Persistencia a los inhibidores de la aromatasa en la cohorte SIDIAP: mortalidad e influencia de los bifosfonatos / Persistence to aromatase inhibitors in the SIDIAP cohort: mortality and influence of bisphosphonates

OBJETIVO: Evaluar la persistencia a la terapia con inhibidores de la aromatasa (IA), la mortalidad asociada a la discontinuidad al tratamiento y la influencia de los bifosfonatos (BF) orales, en la práctica clínica habitual. MATERIAL Y MÉTODOS: Estudio prospectivo observacional de mujeres con cáncer de mama en tratamiento con IA entre enero de 2006 y diciembre de 2015, registradas en la base de datos SIDIAP. Se excluyeron aquellas tratadas previamente con tamoxifeno. Se estudió la persistencia al tratamiento con IA con un análisis de supervivencia: se calculó el estimador de Kaplan-Meier, y se realizó un modelo de los riesgos proporcionales (regresión de Cox) entre usuarias y no usuarias de BF ajustando por edad. Se llevó a cabo un análisis de sensibilidad teniendo en cuenta la mortalidad como riesgo competitivo (modelos de Fine y Gray). Se comparó la diferencia de mortalidad entre grupos mediante una prueba Chi cuadrado. RESULTADOS: Se observó una persistencia a los IA del 87% a 5 años de tratamiento, con una mortalidad global del 19,75%. Se registró un 7,7% menos de mortalidad en aquellas pacientes que completaron los 5 años de tratamiento respecto a las que no. Las pacientes con BF mostraron una disminución de la mortalidad (6,6%) y una disminución del riesgo de abandono de la terapia (SHR ajustado: 0,62 [IC 95%: 0,55 a 0,70]) respecto a las no usuarias. CONCLUSIONES: La permanencia a los IA y el uso de BF está asociada a una disminución de la mortalidad global. Además, el uso de BF resulta en un aumento de la adherencia al tratamiento con IA

OBJETIVE: To assess the persistence of aromatase inhibitor (AI) therapy, mortality associated with treatment discontinuation and the influence of oral bisphosphonates (BP) in routine clinical practice. MATERIAL AND METHODS: Prospective observational study of women with breast cancer undergoing AI treatment between January 2006 and December 2015, registered in the SIDIAP database. Those previously treated with tamoxifen were excluded. AI persistence was studied with a survival analysis: the Kaplan-Meier estimator was calculated, and a proportional hazards model (Cox regression) was performed between users and non-users of BP adjusting for age. A sensitivity analysis was carried out taking into account mortality as a competitive risk (Fine and Gray models). The difference in mortality between groups was compared using a Chi square test. RESULTS: A persistence to AI of 87% was observed after 5 years of treatment, with an overall mortality of 19.75%. There was 7.7% less mortality in those patients who completed the 5 years of treatment compared to those who did not. Patients with BP showed a decrease in mortality (6.6%) and a decrease in the risk of discontinuing therapy (adjusted SHR: 0.62 [95% CI: 0.55 to 0.70]) compared to non-users. CONCLUSIONS: Persistence to AI and BP use are associated with a decrease in overall mortality. Furthermore, the use of BP increases adherence to AI treatment

Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss.

Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management.

Failure of regulation results in an amplified oxidation burst by neutrophils in children with primary nephrotic syndrome.

The mechanism responsible for proteinuria in non-genetic idiopathic nephrotic syndrome (iNS) is unknown. Animal models suggest an effect of free radicals on podocytes, and indirect evidence in humans confirm this implication. We determined the oxidative burst by blood CD15+ polymorphonucleates (PMN) utilizing the 5-(and-6)-carboxy-2',7'-dichlorofluorescin diacetate (DCF-DA) fluorescence assay in 38 children with iNS. Results were compared with PMN from normal subjects and patients with renal pathologies considered traditionally to be models of oxidative stress [six anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, seven post-infectious glomerulonephritis]. Radicals of oxygen (ROS) production was finally determined in a patient with immunodeficiency, polyendocrinopathy, enteropathy X-linked (IPEX) and in seven iNS children after treatment with Rituximab. Results demonstrated a 10-fold increase of ROS production by resting PMN in iNS compared to normal PMN. When PMN were separated from other cells, ROS increased significantly in all conditions while a near-normal production was restored by adding autologous cells and/or supernatants in controls, vasculitis and post-infectious glomerulonephritis but not in iNS. Results indicated that the oxidative burst was regulated by soluble factors and that this regulatory circuit was altered in iNS. PMN obtained from a child with IPEX produced 100 times more ROS during exacerbation of clinical symptoms and restored to a near normal-level in remission. Rituximab decreased ROS production by 60%. In conclusion, our study shows that oxidant production is increased in iNS for an imbalance between PMN and other blood cells. Regulatory T cells (Tregs) and CD20 are probably involved in this regulation. Overall, our observations reinforce the concept that oxidants deriving from PMN are implicated in iNS.

