Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Quantitative Cytochrome P450 3A4 Induction Risk Assessment Using Human Hepatocytes Complemented with Pregnane X Receptor-Activating Profiles.

Reliable in vitro to in vivo translation of cytochrome P450 (CYP) 3A4 induction potential is essential to support risk mitigation for compounds during pharmaceutical discovery and development. In this study, a linear correlation of CYP3A4 mRNA induction potential in human hepatocytes with the respective pregnane-X receptor (PXR) activation in a reporter gene assay using DPX2 cells was successfully demonstrated for 13 clinically used drugs. Based on this correlation, using rifampicin as a positive control, the magnitude of CYP3A4 mRNA induction for 71 internal compounds at several concentrations up to 10 µM (n = 90) was predicted within 2-fold error for 64% of cases with only a few false positives (19%). Furthermore, the in vivo area under the curve reduction of probe CYP substrates was reasonably predicted for eight marketed drugs (carbamazepine, dexamethasone, enzalutamide, nevirapine, phenobarbital, phenytoin, rifampicin, and rufinamide) using the static net effect model using both the PXR activation and CYP3A4 mRNA induction data. The liver exit concentrations were used for the model in place of the inlet concentrations to avoid false positive predictions and the concentration achieving twofold induction (F2) was used to compensate for the lack of full induction kinetics due to cytotoxicity and solubility limitations in vitro. These findings can complement the currently available induction risk mitigation strategy and potentially influence the drug interaction modeling work conducted at clinical stages. SIGNIFICANCE STATEMENT: The established correlation of CYP3A4 mRNA in human hepatocytes to PXR activation provides a clear cut-off to identify a compound showing an in vitro induction risk, complementing current regulatory guidance. Also, the demonstrated in vitro-in vivo translation of induction data strongly supports a clinical development program although limitations remain for drug candidates showing complex disposition pathways, such as involvement of auto-inhibition/induction, active transport and high protein binding.

Factors associated with quality of life in patients with kidney failure managed conservatively and with dialysis: a cross-sectional study.

BACKGROUND: Later stage chronic kidney disease (CKD) is associated with poorer self-perceived health-related quality of life (HRQOL), a major consideration for many patients. Psychological factors such as depression and anxiety have been linked with poorer HRQOL. We aimed to determine if anxiety or depressive symptoms are significantly associated with self-perceived health-related quality of life, in patients with CKD Stage 5. The secondary aim was to determine which patient-associated factors are associated with HRQOL in patients with CKD Stage 5. METHODS: This retrospective cross-sectional study included patients that attended the St George Hospital Kidney Supportive Care (KSC) clinic between 1 and 2015 and 30 June 2022 with CKD Stage 5 (either conservatively-managed or receiving dialysis). Patients completed surveys of their functional 'domains' and quality of life (EQ-5D-5L) and symptom surveys (IPOS-Renal) at their first visit. We performed multivariable linear regression analysis with the outcome of interest being HRQOL, measured using the EQ-VAS, a continuous 100-point scale, for patients undergoing conservative management or dialysis. Pre-specified variables included age, sex, eGFR (for those conservatively-managed), "feeling depressed" (IPOS-Renal), "feeling anxious" (IPOS-Renal) and "anxiety/depression" (EQ-5D-5L). RESULTS: We included 339 patients. 216 patients received conservative kidney management (CKM) and 123 patients received dialysis. Patients receiving CKM were significantly older than those on dialysis, (median age 83 years vs. 73 years, p < 0.001). For conservatively-managed patients, variables independently associated with poorer EQ-VAS were difficulty performing usual activities (EQ-5D-5L), drowsiness (IPOS-Renal) and shortness of breath (IPOS-Renal). For patients receiving dialysis, variables that were independently associated with poorer EQ-VAS were reduced ability to perform self-care (EQ-5D-5L) and lack of energy (IPOS-Renal). Anxiety and depressive symptoms were not significantly associated with poorer EQ-VAS for either group of patients. CONCLUSIONS: Symptoms associated with reduced HRQOL include shortness of breath, drowsiness and impaired functional ability. Optimization of multidisciplinary teams focusing on these issues are likely to be of benefit.

