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)

Optimización del tratamiento con hierro endovenoso en hemodiálisis: Estudio clínico prospectivo a largo plazo / Optimizing iron therapy in hemodialysis: a prospective long term clinical study

A pesar del amplio uso del hierro endovenoso en hemodiálisis, resta aún identificar un índice adecuado para optimizar esta terapéutica en el largo plazo. Con ese objetivo, se diseñó un estudio prospectivo de cohorte, de larga duración, que consistió en un período basal (PB) y dos períodos experimentales: PI y PII. Se infundió hierro dextran de bajo peso molecular a 100, 150 y 200 mg/mes, respectivamente, durante 6 meses y al final de cada periodo se determinaron: saturación de transferrina (TSAT), ferritina (FERR), porcentaje de eritrocitos hipocrómicos (HYPO) y contenido de hemoglobina en reticulocitos (HCr). Durante el estudio la albúmina aumentó significativamente, pero la Hgb, la dosis de EPO y la proteína C-reactiva se mantuvieron sin cambios. Los cambios en HYPO y FERR fueron inespecíficos. Sólo TSAT (desde 21.4 ± 6 en PB a 34 ± 7.1% en PII, p = 0.01) y HCr (desde 27.5 ± 1.3 en PB a 29.3 ± 1.7 pg en PII, P = 0.045) respondieron específicamente, pero el porcentaje de aumento de TSAT fue de 65% (IC95% 22), y el de HCr sólo 6% (IC95% 2.3; p = 0.0002). Esta diferencia a favor de TSAT se observó en todos los pacientes. Los resultados sugieren la utilización de 200 mg/FeIV/mes y que, de los índices estudiados, TSAT sería el más adecuado para optimizar el uso a largo plazo del hierro endovenoso en hemodiálisis.

The usefulness of intravenous iron therapy in hemodialysis is evidence-based. However, controversy still arises about the most suitable iron marker to optimize this treatment in the long term. We aimed to determine the most suitable marker with a prospective, cohort study, designed to comprise a basal period (BP) and two consecutive experimental periods (PI, PII). Low molecular weight iron dextran was infused at 100, 150 and 200 mg/month respectively, on a biweekly basis, during 6 months. At the end of each period, the following were determined: transferrin saturation (TSAT), ferritin (FERR), percentage of hypochromic eritrocytes (HYPO) and haemoglobin content in reticulocytes (HCr). During the study, albumin increased significantly, whereas no significant changes in hemoglobin, EPO doses and C-reactive protein were observed. Changes in HYPO and FERR were unspecific. Only TSAT (from 21.4 ± 6 in PB to 34 ± 7.1% in PII, p < 0.01) and HCr (from 27.5 ± 1.3 in PB to 29.3 ± 1.7 pg in PII, P < 0.05 ) responded specifically to changes in Fe doses, but change of TSAT was 65% (CI 95% 22), whereas change of HCr was just 6% (CI 95% 2.3; p = 0.0002). The difference was observed in all patients. Results suggest that 200 mg/FeIV/month is effective and that, of the markers tested in this study, TSAT would be the most suitable one to the practicing nephrologist to optimize intravenous iron in the long term.

Adherence and side effects of three ferrous sulfate treatment regimens on anemic pregnant women in clinical trials / Adesão e efeitos colaterais em ensaio clínico comparando três esquemas de tratamento com sulfato ferroso em gestantes anêmicas

The objective of this study was to analyze adherence and side effects of three iron supplement regimens (ferrous sulfate) on anemic pregnant women. The clinical trial involved 150 women between the 16th and 20th gestational weeks, at low obstetric risk and with hemoglobin concentration of between 8.0 and 11.0g/dL. Treatment was provided by ferrous sulfate with 60mg of elemental iron during 16 (± 1) weeks, in three regimens: single tablet a week (n = 48); single tablet twice a week (n = 53) or single tablet a day (n = 49). The outcomes were adherence, assessed through interviews and by counting tablets, and side effects, according to patient information. The adherence showed a declining trend (92 percent, 83 percent and 71 percent; p = 0.010) and the side effects revealed a growing trend (40 percent, 45 percent and 71 percent; p = 0.002) as the dosage increased. Diarrhea and epigastric pain were significantly associated with the dose administered (p = 0.002). These results suggest that in anemic pregnant women, complaints are directly proportional and the compliance is inversely proportional to the amount of medicinal iron.

