Urate-lowering therapy in patients with hyperuricemia and heart failure: A retrospective cohort study using the UK Clinical Practice Research Datalink.

BACKGROUND: Elevated serum uric acid (sUA) is associated with heart failure (HF). HYPOTHESIS: Urate-lowering therapy (ULT) in HF is associated with lower risk of HF hospitalization (hHF) and mortality. METHODS: Data on patients with HF and gout or hyperuricemia in the Clinical Practice Research Datalink database linked to the Hospital Episode Statistics and the Office for National Statistics in the United Kingdom were analyzed. Risks of hHF and all-cause mortality or cardiovascular-related mortality by ULT exposure (ULT initiated within ≤6 months of gout or hyperuricemia diagnosis) were analyzed in a propensity score-matched cohort using adjusted Cox proportional hazards regression models. RESULTS: Of 2174 propensity score-matched pairs, patients were predominantly male, aged >70 years, with mean ± standard deviation sUA 9.3 ± 1.8 (ULT-exposed) and 9.4 ± 1.9 mg/dL (ULT-unexposed). At 5 years, ULT-exposed patients had a 43% lower risk of hHF or all-cause mortality (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.51-0.65) and a 19% lower risk of hHF or cardiovascular-related mortality (adjusted HR: 0.81; 95% CI: 0.71-0.92) versus no ULT exposure. CONCLUSION: ULT was associated with reduced risk of adverse clinical outcomes in patients with HF and gout or hyperuricemia over 5 years.

Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis.

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management.

Chronic kidney disease (CKD) has a high clinical, economic, and societal burden and it affects approximately 8-16% of the global population. The progressive nature of CKD may lead to complications, co-morbidities, and mortality, costing healthcare systems millions and consuming a large proportion of healthcare resources. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, has been demonstrated to slow CKD progression and reduce cardio-renal complications, as demonstrated in the DAPA-CKD trial. With the emergence of dapagliflozin as a treatment for CKD, it is important for clinicians and healthcare providers to understand how effective treatment can positively affect short-term healthcare service delivery and associated costs. This medical care cost offset modelling analysis considers a scalable population of 100,000 patients in 31 countries/regions worldwide. The analysis estimates treatment with dapagliflozin plus standard therapy to be offset by a 33% reduction in costs associated with key cardio-renal outcomes, translating to an average $264 million in cost offsets per 100,000 treated patients. This modelling analysis of pivotal trial data shows dapagliflozin could have considerable benefits to healthcare systems worldwide that are under strain from the rising burden of CKD.

Health Care Resource Utilization and Related Costs of Patients With CKD From the United States: A Report From the DISCOVER CKD Retrospective Cohort.

Introduction: It is well established that chronic kidney disease (CKD) results in a significant burden on patients' health and health care providers. However, detailed estimates of the health care resource utilization (HCRU) of CKD are limited, particularly those which consider severity, comorbidities, and payer type. This study aimed to bridge this evidence gap by reporting contemporary HCRU and costs in patients with CKD across the US health care providers. Methods: Cost and HCRU estimates of CKD and reduced kidney function without CKD (estimated glomerular filtration rate [eGFR]: 60-75 and urine albumin-to-creatinine ratio [UACR]: <30) were derived for US patients included in the DISCOVER CKD cohort study, using linked inpatient and outpatient data from the limited claims-EMR data set (LCED) and TriNetX database. Patients with a history of transplant or undergoing dialysis were not included. HCRU and costs were stratified by CKD severity using UACR and eGFR. Results: Overall health care costs ranged from $26,889 (A1) to $42,139 (A3), and from $28,627 (G2) to $42,902 (G5) per patient per year (PPPY), demonstrating a considerable early disease burden which continued to increase with declining kidney function. The PPPY costs of later stage CKD were particularly notable for patients with concomitant heart failure ($50,191 [A3]) and those covered by commercial payers ($55,735 [A3]). Conclusions: Health care costs and resource use associated with CKD and reduced kidney function pose a substantial burden across health care systems and payers, increasing in line with CKD progression. Early CKD screening, particularly of UACR, paired with proactive disease management may provide both an improvement to patient outcomes and a significant HCRU and cost saving to health care providers.

