The failing heart and kidney: improving prevention and treatment

The Cardiorenal Forum’s recent 18^th Annual Scientific meeting looked at the latest updates in the failing heart and kidney. Held in London on 6^th October 2023, this popular meeting mixed presentations from experts in cardiology, diabetes and renal medicine with the opportunity for delegates to network, share and discuss their knowledge and expertise. Dr Mohammad Wasef and Dr Sarah Birkhoelzer report its highlights.

The Cardiorenal Forum

New generation diabetes drugs – a cardiorenal done deal?

The meeting was opened by Professor William Herrington (Honorary Consultant Nephrologist, Oxford Kidney Unit) who discussed the impact of the new generation diabetes drugs on kidney outcomes.¹ A meta-analysis of over 90,000 patients showed that sodium glucose co-transporter-2 (SGLT2) inhibitors slowed chronic kidney disease (CKD) progression by 37%, and decreased the risk of acute kidney injury, cardiovascular (CV) death or heart failure hospitalisation by 23%, regardless, the presence of diabetes or type of SGLT2 inhibitor used. Implementing these drugs is simple and can be done by the cardiology team, renal team and in primary care. SGLT2 inhibitors are currently recommended in heart failure irrespective of ejection fraction, and in patients with CKD irrespective of primary disease or baseline kidney function.¹

Professor Herrington highlighted the class IA indication for glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with CKD and diabetes. These drugs lower the risk of hypoglycaemia and also have a beneficial effect on weight, CV risk and albuminuria.² The effects are more modest than with SGLT2 inhibitors and further renal data is awaited next year.

These studies looked at cardiorenal outcomes rather than glycated haemoglobin (HbA1c) as a quality marker of diabetic control.

Intervention timing in severe AS in patients with multimorbidity

Professor Gerry McCann (Professor of Cardiac Imaging, University of Leicester) emphasised that symptomatic aortic stenosis (AS) is a malignant disease with mortality rates similar to some cancers, but without medical therapies to slow progression. Valve replacement should therefore be considered urgently in these patients. Evidence favours transcatheter aortic valve implantation (TAVI) for those with high surgical risk, but one-year mortality rate post-TAVI remains high – up to 30.7% due to comorbidities, prevalence of coronary artery disease and advanced age.³

In low- to intermediate-risk groups, TAVI was not inferior to surgery, with one-year all-cause mortality decreased to 4.6%.⁴ Trials are in progress to investigate the effect of TAVI in patients with symptomatic, moderate AS. Patients with type 2 diabetes mellitus are over-represented in studies of surgical or transcatheter aortic valve replacement raising the hypothesis that diabetes, associated inflammation and adverse remodelling, impact disease progression but also peri-procedural outcomes. The impact of new diabetes therapies in patients with AS needs further exploration. Furthermore, whether patients with asymptomatic, severe AS should be offered valve replacement is unclear. Ongoing trials will determine whether early intervention based on late gadolinium enhancement echocardiography and brain natriuretic peptide (BNP) is beneficial.

Intravenous iron in heart failure

Iron deficiency is common in patients with heart failure and associated with worse symptoms and prognosis irrespective of anaemia. European Society for Cardiology (ESC) Guidelines recommend screening all patients with heart failure and reduced ejection fraction for iron deficiency and intravenous (IV) iron to improve symptoms, quality of life, exercise capacity and quality of life.⁵

Professor Paul Kalra (Consultant Cardiologist, Portsmouth Hospitals NHS Trust) presented the IRONMAN study showing a reduction in heart failure hospitalisations and CV death (hazard ratio [HR] 0.82, confidence interval [CI] 95% 0.66–1.02; P=0.07),⁶ which is in line with the meta-analysis by Graham et al. demonstrating that high-dose IV iron was associated with a significant reduction in a composite of heart failure hospitalisation and CV death (rate ratio (RR) 0.75; CI 95% 0.61–0.93; P<0.01).⁷

In IRONMAN, there was a 60% statistically significant decrease in hospitalisations during the SARS-CoV-2 (COVID-19) pandemic in patients taking IV iron, compared to usual care. Further studies are required to confirm the exact cut-off of iron deficiency, dosing of IV iron, effect in patients with preserved ejection fraction and interplay with SGLT2 inhibitors.

