Treatment Of Renal Anemia Research Articles

Current and Emerging Drugs in the Treatment of Anemia in Patients with Chronic Kidney Disease.

Anemia is a common complication of chronic kidney disease (CKD), and its prevalence has shown a tendency to increase in many countries. Anemia is associated with incident heart failure and increases mortality in CKD patients, garnering public attention. Here, we reviewed recent studies about CKD with anemia, and tried to summarize the risks and causes and new progress in the treatment of renal anemia. Among the risks and causes, calciumand phosphorusmetabolismdisorders should be pointed out along with common causes such as iron and erythropoietin deficiencies, hypoxia, inflammation and uremic toxins, and so on. The new anti-anemia treatments mainly include hematopoietic materials supplementation, erythropoietin-stimulating agents, calcium and phosphorus regulators and hypoxia-inducible factor prolyl hydroxylase inhibitors.

Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor

The three hypoxia-inducible factor (HIF) prolyl-4-hydroxylase domain (PHD) 1–3 enzymes confer oxygen sensitivity to the HIF pathway and are novel therapeutic targets for treatment of renal anemia. Inhibition of the PHDs may further be beneficial in other hypoxia-associated diseases, including ischemia and chronic inflammation. Several pharmacologic PHD inhibitors (PHIs) are available, but our understanding of their selectivity and its chemical basis is limited. We here report that the PHI JNJ-42041935 (JNJ-1935) is structurally similar to the firefly luciferase substrate D-luciferin. Our results demonstrate that JNJ-1935 is a novel inhibitor of firefly luciferase enzymatic activity. In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA, BIQ, IOX3, YM 311) did not affect firefly luciferase. The JNJ-1935 mode of inhibition is competitive with a Ki of 1.36 μM. D-luciferin did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.

Antibody-mediated pure red cell aplasia related with epoetin-beta pegol (C.E.R.A.) as an erythropoietic agent: case report of a dialysis patient

BackgroundErythropoietin-stimulating agents (ESAs) are used to treat anemia in patients with chronic kidney disease, enabling maintenance of stable hemoglobin levels and eliminating the need for multiple transfusions. Epoetin-beta pegol (C.E.R.A.) is a continuous erythropoietin receptor activator created by integrating a large methoxy-polyethylene-glycol-polymer chain into the erythropoietin molecule, which provides it with a longer half-life. On rare occasions, cases of antibody-mediated pure red cell aplasia (PRCA) related to ESAs are reported. They are characterized by abrupt onset of severe transfusion-dependent anemia, despite ESA therapy. We herein report a case of antibody-mediated PRCA in a dialysis patient receiving C.E.R.A.Case presentationA 44-year-old man with end-stage renal failure had been receiving continuous ambulatory peritoneal dialysis for 2 years. C.E.R.A. was administered subcutaneously as a sole ESA once a month at the hospital since 4 years ago for the treatment of renal anemia and his hemoglobin level was well controlled at 12 g/dl. From 10 months before diagnosis, however, his hemoglobin level suddenly declined, necessitating frequent transfusions. Based on the results of a bone marrow examination and detection of anti-C.E.R.A. antibodies, the patient was diagnosed with antibody-mediated PRCA. After successful elimination of the antibodies using oral prednisolone plus cyclosporine, the patient was re-administrated C.E.R.A. intravenously, as there are few reports of antibody-mediated PRCA related to ESA using that administration route. He responded to the C.E.R.A., and his anemia dramatically improved, eliminating the need for blood transfusions.ConclusionsThis is the first reported case of recovery from an antibody-mediated PRCA with C.E.R.A. after its re-administration following a reversal of the antibody. It has been suggested that the additional large pegylation chain makes C.E.R.A. less likely to trigger antibody generation than other ESAs. Following successful treatment of antibody-mediated PRCA using immunosuppressive therapy, C.E.R.A. can be re-administered intravenously to treat renal anemia.

