The long-term effects of dapagliflozin in chronic kidney disease: a time-to-event analysis.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The DAPA-CKD trial demonstrated that patients with or without type 2 diabetes (T2D) who were treated with dapagliflozin experienced slower progression of CKD versus placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. METHODS: Patient-level data from the DAPA-CKD trial were used to parameterise a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure). Data were pooled with a subpopulation of the DECLARE-TIMI 58 trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. RESULTS: In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function, and hospitalisation for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years (dapagliflozin: 25.2, 95%CI: 19.0-31.5; standard therapy: 18.5, 95%CI: 14.7-23.4) in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95%CI: 31.9-38.3; standard therapy: 29.6, 95%CI: 25.5-34.7). CONCLUSION: Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression.

Dapagliflozin in chronic kidney disease: cost-effectiveness beyond the DAPA-CKD trial.

Background: The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial enrolled patients with estimated glomerular filtration rate 25-75 mL/min/1.73 m2 and urine albumin-to-creatinine ratio >200 mg/g. The Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial enrolled patients with type 2 diabetes, a higher range of kidney function and no albuminuria criterion. The study objective was to estimate the cost-effectiveness of dapagliflozin in a broad chronic kidney disease population based on these two trials in the UK, Spain, Italy and Japan. Methods: We adapted a published Markov model based on the DAPA-CKD trial but to a broader population, irrespective of urine albumin-to-creatinine ratio, using patient-level data from the DAPA-CKD and DECLARE-TIMI 58 trials. We sourced cost and utility inputs from literature and the DAPA-CKD trial. The analysis considered healthcare system perspectives over a lifetime horizon. Results: Treatment with dapagliflozin was predicted to attenuate disease progression and extend projected life expectancy by 0.64 years (12.5 versus 11.9 years, undiscounted) in the UK, with similar estimates in other settings. Clinical benefits translated to mean quality-adjusted life year (QALY; discounted) gains between 0.45 and 0.68 years across countries. Incremental cost-effectiveness ratios in the UK, Spain, Italy and Japan ($10 676/QALY, $14 479/QALY, $7771/QALY and $13 723/QALY, respectively) were cost-effective at country-specific willingness-to-pay thresholds. Subgroup analyses suggest dapagliflozin is cost-effective irrespective of urinary albumin-to-creatine ratio and type 2 diabetes status. Conclusion: Treatment with dapagliflozin may be cost-effective for patients across a wider spectrum of estimated glomerular filtration rates and albuminuria than previously demonstrated, with or without type 2 diabetes, in the UK, Spanish, Italian and Japanese healthcare systems.

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.

Global Economic Burden Associated with Chronic Kidney Disease: A Pragmatic Review of Medical Costs for the Inside CKD Research Programme.

INTRODUCTION: Chronic kidney disease (CKD) is a progressive disease of growing prevalence, posing serious concerns for global public health. While the economic burden of CKD is substantial, data on the cost of CKD is limited, despite growing pressures on healthcare systems. In this review, we summarise the available evidence in 31 countries and regions and compile a library of costing methodology and estimates of CKD management and disease-associated complications across 31 countries/regions within the Inside CKD programme. METHODS: We collected country/region-specific CKD costs via a pragmatic rapid literature review of local literature and engagement with local experts. We extracted cost data and definitions from identified sources for CKD stages G3a-5, kidney failure with replacement therapy by modality, covering haemodialysis, peritoneal dialysis, and kidney transplants, and disease-associated complications in local currency, converted to United States dollars (USD) and inflated to 2022. RESULTS: Annual direct costs associated with CKD management rose by an average factor of 4 in each country/region upon progression from stage G3a to G5. Mean annual costs per patient increased considerably more from early stages versus dialysis (stage G3a, mean: $3060 versus haemodialysis, mean: $57,334; peritoneal dialysis, mean: $49,490); with estimates for annual costs of transplant also substantially higher (incident: $75,326; subsequent: $16,672). The mean annual per patient costs of complications were $18,294 for myocardial infarction, $8463 for heart failure, $10,168 for stroke and $5975 for acute kidney injury. Costing definitions varied widely in granularity and/or definition across all countries/regions. CONCLUSION: Globally, CKD carries a significant economic burden, which increases substantially with increasing disease severity. We identified significant gaps in published costs and inconsistent costing definitions. Cost-effective interventions that target primary prevention and disease progression are essential to reduce CKD burden. Our results can be used to guide cost collection and facilitate better comparisons across countries/regions to inform healthcare policy.

