Clinical

New KDIGO report helps define risks, treatment approach for arrhythmias in patients with kidney disease

Clinicians have long recognized a link between the presence of cardiovascular disease in patients with chronic kidney disease. Many such patients are predisposed to heart rhythm disorders.

“[Chronic kidney disease] CKD patients may present with a wide spectrum of arrhythmias ranging from supraventricular arrhythmias and ectopics, atrial fibrillation and flutter, ventricular ectopics and sustained and non-sustained ventricular tachycardia, and sudden cardiac death (SCD),” Mintu Turakhia, MD, MAS, and colleagues, wrote in a recently published report on cardiac arrhythmias and CKD. “There is a strong public health and economic imperative to improve outcomes for people with kidney disease and heart rhythm disorders.”

The authors were part of a conference assembled by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in October 2016 to address the treatment of CKD patients who experience disorders like atrial fibrillation and stroke. The conference included a global panel of multidisciplinary clinical and scientific experts to identify key issues relevant to the optimal prevention, management and treatment of arrhythmias and their complications in patients with kidney disease. The objective of the conference was to assess the current state of knowledge related to the epidemiology of atrial fibrillation and stroke in kidney disease; stroke prevention in atrial fibrillation and CKD; prognostication and prevention of SCD in CKD; maintenance of electrolyte homeostasis in CKD and dialysis, particularly hyperkalemia; and rate vs. rhythm control in atrial fibrillation in CKD.

Nephrology News & Issues asked two members of the working group – Wolfgang Winkelmayer, MD, ScD, the Gordon A. Cain chair in nephrology and section chief of medicine-nephrology at Baylor College of Medicine in Houston, and Charles Herzog, MD, professor of medicine at Hennepin County Medical Center/University of Minnesota in Minneapolis, to summarize the recommendations and how they might reduce the risks of sudden deaths in patients with CKD.

NN&I: We know about the high risk of sudden death in patients with CKD. Can you review the causative factors that make these patients vulnerable from nephrological and cardiac perspectives?

Mintu Turakhia

Wolfgang Winkelmayer, MD: Patients with advanced CKD exhibit typical complications in anemia, disturbances in the mineral bone disease axis, and derangements in fluid and electrolyte balance. Interrelated are dysautonomia, heightened inflammation and oxidative stress. In concert, all these manifest in cardiac hypertrophy, myocardial fibrosis, conduction abnormalities and decreased stress tolerance. Now add a patient’s transition to dialysis, with the ensuing cyclical swings in fluid and electrolyte status from an un-physiological procedure. Too little is understood about these phenomena from the molecular to the clinical level and the new KDIGO report from the arrhythmia and CKD controversies conference in the European Heart Journal exposes blatant evidence gaps and highlights important research questions.

Charles Herzog, MD: Patients with CKD, particularly those with stage G5D, are a population at particularly high risk for SCD. Dialysis patients frequently have left ventricular hypertrophy and myocardial fibrosis. Both are factors leading to susceptibility to arrhythmic death. Additionally, these patients are vulnerable to myocardial ischemia and, in patients on conventional thrice weekly hemodialysis, large non-physiologic electrolyte shifts leading to a further increased risk of arrhythmic death.

Wolfgang Winkelmayer

NN&I: What guidelines were in place prior to the KDIGO directive to help address the cardiac risks in patients with CKD?

Herzog: Our KDIGO Cardiovascular Controversies Conference in London in 2010, which I co-chaired with Eberhard Ritz, MD, PhD, and published in 2011 in Kidney International dealt with similar issues but with a broader focus. It provided the rationale for revisiting the topic of arrhythmias in Berlin half a decade later. The Acute Dialysis Quality Initiative group has focused on the cardiorenal syndromes and heart failure. One result of the ADQI XI conference in 2012 was to propose a new definition of heart failure specific to dialysis patients. Only one attempt has been made at formal guideline recommendations specifically related to cardiovascular disease in dialysis patients: the 2005 Kidney Disease Outcomes Quality Initiative guidelines, which were published in American Journal of Kidney Diseases in 2005. I was the sole cardiologist on the task force for those guidelines.

My hope is that the Berlin KDIGO conference and other KDIGO Cardiovascular Controversies in CKD conferences, will lead to a new effort at practice guideline formulation pertaining to CVD, including arrhythmias, across the spectrum of CKD. I would characterize the Cardiovascular Controversies conference series as “nephrocardiology.” In May 2017, our second conference in the series dealt with heart failure in patients with CKD. Our third in the conference series will cover ischemic and valvular heart disease in patients with CKD in June in Vienna. One unifying theme of our Conference Series is the melding of experts in nephrology, cardiology and other specialties, such as neurology, to deal with cardiovascular disease in patients with CKD. The conferences bring together equal numbers of cardiologists and nephrologists. This KDIGO Cardiovascular Controversies Series is unprecedented and I believe will foster the development of the emerging area of “nephrocardiology.”

