Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association.

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis-stimulating agents (ESAs) and blood transfusions has been the mainstay for treatment of anaemia in CKD for more than 3 decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalization, cardiovascular events and CKD progression in CKD patients, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in >30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis, with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumour growth needs to be fully elucidated. This article presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties and discusses their place in the treatment of anaemia in CKD according to the available evidence.

Effect of Antidiabetic Drugs on Bone Health in Patients with Normal Renal Function and in Chronic Kidney Disease (CKD): Insight into Clinical Challenges in the Treatment of Type 2 Diabetes.

Among the metabolic changes occurring during the course of type 2 diabetes (T2DM) and diabetic kidney disease (DKD), impaired bone health with consequent increased fracture risk is one of the most complex and multifactorial complications. In subjects with diabetic kidney disease, skeletal abnormalities may develop as a consequence of both conditions. In the attempt to define a holistic approach to diabetes, potential effects of various classes of antidiabetic drugs on the skeleton should be considered in the setting of normal kidney function and in DKD. We reviewed the main evidence on these specific topics. Experimental studies reported potential beneficial and harmful effects on bone by different antidiabetics, with few data available in DKD. Clinical studies specifically designed to evaluate skeletal effects of antidiabetics have not been performed; notwithstanding, data gleaned from randomized controlled trials and intervention studies did not completely confirm observations made by basic research. In the aggregate, evidence from meta-analyses of these studies suggests potential positive effects on fracture risk by metformin and glucagon-like peptide-1 receptor agonists, neutral effects by dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and sulfonylureas, and negative effects by insulin and thiazolidinediones. As no clinical recommendations on the management of antidiabetic drugs currently include fracture risk assessment among the main goal of therapy, we propose an integrated approach with the aim of defining a patient-centered management of diabetes in chronic kidney disease (CKD) and non-CKD patients. Future clinical evidence on the skeletal effects of antidiabetics will help in optimizing the approach to a personalized and more effective therapy of diabetes.

ESA, Iron Therapy and New Drugs: Are There New Perspectives in the Treatment of Anaemia?

Anemia is a well-known consequence of chronic kidney disease (CKD); it is mainly due to a relative insufficiency of erythropoietin synthesis by the failing kidneys. Over the years, the combination of erythropoiesis stimulating agents (ESA) and iron has become the standard of care of anemia. All ESAs effectively increase hemoglobin (Hb) levels in a substantial percentage of patients. However, in the last decade, their use has been surrounded by safety issues in increased cardiovascular risk, especially when used at high doses in inflamed and hyporesponsive patients. This has led to the definition of a more cautious Hb target. Iron deficiency is very frequent in CKD patients, with a higher frequency in non-dialysis patients. Traditionally, iron supplementation is mostly used as supportive therapy for anemia control. However, the concept is growing that intravenous iron therapy per se could be beneficial in the presence of heart failure. A new class of drugs, prolyl hydroxylase domain (PHD) inhibitors (PHD inhibitors) is becoming available for the treatment of anemia in CKD patients. Theoretically, these agents have a number of advantages, the main ones being that of stimulating the synthesis of endogenous erythropoietin and increasing iron availability. The impact of their future use in clinical practice is still to be defined. Another possible strategy could be targeting serum hepcidin and its related pathways. This possibility is fascinating from the scientific point of view, but at present its development phase is still far from clinical application.

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.

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.

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.

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.

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.

Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients.

BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.