 1 diabetic patients DN (age 39 (28-48) years (mean (range))) with EPO-deficient anaemia (haemoglobin, Hb 10.6 (9.5-12.0) g/dl, EPO 5.0 (3.2-6.5) IU/l) and early diabetic nephropathy (persistent proteinuria 1161.6 (130-2835) mg/day, serum creatinine 97.6 (63-123) micromol/l)) were compared with nine normal subjects (age 31 (24-39) years, Hb 13.4 (11.8-15.7) g/dl, EPO 7.6 (5.6-10.3) IU/l) and four patients with non-diabetic advanced chronic renal failure RF (proteinuria 2157.5 (571-4578) mg/day, serum creatinine 490.2 (406-659) micromol/l, Hb 10.3 (9.0-11.3) g/dl, EPO 4.6 (2.9-8.5) IU/l). The subjects were exposed to 6 h of hypoxia (inspired oxygen 11.6-12.6%) by breathing a gas mixture via a hood. Hourly serum EPO levels were measured. RESULTS: All groups showed a rise in EPO production after 2 h. The diabetic DN group achieved a similar maximal response to the normal subjects at 6 h (EPO 17.3 +/-5.4 vs. 17.8 +/-7.9 IU/l). The renal failure patients mounted an EPO response to hypoxia but at lower EPO levels. CONCLUSIONS: Although the DN patients have inappropriately low EPO levels for the severity of their anaemia, they can mount an appropriate EPO response to moderate hypoxia. The mechanism underlying the EPO-deficient anaemia present in some diabetic patients remains unclear.

Individualizing target haemoglobin concentrations--tailoring treatment for renal anaemia.

Despite the publication of National Kidney Foundation and European Best Practice Guidelines, there is still uncertainty among nephrologists regarding the optimum target haemoglobin (Hb) concentration for patients treated with erythropoietin. For most patients, the target Hb concentration is 11-12 g/dl, resulting in only partial correction of anaemia. However, there is a link between subnormal Hb concentration and the development of cardiovascular disease. Thus, it may be more beneficial to normalize Hb, although this has to be balanced against the concern that full correction of anaemia may result in adverse effects, such as hypertension and progression of renal disease. There is increasing evidence that it may be appropriate to treat each patient individually, and to tailor treatment according to a number of physiological and lifestyle variables, avoiding higher Hb concentrations in certain patient groups (such as those with cardiac problems). This was supported by the results of a survey of nephrologists and specialists in the field of renal anaemia. It was generally agreed that a higher target Hb concentration (12-14 g/dl) might be appropriate for a fit, young patient with no significant co-morbidity, whereas a lower target Hb (10-12 g/dl) might be appropriate for an elderly patient with multiple medical problems. In conclusion, guidelines for target Hb in the US and Europe are probably not applicable to all patients. It is important that renal anaemia patients are considered as individuals, and their treatment tailored accordingly. It is time to establish evidence-based criteria for individualizing renal anaemia treatment.

Intravenous iron sucrose: establishing a safe dose.

It is now recognized that the majority of patients on epoetin therapy require intravenous (IV) iron supplementation to maximize the response to treatment. Of the IV iron preparations available, iron sucrose has proved its efficacy and safety; however, there are no guidelines or systematic studies examining the optimum safe dosage regimen for this compound. The aim of the present study was to investigate prospectively a variety of dosing regimens for IV iron sucrose in patients with renal failure to develop treatment strategies for this preparation. A total of 335 iron infusions was administered to 249 patients in this study, which was conducted in four phases. In phase I, 89 patients were administered a dose of 200 mg as an IV infusion over 2 hours. No adverse events were seen. A 500-mg dose by 2-hour infusion was then assessed, but was abandoned after 8 of 22 patients developed reactions characterized by dizziness, hypotension, and nausea. The dose was then reduced to 300 mg by 2-hour infusion for the next 189 patients, and again, no adverse reactions were witnessed. Finally, a 400-mg dose by 2-hour infusion was examined in 35 patients, but 2 patients experienced such symptoms as hypotension, nausea, and lower back pain. Both the 200- and 300-mg doses of IV iron sucrose administered over 2 hours appear to be safe. The incidence of adverse events with the 400- and 500-mg doses administered as a 2-hour infusion seems too high to recommend their routine use, although it may be possible to administer these doses over a longer period.

