Validation of the FINE-CKD model for future health technology assessments for finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). OBJECTIVE: To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models. METHODS: Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models. RESULTS: The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model. CONCLUSIONS: This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

A Unique Multi- and Interdisciplinary Cardiology-Renal-Endocrine Clinic: A Description and Assessment of Outcomes.

BACKGROUND: Patients with diabetes and co-existing chronic kidney disease and/or cardiovascular disease have complex medical needs with multiple indications for different guideline-directed medical therapies and require high health care resource utilization. The Cardiac and Renal Endocrine Clinic (C.a.R.E. Clinic) is a multi- and interdisciplinary clinic offering a unique care model to this population to overcome barriers to optimal care. OBJECTIVE: To describe the patient characteristics and clinical data of consecutive patients seen in the C.a.R.E. Clinic between 2014 and 2020, with a focus on the feasibility, strengths, and challenges of this outpatient care model. DESIGN: Single-center retrospective cohort study. SETTING: The C.a.R.E. Clinic is a multi- and interdisciplinary clinic at Toronto General Hospital in Toronto, Canada. PATIENTS: We reviewed the charts of all 118 patients who had been referred to the C.a.R.E. Clinic with type 2 diabetes mellitus, co-existing renal disease, and/or cardiovascular disease. MEASUREMENTS: Demographic data, medication data, clinic blood pressure measurements, and laboratory data were assessed at the first and last available clinic visit. METHODS: Data were extracted via manual chart review of paper and electronic medical records. RESULTS: First and last attended clinic visit data were available for descriptive analysis in 74 patients. There was a significant improvement in low-density lipoprotein (LDL) cholesterol (1.9 mmol/L vs 1.5 mmol/L, P < .01), hemoglobin A1C (7.5% vs 7.1%, P = .02), and the proportion of patients with blood pressure at target (52.7% vs 36.5%, P = .04), but not body mass index (29.7 kg/m² vs 29.6 kg/m², P = .15) between the last and first available clinic visits. There was higher uptake in evidence-based medication use including statins (93.2% vs 81.1%, P = .01), SGLT-2i (35.1% vs 4.1%, P < .01), and GLP-1 receptor agonists (13.5% vs 4.1%, P = .02), while RAAS inhibitor use was already high at baseline (81.8% vs 78.4%, P = .56). There remains a significant opportunity for therapy with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. LIMITATIONS: This is a retrospective chart review lacking a control group, therefore clinical improvements cannot be causally attributed to the clinic alone. New evidence and changes to guideline-recommended therapies also contributed to practice changes during this time period. CONCLUSIONS: A multi- and interdisciplinary clinic is a feasible and potentially effective way to improve evidence-based and patient-centered care for patients with diabetes, kidney, and cardiovascular disease.

CONTEXTE: Les patients diabétiques présentant une néphropathie chronique et/ou maladie cardiovasculaire co-existante ont des besoins complexes avec de multiples indications concernant différents traitements médicaux recommandés par les lignes directrices. En outre, ces patients nécessitent une utilisation élevée des ressources de santé. La clinique C.a.R.E. (Cardiac and Renal Endocrine Clinic) est une clinique interdisciplinaire et multidisciplinaire offrant un modèle de soins unique qui permet de surmonter les obstacles aux soins optimaux pour cette population. OBJECTIF: Décrire les caractéristiques et les données cliniques des patients consécutifs suivis à la clinique C.a.R.E. entre 2014 et 2020, en se concentrant sur la faisabilité et sur les avantages et les défis de ce modèle de soins ambulatoires. TYPE D'ÉTUDE: Étude de cohorte rétrospective menée dans un seul centre. CADRE: La clinique C.a.R.E. est une clinique multidisciplinaire et interdisciplinaire de l'Hôpital général de Toronto (Canada). SUJETS: Nous avons examiné les dossiers des 118 patients diabétiques de type 2 atteints d'une néphropathie et/ou maladie cardiovasculaire qui ont été dirigés vers la clinique C.a.R.E. au cours de la période étudiée. MESURES: Les données démographiques, les données sur les ordonnances, les mesures cliniques de la pression artérielle et les données de laboratoire ont été évaluées pour la première et la dernière visite à la clinique disponibles. MÉTHODOLOGIE: Les données ont été extraites par un examen manuel des dossiers médicaux papier et électronique. RÉSULTATS: Les données d'intérêt pour la première et la dernière visite à la clinique étaient disponibles pour l'analyse descriptive chez 74 patients. Entre la première et la dernière visite disponible, on a observé une amélioration significative du taux de cholestérol LDL (1,9 mmol/L vs 1,5 mmol/L; p < 0,01), de l'hémoglobine A1c (7,5 % vs 7,1 %; p = 0,02) et de la proportion de patients avec une mesure de pression artérielle dans les valeurs cibles (52,7 % vs 36,5 %; p = 0,04) alors que l'indice de masse corporelle est demeuré inchangé (29,7 kg/m² vs 29,6 kg/m²; p = 0,15). Les ordonnances de thérapies fondées sur les données probantes ont été plus fréquentes, notamment pour les statines (93,2 % vs 81,1 %; p = 0,01), le SGLT-2i (35,1 % vs 4,1 %; p < 0,01) et les agonistes des récepteurs GLP-1 (13,5 % vs 4,1 %; p = 0,02); l'utilisation d'inhibiteurs du SRAA était déjà élevée au départ (81,8 % vs 78,4 %; p = 0,56). De grandes possibilités de traitement demeurent pour les inhibiteurs du cotransporteur-2 de sodium-glucose et les agonistes des récepteurs du peptide-1 de type glucagon. LIMITES: Il s'agit d'un examen rétrospectif des dossiers sans groupe témoin; les améliorations cliniques ne peuvent être attribuées de façon causale à la clinique seule. Pendant la période étudiée, de nouvelles données probantes et des changements aux traitements recommandés par les lignes directrices ont également entraîné des changements dans la pratique. CONCLUSION: Une clinique multidisciplinaire et interdisciplinaire est une solution viable et potentiellement efficace pour améliorer les soins axés sur les patients et les traitements fondés sur les données probantes pour les patients diabétiques atteints de néphropathie et/ou de maladies cardiovasculaires.