Extrapolated longer-term effects of the DAPA-CKD trial: a modelling analysis.

BACKGROUND: The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial assessed dapagliflozin versus placebo, in addition to standard therapy, in patients with chronic kidney disease (CKD) and albuminuria, and was terminated prematurely due to overwhelming efficacy. The study objective was to model the long-term clinical outcomes of DAPA-CKD beyond the trial follow-up. METHODS: A Markov model extrapolated event incidence per 1000 patients and CKD progression rates for patients receiving dapagliflozin or placebo over a 10-year time horizon. We derived treatment-specific CKD stage transition matrices using DAPA-CKD trial data. We extrapolated relevant efficacy endpoints using parametric survival equations for all-cause mortality and generalized estimating equations for recurrent events. RESULTS: When extrapolated over a 10-year period, patients randomized to dapagliflozin spent more time in CKD stages 1-3 and less in stages 4-5 than placebo [0.65 (95% CrI 0.41, 0.90) and -0.23 (95% CrI -0.45, 0.00) years per patient, respectively]. Dapagliflozin prevented an estimated 83 deaths and 51 patients initiating kidney replacement therapy per 1000 patients over 10 years. Predicted rates of hospitalized heart failure and abrupt declines in kidney function were reduced (19 and 39 estimated events per 1000 patients, respectively). CONCLUSIONS: Adding dapagliflozin to standard therapeutic management of CKD is expected to have long-term cardiorenal benefit beyond what has been demonstrated in the DAPA-CKD trial, with patients predicted to live longer with fewer complications.

Healthcare resource utilisation and related costs of patients with CKD from the UK: a report from the DISCOVER CKD retrospective cohort.

Background: Chronic kidney disease (CKD) is widely reported to decrease quality of life, increase morbidity and mortality and cause increased healthcare resource utilisation (HCRU) as the disease progresses. However, there is a relative paucity of accurate and recent estimates of HCRU in this patient population. Our aim was to address this evidence gap by reporting HCRU and related costs in patients with CKD from the UK primary and secondary care settings. Methods: HCRU and cost estimates of CKD were derived for UK patients included in the DISCOVER CKD cohort study using clinical records from the Clinical Practice Research Datalink linked to external databases. Patients with a history of transplant or undergoing dialysis were not included. HCRU and costs were stratified by CKD severity using the urinary albumin:creatinine ratio (UACR) and estimated glomerular filtration rate. Results: Hospitalisation rates more than tripled between low (A1) and high (A3) UACR categories and the mean annual per-patient costs ranged from £4966 (A1) to £9196 (A3) and from £4997 (G2) to £7595 (G5), demonstrating that a large healthcare burden can be attributed to a relatively small number of patients with later stage CKD, including those with kidney failure and/or albuminuria. Conclusions: HCRU and costs associated with CKD impose a substantial burden on the healthcare system, particularly in the more advanced stages of CKD. New interventions that can delay the progression of CKD to kidney failure may not only prolong the patient's life, but would also provide significant resource and cost savings to healthcare providers.

Low Adherence to Kidney Disease: Improving Global Outcomes 2012 CKD Clinical Practice Guidelines Despite Clear Evidence of Utility.

Introduction: Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines classify chronic kidney disease (CKD) risk or prognosis using estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). We assessed patient characteristics and outcomes according to the KDIGO classification, using data from DISCOVER CKD (NCT04034992). Methods: Data were extracted from the US integrated Limited Claims and Electronic Health Record Dataset and TriNetX databases, and the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics databases. Eligible patients were aged ≥18 years with CKD, and identified by 2 consecutive eGFR measures (5 to <75 ml/min/1.73 m2; ≥90 days apart [maximum 730]) from January 2008. Index date was the second eGFR measurement; patients were categorized using the UACR measure closest to the index. Outcomes included patient characteristics, eGFR or UACR measurement frequency, and clinical outcomes per baseline KDIGO classification. Results: Across databases, only 8.6% of patients with 2 eGFR measures had ≥1 UACR measures. Among 123,807 eligible patients, prevalence of heart failure, hypertension, and type 2 diabetes increased with increasing albuminuria. Incidence rates of mortality and adverse cardiovascular and renal outcomes increased with declining baseline eGFR, and particularly with increasing albuminuria. Median number of eGFR and UACR tests per year post-index ranged from 1.6 to 2.5 and 0.5 to 0.6, respectively, across databases; there was no clear increase in UACR testing frequency following the KDIGO 2012 guidelines. Conclusion: Albuminuria monitoring is critical for optimal risk stratification in CKD, and our findings highlight an imperative for more regular UACR testing in clinical practice.

