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Background: Inadequate dialysis dose is closely related to mortality and morbidity of maintenance haemodialysis (MHD) patients. According to the DOQI guidelines a minimum prescribed dialysis dose of single-pool Kt/V (Kt/Vsp)=1.3, equivalent to equilibrated double pool Kt/V (e-Kt/Vdp)=1.1, is recommended. Knowledge of patient-related risk factors for inadequate delivery of haemodialysis would be helpful to select patient subgroups for intensive control of dialysis adequacy. [ABSTRACT FROM PUBLISHER]

Osmoregulation is influenced by a wide variety of biotic and abiotic variables, and maintenance of systemic osmoregulatory homeostasis is critical to insect fitness. Because insects are so small, accurately quantifying renal organ function is technically challenging, and often requires specialized equipment. On top of this, nearly a century of toiling in the laboratory has led to a wide and still growing variety of methods that can be difficult for novice researchers to disentangle. Here, we provide a reference guide for the most used in vitro approaches in the study of insect osmoregulation, including the Ramsay assay, Ussing chamber, epithelial potential measurement, scanning ion-selective electrode technique, and hindgut assays. Along the way, we highlight the history of each methodological innovation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the cold, chill susceptible insects lose the ability to regulate ionic and osmotic gradients. This leads to hemolymph hyperkalemia that drives a debilitating loss of cell membrane polarization, triggering cell death pathways and causing organismal injury. Biotic and abiotic factors can modulate insect cold tolerance by impacting the ability to mitigate or prevent this cascade of events. In the present study, we test the combined and isolated effects of dietary manipulations and thermal acclimation on cold tolerance in fruit flies. Specifically, we acclimated adult Drosophila melanogaster to 15 or 25 °C and fed them either a K + -loaded diet or a control diet. We then tested the ability of these flies to recover from and survive a cold exposure, as well as their capacity to protect transmembrane K + gradients, and intracellular Na + concentration. As predicted, cold-exposed flies experienced hemolymph hyperkalemia and cold-acclimated flies had improved cold tolerance due to an improved maintenance of the hemolymph K + concentration at low temperature. Feeding on a high-K + diet improved cold tolerance additively, but paradoxically reduced the ability to maintain extracellular K + concentrations. Cold-acclimation and K + -feeding additively increased the intracellular K + concentration, aiding in maintenance of the transmembrane K + gradient during cold exposure despite cold-induced hemolymph hyperkalemia. There was no effect of acclimation or diet on intracellular Na + concentration. These findings suggest intracellular K + loading and reduced muscle membrane K + sensitivity as mechanisms through which cold-acclimated and K + -fed flies are able to tolerate hemolymph hyperkalemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Insect performance is linked to environmental temperature, and surviving through winter represents a key challenge for temperate, alpine and polar species. To overwinter, insects have adapted a range of strategies to become truly cold hardy. However, although the mechanisms underlying the ability to avoid or tolerate freezing have been well studied, little attention has been given to the challenge of maintaining ion homeostasis at frigid temperatures in these species, despite this limiting cold tolerance for insects susceptible to mild chilling. Here, we investigated how prolonged exposure to temperatures just above the supercooling point affects ion balance in freeze-avoidant mountain pine beetle (Dendroctonus ponderosae) larvae in autumn, mid-winter and spring, and related it to organismal recovery times and survival. Hemolymph ion balance was gradually disrupted during the first day of exposure, characterized by hyperkalemia and hyponatremia, after which a plateau was reached and maintained for the rest of the 7-day experiment. The degree of ionoregulatory collapse correlated strongly with recovery times, which followed a similar asymptotical progression. Mortality increased slightly during extensive cold exposures, where hemolymph K+ concentration was highest, and a sigmoidal relationship was found between survival and hyperkalemia. Thus, the cold tolerance of the freeze-avoiding larvae of D. ponderosae appears limited by the ability to prevent ionoregulatory collapse in a manner similar to that of chill-susceptible insects, albeit at much lower temperatures. Based on these results, we propose that a prerequisite for the evolution of insect freeze avoidance may be a convergent or ancestral ability to maintain ion homeostasis during extreme cold stress., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The physiology of insects is directly influenced by environmental temperature, and thermal tolerance is therefore intrinsically linked to their thermal niche and distribution. Understanding the mechanisms that limit insect thermal tolerance is crucial to predicting biogeography and range shifts. Recent studies on locusts and flies suggest that the critical thermal minimum (CTmin) follows a loss of CNS function via a spreading depolarization. We hypothesized that other insect taxa share this phenomenon. Here, we investigate whether spreading depolarization events occur in butterflies exposed to cold. Supporting our hypothesis, we found that exposure to stressful cold induced spreading depolarization in all 12 species tested. This reinforces the idea that spreading depolarization is a common mechanism underlying the insect CTmin. Furthermore, our results highlight how CNS function is tuned to match the environment of a species. Further research into the physiology underlying spreading depolarization will likely elucidate key mechanisms determining insect thermal tolerance and ecology., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background and Objectives: Studies analysing the association of albuminuria and prevalent frailty in community-dwelling very old adults are scarce and lack information on incident frailty. We investigated the association of kidney function decline and increase of albuminuria with frailty worsening or death in very old adults., Design: Longitudinal analyses with biennial visits of the Berlin Initiative (cohort) Study and a frailty follow-up of 2.1 years., Setting/subjects: 1,076 participants with a mean age of 84.3 (5.6) years of whom 54% were female., Methods: Partial proportional odds models were used to assess the association of estimated glomerular filtration rate (eGFR) decline and/or albuminuria (albumin creatinine ratio, ACR) with frailty worsening or death., Results: At frailty baseline, 1,076 participants with an eGFR of 50 (13) ml/min/1.73 m2, 48% being prefrail and 31% frail were included. After median 2.1 years, 960 (90%) participants had valid information on frailty transition: 187 (17.5%) worsened and 111 (10.3%) died. In the multivariable model, the odds of frailty worsening for participants with albuminuria in combination with eGFR <60 ml/min/1.73 m2 were elevated [OR (95% CI): 2.47 (1.41-4.31)] compared to participants without albuminuria and eGFR ≥60 ml/min/1.73 m2 as there was a rapid eGFR decline of ≥3 ml/min/1.73 m2 per year [1.55 (1.04-2.33)] and albuminuria trajectories six years prior [1.53 (1.11-2.10)] to frailty baseline. The odds of death for each exposure were even higher., Conclusions: In older adults, advanced stages of CKD and albuminuria alone were associated with 2-fold odds of frailty worsening independent of death., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most insects can acclimate to changes in their thermal environment and counteract temperature effects on neuromuscular function. At the critical thermal minimum, a spreading depolarization (SD) event silences central neurons, but the temperature at which this event occurs can be altered through acclimation. SD is triggered by an inability to maintain ion homeostasis in the extracellular space in the brain and is characterized by a rapid surge in extracellular K+ concentration, implicating ion pump and channel function. Here, we focused on the role of the Na+/K+-ATPase specifically in lowering the SD temperature in cold-acclimated Drosophila melanogaster. After first confirming cold acclimation altered SD onset, we investigated the dependency of the SD event on Na+/K+-ATPase activity by injecting the inhibitor ouabain into the head of the flies to induce SD over a range of temperatures. Latency to SD followed the pattern of a thermal performance curve, but cold acclimation resulted in a left-shift of the curve to an extent similar to its effect on the SD temperature. With Na+/K+-ATPase activity assays and immunoblots, we found that cold-acclimated flies have ion pumps that are less sensitive to temperature, but do not differ in their overall abundance in the brain. Combined, these findings suggest a key role for plasticity in Na+/K+-ATPase thermal sensitivity in maintaining central nervous system function in the cold, and more broadly highlight that a single ion pump can be an important determinant of whether insects can respond to their environment to remain active at low temperatures., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Hemodiafiltration (HDF), in which both convective and diffusion methods are combined, yields an increased overall solute clearance compared with hemodialysis (HD), specifically for medium and larger molecular weight uremic toxins. Due to uncertainty in the treatment effects, the nephrology community still perceives the implementation of HDF and the achievement of high convective volume as complex. In this article, we review practical aspects of the implementation of HDF that can effectively deliver a high-volume HDF therapy and assure clinical performance to most patients. We also present an overview of the impact of high-volume HDF (compared to HD) on a series of relevant biochemical, patient-reported, and clinical outcomes, including uremic toxin removal, phosphate, Inflammation and oxidative stress, hemodynamic stability, cardiac outcomes, nutritional effects, health-related quality of life, morbidity, and mortality., (© 2022 Wiley Periodicals LLC.)