NN&I: Once we have the risks identified, what has made surveillance and preventative care difficult? For example, is CKD going undetected in patients with cardiac disease as well?

Winkelmayer: In this day and age, every cardiac patient will have a basic metabolic panel assessed and an estimated glomerular filtration rate reported. Hence, CKD will be detected, but awareness or knowledge on what to do with this information is a different story. Almost 15 years ago, our colleague Glenn M. Chertow, MD, MPH, coined the term “renalism,” meaning under-treatment of patients with more advanced CKD by otherwise highly established interventions. Since then, we have learned about the complexity of causes underlying and contributing to the many facets of renalism, and we have come to the realization that there is no simple answer.

Charles Herzog

What has become increasingly evident is that the lack of inclusion of patients with advanced CKD in large evidence-defining trials has created a cloud of uncertainty, especially considering evidence that some interventions simply do not work in advanced CKD, especially for patients on dialysis. We need to shift the mindset of our colleagues and accept that the situation will only get better if all of us are willing to acknowledge these evidence gaps, suppress our tendency to “know” what is best for the patient in front of us, and instead direct eligible patients to participate in the trials that do focus on these advanced CKD or dialysis patient populations.

Herzog: In my opinion, the problem is not that CKD is going undetected. The reporting of eGFR by clinical laboratories has become routine. The real problem is the paucity of high-quality evidence to guide surveillance and treatment of cardiovascular disease in patients with advanced CKD. It has been challenging to conduct randomized control trials relating to cardiovascular disease in patient with CKD G4+. A good example is the evidence base for using direct oral anticoagulants to prevent ischemic stroke in patients with atrial fibrillation. Large randomized prospective trials confirmed the safety and efficacy of these agents, but the lowest eCrCl for entry was 25. Essentially, we have no RCT data to guide us in patients with CKD stages 4 or 5. In most clinical scenarios, we have been forced to either extrapolate studies done in patients without CKD or “expert opinion” – neither of which is entirely satisfying or satisfactory. The identification of broad areas of knowledge gaps is an important part of the KDIGO Controversies Conferences.

NN&I: Why are patients with CKD at a higher risk for arrhythmias, particularly afibrillation? Why is the management complex?

Winkelmayer: The risk factors for CKD also confer increased risks of various arrhythmias, be it non-modifiable factors (demographics) or traditional and non-traditional potentially modifiable factors, such as inflammation, oxidative stress and pro-fibrotic factors. Management is complicated by polypharmacy in these patients, lack of a solid evidence base specific to this population and lack of labeled indication, evidence on dosing or mere contraindication of some treatments in patients with advanced CKD. Importantly, the realization that what works in populations free from advanced kidney disease may simply not work in those with it.

NN&I: What are the most important take-away points from the KDIGO conference report. What can we do differently to address arrhythmias in patients with CKD?

Winkelmayer: The most important take-away point from the conference was it is enlightening when physicians of different disciplines, in this case nephrologists, cardiovascular specialists and stroke neurologists, discuss from different angles the difficult clinical issues that require coordinated care, but are often seen from each discipline’s own ivory tower. The excitement in the rooms was palpable and did not wane over 2.5 long and intense days. The fact the conference report was published in a leading cardiovascular journal gives the kidney perspective important exposure in the cardiovascular community and hopefully will lead to increased clinical and scientific collaboration. KDIGO staged a second cardiovascular and kidney conference on heart failure last year and will have another one focused on cardiovascular and valvular disease this summer. Separating these topics has provided the necessary time and resources to drill deep into each of these issues, something that previous formats could not accommodate.

Herzog: One key point is we have now defined a dialysis-specific definition of sudden cardiac death, something that did not previously exist, which will help in the design of interventional trials to prevent SCD in patents with CKD stage 5D. We also need to better inform patients of the risk of sudden cardiac death. The conference report highlights the huge knowledge gaps in the treatment of atrial fibrillation, particularly anticoagulation, in patients with CKD, and like the 2010 KDIGO Conference, provides a roadmap for designing future clinical trials. Finally, the most important take-home point from my perspective as a cardiologist and perhaps “nephrocardiologist,” is the importance of an interdisciplinary approach to cardiovascular disease in patients with CKD. In modern cardiology practice, we refer to a “heart team approach” in the management of cardiovascular disease. From my perspective, nephrologists are a key part of the heart team caring for patients with CKD and cardiovascular disease. We need to have an inclusive concept of the heart team, which draws on a wide range of clinical expertise and patient preference. The same expertise should inform us in the design and successful completion of clinical trials on the prevention and treatment of all types of cardiovascular disease, including arrhythmias, in patients with CKD.

Disclosures: Herzog and Winkelmayer report no relevant financial disclosures.