Acute effects of simultaneous intraperitoneal infusion of glucose and amino acids.

BACKGROUND: The feasibility of simultaneously infusing glucose and amino acid (AA)-based peritoneal dialysis solutions was tested to determine whether peritoneal dialysis patients could achieve an adequate nonprotein calorie/nitrogen ratio while preventing a marked increase in blood urea nitrogen (BUN), which is usually seen if the AAs are administered without glucose. METHODS: An automatic peritoneal dialysis cycler was used to infuse glucose and AA solutions (3:1) simultaneously during the night. Eight infusions of 1000 mL m2 of body surface area (BSA), with a 60 minute dwell time, were performed in 10 children on peritoneal dialysis. The dialytic effluent was analyzed at every exchange and totaled at eight hours to evaluate volume, glucose, and AA concentration. Blood samples for plasma, glucose, insulin, and free AA determination were drawn at the beginning of automated peritoneal dialysis (APD) session and at each instillation of peritoneal dialysate. RESULTS: The mean glucose absorption was 33.7 +/- 10.0% and the AA absorption was 55.2 +/- 13.2% of the infused amount, and the ratio of nonprotein calorie (derived from glucose) to nitrogen (derived from AA) was 115.4:1. The insulin levels returned to normal only three hours after the beginning of APD. The free AA plasma levels were already increased two hours after dinner and remained high for the entire APD treatment because of the continuous absorption of AA from the peritoneum. The BUN levels did not increase despite the supply of AA. CONCLUSIONS: This APD procedure may improve utilization of AA for protein synthesis, as suggested by the lack of increase of the BUN levels with this regimen.

Characterization of a DNA binding site that mediates the stimulatory effect of cyclosporin-A on type III collagen expression in renal cells.

BACKGROUND: Previous work from our laboratory demonstrated upregulation of type III collagen by cyclosporin A (CsA) in a cellular model of renal fibroblasts 'in vitro', suggesting that a mechanism of gene transcriptional activation might be responsible for collagen accumulation in renal fibrosis resulting from chronic CsA treatment. METHODS: We analysed in the same cellular model: (i) COL3A1 mRNA expression by RT-PCR; (ii) COL3A1 promoter activity by transfection of renal fibroblasts with constructs containing promoter fragments of different length fused to a reporter gene; (iii) expression of transcription factors by western blot analysis; (iv) DNA-protein binding by gel retardation assays with nuclear extracts from CsA-treated and untreated cells; and (v) site-directed mutagenesis of COL3A1 promoter to verify the role of a short DNA segment as CsA responsive element. RESULTS: CsA induced a 3-5-fold increase in COL3A1 mRNA that was paralleled by a stimulation of the COL3A1 promoter. Degradation of COL3A1 mRNA was comparable in CsA-treated and -untreated cells. The target region was first limited to a 178 bp fragment from -117 to +61 (pFV1). By gel retardation, utilizing several oligonucleotides that covered the whole length of pFV1, we detected a factor able to bind the promoter DNA (oligo 31) in nuclear extracts after 3 h treatment with CsA. The binding was absent in untreated cells and it was not detected when a 10-base mutation was introduced in oligonucleotide 31. Finally, the same substitution mutation at the site of binding of this factor abolished the stimulatory effect of CsA on COL3A1 promoter. Some transcription factors, whose potential binding sites are included in the above promoter fragment, were induced by CsA treatment either soon (3 h) or late (24-72 h) after treatment and were detected by western blot analysis. CONCLUSIONS: CsA induces the synthesis of type III collagen by stimulating a pathway leading to activation of COL3A1 promoter and upregulation of COL3A1 mRNA. A short promoter fragment, proximal to the transcription start site, is the target of CsA stimulation.