Chemical characterisation and quantification of the major constituents in the Chinese herbal formula Jian-Pi-Yi-Shen pill by UPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

Jian-Pi-Yi-Shen pill (JPYSP) is a Chinese medicine formula developed for the treatment of anaemic patients with chronic kidney disease (CKD). To investigate the chemical profile of JPYSP in the treatment of renal anaemia. A method coupling ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was established to characterise the chemical constituents present in JPYSP. Subsequently, a high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) was developed to quantify the major constituents from the identified compounds related to the treatment of CKD and anaemia. A total of 71 compounds were tentatively identified from JPYSP, including saponins, flavonoids, sesquiterpenoids, coumarins, phenylpropanoids, anthranones, anthraquinones, tannins, phenolic acids and others. Amongst them, 12 compounds (i.e. astragaloside IV, calycosin, calycosin 7-O-glucoside, salvianolic acid A, rosmarinic acid, rhein, liquiritin, formononetin, atractylenolide I, dioscin, tanshinone IIA, and acteoside) were further quantified simultaneously by HPLC-QQQ-MS/MS. The newly developed approach is suitable for the chemical profiling analysis and quality control of JPYSP, and could lead to additional pharmacodynamic studies involving the components of JPYSP.

The prolyl hydroxylase inhibitor roxadustat: Paradigm in drug discovery and prospects for clinical application beyond anemia

Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug.

Inhibition of oxygen-sensing prolyl hydroxylases increases lipid accumulation in human primary tubular epithelial cells without inducing ER stress

The role of the hypoxia-inducible transcription factor (HIF) pathway in renal lipid metabolism is largely unknown. As HIF stabilizing prolyl hydroxylase (PHD) inhibitors are currently investigated in clinical trials for the treatment of renal anemia, we studied the effects of genetic deletion and pharmacological inhibition of PHDs on renal lipid metabolism in transgenic mice and human primary tubular epithelial cells (hPTEC). Tubular cell-specific deletion of HIF prolyl hydroxylase 2 (Phd2) increased the size of Oil Red-stained lipid droplets in mice. In hPTEC, the PHD inhibitors (PHDi) DMOG and ICA augmented lipid accumulation, which was visualized by Oil Red staining and assessed by microscopy and an infrared imaging system. PHDi-induced lipid accumulation required the exogenous availability of fatty acids and was observed in both proximal and distal hPTEC. PHDi treatment was not associated with structural features of cytotoxicity in contrast to treatment with the immunosuppressant cyclosporine A (CsA). PHDi and CsA differentially upregulated the expression of the lipid droplet-associated genes PLIN2, PLIN4 and HILPDA. Both PHDi and CsA activated AMP-activated protein kinase (AMPK) indicating the initiation of a metabolic stress response. However, only CsA triggered endoplasmic reticulum (ER) stress as determined by the increased mRNA expression of multiple ER stress markers but CsA-induced ER stress was not linked to lipid accumulation. Our data raise the possibility that PHD inhibition may protect tubular cells from toxic free fatty acids by trapping them as triacylglycerides in lipid droplets. This mechanism might contribute to the renoprotective effects of PHDi in experimental kidney diseases.

Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF\u2013PH inhibitor for the treatment of renal anaemia

PurposeThe present studies assessed the drug–drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD).MethodsForty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12–15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics.ResultsDepending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50–75% and 46–84%, respectively, and EPO AUC(0-24) and Cmax by 31–44% and 36–48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated.ConclusionsIn contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.