Prevalence of Taste Changes and Association with Other Nutrition-Related Symptoms in End-Stage Kidney Disease Patients.

OBJECTIVES: Gastrointestinal symptoms are common in end-stage kidney disease (ESKD) and have been associated with reduced health-related quality of life and malnutrition. The aim of this study is to describe the prevalence of taste changes in an ESKD population and to evaluate whether taste changes are associated with the presence or severity of other nutrition-related symptoms and malnutrition. METHODS: We conducted a retrospective audit of people with ESKD on conservative, nondialysis management or renal replacement therapy who had completed a taste change assessment. Taste change was assessed on a Likert scale from none to overwhelming. Descriptions of taste changes were also collected. Other outcomes included gastrointestinal symptoms collected using the iPOS-renal symptom inventory, nutritional status, and biochemical parameters. RESULTS: In total, 298 patients were included in our analysis. Taste changes were reported in 38% of this cohort. Taste changes were significantly associated with upper gastrointestinal symptoms (nausea, vomiting, anorexia, and dry/sore mouth) and malnutrition. CONCLUSIONS: Our findings indicate that taste changes are highly prevalent and probably under-recognized in ESKD. Further investigation of the association with malnutrition is needed. Future trials are needed to evaluate strategies to manage taste changes in this population.

Application of a gut-immune co-culture system for the study of N-glycan-dependent host-pathogen interactions of Campylobacter jejuni.

An in vitro gut-immune co-culture model with apical and basal accessibility, designed to more closely resemble a human intestinal microenvironment, was employed to study the role of the N-linked protein glycosylation pathway in Campylobacter jejuni pathogenicity. The gut-immune co-culture (GIC) was developed to model important aspects of the human small intestine by the inclusion of mucin-producing goblet cells, human enterocytes and dendritic cells, bringing together a mucus-containing epithelial monolayer with elements of the innate immune system. The utility of the system was demonstrated by characterizing host-pathogen interactions facilitated by N-linked glycosylation, such as host epithelial barrier functions, bacterial invasion and immunogenicity. Changes in human intestinal barrier functions in the presence of 11168 C. jejuni (wildtype) strains were quantified using GICs. The glycosylation-impaired strain 11168 ΔpglE was 100-fold less capable of adhering to and invading this intestinal model in cell infectivity assays. Quantification of inflammatory signaling revealed that 11168ΔpglE differentially modulated inflammatory responses in different intestinal microenvironments, suppressive in some but activating in others. Virulence-associated outer membrane vesicles produced by wildtype and 11168ΔpglE C. jejuni were shown to have differential composition and function, with both leading to immune system activation when provided to the gut-immune co-culture model. This analysis of aspects of C. jejuni infectivity in the presence and absence of its N-linked glycome is enabled by application of the gut-immune model, and we anticipate that this system will be applicable to further studies of C. jejuni and other enteropathogens of interest.

Prescribing in renal supportive care.

Renal supportive care incorporates the principles of palliative care into the management of patients with advanced kidney disease. Its focus is on improving the quality of life for patients with a high burden of symptoms Common problems include pain, restless legs syndrome and uraemic pruritus. Symptom management must involve patient participation, education and non-pharmacological strategies to address both physical and psychosocial problems, and to prioritise patient-centred goals The patients are medically complex and polypharmacy is common. When prescribing, it is important to consider the altered pharmacokinetics, potential drug interactions and the clearance of drugs by dialysis

The effectiveness of cervical transforaminal epidural steroid injections for the treatment of cervical radicular pain: A prospective cohort study reporting 12-month outcomes.

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Prognostication After Dialysis Withdrawal.