Children on continuous ambulatorial peritoneal dialysis: muscle and plasma proteins, amino acids and nutritional status.

The aim of the study was to investigate plasma and muscle amino acid (AA) levels in children on continuous ambulatory peritoneal dialysis (CAPD) and their relationship to various indices of nutritional status. Ten children with a mean age of 6.4 +/- 5.6 yrs were evaluated. Muscle biopsies and venous blood samples were taken after an overnight fast. Muscle samples were obtained from rectus abdominis. Data were compared with those of a control group of 22 children who were undergoing elective surgery. Informed consent was obtained from the parents. The plasma concentration of most of the essential AA (valine, leucine, isoleucine, lysine, methionine and tyrosine) were significantly reduced and the levels of some non essential AA (aspartic acid, glycine, citrulline, 1-3 methihystidine, taurine + alanine) were significantly higher than in the controls. Muscle intracellular free essential AA concentrations, except the low levels of valine and leucine did not differ significantly from values in the controls. Among non essential AA, aspartic acid, glutamic acid and ornitine showed significantly increased intracellular concentrations. No significant correlations were found between plasma and muscle AA concentration and ASP (alkali-soluble protein)/DNA ratio, serum albumin, transferrin, bicarbonate levels and duration of CAPD. Instead, a significant correlation was noted between the muscle ASP/DNA ratio, an indicator of the amount of cell proteins per cell unit, and age (r = 0.714, p < 0.05). Muscle Branched chain AA levels were significantly correlated to body mass index (BMI) (r = 0.648, p < 0.05).

Protein and calorie intake, nitrogen losses, and nitrogen balance in children undergoing chronic peritoneal dialysis.

We performed 22 nitrogen balance (NB) studies of three days' duration in 19 children (8.7 +/- 3.8 years) on chronic peritoneal dialysis (CPD) for 19.4 +/- 16.4 months. The dietary intakes were assessed by the double weighing method. Total nitrogen, protein, urea, and creatinine were analyzed in the dialysate and urine collected daily. Total nitrogen was also determined in the feces collected over the whole NB study period, using vegetable charcoal as a marker. The protein intake was 1.64 +/- 0.50 g/kg/day, corresponding to 126 +/- 40% of the recommended daily allowance (RDA) for normal children of the same age, and the calorie intake (diet+glucose from dialysate) reached 75 +/- 26% of RDA. Nitrogen losses were: 0.177 +/- 0.052 g/kg/day with peritoneal fluid and urine, and 0.028 +/- 0.018 g/kg/day with feces. The NB, positive in 17 out of 22 studies, ranged from -116 to +167 mg/kg/day (mean 44.0 +/- 66.2 mg/kg/day). A direct and significant correlation between NB and nitrogen intake (g/kg/day) (r = 0.562, p < 0.05) and total calorie intake (cal/kg/day) (r = 0.483, p < 0.05) has been observed. These data confirm the need to ensure in children on CPD an adequate nutritional intake, and further support the efforts to improve calorie intake.

Nutritional status in children receiving chronic peritoneal dialysis.

Chronic peritoneal dialysis (CPD), widely used in uremic children, may have contrasting effects on the nutritional status of patients. Metabolic and nutritional abnormalities due to the combined effects of uremia per se, glucose absorption from the dialysate and catabolic factors, such as protein and amino acid losses into dialysate, poor appetite, and recurrent episodes of peritonitis are the most important. Although CPD allows for fewer dietary restrictions and supplies an extra amount of calories by glucose absorbed with the peritoneal fluid, when protein and energy intakes are assessed the protein intake was almost sufficient or more than that prescribed, whereas the energy intake was low. In CPD children the standard deviation score for weight, height, triceps skinfold thickness, and midarm circumference has been reported as more severely impaired in children less than ten years old. Anthropometric parameters did not worsen during CPD treatment. Plasma proteins and albumin are reported as being low in CPD children. The dietary intake and protein losses have been considered to be the most important determinants of the albumin level in CPD patients. The reported average dialysate losses of free amino acids (AA) during CPD in children vary from 0.02 to 0.03 g/kg/day in different studies. The patterns of plasma AA in CPD is represented by reduced levels of branched chain AA and of other essential amino acids and increased concentrations of some nonessential AA. Several factors may influence plasma AA profile: uremia per se, hormonal alterations, protein and AA losses, and dietary intake. A more specific uremic AA pattern is found in muscle, the largest pool of free AA in the body. Studies on muscle AA in adults on CPD are conflicting: some authors have reported several muscle AA alterations, but others have shown an almost normal pattern. Low valine and leucine muscle levels have been reported in children on CPD.