FINE-CKD model to evaluate economic value of finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications. OBJECTIVE: To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD. METHODS: A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review. RESULTS AND CONCLUSIONS: The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

Preventing CKD in Developed Countries.

Chronic kidney disease (CKD) is an important public health concern in developed countries because of both the number of people affected and the high cost of care when prevention strategies are not effectively implemented. Prevention should start at the governance level with the institution of multisectoral polices supporting sustainable development goals and ensuring safe and healthy environments. Primordial prevention of CKD can be achieved through implementation of measures to ensure healthy fetal (kidney) development. Public health strategies to prevent diabetes, hypertension, and obesity as risk factors for CKD are important. These approaches are cost-effective and reduce the overall noncommunicable disease burden. Strategies to prevent nontraditional CKD risk factors, including nephrotoxin exposure, kidney stones, infections, environmental exposures, and acute kidney injury (AKI), need to be tailored to local needs and epidemiology. Early diagnosis and treatment of CKD risk factors such as diabetes, obesity, and hypertension are key for primary prevention of CKD. CKD tends to occur more frequently and to progress more rapidly among indigenous, minority, and socioeconomically disadvantaged populations. Special attention is required to meet the CKD prevention needs of these populations. Effective secondary prevention of CKD relies on screening of individuals at risk to detect and treat CKD early, using established and emerging strategies. Within high-income countries, barriers to accessing effective CKD therapies must be recognized, and public health strategies must be developed to overcome these obstacles, including training and support at the primary care level to identify individuals at risk of CKD, and appropriately implement clinical practice guidelines.

Neuropathy and presence of emotional distress and depression in longstanding diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIM: To determine the association of neuropathy and other complications with emotional distress and depression among patients with longstanding type 1 diabetes (T1DM). METHODS: Canadians with ≥50years of T1DM completed a questionnaire including assessment of distress and depression by the Problem Areas in Diabetes Scale (PAID) and Geriatric Depression Scale (GDS), respectively. Complications were determined using the Michigan Neuropathy Screening Instrument (Questionnaire Component), fundoscopy reports, renal function tests, and self-reported peripheral-(PVD) and cardiovascular (CVD) disease. Associations were analyzed by Poisson regression. RESULTS: Among 323 participants, 137 (42.4%) had neuropathy, 113 (36.5%) nephropathy, 207 (69.5%) retinopathy, 95 (29.4%) CVD, and 31 (9.8%) PVD. The neuropathy subgroup had higher prevalence of distress (13 (9.5%) vs. 6 (3.3%), p=0.029) and depression (34 (24.9%) vs. 12 (6.5%), p<0.001). Adjusting for diabetes complications, neuropathy was associated with higher PAID (adjusted RR 1.44 (95% CI 1.14-1.82), p=0.003) and GDS scores (adjusted RR1.57 (1.18-2.11), p=0.002). Independent of potential confounders, neuropathy remained associated with higher PAID (adjusted RR 1.39 (1.10-1.76), p=0.006) and GDS scores (adjusted RR 1.37 (1.03-1.83), p=0.032). Associations with neuropathy were not fully explained by neuropathic pain. CONCLUSION: Compared to other complications, neuropathy had the greatest association with distress and depression in longstanding T1DM, independent of pain. Strategies beyond pain management are needed to improve quality of life in diabetic neuropathy.

Assessment of urinary microparticles in normotensive patients with type 1 diabetes.