Clinical perspectives on the treatment of renal anemia with HIF stabilizers

Clinical perspectives on the treatment of renal anemia with HIF stabilizers

Renal anemia refractory to erythropoietin

Background Anemia is a common feature of chronic kidney disease and is associated with poor outcomes. Renal anemia has a multifactorial etiology, and the major cause is decreased production of erythropoietin (EPO). The standard of care for the treatment of the renal anemia is EPO for achieving target of hemoglobin levels (11gm /dl), but some causes lead to inadequate response to EPO. Aim The study aimed to determine the frequency and various factors contributing to the etiology of renal anemia refractory to EPO in patients with end-stage renal disease (ESRD) on hemodialysis (HD). A descriptive longitudinal study was performed. The study was carried out on 30 patients with ESRD on HD selected randomly and received EPO drug at the Nephrology Unit and Outpatient Clinic at the Department of Internal Medicine of Assiut University Hospital. The data were obtained from full medical history and clinical examination, such as general data concerning patients (age, sex, comorbidities, and used medications), which were recorded directly from the patients or from their hospital files, laboratory investigations, and follow-up of patients for 4 months, with complete blood count examination every month. Patients and methods The study found that of 30 studied patients, 23 (76.7%) had partial response to reach the targeted hemoglobin level and seven (23.3%) had complete response to reach the targeted hemoglobin level of 11 g/dl. The 23 patients who had partial response had poor nutrition, iron-deficiency anemia (IDA), inadequate dialysis, arteriovenous fistula and chest infections, drugs containing aluminum, acute blood loss, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. These may be possible risk factors of renal anemia refractory to EPO. Results Anemia is a common complication of uremia and a major contributor to morbidity and mortality in HD patients. The availability of recombinant human EPO has led to almost complete disappearance of severe anemia in HD patients; however, despite an increase in its use and average dose, a substantial percentage of patients still fail to achieve the Hb targets recommended by the international guidelines. Anemia refractory to EPO is common in HD patients (76.6%), which may be owing to several factors such as bad nutrition, IDA, inadequate dialysis, arteriovenous fistula and chest infection, aluminum-containing drugs, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. Conclusions The study recommends to monitor serum levels of iron, calcium, phosphate, and parathyroid hormone at the start, with follow-up by complete blood count monthly, as well as treatment of the possible causes, that is, iron for IDA, antibiotic for infections, calcium therapy for hypocalcemia, and management of hyperphosphatemia and secondary hyperparathyroidism, during treatment of renal anemia by erythropoietin (EPO) drug to responded to it. Moreover, the study recommends performing more studies on a larger number of patients with ESRD having renal anemia for more demonstration of the possible causes of this condition.

Hypoxic response as a therapeutic target of human diseases

Hypoxic responses are mainly regulated by heterodimeric transcription factor HIF, composed of unstable α-subunit (HIFα) and stable β-subunit (HIF1β/ARNT). Protein stability of HIFα depends on the hydroxylation status of its specific proline residue(s). Prolyl hydroxylation of HIFα is regulated by iron- and 2-oxoglutarate (2-OG)-dependent dioxygenase PHDs, whose enzyme activities are oxygen-dependent. Hence, PHDs act as an oxygen sensor, and inhibiting PHDs can activate the hypoxic response regardless of the normoxic environment. Small compounds that inhibit PHDs have been developed as the therapeutics for renal anemia. Here we also introduce the medical application of the PHD-inhibitors other than the renal anemia treatment. Finally, it is a great pleasure to announce here that the Nobel Prize in Physiology or Medicine 2019 was awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza, who have been studying how cells sense and adapt to oxygen availability over the years.

Real-world treatment patterns of renal anemia in hemodialysis patients: A multicenter cohort study performed using DialysisNet (RRAHD study).

A multicenter cohort study.The DialysisNet was previously developed for the management of hemodialysis (HD) patients based on the American Society for Testing and Materials Continuity of Care Records by metadata transformation. DialysisNet is a dialysis patient management program created by using the personal health record care platform to overcome the problems of registry studies, in real-time.Here, we aimed to investigate the pattern of treatment for renal anemia in HD patients using DialysisNet.We performed a multicenter cohort study among HD patients who were treated at one of the three Korean university-affiliated hospitals from January 2016 to December 2016. Subjects were divided into 4 hemoglobin variability groups by quartiles. The variable anemia treatment pattern was reviewed. To determine renal anemia treatment patterns, we automatically collected information on the practice of anemia treatment patterns such as erythropoietin stimulating agent (ESA) doses and administration frequencies, and targeted hemoglobin maintenance rate. Individual hemoglobin variabilities were expressed as (standard deviations)/(√(n/[n–1]).The records of 159 patients were analyzed (Hospital A: 35, Hospital B: 21, Hospital C: 103). Mean patients’ age was 65.6 ± 12.8 years, and 61.6% were men. Overall, hemoglobin level was 10.5[7.43;13.93] g/dL. 158 (99.3%) patients were using ESA; and overall, the epoetin alfa dose was 33,000[4000;136,800] U per week. Hemoglobin levels (P = .206) and epoetin alfa doses were similar (P = .924) for patients with different hemoglobin variabilities. The hemoglobin target maintenance rate was lower in the highest hemoglobin variability group than in the lowest variability group (P = .045).In this study, detailed information on the actual anemia treatment patterns were obtained using the DialysisNet. We expect that DialysisNet will simplify and improve the renal anemia management for both dialysis patients and health care providers.