Muscle and plasma amino acids and nutritional status in kidney-transplanted children.

Nutritional status, assessed by anthropometric and biochemical methods, protein and amino-acid (AA) composition and muscle water were evaluated in 11 kidney transplanted children and in a control group of 10 children with normal renal function who were undergoing elective surgery. Samples of the rectus abdominis muscle were taken when surgery was performed in the control children and when the peritoneal catheter was removed in the transplanted children. The mean time from the transplantation to the study time was 97 +/- 14 days (range 72-114 days). Height was reduced in the transplanted children compared to the controls but skinfold thickness, arm muscle circumference and serum proteins (total protein, albumin, transferrin, pseudocholinesterase) were normal. The body mass index was over the 50 degree percentile in nine of the eleven children. The muscle contents of total, extracellular, and intracellular water, alkali-soluble protein (ASP), DNA and the ASP/DNA ratio were not significantly different in transplanted children from those in the controls. Plasma leucine and taurine levels were significantly decreased, whereas plasma citrulline and alanine levels and the glycine/serine ratio were increased. Muscle threonine, alanine+taurine, glycine and aspartic acid levels as well as the glycine/serine ratio were increased in the transplanted children. Transplanted children show an almost normal muscle AA profile and a plasma AA pattern that seems to be related to the prednisone therapy.

Proteolytic activity and free amino acid concentrations in polymorphonuclear leucocytes.

Polymorphonuclear granulocytes (PMN) are valuable tools for evaluating amino acid (AA) metabolism in nucleated cells, although variations of free amino acid concentrations due to the methods used for the separation of the cells and the procedures used for lysis have been reported. Furthermore, analytical variations in PMN AA concentration may be induced by protease activation during preparation, so that free AA detected in cells could originate from proteolysis other than from the physiological metabolic pathways and transport systems. To study this possibility we measured granulocyte protease activity and AA concentrations in cell suspensions processed with and without the addition of antiproteolytic agents. Granulocyte AA concentrations and protease activity in samples treated with antiproteolytics were 8-15 times lower than in samples processed without antiproteolytics. The use of protease inhibitors throughout the sample preparation is necessary for reliable estimation of free AA in granulocytes.

Nutritional status and muscle amino acids in children with end-stage renal failure.

Nutritional status, assessed by anthropometric and biochemical methods, and muscle water, protein and amino acid composition, were evaluated in a control group of 10 children with normal renal function who were undergoing elective surgery, and in 15 children with end-stage chronic renal failure. Samples of the rectus abdominis muscle were taken when surgery was performed in the control children and when a peritoneal catheter was implanted in the uremic children. Height and body weight were reduced in the uremic children compared to the controls but skinfold thickness, arm muscle circumference and serum proteins (total protein, albumin, transferrin, pseudocholinesterase) were essentially normal. The muscle contents of total, extracellular and intracellular water, and of alkali-soluble protein (ASP), DNA and the ASP-DNA ratio were not significantly different in uremic children from those in the controls. Plasma leucine, isoleucine, tyrosine, valine, and serine levels were significantly decreased, whereas plasma citrulline, 1-methylhistidine and 3-methylhistidine levels were increased. Muscle isoleucine and valine levels and the valine/glycine ratio were low in the uremic children. Our results demonstrate that children with chronic renal failure and growth retardation may maintain a satisfactory nutritional status but exhibit amino acid abnormalities typical of uremia.