Patient Management and Clinical Outcomes Associated with a Recorded Diagnosis of Stage 3 Chronic Kidney Disease: The REVEAL-CKD Study.

INTRODUCTION: Guidelines for the treatment of chronic kidney disease (CKD) recommend early intervention and management to slow disease progression. However, associations between diagnosis and CKD progression are not fully understood. METHODS: REVEAL-CKD (NCT04847531) is a retrospective observational study of patients with stage 3 CKD. Data were extracted from the US TriNetX database. Eligible patients had two consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD (≥ 30 and < 60 ml/min/1.73 m2) recorded 91-730 days apart from 2015 to 2020. Diagnosed patients were included if their first CKD diagnosis code was recorded at least 6 months after their second qualifying eGFR measurement. We assessed CKD management and monitoring practices for the 180 days before and after CKD diagnosis, annual eGFR decline in the 2 years before and after CKD diagnosis, and associations between diagnostic delay and post-diagnosis event rates. RESULTS: The study included 26,851 patients. After diagnosis, we observed significant increases in the prescribing rate of guideline-recommended medications such as angiotensin-converting enzyme inhibitors (rate ratio [95% confidence interval]: 1.87 [1.82, 1.93]), angiotensin receptor blockers (1.91 [1.85, 1.97]) and mineralocorticoid receptor antagonists (2.23 [2.13, 2.34]). Annual eGFR decline was significantly reduced following a CKD diagnosis, from 3.20 ml/min/1.73 m2 before diagnosis to 0.74 ml/min/1.73 m2 after diagnosis. Delayed diagnosis (by 1-year increments) was associated with elevated risk of CKD progression to stage 4/5 (1.40 [1.31-1.49]), kidney failure (hazard ratio [95% confidence interval]: 1.63 [1.23-2.18]) and the composite of myocardial infarction, stroke and hospitalization for heart failure (1.08 [1.04-1.13]). CONCLUSIONS: A recorded CKD diagnosis was associated with significant improvements in CKD management and monitoring practices and attenuated eGFR decline. Recorded diagnosis of stage 3 CKD is an important first step to reduce the risk of disease progression and minimize adverse clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04847531.

Chronic kidney disease (CKD) is a long-term condition in which the function of the kidneys is reduced. Kidney function is monitored using a measurement called the estimated glomerular filtration rate. CKD can be separated into stages of severity, ranging from 1 (mild) to 5 (severe), using estimated glomerular filtration rate. Mild to moderate CKD (stages 1­3) is difficult to diagnose because there are usually no symptoms. In this study from the REVEAL-CKD programme, we looked at the effects of having undiagnosed stage 3 (moderate) CKD and examined how a CKD diagnosis affects disease management and worsening of the condition. Using a database of medical records for patients in the USA called TriNetX, we looked at data from over 26,000 patients with stage 3 CKD who were identified using estimated glomerular filtration rate measurements. We found that healthcare teams prescribed significantly more guideline-recommended medications and did more clinical monitoring in the 180 days after a CKD diagnosis than they did before the diagnosis. Additionally, the rate of decline in kidney function slowed after a CKD diagnosis. Delaying diagnosis by 1 year increased the risk of deterioration of the condition by 40%, the risk of needing a kidney transplant or long-term dialysis treatment by 63% and the risk of major heart and blood vessel diseases (known as cardiovascular events) by 8%. Our findings suggest that diagnosis of stage 3 CKD is an important first step to reduce the risk of the disease worsening and other complications. Video Abstract (MP4 82773 KB).

Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study.

OBJECTIVES: REVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD). DESIGN: Multinational, observational study. SETTING: Data from six country-specific electronic medical records and/or insurance claims databases from five countries (France, Germany, Italy, Japan and the USA [two databases]). PARTICIPANTS: Eligible participants (≥18 years old) had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements (calculated from serum creatinine values, sex and age) taken from 2015 onwards that were indicative of stage 3 CKD (≥30 and <60 mL/min/1.73 m2). Undiagnosed cases lacked an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before, and up to 6 months after, the second qualifying eGFR measurement (study index). MAIN OUTCOME MEASURES: The primary outcome was point prevalence of undiagnosed stage 3 CKD. Time to diagnosis was assessed using the Kaplan-Meier approach. Factors associated with lacking a CKD diagnosis and risk of diagnostic delay were assessed using logistic regression adjusted for baseline covariates. RESULTS: The prevalence of undiagnosed stage 3 CKD was 95.5% (19 120/20 012 patients) in France, 84.3% (22 557/26 767) in Germany, 77.0% (50 547/65 676) in Italy, 92.1% (83 693/90 902) in Japan, 61.6% (13 845/22 470) in the US Explorys Linked Claims and Electronic Medical Records Data database and 64.3% (161 254/250 879) in the US TriNetX database. The prevalence of undiagnosed CKD increased with age. Factors associated with undiagnosed CKD were female sex (vs male, range of odds ratios across countries: 1.29-1.77), stage 3a CKD (vs 3b, 1.81-3.66), no medical history (vs a history) of diabetes (1.26-2.77) or hypertension (1.35-1.78). CONCLUSIONS: There are substantial opportunities to improve stage 3 CKD diagnosis, particularly in female patients and older patients. The low diagnosis rates in patients with comorbidities that put them at risk of disease progression and complications require attention. TRIAL REGISTRATION: NCT04847531.

