Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

Aim To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction. Methods A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: ‘alive and event-free’, ‘alive after non-fatal hospitalisation for heart failure’ and ‘dead’. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually. Results Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively. Conclusion Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.

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Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.

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Background The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial demonstrated that dapagliflozin reduced heart failure hospitalisations and mortality in patients with established heart failure, regardless of diabetic status. Purpose To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure, from the perspective of the Australian public healthcare system. Methods A Markov model populated with 1000 hypothetical individuals was constructed based on the DAPA-HF trial to assess the clinical outcomes and costs of patients with established heart failure and reduced ejection fraction over a lifetime time horizon. The model consisted of three health states: “Alive and event-free”, “Alive after non-fatal hospitalisation for heart failure” or “Dead”. Costs and utilities were estimated from published sources. Outcomes of interest were the incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained and cost per year of life saved (YoLS). All outcomes were discounted at a rate of 5% annually. Results Over a lifetime analysis, addition of dapagliflozin to standard care in patients with chronic heart failure prevented 88 acute heart failure hospitalisations (including readmission), and saved 416 (discounted) years of life and 288 (discounted) QALYs, at an additional cost of A$3,692,440 or €2,263,204 (discounted). This resulted in ICERs of A$8,875 (€5,439) per YoLS and A$12,482 (€7,650) per QALY gained, well below the Australian arbitrary willingness-to-pay threshold of A$50,000 (€30,645). Conclusion From the Australian public healthcare perspective, dapagliflozin is cost-effective when used as an adjunct therapy to standard care compared to standard care alone for the treatment of chronic heart failure with reduced ejection fraction. Funding Acknowledgement Type of funding source: None