Clinical and genetic markers of erythropoietin deficiency anemia in chronic kidney disease (predialysis) patients.

Aim: To determine the clinical and genetic markers associated with erythropoietin deficiency anemia in predialysis individuals. Materials & methods: Patients were categorized into cases and control group. Demographic characteristics and clinical parameters were obtained from medical record review and serum EPO and ferritin were obtained with ELISA. HIF-1α (rs2057482), IL-1ß (rs1143627) and EPO (rs1617640) gene polymorphism were genotyped. Results: Female gender, glomerular filtration rate, treatment with hematinics, anticoagulant and diuretic were strong predictors of EPO-deficient anemia in predialysis chronic kidney disease patients. Genetic polymorphism in the HIF-1α recessive model was associated with non-EPO-deficiency, followed by EPO recessive allele associated with low-serum erythropoietin and IL-1ß recessive model with low hemoglobin level. Conclusion: EPO-deficiency anemia can be diagnosed more conveniently in the presence of biomarkers.

Aportes de la biotecnología al diagnóstico y tratamiento de la enfermedad renal crónica y comorbilidades frecuentes / Biotechnology contribution to the diagnosis and treatment of chronic kidney disease and frequent comorbidities

Este trabajo tiene como objetivo revisar las contribuciones de la biotecnología, en relación con el tratamiento, diagnóstico y la monitorización de la enfermedad renal crónica (ERC) y sus comorbilidades más frecuentes, especialmente la anemia. En relación con los tratamientos, enfocamos el desarrollo de productos biofarmacéuticos como los agentes estimulantes de la eritropoyesis (ESA), que fueron los primeros biofármacos utilizados para el tratamiento de la anemia asociada a la ERC; analizamos sus características y utilización actual después de varios años de experiencia clínica, así como también otras alternativas en desarrollo. Revisamos distintos tipos de bioterapias, la utilización de las células estromales mesenquimales de médula ósea (MSC) y tratamientos alternativos con modificaciones dietarias, que se basan en la asociación entre la microbiota intestinal de los pacientes renales crónicos y sus condiciones fisiopatológicas. Finalmente, en relación con el diagnóstico y monitorización, nos referimos al estudio y validación de biomarcadores diagnósticos, predictivos y terapéuticos que han permitido optimizar los resultados clínicos en este tipo de pacientes. (AU)

The aim of this work is to review the contributions of biotechnology, in relation to the treatment, diagnosis and monitoring of chronic kidney disease (CKD) and its most frequent comorbidities, especially anemia. Regarding the treatment, we focus on the development of biopharmaceutical products such as erythropoiesis stimulating agents (ESA), which were the first biopharmaceuticals used to treat anemia associated with chronic kidney disease (CKD). We analyzed their characteristics and their current use after several years of clinical experience, as well as other alternatives in development. We also review different types of biotherapies, the use of bone marrow mesenchymal stromal cells (MSC) and alternative treatments with dietary modifications, which are based on the association between the intestinal microbiota of chronic kidney patients and their pathophysiological conditions. Finally, in relation to diagnosis and monitoring, we refer to the study and validation of diagnostic, predictive and therapeutic biomarkers that have made clinical results possible to be optimized in this type of patient. (AU)

How I treat renal anemia.

Anemia is a frequent complication of kidney disease. When severe, it causes symptoms that can be debilitating. The course of anemia tends to track the decline in kidney function, with prevalence increasing in more advanced disease. Although the most common cause is relative erythropoietin deficiency, other factors such as reduced iron availability contribute to the pathobiology. In this review, we use cases to explore the surprising complexity of decision-making in management of renal anemia.

Relationship between protein-energy wasting in adults with chronic hemodialysis and the response to treatment with erythropoietin.

BACKGROUND: It is known that one of the leading causes of morbidity in chronic kidney disease (CKD) is the anemic syndrome. Although the pathogenic mechanisms of anemia are multiple, erythropoietin deficiency appears as the dominant factor. Patients in hemodialysis (HD) have a high prevalence of protein energy wasting (PEW) that may explains the poor response to Erythropoietin (EPO). METHODS: Retrospective cohort study of patients on HD from January to December 2014. The participants were classified according to a diagnostic of PEW using the "Malnutrition Inflammation Score" (MIS) and bioimpedance analysis (BIA) measurement of body composition at the start of erythropoietin therapy and after 3 months of follow up. We performed descriptive statistics and analyzed the differences between groups with and without PEW considering their responsiveness. In addition, we calculated the relative risk of EPO resistance, considering p value < 0.05 as statistically significant. RESULTS: Sixty-one patients ended the follow up. Both groups were similar in basal hemoglobin, hematocrit and other hematopoiesis markers (p = NS). Patients without PEW have a decrease risk for poor response to treatment with EPO (RR = 0.562 [95% CI, 0.329-0.961-]) than those with PEW. Finally, hemoglobin concentrations were evaluated at baseline and every four weeks until week 12, finding a statistically significant improvement only in patients without PEW according MIS (p < 0.05). CONCLUSIONS: PEW is an incremental predictor of poor responsiveness to EPO in HD patients, thus, it is important to consider correcting malnutrition or wasting for a favorable response to treatment with EPO.

