Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease.

BACKGROUND: Ataxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa). OBJECTIVE: To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status. DESIGN SETTING AND PARTICIPANTS: This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: TURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM). RESULTS AND LIMITATIONS: Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34-3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups. CONCLUSIONS: Decreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor-targeted therapies, as well as platinum-based chemotherapies. PATIENT SUMMARY: Lower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.

Dipeptidyl Peptidase-4 Inhibitors in Chronic Kidney Disease: A Systematic Review of Randomized Clinical Trials.

BACKGROUND: Chronic kidney disease (CKD) is common in patients with type 2 diabetes mellitus (T2DM) and limits therapeutic options. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of oral glucose-lowering agents and are known to be safe and effective in the general population. METHODS: We searched Cochrane, EMBASE, and PubMed from the time of their inception until March 2015. We included randomized controlled trials analyzing the efficacy (change in hemoglobin A1C [HbA1C]) and safety of DPP-4 agents in individuals with reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m2). We extracted study characteristics, participants' baseline characteristics, and safety outcomes from eligible studies. We performed a random effects meta-analysis to summarize the change in HbA1C and the relative risk of cardiovascular events in patients with T2DM and CKD. We also collected data on hypoglycemia, other serious adverse events, and mortality. RESULTS: We reviewed 12 studies with 4,403 patients with CKD and 239 on dialysis, finding a mean weighted decline in HbA1C of -0.48 (95% CI -0.61 to -0.35) with DPP-4 inhibitor therapy compared to placebo. DPP-4 inhibitors did not result in any additional adverse events, hypoglycemic episodes, or increased mortality. Restricting to studies with low risk of bias did not alter these findings. CONCLUSIONS: DPP-4 inhibitors can lower HbA1C without increasing the risk of cardiovascular or other major adverse events in patients with CKD. Few studies reported critical adverse events such as heart failure and hypersensitivity. If compared with other oral antiglycemic drugs, the effect of DPP-4 inhibitors is limited; however, their low risk of hypoglycemia may favor their use in patients with CKD. SUMMARY: This systematic review of DPP-4 inhibitors in CKD suggests that they reduce HbA1C by about 0.5%. Furthermore, there was not any increase in the risk for significant adverse events. More research is needed to determine the safety and efficacy of DPP-4 inhibitors in CKD.

Frailty and physical function in chronic kidney disease: the CanFIT study.

BACKGROUND: Frailty, a manifestation of unsuccessful aging, is highly prevalent in people with chronic kidney disease (CKD) and is associated with comorbid conditions in cross-sectional studies. Longitudinal studies investigating the progression of frailty in those with advanced non-dialysis CKD are lacking. OBJECTIVES: Canadian Frailty Observation and Interventions Trial (CanFIT). To determine the natural history, prevalence of perceived and measured frailty and its association with dialysis treatment choices and adverse outcomes in patients with advanced CKD. DESIGN: Longitudinal observational study, designed to collect data from 600 participants over 2 years. SETTING: Interprofessional non-dialysis CKD clinics at four tertiary health care centres in central Canada. PATIENTS: People with CKD stage 4 and 5 (eGFR <30 ml/min/1.73 m(2)) who are not on dialysis at enrollment. MEASUREMENTS: Multiple Frailty Definitions: Short Physical Performance Battery (SPPB), Fried Frailty Criteria, Frailty Index. Dialysis start: In-Centre Hemodialysis, Home Hemodialysis or Peritoneal Dialysis Outcomes: Death, Opt-out or Lost to follow up. METHODS: We will perform physical and cognitive assessments annually. We plan to analyze the relationships between frailty, treatment choices and patient centered outcomes. RESULTS: We have recruited 217 participants in 2 centres; of these, 56 % had reduced physical function at baseline, as defined by the SPPB. Risk of reduced physical function was 8 fold higher in those with diabetes after adjusting for age, gender, eGFR and comorbidities. LIMITATIONS: Referred population, use of SPPB as a measure of frailty, inter-operator variability in measurement of hand grip and gait speed, cross-sectional analysis of baseline data in the subset recruited to date. CONCLUSIONS: People with advanced CKD have a high burden of reduced physical function, especially those with diabetes. We will continue enrollment into the CanFIT study to further understand the clinical history of CKD and frailty in this population.