Understanding the patient experience of chronic kidney disease stages 2-3b: a qualitative interview study with Kidney Disease Quality of Life (KDQOL-36) debrief.

BACKGROUND: Qualitative patient interviews and patient-reported outcome instruments are important tools to understand the patient experience of disease. The aim of this study was to use patient interviews to identify concepts relevant and important to patients living with chronic kidney disease (CKD) stages 2-3b, develop a comprehensive conceptual model of the patient experience and debrief the Kidney Disease Quality of Life 36-item instrument (KDQOL-36) for patients with CKD stages 2-3b. METHODS: Concept elicitation interviews were conducted with patients with CKD stages 2-3b to identify signs/symptoms and impacts most relevant and important to patients (i.e., 'salient' concepts) and develop a conceptual model for the disease. Based on the salient concepts identified in the interviews, new items were proposed to supplement the KDQOL-36. Cognitive debriefing was performed to evaluate the KDQOL-36 and the additional items. RESULTS: A total of 31 patients were interviewed in this study (22 for concept elicitation and 15 for cognitive debriefing). The interviews identified 56 concepts (33 signs/symptoms and 23 impacts), 17 of which had not been identified in a previous literature review. Four signs/symptoms ('fatigue/lack of energy/tiredness', 'sleep problems', 'increased urination [including nocturia]' and 'swelling in legs/ankles/feet') and two impacts ('anxiety/worry' and 'general negative emotional/mental impact') were identified as salient. Of the salient signs/symptoms, three were not covered by the KDQOL-36 (sleep problems, increased urination and swelling in legs/ankles/feet) and were represented during cognitive debriefing interviews through four additional items (trouble falling asleep, trouble staying asleep, increased urination [including nocturia] and swelling in legs/ankles/feet) generated in the style of the KDQOL-36. All patients found the KDQOL-36 plus the four additional items relevant, and the majority found them clear. CONCLUSIONS: By identifying previously unknown concepts and augmenting the understanding of which are most important to patients, a comprehensive conceptual model was developed for patients who have CKD stages 2-3b. This study also demonstrates the suitability of the KDQOL-36 for patients who have CKD stages 2-3b and provides suggestions for how the instrument could be further developed to more comprehensively capture patient experience.

Metagenomic and HT-qPCR analysis reveal the microbiome and resistome in pig slurry under storage, composting, and anaerobic digestion.

Direct application of pig slurry to agricultural land, as a means of nutrient recycling, introduces pathogens, antibiotic resistant bacteria, or genes, to the environment. With global environmental sustainability policies mandating a reduction in synthetic fertilisation and a commitment to a circular economy it is imperative to find effective on-farm treatments of slurry that maximises its fertilisation value and minimises risk to health and the environment. We assessed and compared the effect of storage, composting, and anaerobic digestion (AD) on pig slurry microbiome, resistome and nutrient content. Shotgun metagenomic sequencing and HT-qPCR arrays were implemented to understand the dynamics across the treatments. Our results identified that each treatment methods have advantages and disadvantages in removal pollutants or increasing nutrients. The data suggests that storage and composting are optimal for the removal of human pathogens and anaerobic digestion for the reduction in antibiotic resistance (AMR) genes and mobile genetic elements. The nitrogen content is increased in storage and AD, while reduced in composting. Thus, depending on the requirement for increased or reduced nitrogen the optimum treatment varies. Combining the results indicates that composting provides the greatest gain by reducing risk to human health and the environment. Network analysis revealed reducing Proteobacteria and Bacteroidetes while increasing Firmicutes will reduce the AMR content. KEGG analysis identified no significant change in the pathways across all treatments. This novel study provides a data driven decision tree to determine the optimal treatment for best practice to minimise pathogen, AMR and excess or increasing nutrient transfer from slurry to environment.