Low 1,25-dihydroxyvitamin D level is associated with erythropoietin deficiency and endogenous erythropoietin resistance in patients with chronic kidney disease.

PURPOSE: Erythropoietin (EPO) deficiency and resistance to endogenous EPO is an important pathophysiological feature in anemia of chronic kidney disease (CKD). Low 1,25 dihydroxyvitamin D [1,25(OH)2D] level is known to contribute to anemia of CKD. We aimed to investigate the associations between serum 1,25(OH)2D and anemia, EPO deficiency, and endogenous EPO resistance in patients with CKD. METHODS: This study included 409 patients with CKD [glomerular filtration rate (GFR) < 60 ml/min/1.73 m2] who were not on dialysis therapy. Patients on exogenous EPO therapy and patients with iron deficiencies were excluded. Endogenous EPO resistance was assessed by calculating the ratio of endogenous EPO to hemoglobin (Hb) (endogenous EPO/Hb ratio). The associations of Hb level, endogenous EPO level, and the endogenous EPO/Hb ratio with clinical and laboratory variables were investigated by univariate and multivariate analyses. RESULTS: In univariate analysis, serum 1,25(OH)2D level was correlated with the Hb level, endogenous EPO level, and the endogenous EPO/Hb ratio. Multiple regression analysis revealed that the serum 1,25(OH)2D level remained significantly associated with the Hb level (ß = 0.532, P < 0.001), endogenous EPO level (ß = 0.149, P = 0.010), and the endogenous EPO/Hb ratio (ß = - 0.187, P = 0.002), even after adjusting for other confounding factors, including the levels of parathyroid hormone and the inflammatory marker C-reactive protein. CONCLUSION: The serum 1,25(OH)2D level exhibited significant associations with anemia, EPO deficiency, and endogenous EPO resistance in CKD patients. These associations were independent of secondary hyperparathyroidism and inflammation status.

Treatment of Posttransplantation Anemia.

Kidney transplantation represents a renal replacement therapy for end-stage renal failure, with outcomes improving from year to year. With the improved survival prognosis, treatment of complications of chronic kidney disease after transplantation is becoming increasingly important. In particular, posttransplantation anemia (PTA) is often protracted, which could be related to a variety of factors, including the renal function status, graft rejection episodes, and infectious causes. PTA occurs in about 30-40% of transplant recipients, and is known to affect the function of the transplanted kidney as well as patient survival. Early PTA is associated with a risk of death and cardiovascular disorders, however, during this phase, priority is given to the appropriate maintenance of immunosuppression rather than to the treatment of anemia. Maintenance-phase PTA exerts a strong influence on the survival, prognosis of the transplanted kidney, quality of life, etc. Unlike the disease state and treatment of usual renal anemia, it has been suggested that PTA may possibly reflect the functional state of the transplanted kidney. Therefore, it has been suggested that proper renal function may be maintained by ensuring a normal hemoglobin level in kidney transplant recipients. Proper management of PTA could be expected to be associated with an improved prognosis of the transplanted kidney and improved patient survival in kidney transplant recipients. It is advisable to provide appropriate treatment by setting target levels in accordance with the dialysis vintage, primary disease, cardiovascular complications, and kidney transplant function and delineation of the transplant recipient characteristics.

Epoetin alfa resistance in hemodialysis patients with chronic kidney disease: a longitudinal study.