CONTEXTE: La fragilité, une manifestation du vieillissement malheureux, est très répandue chez les personnes atteintes d'insuffisance rénale chronique (IRC) et est associée à des conditions de comorbidité dans les études transversales. Rares sont les études longitudinales destinées à étudier la progression de la fragilité chez les personnes atteintes d'IRC avancée qui ne reçoivent pas de dialyse. OBJECTIFS: Canadian Frailty Observation and Interventions Trial (CanFIT). Déterminer l'évolution naturelle, la prévalence de la fragilité perçue et mesurée, de même que son association avec les options de traitement à la dialyse et les effets indésirables sur les patients atteints d'IRC avancée. TYPE D'ÉTUDE: Étude longitudinale d'observation visant à recueillir les données de 600 patients sur deux ans. CONTEXTE: Des unités interprofessionnelles d'IRC qui ne pratiquent pas la dialyse dans quatre centres de soins tertiaires du centre du Canada. PARTICIPANTS: Des personnes atteintes d'IRC de stade 4 et 5 (R-EGF <30 ml/min/1,73 m2) qui ne recevaient pas de dialyse au moment de l'inscription. MESURES: Diverses définitions de la fragilité : le Short Physical Performance Battery (SPPB), les critères de fragilité de Fried et l'indice de fragilité. Le lieu de l'amorce de la dialyse : la dialyse en centre, la dialyse à domicile; ou les résultats de la dialyse péritonéale : le décès, le refus ou la perte de suivi. MÉTHODES: Nous effectuerons des examens physiques et cognitifs sur une base annuelle. Nous planifions analyser la relation entre la fragilité, le choix du traitement et les résultats axés sur le patient. RÉSULTATS: Nous avons recruté 217 participants dans 2 centres; parmi ceux-ci, 56 % présentaient d'entrée de jeu une réduction des fonctions physiques, telles que définies par le SPPB. Les risques de subir une réduction des fonctions physiques étaient 8 fois supérieurs chez les patients souffrant de diabète, après ajustement selon l'âge, le sexe, le R-EGF et les comorbidités. LIMITES DE L'ÉTUDE: La population désignée, le recours au SPPB pour mesurer la fragilité, la variabilité des intervenants dans la mesure de la vitesse de préhension et de marche, l'analyse transversale des données de référence du sous-ensemble recruté jusqu'à maintenant. CONCLUSIONS: Les personnes atteintes d'IRC avancée sont accablées d'une forte réduction de la fonction physique, et particulièrement celles qui sont atteintes de diabète. Nous poursuivrons l'inscription à l'étude de CanFIT afin d'approfondir les connaissances au sujet de l'évolution clinique de l'IRC et la fragilité des personnes atteintes.

An Economic Assessment Model of Rural and Remote Satellite Hemodialysis Units.

BACKGROUND: Kidney Failure is epidemic in many remote communities in Canada. In-centre hemodialysis is provided within these settings in satellite hemodialysis units. The key cost drivers of this program have not been fully described. Such information is important in informing the design of programs aimed at optimizing efficiency in providing dialysis and preventative chronic kidney disease care in remote communities. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We constructed a cost model based on data derived from 16 of Manitoba, Canada's remote satellite units. We included all costs for operation of the unit, transportation, treatment, and capital costs. All costs were presented in 2013 Canadian dollars. RESULTS: The annual per-patient cost of providing hemodialysis in the satellite units ranged from $80,372 to $215,918 per patient, per year. The median per patient, per year cost was $99,888 (IQR $89,057-$122,640). Primary cost drivers were capital costs related to construction, human resource expenses, and expenses for return to tertiary care centres for health care. Costs related to transport considerably increased estimates in units that required plane or helicopter transfers. CONCLUSIONS: Satellite hemodialysis units in remote areas are more expensive on a per-patient basis than hospital hemodialysis and satellite hemodialysis available in urban areas. In some rural, remote locations, better value for money may reside in local surveillance and prevention programs in addition support for home dialysis therapies over construction of new satellite hemodialysis units.

Chronic kidney disease, frailty, and unsuccessful aging: a review.

The global prevalence of chronic kidney disease (CKD) is rising, particularly among the elderly population. Defining aging as successful or unsuccessful has become clinically relevant in the last 15 years, with an increased recognition of the frail phenotype. Frailty has been shown to be associated with CKD and poorer outcomes, such as death or dialysis. It is likely that the mechanisms of disease in CKD such as altered protein metabolism, inflammation, oxidative stress, and anemia accelerate normal aging and lead to worsening frailty in elderly patients with CKD.

Association of frailty and physical function in patients with non-dialysis CKD: a systematic review.

BACKGROUND: Frailty is a condition characterized by a decline in physical function and functional capacity. Common symptoms of frailty, such as weakness and exhaustion, are prevalent in patients with chronic kidney disease (CKD). The increased vulnerability of frail patients with coexisting CKD may place them at a heightened risk of encountering additional health complications. The purpose of this systematic review was to explore the link between frailty, CKD and clinical outcomes. METHODS: We searched for cross sectional and prospective studies in the general population and in the CKD population indexed in EMBASE, Pubmed, Web of Science, CINAHL, Cochrane and Ageline examining the association between frailty and CKD and those relating frailty in patients with CKD to clinical outcomes. RESULTS: We screened 5,066 abstracts and retrieved 108 studies for full text review. We identified 7 studies associating frailty or physical function to CKD. From the 7 studies, we identified only two studies that related frailty in patients with CKD to a clinical outcome. CKD was consistently associated with increasing frailty or reduced physical function [odds ratios (OR) 1.30 to 3.12]. In patients with CKD, frailty was associated with a greater than two-fold higher risk of dialysis and/or death [OR from 2.0 to 5.88]. CONCLUSIONS: CKD is associated with a higher risk of frailty or diminished physical function. Furthermore, the presence of frailty in patients with CKD may lead to a higher risk of mortality. Further research must be conducted to understand the mechanisms of frailty in CKD and to confirm its association with clinical outcomes.