Short‐acting erythropoiesis‐stimulating agents for anaemia in predialysis patients

Background The benefits of erythropoiesis‐stimulating agents (ESA) for chronic kidney disease (CKD) patients have been previously demonstrated. However, the efficacy and safety of short‐acting epoetins administered at larger doses and reduced frequency as well as of new epoetins and biosimilars remains uncertain. Objectives This review aimed to evaluate the benefits and harms of different routes, frequencies and doses of epoetins (epoetin alpha, epoetin beta and other short‐acting epoetins) for anaemia in adults and children with CKD not receiving dialysis. Search methods We searched the Cochrane Kidney and Transplant Specialised Register to 12 September 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria We included randomised control trials (RCTs) comparing different frequencies, routes, doses and types of short‐acting ESAs in CKD patients. Data collection and analysis Two authors independently assessed study eligibility and four authors assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random‐effects model. Main results We identified 14 RCTs (2616 participants); nine studies were multi‐centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies. Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses. Data from only 7/14 studies could be included in our meta‐analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD ‐0.20 g/dL, 95% CI ‐0.33 to ‐0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD ‐0.16 g/dL, 95% CI ‐0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI ‐0.19 to 0.53). Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD ‐0.02 g/dL, 95% CI ‐0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti‐epoetin antibodies and no results were available. Adverse events were poorly reported in all studies and did not differ significantly within comparisons. Mortality was only detailed adequately in four studies and only one study included quality of life data. Authors' conclusions Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non‐inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non‐dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient‐centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis

Biomedical systems analysis program

Biomedical monitoring programs which were developed to provide a system analysis context for a unified hypothesis for adaptation to space flight are presented and discussed. A real-time system of data analysis and decision making to assure the greatest possible crew safety and mission success is described. Information about man's abilities, limitations, and characteristic reactions to weightless space flight was analyzed and simulation models were developed. The predictive capabilities of simulation models for fluid-electrolyte regulation, erythropoiesis regulation, and calcium regulation are discussed

Anemia management in end stage renal disease patients undergoing dialysis: a comprehensive approach through machine learning techniques and mathematical modeling

Kidney impairment has global consequences in the organism homeostasis and a disorder like Chronic Kidney Disease (CKD) might eventually exacerbates into End Stage Renal Disease (ESRD) where a complete renal replacement therapy like dialysis is necessary. Dialysis partially reintegrates the blood ltration process; however, even when it is associated to a pharmacological therapy, this is not su fficient to completely replace the renal endocrine role and causes the development of common complications, like CKD secondary anemia (CKD-anemia) The availability of exogenous Erythropoiesis Stimulating Agents (ESA, synthetic molecules with similar structure and same mechanism of action as human erythropoietin) improved the treatment of CKD-anemia although the clinical outcomes are still not completely successful. In particular, for ERSD dialysis patients main di culties in the selection of an optimal therapy dosing derive from the high intra- and inter-individual response variability and the temporal discrepancy between the short ESA permanence in the blood (hours) and the long Red Blood Cells lifespan (months). The aim of this thesis has been to describe the development of the Anemia Control Model (ACM), a tool designed to support physicians in managing anemia for ESRD patines undergoing dialysis. Five main pillars constitute the foundation of this work: - Understanding the medical problem; - Availability of the data needed to derive the models; - Mathematical and Machine Learning modeling; - Development of a product usable at the point of care; - Medical device certi cation and clinical evaluation of the developed product. The understanding of the medical problem is fundamental for two reasons: firstly because the medical problem must be the driver of the product scope and consequently of its design; secondly because a good understanding of the medical problem is of fundamental importance to develop optimized models. In the case of anemia management the drug dosing is an important task where predictive models could support physicians to improve the treatment quality. In particular, considering that hemoglobin is the typical parameter used to measure anemia, our model were tailored to predict hemoglobin response to the two main drugs normally used to correct anemia, that is ESA and Iron. In a mathematical model based on di erential equations, like the one presented in this thesis, the knowledge of the main physiological processes related to anemia is the base to properly design the equations. A machine learning approach in principle can be built with no hypotesis, because it relays in learning from data, nevertheless knowledge of the domain helps to make better use of the available data. The medical problem has been discussed in Chapter 1. The availability of a huge database of very well structured data was basic for the development of models. Quality of the data is another important aspect. Chapter 2 gives the reader an overview of the available data.. The core of the ACM is the capability to predict for each patient the future hemoglobin concentrations as a function of past patient's clinical history and future drug prescription. By means of well performing and personalized predictive model it is possible to simulate how, for each specific c patient, di erent doses would a ffect hemoglobin trends. Mathematical and machine learning models present both advantages and limitations. Chapter 3 describes the mathematical model and analyzes its performances, while Chapter 4 is dedicated to the machine learning models. In our case the machine learning approach resulted more suitable for our scope, because its was well performing on the entire population, more stable and, once trained, very quick in elaborating the prediction. Once the predictive model was obtained, the next step was to wrap it into a service that could be consumed by a third party system (for example an app or a clinical system) where physicians could benefi t from the model prediction capability. To achieve that, firstly an algorithm for the dose selection was developed; secondly, a data structure for the communication with the third party system was defi ned; fi nally, the whole package was wrapped in a web service. These arguments have been discussed in the rst part of Chapter 5. Mistakes in ESA or Iron dosing might have serious consequences on patients' health, for this reason ACM intended use was limited to provide dose suggestions only; physicians must evaluate them and decide whether to accept or reject them. Nevertheless, such a tool could be considered as Medical Device under European Medical Device Directive (MDD); for this reason, to be on the safe side, it was decided to certify the ACM as medical device. A novel approach was developed to perform the risk assessment, the main idea being that ACM might generate risks when a dose suggestion is produced based on a wrong prediction. To assess this risk the model error distribution over the test set was utilized as estimation of the error distribution of the live system. Finally, a clinical evaluation of the ACM in three pilot clinics has been performed before deciding to roll-out the tool in more clinics. These arguments have been discussed in the second part of Chapter 5

