The ABCs in the Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease

Today, the nephrology community is seeking to advance knowledge in the field of overwhelming cardiovascular risk faced by patients with kidney disease. Treatments to reduce adverse outcomes all deserve specific considerations. In a series of four articles in this issue of the Clinical Journal of the American Society of Nephrology (CJASN), the most important topics in the field and potential treatments are discussed (1–4). The Board of Editors of the CJASN felt that it was the most pertinent to look at mapping progress in four areas: (1) heart failure in patients with kidney disease, (2) atrial fibrillation, (3) managing volume overload, and (4) sudden cardiac death (1–4). Each of these comorbid conditions is more prevalent in patients with CKD or patients on dialysis.

Experts in the field provided their views on the prevalence and the pathogenesis of the disease as well as the treatment options in reducing cardiovascular risk in individuals with kidney disease. All experts also provide high-priority areas of research and propose strategies for where to go in the future. The readers can expect answers in several clinical hot topics, especially around emerging questions. Controversies in the four areas are provocatively formulated. In the first area, the controversies are as follows.

• (1) Heart failure with reduced ejection fraction is frequent in advanced stages of CKD and even more frequent in subjects with preserved ejection fraction, but why can standard of care not be fully implemented?

• (2) Will sodium glucose cotransporter 2 inhibitors be included into the new standard of care after results of dedicated outcome trials become available?

• (3) Do emerging treatments (selective mineralocorticoid receptor antagonists, angiotensin receptor neprilysin inhibitor, and lowering high potassium) develop into individualized treatments or standard of care?

In the second area, the controversies are as follows.

• (1) Is oral anticoagulation in patients with atrial fibrillation and on dialysis in general efficacious and beneficial, and do benefits and risks differ among oral anticoagulants?

• (2) Are we going to replace vitamin K antagonists with no treatment or direct oral anticoagulants in the absence of clinical trials (e.g., safety and efficacy data)?

• (3) Are we giving up on generating solid data to prevent thromboembolism and stroke (a plea to contribute to ongoing clinical trials in Europe and the United States)?

In the third area, the controversies are as follows.

• (1) Managing volume overload: should we conserve our energies educating individuals with CKD to chronically restrict dietary sodium due to lack of efficacy in the long term?

• (2) Is a “personal salt manager” (point of care technology) a reasonable strategy to be adopted by patients with chronic volume overload and asymptomatic lung congestion?

• (3) Is appropriate diuretic use stringently accompanied by diagnostic measures, such as bioimpedance spectroscopy and lung ultrasound, fundamental to manage hypervolemia?

In the fourth area, the controversies are as follows.

• (1) Should sudden cardiac death prevention require a differential look into three distinct phases when moving to kidney replacement therapy (i.e., the predialysis/transition phase, the early [0–1 year] phase, and the middle to late [>1 year] phase)?

• (2) Should we focus on bradyarrhythmias rather than ventricular tachycardia/ventricular fibrillation, especially in the first 90 days of dialysis, to prevent sudden cardiac death?

• (3) Should miniaturized, leadless, implantable cardiac monitors be integrated into a new person-centered program and accompanied by discontinuation of β-blocker therapy in patients with bradyarrhythmia on dialysis?

Interestingly, the authors Bansal (1), Winkelmayer (2), Zoccali and Mallamaci (3), and Shafi and Guallar (4) map the process/progress differently in various stages of CKD and see it differently as the cardiac and vascular risks are changing. They distinguish G4/G5 from G5 dialysis, and Shafi and Guallar (4) even see an early-risk phase and a late-risk phase in patients on dialysis. The explanation for that may reside in the structural and functional changes that the heart and the vascular tree undergo when kidney function declines and kidney replacement therapy is required (5). Development of cardiac and vascular disease is rapid, especially in young patients, and the phenotype resembles all aspects of an accelerated ageing process. Different risk factors, different from the traditional ones, termed CKD or uremia related are operative in different stages of CKD. In addition, pharmacologic interventions have to account for kidney function, drug and metabolite excretion, accumulation, side effects, and toxicity. As a consequence of this complexity, patients with an eGFR below 30 ml/min per 1.73 m² are usually excluded from clinical trials. Mapping the progress according to stages of kidney disease makes sense and can be well understood.

Mapping the progress and implementing new promising interventions, derived from large outcome trials, have to come on top of standard of care. Standard of care often raises barriers when new treatments seek implementation because of the many medications that patients with kidney disease are already taking. The specific implications on current clinical practice are drug adherence and polypharmacy in the elderly. These practical aspects usually do not find acknowledgment when progress is mapped.

The so-called standard of care interventions in comorbid patients with kidney disease and cardiovascular disease or high cardiac and vascular risk currently include renin-angiotensin-aldosterone system inhibitors, statins, and aspirin as well as interventions for glucose and BP control. Today, nephrologists group adjunctive treatments for anemia, metabolic acidosis, and mineral and bone disorders to the realm of standard of care. Individuals with an eGFR between 30 and 60 ml/min per 1.73 m² who are enrolled in the German CKD Cohort Study take, on average, seven to eight different classes of drugs (K.-U. Eckardt, personal communication). In certain individuals and the elderly, there is limited room for modern interventions given the existing burden of pills and adherence. We are often asking the question in our daily clinical practice of which interventions are important for a given patient. In studies in the future, it will be important to consider implementing a multilevel intervention aimed at improving patient adherence. Thus, the new emerging interventions will come on top of the “old” established “standard of care.” One of the most prominent to include in such interventions will be inhibitors of the sodium glucose cotransporter 2.

However, the so-called established treatments may show a signal of harm after many years of experience in patients with kidney disease. A typical example is the use of vitamin K antagonists. Experimental and biomarker studies as well as anecdotal observations make us believe that inhibiting vitamin K enhances the risk of calcification. Is this risk so high to unbalance the risk-to-benefit ratio? Do we have to accept that several of the tantalizing questions will never be answered, because trials cannot or will not be done owing to the fact some interventions are now available at very low costs?

The overarching task when mapping the progress is avoiding risk and adapting the patients to new situations (e.g., hypoglycemia and risk of nocturnal bradycardia) with declining kidney function. However, we should never stop trying to achieve a better understanding on the pathophysiology of the diseases, develop better treatment strategies, and advance the high priorities of research.

We should establish a cardiorenal curriculum among nephrologists or dialysis nurses (4). Focused training on heart failure, volume management, rhythm control, electrolyte management, and device handling is required. This clinical curriculum and knowledge have to be increased among the nephrologists, and we cannot always rely on other specialist outside our field. Processes and progress, carefully mapped, may potentially lead to the prevention of sudden cardiac death in advanced stages of CKD and kidney replacement therapy.

Disclosures

None.