Cost of End-of-Life Inpatient Encounters in Patients with Chronic Kidney Disease in the United States: A Report from the DISCOVER CKD Retrospective Cohort.

INTRODUCTION: Real-world data reporting healthcare resource utilisation and costs associated with end-of-life care for patients with chronic kidney disease (CKD) are limited. We examined length of hospitalisation and costs associated with end-of-life inpatient encounters using retrospective data from DISCOVER CKD. METHODS: Data on inpatient encounters for patients with CKD aged ≥ 18 years between January 2016 and March 2020 were extracted from the US Premier Hospital Database. Encounters ending in death were identified and grouped by reason for the encounter, using the International Classification of Diseases, Tenth Revision, and by their insurance coverage. Encounters were evaluated overall and stratified according to cardiovascular (CV), kidney failure and infection-related reasons, and by their coverage by commercial, Medicaid, Medicare or other insurers. Length of hospitalisation and total costs were calculated for encounters. RESULTS: Among 237,734 encounters ending in death, the mean [standard deviation (SD)] age was 74.2 (12.4) years, and 45.3% of patients were female. In total, 25,118, 4210 and 76,307 encounters were classified as relating to CV reasons, kidney failure and infection, respectively. Among all encounters, the mean (SD) length of hospitalisation ranged from 9.1 (11.2) (Medicare) to 12.8 (18.4) (Medicaid) days. Across insurers, encounters related to kidney failure were associated with the longest hospitalisations compared with CV and infection [mean range (days): 10.7-15.9 vs. 7.5-10.5 and 8.7-12.7, respectively]. The median [interquartile range (IQR)] total cost of any inpatient encounter was $17,057 ($8040-35,873). Kidney failure-related encounters had higher costs compared with CV and infection [median (IQR), $18,469 ($8673-38,315) vs. $17,503 ($7766-39,693) and $16,403 ($7762-34,910), respectively]. Medicaid-covered encounters had the highest costs of all insurers [median (IQR), $16,189 ($7725-33,443)]. CONCLUSIONS: Among patients with CKD, end-of-life encounters were most frequently related to infection. Encounters relating to kidney failure incurred the highest costs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04034992.

Quantitative microbial risk assessment associated with ready-to-eat salads following the application of farmyard manure and slurry or anaerobic digestate to arable lands.

Farmyard manure and slurry (FYM&S) and anaerobic digestate are potentially valuable soil conditioners providing important nutrients for plant development and growth. However, these organic fertilisers may pose a microbial health risk to humans. A quantitative microbial risk assessment (QMRA) model was developed to investigate the potential human exposure to pathogens following the application of FYM&S and digestate to agricultural land. The farm-to-fork probabilistic model investigated the fate of microbial indicators (total coliforms and enterococci) and foodborne pathogens in the soil with potential contamination of ready-to-eat salads (RTEs) at the point of human consumption. The processes examined included pathogen inactivation during mesophilic anaerobic digestion (M-AD), post-AD pasteurisation, storage, dilution while spreading, decay in soil, post-harvest washing processes, and finally, the potential growth of the pathogen during refrigeration/storage at the retail level in the Irish context. The QMRA highlighted a very low annual probability of risk (Pannual) due to Clostridium perfringens, norovirus, and Salmonella Newport across all scenarios. Mycobacterium avium may result in a very high mean Pannual for the application of raw FYM&S, while Cryptosporidium parvum and pathogenic E. coli showed high Pannual, and Listeria monocytogenes displayed moderate Pannual for raw FYM&S application. The use of AD reduces this risk; however, pasteurisation reduces the Pannual to an even greater extent posing a very low risk. An overall sensitivity analysis revealed that mesophilic-AD's inactivation effect is the most sensitive parameter of the QMRA, followed by storage and the decay on the field (all negatively correlated to risk estimate). The information generated from this model can help to inform guidelines for policymakers on the maximum permissible indicator or pathogen contamination levels in the digestate. The QMRA can also provide the AD industry with a safety assessment of pathogenic organisms resulting from the digestion of FYM&S.

