Cover Story | By Debra L. Beck

In health, the relationship between the kidneys and the heart reveals itself to be one of mutual interdependence. Up to one quarter of cardiac output goes straight to the kidneys, and, in turn, the kidneys play an important role in electrolyte balance, protein production, and blood pressure regulation.

However, when things go south health-wise, this relationship can quickly become codependent—a term defined by the American Heritage^® Dictionary as “mutually dependent... in an unhealthy way” or broadly (by Merriam-Webster’s Dictionary) as “dependence on the needs of or control by another.” In our example, dysfunction in one organ supports or enables the dysfunction of the other organ, and it’s frankly hard to know which organ to blame for what.

One factor complicating this issue: many cardiologists and nephrologists don’t enjoy any relationship at all—not dependent, interdependent, or codependent. Cardiac-focused clinical trials often exclude patients with significant kidney disease and practice guidelines don’t provide great guidance on how to best manage these patients. However, our organs didn’t get the memo on this artificial divide, leaving cardiologists scrambling to manage kidney dysfunction complicating cardiovascular disease (CVD). Thankfully, new efforts are shedding light on the complex interaction between heart and kidneys that should improve guidance and outcomes for both organs.

Check the Heart by Way of the Kidneys

Individuals with chronic kidney disease (CKD) are at high risk of CVD. So high, in fact, that many die from heart issues long before they develop end-stage renal disease. Despite this, controversy surrounds the question of whether to include measures of kidney status in cardiovascular risk prediction models. Why? Partly because several studies have looked at prediction improvement with estimated glomerular filtration rate (eGFR), albuminuria, or both, in the primary prevention setting, and the results have provided no definitive answers.

The guidelines reflect this lack of clarity, often leaving kidney function out of risk assessment. “Why” is spelled out in the recent risk ACC/AHA assessment guidelines: The contribution of ApoB (apolipoprotein B), chronic kidney disease, albuminuria, and cardiorespiratory fitness to risk assessment for a first ASCVD (atherosclerotic cardiovascular disease) event is uncertain at present.¹ But a new study sponsored by the U.S. National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases may change that.

Matsushita and colleagues from the Chronic Kidney Disease Prognosis Consortium (CKD-PC), led by Josef Coresh, MD, PhD, from Johns Hopkins Bloomberg School of Public Health, analyzed data from 24 studies that included 637,315 individuals with no history of CVD.² Their meta-analysis assessed the prognostic value of adding eGFR and albuminuria to traditional risk factors for prediction of CV risk.

They found that the addition of either eGFR or albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria) significantly improved the discrimination of CV outcomes, with additional benefit gained when the two were combined.

Albuminuria predominated as a stronger predictor than eGFR, outperforming cholesterol levels and systolic blood pressure—and even smoking history—as a risk factor for heart failure (HF) and death from myocardial infarction or stroke.

Most of the individuals studied came from the general population, but three cohorts included high-risk individuals with diabetes and two cohorts enrolled only patients with CKD. In this latter group, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors.

Measures of kidney function were particularly useful predictors of CV risk in individuals with diabetes or hypertension, but in the case of ACR, this ratio foretold the likelihood of cardiovascular mortality and heart failure even in healthy individuals.

“Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when they are already assessed for clinical purposes,” said lead author Kunihiro Matsushita, MD, from Johns Hopkins Bloomberg School of Public Health. The expanded use of ACR especially could hold “particularly broad” implications for risk assessment.

Adding support for the use of eGFR and ACR is the fact that they are already commonly measured in several clinical scenarios. Assessment of kidney function is recommended in patients with diabetes and hypertension, with about 290 million tests of serum creatinine done every year in the U.S. This takes the cost effectiveness issue off the table for a wide swath of the at-risk population: those with CKD, diabetes, or hypertension.

