A novel scenario in the therapeutic management of anemia of chronic kidney disease: placement and use of roxadustat.

Anemia is a frequent and early chronic kidney disease (CKD) complication. Its management is currently based on oral or intravenous iron supplements, erythropoiesis-stimulating agents, and red blood cell transfusions, when the benefits of transfusion outweigh the risks. Anemia in CKD patients is underdiagnosed and undertreated. Current standard of care is associated with challenges and therefore new treatment approaches have been sought. Hypoxia-inducible factor-prolyl-hydroxylase enzyme inhibitors are a new class of orally administered drugs used to treat anemia associated with CKD. Small-molecule hypoxia-inducible factor-prolyl-hydroxylase inhibitors have a novel mechanism of action that activates the hypoxia-inducible factor (oxygen-sensing) pathway resulting in a coordinated erythropoietic response, leading to increased endogenous erythropoietin production, improved iron absorption and transport, and reduced hepcidin. Roxadustat is the first hypoxia-inducible factor-prolyl-hydroxylase inhibitor approved by the European Medicines Agency (EMA) and reimbursed in Italy by the Italian Medicines Agency (AIFA) for the treatment of adult patients with symptomatic CKD-related anemia. This authorization was based on the outcome of a globally-conducted phase 3 clinical trial program comprising eight pivotal multicenter randomized studies. In the absence of up-to-date guidelines, we performed a critical appraisal of the placement and use of roxadustat in this therapeutic context.

Iron Parameters in Patients Treated with Roxadustat for Anemia of Chronic Kidney Disease.

Roxadustat is a novel agent with a distinct mechanism of action compared to erythropoiesis-stimulating agents (ESAs) and a potentially different combination of effects on iron parameters. This narrative review describes the effects of roxadustat on iron parameters and on hemoglobin levels in the context of iron supplementation in patients with anemia of non-dialysis-dependent (NDD) or dialysis-dependent (DD) chronic kidney disease (CKD). Roxadustat use was associated with a greater reduction in serum ferritin levels than seen with ESAs and an increase in serum iron levels compared to a decrease with ESAs. Decreases in transferrin saturation in patients treated with roxadustat were relatively small and, in the case of patients with NDD CKD, not observed by Week 52. These changes reflect the concomitant increases in both serum iron and total iron-binding capacity. Compared to placebo and an ESA, roxadustat improved iron availability and increased erythropoiesis while requiring less intravenous iron use. Hepcidin levels generally decreased in patients who received roxadustat compared to baseline values in all CKD populations; these decreases appear to be more robust with roxadustat than with an ESA or placebo. The mechanisms behind the effects of roxadustat and ESAs on iron availability and stores and erythropoiesis appear to differ and should be considered holistically when treating anemia of CKD.

[Nutritional diet therapy in the management of the patient with Chronic Kidney Disease in advanced phase to delay the beginning and reduce the frequency of dialysis. An option also in the pre-emptive transplant program].

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and / or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty (20) essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

Nutritional treatment of advanced CKD: twenty consensus statements.

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and/or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

Evaluating the effectiveness of IV iron dosing for anemia management in common clinical practice: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice. METHODS: 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0, <300, ≥300 mg/month) with 3-month change in Hgb, TSAT, ferritin, and ESA dose were evaluated using adjusted GEE models. RESULTS: Relative change: Monotonically positive associations between IV iron dose and Hgb, TSAT, and ferritin change, and inverse associations with ESA dose change, were observed across multiple strata of prior Hgb, TSAT, and ferritin levels. Absolute change: TSAT, ferritin, and ESA dose changes were nearest zero with IV iron <300 mg/month, rather than 0 mg/month or ≥300 mg/month by maintenance or replacement dosing. Findings were robust to numerous sensitivity analyses. CONCLUSIONS: Though residual confounding cannot be ruled out in this observational study, findings suggest that IV iron dosing <300 mg/month, as commonly seen with maintenance dosing of 100-200 mg/month, may be a more effective approach to support Hgb than the higher IV iron doses (300-400 mg/month) often given in many European and North American hemodialysis clinics. Alongside studies supporting the safety of IV iron in 100-200 mg/month dose range, these findings help guide the rational dosing of IV iron in anemia management protocols for everyday hemodialysis practice.