Clinicians have long recognized a link between the presence of cardiovascular disease in patients with chronic kidney disease. Many such patients are predisposed to heart rhythm disorders.

“[Chronic kidney disease] CKD patients may present with a wide spectrum of arrhythmias ranging from supraventricular arrhythmias and ectopics, atrial fibrillation and flutter, ventricular ectopics and sustained and non-sustained ventricular tachycardia, and sudden cardiac death (SCD),” Mintu Turakhia, MD, MAS, and colleagues, wrote in a recently published report on cardiac arrhythmias and CKD. “There is a strong public health and economic imperative to improve outcomes for people with kidney disease and heart rhythm disorders.”

The authors were part of a conference assembled by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in October 2016 to address the treatment of CKD patients who experience disorders like atrial fibrillation and stroke. The conference included a global panel of multidisciplinary clinical and scientific experts to identify key issues relevant to the optimal prevention, management and treatment of arrhythmias and their complications in patients with kidney disease. The objective of the conference was to assess the current state of knowledge related to the epidemiology of atrial fibrillation and stroke in kidney disease; stroke prevention in atrial fibrillation and CKD; prognostication and prevention of SCD in CKD; maintenance of electrolyte homeostasis in CKD and dialysis, particularly hyperkalemia; and rate vs. rhythm control in atrial fibrillation in CKD.

Nephrology News & Issues asked two members of the working group – Wolfgang Winkelmayer, MD, ScD, the Gordon A. Cain chair in nephrology and section chief of medicine-nephrology at Baylor College of Medicine in Houston, and Charles Herzog, MD, professor of medicine at Hennepin County Medical Center/University of Minnesota in Minneapolis, to summarize the recommendations and how they might reduce the risks of sudden deaths in patients with CKD.

NN&I: We know about the high risk of sudden death in patients with CKD. Can you review the causative factors that make these patients vulnerable from nephrological and cardiac perspectives?

Mintu Turakhia

Wolfgang Winkelmayer, MD: Patients with advanced CKD exhibit typical complications in anemia, disturbances in the mineral bone disease axis, and derangements in fluid and electrolyte balance. Interrelated are dysautonomia, heightened inflammation and oxidative stress. In concert, all these manifest in cardiac hypertrophy, myocardial fibrosis, conduction abnormalities and decreased stress tolerance. Now add a patient’s transition to dialysis, with the ensuing cyclical swings in fluid and electrolyte status from an un-physiological procedure. Too little is understood about these phenomena from the molecular to the clinical level and the new KDIGO report from the arrhythmia and CKD controversies conference in the European Heart Journal exposes blatant evidence gaps and highlights important research questions.

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Charles Herzog, MD: Patients with CKD, particularly those with stage G5D, are a population at particularly high risk for SCD. Dialysis patients frequently have left ventricular hypertrophy and myocardial fibrosis. Both are factors leading to susceptibility to arrhythmic death. Additionally, these patients are vulnerable to myocardial ischemia and, in patients on conventional thrice weekly hemodialysis, large non-physiologic electrolyte shifts leading to a further increased risk of arrhythmic death.

Wolfgang Winkelmayer

NN&I: What guidelines were in place prior to the KDIGO directive to help address the cardiac risks in patients with CKD?

Herzog: Our KDIGO Cardiovascular Controversies Conference in London in 2010, which I co-chaired with Eberhard Ritz, MD, PhD, and published in 2011 in Kidney International dealt with similar issues but with a broader focus. It provided the rationale for revisiting the topic of arrhythmias in Berlin half a decade later. The Acute Dialysis Quality Initiative group has focused on the cardiorenal syndromes and heart failure. One result of the ADQI XI conference in 2012 was to propose a new definition of heart failure specific to dialysis patients. Only one attempt has been made at formal guideline recommendations specifically related to cardiovascular disease in dialysis patients: the 2005 Kidney Disease Outcomes Quality Initiative guidelines, which were published in American Journal of Kidney Diseases in 2005. I was the sole cardiologist on the task force for those guidelines.

My hope is that the Berlin KDIGO conference and other KDIGO Cardiovascular Controversies in CKD conferences, will lead to a new effort at practice guideline formulation pertaining to CVD, including arrhythmias, across the spectrum of CKD. I would characterize the Cardiovascular Controversies conference series as “nephrocardiology.” In May 2017, our second conference in the series dealt with heart failure in patients with CKD. Our third in the conference series will cover ischemic and valvular heart disease in patients with CKD in June in Vienna. One unifying theme of our Conference Series is the melding of experts in nephrology, cardiology and other specialties, such as neurology, to deal with cardiovascular disease in patients with CKD. The conferences bring together equal numbers of cardiologists and nephrologists. This KDIGO Cardiovascular Controversies Series is unprecedented and I believe will foster the development of the emerging area of “nephrocardiology.”