Commenting on the research in an editorial entitled, “Humble kidneys predict mighty heart troubles,”³ Alberto Ortiz, MD, PhD, and Beatriz Fernandez-Fernandez, MD (both from the Universidad Autonoma de Madrid in Spain), said that the guidelines “should consider incorporating urinary ACR into algorithms for estimation of cardiovascular risk.”

They also suggested that the data help “settle the debate” on the predictive value of ACR and highlight the need to better understand the pathophysiological pathways involved in albuminuria changes and the therapies best suited to treat patients deemed at high risk based on this measure.

Whether to extend the measurement of creatinine-based eGFR and ACR to the general population remains unclear. However, most assessments have prioritized eGFR over ACR. Based on their new data, Matsushita argued, using ACR rather than eGFR would offer better targeting of at-risk individuals.

“In terms of potential target populations, ACR assessment led to a particularly improved cardiovascular prediction among black people in our study, supporting a recent report of stronger association of ACR with incident cardiovascular events in black people than in white people,” said Matsushita. However, more study is needed to know how to expand the use of ACR beyond those who are already being tested, he added.

The CKD-PC study investigators also suggested that the previous studies that failed to show predictive improvement in the primary prevention setting used eGFR and not ACR. “ACR was one of the strongest predictors of cardiovascular outcomes other than coronary heart disease among general population in our study,” they wrote. Albuminuria results mainly from damage to the glomerulus and thus may be a general marker of vascular damage or microvascular disease in addition to kidney disease, “which might account for its strong contribution to cardiovascular prediction.”

In a second new study, this one published in the August 2015 issue of the Journal of Hypertension, elevated ACR (p= 0.002) identified a subgroup of moderate Systematic COronary Risk Evaluation (SCORE) risk patients and high-intermediate Framingham risk score patients who could be appropriately reclassified at high cardiovascular risk.⁴ The authors suggested that ACR might be a cost-effective manner of identifying individuals with seemingly moderate or intermediate risk who would benefit from primary prevention.

Cardiorenal Syndrome

The term cardiorenal syndrome is less than a decade old, having been formalized by Claudio Ronco, MD, Director of the International Renal Research Institute (IRRIV), San Bortolo Hospital, Vicenza, Italy, and colleagues during a 2008 meeting of the Acute Dialysis Quality Initiative (AQDI) in Vicenza, Italy. Founded in 2000, ADQI is an international, interdisciplinary organization that seeks consensus and evidence-based recommendations in the field of acute kidney injury (AKI). 

Cardiorenal syndrome (CRS) refers to pathophysiologic disorders of the heart or kidneys where acute or chronic dysfunction of one organ induces acute or chronic dysfunction in the other. (See table.) The term is most commonly applied to patients with HF (as in Cardiorenal Syndrome Types 1 and 2), but technically covers heart-kidney involvement in many other conditions, such as sepsis, diabetes, and AKI.

In type 3 acute renocardiac syndrome, for example, the kidneys stand as the lead organ, as Peter A. McCullough, MD, MPH, FACC explained in an interview with CSWN. McCullough, from the Baylor Heart and Vascular Institute in Dallas, Texas, is a recognized authority on the role of CKD as a cardiovascular risk state with more than 1,000 publications, including the “Interface between Renal Diseases and Cardiovascular Illness” in the seminal text Braunwald’s Heart Disease, 10th Edition. He is the current Chair of the National Kidney Foundation’s Kidney Early Evaluation Program, the nation’s largest community screening effort for chronic diseases.

“Type 3 is acute kidney injury that leads to cardiac decompensation and will be seen mostly in the hospital setting with serious forms of acute kidney injury, where primary volume overload and neurohormonal signaling lead to cardiac decompensation,” said McCullough. “We see this fairly rarely in patients with crush injury, but you’ll hear about individuals who have severe trauma, for example, and go into kidney failure because of the volume overload, and then even a healthy heart can go into heart failure.”

Type 4 CRS describes CKD, leading primarily to HF, but possibly to acute coronary syndromes, stroke, or arrhythmias, too. Finally, CRS type 5 describes a systemic insult to both the heart and the kidneys, such as sepsis, where both organs are injured simultaneously in persons with previously normal heart and kidney function.

