Effects of haemodialysis on myocardial perfusion

    Home / Themes / Great British Research / Effects of haemodialysis on myocardial perfusion

Effects of haemodialysis on myocardial perfusion

  The effects of haemodialysis on myocardial perfusion…. understanding the ‘dark side’ of dialysis

 Chris McIntyre


The challenge we face

When I started   as a consultant nephrologist at Derby City General Hospital in 1999, it was a quarter of a century  since  Belding Scribner’s seminal description of excess cardiovascular mortality in haemodialysis (HD) patients 1. In it he identified the understanding and addressing of cardiovascular disease in HD patients as a primary focus for ongoing research and care. But most of us became tone deaf to this challenge, in part perhaps because of the overwhelming day to day burden of care that came with the  exponential growth in access to maintenance dialysis. This  led to a widely held sense of learned helplessness, where we accept that dialysis patients will of course feel terrible and die prematurely.

Our goals in Derby

I was appointed as a consultant in Derby to join my friend and colleague, Richard Fluck. We had taken responsibility between us for a mature renal programme which had been established in the first wave of dialysis units in 1969, and had, until Richard’s appointment always  been led by a single-handed nephrologist (Geoffrey Cohen). Both Richard and I  had been trained at St Barts and the Royal London, with our laboratory-based research fellowships under the  supervision of John Cunningham and Tony Raine respectively. Our tertiary level renal service covering south Derbyshire and  sat somewhat incongruously in a rather traditional district general hospital setting but we were united  in our ambition to transform it into a programme with global impact. And Maarten Taal who soon joined us as  a consultant also shared that vision. From the beginning we knew that quality original research output was a vital currency in this pursuit, and we embarked  on the journey to achieve this,  somewhat unfettered by peer expectations (it was only Derby after all).

We had  no formal affiliation to an academic centre,  and there was no local academic infrastructure of any real note. Molecular biology was  already the dominant force in the national renal research environment and ‘old fashioned’ cardiovascular physiology was largely relegated to the recently retired or chronically underfunded. Tony Raine (before his tragically early death) was at the forefront of the renaissance in recognizing that kidney disease was inextricably linked to cardiovascular disease. This was strongly inoculated into both Richard and me. My entire research career has stemmed from empirical observation of our dialysis patients through that lens.

Clinical observation defines the problem

At Derby my first office was adjacent to the main dialysis unit waiting room. It was bereft of natural light or any form of ventilation, so the door was always open. For 18 months I watched  dialysis patients arriving   pink, perfused and conversant and leaving looking grey and largely silent. The four-hour interregnum on the dialysis machine left them  with   what looked for all the world like low output cardiac failure. My great friend Chris Baker was at the time studying for his PhD at the Hammersmith Hospital, under Paolo Camici. Chris was using a pig model to surgically induce recurrent segmental non-lethal myocardial ischemia (imaged using cardiac PET scanning). This repetitive process had been termed ‘myocardial stunning’ and was already recognised as an important pathophysiological mechanism leading to loss of contractile function,  in tissue not yet dead (hibernation),   progressing onwards to fibrosis and fixed heart failure 2,3.

I  must acknowledge the importance of good wine in the research process, as during a particularly long lunch we postulated that the circulatory stress of HD was sufficient to induce this phenomenon; and that the dialysis process itself might   be driving the development of ‘uremic cardiomyopathy’, rather than the plethora of effects being attributed to the uraemic milieu. The uraemic  milieu might   be important, but predominately by priming the heart to experience demand ischemia. This postulate was almost entirely untested, with only a smattering of data from  intradialytic ECG changes to support it. I decided to make this the central tenet of our attempts to develop a research programme.

A small beginning

The first public output was an abstract, which we presented at the Renal Association meeting in Autumn 2002. This reported the association of higher levels of circulating troponin in patients with intradialytic hemodynamic instability. In it we hypothesised that ‘elevated levels of cardiac troponins may result from multiple ischemic events sustained during hemodynamically traumatic extracorporeal blood purification’. I am impressed looking back at it now, that  I seemed to prefer   using five words when one would do! But we had arrived at a core hypothesis which I am continuing to explore to this day. I had stumbled on a narrative that has been consistent and persistent – effective messaging which has proven central to the impact of the work over the last 20 years.

