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
1. Ronco C, Bellasi A, Di Lullo L. Cardiorenal syndrome: an overview. Adv Chronic Kidney Dis 2018;25:382–90. https://doi.org/10.1053/j.ackd.2018.08.004
2. McIntyre C, Burton J, Selby N et al. Hemodialysis-induced cardiac dysfunction is associated with an acute reduction in global and segmental myocardial blood flow. Clin J Am Soc Nephrol 2007;3:19–26. https://doi.org/10.2215/CJN.03170707
3. Sacher F, Jesel L, Borni-Duval C et al. Cardiac rhythm disturbances in hemodialysis patients: early detection using an implantable loop recorder and correlation with biological and dialysis parameters. JACC Clin Electrophysiol 2018;4:397–408. https://doi.org/10.1016/j.jacep.2017.08.002
4. Eckardt KU, Gillespie IA, Kronenberg F et al. High cardiovascular event rates occur within the first weeks of starting hemodialysis. Kidney Int 2015;88:1117–25. https://doi.org/10.1038/ki.2015.117
5. United States Renal Data System. Chapter 8: cardiovascular disease in patients with ESRD. AJKD 2018;71:S417–S432. https://doi.org/10.1053/j.ajkd.2018.01.021
6. United States Renal Data System. Chapter 9: cardiovascular disease in patients with ESRD. AJKD 2016;67:S259–S264. https://doi.org/10.1053/j.ajkd.2016.02.020
7. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342:1478–83. https://doi.org/10.1056/NEJM200005183422003
8. Bhandari S. Risk factors and metabolic mechanisms in the pathogenesis of uraemic cardiac disease. Front Biosci (Landmark Ed) 2011;16:1364–87. https://doi.org/10.2741/3794
9. Roy-Chaudhury P, Tumlin J, Koplan B et al. Primary outcomes of the Monitoring in Dialysis Study indicate that clinically significant arrhythmias are common in hemodialysis patients and related to dialytic cycle. Kidney Int 2018;93:941–51. https://doi.org/10.1016/j.kint.2017.11.019
10. Roberts PR, Zachariah D, Morgan JM et al. Monitoring of arrhythmia and sudden death in a hemodialysis population: the CRASH-ILR study. PLoS One 2017;12:e0188713. https://doi.org/10.1371/journal.pone.0188713
11. Poulikakos D, Hnatkova K, Skampardoni S, Green D, Kalra P, Malik M. Sudden cardiac death in dialysis: arrhythmic mechanisms and the value of non-invasive electrophysiology. Front Physiol 2019;10:144. https://doi.org/10.3389/fphys.2019.00144
12. Jukema J, Timal R, Rotmans J et al. Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients. Circulation 2019;139:2628–38. https://doi.org/10.1161/CIRCULATIONAHA.119.039818
13. Pun PH, Hellkamp AS, Sanders GD et al. Primary prevention implantable cardioverter defibrillators in end-stage kidney disease patients on dialysis: a matched cohort study. Nephrol Dial Transplant 2015;30:829–35. https://doi.org/10.1093/ndt/gfu274
14. Szummer K, Lindhagen L, Evans M et al. Treatments and mortality trends in cases with and without dialysis who have an acute myocardial infarction: an 18-year nationwide experience. Circ Cardiovasc Qual Outcomes 2019;12:e005879. https://doi.org/10.1161/CIRCOUTCOMES.119.005879
15. Washam JB, Holmes DN, Thomas LE et al. Pharmacotherapy for atrial fibrillation in patients with chronic kidney disease: insights from ORBIT-AF. J Am Heart Assoc 2018;7:e008928. https://doi.org/10.1161/JAHA.118.008928
16. Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://doi.org/10.1056/NEJMoa0904327
17. Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. https://doi.org/10.1056/NEJMoa0706482
18. Ischemiackd.org. ISCHEMIA-CKD Trial Results. 2020 [accessed 12 March 2020]. Available at: http://ischemiackd.org/study-results
19. Siontis KC, Zhang X, Eckard A et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation 2018;138:1519–29. https://doi.org/10.1161/CIRCULATIONAHA.118.035418
20. Pokorney S, Kumbhani D, Batt D. RENal hemodialysis patients ALlocated apixaban versus warfarin in Atrial Fibrillation – RENAL-AF. American College of Cardiology, 17 November 2019 [accessed 12 March 2020]. Available at: https://www.acc.org/latest-in-cardiology/clinical-trials/2019/11/15/17/29/renal-af
21. Bhandari S, Ives N, Brettell EA et al. Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial. Nephrol Dial Transplant 2016;31:255–61. https://doi.org/10.1093/ndt/gfv346
22. Charytan DM, Himmelfarb J, Ikizler TA et al. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. Kidney Int 2019;95:973–82. https://doi.org/10.1016/j.kint.2018.08.034
23. Hammer F, Malzahn U, Donhauser J et al. A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients. Kidney Int 2019;95:983–91. https://doi.org/10.1016/j.kint.2018.11.025
24. Swedberg K, Komajda M, Böhm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85. https://doi.org/10.1016/S0140-6736(10)61198-1
25. Okonko DO, Grzeslo A, Witkowski T et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008;51:103–12. https://doi.org/10.1016/j.jacc.2007.09.036
26. Filippatos G, Farmakis D, Colet JC et al. Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. Eur J Heart Fail 2013;15:1267–76. https://doi.org/10.1093/eurjhf/hft099
27. Macdougall IC, White C, Anker SD et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med 2019;380:447–58. https://doi.org/10.1056/NEJMoa1810742
28. EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012;367:2482–94. https://doi.org/10.1056/NEJMoa1205624
29. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744
30. McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303