VO Open: Cardiovascular disease, it’s the number one cause of death for people with kidney disease. Over the past 60 years since the origin of chronic dialysis, we’ve effectively eliminated kidney failure as a cause of death, but in its place, we’re left with malignant cardiac disease. Joining me today on Dialogues are Doctors Bernard Canaud and Alan Collins, Senior Chief Scientists at Fresenius Medical Care. Welcome, gentlemen. You all are experts on kidney disease and on its impact on the heart. Let’s start with you, Alan. Tell me why cardiac disease is such a problem in our kidney failure patients.
Alan Collins: Well, what’s been known for decades now is hypertension is present in about 80% to 90% of the patients who start end-stage renal disease and that hypertension control is really quite difficult. Volume overload contributes to hypertension, but the cyclical nature of the therapy three times a week allows this fluid to accumulate and then we remove it and accumulate, thereby exacerbating the hypertension and the structures of the heart, which ultimately lead to heart failure.
Frank Maddux: So, tell me what cardioprotection actually means. When we say that, what are we actually talking about?
Alan Collins: So, we have two dimensions of cardioprotection that we really have to deal with. One is intervention, where those who have cardiac disease and are worse, where we come up with an alternative way of treating them to ameliorate some of their signs and symptoms and improve their stability on dialysis treatment. The second element which is more primary prevention is how can we take incident patients and treat them more effectively to prevent them from getting the cardiac and progressive cardiac complications that have been present and noted in the prevalent dialysis population?
Frank Maddux: Bernard, I have a question for you around the nature of the cardiac disease across the various stages of CKD. We see that atherosclerotic disease versus pump dysfunction and other volume stress and rhythm-related disturbances happen at different times. Can you discuss a little bit about your thoughts about the different types of cardiac disease on the various stages or vintage of the patients that we see?
Bernard Canaud: That’s a good question because we know also for several decades that cardiovascular disease progresses at the same rate as CKD progression. We know also that there is a self-aggravating CKD/CVD process, meaning at the end, as soon as you act on CKD to reduce progression of kidney disease, this is beneficial on the cardiac system. As Alan mentioned, we have different elements to act on. One is, salt accumulation, meaning, that salt, volume expansion and pressure increase will induce mechanical stress, which is acting on the vasculature system and particularly on the heart. Other elements are more on the metabolic side. As an example, chronic kidney disease and uremia are associated with inflammation, oxidative stress, lipid disorders, anemia that contribute to cardiovascular disease. As indicated, we have mechanical and metabolic factors to in order to halt the progression of cardiovascular disease and chronic kidney disease progression. All interventions aiming to reduce fluid overload by dialysis, as mentioned, but also including salt dietary intake reduction are very important factors. Dietary interventions, but also use of diuretics, and pressure control with medications are required in combination. Correcting fluid overload and hypertension are priority actions to prevent mechanical consequences on vasculature and cardiac system. In addition, correction of inflammation, oxidative stress, and anemia are part of this care to reduce progression of the vascular disease. Heart structure and function modifications are reflecting all these factors. Mechanical, inflammation, oxidative stress and anemia corrections should be considered at the same level of risk and corrected with the same intensity. Diet intervention, dialysis prescription, cardiac medications and anemia correction should be considered for preserving cardiac health.
Frank Maddux: So, let’s roll back just a little bit to earlier stages of CKD. We know that more people die of cardiac disease in mid to late-stage CKD than ever progressed to end-stage kidney disease. If you’re a practicing physician, nephrologist at the time, what should be your focus? Is it atherosclerotic disease? Is it volume and pump dysfunction? Tell me a little bit about your thoughts about that earlier stage CKD patient and when the cardiac disease needs intervention in these days?
Bernard Canaud: Early intervention in kidney disease management is of crucial importance to prevent further cardiac consequences and reduce mortality in dialysis. Patient education and empowerment to better control salt intake is of tremendous importance to control blood pressure and to enable hypertension control by medications. Patient education and diet intervention with appropriate use of medication side in particular loop diuretics and renin angiotensin blocker medications are crucial to reduce mechanical consequences on the vasculature and the cardiac structure. This is a way to reduce atherosclerotic process of the early stage of CKD and then prevent secondary atheromatous to occur. Also, it is a way to prevent early development of vascular and on myocardial damages. When kidney disease progress to more advanced stage such as 3B or 4, then anemia will occur meaning that anemia correction by iron supplementation or ESA use might of importance to reduce further cardiovascular stress and damage.
Frank Maddux: So, Alan, let’s segue to the next phase of a patient’s life and journey with kidney disease. An incident patient suffers a variety of challenges depending on the mode of therapy that they initiate dialysis with. What are some of the cardioprotection sort of features that you think need special attention from nephrologists during the incident period? We’ll talk about the prevalent period later.