And Lung Makes 3

A June JACC State-of-the-Art review by Faeq Husain-Syed, MD, and colleagues explained the complex interactions between the heart, lungs, and kidneys, their perpetuating nature, and the “cycles of increased susceptibility and reciprocal progression.”⁵ Husain-Syed is also from the IRRIV in Vicenza.

McCullough, a second author on the review, observed that the lungs are caught right in the crossfire in this cycle of multi-organ crosstalk. They are also highly immunologic, representing a gateway to the environment, and have important pathophysiological connections to the failing heart and kidneys. However, he added, the lungs play more the part of a “victim” than a “participant” in the organ injury syndrome.

“The heart and kidneys are signaling each other back and forth fiercely in both health and disease; there are probably 8 to 12 known neurohormonal self-signaling systems where the heart and kidneys are communicating,” said McCullough. “The lungs are less active in terms of signaling, but they certainly bear the consequences of excessive volume overload, and capillary and then pulmonary edema.”

Multiple dependent inflammatory pathways promote injury and elevate the risk for chronic disease of the heart, lung, and kidney, including increased expression of soluble pro-inflammatory mediators, innate and adaptive immunity, physiological derangements, and cellular apoptosis. (See Figure 1.)

McCullough doesn’t think the term cardiopulmonary renal interactions (CPRI) is going to replace the better-known “cardiorenal syndromes,” but rather the goal of the review was more to serve as a reminder that the lungs function as more than a silent partner in cardiorenal syndromes and shouldn’t be forgotten.

“We are working on finding active prevention and treatment approaches for the heart and kidneys: cellular protectants, drugs that influence a whole variety of cellular processes, drugs that interfere with adverse cell signaling -- and we’re hoping for a breakthrough, which, I think when we find one, is going to have a major impact worldwide.”

“Evidence-free Zone”

“Although the heart has intense relationships with other organs, the marriage to the kidneys is particularly special,” said Kevin Damman, MD, and Jeffrey M. Testani, MD, FACC in a European Heart Journal clinical update on the kidney’s role in heart failure.⁶ Damman is from the University of Groningen, The Netherlands, and Testani is from Yale University, New Haven, CT.

But the hidden secret of that marriage is that codependency we talked about earlier: while the heart is directly dependent on regulation of salt and water content in the body, the kidneys are dependent on blood flow and pressure generated by the heart. With conditions of increased congestion and extracellular water content, like HF, the interdependency of both organs “can result in a vicious circle where deterioration of either organ results in a severe, potentially self-perpetuating, high-mortality condition.”

Renal dysfunction is extremely common in heart failure and it about doubles the risk for patients. In the general population, about 4.5% of individuals have an eGFR in the CKD range of <60 ml/min/1.73 m2, but looking at folks with chronic and acute heart failure, this rate rises above 50%.

“It’s actually the rule rather than the exception, and only a small proportion of patients with heart failure actually have normal kidney function,” said. Testani in an ACC.15 presentation on the subject.

So it might seem a bit surprising, as noted by Damman and Testani, that “that there is no specific evidence-based effective treatment of patients with HF experiencing deterioration of renal function, although currently available HF treatment is not always insufficient.”

While the cause of renal dysfunction in HF is multifactorial, clearly activation of multiple neurohormonal systems plays a modulating role, so it “seems obvious that we should be using antagonists of the renin-angiotensin-aldosterone system and the sympathetic nervous system” to treat these patients, according to Mariell Jessup, MD, FACC from the University of Pennsylvania, Philadelphia, PA, also at ACC.15.

“I say obvious, but the guidelines—that have been so carefully crafted with our stage A, B, C, and D, and our goals of therapy and treatments—have embarrassingly, and I say embarrassingly because I have been an author on the guidelines for many years, really have not paid much attention to the idea that there are patients with renal dysfunction,” said Jessup. “This is probably because we’re not quite sure what to say.”