Hemodialysis Disparities in African Americans: The Deeply Integrated Concept of Race in the Social Fabric of Our Society.

End-stage renal disease (ESRD) is one of the starkest examples of racial/ethnic disparities in health. Racial/ethnic minorities are 1.5 to nearly 4 times more likely than their non-Hispanic White counterparts to require renal replacement therapy (RRT), with African Americans suffering from the highest rates of ESRD. Despite improvements over the last 25 years, substantial racial differences are persistent in dialysis quality measures such as RRT modality options, dialysis adequacy, anemia, mineral and bone disease, vascular access, and pre-ESRD care. This report will outline the current status of racial disparities in key ESRD quality measures and explore the impact of race. While the term race represents a social construct, its association with health is more complex. Multiple individual and community level social determinants of health are defined by the social positioning of race in the U.S., while biologic differences may reflect distinct epigenetic changes and linkages to ancestral geographic origins. Together, these factors conspire to influence dialysis outcomes among African Americans with ESRD

How oral infections can influence chronic kidney disease – a review of the literature

A healthy mouth is necessary for optimal health and quality of life. However, oral health is often compromised in adults with chronic kidney disease (CKD). The aim of this review was to present the scientific foundations behind the connection between oral diseases and chronic kidney disease (CKD) in adults, discuss common oral conditions and their systemic effects, investigate biological pathways through which oral infections affect the body and provide guidelines for physicians/nephrologists. Prevalence of oral disease is increased in CKD, including periodontal disease, oral mucosal lesions, edentulousness, xerostomia, gingival overgrowth in immunosuppressed patients and potentially caries. There is moderate to strong evidence to support a negative impact of oral infections in CKD, particularly periodontal disease, with systemic inflammation, bacteraemia of oral origin, endothelial function and gut dysbiosis being potential pathways for this interaction. Poor oral health can be a hidden source of infection and has been associated with increased mortality in CKD patients. Elimination of potential foci for oral infections is crucial before renal transplantation. Frequent dental monitoring is crucial for these patients and should be part of a multidisciplinary approach to manage CKD, with special attention to end-stage kidney disease

Digest of Russian Space Life Sciences, issue 33

This is the thirty-third issue of NASA's USSR Space Life Sciences Digest. It contains abstracts of 55 papers published in Russian journals. The abstracts in this issue have been identified as relevant to the following areas of space biology and medicine: biological rhythms, body fluids, botany, cardiovascular and respiratory systems, developmental biology, endocrinology, equipment and instrumentation, gastrointestinal system, genetics, hematology, human performance, metabolism, microbiology, musculoskeletal system, neurophysiology, nutrition, operational medicine, psychology, radiobiology, and reproductive system