Latest developments in glomerulonephritis

The latest developments in glomerulonephritis, with a focus on new pathogenesis and treatments, were presented by Dr Lisa Willcocks (Consultant Nephrologist, Addenbrooke’s Hospital, Cambridge). She discussed the increasing recognition of proteinuria as a surrogate for progressive kidney disease, which has been helpful in developing trials without waiting for patients to develop end-stage kidney disease (ESKD). The talk also covered the transition in the treatment of immunoglobulin A (IGA) nephropathy, the commonest cause of glomerulonephritis, towards new era treatments following the DAPA CKD (Dapagliflozin in Patients with Chronic Kidney Disease)⁸ and EMPA KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease)⁹ trials. Insights into disease pathogenesis have guided the development of new targeted treatments, including gut-targeted glucocorticoids, monoclonal inhibitors, and complement inhibition (see table 1). Trials are currently underway to explore the use of immunosuppressive drugs to manage IGA nephropathy and prevent the progression to end-stage kidney disease.

Table 1. Targeted treatments for IGA nephropathy

Trial	Treatment	Key results
Barratt et al.¹⁰	Gut-targeted glucocorticoids	At nine months, UPCR was 27% lower in the targeted-release budesonide (Nefecon) group with benefit in eGFR preservation of 3.87 ml/min/1.73m² compared to placebo
Lafayette et al.¹¹	Monoclonal inhibitors	At week 36, proteinuria was 43% lower in the atacicept 150 mg group with benefit in eGFR preservation of 5.8 mL/min/1.73m² compared to placebo
Barratt et al.¹²	Complement inhibition	UPCR reduction of up to 40% from baseline up to 6 months in the iptacopan 200 mg bid arm compared to placebo (80% CI: 16–53%)
Key: eGFR = estimated glomerular filtration rate; IGA = immunoglobulin A; UPCR = urine-protein-to-creatinine ratio

Dr Willcocks also discussed membranous glomerulonephritis, the commonest cause of nephrotic syndrome in non-diabetic patients and described the treatment approaches for different patient groups. She highlighted the importance of new insight into its pathogenesis and the development of promising targeted treatments.

Her talk finished with a focus on minimal change disease, when she emphasised the challenge of disease recurrence post-transplant and the prolonged use of steroids for nephrotic patients to achieve remission. Children were noted to be highly responsive to steroids but frequently relapse. NHS England is funding rituximab for children with relapsing nephrotic syndrome, with ongoing trials in adults showing promising results. She highlighted the importance of differentiating between primary and secondary nephrotic syndrome, as the latter is less likely to respond to immunosuppression. Supportive care with angiotensin-converting enzyme (ACE) inhibitors, SGLT2 inhibitors, and sparsentan was recommended for non-nephrotic patients.¹³

Overall, her talk provided valuable insights into the complexities of managing minimal change disease and the potential for innovative treatments to improve patient outcomes.

Decongestion in cardiorenal disease

The complexity encountered in real-life cases for patients suffering from fluid overload with existing heart and kidney problems was discussed by Professor Darren Green (Consultant Nephrologist, Salford Royal NHS Foundation Trust) and Dr Peter Cowburn (Consultant Cardiologist, University Hospital, Southampton).

Congestion in cardiorenal disease is a challenging issue that healthcare professionals need to address, especially in patients with existing heart and kidney problems. The debate about whether chronic fluid overload triggers heart failure or vice versa is ongoing, but it’s clear that these patients are at high risk with poor prognosis and high mortality. The key to managing these complex cases lies in the collaboration of multidisciplinary teams, shared medical decisions with patients and family, and effective diuresis. There is also a need for longer term plans for medication optimisation, ensuring patient compliance, and providing intensive follow up for this vulnerable group of patients.

One of the main concerns is the under treatment of congestion when patients have low kidney function, and the effects of falsely branded ‘nephrotoxic drugs’, such as ACE inhibitors and diuretics, on renal function, decongestion and outcomes. Despite low kidney function, plasma B-type natriuretic peptide (BNP) is still linked to cardiovascular risk, highlighting the complexities of managing congestion in cardiorenal disease.