Treatments for Chronic Kidney Disease: A Systematic Literature Review of Randomized Controlled Trials.

Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment renin-angiotensin-aldosterone system (RAAS) inhibitors as the standard of care have scarcely met their primary endpoints until recently. This systematic literature review explored treatments evaluated in patients with CKD since 1990 to understand what contemporary data add to the treatment landscape. Eighty-nine clinical trials were identified that had enrolled patients with estimated glomerular filtration rate 13.9-102.8 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 29.9-2911.0 mg/g, with (75.5%) and without (20.6%) type 2 diabetes (T2D). Clinically objective outcomes of kidney failure and all-cause mortality (ACM) were reported in 32 and 64 trials, respectively. Significant reductions (P < 0.05) in the risk of kidney failure were observed in seven trials: five small trials published before 2008 had evaluated the RAAS inhibitors losartan, benazepril, or ramipril in patients with (n = 751) or without (n = 84-436) T2D; two larger trials (n = 2152-2202) published onwards of 2019 had evaluated the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (in patients with T2D and UACR > 300-5000 mg/g) and dapagliflozin (in patients with or without T2D and UACR 200-5000 mg/g) added to a background of RAAS inhibition. Significant reductions in ACM were observed with dapagliflozin in the DAPA-CKD trial. Contemporary data therefore suggest that augmenting RAAS inhibitors with new drug classes has the potential to improve clinical outcomes in a broad range of patients with CKD.

Quantitative microbial human exposure model for faecal indicator bacteria and risk assessment of pathogenic Escherichia coli in surface runoff following application of dairy cattle slurry and co-digestate to grassland.

Animal waste contains high numbers of microorganisms and therefore can present a potential biological threat to human health. During episodic rainfall events resulting in runoff, microorganisms in the waste and soil may migrate into surface runoff, contaminating surface water resources. A probabilistic human exposure (HE) model was created to determine exposure to faecal indicator bacteria (FIB): total coliforms (TC), E. coli and enterococci following application of bio-based fertiliser (dairy cattle slurry, digestate) to grassland; using a combination of experimental field results and literature-based data. This step was followed by a quantitative microbial risk assessment (QMRA) model for pathogenic E. coli based on a literature-based dose-response model. The results showed that the maximum daily HE (HEdaily) is associated with E. coli for unprocessed slurry (treatment T1) on day 1, the worst-case scenario where the simulated mean HEdaily was calculated as 2.84 CFU day -1. The results indicate that the overall annual probability of risk (Pannual) of illness from E. coli is very low or low based on the WHO safe-limit of Pannual as 10 -6. In the worst-case scenario, a moderate risk was estimated with simulated mean Pannual as 1.0 × 10 -5. Unpasteurised digestate application showed low risk on day 1 and 2 (1.651 × 10 -6, 1.167 × 10 -6, respectively). Pasteurised digestate showed very low risk in all scenarios. These results support the restriction imposed on applying bio-based fertiliser if there is any rain forecast within 48 h from the application time. This study proposes a future extension of the probabilistic model to include time, intensity, discharge, and distance-dependant dilution factor. The information generated from this model can help policymakers ensure the safety of surface water sources through the quality monitoring of FIB levels in bio-based fertiliser.

Evaluation of pathogen concentration in anaerobic digestate using a predictive modelling approach (ADRISK).