Iron-based phosphate binders: a paradigm shift in the treatment of hyperphosphatemic anemic CKD patients?

The partial correction of anemia and the normalization of phosphate and blood pressure are the mainstay of treatment of patients with chronic kidney disease (CKD). Available anti-hypertensive drugs, erythropoiesis stimulating agents (ESAs) and iron supplements have resolved quite satisfactorily the goal of controlling hypertension and partially correcting anemia. Unfortunately, the treatment of hyperphosphatemia is still far from resolved. Phosphate binders have poor tolerability and/or limited efficacy, leading to the prescription of many tablets that achieve only a mild-to-moderate effect. Moreover, increased consumption of tablets is associated with increased low tolerability, thus jeopardizing patient compliance and, in turn, the efficacy of phosphate binding. Compared to calcium-free binders, the cheaper calcium salts increase the risk of hypercalcemia, calciphylaxis and vascular calcification and possibly all-cause mortality. Calcium-free phosphate binders decrease serum phosphate levels without increasing the serum calcium concentration. The higher phosphate-binding efficacy of lanthanum carbonate compared to sevelamer should be balanced against its lack of pleiotropic effects on lipid metabolism and inflammation and the accumulation in bones. New iron-based phosphate binders are available. In addition to their phosphate binding capacity, they could also be useful to treat anemia. Iron citrate is seeking for such an indication because its iron absorption is significant. This could be of clinical importance, particularly in CKD patients not on dialysis, obviating the need for extra oral iron administration and possibly favoring compliance. In conclusion, the use of iron-based phosphate binders with significant iron absorption properties could represent a novel paradigm for correcting anemia and hyperphosphatemia in CKD patients.

Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients.

BACKGROUND: Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses. SUMMARY: This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.

Dietary Management of Incremental Transition to Dialysis Therapy: Once-Weekly Hemodialysis Combined With Low-Protein Diet.

Initiation of thrice-weekly hemodialysis often results in a rapid loss of residual kidney function (RKF) including reduction in urine output. Preserving RKF longer is associated with better outcomes including greater survival in dialysis patients. An alternative approach aimed at preserving RKF is an incremental transition with less frequent hemodialysis sessions at the beginning with gradual increase in hemodialysis frequency over months. In addition to favorable clinical and economic implications, an incremental transition would also enhance a less stressful adaptation of the patient to dialysis therapy. The current guidelines provide only limited recommendations for incremental hemodialysis approach, whereas the potential role of nutritional management of newly transitioned hemodialysis patients is largely overlooked. We have reviewed previous reports and case studies of once-weekly hemodialysis treatment combined with low-protein, low-phosphorus, and normal-to-high-energy diet especially for nondialysis days, whereas on dialysis days, high protein can be provided. Such an adaptive dietary regimen may elicit more favorable outcomes including better preserved RKF, lower ß2-microglobulin levels, improved phosphorus control, and lower doses of erythropoiesis-stimulating agents. Clinical and nutritional status and RKF should be closely monitored throughout the transition to once and then twice-weekly regimen and eventually thrice-weekly hemodialysis. Further studies are needed to verify the long-term safety and implications of this approach to dialysis transition.

New Treatment Approaches for the Anemia of CKD.