Alan Collins: While I was at USRDS, we published a number of papers that looked at the transitional period and how big a risk that was. Strokes go up near initiation. Myocardial infarcts go up. Heart failure hospitalizations go up and arrhythmias, etc., which Bernard mentioned, are sources of metabolic control issues. So, the real challenge for the nephrologist is what tools do I have that I can actually use to help mitigate some of these problems and within nephrology, there is a conflict that is actually going on right now. Do you use the best cardioprotective drugs that the cardiologists have shown in the non-CKD and dialysis population, ACEs, ARBs, mineralocorticoid receptor antagonists, renin inhibitors to treat heart failure and to control blood pressures or as CKD progresses, there are those who have said those drugs actually reduce kidney function and therefore should be stopped and when you look at the data that looks at how the medication profile is changing during the incident period when patients go from stage 4 or 5 on to dialysis, there is a dramatic fall in the uses of ACEs, ARBs, mineralocorticoid receptor antagonists and a large increase in the use of calcium channel blockers and diuretics, which is really this dilemma that heart failure is the number one hospitalization and hypertension is really difficult to control. So, in the current era, the challenge has been “What are you going to do and what I think Bernard and I have tried to articulate is the mechanical aspects of salt and water and volume overload contributing to hypertension are really the core issues that we’ll have to address and we’ll have to do that in a way that allows us to use the cardioprotective medications to help us, given the fact that the dialysis population has a dialysis schedule that is not physiologic by any standard.
Frank Maddux: So, let’s actually segue a little bit to the physiology of the prevalent patient on dialysis and the majority of those people are on hemodialysis or some version of that. Talk a little bit about the long interdialytic interval, the three-day per week sessions that we have, the concepts around frequent hemodialysis and its impact on cardioprotection because it strikes me that we are in a position to look at these somewhat differently than we have in the past, knowing that 51% of cardiac deaths are, in fact, from individuals that have rhythm disturbances.
Alan Collins: So, I think the sudden death issue as being a dominant cause of death from cardiac disease sort of masks the underlying phenomenon that this three times a week cycle of volume up, volume down, volume up and then over the long interval, volume way up is really stressing the myocardium and it’s stretching the atrium and the cardiologists have shown us more than 20 years ago that if you stretch the atria, you get atrial fibrillation, which is among the most common rhythm disorders in the 12 hours before you start dialysis. Interestingly enough, other rhythm disorders actually occur during or at the end of the dialysis session, but they’re not as common as atrial fibrillation, which really looks like a volume stretching phenomenon of the atrium. So, from that standpoint, the control of the salt and water that Bernard talked about by a whole host of tools that are available would be central to the improvement of controlling hypertension and controlling the volume effects on the heart.
Frank Maddux: I’ll throw this out to both of you and have either of you-- we’ve read some of the literature on this parasympathetic system, sympathetic system imbalance that occurs as you get further away from your last dialysis treatment. To what degree do you think this sympathetic overdrive and imbalance is responsible for some of the rhythm disturbances that we’re seeing that can be part of that sudden cardiac death problem?
Bernard Canaud: That’s certainly a good point. It is well known that there is an autonomous dysfunction with an increase sympathetic activity in chronic kidney disease and dialysis patients. This imbalance in nervous tone contributes to facilitate arrythmias. Change in QT intervals are among earlier manifestations. Apart from cardiac consequences, autonomic dysfunctions are also implicated in sleep disorders and sleep apnea. All these factors contribute to cardiac risks. Sudden cardiac death is strongly linked with arrythmia in particular bradyarrhythmia’s that can occur during the dialysis session or within the interdialytic phase, in particular during night of the long dialytic interval. That could be interpretated as a manifestation of high sympathetic activity. Sleep disorders in dialysis patients should be considered as a CV risk factors. Increasing treatment time or frequency and reducing dialysis induced stress, may be beneficial, as it was mentioned. Also moving to every other day dialysis to suppress long dialytic interval might be beneficial, but that needs to be explored prospectively.
Frank Maddux: Alan, we’re living in a connected health environment right now. Should we be monitoring our patients because we know they have these increased risks for Afib or bradycardia or other rhythm disturbances, some of which are quite onerous?
Alan Collins: So, the challenge has been that many of us have done these monitoring exercises and been unable to intervene. In fact, there was a clinical trial done with a wearable cardiac defibrillator device to see whether or not that would improve it. I think the nature of the arrythmias, which Bernard is pointing out, is critical to understand. Bradyarrhythmia and asystole is the most common cause of sudden death. It’s not clear what we’re supposed to do to figure out how to prevent that. That is not clear. The atrial fibrillation is a little more straightforward in that atrial stretch within the 12 hours before dialysis looks like a reasonable mechanism by which that atrial fibrillation is being precipitated. But Bernard, perhaps you can comment on what do you think about this bradycardia and asystole that’s actually going on in the post-dialysis period.
Bernard Canaud: Sure. By reducing fluid overload and cardiac stretching or cycles of stretching/shrinking by applying nocturnal hemodialysis through eight hours or twelve hours treatment, fluid overload could be reduced as well as mechanical stress on the cardiac pump system. That’s certainly a very important factor. Also, longer exposure to such treatment regime, several months, would be necessary to observe structural and functional echocardiography changes. Hemodynamic changes in the cardiac system require time to observe cardiac structural improvements. Reducing atrial fibrillation or arrythmia or asystole is possible but time is an important factor after correction of fluid overload. We all agree, that increasing treatment time and/or frequency would be an important factor in addition to cardiac medications, such as beta blockers, to improve cardiac health. Reducing dialysis-induced stress is a crucial factor, as you mentioned, to improve cardiac outcomes in dialysis.
