The current President of the United States once stated that “the kidney has a very special place in the heart”; despite the questionable anatomical reference, the truth is that the kidneys and heart are intertwined, affected by common pathophysiological processes and sharing many of the same disease-causing risk factors. Ronco and colleagues have previously classified the complex array of inter-related derangements that simultaneously involve both organs, and this serves as a useful starting point in understanding their important physiological and pathophysiological inter-dependence.1
End-stage renal disease (ESRD) represents a state of dysregulation of many processes including inflammation, endothelial dysfunction, vascular calcification, bone mineral metabolism, oxidative stress, autonomic balance, uraemia, volume control, coagulation, insulin resistance, and haematopoiesis. The process of haemodialysis, the most common form of renal replacement therapy, causes myocardial stunning, leading to strain and potential damage,2 and can create a pro-arrhythmic environment.3 The early dialysis period is indeed high risk, with more cardiovascular events reported within the first five months of dialysis.4 It is, therefore, not an exaggeration to state that ESRD, with its ‘cardiotoxic’ milieu, represents the ‘perfect storm’ for the occurrence of cardiac complications.
The daunting figures and sudden cardiac death (SCD)
The prevalence of cardiovascular disease in patients undergoing dialysis in the US reaches 70.6%,5 with SCD representing the most common cause of mortality (37%).6 As many as 40.2% of patients on haemodialysis suffer from coronary artery disease (CAD), and 40.4% have heart failure (HF); their prevalence increases with age, however, it is still striking that CAD and HF exists in 20.2% and 28.3%, respectively, of the haemodialysis population aged 22–44 years.5 This is not surprising given the progressive coronary calcification in young dialysis patients, as noted by Goodman et al.,7 and the uraemia impact on cardiac function.8
Sudden cardiac death is an area of increasing interest; focus centres on identification of trigger patterns and prevention. The cardiac rhythm prior to death in this population is dominated by bradycardia and asystole (unlike the general population), as noted by the Monitoring in Dialysis trial (MiD)9 and the Cardio Renal Arrhythmia Study in Haemodialysis Patients Using Implantable Loop Recorders (CRASH-ILR).10 Innovative work on non-invasive electrophysiology and the use of the QRS-T angle in predicting risk is ongoing.11 The idea of implantable cardiac defibrillators (ICDs) holding the key has been recently dismissed through the ICD2 trial stopping prematurely due to futility reasons,12 supporting the results of previous retrospective reviews.13
Outcomes and current management – is there something missing?
Outcomes in patients with ESRD are poor: two-year survival of ESRD patients following acute myocardial infarction in 2015–2016 in the US was 58.5%, compared with 78.2% in the rest of the population. This can be partly explained by the disparity in management of cardiac complications, evident in reviews of large registries.6,14,15
In CAD, the timing of revascularisation and pharmacotherapy in patients with ESRD come under question, as the use of novel antiplatelet agents (e.g. ticagrelor, prasugrel) is not advocated by the European Society of Cardiology (ESC) or the American Heart Association (AHA) due to lack of evidence. Landmark trials including PLATO (Platelet Inhibition and Patient Outcomes) and TRITON TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel – Thrombolysis In Myocardial Infarction 38) did not involve ESRD patients.16,17 The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches – Chronic Kidney Disease trial (ISCHEMIA-CKD) attempted to determine whether early invasive therapy instead of conservative management was beneficial in patients with stable angina and an estimated glomerular filtration rate (eGFR) ≤30 ml/min/1.73 m2 or on dialysis. Early invasive therapy was not associated with a decrease in myocardial infarction, death or hospitalisation incidence.18
Similarly, atrial fibrillation (AF) patients with kidney disease are less likely to receive anti-arrhythmic medications and oral anticoagulation, especially as eGFR decreases.15 The Kidney Disease: Improving Global Outcomes (KDIGO) foundation, in 2017, advocated a cautious approach in the use of direct oral anticoagulants (DOACs) given the absence of representation of patients with ESRD in clinical trials – matching the situation exhibited with novel antiplatelet agents. However, in 2018, the US Food and Drug Administration (FDA) extended apixaban’s licence for use in patients with AF and ESRD; evidence from observational reviews and randomised-controlled trials are encouraging.19,20 The interventional management of AF in ESRD remains a relatively evidence-free area, with a study revolving around the use of left atrial appendage occlusion in this group recently halted due to poor recruitment (NCT02039167).