Straight to in vivo studies

We made a conscious decision to do experiments which might allow us to ‘fail early’. If our hypothesis could not be demonstrated to be biologically plausible, then there was no point pursuing it further. Instead of a slow incremental process of evidence formulation (epidemiology, observation, animal work and so on) we decided to attempt the direct experimental study of HD-induced myocardial stunning in man. This would involve, for the first-time, performing HD combined with cardiac PET scanning. To measure cardiac output we needed   radioactive water produced from an adjacent cyclotron to be used instantly given its very short half-life (a few minutes). There was no way to perform these studies in Derby and only the Hammersmith Hospital possessed the necessary equipment. This project proved impossible to fund through conventional grant applications – in the eyes of the reviewers uncertainty about the feasibility of the project  associated with my perceived lack of research pedigree scuppered us. . However, soft money was scraped together and with the crucial assistance of our much missed Chief Renal Technician, Paul Froom, we installed a HD facility in the PET scanner at Hammersmith. Next we overcame the research governance logistics and approvals necessary for us to work at Hammersmith, before patients were transported from Derby, placed in a (very cheap) hotel, studied the next day and returned home- all in the same van as the dialysis equipment.

This original study (published in 2008)  established that HD did indeed produce segmental ischemic myocardial injury which  could be detected by simultaneous echocardiography; with ischemia being inferred by the loss of contractile function. 4 Unfortunately our Derby cardiology colleagues were less than enamoured with the prospect of supporting our wish   for frequent serial echocardiography in the dialysis unit. So instead we progressed through the slightly sly acquisition of a  rather venerable Vivid 7 echo machine (bought by the League of Friends) and a ‘home-made’ training program for image acquisition. This meant we could now study  myocardial stunning in the dialysis unit during routine care, and swiftly we were able to demonstrate it was common and associated with excessive fluid removal and hypotension. 5 It was progressive and resulted in heart failure and cardiac mortality 6. It was independent of traditional concepts of epicardial coronary artery disease, with even children being affected 7,8. Early on we could also show that the  HD-induced myocardial stunning was important, but it wasn’t hopeless. Dialysis based interventions to improve the tolerability of treatment were able to abrogate this injury.9,10 I am particularly grateful for the work of Nick Selby and James Burton, who were pivotal in generating this early evidence during their time as research fellows at Derby, before developing as independent in professorial investigators  – Nick Selby in Derby, James Burton in Leicester.

The following years have seen remarkable expansion of the concept of dialysis related harm being central to understanding the pathophysiology of both subjective and objective negative outcomes in dialysis. The studies have gone on  confirm the same process occurring in brain 11, kidneys 12, gut 13 and liver 14. And crucially we have developed  a variety of simple and scalable dialysis-based interventions to improve outcomes by addressing these preventable harms. 15,16

Looking forward

Since I transferred my research program in 2015 to Western University in London Ontario in Canada I have been able to  include additional imaging modalities, such as MRI 11,17 and novel forms of CT, to explore intersections with emerging concepts of sodium as an uraemic toxin 18,19, and to set up the rodent models of HD and ischemic injury that I probably should have established at the beginning 20. Since moving to Canada we have also managed to design and execute the largest to date (around 4.3 million treatments in more than 15,000 patients) RCT to be performed in HD patients- studying cooling, one of the candidate interventions. 21 These assembled insights have influenced national and global dialysis treatment guidelines   and directly informed US based reimbursement policies, with the aim of reducing  the degree of circulatory stress  to which dialysis patients are  subjected. Our research program continues, it is increasingly internationally collaborative, and it has provided higher degree training for over 40 individuals   from a variety of professional backgrounds. I am indebted to each and every one of them.

The interaction of patient, kidney disease and treatment is so complex we will need to increasingly gravitate towards complex interventions. As a community we have been successful in industrializing dialysis; unfortunately, we have also promulgated a swathe of negative biological consequences. We urgently need to develop and implement an equally industrialized precision medicine approach. The discovery and exploitation of dialysis based ischemic harm is one possible expression of this.

Looking back

Improbable as it may seem the gestation of this large and continuing body of research included a white van chugging up and down the M1 between Derby and west London full of equipment, researchers, and patients. But that early proof that HD-induced myocardial stunning happened and could be measured laid the ground for all that has followed.

And none of this work would have been possible without the crucible of possibility and creativity of those early days in Derby and the shared vision and support of my two erstwhile senior colleagues, Richard Fluck and Maarten Taal, and my wife Natasha.