O objetivo deste estudo foi analisar a adesão e os efeitos colaterais de três esquemas de suplementação com sulfato ferroso em gestantes anêmicas. O ensaio clínico incluiu 150 mulheres entre a 16ª e 20ª semanas de gestação, de baixo risco obstétrico e com concentração de hemoglobina entre 8,0 e 11,0g/dL. A intervenção foi realizada com 60mg de ferro elementar, durante 16 (±1) semanas, em três esquemas: uma drágea semanal (n = 48); uma drágea duas vezes por semana (n = 53) ou uma drágea diariamente (n = 49). Os desfechos foram adesão, verificada por entrevista e contagem das drágeas, e efeitos colaterais auto-relatados pelas pacientes. A adesão apresentou tendência declinante (92 por cento, 83 por cento e 71 por cento; p = 0,010) e os efeitos colaterais, ascendente (40 por cento, 45 por cento e 71 por cento; p = 0,002) com o aumento da dose prescrita. Diarréia e dor epigástrica estiveram significativamente associadas à dose administrada (p = 0,002). Os resultados sugerem que em gestantes anêmicas as queixas e a adesão ao tratamento com sulfato ferroso são, respectivamente, direta e inversamente proporcionais à quantidade do ferro medicamentoso.

Impact of iron-folic acid supplementation on cognitive abilities of school girls in vadodara.

OBJECTIVES: To assess impact of daily and intermittent iron-folate (IFA) supplementation on cognition of underprivileged primary schoolgirls in Vadodara. DESIGN: Experimental-control longitudinal study. SETTING: Municipal primary schools. PARTICIPANTS: Schoolgirls (n=161) in the age group of 9 - 13 years. Intervention: Participants at three randomly selected schools were given IFA tablets (100 mg elemental iron + 0.5 mg folic acid) either once weekly or twice weekly or daily for one year. The fourth was the control school. OUTCOME MEASURES: Digit span, maze test, visual memory test, and clerical task scores. RESULTS: IFA supplementation given daily and twice-weekly significantly improved cognition in most tests; the effect was not seen in once-weekly or control groups. In daily and twice weekly IFA groups, positive change in cognition test scores was relatively higher in girls with good compliance(< 70 % dose) vs. poor compliance; in anemic (hemoglobin < 11 g/dL) vs non-anemic girls and in those with higher hemoglobin (Hb) gain (< 1g/dL) vs. lower Hb gain. CONCLUSION: Twice weekly IFA supplementation is comparable to daily IFA in terms of beneficial effects on cognition in young adolescent girls.

Treament and prevention of anemia with ferrous sulfate plus folic acid in children attending daycare centers in Goiânia, Goiás State, Brazil: a randomized controlled trial / Resposta terapêutica e profilática com ferro e ácido fólico na anemia em crianças de creches públicas em Goiânia, Goiás, Brasil: ensaio clínico randomizado

The objective of this study was to assess the prevalence of anemia and the therapeutic and prophylactic response to ferrous sulfate and folic acid. A double-blind, randomized, controlled clinical trial was conducted with 196 children 6 to 24 months of age enrolled in municipal daycare centers in Goiânia, Goiás State, Brazil. The children were assigned to two treatment groups that received a daily dose (5 times a week) of either 4.2mg/kg/day of ferrous sulfate + folic acid (50µg) or 4.2mg/kg/day of ferrous sulfate + folic acid placebo. One of the prevention groups received 1.4mg/kg/day of ferrous sulfate + folic acid (50µg/day) and the other 1.4mg/kg/day of ferrous sulfate + folic acid placebo. Supplementation lasted approximately three months. Baseline anemia prevalence was 56.1 percent (95 percentCI: 48.9-63.1). After treatment, anemia prevalence in the folic acid group (14 percent) was lower than in the placebo group (34.9 percent) (p = 0.02). After prophylaxis in the non-anemic children, the incidence of anemia did not differ between the groups, but there was an increase in hemoglobin level in the folic acid group (p = 0.003). Iron plus folic acid was effective for the treatment of anemia and improvement of hemoglobin level in non-anemic children.