And the evidence is even scarcer when it comes to devices for heart failure, said Jessup. Many of the studies providing the foundation for the use of implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT) in HF did not mention baseline renal function nor have they done subgroup analyses according to renal function. “So when we throw in an ICD for primary prevention in a low ejection fraction patient with renal dysfunction, it is in an evidence-free zone,” she said.

The good news: where there is evidence available, it appears that most of the drugs used to treat heart failure offer benefits in patients with moderate (stage 3) renal dysfunction and actually appear to provide added benefit compared to those with preserved renal function. With greater renal insufficiency (CKD stage 4 or 5), the data remain scarce.

“Although there is less robust evidence of benefit in HF patients with a reduced GFR, subgroup analyses of the trials testing the major classes of drugs (ACE-I, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor blockers) and devices (ICD/CRT) suggest that the relative risk reductions are similar (and absolute risk reductions greater), although these therapies might cause unwanted effects,” wrote Damman et al. in a review of the evidence published last year.⁷ (See Figure 2.)

“Especially in patients with stage 4 and 5 CKD, care should be taken to assess whether possible beneficial effects might outweigh the potential risks associated with the initiation of this therapy,” wrote Damman et al.

No Trials = No Guidelines

How can the heart failure treatment guidelines ignore half of the HF population? According to McCullough, the problem starts with drug and device development.

“These patients are excluded from clinical trials because of the fact that they’re high risk and they tend to be very complicated, and many of the manufacturers want to eliminate confounding and get a clean look at their drugs,” he said.

Even worse, because many drugs have to be dose adjusted for patients with renal dysfunction, the agents really need to be properly studied rather than just used in CKD patients because they’ve shown safety and efficacy in non-CKD patients. Many companies never really define drug dosing for renal patients.

“To this day, we use heparin all the time and we really don’t have accepted drug-dosing adjustments for heparin, or enoxaparin as another example, which is contraindicated below a certain level of renal function,” said McCullough.

Exclusion from clinical guidelines is not surprising given that “one of the rules of guidelines is that you need evidence, so if you don’t have evidence you don’t get in the guidelines.” Now there is a Catch-22.

Several groups are now working with the National Institutes of Health and industry sponsors to have kidney-disease pre-specified subgroups in the larger clinical trials. The best example of this new era in clinical trial research, stated McCullough, is the National Heart, Lung, and Blood Institute-funded ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches). The main trial is testing the best management strategy—invasive or conservative—for patients with moderate-to-severe cardiac ischemia on stress testing. Designed to run in parallel, the ISCHEMIA-CKD trial is due to randomize 1,000 patients with CKD (eGFR <30 or on dialysis). It is the largest treatment strategy trial in severe CKD patients with stable ischemic heart disease to date.

Giving Kidneys a Voice in Revascularization

Finally, a lot of bits and bytes have been consumed comparing the effectiveness of percutaneous coronary intervention (PCI) versus coronary artery bypass graft surgery (CABG) in patients with multivessel disease. This row over revascularization may be another spot where the kidneys need to weigh in. One year ago, Chang et al. reported two- to three-fold higher adjusted risk for AKI in more patients undergoing multivessel revascularization with CABG (n=1,933) compared with PCI (n=1,004).⁸

In an accompanying editorial comment, Mandeep Singh, MD, MPH, at the Mayo Clinic, Rochester, MN, noted that the study significantly advances our knowledge and will help in the selection of revascularization.⁹ He wrote, “There is an evolution in our thinking as we strategize the choice of revascularization for an average patient, taking into consideration some readily available covariates.”

Since information regarding function is commonly available in patient records, it is highly likely that this information will prove increasingly useful going forward in selecting therapy, be it pharmacological or interventional.

No matter how we proceed, the cross-talk we experience with heart, kidneys, lungs, and other organs joining the chorus is only going to grow louder as we learn more. We can’t just put in earplugs; learning how to make them harmonize and help— function versus dysfunction—will be beautiful music for professionals and patients alike.