Structure-Activity Relationship and Crystallographic Studies on 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors.

The 2‐oxoglutarate‐dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4‐hydroxypyrimidine‐containing PHD inhibitors.

Alteration of the DNA Methylation Signature of Renal Erythropoietin-Producing Cells Governs the Sensitivity to Drugs Targeting the Hypoxia-Response Pathway in Kidney Disease Progression.

Chronic kidney disease (CKD) affects more than 10% of the population worldwide and burdens citizens with heavy medical expenses in many countries. Because a vital erythroid growth factor, erythropoietin (EPO), is secreted from renal interstitial fibroblasts [renal EPO-producing (REP) cells], anemia arises as a major complication of CKD. We determined that hypoxia-inducible factor 2α (HIF2α), which is inactivated by HIF-prolyl hydroxylase domain-containing proteins (PHDs) in an oxygen-dependent manner, tightly regulates EPO production in REP cells at the gene transcription level to maintain oxygen homeostasis. HIF2α-mediated disassembly of the nucleosome in the EPO gene is also involved in hypoxia-inducible EPO production. In renal anemia patients, anemic and pathological hypoxia is ineffective toward EPO induction due to the inappropriate over-activation of PHDs in REP cells transformed into myofibroblasts (MF-REP cells) due to kidney damage. Accordingly, PHD inhibitory compounds are being developed for the treatment of renal anemia. However, our studies have demonstrated that the promoter regions of the genes encoding EPO and HIF2α are highly methylated in MF-REP cells, and the expression of these genes is epigenetically silenced with CKD progression. This finding notably indicates that the efficacy of PHD inhibitors depends on the CKD stage of each patient. In addition, a strategy for harvesting renal cells, including REP cells from the urine of patients, is proposed to identify plausible biomarkers for CKD and to develop personalized precision medicine against CKD by a non-invasive strategy.

Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage

Hypoxia-inducible factor (HIF) mediates protection via hypoxic preconditioning in both, invitro and invivo ischemia models. However, the underlying mechanism remains largely unknown. Prolyl hydroxylase domain proteins serve as the main HIF regulator via hydroxylation of HIFα leading to its degradation. At present, prolyl hydroxylase inhibitors including enarodustat are under clinical trials for the treatment of renal anemia. In an invitro model of ischemia produced by oxygen-glucose deprivation of renal proximal tubule cells in culture, enarodustat treatment and siRNA knockdown of prolyl hydroxylase 2, but not of prolyl hydroxylase 1 or prolyl hydroxylase 3, significantly increased the cell viability and reduced the levels of reactive oxygen species. These effects were offset by the simultaneous knockdown of HIF1α. In another invitro ischemia model induced by the blockade of oxidative phosphorylation with rotenone/antimycin A, enarodustat-enhanced glycogen storage prolonged glycolysis and delayed ATP depletion. Although autophagy is another possible mechanism of prolyl hydroxylase inhibition-induced cytoprotection, gene knockout of a key autophagy associated protein, Atg5, did not affect the protection. Enarodustat increased the expression of several enzymes involved in glycogen synthesis, including phosphoglucomutase 1, glycogen synthase 1, and 1,4-α glucan branching enzyme. Increased glycogen served as substrate for ATP and NADP production and augmented reduction of glutathione. Inhibition of glycogen synthase 1 and glutathione reductase nullified enarodustat's protective effect. Enarodustat also protected the kidneys in a rat ischemia reperfusion injury model and the protection was partially abrogated by inhibiting glycogenolysis. Thus, prolyl hydroxylase inhibition protects the kidney from ischemia via upregulation of glycogen synthesis.

Mechanisms of hypoxia signalling: new implications for nephrology.

Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.

Treatment for renal anemia and outcomes in non-dialysis patients with chronic kidney disease: the current status of regional medicine according to the Kyoto Fushimi Renal Anemia (KFRA) study.

The baseline data obtained in the CKD-JAC demonstrated that insufficient treatment was being provided for renal anemia by institutions specializing in renal disease. The objective of this study was to investigate the status of treatment for renal anemia, including renal/cardiovascular outcomes and mortality, at regional medical facilities since the development of long-acting erythropoiesis-stimulating agents (LA-ESA). Non-dialysis outpatients with chronic kidney disease and renal anemia were eligible. Anemia was treated based on the clinical condition of each patient and targeted hemoglobin (Hb) levels. A total of 283 patients from 21 institutions were enrolled and followed up for a maximum of 3years. A doubling of the serum creatinine level was observed in 89 patients, and renal replacement therapy was initiated in 57 patients. Multivariate Cox regression analysis revealed that a lower mean Hb level (mHb) and receiving fewer frequency of ESA during the follow-up period were independent determinants of the composite renal outcome and overall mortality. During the follow-up period, the percentages of patients with mHb of 10-10.9g/dL and ≥ 11g/dL were increased. Similar trends were seen regardless of whether the patients were treated by nephrologists or non-nephrologists. The frequency of ESA treatment was increased among the patients treated by non-nephrologists; however, it was much lower than nephrologists. This study demonstrated that, in the era of LA-ESA treatment, higher Hb levels are associated with reduced composite renal outcomes at regional medical facilities. The importance of renal anemia management should be highlighted, even among non-nephrologists.

Molidustat for the treatment of renal anaemia in patients with non-dialysis-dependent chronic kidney disease: design and rationale of two phase III studies

IntroductionAnaemia is a common complication of chronic kidney disease (CKD). Owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care, there is a need to develop new...

Molidustat for the treatment of renal anaemia in patients with dialysis-dependent chronic kidney disease: design and rationale of three phase III studies

IntroductionNew medications for anaemia associated with chronic kidney disease (CKD) are desirable, owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care. Molidustat is a novel hypoxia-inducible...

Chronic Renal Failure, Anemia, and Parenteral Iron Treatment: From Bench to Bedside

Chronic Renal Failure, Anemia, and Parenteral Iron Treatment: From Bench to Bedside

Hepcidin as a therapeutic target for anemia and inflammation associated with chronic kidney disease

ABSTRACTIntroduction: Anemia is a common manifestation of chronic kidney disease (CKD). The pathogenesis of CKD-associated anemia is multifactorial. Our understanding of the molecular control of iron metabolism has improved dramatically because of the discovery of hepcidin and attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway have recently emerged.Areas covered: We examine the possible role of hepcidin in iron metabolism and regulation and the potential therapeutic options involving hepcidin and hepcidin-ferroportin axis in renal anemia treatment. We focus on therapeutic targeting of hepcidin, the hepcidin-ferroportin axis and key molecules such as anti-hepcidin antibodies, spigelmers, and anticalins. We also discuss compounds affecting the bone morphogenetic protein receptor [BMP/BMPR] complex and molecules that influence hepcidin, such as hypoxia-inducible factor 1 stabilizers.Expert opinion: Hepcidin is a key regulator of iron availability and is a potential future therapeutic target for managing anemia that is associated with CKD. There are potential risks and benefits associated with novel sophisticated therapies and there are several novel options on the horizon; however, clinical data are currently limited and need development. Inhibition of hepcidin via various pathways might be a viable adjunctive therapeutic option in other clinical situations.