Enzymes involved in l-lactate metabolism in humans.

l-lactate formation occurs via the reduction of pyruvate catalyzed by lactate dehydrogenase. l-lactate removal takes place via its oxidation into pyruvate, which may be oxidized or converted into glucose. Pyruvate oxidation involves the cooperative effort of pyruvate dehydrogenase, the tricarboxylic acid cycle, and the mitochondrial respiratory chain. Enzymes of the gluconeogenesis pathway sequentially convert pyruvate into glucose. In addition, pyruvate may undergo reversible transamination to alanine by alanine aminotransferase. Enzymes involved in l-lactate metabolism are crucial to diabetes pathophysiology and therapy. Elevated plasma alanine aminotransferase concentration has been associated with insulin resistance. Polymorphisms in the G6PC2 gene have been associated with fasting glucose concentration and insulin secretion. In diabetes patients, pyruvate dehydrogenase is down-regulated and the activity of pyruvate carboxylase is diminished in the pancreatic islets. Inhibitors of fructose 1,6-bisphosphatase are being investigated as potential therapy for type 2 diabetes. In addition, enzymes implicated in l-lactate metabolism have revealed to be important in cancer cell homeostasis. Many human tumors have higher LDH5 levels than normal tissues. The LDHC gene is expressed in a broad range of tumors. The activation of PDH is a potential mediator in the body response that protects against cancer and PDH activation has been observed to reduce glioblastoma growth. The expression of PDK1 may serve as a biomarker of poor prognosis in gastric cancer. Mitochondrial DNA mutations have been detected in a number of human cancers. Genes encoding succinate dehydrogenase have tumor suppressor functions and consequently mutations in these genes may cause a variety of tumors.

Evolución del índice de resistencia a darbepoetina alfa en pacientes dializados que cambian de administración semanal a quincenal en la práctica clínica / Evolution of the darbepoetin alpha resistance index in patients on dialysis who change from weekly to fortnightly treatments in clinical practice

Antecedentes: Diversos estudios han demostrado la eficacia de darbepoetina alfa (DA) administrada quincenalmente (C2S), lo que permite simplificar el tratamiento para la anemia, pero faltan datos acerca de la evolución del índice de resistencia (IRE) tras el espaciamiento desde una frecuencia semanal (CS) en la práctica clínica. Material y métodos: Estudio observacional, multicéntrico, retrospectivo, con 16 semanas de seguimiento, en pacientes dializados estables convertidos de DA CS a C2S. El espaciamiento se realizó según ficha técnica (duplicación de dosis semanal). El cálculo del IRE fue: dosis DA (µg/sem.kg*200)/Hb (g/dl). Se analizó la evolución del IRE mediante un ANOVA multivariado de medidas repetidas, ajustando por variables confusoras. Resultados: Se reclutaron 202 pacientes (137 en hemodiálisis [HD], DA intravenosa, y 65 con diálisis peritoneal [DP], DA subcutánea). La edad media (DE) fue 66 (17) años, y el 61% eran hombres. Se apreció una gran variabilidad intercentro en el IRE basal (coeficiente de variación del 88%, p <0,001 para diferencias entre centros). En el análisis univariado los factores predictores de IRE elevado fueron un bajo nivel de albúmina, la HD, o los antecedentes de enfermedad cardiovascular. Durante el seguimiento, el IRE aumentó ligeramente en los pacientes con HD (9,3 [8,4] basal frente a 11,1 [7,3] a 16 semanas; p <0,05), y se mantuvo estable en los pacientes con DP (6,8 [4,6] frente a 6,7 [4,0], respectivamente; NS). En el análisis multivariado, tras ajustar por los niveles de albúmina y el centro, el IRE global no presentó cambios significativos (media [IC 95%] basal de 10,0 [8,7-11,4] frente a 10,5 [9,3-11,8] a las 16 semanas, cambio ajustado de +0,5 [–0,67; 1,67]; NS). Conclusiones: La conversión de frecuencia semanal a quincenal de DA logró mantener el IRE, con independencia del tipo de diálisis. El análisis multivariado refleja que, una vez ajustado por las variables centro y estado de inflamación/nutricional del paciente, no hay cambios en el IRE en las primeras 16 semanas tras el espaciamiento (AU)