PAGE BREAK

NN&I: Once we have the risks identified, what has made surveillance and preventative care difficult? For example, is CKD going undetected in patients with cardiac disease as well?

Winkelmayer: In this day and age, every cardiac patient will have a basic metabolic panel assessed and an estimated glomerular filtration rate reported. Hence, CKD will be detected, but awareness or knowledge on what to do with this information is a different story. Almost 15 years ago, our colleague Glenn M. Chertow, MD, MPH, coined the term “renalism,” meaning under-treatment of patients with more advanced CKD by otherwise highly established interventions. Since then, we have learned about the complexity of causes underlying and contributing to the many facets of renalism, and we have come to the realization that there is no simple answer.

Charles Herzog

What has become increasingly evident is that the lack of inclusion of patients with advanced CKD in large evidence-defining trials has created a cloud of uncertainty, especially considering evidence that some interventions simply do not work in advanced CKD, especially for patients on dialysis. We need to shift the mindset of our colleagues and accept that the situation will only get better if all of us are willing to acknowledge these evidence gaps, suppress our tendency to “know” what is best for the patient in front of us, and instead direct eligible patients to participate in the trials that do focus on these advanced CKD or dialysis patient populations.

Herzog: In my opinion, the problem is not that CKD is going undetected. The reporting of eGFR by clinical laboratories has become routine. The real problem is the paucity of high-quality evidence to guide surveillance and treatment of cardiovascular disease in patients with advanced CKD. It has been challenging to conduct randomized control trials relating to cardiovascular disease in patient with CKD G4+. A good example is the evidence base for using direct oral anticoagulants to prevent ischemic stroke in patients with atrial fibrillation. Large randomized prospective trials confirmed the safety and efficacy of these agents, but the lowest eCrCl for entry was 25. Essentially, we have no RCT data to guide us in patients with CKD stages 4 or 5. In most clinical scenarios, we have been forced to either extrapolate studies done in patients without CKD or “expert opinion” – neither of which is entirely satisfying or satisfactory. The identification of broad areas of knowledge gaps is an important part of the KDIGO Controversies Conferences.

PAGE BREAK

NN&I: Why are patients with CKD at a higher risk for arrhythmias, particularly afibrillation? Why is the management complex?

Winkelmayer: The risk factors for CKD also confer increased risks of various arrhythmias, be it non-modifiable factors (demographics) or traditional and non-traditional potentially modifiable factors, such as inflammation, oxidative stress and pro-fibrotic factors. Management is complicated by polypharmacy in these patients, lack of a solid evidence base specific to this population and lack of labeled indication, evidence on dosing or mere contraindication of some treatments in patients with advanced CKD. Importantly, the realization that what works in populations free from advanced kidney disease may simply not work in those with it.

NN&I: What are the most important take-away points from the KDIGO conference report. What can we do differently to address arrhythmias in patients with CKD?

Winkelmayer: The most important take-away point from the conference was it is enlightening when physicians of different disciplines, in this case nephrologists, cardiovascular specialists and stroke neurologists, discuss from different angles the difficult clinical issues that require coordinated care, but are often seen from each discipline’s own ivory tower. The excitement in the rooms was palpable and did not wane over 2.5 long and intense days. The fact the conference report was published in a leading cardiovascular journal gives the kidney perspective important exposure in the cardiovascular community and hopefully will lead to increased clinical and scientific collaboration. KDIGO staged a second cardiovascular and kidney conference on heart failure last year and will have another one focused on cardiovascular and valvular disease this summer. Separating these topics has provided the necessary time and resources to drill deep into each of these issues, something that previous formats could not accommodate.

Herzog: One key point is we have now defined a dialysis-specific definition of sudden cardiac death, something that did not previously exist, which will help in the design of interventional trials to prevent SCD in patents with CKD stage 5D. We also need to better inform patients of the risk of sudden cardiac death. The conference report highlights the huge knowledge gaps in the treatment of atrial fibrillation, particularly anticoagulation, in patients with CKD, and like the 2010 KDIGO Conference, provides a roadmap for designing future clinical trials. Finally, the most important take-home point from my perspective as a cardiologist and perhaps “nephrocardiologist,” is the importance of an interdisciplinary approach to cardiovascular disease in patients with CKD. In modern cardiology practice, we refer to a “heart team approach” in the management of cardiovascular disease. From my perspective, nephrologists are a key part of the heart team caring for patients with CKD and cardiovascular disease. We need to have an inclusive concept of the heart team, which draws on a wide range of clinical expertise and patient preference. The same expertise should inform us in the design and successful completion of clinical trials on the prevention and treatment of all types of cardiovascular disease, including arrhythmias, in patients with CKD.

PAGE BREAK

Disclosures: Herzog and Winkelmayer report no relevant financial disclosures.