Dr Peter Cowburn highlighted that treating congestion in heart failure management is crucial, as it improves symptoms, reduces hospitalisation, and may prolong life. A key goal discussed was achieving euvolemia and monitoring patients’ offloading, alongside the importance of introducing and up-titrating evidence-based neurohormonal blockade/SGLT2 inhibition. The use of aggressive diuresis was proven to be generally safe and is an essential part of managing decompensated patients. Monitoring clinical signs and using right-sided echo parameters and Swan Ganz catheters can help achieve euvolemia, as well as the use of implantable haemodynamic monitors for remote monitoring and readjusting therapy.

Trials such as MONITOR-HF (Remote Haemodynamic Monitoring of Patients with Chronic Heart Failure), which randomised patients to haemodynamic monitoring with the cardioMEMS system versus standard care, showed that haemodynamic monitoring improved quality of life and reduced heart failure hospitalisations in patients with moderate-to-severe heart failure.¹⁴ An ongoing study is looking at the FIRE1 system, a sensor implanted in the inferior vena cava, which can assess congestion status and heart failure outcomes.

The management of congestion in cardiorenal disease requires a collaborative approach between nephrology and cardiology, with a focus on effective diuresis, medication optimisation, and intensive follow up to improve outcomes for these high-risk patients.

Cardiorenal clinical trials update

Cardiac trials

A personal round up of the latest clinical trials in cardiology, presented in table 2, was given by Dr Geraint Morton (Consultant Cardiologist, Portsmouth Hospitals NHS Trust).

Table 2. Cardiology trials update

Trial name	Take-home message
Weekend Warrior Exercise¹⁵	The majority of people do not meet the World Health Organisation’s recommended levels of physical activity Timing of exercise does not matter with significant benefits seen even with small amounts of exercise at weekends
Strong HF¹⁶	Rapid uptitration of heart failure drugs up with intensive follow-up is likely to be beneficial in selected patients There are workforce challenges involved in implementing this regimen
NOAH AFNET 6¹⁷	Should patients with AHRE be anticoagulated? These are seen in around one in five older patients under continuous monitoring Trial stopped early due to safety signals and a trend towards futility in the treatment arm Anticoagulating patients with AHRE increases bleeding without reducing stroke
ECLS-Shock¹⁸	Outcome of patients with acute myocardial infarction and cardiogenic shock receiving ECLS is not better than those who received medical therapy alone
Key: AHRE = atrial high-rate episodes; ECLS= Extracorporeal Life Support; NOAH AFNET= Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes

Renal trials

Dr David Lappin (Consultant Nephrologist, Galway University Hospitals) gave his personal selection of renal trials from 2023 (see table 3).

Table 3. Renal trials update

Trial name	Take-home message
EMPA Kidney⁹	SGLT2 inhibitors should be considered in all patients who have proteinuria with eGFR between 20 and 90 mls/min OR irrespective of ACR with eGFR between 20 and 45 ml/min
Nefigard¹⁹	Promising novel approach to IgA nephropathy management with lower risk of steroid associated adverse effects Synergistic effect with SGLT2 inhibitors or other novel agents such as finerenone and sparsentan May need to consider longer durations of therapy as antiproteinuric effect diminishes with time off drug
Haemodialysis convince²⁰	High dose haemofiltration can result in improved clinical outcome in a very selected group Mortality benefit looks to be driven by reduced risk of infection-related deaths with no difference in cardiovascular related deaths
Zailibeseran for hypertension²¹	Novel subcutaneous injectable zilebesiran (an RNA interference therapeutic agent) improves blood pressure compared with placebo at three months
Baxdrostat for resistant hypertension²²	Short term study Promising novel approach to resistant hypertension with good short-term safety profile
Sexual frequency and all-cause mortality association in patients with hypertension²³	Increased sexual activity frequency may have protective effects on general health and better quality of life in patients with hypertension
Key: ACR = albumin-creatine ratio; eGFR= estimated glomerular filtration rate; EMPA = Empagliflozin; IgA= immunoglobulin A; Nefigard = Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy

Pruritus: the silent epidemic in patients on dialysis

Dr Kieran McCafferty (Consultant Nephrologist, Barts Health NHS Trust, London) shed light on the widespread issue of CKD-associated pruritus (CKD AP) in patients on dialysis. More than 60% of dialysis patients suffer from this condition, which significantly reduces their quality of life and increases mortality. The causes of CKD AP are multifaceted, including toxins, neuropathy and immune system dysregulation. Currently, treatment options are limited, with antihistamines being the most commonly used, although these have little effect. Recent trials have shown promise for difelikefalin, an IV-administered treatment that has proven effective in reducing CKD AP and is well tolerated. Ongoing research is also exploring treatments for non-dialysis CKD patients. This often overlooked condition deserves more attention and effective treatment options for these patients.

Maximising heart health in end-stage kidney disease

The challenges in managing patients with cardiorenal syndrome, where heart failure and CKD often coexist and worsen outcomes, was discussed by Dr Matt Graham-Brown (Honorary Consultant Nephrologist, University of Leicester). With 40% of patients on dialysis suffering from heart failure and nearly half of all mortalities in ESKD attributed to cardiovascular disease, the need for effective therapies is evident. Diagnosis is complicated by overlapping symptoms; echocardiography and BNP measurements often yield inaccurate results. When managing these patients, it is crucial to address volume control, optimise dialysis strategy, and manage anaemia. Although foundation therapies for heart failure have clear cardiovascular benefits, their use in advanced CKD and in patients on dialysis is not well-studied.

While smaller trials have shown some benefits of particular medications, such as ACE inhibitors and angiotensin II receptor blockers (ARBs), the evidence for other medications, such as mineralocorticoid receptor antagonists (MRAs) and angiotensin receptor-neprilysin inhibitors (ARNIs), remains limited. The risk of hyperkalaemia may not outweigh the potential benefits, even with the availability of potassium binders. Ongoing trials for heart failure therapies in ESKD provide hope for improved future management.

Interactive cases

The popular interactive cases session ended the meeting. The first case, presented by Dr Sarah Birkhoelzer (Clinical Research Fellow, University of Oxford), looked at initiating the four pillars of heart failure treatment in one month. The case was one that healthcare professionals commonly face in the community: symptoms of heart failure, left bundle branch block and high NTproBNP. Firstly, the diagnostic challenges were highlighted – long waiting lists for echocardiography and specialist reviews. Secondly, the timing of initiating prognostic drugs was discussed, and she highlighted that early initiation of SGLT2 inhibitors and ACE inhibitors are encouraged, even prior to confirmation of ejection fraction via echocardiogram. Thirdly, the challenges of resources to match the uptitration strategy used in the STRONG HF trial was discussed.¹⁶ The huge variations in practice across the country became apparent in the discussion of the case.

The second case looked at conservative management of ESKD and hypoxia inducible factor (HIF) stabilisers. Ms Karen Jenkins (Consultant Nurse, East Kent Hospitals) presented a case of a patient with stage 5 CKD who being managed conservatively based on his preference. His haemoglobin levels gradually dropped to below 90 g/L and so oral HIF stabilisers were initiated. These inhibit HIF prolyl hydroxylase domain enzyme (HIF-PHD), leading to activation of erythropoietin. Despite remarkable results to treatment, challenges were raised, particularly in the frequent blood testing for monitoring purposes. The key take-home message from this case was the collaboration with the patient with minimal invasive monitoring.

Acknowledgements

The Cardiorenal Forum would like to thank the following companies for their funding and support of this independent meeting: AstraZeneca, the alliance of Boehringer-Ingelheim and Eli Lilly & Company, CSL Vifor UK Ltd, and A Menarini Farmaceutica Internazionale SRL, as well as the following societies for their endorsement of the meeting: the British Society for Heart Failure, the Irish Nephrology Society, Kidney Disease Improving Global Outcomes, the UK Kidney Association, and the UK Renal Pharmacy Group.

Conflicts of interest

None declared.

Diary date

The 19th Annual Scientific Meeting of the Cardiorenal Forum will take place on Friday 4th October 2024 at the King’s Fund, 11–13 Cavendish Square, London W1G 0AN. Contact [email protected] for more information and to sign up for updates. The website www.cardiorenalforum.com will also carry full details of the next meeting.

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