Background and Objectives: In older adults, data on the age-related course of GFR are scarce, which might lead to misjudgment of the clinical relevance of reduced GFR in old age., Design, Setting, Participants, & Measurements: To describe the course of eGFR in older adults and derive reference values in population-based individuals, we used the longitudinal design of the Berlin Initiative Study (BIS) with a repeated estimation of GFR over a median of 6.1 years of follow-up. In 2069 community-dwelling older individuals (mean inclusion age 80 years, range 70-99), GFR was estimated biennially with the BIS-2 equation, including standardized creatinine and cystatin C levels, sex, and age. We described the crude and adjusted course using a mixed-effects model and analyzed the influence of death on the GFR course applying joint models. GFR slopes were compared using GFR equations on the basis of creatinine and/or cystatin C., Results: We observed a decreasing, thus nonlinear, eGFR decline with increasing age in a population of old adults. The estimated 1-year slope for ages 75 and 90 diminished for men from -1.67 to -0.99 and for women from -1.52 to -0.97. The modeled mean eGFR for men aged ≥79 and women ≥78 was below 60 ml/min per 1.73 m 2 . Multivariable adjustment attenuated slopes only minimally. Taking death into account by applying joint models did not alter the nonlinear eGFR decline. Using eGFR equations on the basis of creatinine only showed linear slope patterns in contrast to nonlinear patterns for equations including cystatin C., Conclusions: The eGFR decline depended on sex and age and changed only marginally after multivariable adjustment but decelerated with increasing age. Equations including cystatin C demonstrated a nonlinear slope challenging the previously assumed linearity of the decline of eGFR in old age., (Copyright © 2022 by the American Society of Nephrology.)

The spotted wing drosophila (SWD), Drosophila suzukii, is a major invasive fruit pest. There is strong consensus that low temperature is among the main drivers of SWD population distribution, and the invasion success of SWD is also linked to its thermal plasticity. Most studies on ectotherm cold tolerance focus on exposure to a single stressful temperature but here we investigated how cold stress intensity affected survival duration across a broad range of low temperatures (-7 to +3 °C). The analysis of Lt 50 at different stressful temperatures (Thermal Death Time curve - TDT) is based on the suggestion that cold injury accumulation rate increases exponentially with the intensity of thermal stress. In accordance with the hypothesis, Lt 50 of SWD decreased exponentially with temperature. Further, comparison of TDT curves from flies acclimated to 15, 19 and 23 °C, respectively, showed an almost full compensation with acclimation such that the temperature required to induce mortality over a fixed time decreased almost 1 °C per °C lowering of acclimation temperature. Importantly, this change in cold tolerance with acclimation was uniform across the range of moderate to intense cold stress exposures examined. To understand if cold stress at moderate and intense exposures affects the same physiological systems we examined how physiological markers/symptoms of chill injury developed at different intensities of the cold stress. Specifically, hsp23 expression and extracellular [K + ] were measured in flies exposed to different intensities of cold stress (-6, -2 and +2 °C) and at various time points corresponding to the same progression of injury (equivalent to 1/3, 2/3 or 3/3 of Lt 50 ). The different cold stress intensities all triggered hsp23 expression following 2 h of recovery, but patterns of expression differed. At the most intense cold stress (-6 and -2 °C) a gradual increase with time was found. In contrast, at +2 °C an initial increase was followed by a dissipating expression. A gradual perturbation of ion balance (hyperkalemia) was also found at all three cold stress intensities examined, with only slight dissimilarities between treatment temperatures. Despite some differences between the three cold intensities examined, the results generally support the hypothesis that intense and moderate cold stress induces the same physiological perturbation. This suggests that cold stress experienced during natural fluctuating conditions is additive and the results also illustrate that the rate of injury accumulation increases dramatically (exponentially) with decreasing temperature (increasing stress)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