Avaliar a prevalência de anemia e a resposta terapêutica e profilática do sulfato ferroso e ácido fólico. Realizou-se um ensaio clínico controlado randomizado, duplo-cego, com 196 crianças de 6 a 24 meses, dos Centros Municipais de Educação Infantil de Goiânia, Goiás, Brasil. As crianças foram alocadas em dois grupos de tratamento que receberam dose diária (5x/semana) com 4,2mg/kg/dia de sulfato ferroso + ácido fólico (50µg) ou 4,2mg/kg/dia de sulfato ferroso + placebo de ácido fólico. Um dos grupos de prevenção recebeu 1,4 mg/kg/dia de sulfato ferroso + ácido fólico (50µg/dia) e o outro 1,4mg/kg/dia de sulfato ferroso + placebo de ácido fólico. A suplementação durou cerca de três meses. A prevalência de anemia inicial foi de 56,1 por cento (IC95 por cento: 48,9-63,1). Após o tratamento, a prevalência de anemia no grupo ácido fólico (14 por cento) foi menor que no grupo placebo (34,9 por cento; p = 0,02). Após profilaxia dos não anêmicos, a incidência de anemia não diferiu entre os grupos, porém, houve incremento da hemoglobina no grupo ácido fólico (p = 0,003). O ferro associado com ácido fólico foi eficaz no tratamento da anemia e na melhoria da hemoglobina nos não anêmicos.

Antianemic effect of once weekly regimen of epoetin alfa 40,000 units in anemic cancer patients receiving chemotherapy.

BACKGROUND: Anemia is a common problem in the cancer population that is the result of clinical consequences. It also has adverse effects on patients' perceived quality of life. Good management of anemia in the cancer population is therefore essential. A recent published clinical trial has demonstrated statistically significant increases in hemoglobin levels and significantly increased QOL assessment following the administration of recombinant erythropoietin. OBJECTIVE: To evaluate the effectiveness, the safety, and the quality of life by using once weekly dosing of Epoetin alfa (Eprex, Janssen-cilag) 40,000 units in the treatment of anemia in cancer patients receiving chemotherapy. SETTING: Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University Bangkok, Thailand. MATERIAL AND METHOD: This was an open label, non-randomized study, in 41 adult male and female anemic cancer patients who had non-myeloid malignancies in the upper area of the body part and hemoglobin ranging from 9-11 g/dL receiving chemotherapy at least 8 weeks with or without concurrent radiotherapy. The subjects were treated with Epoetin alfa 40,000 units once a week subcutaneously. If, the hemoglobin did not increase by > 1.0 g/dl after 4 weeks of treatment, the dose of Epoetin alfa was then increased to 60,000 units per dose subcutaneously at week 5. The Epoetin alfa treatment would continue for a total of 16 weeks. Clinical outcome was evaluated based on quality of life by using the linear analog scale assessment (LASA) and the functional assessment of cancer therapy-anemia (CU-QOL) instrument. Analyses were performed to determine the incremental change in QOL associated with hemoglobin increases. RESULTS: Seventy six percent of patients receiving Epoetin alfa subcutaneously showed good response with hemoglobin increases of > or = 1 g/dL (Hb level before and after = 9.82 +/- 0.78 g/dL and 12.56 +/- 1.49 g/dL, respectively; p < 0. 001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level and ability to do daily activities evaluated from LASA and fatigue assessed from CU-QOL, were significantly greater (p < 0.01) for week 16 (233.94 +/- 56.01 and 18.45 +/- 13.07) compared to the baseline (202.58 +/- 36.74 and 25.09 +/- 11.00). Epoetin alfa was well tolerated in all patients. CONCLUSION: Once weekly dosing of Epoetin alfa 40,000 units therapy is safe and effective in remodeling anemia and significantly improves the quality of life in cancer patients receiving chemotherapy. Therefore, the physician should maintain hemoglobin concentration of cancer patients in normal level to improve their quality of life through the chemotherapy period.