Present and future strategies in the treatment of renal anaemia.

Recombinant human erythropoietin therapy has transformed the management of renal anaemia over the last decade or so. We have learned much about the optimum regimens for using this drug, including the route of administration, dosage frequency, use of iron supplementation, and management of poor response. Thus, dosage requirements of epoetin are generally lower if the drug is administered subcutaneously, and the most commonly used dosage frequency is two or three times weekly. The vast majority of patients respond very well to treatment, but approximately 5-10% of patients show some resistance to epoetin, the most common cause of which is iron deficiency. The presence of infection or inflammation and underdialysis are other important causes of a poor response to epoetin. There is increasing interest in treating renal anaemia at an earlier stage in the course of the disease, and there is much circumstantial evidence to support this strategy. This usually involves giving epoetin to pre-dialysis patients, and a study has also recently commenced to investigate the effects of preventing renal anaemia ever developing. Other erythropoietic substances are being developed, and the first of these to be ready for clinical use is novel erythropoiesis stimulating protein (NESP), which is an analogue of erythropoietin containing two extra N-linked carbohydrate side-chains. Other potential erythropoietic substances are still at the laboratory stage of development, but may be available for therapeutic use in the next decade or so.

An overview of the efficacy and safety of novel erythropoiesis stimulating protein (NESP).

Novel erythropoiesis stimulating protein (NESP, also known as darbepoetin alfa) is a molecule that stimulates erythropoiesis by the same mechanism as both native and recombinant human erythropoietin (rHuEPO). The extra sialic residues on NESP, however, allow it to be more stable in vivo with a 2- to 3-fold longer elimination half-life. Thus, following intravenous administration, the mean elimination half-life of NESP is 25.3 vs 8.5 h for rHuEPO. After subcutaneous administration, the mean terminal half-life for NESP is 48.8 h. The mean bioavailability of NESP after subcutaneous administration is approximately 37%, similar to that reported for rHuEPO. The pharmacokinetic data suggested that patients with renal anaemia would require less frequent dosing with NESP than with rHuEPO. NESP 0.45 microg/kg administered once weekly either intravenously or subcutaneously has been evaluated for the correction of chronic renal failure (CRF)-associated anaemia. The study population included CRF patients not receiving dialysis, along with those on haemodialysis or peritoneal dialysis. In patients who are rHuEPO-naïve, NESP has a similar effect in correcting the anaemia as is seen with rHuEPO, but with less frequent dosing. Similarly, in patients previously receiving rHuEPO, NESP (whether administered intravenously or subcutaneously) is as effective as rHuEPO treatment for maintaining haemoglobin concentration when administered at a reduced frequency (i.e. either once weekly or once every other week). NESP is well tolerated, adverse effects are similar to those seen with rHuEPO, and no antibodies have been detected in >1500 patients exposed to NESP thus far.

Anemia with erythropoietin deficiency occurs early in diabetic nephropathy.

OBJECTIVE: The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity. RESEARCH DESIGN AND METHODS: A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy. RESULTS: We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients. CONCLUSIONS: Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.

Role of uremic toxins in exacerbating anemia in renal failure.

The anemia associated with renal failure is largely due to inappropriate erythropoietin production. There is also good evidence, however, that substances present in uremic serum can inhibit erythropoiesis, although the exact identity of these substances and the mechanism(s) by which they exert this effect remain obscure. Candidates that have been suggested to play a role in uremic inhibition of erythropoiesis include the polyamines (such as spermine, spermidine, putrescine, and cadaverine), parathyroid hormone, and some of the inflammatory cytokines. The potential role of each of these inhibitory substances is discussed in this article.