At low temperature many insects lose extracellular ion homeostasis and the capacity to mitigate homeostatic imbalance determines their cold tolerance. Extracellular homeostasis is ensured by the osmoregulatory organs and recent research has emphasized key roles for the Malpighian tubules and hindgut in modulating insect cold tolerance. Here, we review the effects of low temperature on transport capacity of osmoregulatory organs and outline physiological processes leading from cold exposure to disruption of ion homeostasis and cold-injury in insects. We show how cold adaptation and cold acclimation are associated with physiological modifications to transport capacity in Malpighian tubules and hindgut. These responses mitigate loss of homeostasis and we highlight how further study of molecular and cellular mechanisms are critical to fully appreciate the adaptations that facilitate insect cold tolerance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: treatment goals for blood pressure (BP) lowering in older patients with heart failure (HF) are unclear., Objective: to assess whether BP control < 140/90 mmHg is associated with a decreased risk of mortality in older HF patients., Design: population-based prospective cohort study., Setting/subjects: participants of the Berlin Initiative Study, a prospective cohort of community-dwelling older adults launched in 2009. Clinical information was obtained in face-to-face interviews and linked to administrative healthcare data., Methods: Cox proportional hazards models estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular death and all-cause mortality associated with normalised BP (systolic BP < 140 mmHg and diastolic BP < 90 mmHg) compared with non-normalised BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) in HF patients. The primary analysis considered only baseline BP ('time-fixed'); an additional analysis updated BP during follow-up ('time-dependent')., Results: at baseline, 544 patients were diagnosed with HF and treated with antihypertensive drugs (mean age 82.8 years; 45.4% female). During a median follow-up of 7.5 years and compared with non-normalised BP, normalised BP was associated with similar risks of cardiovascular death (HR, 1.24; 95% CI, 0.84-1.85) and all-cause mortality (HR, 1.16; 95% CI, 0.89-1.51) in the time-fixed analysis but with increased risks of cardiovascular death (HR, 1.79; 95% CI, 1.23-2.61) and all-cause mortality (HR, 1.48; 95% CI, 1.15-1.90) in the time-dependent analysis., Conclusions: BP control < 140/90 mmHg was not associated with a decreased risk of mortality in older HF patients. The increased risk in the time-dependent analysis requires further corroboration., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Insects, like the model species Drosophila melanogaster, lose neuromuscular function and enter a state of paralysis (chill coma) at a population- and species-specific low temperature threshold that is decreased by cold acclimation. Entry into this coma is related to a spreading depolarization in the central nervous system, while recovery involves restoration of electrochemical gradients across muscle cell membranes. The Na + /K + -ATPase helps maintain ion balance and membrane potential in both the brain and hemolymph (surrounding muscles), and changes in thermal tolerance traits have therefore been hypothesized to be closely linked to variation in the expression and/or activity of this pump in multiple tissues. Here, we tested this hypothesis by measuring activity and thermal sensitivity of the Na + /K + -ATPase at the tagma-specific level (head, thorax and abdomen) in warm- (25 °C) and cold-acclimated (15 °C) flies by measuring Na + /K + -ATPase activity at 15, 20, and 25 °C. We relate differences in pump activity to differences in chill coma temperature, spreading depolarization temperature, and thermal dependence of muscle cell polarization. Differences in pump activity and thermal sensitivity induced by cold acclimation varied in a tissue-specific manner: While thermal sensitivity remained unchanged, cold-acclimated flies had decreased Na + /K + -ATPase activity in the thorax (mainly muscle) and head (mainly composed of brain). We argue that these changes may assist in maintenance of K + homeostasis and membrane potential across muscle membranes, and discuss how reduced Na + /K + -ATPase activity in the brain may counterintuitively help insects delay coma onset in the cold., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Academy of Nutrition and Dietetics and the National Kidney Foundation collaborated to provide an update to the Clinical Practice Guidelines (CPG) for nutrition in chronic kidney disease (CKD). These guidelines provide a valuable update to many aspects of the nutrition care process. They include changes in the recommendations for nutrition screening and assessment, macronutrients, and targets for electrolytes and minerals. The International Society of Renal Nutrition and Metabolism assembled a special review panel of experts and evaluated these recommendations prior to public review. As one of the highlights of the CPG, the recommended dietary protein intake range for patients with diabetic kidney disease is 0.6-0.8 g/kg/day, whereas for CKD patients without diabetes it is 0.55-0.6 g/kg/day. The International Society of Renal Nutrition and Metabolism endorses the CPG with the suggestion that clinicians may consider a more streamlined target of 0.6-0.8 g/kg/day, regardless of CKD etiology, while striving to achieve intakes closer to 0.6 g/kg/day. For implementation of these guidelines, it will be important that all stakeholders work to detect kidney disease early to ensure effective primary and secondary prevention. Once identified, patients should be referred to registered dietitians or the region-specific equivalent, for individualized medical nutrition therapy to slow the progression of CKD. As we turn our attention to the new CPG, we as the renal nutrition community should come together to strengthen the evidence base by standardizing outcomes, increasing collaboration, and funding well-designed observational studies and randomized controlled trials with nutritional and dietary interventions in patients with CKD., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) are associated with cardiovascular events in the general population but their utility among older adults is unclear. We investigated the associations of eGFR and UACR with stroke, myocardial infarction (MI), and death among older adults., Study Design: Population-based cohort study., Setting & Participants: 1,581 participants (aged≥70 years) in the Berlin Initiative Study (BIS) without prior stroke or MI., Exposures & Predictors: Serum creatinine- and cystatin C-based eGFR, UACR categories, and measured GFR (n=436)., Outcomes: Stroke, MI, and all-cause mortality., Analytical Approach: HRs and 95% CIs derived from multivariable-adjusted Cox proportional hazards models for association analyses. Net reclassification improvement (NRI) and C statistic differences comparing the predictive benefit of kidney measures with a traditional cardiovascular risk model., Results: During a median follow-up of 8.2 years, 193 strokes, 125 MIs, and 531 deaths occurred. Independent of UACR, when GFR was estimated using the creatinine- and cystatin C-based BIS equation, eGFR of 45 to 59mL/min/1.73m 2 (vs eGFR>60mL/min/1.73m 2 ) was associated with stroke (HR, 2.23; 95% CI, 1.55-3.21) but not MI or all-cause mortality. For those with eGFR<45mL/min/1.73m 2 , the HRs were 1.99 (95% CI, 1.23-3.20) for stroke, 1.38 (95% CI, 0.81-2.36) for MI, and 1.57 (95% CI, 1.20-2.06) for mortality. Compared with UACR<30mg/g, UACR of 30 to 300mg/g was not associated with stroke (HR, 0.91; 95% CI, 0.63-1.33) but was associated with MI (HR, 1.65; 95% CI, 1.09-2.51) and all-cause mortality (HR, 1.63; 95% CI, 1.34-1.98). Prediction analysis for stroke showed significant positive NRI for eGFR calculated using the cystatin C-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the creatinine- and cystatin C-based BIS and Full Age Spectrum equations. UACR demonstrated significant positive NRIs for MI and mortality., Limitations: eGFR and UACR categorization based on single assessments; lack of cause-specific death data., Conclusions: eGFR of 45 to 59mL/min/1.73m 2 without albuminuria was associated with stroke but not MI or all-cause mortality in older adults. In contrast, UACR of 30 to 300mg/g was associated with MI and all-cause mortality but not with stroke. Furthermore, cystatin C-based eGFR improved risk prediction for stroke in this cohort of older adults., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

There is a growing appreciation that insect distribution and abundance are associated with the limits of thermal tolerance, but the physiology underlying thermal tolerance remains poorly understood. Many insects, like the migratory locust ( Locusta migratoria ), suffer a loss of ion and water balance leading to hyperkalaemia (high extracellular [K + ]) in the cold that indirectly causes cell death. Cells can die in several ways under stress, and how they die is of critical importance to identifying and understanding the nature of thermal adaptation. Whether apoptotic or necrotic cell death pathways are responsible for low-temperature injury is unclear. Here, we use a caspase-3 specific assay to indirectly quantify apoptotic cell death in three locust tissues (muscle, nerves and midgut) following prolonged chilling and recovery from an injury-inducing cold exposure. Furthermore, we obtain matching measurements of injury, extracellular [K + ] and muscle caspase-3 activity in individual locusts to gain further insight into the mechanistic nature of chilling injury. We found a significant increase in muscle caspase-3 activity, but no such increase was observed in either nervous or gut tissue from the same animals, suggesting that chill injury primarily relates to muscle cell death. Levels of chilling injury measured at the whole animal level, however, were strongly correlated with the degree of haemolymph hyperkalaemia, and not apoptosis. These results support the notion that cold-induced ion balance disruption triggers cell death but also that apoptosis is not the main form of cell damage driving low-temperature injury.