Introduction: Dialysis withdrawal represents an increasingly common cause of death in patients receiving kidney replacement therapy internationally. Prognostic information about stopping dialysis guides clinicians counseling patients and families regarding end-of-life care. However, few studies examine prognostication after withdrawal. We aimed to determine median survival time after withdrawal of dialysis, and to determine which patient and dialysis-related factors are significantly associated with prognosis. Methods: This retrospective cohort study used registry data. We included all adult patients from the Western Renal Services who were receiving peritoneal dialysis (PD) or hemodialysis prior to death, whose cause of death was documented as "withdrawal from dialysis" and whose date of death was between January 1, 2016 and June 30, 2022. Demographic, clinical, and biochemical data was extracted. The primary outcome was time-to-death, defined as days from last dialysis session to date of death. Results: Median survival time from last dialysis to death for the PD group (n = 53) was 4 days (interquartile range [IQR]: 3-10 days), not significantly different from the hemodialysis group which was 6 days (IQR: 2-11 days, P = 0.72). For PD, the only variable significantly associated with survival time was reason for withdrawing (P = 0.01). Median survival time was significantly longer for patients withdrawing for psychosocial reasons compared to those withdrawing for other reasons (P = 0.002). For hemodialysis (n = 186), variables significantly associated with survival time from last dialysis to death was reason for withdrawing (P = 0.001), urine production at the time of withdrawal (P = 0.005), serum sodium (P = 0.02) and smoking status (P = 0.009). Conclusion: Median survival time was longer for withdrawals for psychosocial reasons compared to medical reasons. The data presented could inform withdrawal discussions regarding prognostication and end-of-life planning with patients and family.

Assessing Covariate Balance with Small Sample Sizes.

Propensity score adjustment addresses confounding by balancing covariates in subject treatment groups through matching, stratification, inverse probability weighting, etc. Diagnostics ensure that the adjustment has been effective. A common technique is to check whether the standardized mean difference for each relevant covariate is less than a threshold like 0.1. For small sample sizes, the probability of falsely rejecting the validity of a study because of chance imbalance when no underlying balance exists approaches 1. We propose an alternative diagnostic that checks whether the standardized mean difference statistically significantly exceeds the threshold. Through simulation and real-world data, we find that this diagnostic achieves a better trade-off of type 1 error rate and power than standard nominal threshold tests and not testing for sample sizes from 250 to 4000 and for 20 to 100,000 covariates. In network studies, meta-analysis of effect estimates must be accompanied by meta-analysis of the diagnostics or else systematic confounding may overwhelm the estimated effect. Our procedure for statistically testing balance at both the database level and the meta-analysis level achieves the best balance of type-1 error rate and power. Our procedure supports the review of large numbers of covariates, enabling more rigorous diagnostics.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Conservative Kidney Management: When, Why, and For Whom?

Deciding between dialysis and conservative kidney management (CKM) in an elderly or seriously ill person with kidney failure is complex and requires shared decision making. Patients and families look to their nephrologist to provide an individualized recommendation that aligns with patient-centered goals. For a balanced and considered decision to be made, dialysis should not be the default and nephrologists need to be familiar with relevant prognostic information including survival, symptom burden, functional trajectory, and quality of life with dialysis and with CKM. CKM is a holistic, proactive, and multidisciplinary treatment for kidney failure. For some elderly comorbid patients, CKM improves symptom burden and aligns with quality-of-life goals, with modest or no loss of longevity. CKM can be provided by a nephrologist alone but ideally is managed through partnership with a dedicated supportive or palliative care service embedded within the nephrology practice. Treatment decisions are best discussed early in the disease trajectory and occur over many consultations, and nephrologists should be upskilled in communication to better support patients and families in these important conversations. Nephrologists should remain actively involved in their patients' care through to end-of-life care.

Kidney failure end-of-life care: impact of advance care planning - retrospective observational study.