O uso intravenoso de sacarato de hidróxido de ferro III em pacientes com anemia ferropriva / Evaluation of the efficacy of intravenous iron III-hydroxide saccharate for treating adult patients with iron deficiency anemia

OBJETIVO: Avaliar a eficácia do uso intravenoso de sacarato de hidróxido de ferro III no tratamento de pacientes adultos com anemia ferropriva que não obtiveram resposta satisfatória à terapia com ferro oral. MÉTODOS: No período de janeiro de 2003 a janeiro de 2004, estudamos 25 pacientes com anemia ferropriva que apresentaram intolerância e/ou resposta inadequada ao tratamento com ferro por via oral e/ou valor de hemoglobina < 7 g/dl. Os principais exames laboratoriais realizados foram: hemograma completo, contagem de reticulócitos, ferro sérico, capacidade total de ligação de ferro e ferritina sérica. Os pacientes receberam uma dose semanal de 200 mg de sacarato de hidróxido de ferro III diluído em 250 ml de soro fisiológico 0,9 por cento administrado por via intravenosa em 30 minutos. O tratamento foi realizado até a obtenção dos valores de hemoglobina =12 g/dl para mulheres e =13 g/dl para homens, ou até a administração da dose total de ferro parenteral recomendada para cada paciente. RESULTADOS: A idade mediana dos 25 pacientes estudados foi de 45 anos, variando entre 31 e 70 anos; 19 (76 por cento) eram do sexo feminino. A causa mais comum de anemia ferropriva no sexo feminino foi sangramento uterino anormal observado em 13/19 pacientes (68 por cento) e, no sexo masculino, gastrectomia parcial observada em 4/6 (67 por cento). Dezessete (68 por cento) pacientes foram incluídos neste estudo por falta de resposta à terapia com ferro oral, 6/25 (24 por cento) por intolerância ao ferro oral e 2/25 (8 por cento) por hemoglobina < 7 g/dL. Correção da anemia foi obtida em 12/19 (63 por cento) dos pacientes do sexo feminino e em 5/6 (83 por cento) dos pacientes do sexo masculino. Os valores médios da hemoglobina e da ferritina eram de 8,09 g/dl e 4,20 ng/ml (pré-tratamento) e 12,42 g/dl e 87,78 ng/ml (pós-tratamento) (p<0,001), respectivamente. O aumento médio de hemoglobina foi de 3,74 g/dl, variando entre 1,30 g/dl e 7,60 g/dl. Nenhum paciente recebeu transfusão de sangue durante ou após o tratamento com ferro intravenoso. CONCLUSÃO: O uso intravenoso de sacarato de hidróxido de ferro III é uma opção eficaz e segura no tratamento de pacientes adultos com anemia ferropriva que não obtiveram resposta satisfatória com a utilização do ferro oral. Esta opção terapêutica deve ser levada em consideração sobretudo nos pacientes com intensa anemia a fim de se obter rápido aumento dos valores da hemoglobina e se evitar transfusão de sangue.

Clinical benefits of epoetin alfa (Eprex) 10,000 units subcutaneously thrice weekly in Thai cancer patients with anemia receiving chemotherapy.