Farmyard manure and slurry (FYM&S) is a valuable feedstock for anaerobic digestion (AD) plants. However, FYM&S may contain high concentrations of pathogens, and complete inactivation through the AD process is unlikely. Thus, following land application of digestate, pathogens may contaminate a range of environmental media posing a potential threat to public health. The present study aimed to combine primary laboratory data with literature-based secondary data to develop an Excel-based exposure assessment model (ADRISK) using a gamma generalised linear model to predict the final microorganism count in the digestate. This research examines the behaviour of a suite of pathogens (Cryptosporidium parvum, norovirus, Mycobacterium spp., Salmonella spp., Listeria monocytogenes, Clostridium spp., and pathogenic Escherichia coli) and indicators (total coliforms, E. coli, and enterococci) during mesophilic anaerobic digestion (M-AD) at 37 °C, pre/post-AD pasteurisation, and after a period of storage (with/without lime) for different feedstock proportions (slurry:food waste: 0:1, 1:3, 2:1, and 3:1). ADRISK tool simulations of faecal indicator bacteria levels across all scenarios show that the digestate can meet the EU standard without pasteurisation if the AD runs at 37 °C or a higher temperature with a higher C:N ratio (recipe 3) and a hydraulic retention time ≥ 7 days. The storage of digestate also reduced levels of microorganisms in the digestate. The Irish pasteurisation process (60 °C for 4 days), although more energy-intensive, is more effective than the EU pasteurisation (70 °C for 1 h) specification. Pre-AD pasteurisation was more effective for C. parvum, norovirus, Mycobacterium thermoresistibile. However, post-AD literature-based pasteurisation is most likely to assure the safety of the digestate. The information generated from this model can inform policy-makers regarding the optimal M-AD process parameters necessary to maximise the inactivation of microorganisms, ensuring adverse environmental impact is minimised, and public health is protected.

Clinical Outcomes and Healthcare Resource Utilization in a Real-World Population Reflecting the DAPA-CKD Trial Participants.

INTRODUCTION: The DAPA-CKD trial assessed dapagliflozin in patients with chronic kidney disease (CKD) with or without type 2 diabetes (T2D). To aid interpretation of results, renal and cardiovascular outcomes plus healthcare resource utilization (HCRU) and costs were assessed in a real-world population similar to that of DAPA-CKD. METHODS: Henry Ford Health System (2006-2016) data were used to identify patients with CKD stages 2-4 [estimated glomerular filtration rate (eGFR) 25-75 ml/min/1.73 m2 at index and urine albumin-to-creatinine ratio (UACR) 0-5000 mg/g; n = 22,251]. Included patients had confirmatory eGFR ≥ 90 days post-index and no kidney transplant or progression to end-stage kidney disease during 12 months pre-index. The final population (n = 6557) was stratified by UACR (0-29, 30-199 and 200-5000 mg/g; the last comprising the DAPA-CKD-like cohort). Patients were followed for 5 years post-index. RESULTS: Adverse clinical outcomes incidence increased with UACR and was highest for the DAPA-CKD-like cohort (UACR 200-5000 mg/g) versus lower UACR categories (0-29 mg/g and 30-199 mg/g): renal composite outcome (progression to CKD stage 5, dialysis, transplant, ≥ 50% sustained eGFR decline): 26.0% versus 2.2% and 5.8%; heart failure (HF): 36.1% versus 13.9% and 24.6%; myocardial infarction: 11.3% versus 4.7% and 7.4%; stroke: 8.9% versus 4.0% and 5.7%; and mortality: 18.5% versus 6.0% and 11.7%, respectively. Within the DAPA-CKD-like cohort, patients with versus without T2D or HF had a higher frequency of adverse outcomes. The DAPA-CKD-like cohort also had significantly higher annualized per-patient healthcare costs ($39,222/year versus $19,547/year), hospital admission rate (0.55/year versus 0.20/year) and outpatient specialist visit rate (7.55/year versus 6.74/year) versus the lowest UACR category. CONCLUSION: The significant adverse renal and cardiovascular outcomes observed, particularly in the DAPA-CKD-like cohort, represent a substantial burden resulting in increased mortality, HCRU and costs, demonstrating the need for additional treatment options.

Burden of Chronic Kidney Disease by KDIGO Categories of Glomerular Filtration Rate and Albuminuria: A Systematic Review.