Maintaining extracellular osmotic and ionic homeostasis is crucial for organismal function. In insects, hemolymph volume and ion content is regulated by the secretory Malpighian tubules and reabsorptive hindgut. When exposed to stressful cold, homeostasis is gradually disrupted, characterized by a debilitating increase in extracellular K + concentration (hyperkalemia). Accordingly, studies have found a strong link between species-specific cold tolerance and the ability to maintain ion and water homeostasis at low temperature. This is also true for drosophilids where inter- and intra-specific differences in cold tolerance are linked to the secretory capacity of Malpighian tubules. There is, however, little information on the reabsorptive capacity of the hindgut in Drosophila To address this, we developed a novel method that permits continuous measurements of hindgut ion and fluid reabsorption in Drosophila We demonstrate that this assay is temporally stable (∼2 h) and responsive to cAMP stimulation and pharmacological intervention in accordance with the current insect hindgut reabsorption model. We then investigated how cold acclimation or cold adaptation affected hindgut reabsorption at benign (24°C) and low temperature (3°C). Cold-tolerant Drosophila species and cold-acclimated D. melanogaster maintain superior fluid and Na + reabsorption at low temperature. Furthermore, cold adaptation and acclimation caused a relative reduction in K + reabsorption at low temperature. These characteristic responses of cold adaptation/acclimation will promote maintenance of ion and water homeostasis at low temperature. Our study of hindgut function therefore provides evidence that adaptations in the osmoregulatory capacity of insects are critical for their ability to tolerate cold., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: Older adults have the highest drug utilization due to multimorbidity. Although the number of people over age 70 is expected to double within the next decades, population-based data on their medication patterns are scarce especially in combination with polypharmacy and potentially inappropriate medication (PIM). Our objective was to analyse the frequency of polypharmacy, pattern of prescription (PD) and over-the-counter (OTC) drug usage, and PIMs according to age and gender in a population-based cohort of very old adults in Germany., Methods: Cross-sectional baseline data of the Berlin Initiative Study, a prospective cohort study of community-dwelling adults aged ≥70 years with a standardized interview including demographics, lifestyle variables, co-morbidities, and medication assessment were analysed. Medication data were coded using the Anatomical Therapeutic Chemical (ATC) classification. Age- and sex-standardized descriptive analysis of polypharmacy (≥5 drugs, PD and OTC vs. PD only and regular and on demand drugs vs regular only), medication frequency and distribution, including PIMs, was performed by age (

When insects are cooled, they initially lose their ability to perform coordinated movements at their critical thermal minima (CT min ). At a slightly lower temperature, they enter a state of complete paralysis (chill coma onset temperature - CCO) and if they are returned to permissive temperatures they regain function after a recovery period which is termed chill coma recovery time (CCRT). These three phenotypes (CT min , CCO, and CCRT) are all popular measures of insect cold tolerance and it is therefore important to characterize the physiological processes that are responsible for these phenotypes. In the present study we measured extracellular field potentials in the central nervous system (CNS) and muscle membrane potential (V m ) during cooling and recovery in three Drosophila species that have different cold tolerances. With these measurements we assess the role of the CNS and muscle V m in setting the lower thermal limits (CT min and CCO) and in delaying chill coma recovery (CCRT). The experiments suggest that entry into chill coma is primarily caused by the onset of a spreading depolarization in the CNS for all three species. In the two most cold-sensitive species we observed that the loss of CNS function was followed closely by a depolarization of muscle V m which is known to compromise muscle function. When flies are returned to benign temperature after a cold exposure we observe a rapid recovery of CNS function, but functional recovery was delayed by a slower recovery of muscle polarization. Thus, we demonstrate the primacy of different physiological systems (CNS vs. muscle) as determinants of the most commonly used cold tolerance measures for insects (CT min vs. CCRT)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To assess whether blood pressure (BP) values below 140/90 mmHg during antihypertensive treatment are associated with a decreased risk of all-cause mortality in community-dwelling older adults., Methods and Results: Within the Berlin Initiative Study, we assembled a cohort of patients ≥70 years treated with antihypertensive drugs at baseline (November 2009-June 2011). End of prospective follow-up was December 2016. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality associated with normalized BP [systolic BP (SBP) <140 mmHg and diastolic BP (DBP) <90 mmHg] compared with non-normalized BP (SBP ≥140 mmHg or DBP ≥90 mmHg) overall and after stratification by age or previous cardiovascular events. Among 1628 patients (mean age 81 years) on antihypertensive drugs, 636 exhibited normalized BP. During 8853 person-years of follow-up, 469 patients died. Compared with non-normalized BP, normalized BP was associated with an increased risk of all-cause mortality (incidence rates: 60.3 vs. 48.5 per 1000/year; HR 1.26; 95% CI 1.04-1.54). Increased risks were observed in patients ≥80 years (102.2 vs. 77.5 per 1000/year; HR 1.40; 95% CI 1.12-1.74) and with previous cardiovascular events (98.3 vs. 63.6 per 1000/year; HR 1.61; 95% CI 1.14-2.27) but not in patients aged 70-79 years (22.6 vs. 22.7 per 1000/year; HR 0.83; 95% CI 0.54-1.27) or without previous cardiovascular events (45.2 vs. 44.4 per 1000/year; HR 1.16, 95% CI 0.90-1.48)., Conclusion: Blood pressure values below 140/90 mmHg during antihypertensive treatment may be associated with an increased risk of mortality in octogenarians or elderly patients with previous cardiovascular events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: 10-20% of hospitalized patients develop acute kidney injury (AKI)/acute renal failure during their hospital stay. The mortality of nosocomial AKI is approximately 30%., Methods: This review is based on relevant publications retrieved by a search in multiple databases (PubMed and Uptodate), archives, and pertinent medical journals., Results: The most common causes of nosocomial AKI are volume depletion, sepsis, heart diseases, polytrauma, liver diseases, and drug toxicity. AKI can also be of postrenal (obstructive) origin, or a result of renal diseases including glomeruloneph- ritis, vasculitis, tubulointerstitial nephritis, and cholesterol embolism. In about 13% of cases, nosocomial AKI develops on the basis of pre-existing chronic renal disease. Patients with AKI are at elevated risk of developing chronic renal disease and must be followed up appropriately after they are discharged from the hospital. Indispens- able elements of the evaluation of nosocomial AKI include renal ultrasonography, the exclusion of postrenal obstruction, urine chemistry, and microbiological urinaly- sis. Potentially nephrotoxic drugs and those that impair renal hemodynamics must be avoided to the greatest possible extent in patients with acute renal damage. Hypotension must be avoided as well., Conclusion: Early, specific nephrological diagnosis and treatment are important components of the management of nosocomial AKI, particularly because causally directed treatment is available for some of the conditions that underlie it.