Normocytic normochromic anemia is a common complication in chronic kidney disease and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical practice was a success story, mediating an increase in hemoglobin concentrations without the risk for recurrent blood transfusions and improving quality of life substantially. However, recombinant ESAs are still expensive and require a parenteral route of administration. Moreover, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm. This, together with changes in ESA reimbursement policy in some countries, has resulted in a significant reduction in ESA prescribing and the hemoglobin level targeted during therapy. Several attempts are being made to develop new drugs with improved characteristics and/or easier manufacturing processes compared with currently available ESAs, including new treatment approaches that may indirectly improve erythropoiesis. We give an update on the new investigational strategies for increasing erythropoiesis, examining in depth their characteristics and possible advantages in the clinical setting and the caveats to be aware of at the present stage of development.

Long-Term Evaluation of Colestilan in Chronic Kidney Disease Stage 5 Dialysis Patients with Hyperphosphataemia.

BACKGROUND: This study investigated in a North American patient population the longer-term treatment effects of the phosphate binder, colestilan, in patients with CKD Stage 5D and hyperphosphataemia. METHODS: One hundred and sixteen CKD Stage 5D patients with hyperphosphataemia were entered into a multi-centre, open-label study where they received flexible dose colestilan (6-15 g/day) to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl. The primary endpoint was safety, assessed by treatment-emergent adverse events. Efficacy was assessed by changes in serum phosphorus, mineral metabolism, lipids, HbA1c, uric acid and bone markers. RESULTS: Serum phosphorus was significantly reduced by 1.18 mg/dl (p < 0.001), from 6.99 mg/dl at baseline to 5.80 mg/dl at week 52. LDL-cholesterol was also significantly reduced as well as uric acid. Significant change was observed only for one bone marker - PINP. Most adverse events were of mild or moderate intensity. Nausea (22.4%), vomiting (21.6%), and diarrhoea (19.8%) were most commonly reported. CONCLUSIONS: Long-term flexible dosing with colestilan reduces serum phosphorus and demonstrates an acceptable safety and tolerability profile.

Randomized, Double-Blind, Placebo-Controlled, Withdrawal Study of Colestilan after Dose Titration in Chronic Kidney Disease Dialysis Patients with Hyperphosphatemia.

BACKGROUND/AIMS: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period. RESULTS: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal. CONCLUSION: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels.

Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study.

BACKGROUND: Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. METHODS: COSMOS is a 3-year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. RESULTS: Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. CONCLUSIONS: COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.

Anemia in chronic kidney disease patients: treatment recommendations and emerging therapies.

Erythropoiesis-stimulating agents (ESA) and iron have been available since decades to treat anemia of chronic kidney disease (CKD). However, many grey areas surround the field. The optimal hemoglobin (Hb) target to aimed at with ESA, the general safety of ESA and boundaries to not be exceeded with iron supplementation are still to be clearly defined. New strategies to stimulate erythropoiesis and new iron molecules have been developed; the most promising approach is the manipulation of the hypoxia-inducible transcription factor (HIF) system. The regulation of activin A pathway is another option with good potential, also considering the additional advantage of increasing bone mass. New iron molecule for intravenous administration may be useful to reduce the number of doses to be administered.

The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study.

BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS: Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer.

Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics.

BACKGROUND: Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS: We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS: Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS: This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.

Therapy of anemia: is it only a number to reach or are there other variables to control?

Following the publication of the TREAT study, the treatment of anemia in patients with chronic kidney disease (CKD) has become much more complicated than before. The nephrologist needs to analyze the individual patient and prescribe the best treatment option for that patient. Treatment individualization has thus become the mainstay of anemia management. This paradigm needs to take into account the hemoglobin (Hb) level at the start and during erythropoiesis-stimulating agent (ESA) therapy, ESA dose, patient comorbidities and concomitant iron therapy. All these factors are strictly interrelated. Caution is suggested when using ESA at high dose, especially in patients with comorbidities and/or in those who are hyporesponsive to treatment. According to KDIGO guidelines, Hb levels should not exceed the value of 11.5 g/dl during ESA therapy. Recently, iron therapy has received growing attention in an effort to use the lowest possible dose of ESA. However, the long-term risk in maintaining CKD patients with very high ferritin values is still unknown.