Background: Darbepoetin alfa (DA) administered every-other-week (Q2W) is efficacious and safe for the treatment of anaemia in patients undergoing dialysis. There are no data available regarding the evolution of erythropoietic resistance index (ERI) after conversion from weekly (QW) to Q2W administration of DA in clinical practice. Material and methods: Multicenter, observational, retrospective, 16-weeks study, which included stable patients undergoing dialysis who were converted from DA QW to DA Q2W in clinical practice. Conversion was done according to product specifications (duplicating QW dose). The ERI to DA was calculated by dividing the weekly DA dose per kilogram of weight (µg/wk.kg)*200 by the Hb level (g/dL). ERI evolution with time was evaluated by multivariate repeated measures ANOVA, adjusting for significant covariates. Results: A total of 202 patients were included (137 patients undergoing haemodialysis [HD], intravenous (IV) DA, and 65 patients receiving peritoneal dialysis [PD], subcutaneous DA). Mean (SD) age was 66 (17) years; 61% of patients were men. Large intercentre variability was observed for the ERI at conversion time (coefficient of variation of 88%, p <0.001 for differences between centres). In the univariate analysis, predictor factors for high baseline ERI were low albumin level (r = –0.29; p =0.001), HD (mean ERI of 9.3 [8.4] vs 6.8 [4.6] for PD; p = 0.005), or previous cardiovascular disease (9.9 [8.7] vs 7.4 [6.3] for patients without history; p =0.025). During the follow up, the ERI was slightly increased in HD patients (9.3 [8.4] at conversion vs 11.1 [7.3] at 16 weeks; p <0.05), and remained stable in PD patients (6.8 [4.6] vs 6.7 [4.0], respectively; NS). In the multivariate analysis, there were no significant differences in ERI during the 16 weeks post-conversion after adjusting for albumin levels and centre (adjusted baseline mean [95% CI] of 10.0 [8.7-11.4] vs 10.5 [9.3-11.8] at 16 weeks, adjusted change of +0.5 [–0.67; 1.67] ; NS). After 16 weeks, only 7 patients (3.5%) had discontinued Q2W administration. Conclusions: Extension from weekly to once every-other-week darbepoetin alfa allows to simplify anaemia treatment without increasing the resistance index, regardless of dialysis type. The multivariate analysis shows that, after adjusting by center and inflammation/nutritional status, there were no changes in the response to darbepoetin alfa during the first 16 weeks after conversion in clinical practice (AU)

[Evolution of the darbepoetin alpha resistance index in patients on dialysis who change from weekly to fortnightly treatments in clinical practice]. / Evolución del índice de resistencia a darbepoetina alfa en pacientes dializados que cambian de administración semanal a quincenal en la práctica clínica.

BACKGROUND: Darbepoetin alpha (DA) administered every-other-week (Q2W) is efficacious and safe for the treatment of anaemia in patients undergoing dialysis. There are no data available regarding the evolution of erythropoietic resistance index (ERI) after conversion from weekly (QW) to Q2W administration of DA in clinical practice. MATERIAL AND METHODS: Multicenter, observational, retrospective, 16-weeks study, which included stable patients undergoing dialysis who were converted from DA QW to DA Q2W in clinical practice. Conversion was done according to product specifications (duplicating QW dose). The ERI to DA was calculated by dividing the weekly DA dose per kilogram of weight (microg/wk.kg)*200 by the Hb level (g/dL). ERI evolution with time was evaluated by multivariate repeated measures ANOVA, adjusting for significant covariates. RESULTS: A total of 202 patients were included (137 patients undergoing haemodialysis [HD], intravenous (IV) DA, and 65 patients receiving peritoneal dialysis [PD], subcutaneous DA). Mean (SD) age was 66 (17) years; 61% of patients were men. Large intercentre variability was observed for the ERI at conversion time (coefficient of variation of 88%, p < 0.001 for differences between centres). In the univariate analysis, predictor factors for high baseline ERI were low albumin level (r = -0.29; p =0.001), HD (mean ERI of 9.3 [8.4] vs 6.8 [4.6] for PD; p = 0.005), or previous cardiovascular disease (9.9 [8.7] vs 7.4 [6.3] for patients without history; p =0.025). During the follow up, the ERI was slightly increased in HD patients (9.3 [8.4] at conversion vs 11.1 [7.3] at 16 weeks; p < 0.05), and remained stable in PD patients (6.8 [4.6] vs 6.7 [4.0], respectively; NS). In the multivariate analysis, there were no significant differences in ERI during the 16 weeks post-conversion after adjusting for albumin levels and centre (adjusted baseline mean [95% CI] of 10.0 [8.7-11.4] vs 10.5 [9.3-11.8] at 16 weeks, adjusted change of +0.5 [-0.67; 1.67]; NS). After 16 weeks, only 7 patients (3.5%) had discontinued Q2W administration. CONCLUSIONS: Extension from weekly to once every other-week darbepoetin alpha allows to simplify anaemia treatment without increasing the resistance index, regardless of dialysis type. The multivariate analysis shows that, after adjusting by center and inflammation/nutritional status, there were no changes in the response to darbepoetin alpha during the first 16 weeks after conversion in clinical practice.