AIMS/HYPOTHESIS: Assessment of urinary extracellular vesicles including exosomes and microparticles (MPs) is an emerging approach for non-invasive detection of renal injury. We have previously reported that podocyte-derived MPs are increased in diabetic mice in advance of albuminuria. Here, we hypothesised that type 1 diabetes and acute hyperglycaemia would increase urinary podocyte MP levels in uncomplicated diabetes. METHODS: In this post hoc exploratory analysis, we examined archived urine samples from normoalbuminuric patients with uncomplicated type 1 diabetes studied under clamped euglycaemia and hyperglycaemia and compared with healthy controls. Urinary vesicles were assessed by electron microscopy and nanoparticle tracking while podocyte MPs were assessed by flow cytometry. RESULTS: Neither vesicle size nor total number were significantly altered in type 1 diabetes or acute hyperglycaemia. By contrast, urinary podocyte MP levels were higher in type 1 diabetes (0.47 [0.00-3.42] MPs/µmol creatinine [Cr]) compared with healthy controls (0.00 [0.00-0.00] MPs/µmol Cr, p < 0.05) and increased under hyperglycaemic clamp (0.36 [0.00-4.15] MPs/µmol Cr during euglycaemia vs 2.70 [0.00-15.91] MPs/µmol Cr during hyperglycaemia, p < 0.05). Levels of urinary albumin to creatinine ratio and nephrin (surrogates of podocyte injury) were unchanged by type 1 diabetes or acute hyperglycaemia. CONCLUSION/INTERPRETATION: Taken together, our data show that urinary podocyte MP levels are higher in patients with type 1 diabetes in advance of changes in other biomarkers (albuminuria, nephrin). Examination of podocyte MPs may serve as an early biomarker of glomerular injury in uncomplicated type 1 diabetes.

Longitudinal assessment of inflammation in recipients of continuous-flow left ventricular assist devices.

BACKGROUND: The long-term effects of continuous-flow left ventricular assist device (CF-LVAD) support on trends of inflammatory markers over time are unknown. We examined the hypothesis that the levels of inflammatory markers in CF-LVAD recipients are higher than in healthy controls and that these levels increase over time with long-term CF-LVAD support. METHODS: We examined the levels of inflammatory markers longitudinally at baseline before CF-LVAD implantation and at 3, 6, and 9 months after implantation. We then compared the levels of inflammatory markers to those in a healthy control group. RESULTS: Compared with baseline values before CF-LVAD implantation, left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) decreased significantly at 3, 6, and 9 months after CF-LVAD implantation. Brain natriuretic peptide (BNP) levels dropped significantly after CF-LVAD implantation but did not normalize. Improvements in ejection fraction at 3, 6, and 9 months after CF-LVAD implantation did not reach significance. Monocyte chemoattractant protein-1, interferon γ-induced protein, and C-reactive protein levels were higher in the CF-LVAD recipients at each of the time points (baseline before CF-LVAD implantation and 3, 6, and 9 months after implantation) compared with levels in healthy controls. In CF-LVAD recipients, serum interleukin-8, tumour necrosis factor-α, and macrophage inflammatory protein-ß increased significantly at 9 months, and macrophage-derived chemokine increased at 6 months after CF-LVAD implantation compared with baseline. CONCLUSIONS: Despite improvements in LV dimensions and BNP levels, markers of inflammation remained higher in CF-LVAD recipients. High levels of inflammation in CF-LVAD recipients may result from heart failure preconditioning or the long-term device support, or both. Because inflammation may be detrimental to CF-LVAD recipients, future studies should determine whether inflammatory pathways are reversible.

Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia.

CONTEXT: Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. OBJECTIVE: We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. DESIGN AND SETTING: Physiological assessments were conducted at an academic center. PARTICIPANTS: Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). INTERVENTIONS: Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). MAIN OUTCOME MEASURES: Response to LBNP and ANG II was evaluated. RESULTS: RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. CONCLUSIONS: Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

College and university environmental programs as a policy problem (part 2): strategies for improvement.

Environmental studies and environmental sciences programs in American and Canadian colleges and universities seek to ameliorate environmental problems through empirical enquiry and analytic judgment. In a companion article (Part 1) we describe the environmental program movement (EPM) and discuss factors that have hindered its performance. Here, we complete our analysis by proposing strategies for improvement. We recommend that environmental programs re-organize around three principles. First, adopt as an overriding goal the concept of human dignity-defined as freedom and social justice in healthy, sustainable environments. This clear higher-order goal captures the human and environmental aspirations of the EPM and would provide a more coherent direction for the efforts of diverse participants. Second, employ an explicit, genuinely interdisciplinary analytical framework that facilitates the use of multiple methods to investigate and address environmental and social problems in context. Third, develop educational programs and applied experiences that provide students with the technical knowledge, powers of observation, critical thinking skills and management acumen required for them to become effective professionals and leaders. Organizing around these three principles would build unity in the EPM while at the same time capitalizing on the strengths of the many disciplines and diverse local conditions involved.