Short-time effects of spa rehabilitation on pain, mood and quality of life among patients with degenerative or post-surgery musculoskeletal disorders.

Clinical trials have demonstrated traditional spa therapy effects in musculoskeletal disorders (MSDs). This is the first observational study in Italy aimed at evaluating in real-life the short-time effects of spa rehabilitation on pain, mood and quality of life (QoL) among degenerative or post-surgery MSDs patients. Through the involvement of six Italian spa facilities, 160 patients were enrolled; data from 123 patients were finally analysed. Seventy-nine patients (64.3%) accessed the spa for degenerative MSDs, while 44 (35.8%) had a post-surgical condition. All the patients included in the study underwent 12 sessions of water-based exercise (joint exercises, muscle strengthening, gait training, proprioceptive and balance techniques) conducted in thermal or in warm water pools, six sessions per week, for a period of 2 weeks from March 2019 up to October 2019. A group of 45 patients (36.6%) also received traditional thermal therapies, including 12 mud therapy sessions and 12 thermal baths, six times each week, for 2 weeks. Evaluation before and after the treatment included the Numerical Rating Scale (NRS), the Short Form Health Survey (SF-12) and the EuroQol-5D (EQ-5D). The analysis of the scores reported in the questionnaires after the treatment showed a significant improvement in all the scores evaluated. Comparison between patients that performed water-based exercise protocols alone (group A) and patients that in addition to water exercise performed traditional thermal interventions (group B) showed no statistically significant differences in NRSp, NRSa, NRSm, SF-12 PCS, SF-12 MCS and EQ-5D variations; only NRSa value reduction was lower in group B. Sulphate water was found to be associated with a lower reduction of all the scores considered, when compared to the other water types. Patients with degenerative or post-surgery MSDs showed favourable effects on pain, mood and QoL after water exercise training alone or in combination with traditional thermal therapy. Our research provides the first proof that spa rehabilitation can be in real-life conditions an appropriate alternative strategy for post-orthopaedic surgical outcomes recovery. In the future, these results will need to be further investigated.

A new calculation method for the free electron fraction of an ionization chamber in the ultra-high-dose-per-pulse regimen.

The free electron fraction is the fraction of electrons, produced inside the cavity of an ionization chamber after irradiation, which does not bind to gas molecules and thereby reaches the electrode as free electrons. It is a fundamental quantity to describe the recombination processes of an ionization chamber, as it generates a gap of positive charges compared to negative ones, which certainly will not undergo recombination. The free electron fraction depends on the specific chamber geometry, the polarizing applied voltage and the gas thermodynamic properties. Therefore, it is necessary to evaluate such fraction in an accurate and easy way for any measurement condition. In this paper, a simple and direct method for evaluating the free electron fraction of ionization chambers is proposed. We first model the capture process of the electrons produced inside an ionization chamber after the beam pulse; then we present a method to evaluate the free electron fraction based on simple measurements of collected charge, by varying the applied voltage. Finally, the results obtained using an Advanced Markus chamber irradiated with a Flash Radiotherapy dedicated research Linac (ElectronFlash) to estimate the free electron fraction are presented. The proposed method allows the use of a conventional ionization chamber for measurements in ultra-high-dose-per-pulse (UHDP) conditions, up to values of dose-per-pulse at which the perturbation of the electric field due to the generated charge can be considered negligible.

Investigating the global prevalence and consequences of undiagnosed stage 3 chronic kidney disease: methods and rationale for the REVEAL-CKD study.