References:

1. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. Am Coll Cardiol. 2014;63 2935-59.
2. Matsushita K, Coresh J, Sang Y, et al. Lancet Diabetes Endocrinol. 2015;3:514-25.
3. Ortiz A, Fernandez-Fernandez B. Lancet Diabetes Endocrinol. 2015;3:489-91.
4. Greve SV, Blicher MK, Sehestedt T, et al. J Hypertens. 2015;33:1563-70.
5. Husain-Syed F, McCullough PA, Birk H, et al. J Am Coll Cardiol. 2015;65:2433-48.
6. Damman K, Testani JM. Eur Heart J. 2015;36:1437-44.
7. Damman K, Tang W, Felker G, et al. J Am Coll Cardiol. 2014;63:853-71.
8. Chang TI, Leong TK, Boothroyd DB, et al. J Am Coll Cardiol. 2014;64:985-94.
9. Singh M. J Am Coll Cardiol. 2014;64:995-6.

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Getting Hyped Over a Possible Hyperkalemia Solution

The potassium from your daily banana may be wonderful for the heart, but eat a bunch or a boatload, and the excess of potassium can be deadly. Hyperkalemia is generally defined as occurring when the body’s potassium concentration exceeds 5.0 mEq/l, and it is often considered a medical emergency. Clinically, hyperkalemia can manifest as electrocardiographic changes ranging from peaked T waves and progressive paralysis of the atria to conduction abnormalities, bradycardias, and cardiac arrest due to ventricular fibrillation, asystole, or pulseless electrical activity.1 Not something to mess around with.

While relatively rare in the general population, hyperkalemia is more common in patients with chronic kidney disease (CKD), and more common yet in patients with CKD and comorbid diabetes, cardiovascular disease, or acute kidney injury. Several medications have the potential to raise serum potassium levels, including beta-blockers and heparin, but their effects are small.

“The most important medication class linked to hyperkalemia are inhibitors of the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers,” according to Csaba P. Kovesdy, MD, University of Tennessee Health Science Center, Memphis, TN, in a review on the management of hyperkalemia published in late June.2

RAAS dual therapy is associated with hyperkalemia incidence between 5% and 10% in patients with CKD. Unfortunately, these agents have proven survival benefits in heart failure and are also renoprotective. Since one of the most effective treatments of drug-related hyperkalemia is to stop the drug, potassium elevations often leave the patients who most need RAAS inhibitors without them.

Aldosterone inhibitors, such as spironolactone and eplerenone (or the new-generation mineralocorticoid receptor antagonist [MRA] finerenone), are also associated with increased potassium levels. These agents help control hypertension, decrease left ventricular mass and left atrial size, reduce hospitalizations, and may reduce cardiovascular mortality in high risk patients.³

Their use, however, has been limited, in part, because of hyperkalemia concerns. Some researchers have labeled this risk quite low, but Abbas et al.⁴ recently published some worrisome data from a massive German nested case-control study of heart failure patients receiving spironolactone plus continuous ACE/ARB therapy (n = 1,491,894). In this diverse real-world population, the risk of hyperkalemia associated with spironolactone use in those taking continuous ACE/ARB therapy was much higher (with odds ratio, 13.59) than that observed in clinical trials.

Previously, treatment of hyperkalemia was limited to drug cessation, cardiac monitoring, administration of potassium-lowering mediations, or emergency dialysis. In patients with sufficient renal function, forced diuresis with loop diuretics might be employed to remove potassium that has been redistributed into the extracellular space by other therapies.

The only agent currently available in the U.S. that actually lowers total body potassium levels is sodium-polystyrene sulfonate, which was approved based on a trial from the early 1960s conducted in 32 hyperkalemic patients with azotemia at a time before dialysis was available, said Kovesdy. Its effects on serum potassium are considered unpredictable.