OBJECTIVES: Patients with kidney failure (KF) have poor prognosis yet receive aggressive medical interventions at the end of life. Advance care planning (ACP) aims to respect patients' treatment preference and facilitate good death, though whether these are achieved in KF is unknown.This study examines the utility of ACP for end-of-life care in KF patients. METHODS: A retrospective observational study of KF patients who completed an ACP document 2012-2019 and died in an Australian hospital. Medical records were reviewed to assess treatment concordance to the ACP document and quality of end-of-life care received. RESULTS: 65 KF patients (29 dialysis, 36 conservative) had a median age of 84 years and 57% males. 86% of deaths followed an emergency admission. ACP documents recorded patients' preference to avoid cardiopulmonary resuscitation (91%) and forego dialysis (86%). 95% patients received treatment concordant with ACP. One patient was resuscitated, and one conservative patient dialysed. A good quality death was achieved for most, including dialysis withdrawal (80%), palliative care referral (88%), discussion of prognosis (95%), rationalised medications (89%) and anticipatory end-of-life medications (92%). CONCLUSION: ACP documents are useful facilitating treatment concordant with KF patients' preferences. Most patients avoided aggressive medical interventions and received good quality end-of-life care.

Neural circuit-wide analysis of changes to gene expression during deafening-induced birdsong destabilization.

Sensory feedback is required for the stable execution of learned motor skills, and its loss can severely disrupt motor performance. The neural mechanisms that mediate sensorimotor stability have been extensively studied at systems and physiological levels, yet relatively little is known about how disruptions to sensory input alter the molecular properties of associated motor systems. Songbird courtship song, a model for skilled behavior, is a learned and highly structured vocalization that is destabilized following deafening. Here, we sought to determine how the loss of auditory feedback modifies gene expression and its coordination across the birdsong sensorimotor circuit. To facilitate this system-wide analysis of transcriptional responses, we developed a gene expression profiling approach that enables the construction of hundreds of spatially-defined RNA-sequencing libraries. Using this method, we found that deafening preferentially alters gene expression across birdsong neural circuitry relative to surrounding areas, particularly in premotor and striatal regions. Genes with altered expression are associated with synaptic transmission, neuronal spines, and neuromodulation and show a bias toward expression in glutamatergic neurons and Pvalb/Sst-class GABAergic interneurons. We also found that connected song regions exhibit correlations in gene expression that were reduced in deafened birds relative to hearing birds, suggesting that song destabilization alters the inter-region coordination of transcriptional states. Finally, lesioning LMAN, a forebrain afferent of RA required for deafening-induced song plasticity, had the largest effect on groups of genes that were also most affected by deafening. Combined, this integrated transcriptomics analysis demonstrates that the loss of peripheral sensory input drives a distributed gene expression response throughout associated sensorimotor neural circuitry and identifies specific candidate molecular and cellular mechanisms that support the stability and plasticity of learned motor skills.

Real-World Clinical Outcomes for Patients with EGFR and HER2 Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer.

(1) Background: Exon 20 insertion mutations (ex20ins) in EGFR and HER2 are uncommon driver mutations in non-small-cell lung cancer (NSCLC), with a poor prognosis and few targeted therapy options, and there are limited real-world data. Here, we report the clinicopathologic features and outcomes for patients with ex20ins NSCLC across British Columbia, Canada. (2) Methods: NSCLC patients with ex20ins in EGFR or HER2 were identified via tumour testing between 1 January 2016 and 31 December 2021 (n = 7233). Data were collected by chart review. Survival analyses were performed using the Kaplan-Meier method using the log-rank test. (3) Results: A total of 131 patients were identified. The median age was 66. Thirty-three percent of patients had brain metastases. For the EGFR cohort, the median OS was 18.6 months for patients who received any systemic therapy (ST) vs. 2.6 months for patients who did not (p < 0.001). Median OS was similar for patients treated with ex20ins-specific tyrosine kinase inhibitors (TKIs) vs. other STs (18.6 vs. 15.9 months; p = 0.463). The median first-line PFS was 4.1 vs. 7.4 months for patients treated with a TKI vs. other ST (p = 0.744). For the HER2 cohort, the median OS was 9.0 months for patients who received any ST vs. 4.9 months for patients who did not (p = 0.015). The median OS was 23.0 months for patients treated with an ex20ins TKI vs. 5.6 months for patients who were not (p = 0.019). The median first-line PFS was 5.4 vs. 2.1 months for patients treated with a TKI vs. other ST (p = 0.343). (4) Conclusions: Overall survival was significantly longer among ex20ins patients who received any systemic therapy vs. those who did not. Overall survival was significantly better among HER2 ex20ins patients who received ex20ins-specific TKIs.