Drosophila suzukii, an invasive species recently introduced in Europe, lays eggs in thin-skinned fruits and causes huge financial losses to fruit growers. One potential way to control this pest is the sterile insect technique (SIT) which demands a large stock of reproductive females to produce millions of sterile males to be released on demand. Unfortunately, Drosophila stocks age quickly, show declining fecundity when maintained at warm temperatures and conversely, they die from chill injury if they are maintained at constant low temperature. Here we investigate the potential of fluctuating thermal regime (FTR) as a storage method that harness the benefits of both warm and cold storage. Using a FTR with a daily warm period (1 h 20 at 25 °C) and cold period (20 h at 3 °C), interspaced by gradual heating and cooling, we compared longevity, fecundity and physiological condition between FTR females and females exposed to constant 25 °C and 3 °C. As hypothesised, FTR flies experienced much slower senescence (>3-fold increase in lifespan) and they preserved fecundity to a much higher age than flies from constant 25 °C. Flies maintained at constant 3 °C quickly died from chill injuries caused by a gradual loss of ion and water balance. In contrast, FTR flies were able to maintain ion and water balance (similar to 25 °C flies) as they were allowed to recover homeostasis during the short warm periods. Together these results demonstrate that FTR represents a useful protocol for storage of Drosophila stocks, and more broadly, this shows that the benefits of FTR are tightly linked with the insect ability to recover physiological homeostasis during the short warm periods., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cold tolerance of insects is arguably among the most important traits defining their geographical distribution. Even so, very little is known regarding the causes of cold injury in this species-rich group. In many insects it has been observed that cold injury coincides with a cellular depolarization caused by hypothermia and hyperkalemia that develop during chronic cold exposure. However, prior studies have been unable to determine if cold injury is caused by direct effects of hypothermia, by toxic effects of hyperkalemia, or by the depolarization that is associated with these perturbations. Here we use a fluorescent DNA-staining method to estimate cell viability of muscle and hindgut tissue from Locusta migratoria and show that the cellular injury is independent of the direct effects of hypothermia or toxic effects of hyperkalemia. Instead, we show that chill injury develops due to the associated cellular depolarization. We further hypothesized that the depolarization-induced injury was caused by opening of voltage-sensitive Ca 2+ channels, causing a Ca 2+ overload that triggers apoptotic/necrotic pathways. In accordance with this hypothesis, we show that hyperkalemic depolarization causes a marked increase in intracellular Ca 2+ levels. Furthermore, using pharmacological manipulation of intra- and extracellular Ca 2+ concentrations as well as Ca 2+ channel conductance, we demonstrate that injury is prevented if transmembrane Ca 2+ flux is prevented by removing extracellular Ca 2+ or blocking Ca 2+ influx. Together these findings demonstrate a causal relationship between cold-induced hyperkalemia, depolarization, and the development of chill injury through Ca 2+ -mediated necrosis/apoptosis., Competing Interests: The authors declare no conflict of interest.

When cooled, insects first lose their ability to perform coordinated movements (CT min ) after which they enter chill coma (chill coma onset, CCO). Both these behaviours are popular measures of cold tolerance that correlate remarkably well with species distribution. To identify and understand the neuromuscular impairment that causes CT min and CCO we used inter- and intraspecific model systems of Drosophila species that have varying cold tolerance as a consequence of adaptation or cold acclimation. Our results demonstrate that CT min and CCO correlate strongly with a spreading depolarization (SD) within the central nervous system (CNS). We show that this SD is associated with a rapid increase in extracellular [K + ] within the CNS causing neuronal depolarization that silences the CNS. The CNS shutdown is likely to be caused by a mismatch between passive and active ion transport within the CNS and in a different set of experiments we examine inter- and intraspecific differences in sensitivity to SD events during anoxic exposure. These experiments show that cold adapted or acclimated flies are better able to maintain ionoregulatory balance when active transport is compromised within the CNS. Combined, we demonstrate that a key mechanism underlying chill coma entry of Drosophila is CNS shutdown, and the ability to prevent this CNS shutdown is therefore an important component of acute cold tolerance, thermal adaptation and cold acclimation in insects., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Oxygen limitation plays a key role in many pathologies; yet, we still lack a fundamental understanding of the mechanisms responsible for variation in anoxia tolerance. Most vertebrate studies suggest that anoxia tolerance involves the ability to maintain cellular ATP despite the loss of aerobic metabolism. However, insects such as adult Drosophila melanogaster are able to survive long periods of anoxia (LT 50 : ∼8 h) in a hypo-energetic state characterized by low [ATP]. In this study, we tested for possible mechanisms that allow D. melanogaster adults to survive long periods of anoxia. Adults are paralyzed within 30 s, and after 2 h of anoxia, ATP was 3% of normal, extracellular potassium concentration ([K + ] o ) increased threefold, pH dropped 1 unit, yet survival was 100%. With 0.5-6 h of anoxia, adults maintained low but constant ATP levels while [K + ] o and pH o continued to change. When returned to normoxia, adults restored [K + ] o and activity. With longer durations of anoxia, ATP levels decreased and [K + ] o rose further, and both correlated tightly with decreased survival. This response contrasts with the anoxia-sensitive larval stage (LT 50 : ∼1 h). During anoxia, larvae attempted escape for up to 30 min and after 2 h of anoxia, ATP was <1% of resting, [K + ] o increased by 50%, hemolymph pH fell by 1 unit, and survival was zero. The superior anoxia tolerance of adult D. melanogaster appears to be due to the capacity to maintain a paralytic hypometabolic state with low but non-zero ATP levels, and to be able to tolerate extreme extracellular ionic variability., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Insect chill tolerance is strongly associated with the ability to maintain ion and water homeostasis during cold exposure. Maintenance of K + balance is particularly important due to its role in setting the cell membrane potential that is involved in many aspects of cellular function and viability. In most insects, K + balance is maintained through secretion at the Malpighian tubules, which balances reabsorption from the hindgut and passive leak arising from the gut lumen. Here, we used the scanning ion-selective electrode technique (SIET) at benign (23°C) and low (6°C) temperatures to examine K + flux across the Malpighian tubules and the rectal pads in the hindgut in five Drosophila species that differ in cold tolerance. We found that chill-tolerant species were better at maintaining K + secretion and suppressing reabsorption during cold exposure. In contrast, chill-susceptible species exhibited large reductions in secretion with no change, or a paradoxical increase, in K + reabsorption. Using an assay to measure paracellular leak, we found that chill-susceptible species experience a large increase in leak during cold exposure, which could explain the apparent increase in K + reabsorption found in these species. Our data therefore strongly support the hypothesis that cold-tolerant Drosophila species are better at maintaining K + homeostasis through an increased ability to maintain K + secretion rates and through reduced movement of K + towards the hemolymph. These adaptations are manifested both at the Malpighian tubule and at the rectal pads in the hindgut, and ensure that cold-tolerant species experience less perturbation of K + homeostasis during cold stress., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Objective: We report on the effect of hemoadsorption therapy to reduce cytokines in septic patients with respiratory failure., Methods: This was a randomized, controlled, open-label, multicenter trial. Mechanically ventilated patients with severe sepsis or septic shock and acute lung injury or acute respiratory distress syndrome were eligible for study inclusion. Patients were randomly assigned to either therapy with CytoSorb hemoperfusion for 6 hours per day for up to 7 consecutive days (treatment), or no hemoperfusion (control). Primary outcome was change in normalized IL-6-serum concentrations during study day 1 and 7., Results: 97 of the 100 randomized patients were analyzed. We were not able to detect differences in systemic plasma IL-6 levels between the two groups (n = 75; p = 0.15). Significant IL-6 elimination, averaging between 5 and 18% per blood pass throughout the entire treatment period was recorded. In the unadjusted analysis, 60-day-mortality was significantly higher in the treatment group (44.7%) compared to the control group (26.0%; p = 0.039). The proportion of patients receiving renal replacement therapy at the time of enrollment was higher in the treatment group (31.9%) when compared to the control group (16.3%). After adjustment for patient morbidity and baseline imbalances, no association of hemoperfusion with mortality was found (p = 0.19)., Conclusions: In this patient population with predominantly septic shock and multiple organ failure, hemoadsorption removed IL-6 but this did not lead to lower plasma IL-6-levels. We did not detect statistically significant differences in the secondary outcomes multiple organ dysfunction score, ventilation time and time course of oxygenation.