INTRODUCTION: The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines recommend classifying patients by glomerular filtration rate (GFR) and albuminuria to predict chronic kidney disease (CKD) prognosis. The aim of this systematic review was to explore the epidemiological burden of CKD stratified by the KDIGO 2012 categories. METHODS: MEDLINE® and Embase were searched for observational studies of patients with CKD with results stratified according to the KDIGO 2012 classification. Investigated outcomes were prevalence, incidence, and risk factors and complications of CKD, including mortality. RESULTS: The review included ten observational studies with 3033 to 46,949 participants, conducted in the USA, China, France, Italy and Spain. The most frequently reported outcome was the prevalence of CKD (GFR categories G3-5), ranging from 2% to 17%. Most participants were normoalbuminuric, with 0.4-3.2% macroalbuminuric, and most fell within the KDIGO 2012 low-risk or moderate-risk groups, with 0.9-5.6% in the high-risk and 0.3-4.8% in the very high-risk groups. Although scarce, data on the prevalence of comorbidities in CKD according to the KDIGO classification suggest that they increase with albuminuria severity. CONCLUSIONS: Patients with CKD frequently have complications, but only a small proportion have severely increased albuminuria or fall within the KDIGO high-risk or very high-risk groups. These groups, however, are associated with the highest burden of disease, as comorbidities are more prevalent with increasing albuminuria severity. New studies framed by the KDIGO 2012 classification are needed to address key gaps in the understanding of CKD burden and outcomes.

A Small Study of Bacterial Contamination of Anaerobic Digestion Materials and Survival in Different Feed Stocks.

If pathogens are present in feedstock materials and survive in anaerobic digestion (AD) formulations at 37 °C, they may also survive the AD process to be disseminated in digestate spread on farmland as a fertilizer. The aim of this study was to investigate the prevalence of Salmonella spp., Escherichia coli O157, Listeria monocytogenes, Enterococcus faecalis and Clostridium spp. in AD feed and output materials and survival/growth in four formulations based on food waste, bovine slurry and/or grease-trap waste using International Organization for Standardization (ISO) or equivalent methods. The latter was undertaken in 100 mL Ramboldi tubes, incubated at 37 °C for 10 d with surviving cells enumerated periodically and the T90 values (time to achieve a 1 log reduction) calculated. The prevalence rates for Salmonella spp., Escherichia coli O157, Listeria monocytogenes, Enterococcus faecalis and Clostridium spp. were 3, 0, 5, 11 and 10/13 in food waste, 0, 0, 2, 3 and 2/3 in bovine slurry, 1, 0, 8, 7 and 8/8 in the mixing tank, 5, 1, 17, 18 and 17 /19 in raw digestate and 0, 0, 0, 2 and 2/2 in dried digestate, respectively. Depending on the formulation, T90 values ranged from 1.5 to 2.8 d, 1.6 to 2.8 d, 3.1 to 23.5 d, 2.2 to 6.6 d and 2.4 to 9.1 d for Salmonella Newport, Escherichia coli O157, Listeria monocytogenes, Enterococcus faecalis and Clostridium sporogenes, respectively. It was concluded that AD feed materials may be contaminated with a range of bacterial pathogens and L. monocytogenes may survive for extended periods in the test formulations incubated at 37 °C.

Anaerobic digestion of agricultural manure and biomass - Critical indicators of risk and knowledge gaps.

Anaerobic digestion (AD) has been identified as a potential green technology to treat food and municipal waste, agricultural residues, including farmyard manure and slurry (FYM&S), to produce biogas. FYM&S and digestate can act as soil conditioners and provide valuable nutrients to plants; however, it may also contain harmful pathogens. This study looks at the critical indicators in determining the microbial inactivation potential of AD and the possible implications for human and environmental health of spreading the resulting digestate on agricultural land. In addition, available strategies for risk assessment in the context of EU and Irish legislation are assessed. Storage time and process parameters (including temperature, pH, organic loading rate, hydraulic retention time), feedstock recipe (carbon-nitrogen ratio) to the AD plant (both mesophilic and thermophilic) were all assessed to significantly influence pathogen inactivation. However, complete inactivation of all pathogens is unlikely. There are limited studies evaluating risks from FYM&S as a feedstock in AD and the spreading of resulting digestate. The lack of process standardisation and varying feedstocks between AD farms means risk must be evaluated on a case by case basis and calls for a more unified risk assessment methodology. In addition, there is a need for the enhancement of AD farm-based modelling techniques and datasets to help in advancing knowledge in this area.

Glycaemic, weight, and blood pressure changes associated with early versus later treatment intensification with dapagliflozin in United Kingdom primary care patients with type 2 diabetes mellitus.