  1. Lindner, A., Charra, B., Sherrard, D. J. & Scribner, B. H. Accelerated Atherosclerosis in Prolonged Maintenance Hemodialysis. N. Engl. J. Med. 290, 697–701 (1974).
  2. Braunwald, E. & Kloner, R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 66, 1146–1149 (1982).
  3. Braunwald, E. & Rutherford, J. D. Reversible ischemic left ventricular dysfunction: evidence for the ‘hibernating myocardium’. J. Am. Coll. Cardiol. 8, 1467–1470 (1986).
  4. McIntyre, C. W. et al. Hemodialysis-induced cardiac dysfunction is associated with an acute reduction in global and segmental myocardial blood flow. Clin. J. Am. Soc. Nephrol. CJASN 3, 19–26 (2008).
  5. Burton, J. O., Jefferies, H. J., Selby, N. M. & McIntyre, C. W. Hemodialysis-induced repetitive myocardial injury results in global and segmental reduction in systolic cardiac function. Clin. J. Am. Soc. Nephrol. CJASN 4, 1925–1931 (2009).
  6. Burton, J. O., Jefferies, H. J., Selby, N. M. & McIntyre, C. W. Hemodialysis-induced cardiac injury: determinants and associated outcomes. Clin. J. Am. Soc. Nephrol. CJASN 4, 914–920 (2009).
  7. Hothi, D. K., Rees, L., Marek, J., Burton, J. & McIntyre, C. W. Pediatric myocardial stunning underscores the cardiac toxicity of conventional hemodialysis treatments. Clin. J. Am. Soc. Nephrol. CJASN 4, 790–797 (2009).
  8. Hothi, D. K., Rees, L., McIntyre, C. W. & Marek, J. Hemodialysis-induced acute myocardial dyssynchronous impairment in children. Nephron Clin. Pract. 123, 83–92 (2013).
  9. Selby, N. M., Lambie, S. H., Camici, P. G., Baker, C. S. & McIntyre, C. W. Occurrence of regional left ventricular dysfunction in patients undergoing standard and biofeedback dialysis. Am. J. Kidney Dis. Off. J. Natl. Kidney Found. 47, 830–841 (2006).
  10. Selby, N. M., Burton, J. O., Chesterton, L. J. & McIntyre, C. W. Dialysis-induced regional left ventricular dysfunction is ameliorated by cooling the dialysate. Clin. J. Am. Soc. Nephrol. CJASN 1, 1216–1225 (2006).
  11. Anazodo, U. C. et al. Hemodialysis-Related Acute Brain Injury Demonstrated by Application of Intradialytic Magnetic Resonance Imaging and Spectroscopy. J. Am. Soc. Nephrol. JASN 34, 1090–1104 (2023).
  12. Marants, R., Qirjazi, E., Grant, C. J., Lee, T.-Y. & McIntyre, C. W. Renal Perfusion during Hemodialysis: Intradialytic Blood Flow Decline and Effects of Dialysate Cooling. J. Am. Soc. Nephrol. JASN 30, 1086–1095 (2019).
  13. McIntyre, C. W. et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin. J. Am. Soc. Nephrol. CJASN 6, 133–141 (2011).
  14. Marants, R. et al. Exploring the Link Between Hepatic Perfusion and Endotoxemia in Hemodialysis. Kidney Int. Rep. 6, 1336–1345 (2021).
  15. Odudu, A., Eldehni, M. T., McCann, G. P. & McIntyre, C. W. Randomized Controlled Trial of Individualized Dialysate Cooling for Cardiac Protection in Hemodialysis Patients. Clin. J. Am. Soc. Nephrol. CJASN 10, 1408–1417 (2015).
  16. Eldehni, M. T., Odudu, A. & McIntyre, C. W. Randomized clinical trial of dialysate cooling and effects on brain white matter. J. Am. Soc. Nephrol. JASN 26, 957–965 (2015).
  17. Buchanan, C. et al. Intradialytic Cardiac Magnetic Resonance Imaging to Assess Cardiovascular Responses in a Short-Term Trial of Hemodiafiltration and Hemodialysis. J. Am. Soc. Nephrol. JASN 28, 1269–1277 (2017).
  18. Salerno, F. R. et al. Outcomes and predictors of skin sodium concentration in dialysis patients. Clin. Kidney J. 15, 1129–1136 (2022).
  19. Lemoine, S., Salerno, F. R., Akbari, A. & McIntyre, C. W. Influence of Dialysate Sodium Prescription on Skin and Muscle Sodium Concentration. Am. J. Kidney Dis. Off. J. Natl. Kidney Found. 78, 156–159 (2021).
  20. Intravital microscopic observation of the microvasculature during hemodialysis in healthy rats. vol. 12 (2022).
  21. MyTEMP writing committee. Personalised cooler dialysate for patients receiving maintenance haemodialysis (MyTEMP): a pragmatic, cluster-randomised trial. Lancet Lond. Engl. 400, 1693–1703 (2022).










Last Updated on August 22, 2023 by John Feehally