Anemia is an inevitable complication of hemodialysis, and the primary cause is erythropoietin deficiency. After diagnosis, treatment begins with an erythropoiesis-stimulating agent (ESA). However, some patients remain anemic even after receiving this medication. This study aimed to investigate the factors associated with resistance to recombinant human erythropoietin therapy with epoetin alfa (αEPO). We performed a prospective, longitudinal study of hemodialysis patients receiving treatment with αEPO at our reference hospital from July 2015 to June 2016. Clinical data was collected, and the response to αEPO treatment was evaluated using the erythropoietin resistance index (ERI). The ERI was defined as the weekly weight-adjusted αEPO dose (U/kg per week)/hemoglobin level (g/dL). A longitudinal linear regression model was fitted with random effects to verify the relationships between clinical and laboratory data and ERI. We enrolled 99 patients (average age, 45.7 (±17.6) years; male, 51.5%; 86.8% with hypertension). The ERI showed a significant positive association with serum ferritin and C-reactive protein, percentage interdialytic weight gain, and continuous usage of angiotensin receptor blocker (ARB) hypertension medication. The ERI was negatively associated with serum iron and albumin, age, urea reduction ratio, and body mass index. Our findings indicate that resistance to αEPO was related to a low serum iron reserve, an inflammatory state, poor nutritional status, and continuous usage of ARBs.

Tubular immaturity causes erythropoietin-deficiency anemia of prematurity in preterm neonates.

Kidneys are physiologically hypoxic due to huge oxygen consumption for tubular reabsorption. The physiological hypoxia makes the kidney an appropriate organ for sensitively detecting oxygen levels and producing erythropoietin (EPO). In preterm neonates, immature kidneys cannot produce sufficient EPO, which results in anemia of prematurity (AOP). The cause of EPO insufficiency in AOP has been unclear, therefore current therapeutic options are transfusion and injection of recombinant human EPO. This report shows that the cause of insufficient EPO production in AOP is elevated renal oxygen levels due to poor oxygen consumption by immature tubules. Neonatal mice with AOP showed low tubular transporter expression and elevated renal oxygen levels compared with those without AOP. Enhancing transporter expression in AOP mice induced renal hypoxia and EPO production. In preterm neonates, red blood cell counts, hemoglobin levels, and hematocrit levels correlated with tubular function, but not with serum creatinine, gestational age, or birth weight. Furthermore, pharmacological upregulation of hypoxia signaling ameliorated AOP in mice. These data suggest that tubular maturation with increased oxygen consumption is required for renal EPO production.

Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology. / Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología.

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease.

Epoetin alfa resistance in hemodialysis patients with chronic kidney disease: a longitudinal study

Anemia is an inevitable complication of hemodialysis, and the primary cause is erythropoietin deficiency. After diagnosis, treatment begins with an erythropoiesis-stimulating agent (ESA). However, some patients remain anemic even after receiving this medication. This study aimed to investigate the factors associated with resistance to recombinant human erythropoietin therapy with epoetin alfa (αEPO). We performed a prospective, longitudinal study of hemodialysis patients receiving treatment with αEPO at our reference hospital from July 2015 to June 2016. Clinical data was collected, and the response to αEPO treatment was evaluated using the erythropoietin resistance index (ERI). The ERI was defined as the weekly weight-adjusted αEPO dose (U/kg per week)/hemoglobin level (g/dL). A longitudinal linear regression model was fitted with random effects to verify the relationships between clinical and laboratory data and ERI. We enrolled 99 patients (average age, 45.7 (±17.6) years; male, 51.5%; 86.8% with hypertension). The ERI showed a significant positive association with serum ferritin and C-reactive protein, percentage interdialytic weight gain, and continuous usage of angiotensin receptor blocker (ARB) hypertension medication. The ERI was negatively associated with serum iron and albumin, age, urea reduction ratio, and body mass index. Our findings indicate that resistance to αEPO was related to a low serum iron reserve, an inflammatory state, poor nutritional status, and continuous usage of ARBs.

Total Synthesis of (+)-Medicarpin.

(+)-Medicarpin has been synthesized asymmetrically for the first time in a linear scalable process with an overall yield of 11%. The two chiral centers were constructed in one step via condensation using a chiral oxazolidinone auxiliary. This method will likely accelerate research on medicarpin as an erythropoietin inducer for erythropoietin-deficient diseases.

Increased ventilation in female erythropoietin-deficient mouse line is not progesterone and estrous stage-dependent.

Previous studies suggest that chronic erythropoietin (Epo) deficiency in male mice does not alter normoxic/hypoxic ventilation. As effects of Epo are sex specific and as progesterone could be a respiratory stimulant, we evaluated the impact of Epo deficiency and its possible interaction with progesterone in ventilatory control in female mice during estrous cycle phases. Compared to wild type (WT) animals, Epo-TAgh female mice exhibited higher ventilation in hypoxia. However, when data were separated into luteal and follicular phases of the estrous cycle, basal ventilation and hypoxic ventilation were not different in both mice strains. As progesterone is known to be a potent respiratory stimulant, additional experiments were performed to elucidate its role. Interestingly, after mifepristone treatment, HVR was not modified in WT and Epo-TAgh mice, showing that the ventilatory stimulation observed in females was not directly mediated by progesterone. We conclude that Epo-TAgh female mice show no estrous stage-dependent increase of ventilatory control and progesterone independent response to hypoxia.