Modulation of proteinuria and renal xanthine oxidase activity by dietary proteins in acute adriamycin nephrosis in rats: lack of correlation with intra- and extracellular amino acids.

Protein restriction ameliorates proteinuria in acute adriamycin (ADR) nephrosis and decreases the renal levels of xanthine oxidase (XO), a putative mediator of ADR nephrotoxicity. Hypothetically, the effect of protein restriction on renal XO levels may be due to variations in plasma and tissue proteic amino acids (AA). To elucidate this point, the levels of AA in plasma and in renal homogenates were determined in rats with ADR nephrosis and fed diets with different protein contents: (a) high (35%) casein; (b) standard (21%) casein; (c) low (9%) casein; (d) low casein plus a synthetic mixture of Val, Leu and Ile. The protein content of the diet determined certain marked variations in plasma AA: high levels of Val, Leu and Ile were found in rats fed on a high protein diet, while the same AA were low, in rats on low protein regimen. Supplementation of the low protein diet with a synthetic mixture of branched-chain AA (Val, Leu and Ile) normalized the plasma levels of these AA. In spite of these changes, tissue AA were similar in all groups, regardless of the protein contents of the diets. Furthermore, the levels of renal XO and proteinuria were unrelated to variations in plasma AA, since both parameters were low in protein-restricted and protein-restricted AA-supplemented rats while high in rats fed a high or normoproteic diet. These data demonstrate that low protein diets induce marked alterations in plasma AA composition which are similar in may respects to those found in protein malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effect of amino-acid dialysis solution in children on continuous ambulatory peritoneal dialysis.

The study involved eight metabolically stable children, with chronic renal failure on continuous ambulatory peritoneal dialysis (CAPD) whom we followed for 12-18 months. For the first 6 months CAPD was performed with dextrose; for the subsequent 6-12 months the morning exchange was substituted with a 1% amino-acid (AA) solution. The following parameters did not change during the study: serum creatinine, uric acid, inorganic phosphate, serum bicarbonate, potassium, cholesterol, triglycerides, total protein, albumin and transferrin. The only parameter that changed was blood urea nitrogen, which increased moderately. The anthropometric parameters did not show significant variation before and after AA dialysis. The plasma AA profile, which under basal conditions showed lower levels of several essential AAs, improved during the treatment period, with a partial correction of the imbalance. It is possible that this correction of plasma AAs may positively influence the metabolism of some organs such as the brain, muscle and those of the hepatosplanchnic region. The intracellular pool of free AAs, measured in polymorphonuclear leucocytes, was severely altered before the treatment and after 6 and 12 months showed only minor variations. It is possible that some modifications in the proportion of the different AAs in the dialysis solution or an improvement in the concentration or in the number of exchanges per day are necessary in order to change the nutritional status and to modify the intracellular AA pool.

Continuous ambulatory peritoneal dialysis (CAPD) of children with amino acid solutions: technical and metabolic aspects.

The changes in plasma and dialysate amino acids (AA) in 7 continuous ambulatory peritoneal dialysis (CAPD) children after dialysis with a 1% AA solution were compared with a glucose-containing solution. During the AA-exchange, the plasma levels of individual AA reached their peaks after 1 h, with their percentage increments significantly correlated (p less than 0.001) with the ratio of the amount of AA in the bag to the basal plasma concentration. The plasma concentration of methionine, valine, phenylalanine, and isoleucine remained higher than the basal value at 4 h. The amount of AA absorbed was 66% after 1 h, and 86% after 4 h and 6 h, corresponding to 2574 +/- 253 mumol/kg body wt. During glucose-dialysis (1.36%), levels of histidine, methionine, valine, phenylalanine, and isoleucine were significantly decreased in plasma after 1 h, and stayed low throughout the dialysis period. The loss of AA with the peritoneal effluent was 116 +/- 69 mumol/kg/body wt. From this study, it seems that using an AA dialysis solution, with 1 exchange per day, might limit the daily glucose load and compensate for AA losses by supplying an extra amount of AA and by reducing the loss of other AA not contained in dialysis solutions. The AA pattern in plasma following AA-dialysis resembles that observed after a protein meal, with no signs of persistently high, nonphysiological levels.