Background: Timely diagnosis and treatment of stage 3 chronic kidney disease (CKD) can prevent further loss of kidney function and progression to kidney failure. However, contemporary data on the global prevalence of undiagnosed stage 3 CKD are scarce. REVEAL-CKD is a multinational, multifocal and observational study aiming to provide insights into undiagnosed stage 3 CKD in a large population. Methods: Patients (aged ≥18 years) with data in selected secondary databases from 11 countries will be included if they have at least two estimated glomerular filtration rate (eGFR) measurements from 2015 onwards that are ≥30 and <60 mL/min/1.73 m2, recorded >90 and ≤730 days apart. Undiagnosed cases are those without an International Classification of Diseases 9/10 diagnosis code for CKD (any stage) any time before and up to 6 months after the second qualifying eGFR measurement. Time to diagnosis will be assessed using a Kaplan-Meier approach; patient characteristics associated with undiagnosed CKD will be assessed using adjusted logistical regression analyses. Results: REVEAL-CKD will assess the point prevalence of undiagnosed stage 3 CKD and time to CKD diagnosis in initially undiagnosed cases overall and in individual countries. Trends in undiagnosed CKD prevalence by calendar year will be assessed. Patient characteristics, healthcare resource utilization, adverse clinical outcomes, and CKD management and monitoring practices in patients with versus without a CKD diagnosis will be compared. Conclusions: REVEAL-CKD will increase awareness of the global clinical and economic burden of undiagnosed stage 3 CKD and provide valuable insights to inform clinical practice and policy changes.

Eye Irritation Potential of Microglycine and Microglycine-Containing Ointments: An in vitro Study on Reconstructed Human Corneal Epithelium.

OBJECTIVE: To assess the eye tolerability of a buffered ophthalmic solution containing microglycine (sodium hydroxymethylglycinate, mwaterTM) in an in vitro model. MATERIALS AND METHODS: A multiple endpoint analysis (MEA) approach was applied to the reconstructed human corneal epithelium (HCE) model. Sodium hydroxymethylglycinate solution (0.04%) and two ophthalmic ointments containing microglycine (Protectorial, containing 0.02% of sodium hydroxymethylglycinate, and Edenight, containing 0.04% of sodium hydroxymethylglycinate) were investigated. The buffered solution and the ointments were tested on HCE after acute (one application in 24 hrs, followed or not by 16 hrs of recovery) or repeated (one application per day for three consecutive days) exposures; benzalkonium chloride (BAK) 0.01% and saline isotonic solution were used as positive and negative controls, respectively. Cellular viability, trans-epithelial electrical resistance (TEER), lactate dehydrogenase (LDH) release and histo-morphology were evaluated. RESULTS: BAK 0.01% toxicity in HCE was confirmed for the 24+16 hrs acute and repeated exposure protocols, while, after 24-hours acute treatment, only modifications of the superficial cell layer were visible compared with the negative control. Sodium hydroxymethylglycinate had a very good tolerability profile and a neutral impact on the corneal surface after acute or repeated exposure. The Protectorial and Edenight ointments preserved cell viability in the different exposure protocols, suggesting a good local tolerability profile. Modifications of the superficial layers were observed on histo-morphological analysis and confirmed by increased release of LDH after 24+16 hrs acute exposure (+65% and +76% for Protectorial and Edenight, respectively) and TEER values after 24+16 hrs and 72 hrs exposure protocols. These results were dependent on the ointments' accumulation on the corneal epithelium due to their physical form (semi-solid) and lipophilic properties. CONCLUSION: Sodium hydroxymethylglycinate, alone or as part of eye ointments, was found to be non-toxic after acute or repeated exposure in the reconstructed HCE model.

The array biosensor: portable, automated systems.

With recent advances in surface chemistry, microfluidics, and data analysis, there are ever increasing reports of array-based methods for detecting and quantifying multiple targets. However, only a few systems have been described that require minimal preparation of complex samples and possess a means of quantitatively assessing matrix effects. The NRL Array Biosensor has been developed with the goal of rapid and sensitive detection of multiple targets from multiple samples analyzed simultaneously. A key characteristic of this system is its two-dimensional configuration, which allows controls and standards to be analyzed in parallel with unknowns. Although the majority of our work has focused on instrument automation and immunoassay development, we have recently initiated efforts to utilize alternative recognition molecules, such as peptides and sugars, for detection of a wider variety of targets. The array biosensor has demonstrated utility for a variety of applications, including food safety, disease diagnosis, monitoring immune response, and homeland security, and is presently being transitioned to the commercial sector for manufacturing.