AIMS: Early treatment intensification for type 2 diabetes mellitus (T2DM) is often required to achieve glycaemic control and avoid longer-term complications. We assessed associations between early versus later dapagliflozin initiation with changes in glucose control, weight, and blood pressure using UK Clinical Practice Research Datalink (CPRD) data. METHODS: People with T2DM aged ≥18 years, initiating dapagliflozin between November 2012 and August 2016 and with prior oral T2DM therapy (N = 3774), were included. The relationship between early (first intensification after metformin or sulfonylurea monotherapy) and later (second or higher-order intensification) dapagliflozin use and baseline changes in glycated haemoglobin A1c (HbA1c; ≥1.0% absolute reduction), weight (≥5.0% relative loss), and systolic blood pressure (SBP; ≥2 mmHg absolute reduction) after 6-12 months were assessed. RESULTS: Overall, 25% of patients (951 of 3774) were early users and 75% (2823 of 3774) were later users. Later users were older, more likely to be men, and had longer disease duration. Early and later users had similar baseline mean HbA1c levels. For early versus later users, respectively, baseline-adjusted mean (95% confidence interval [CI]) reductions were 1.54% (-1.65, -1.44) versus 1.02% (-1.08, -0.97) in HbA1c, 3.31% (-4.37, -2.25) versus 4.06% (-5.05, -3.07) in weight, and 2.50 mm Hg (-3.89, -1.11) versus 2.84 mm Hg (-3.67, -2.01) in SBP. Early versus later use was associated with a greater likelihood of adjusted HbA1c reduction of ≥1% (odds ratio: 1.68, 95% CI: 1.15-2.45). CONCLUSIONS: Glycaemic benefits were greater with early versus later dapagliflozin intensification. These results support broader and earlier dapagliflozin use.

Agricultural anaerobic digestion power plants in Ireland and Germany: policy and practice.

The process of anaerobic digestion (AD) is valued as a carbon-neutral energy source, while simultaneously treating organic waste, making it safer for disposal or use as a fertilizer on agricultural land. The AD process in many European nations, such as Germany, has grown from use of small, localized digesters to the operation of large-scale treatment facilities, which contribute significantly to national renewable energy quotas. However, these large AD plants are costly to run and demand intensive farming of energy crops for feedstock. Current policy in Germany has transitioned to support funding for smaller digesters, while also limiting the use of energy crops. AD within Ireland, as a new technology, is affected by ambiguous governmental policies concerning waste and energy. A clear governmental strategy supporting on-site AD processing of agricultural waste will significantly reduce Ireland's carbon footprint, improve the safety and bioavailability of agricultural waste, and provide an indigenous renewable energy source. © 2016 Society of Chemical Industry.

High-mobility group box protein 1: a novel mediator of inflammatory-induced renal epithelial-mesenchymal transition.

BACKGROUND: high-mobility group box protein 1 (HMGB-1) is a chromatin-binding protein that bends DNA, thereby facilitating gene transcription. HMGB-1 has also been observed as an extracellular secreted protein in serum of patients with sepsis and has putative intracellular signalling effects regulating the production of interleukin-1 and tumour necrosis factor in a number of inflammatory conditions. METHODS: we established a model of immune-mediated epithelial-mesenchymal transition (EMT) in human proximal tubular epithelial cells (PTECs). PTECs were cultured with conditioned medium containing supernatant from activated peripheral blood mononuclear cells (aPBMCs). The model was characterized using phenotypic and transcriptomic approaches and suppression subtractive hybridisation was performed to identify differentially regulated genes. RESULTS: activation of PBMCs resulted in increased secretion of HMGB-1. In addition, treatment of PTECs with aPBMC-conditioned medium resulted in significant upregulation of HMGB-1 in PTECs. Direct treatment of PTECs with recombinant human HMGB-1 induced alterations in epithelial morphology consistent with EMT including reduced E-cadherin expression, increased α-smooth muscle actin expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products and through induction of transforming growth factor-ß(1) secretion from PTECs. CONCLUSIONS: these results suggest that HMGB-1 is a key mediator of immune-mediated EMT of PTECs and a potentially important signalling molecule in the development of renal fibrosis.