Effect of a plasma sodium biofeedback system applied to HFR on the intradialytic cardiovascular stability. Results from a randomized controlled study.

BACKGROUND: Intradialytic hypotension (IDH) is still a major clinical problem for haemodialysis (HD) patients. Haemodiafiltration (HDF) has been shown to be able to reduce the incidence of IDH. METHODS: Fifty patients were enrolled in a prospective, randomized, crossover international study focussed on a variant of traditional HDF, haemofiltration with endogenous reinfusion (HFR). After a 1-month run-in period on HFR, the patients were randomized to two treatments of 2 months duration: HFR (Period A) or HFR-Aequilibrium (Period B), followed by a 1-month HFR wash-out period and then switched to the other treatment. HFR-Aequilibrium (HFR-Aeq) is an evolution of the haemofiltration with endogenous reinfusion (HFR) dialysis therapy, with dialysate sodium concentration and ultrafiltration rate profiles elaborated by an automated procedure. The primary end point was the frequency of IDH. RESULTS: Symptomatic hypotension episodes were significantly lower on HFR-Aeq versus HFR (23 ± 3 versus 31 ± 4% of sessions, respectively, P l= l0.03), as was the per cent of clinical interventions (17 ± 3% of sessions with almost one intervention on HFR-Aeq versus 22 ± 2% on HFR, P <0.01). In a post-hoc analysis, the effect of HFR-Aeq was greater on more unstable patients (35 ± 3% of sessions with hypotension on HFR-Aeq versus 71 ± 3% on HFR, P <0.001). No clinical or biochemical signs of Na/water overload were registered during the treatment with HFR-Aeq. CONCLUSIONS: HFR-Aeq, a profiled dialysis supported by the Natrium sensor for the pre-dialysis Na(+) measure, can significantly reduce the burden of IDH. This could have an important impact in every day dialysis practice.

New erythropoiesis-stimulating agents and new iron formulations.

Today, erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the main tool for anemia correction in chronic kidney disease patients. Over the past decades, a number of attempts have been made to modify the erythropoietin molecule in order to improve its pharmacokinetic and pharmacodynamic properties. More recently, small peptides, which are unrelated to erythropoietin but bind to the same receptor, have been developed. In addition to this, other strategies to stimulate erythropoiesis have been followed, such as activin inhibition or stabilization of hypoxia-inducible transcription factors. Interestingly, the latter have the advantage of being administered orally. New iron molecules, such as ferumoxytol, ferric carboxymaltose and iron isomaltoside 1000, have recently been marketed. These new agents can administered at high doses while releasing minimal free iron. Their safety profile is good, but long- term post- marketing data are still needed to evaluate the occurrence of rare adverse events.

Iron treatment and the TREAT trial.

Treatment with erythropoiesis-stimulating agents (ESAs) enables the correction of anaemia in chronic kidney disease (CKD) patients, thus reducing its symptoms and complications. Not only is iron therapy aimed at correcting iron deficiency, but also it is an adjuvant therapy in CKD patients receiving ESAs. Iron stores in CKD patients may be near normal, but there may be insufficient immediately available iron to optimize ESA therapy. In this context, iron therapy significantly reduces ESA dose requirements. Erythropoiesis following ESA therapy may precipitate iron deficiency in association with increased platelet production. In the TREAT trial, the 'placebo group' did not receive a true 'placebo' since 46% of the patients had at least one dose of ESA and achieved progressively increased haemoglobin (Hb) values during follow-up against the common observation. The patients in the 'placebo' group were treated more frequently with intravenous iron than the darbepoetin group. Given that many patients were relatively iron deficient at baseline, iron administration was successful in many of them in obtaining and maintaining partial anaemia correction without the need for ESAs, thus underlining the great importance of iron supplementation in correcting anaemia. The upper safety limit for iron administered to patients in order to minimize, as much as possible, the ESA dose and the upper limit for ESA dosage for maintaining the target Hb range as suggested by the current guidelines are still open questions.