[Erythropoietin stimulating agents in chronic kidney disease: indications and contraindications].

Erythropoietin (EPO) deficiency is important complication of chronic kidney disease. It downregulates red cells maturation and production causing renal anemia. It is associated with reduced quality of life, increased risk of blood transfusions and cardiovascular morbidity. It is possible to substitute EPOwith recombinant human EPOor its derivatives - erythropoiesis stimulating agents (ESA). ESA therapy reduces blood transfusions, improves quality of life and can raise hemoglobin to 10-11.5 g/dl. Higher hemoglobin targets bring more harm than benefit - including increased risk for stroke, hypertension and vascular access thrombosis and mortality. Initiation of ESA therapy should be preceded by excluding the other causes of anemia and balancing ESA advantages and disadvantages in every patient. In patients with previous stroke, previous or current malignancy risks of ESA therapy may outweigh the risks of red cell transfusions.

[Hospital-acquired anemia: Facts, consequences and prevention]. / Anémies nosocomiales : réalité, conséquences et prévention.

Hospital-acquired anemia is common, especially in the most critically ill patients. It may be associated with poor patient outcomes. It may result from increased blood loss, impaired red cell production or reduced red cell life span. Multiple associated factors may contribute simultaneously or sequentially to the decrease in hemoglobin level. Some of them are related to the underlying disease and others are iatrogenic. Clinicians should be aware of the importance and consequences of iatrogenic anemia caused by diagnostic blood sampling. Strategies and measures to minimize iatrogenic blood loss should be prioritized. They may reduce the risk of developing anemia and then red blood cells transfusion requirement.

Pharmacological targeting of the HIF hydroxylases--A new field in medicine development.

In human cells oxygen levels are 'sensed' by a set of ferrous iron and 2-oxoglutarate dependent dioxygenases. These enzymes regulate a broad range of cellular and systemic responses to hypoxia by catalysing the post-translational hydroxylation of specific residues in the alpha subunits of hypoxia inducible factor (HIF) transcriptional complexes. The HIF hydroxylases are now the subject of pharmaceutical targeting by small molecule inhibitors that aim to activate or augment the endogenous HIF transcriptional response for the treatment of anaemia and other hypoxic human diseases. Here we consider the rationale for this therapeutic strategy from the biochemical, biological and medical perspectives. We outline structural and mechanistic considerations that are relevant to the design of HIF hydroxylase inhibitors, including likely determinants of specificity, and review published reports on their activity in pre-clinical models and clinical trials.

Iron therapy in chronic kidney disease: Recent changes, benefits and risks.

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800 ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

Análise da anemia por deficiência relativa de ferro e eritropoietina de pacientes com insuficiênciarenal crônica em tratamento hemodialítico / Analysis of anemia relative deficiency of iron and erythropoietin in patients with chronic renal failure in hemodialysis

Introdução: A anemia ferropriva é uma importante complicação da insuficiência renal crônica, apresentando como causa mais comum, a deficiência de eritropoetina. Objetivo: Analisar a anemia por deficiência relativa de ferro e eritropoietina de pacientes com insuficiência renal crônica em tratamento hemodialítico. Métodos: Trata-se de estudo descritivo, transversal, documental, com abordagem quantitativa realizada em uma clí- nica especializada em tratamento renal na qual a amostra foi constituída por 72 pacientes com doença renal crônica. O estudo foi realizado durante o período de janeiro a dezembro de 2013. Foi utilizado um questionário semiestruturado pró- prio. O tratamento dos dados se deu por epidemiologia descritiva. O projeto foi aprovado pelo Comitê de Ética em Pesquisa, protocolo nº 705677. Foi analisado, através da análise dos prontuários, o registro laboratorial mensal dos ní- veis de hemoglobina, hematócrito, índice de saturação de transferrina e ferritina, no período de um ano. As estatísticas descritivas foram apresentadas em percentuais. As médias anuais da variação dos níveis laboratoriais de cada paciente foram classificadas de acordo com os valores de referência utilizados: em baixa, alvo ou alta. Resultados: A média de idade dos 72 pacientes foi de 44 ± 14, sendo 79% do sexo masculino e 21% feminino. Hemoglobina menor que 11g/dL foi verificada em 25% dos pacientes. Deficiência de ferro (%SAT <20%) foi diagnosticada em 7%. Observou-se que 8% apresentaram níveis de ferritina abaixo do esperado(<200ng/dL). Do total de pacientes com (%SAT< 20%), 4,2% apresentavam ferritina dentro dos parâ- metros normais, um paciente apresentou níveis de ferritina aumentados e um outro paciente mostrou-se com valores de ferritina diminuídos. Dos pacientes considerados anêmicos, 18,05% apresentavam %SAT normal e ferritina elevados. Conclusões: A variabilidade de hemoglobina ocorreu mais comumente para níveis mais elevados do que para valores mais baixos. Torna-se necessária a realização de outros estudos a fim de se obter maiores embasamentos para a correção da anemia em portadores de DRC