Background: Although CKD is said to increase among older adults, epidemiologic data on kidney function in people ≥70 years of age are scarce. The Berlin Initiative Study (BIS) aims to fill this gap by evaluating the CKD burden in older adults., Methods: The BIS is a prospective population-based cohort study whose participants are members of Germany's biggest insurance company. This cross-sectional analysis (i) gives a detailed baseline characterization of the participants, (ii) analyses the representativeness of the cohort's disease profile, (iii) assesses GFR and albuminuria levels across age categories, (iv) associates cardiovascular risk factors with GFR as well as albuminuria and (v) compares means of GFR values according to different estimating equations with measured GFR., Results: A total of 2069 participants (52.6% female, mean age 80.4 years) were enrolled: 26.1% were diabetic, 78.8% were on antihypertensive medication, 8.7% had experienced a stroke, 14% a myocardial infarction, 22.6% had cancer, 17.8% were anaemic and 26.5% were obese. The distribution of comorbidities in the BIS cohort was very similar to that in the insurance 'source population'. Creatinine and cystatin C as well as the albumin:creatinine ratio (ACR) increased with increasing age. After multivariate adjustments, reduced GFR and elevated ACR were associated with most cardiovascular risk factors. The prevalence of a GFR <60 mL/min/1.73 m 2 ranged from 38 to 62% depending on the estimation equation used., Conclusions: The BIS is a very well-characterized, representative cohort of older adults. Participants with an ACR ≥30 had significantly higher odds for most cardiovascular risk factors compared with an ACR <30 mg/g. Kidney function declined and ACR rose with increasing age., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction: The achievement of erythropoiesis in hemodialysis (HD) patients is typically managed with erythropoiesis-stimulating-agents (ESA's) and intravenous iron (IV-iron). Using this treatment strategy, HD patients frequently show an elevated fraction of red blood cells (RBC) with hemoglobin (Hb) content per cell that is below the normal range, called hypochromic RBC. The low Hb content per RBC is the result of the clinical challenge of providing sufficient iron content to the bone marrow during erythropoiesis. Vitamin C supplements have been used to increase Hb levels in HD patients with refractory anemia, which supports the hypothesis that vitamin C mobilizes iron needed for Hb synthesis., Methods: We conducted a cross-sectional survey in 149 prevalent HD patients of the percent hypochromic RBC, defined as RBC with Hb < 300 ng/uL of packed RBC, in relation to plasma vitamin C levels. We also measured high-sensitivity CRP, (hs-CRP), iron, and ferritin levels. and calculated ESA dose., Findings: High plasma levels of vitamin C were negatively associated with hypochromic RBC (P < 0.003), and high ESA doses were positively associated (P < 0.001). There was no significant association of hs-CRP with percent hypochromic RBC., Discussion: This finding supports the hypothesis that vitamin C mobilizes iron stores, improves iron delivery to the bone marrow, and increase the fraction of RBC with normal Hb content. Further research is warranted on development of protocols for safe and effective use of supplemental vitamin C for management of renal anemia., (© 2016 International Society for Hemodialysis.)

The majority of insects enter a state of reversible coma if temperature is lowered sufficiently. If the cold treatment is not too severe these insects recover gradually when returned to benign temperatures in a time-dependent manner that often depends on the duration and intensity of the cold exposure. Previous studies have associated these phenotypes to changes in membrane potential (V m ) and ion balance, and especially hemolymph [K + ] is known to be of importance for the recovery time. In the present study we examined this link in three species of Lepidoptera as insects from this order are known to possess resting hemolymph [K + ] that would severely compromise V m in other insects. Specifically, we exposed larval and adult Manduca sexta, larval Bombyx mori, and adult Heliconius cydno to stressful cold (0°C) for extended periods of time. Subsequently we measured chill coma recovery time (CCRT), ion- and water balance, and muscle V m . As expected we find that resting hemolymph [K + ] is high and that resting hemolymph [Na + ] is low compared to most other insect species. Muscle V m depolarised considerably during acute cold exposure, but did so in a manner that was not associated with changes in ion balance. However, prolonged cold exposure coincided with an increase of hemolymph [K + ] and further depolarisation of V m which correlated well with prolongation of CCRT. Combined this demonstrates how insects with different ionic compositions generally suffer from similar consequences of cold stress as other species, such that cold tolerance of chill-susceptible insects within Lepidoptera is also intimately linked to maintenance of ion balance and membrane polarisation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Most insects have the ability to alter their cold tolerance in response to temporal temperature fluctuations, and recent studies have shown that insect cold tolerance is closely tied to the ability to maintain transmembrane ion gradients that are important for the maintenance of cell membrane potential (V m ). Several studies have therefore suggested a link between preservation of V m and cellular survival after cold stress, but none has measured V m in this context. We tested this hypothesis by acclimating locusts (Locusta migratoria) to high (31°C) and low temperature (11°C) for 4 days before exposing them to cold stress (0°C) for up to 48 h and subsequently measuring ion balance, cell survival, muscle V m , and whole animal performance. Cold stress caused gradual muscle cell death, which coincided with a loss of ion balance and depolarization of muscle V m The loss of ion balance and cell polarization were, however, dampened markedly in cold-acclimated locusts such that the development of chill injury was reduced. To further examine the association between cellular injury and V m we exposed in vitro muscle preparations to cold buffers with low, intermediate, or high [K + ]. These experiments revealed that cellular injury during cold exposure occurs when V m becomes severely depolarized. Interestingly, we found that cellular sensitivity to hypothermic hyperkalaemia was lower in cold-acclimated locusts that were better able to defend V m whilst exposed to high extracellular [K + ]. Together these results demonstrate a mechanism of cold acclimation in locusts that improves survival after cold stress: increased cold tolerance is accomplished by preservation of V m through maintenance of ion homeostasis and decreased K + sensitivity., (© 2017. Published by The Company of Biologists Ltd.)

Background: Continuous intradialytic calf bioimpedance spectroscopy (cBIS) allows assessment of changes in calf extracellular fluid volume (ECV) to determine dry weight (DW) in hemodialysis patients. During dialysis, calf ECV decreases until excessive ECV has been removed and normalized resistivity ρN,5 rises to values comparable to those of a normal population (cBIS-DW). It is not clear whether chronic kidney disease (CKD) itself influences ρN,5 and whether normal values depend on race and ethnicity., Methods: Therefore, we determined ρN,5 in 2 populations consisting of 35 healthy Caucasians and 37 with CKD in KDIGO stages G2-G4. Calf resistivity was determined using a bioimpedance spectrum analyzer (Xitron Technologies, San Diego, CA, USA) and was normalized for body mass index., Results: ρN,5 was significantly higher in healthy subjects than in CKD patients (males: 18.2 ± 2.2 vs. 15.0 ± 2.8 × 10-2·Ωm3kg-1, p < 0.001; females: 19.7 ± 3.2 vs. 16.4 ± 3.3 × 10-2·Ωm3kg-1, p = 0.009). ρN,5 in Caucasians was significantly lower than in previously examined North American healthy subjects with prevailing African American race or Hispanic ethnicity (males: 18.2 ± 2.2 vs. 20.5 ± 2.0 × 10-2·Ωm3kg-1, p < 0.001; females: 19.7 ± 3.2 vs. 21.7 ± 2.6 × 10-2·Ωm3kg-1, p = 0.026)., Conclusion: We present the first determination of ρN,5 values in a Caucasian healthy as well as a non-dialysis dependent CKD population. Both groups differ significantly. Due to higher amounts of extracellular water, subclinical fluid overload already occurs in pre-dialysis stages of CKD. ρN,5 in Caucasians differs significantly from previously established normal ranges in other races/ethnicities. Population-based reference ranges should be established and used in the future to determine DW by means of cBIS., (© 2016 S. Karger AG, Basel.)