BACKGROUND: Recently the American society of clinical oncology and the American society of hematology have jointly launched the clinical practice guideline of epoetin usage in cancer related anemia patients The recommended starting dose is 150-300 unit/kg thrice weekly. The clinical outcome of epoetin alfa 10,000 units subcutaneously thrice weekly regimen has not been evaluated in Thai cancer patients with anemia yet. OBJECTIVES: To determine the clinical benefits and safety of epoetin alfa (Eprex) 10,000 units subcutaneously thrice weekly in anemic cancer patients receiving chemotherapy PATIENTS: The present study was an open label, non-randomized study. Adult patients were eligible for inclusion aged >18 years with a confirmed diagnosis of non-myeloid malignancy in the upper area of the body and scheduled to receive chemotherapy regardless of the concurrent radiotherapy. All patients had hemoglobin (Hb) level less than 11 g/dL, serum ferritin more than 100 ng/dL and had a life expectancy of at least 6 months. MATERIAL AND METHOD: All patients were initially treated with Epoetin alfa 10,000 units subcutaneously thrice weekly. The dose was up to 20,000 units after 4 weeks of therapy, if Hb level did not increase by > 1.0 g/dL. Treatment time was 16 weeks. Target Hb was 12 g/dL Blood transfusion and iron supplement was permitted. Efficacy Assessments: The primary efficacy end point was the proportion of responders (patients with an increase in Hb > or =1 g/dL). Secondary efficacy evaluation was change in Quality of life (QOL) scores by the Linear Analog Scale Assessment (LASA) and Quality of life-Chula (QOL-CU) scale. Statistical Analysis was t-tests, P < 0.05 was considered significant. RESULTS: Forty patients (21 men and 19 women) were enrolled. Twenty five patients (62.5%) had stage of disease in grade III or IV The mean Hb levels at baseline were 8.46 +/- 1.28 g/dL. Eight patients (20%) refused to complete the course during the study. Reasons for refusing to participate included lack of time, changing the resident area or disease progression. Twenty three of 32 patients (71.8%) were responders. These patients completed the study course and showed good response. Their mean Hb levels increased gradually and reach approximately 11 g/dl by week 4 and were maintained through week 16. The significant difference in mean Hb level of baseline was initially found at week 4 of the study (10.26 +/- 1.95 g/dl; p = 0.001 vs baseline). The LASA score increased in all of three items including level of energy, ability to do daily activities, and overall QOL but not statistical significance. However, the improvement of quality of life of cancer patients, evaluated by QOL-CU, was significantly apparent after treatment, (p < 0.05). The most common adverse events were grade I flu like symptoms (17.5%) and recovered the next day. CONCLUSION: Epoetin alfa (Eprex) 10,000 units thrice weekly significantly increased the hemoglobin levels, achieving the target hemoglobin and sustained the level in cancer patients with anemia receiving chemotherapy. Clinical benefits on functional status and quality of life were also improved. The treatment was well tolerated.

Utilização de diferentes concentrações de ferro por adolescentes grávidas também suplementadas com zinco e ácido fólico / Utilization of different iron concentrations on pregnant adolescents also supplemented with zinc and folate

The pregnant teenager is considered at nutritional risk specially due to the fact that most of them still growing and developing. Therefore the demands of pregnancy compete with those of growth causing an extra need for her and the fetus (1). Iron, zinc and folate are essential nutrients that are frequently low on the teenagers diet. Besides that there is not much specific information available about these nutrient recommendations and their interaction among each other. The data available is limited and demands more investigation. This study was conducted at a Public Maternity Hospital located at Teresina, Piauf, Brazil. The main objective of this study was to investigate the effect of different concentrations of iron supplementation (80 and 120 mg of ferrous sulfate) together with folate (250 micrograms) and zinc (5 mg) on the hemoglobin concentration and iron stores (plasma ferritin) of pregnant adolescents. The supplementation was done from the 16th to 20th weeks of gestation until delivery. The data founded proved that either 80 mg or 120 mg of iron supplements had similar effect on the improvement of hemoglobin concentration although results showed no statistical significance.

Anaemia, iron studies and erythropoietin in patients of chronic renal failure.

OBJECTIVE: The use of erythropoietin (EPO) for the amelioration of anemia has dramatically changed the quality of life of the patients with chronic renal failure (CRF). The efficacy of a low dose EPO therapy was assessed in the prospective 6 week trial. METHODS: Assessment of hematological parameters and iron stores was done in 40 patients of CRF: Group A--20 patients of CRF receiving 40 U/kg EPO biweekly for 6 weeks and Group B--20 patients of CRF not receiving EPO. The parameters were studied at the start and at 2, 4 and 6 weeks of the study. RESULTS: A statistically significant rise in mean haemoglobin levels (7.27 +/- 1.26 g/dl to 8.60 +/- 1.66 g/dl); mean packed cell volume (21.4 +/- 4.04% to 25.4 +/- 6.54%) and mean reticulocyte count (1.28 +/- 0.4% to 2.14 +/- 0.86%) was observed on EPO therapy. Patients on EPO developed a significant decline in serum iron, serum ferritin levels, bone marrow iron stores; and a hypochromic-microcytic picture on the peripheral blood film suggestive of iron deficiency. Iron deficiency at the start, chronic infections like tuberculosis and inadequate haemodialysis were identified as causes of hyporesponsiveness to EPO therapy. Low dose EPO therapy was not associated with any major adverse effects. CONCLUSIONS: Low dose EPO (40 U/kg, biweekly) therapy is safe and effective in the management of anaemia of CRF.