Anemia and Chronic Kidney Disease: Making Sense of the Recent Trials

Ramanath, Vinayak; Gupta, Diptesh; Jain, Juhi; Chaudhary, Kunal; Nistala, Ravi

doi:10.2174/157488712802281222

Cited by 19 publications

(21 citation statements)

References 56 publications

(85 reference statements)

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“…It is diagnosed in adults and children >15 years old with CKD when the hemoglobin (Hb) concentration is <13.0 g/dL in male patients and <12.0 g/dL in female patients (KDIGO Anemia Work Group 2012). While the primary cause of anemia is the inadequate production of erythropoietin by the kidneys to support erythropoiesis (Ramanath et al 2012), other factors may contribute to CKD-associated anemia, including decreased red blood cell life span, iron, folate and vitamin B12 deficiencies, blood loss, and accumulation of toxic inhibitors of erythropoiesis (McFarlane et al 2008; Hsu et al 2002). …”

Section: Introductionmentioning

confidence: 99%

Predictors of anemia in a multi-ethnic chronic kidney disease population: a case–control study

et al. 2015

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Anemia is a common complication of chronic kidney disease (CKD). However, risk factors of anemia in CKD patients in Singapore are not well established. Hence, a retrospective, case–control study involving non-dialysis CKD patients was conducted to determine possible predictors of anemia in the local CKD population.Non-dialysis adult CKD patients, not receiving renal replacement therapy or erythropoiesis-stimulating-agents were included. Parameters collected included demographics e.g. age, sex and race; clinical data e.g. CKD stage and medical/medication histories; and laboratory data e.g. serum electrolytes, urinary and hematologic parameters. Patients were classified as anemic or non-anemic using a threshold hemoglobin level of 10 g/dL. The parameters were evaluated for their predictive value for anemia development using multivariate logistical regression and calculation of odds ratios. Statistical analyses were performed using STATA.A total of 457 patients (162 anemic and 295 non-anemic) were analysed. Multivariate analysis showed that probability of developing anemia was greater for patients with stage 5 CKD (OR 16.76, p < 0.001), with hematological disorders (OR 18.61, p < 0.001) and with respiratory disorders (OR 4.54, p = 0.004). The probability of developing anemia was lower for patients with higher previous hemoglobin concentration (OR 0.32, p < 0.001) and in those receiving iron supplements (OR 0.44, p = 0.031). Gender and race were not found to be significant predictors of anemia.Risk of anemia is increased in patients with advanced CKD, haematological disorders, respiratory disorders, and those not taking iron supplements. This study has increased our understanding of the patient subgroups at risk for anemia.

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Section: Introductionmentioning

confidence: 99%

Predictors of anemia in a multi-ethnic chronic kidney disease population: a case–control study

et al. 2015

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“…Recombinant human EPO (rHuEPO) is used in clinical practice for the treatment of several types of anemia, including anemia of end-stage renal disease (3)(4)(5) and chemotherapy-induced anemia (6). It is also illegally administered as a performance-enhancing drug in athletes (7).…”

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confidence: 99%

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

et al. 2015

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Erythropoietin (EPO) primarily regulates red blood cell formation, and EPO serum levels are increased on hypoxic stress (e.g., anemia and altitude). In addition to anemia, recent discoveries suggest new therapeutic indications for EPO, unrelated to erythropoiesis. We investigated the skeletal role of EPO using several models of overexpression (Tg6 mice) and EPO administration (intermittent/continuous, high/low doses) in adult C57Bl6 female mice. Using microcomputed tomography, histology, and serum markers, we found that EPO induced a 32%-61% trabecular bone loss caused by increased bone resorption (+60%-88% osteoclast number) and reduced bone formation rate (-19 to -74%; P < 0.05 throughout). EPO targeted the monocytic lineage by increasing the number of bone monocytes/macrophages, preosteoclasts, and mature osteoclasts. In contrast to the attenuated bone formation in vivo, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, suggesting an indirect effect of EPO on osteoblasts. However, EPO had a direct effect on preosteoclasts by stimulating osteoclastogenesis in isolated cultures (+60%) via the Jak2 and PI3K pathways. In summary, our findings demonstrate that EPO negatively regulates bone mass and thus bears significant clinical implications for the potential management of patients with endogenously or therapeutically elevated EPO levels.

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“…[1][2][3] This hormone is primarily produced by the kidneys and, to a lesser extent, by the liver, and it stimulates normal red blood cell production, maturation, and survival. 4 The inverse relationship between blood oxygen and EPO levels has been demonstrated by hypoxia, leading to induction of EPO gene expression via accumulation of hypoxia-inducible factor 1a (HIF-1a), a transcription factor involved in the cellular adaptation to hypoxia. 4 The inverse relationship between blood oxygen and EPO levels has been demonstrated by hypoxia, leading to induction of EPO gene expression via accumulation of hypoxia-inducible factor 1a (HIF-1a), a transcription factor involved in the cellular adaptation to hypoxia.…”

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confidence: 99%

Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863

Johnson

Stier

Caltabiano

2013

Clinical Pharm in Drug Dev

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Anemia, a frequent complication of chronic kidney disease, is most commonly treated with recombinant human erythropoiesis-stimulating agents. Oral administration of GSK1278863, a prolyl hydroxylase inhibitor, results in the accumulation of hypoxia-inducible factor 1α, and stimulates erythropoiesis by triggering the pathways involved in innate hypoxia. In vitro biotransformation data indicate that GSK1278863 is primarily metabolized by CYP2C8. This study assessed the pharmacokinetics of single-dose (100 mg) GSK1278863 administered alone, or co-administered with a high-fat/high-calorie meal or steady-state gemfibrozil (a strong CYP2C8 and OATP1B1 inhibitor). Co-administration of single-dose 100 mg GSK1278863 with a high-fat/high-calorie meal did not significantly affect the plasma exposure of GSK1278863 or its 6 predominant metabolites. Co-administration of GSK1278863 with steady-state gemfibrozil resulted in an 18.6-fold increase in the area under the curve from time 0 to infinity (AUC(0-∞) ) of GSK1278863. Additionally, the maximum plasma concentration (Cmax ) and terminal elimination half-life increased 3.92- and 3.70-fold, respectively. The appearance of metabolites was delayed, and their Cmax and AUC(0-∞) were reduced by at least 90% and 62%, respectively. These findings indicate that GSK1278863 can be safely administered without regard to food. Until further studies with weaker CYP2C8 inhibitors are conducted, co-administration of GSK1278863 with CYP2C8 inhibitors should be avoided.

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Anemia and Chronic Kidney Disease: Making Sense of the Recent Trials

Cited by 19 publications

References 56 publications

Predictors of anemia in a multi-ethnic chronic kidney disease population: a case–control study

Predictors of anemia in a multi-ethnic chronic kidney disease population: a case–control study

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863

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