Background: The physical-functional and social-emotional health as well as survival of the elderly (≥75 years of age) haemodialysis patient is commonly thought to be poor. In a prospective, multicentre, non-interventional, observational study, the morbidity, mortality and quality of life (QoL) in this patient group were examined and compared with a younger cohort., Methods: In 92 German dialysis centres, 2507 prevalent patients 19-98 years of age on haemodialysis for a median of 19.2 months were included in a drug monitoring study of darbepoetin alfa. To examine outcome and QoL parameters, 24 months of follow-up data in the age cohorts <75 and ≥75 years were analysed. Treatment parameters, adverse and intercurrent events, hospitalizations, morbidity and mortality were assessed. QoL was evaluated by means of the 47-item Functional Assessment of Chronic Illness Therapy-Anaemia score (FACT-An, version 4)., Results: The 2-year mortality rate was 34.7% for the older cohort and 15.8% for the younger cohort. The mortality rate for the haemodialysed elderly patients was 6.2% higher in absolute value compared with the age-matched background population. A powerful predictor of survival was the baseline FACT-An score and a close correlation with the 20-item anaemia subscale (AnS) was demonstrated. While the social QoL in the elderly patients was more stable than in the younger cohort (leading to equivalent values at the end of the study period), a pronounced deterioration of physical and functional status was observed. The median number of all-cause hospital days per patient-year was 12.3 for the elderly cohort and 8.9 for the younger patient population. The overall 24-month hospitalization rate was only marginally higher in the elderly cohort (34.0 versus 33.3%)., Conclusions: In this observational study, the mortality rate of elderly haemodialysis patients was not exceedingly high compared with the age-matched background population. Furthermore, the hospitalization rate was only slightly higher compared with the younger age group and the median yearly hospitalization time trended lower compared with registry data. The social well-being of elderly haemodialysis patients showed a less pronounced decline over time and was equal to the score of the younger cohort at the end of the study period. The physical and functional status in the elderly patients was lower and showed a sharper decline over time. The baseline FACT-An score correlated closely with the 24-month survival probability.

Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included., (© 2016 John Wiley & Sons Ltd.)

Purpose . Pulmonary-renal syndrome (PRS) is characterized by diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis mainly due to autoimmune etiologies. Seronegative PRS is a challenging entity to the clinician, since early diagnosis may be missed leading to delayed appropriate treatment. Materials and Methods . We present the clinical course of a 77-year-old patient who was admitted under the suspected diagnosis of pneumogenic sepsis and septic renal failure with fever, dyspnea, and elevated CRP levels. The diagnosis of pulmonary-renal syndrome was initially missed because of the absence of autoantibodies in all serological findings. Results. Despite delayed initiation of immunosuppressive therapy and a prolonged period of dialysis and extracorporeal membrane oxygenation the patient recovered well and was released to a rehabilitation center with nearly normalized creatinine levels. The diagnosis of PRS was established by renal biopsy. Conclusion . This case illustrates the important differential diagnosis of seronegative pulmonary-renal syndrome in patients with pulmonary and renal impairment.

Recent studies suggest that projected rises of aquatic CO2 levels cause acid-base regulatory responses in fishes that lead to altered GABAergic neurotransmission and disrupted behaviour, threatening fitness and population survival. It is thought that changes in Cl(-) and HCO3 (-) gradients across neural membranes interfere with the function of GABA-gated anion channels (GABAA receptors). So far, such alterations have been revealed experimentally by exposing species living in low-CO2 environments, like many oceanic habitats, to high levels of CO2 (hypercapnia). To examine the generality of this phenomenon, we set out to study the opposite situation, hypothesizing that fishes living in typically hypercapnic environments also display behavioural alterations if exposed to low CO2 levels. This would indicate that ion regulation in the fish brain is fine-tuned to the prevailing CO2 conditions. We quantified pH regulatory variables and behavioural responses of Pangasianodon hypophthalmus, a fish native to the hypercapnic Mekong River, acclimated to high-CO2 (3.1 kPa) or low-CO2 (0.04 kPa) water. We found that brain and blood pH was actively regulated and that the low-CO2 fish displayed significantly higher activity levels, which were reduced after treatment with gabazine, a GABAA receptor blocker. This indicates an involvement of the GABAA receptor and altered Cl(-) and HCO3 (-) ion gradients. Indeed, Goldman calculations suggest that low levels of environmental CO2 may cause significant changes in neural ion gradients in P. hypophthalmus. Taken together, the results suggest that brain ion regulation in fishes is fine-tuned to the prevailing ambient CO2 conditions and is prone to disruption if these conditions change., (© 2016. Published by The Company of Biologists Ltd.)

Bioimpedance analysis (BIA) is accepted for the assessment of total-body water (TBW), intracellular fluid (ICF) and extracellular fluid (ECF). We aimed to compare precision and accuracy of single and multi-frequency-BIA to direct estimation methods (DEMs) of TBW, ECF, and ICF in hemodialysis patients. Linear regression analysis of volume estimates in 49 patients by single- and multi-frequency-BIA correlated significantly with DEMs. Bland-Altman analysis (BAA) found systemic bias for ECF single-frequency-BIA vs. ECF-DEMs. No other systematic biases were found. Proportional errors were found by BAA of ICF and ECF assessments with single- and multi-frequency bioimpedance spectroscopy compared to the DEMs. Comparisons of indirect methods (IEMs) to DEMs showed no significant differences and proportional errors. Root mean-squared-error analysis suggested slightly better accuracy and precision of ICF single-frequency-BIA vs. DEMs over ICF multi-frequency-BIA and IEMs to DEMs, and slightly better performance for ECF multi-frequency-BIA over both respective other methods. Compared to DEMs, there is slightly better accuracy for ECF multi- over single-frequency-BIA and ICF single- over multi-frequency-BIA. However the margin of differences between direct and indirect methods suggests that none of the analyzed methods served as a true "gold standard", because indirect methods are almost equally precise compared to DEMs.