“By today’s standard, sodium-polystyrene sulfonate has never undergone rigorous enough testing in clinical trials to prove its efficacy and safety for treatment of acute or chronic hyperkalemia,” wrote Kovesdy. Indeed, recent reports of colonic necrosis prompted a U.S. Food and Drug Administration (FDA) black box warning in 2009 banning the combination use of sodium-polystyrene sulfonate with 70% sorbitol (often added to alleviate its constipating effect).

Enter patiromer (Relypsa, Inc.) and sodium zirconium cyclosilicate (ZS Pharma), two drugs that bind potassium and clear it from the body, albeit with differing mechanisms of action. Patiromer is a potassium binder in oral suspension form. It has been submitted to the FDA for approval with a decision expected on October 21, 2015. ZS-9 is an insoluble zirconium silicate with a three-dimensional crystalline lattice structure designed to preferentially trap potassium ions. An NDA for ZS-9 was submitted to the FDA on May 26, 2015.

In phase III clinical trials, both drugs normalize plasma potassium levels in hyperkalemic patients with CKD, diabetes, or heart failure receiving RAAS inhibitors.^5,6 In the recently published AMETHYST-DN trial,⁷ Bakris and colleagues conducted a phase II dose-finding trial of patiromer in patients with stage 3 and 4 CKD who received RAAS inhibitors and had a baseline potassium level >5.0 mEq/l. Depending on their level of hyperkalemia, participants were given one of three starting doses, with adjustments made to achieve target potassium concentrations of 5 mEq/l or less.

Potassium concentrations were significantly reduced in each baseline hyperkalemia stratum at 4 weeks, with results persisting to 8 weeks. Perhaps more importantly, over an additional 44 weeks of maintenance therapy, most patiromer-treated patients remained normokalemic, with potassium levels increasing quickly once the study drug was stopped.

“These drugs are going to help markedly keep patients on the drugs that are cardio- and reno-protective,” said Peter McCullough, MD, FACC. “For instance, the MRA drugs—we only use them in about 40% of the patients who need them because we’re limited by hyperkalemia, so this should be a dramatic change in our practice and I think we’re very hopeful that we will see improved outcomes over time once these new drugs get on the market and get in use.”

Once approved based on the surrogate of potassium concentration, the hyperkalemia drugs need to be further tested to see if they will allow patients who are about to or have failed RAAS inhibitor treatment to stay on their drugs, according to nephrologist Wolfgang C. Winkelmayer, MD, ScD, from Baylor College of Medicine, Houston, TX, and an associate editor at JAMA.⁸

Since motivation in industry to do these trials may be lacking, “as part of the approval process, the FDA and other agencies should consider mandating a sizeable postmarketing trial and safety surveillance program to clearly establish whether the assumptions underlying the value proposition of chronic hyperkalemia treatments actually hold,” said Winkelmayer. With this further study, he noted, these agents have “the potential to fundamentally change the current treatment approach for hyperkalemia.”

References

1. “Hyperkalemia.” lifeinthefastlane.com/ecg-library/basics/hyperkalaemia. Accessed on 2015 July 17.
2. Kovesdy CP. Am J Med. 2015 Jun 17. [Epub ahead of print]
3. Miller RJ, Howlett JG. Curr Opin Cardiol. 2015 Jan 8. [Epub ahead of print]
4. Abbas S, Ihle P, Harder S, Schubert I. Parmacoepidemiol Drug Saf. 2015;24:406-13.
5. Weir MR, Bakris GL, Bushinsky DA, et al. N Engl J Med. 2015;372:211-21.
6. Packham DK, Rasmussen HS, Lavin PT, et al. Engl J Med. 2015;372:222-31.
7. Bakris GL, Pitt B, Weir MR, et al. JAMA. 2015;314:151-61.
Winkelmayer WC. JAMA. 2015;314:129-30.

Keywords: CardioSource WorldNews, Kidney Diseases, Cardiovascular Diseases, Cardio-Renal Syndrome, Hyperkalemia

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