DNA methylation markers for kidney function and progression of diabetic kidney disease.

Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation markers associated with baseline estimated glomerular filtration rate (eGFR) and subsequent decline in kidney function (eGFR slope), respectively, in 1,271 type 2 diabetes subjects. Here we show 40 (30 previously unidentified) and eight (all previously unidentified) CpG sites individually reach epigenome-wide significance for baseline eGFR and eGFR slope, respectively. We also develop a multisite analysis method, which selects 64 and 37 CpG sites for baseline eGFR and eGFR slope, respectively. These models are validated in an independent cohort of Native Americans with type 2 diabetes. Our identified CpG sites are near genes enriched for functional roles in kidney diseases, and some show association with renal damage. This study highlights the potential of methylation markers in risk stratification of kidney disease among type 2 diabetes individuals.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

ß-catenin mediates mechanically regulated, transforming growth factor-ß1-induced myofibroblast differentiation of aortic valve interstitial cells.

OBJECTIVE: In calcific aortic valve disease, myofibroblasts and activation of the transforming growth factor-ß1 (TGF-ß1) and Wnt/ß-catenin pathways are observed in the fibrosa, the stiffer layer of the leaflet, but their association is unknown. We elucidated the roles of ß-catenin and extracellular matrix stiffness in TGF-ß1-induced myofibroblast differentiation of valve interstitial cells (VICs). METHODS AND RESULTS: TGF-ß1 induced rapid ß-catenin nuclear translocation in primary porcine aortic VICs in vitro through TGF-ß receptor I kinase. Degrading ß-catenin pharmacologically or silencing it with small interfering RNA inhibited TGF-ß1-induced myofibroblast differentiation without altering Smad2/3 activity. Conversely, increasing ß-catenin availability with Wnt3A alone did not induce differentiation. However, combining TGF-ß1 and Wnt3A caused greater myofibroblast differentiation than TGF-ß1 treatment alone. Notably, in VICs grown on collagen-coated PA gels with physiological stiffnesses, TGF-ß1-induced ß-catenin nuclear translocation and myofibroblast differentiation occurred only on matrices with fibrosa-like stiffness, but not ventricularis-like stiffness. In diseased aortic valves from pigs fed an atherogenic diet, myofibroblasts colocalized with increased protein expression of Wnt3A, ß-catenin, TGF-ß1, and phosphorylated Smad2/3 in the fibrosa. CONCLUSIONS: Myofibroblast differentiation of VICs involves matrix stiffness-dependent crosstalk between TGF-ß1 and Wnt signaling pathways and may explain in part why the stiffer fibrosa is more susceptible to disease.

Survival of Older Patients With Advanced CKD Managed Without Dialysis: A Narrative Review.

Shared decision making is important when deciding the appropriateness of dialysis for any individual, particularly for older patients with advanced chronic kidney disease who have high mortality. Emerging evidence suggests that patients with advanced age, high comorbidity burden, and poor functional status may not have any survival advantage on dialysis compared with those on a conservative kidney management pathway. The purpose of this narrative review is to summarize the existing studies on the survival of older patients with stage 4 or 5 chronic kidney disease managed with or without dialysis and to evaluate the factors that may influence mortality in an effort to assist clinicians with shared decision making. Median survival estimates of conservative kidney management patients are widely varied, ranging from 1-45 months with 1-year survival rates of 29%-82%, making it challenging to provide consistent advice to patients. In existing cohort studies, the selected group of patients on dialysis generally survives longer than the conservative kidney management cohort. However, in patients with advanced age (aged ≥80 years), high comorbidity burden, and poor functional status, the survival benefit conferred by dialysis is no longer present. There is an overall paucity of data, and the variability in outcomes reflect the heterogeneity of the existing studies; further prospective studies are urgently needed.