Frank Maddux: So, Bernard, just expand a little more on what you think nephrologists can do in adjusting their dialysis prescriptions to try to mitigate or minimize or ameliorate the cardiac risk that our patients have. What would be some practical points?
Bernard Canaud: That’s also a very important questions that were addressed by recent retrospective studies. As Alan remind us, treatment time is a very important modifiable factor. Treatment time, but also dialysis frequency are crucial factors to mitigate cardiac risk. Three-day interval or long dialytic interval is the main source of mortality. Attempts to suppress this long term with more frequent dialysis show benefits. In addition, the way of managing patient with too aggressive ultrafiltration is also not good and source of mortality. Our main focus today was volume overload, but it should be stressed that volume depletion and hypovolemia induced by dialysis are also risky. Another risk factor that was not addressed are electrolyte shifts that are induced by dialysis session. As an example, rapid potassium changes, combined with acidotic corrections and calcium and magnesium shifts are major causes of arrhythmias. In this context, we have a perfect cocktail that is prone to rhythmic disorders. It is time to act on these changes to provide more physiologic dialysis. The availability of electrolyte balancing module, acting on sodium and delivering isonatremic dialysis is a first step to manage dialysis patient. In addition, as mentioned, we need to personalize treatment to patient profile. In case of cardiac patient for example, extending treatment time or adding one extra session or an isolated ultrafiltration would be an easy approach to personalize care. There is not a magic treatment that can fit all patients. This is not possible. But certainly, depending on patient risk and profile, there is several approaches to start providing the best treatment option for a specific patient.
Frank Maddux: Before we wind up this short segment on cardioprotection, I want to throw out to you all a question that I know you all are going to be writing about in our annual medical report this year and that is what do you think the impact on cardiac protection that the SGLT2 inhibitors and some of the other newer drugs that may also be helpful in delaying CKD progression. I actually have believed that their cardiac impact may be greater than their renal impact, but what are your all’s thoughts about these. Alan?
Alan Collins: Bernard and I have been recently discussing this as our topic for the annual medical report. What is quite interesting about the SGLT2 inhibitors is what they do to sodium and glucose loss in the kidneys, but not only that, there appears to be an effect on skin sodium, so called non-aqueous sodium content in the skin, which is quite different than all the other drug classes that have been used-- diuretics, ACEs, and ARBs-- and it appears to have an effect on the heart. Bernard may want to comment on this. These drugs not only appear to work on volume through osmotic diuresis with the glucose and the sodium loss, but may also have more direct effects in the skin and other cellular mechanisms on hypertension, which are not related to volume directly.
Bernard Canaud: Right. That’s exactly the point. SGLT2 inhibitors will be a fantastic drug for the chronic kidney disease patient aside diabetic patients. SGLT3 inhibitors have additional properties aside diuresis and natriuresis. SGLT2 inhibitors are still restricted to stage 3A and B in particular with proteinuria. So, what would be the question now. Does this medication would be applicable to dialysis patient? I’m not sure that will be the case. According to the mechanism of action, I don’t see any beneficial effect with these drugs in a patient who has no kidney function or diuresis. We need to know more about effects in very advanced kidney disease patients. The first interesting fact is related to diabetic patients. Two years ago, a study performed in T2DM patients with monitoring of sodium skin content based on MRI has shown that most beneficial effect of the SGLT2 inhibitors in these patients were not only on glycemic control, but also osmotically active sodium (blood pressure), but also on the sodium stored in the skin. Reduction tissue salt content may reduce inflammation, oxidative stress and facilitate peripheral action of insulin. This preliminary report indicates that SGLT2 inhibitors may have metabolic actions aside the traditional ones and be beneficial in CKD patients. Another hypothesis, is that SGLT2 inhibitors may bring CKD patients to the end stage of the kidney disease in better shape and reduce mortality during this transition phase. As Alan mentioned, SGLT2 inhibitors indications should be more carefully explored to prevent becoming harmful for patients. New options need to be evaluated by prospective studies. Unfortunately to date, we missed data to answer precisely what will be future of these drugs.
Frank Maddux: Thank you, Bernard. As we know, these particular drugs are identified predominately for earlier stage kidney disease and have some potential risks and very late-stage kidney disease, but it’s clearly one of the questions where I think throughout the whole continuum, this malignant cardiovascular disease is a substantial issue that I’m sure we will have progressive and more dialogue with our nephrology partners around the world around. I want to thank both of you today. I’ve been with Dr. Bernard Canaud and Dr. Alan Collins talking about cardioprotection for kidney disease and we want to thank you both for joining me today on Dialogues.
Alan Collins: Thank you, Frank.
Bernard Canaud: Thank you very much.