Background: Iron deficiency anemia is a major complication of chronic renal failure, with as most common cause, erythropoietin deficiency. Objective: Analyze the relative deficiency anemia iron and erythropoietin in patients with chronic renal failure undergoing hemodialysis. Methods: This is a descriptive study, cross, document, with a quantitative approach carried out in a clinic specializing in kidney treatment in which the sample consisted of 72 patients with chronic kidney disease. The study was conducted during the period January to December 2013. A semistructured questionnaire itself was used. The processing of data was by descriptive epidemiology. The project was approved by the Research Ethics Committee, protocol number 705677. Was analyzed by analysis of the records, the monthly record of laboratory hemoglobin, hematocrit, transferrin saturation and ferritin index, within one year. Descriptive statistics were presented in percentages. The average annual variation of laboratory levels of each patient were classified according to the reference values used: low, high or target. Results: The average age of the 72 patients was 44 ± 14, 79% male and 21% female. Hemoglobin less than 11g / dl was found in 25% of patients. Iron deficiency (SAT%<20%) was diagnosed in 7%. It was observed that 8% had ferritin levels lower than expected (<200ng/dL). Of all patients with (SATA%<20%), 4.2% had ferritin within normal parameters, one patient had increased ferritin levels, and another patient showed up with decreased ferritin values. Of patients considered anemic, 18.05% had% Normal SAT and high ferritin. Conclusions: The hemoglobin variability occurs most commonly at higher levels than at lower values. It is necessary to carry out further studies in order to obtain larger emplacements for the correction of anemia in patients with CKD

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[Blunted erythropoietic response in the anemia of anorexia nervosa]. / Disminución de la respuesta eritropoyética en pacientes con anorexia nerviosa y anemia.

BACKGROUND AND OBJECTIVE: The cause of the anemia in anorexia nervosa (AN) has not been fully ascertained. Ferritin, folate and cobalamin values are usually within normal ranges. Anemia does not have a relationship with bone marrow changes and erythropoietin (EPO) levels have not been investigated. The objective of this study was to evaluate the EPO response in a small group of AN patients. PATIENTS AND METHODS: EPO levels were measured in serum samples of 41 female AN patients (11 with anemia, and 30 with normal blood cell count). The adequacy of EPO response was assessed by comparing the increase observed in a group of normal weight patients with anemia. RESULTS: EPO concentrations in anemic AN patients were higher than in non-anemic: 20.63mU/mL (4.04-28.46) vs 8.7mU/mL (3.9-20.93), P=.0088, but the increase in EPO was lower than expected (27.85mU/mL [17.7-118.9]), P=.014. BMI and the difference between actual and expected EPO were inversely correlated. CONCLUSIONS: Inadequate EPO response may partly explain anemia in AN, but further studies are necessary.

Pathophysiology of anemia in chronic kidney diseases: A review.

UNLABELLED: Backgroud. Anemia is one of the laboratory and clinical findings of chronic kidney diseases (CKD). The presence of anemia in patients with CKD has a wide range of clinically important consequences. Some of the symptoms that were previously attributed to reduced renal function are, in fact, a consequence of anemia. Anemia contributes to increased cardiac output, the development of left ventricular hypertrophy, angina, and congestive heart failure. According to current knowledge, anemia also contributes to the progression of CKD and is one of the factors that contribute to the high morbidity and mortality in patients with chronic renal failure and their reduced survival. METHODS: MEDLINE search was performed to collect both original and review articles addressing anemia in CKD, pathophysiology of renal anemia, erythropoiesis, erythropoietin, iron metabolism, inflammation, malnutrition, drugs, renal replacement therapy and anemia management CONCLUSION: The present review summarized current knowledge in the field of the pathophysiology of renel anemia. Understanding the pathophysiology of anemia in CKD is crucial for the optimal treatment of anemia according to recent clinical practice guidelines and recommendation, and correct recognition of causes of resistence to treatment of erythropoietin stimulating agents (ESA).