The pharmacotherapeutic dogma of HF does not have a strong evidence base in ESRD. Despite supportive evidence on the use of beta blockers, there are scarce reports on the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), which are indeed contradictory.21 The ongoing STOP-ACEi trial (Multi-centre Randomised Controlled Trial of ACEi/ARB Withdrawal in Advanced Renal Disease) is researching the discontinuation of ACEi/ARBs and whether this leads to an improvement in kidney function with no safety detriment (e.g. cardiovascular events, cardiovascular-related hospitalisation).21 Mineralocorticoid antagonists reviewed in small randomised-controlled trials show promise with regards to safety.22,23 Two large randomised placebo-controlled trials are underway addressing the effect of low-dose spironolactone on survival improvement and cardiovascular event reduction in ESRD (ACHIEVE: NCT03020303; ALCHEMIST: NCT01848639). The Systolic Heart failure treatment with Ivabradine – (the first selective sinus node If channel inhibitor) Trial (SHIFT) did not include any ESRD patients.24
Iron, bones and the future
The relationship between the two disciplines is not only displayed through disease processes, but by how interventions already used in one area, such as the long-standing practice of intravenous iron replacement in renal medicine, are now gaining ground in cardiology through the FERRIC-HF (Ferric Iron in Heart Failure) and FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) trials.25,26 Intravenous iron use is further supported by the PIVOTAL (Proactive IV Iron Therapy in Haemodialysis Patients) study noting a decreased hazard ratio of myocardial infarction or hospitalisation with heart failure in dialysis patients receiving high-dose, as opposed to low-dose, iron.27 Medications, such as cinacalcet, have shown promise in the reduction of cardiovascular events in dialysis.28 The field of sodium-glucose transport protein-2 inhibitors (SGLT2), practically linking multi-morbidity in the form of diabetes, renal dysfunction and cardiac failure, is ever-evolving.29,30
Patients with ESRD have traditionally been under-represented in cardiac studies, but, hopefully, this is changing. The advent of home-monitoring may improve patient enrolment in future studies, as this removes a major constraint in patient participation: the rigid nature and intensity of dialysis schedules leading to patient reluctance for further medical interventions. An ongoing study (NCT04268264) examining the feasibility of starting dialysis incrementally is currently attempting to reduce the early burden of treatment in this patient population, freeing up more patient time to participate in other activities of daily life. This study also examines quality of life, cardiac load and functional status. Cardiac comorbidities and renal disease have a tremendous impact on quality of life and it is important for research to address patient-related outcome measures. These efforts could help in tailoring care and reducing symptom burden.
Steps in the right direction have already been made with the creation of multi-disciplinary task forces, addressing cardiorenal issues. Additional opportunities exist for cooperation between trainees from both disciplines via the creation of groups (such as the Cardiorenal Forum) and through conference topics. Both the British Heart Foundation and Kidney Research UK have formed groups extensively studying inter-disciplinary links. The cooperation between the two specialties is fundamentally important given the absence of a solid evidence base for sound decisions to be taken regarding pharmacotherapy and overall management.
The fact that cardiac complications remain the leading cause of death and morbidity in this vulnerable patient group does not reflect fairly on the advances made in either specialty over the years – however, it reminds us of the importance of shared care and the need to learn from specialist colleagues within other fields of medicine. After all, the patient is neither just the kidneys nor just the heart; managing multi-morbidity is the challenge of the modern physician, with patient-centred care at the core.
Conflicts of interest
None declared.
Funding
None.
References
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