Protein energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes, especially in individuals receiving maintenance dialysis therapy. A multitude of factors can affect the nutritional and metabolic status of CKD patients requiring a combination of therapeutic maneuvers to prevent or reverse protein and energy depletion. These include optimizing dietary nutrient intake, appropriate treatment of metabolic disturbances such as metabolic acidosis, systemic inflammation, and hormonal deficiencies, and prescribing optimized dialytic regimens. In patients where oral dietary intake from regular meals cannot maintain adequate nutritional status, nutritional supplementation, administered orally, enterally, or parenterally, is shown to be effective in replenishing protein and energy stores. In clinical practice, the advantages of oral nutritional supplements include proven efficacy, safety, and compliance. Anabolic strategies such as anabolic steroids, growth hormone, and exercise, in combination with nutritional supplementation or alone, have been shown to improve protein stores and represent potential additional approaches for the treatment of PEW. Appetite stimulants, anti-inflammatory interventions, and newer anabolic agents are emerging as novel therapies. While numerous epidemiological data suggest that an improvement in biomarkers of nutritional status is associated with improved survival, there are no large randomized clinical trials that have tested the effectiveness of nutritional interventions on mortality and morbidity.

To investigate correlates for the well-known impaired response of haemodialysis-patients to a variety of recommended vaccinations, the induction of antigen-specific cellular and humoral immunity was characterised after influenza-vaccination in two following seasons where the identical vaccine-composition was used. Influenza-specific T-cells were flow-cytometrically characterised from whole blood of 24 healthy controls and 26 haemodialysis-patients by proliferation-assays, induction of IFN-γ and TNF-α, and maturation markers. Antibody-titres were quantified using ELISA and hemagglutination-inhibition test. Influenza-specific CD4 T-cells were recently activated CD45RO+/CD27+ Th1-cells. Specific T-cell frequencies significantly increased 1-2 weeks after the first vaccination in both controls (mean increase by 0.50±0.64%, max: 3.01%) and haemodialysis-patients (by 0.55±0.71%, max: 3.44%). Thereafter, T-cell levels continuously decreased to pre-vaccination levels within approximately 7 weeks, whereas antibody-titres were more stable over time. By 6 months, haemodialysis-patients had significantly lower precursor-frequencies of proliferating influenza-specific memory T-cells (p=0.006). In the following season, memory-maintenance in immunocompetent individuals led to a significantly less pronounced increase in cellular immunity after re-vaccination (by only 0.12±0.09%, p=0.003), whereas the vaccine induced a strong increase in a second group of vaccination-naïve controls. Of note, haemodialysis-patients responded like vaccination-naïve individuals, as they showed a strong increase in cellular immunity after re-vaccination that was as pronounced as in the year before. In conclusion, the less pronounced T-cell increase after re-vaccination in controls may indicate maintenance of sufficient immunological memory. In contrast, the more rapid loss of proliferating cells in haemodialysis-patients may represent a sign of relative immunodeficiency and contribute to an increased incidence of recurrent infectious complications., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Mortality in patients with end-stage renal disease (ESRD) remains unacceptably high. Emerging techniques and advances in dialysis technology have the potential to improve clinical outcomes in the ESRD population. This report summarizes the deliberations and recommendations of a conference sponsored by Kidney Disease: Improving Global Outcomes to address the following questions: (1) what is the appropriate frequency and duration of hemodialysis; (2) how should we optimize water quality and dialysate composition; and (3) what technical innovations in blood purification and bioengineering can result in better clinical outcomes? The conference report will augment our current understanding of clinical practice in blood purification and will pose several high-priority research questions.

Background/aims: Dry weight estimation in hemodialysis patients is still a substantial problem. Despite meticulous clinical assessment, fluid overload is common, leading to hypertension and left ventricular hypertrophy (LVH). Segmental calf bioimpedance spectroscopy (cBIS) is a novel tool for dry weight assessment. Here we tested the hypothesis, that its clinical routine use reduces arterial hypertension and left ventricular mass., Methods: Left ventricular mass (determined by magnetic resonance imaging), blood pressure and antihypertensive medication (defined daily doses, ddd) were assessed at baseline (BL). Thereafter post-dialytic target weight was reduced until cBIS-defined dry weight was reached (DW). During a 6-month follow up, DW was re-evaluated monthly by cBIS and end-dialytic weight was adjusted correspondingly. At the end, left ventricular mass, blood pressure and antihypertensive medication were determined a 3rd time (follow-up, FU)., Results: Eleven out of 15 patients were available for analysis after 6 months. Left ventricular mass showed a declining trend during the study period (Mean±SD; BL 145±54 g; DW 142±55 g; FU 137±52 g; p=0.61, linear mixed model). Comparable results were obtained for systolic blood pressure (BL 158±18 mmHg; DW 144±19 mmHg; FU 149±21 mmHg; p=0.07), and antihypertensive medication (BL 3.28±2.82ddd; DW 2.86±2.81ddd; FU 3.36±3.05ddd; p=0.37)., Conclusions: We conclude that attainment of dry weight assessed by cBIS tends to reduce left ventricular mass and blood pressure while antihypertensive medication remains unchanged. While the study was underpowered, its results provide an important hypothesis generating data basis for the design of larger studies., (Copyright © 2013 S. Karger AG, Basel.)

Background: Continuous intradialytic bioelectrical impedance spectroscopy of the calf (cBIS) monitors changes in calf extracellular fluid volume (cECV), thus allowing estimation of hydration in end-stage renal disease patients. Blood volume monitoring (BVM) during hemodialysis (HD) provides information about relative changes in intravascular volume, which indirectly reflects plasma refilling. We hypothesize that the rate of plasma refilling changes when cBIS-determined dry weight (BIS-DW) is reached., Methods: Post-HD weight was reduced from baseline (BL) in 15 patients until dry weight was reached according to cBIS criteria (BIS-DW). The slopes of cBIS and BVM curves were analysed during the first 30 and last 20 min in 31 BL treatments, which were compared to the slopes during 31 treatments when BIS-DW was reached., Results: During BL treatments, BVM slopes did not differ between the first 30 and last 20 min (-0.112 ± 0.157%/min versus -0.089 ± 0.036, P = n.s.), while cBIS slopes were generally steeper at the beginning than at the end of HD (-0.184 ± 0.139%/min versus 0.10 ± 0.127, P < 0.01). During BIS-DW treatments, BVM and cBIS slopes were steeper at the beginning than at the end (BVM: -0.131 ± 0.122 versus -0.064 ± 0.051, P < 0.01; cBIS: -0.192 ± 0.129 versus -0.035 ± 0.012, P < 0.001) and the cBIS slopes were steeper than BVM slopes at the beginning of HD. This relationship is inverted at the end of HD, when BIS-DW is reached (beginning: -0.192 ± 0.129 versus -0.131 ± 0.122, P < 0.05, end: -0.035 ± 0.012 versus -0.064 ± 0.051, P = 0.05)., Conclusions: This study demonstrates that cECV changes faster at the beginning than at the end of HD. A reversal steepness of the cBIS slope in relation to BVM slope is observed at the time when BIS-DW is reached. Therefore, combined analysis of cBIS and BVM aiming at clinical end points may be useful to assess the relationship between plasma refilling and tissue hydration during dialysis.

Background: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease., Objective: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants., Design: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation., Setting: Random community-based population of a large insurance company., Participants: 610 participants aged 70 years or older (mean age, 78.5 years)., Intervention: Iohexol plasma clearance measurement as gold standard., Measurements: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample., Results: The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%)., Limitation: There was no validation by an external data set., Conclusion: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative., Primary Funding Source: Kuratorium für Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine.