Management of Heart Failure Patient with CKD

Epidemiology of CKD in Heart Failure

Patients with heart failure frequently suffer from coexisting CKD (1). A large meta-analysis suggests that approximately half (49%) of patients with heart failure suffer from CKD (excluding registry studies) (2). The incidence of heart failure in patients with CKD was 18/1000 person-years in a large population-based study in the United States (3). Prevalence of heart failure is higher with decreasing kidney function, and approximately 44% of patients on dialysis suffer from heart failure, and half of these have reduced ejection fraction (1). The prognosis of patients with heart failure and CKD is poor, and worsens with deteriorating kidney function, with a higher mortality (odds ratio, 2.34; 95% confidence interval [95% CI], 2.20 to 2.50; P<0.001) (4). The coexisting CKD is usually caused by diabetes, hypertension, or ischemic kidney disease (see case in Box 1). Consider a 54-year-old man with diabetes, hypertension, and heart failure owing to severe coronary artery disease who presents with fluid overload and near ESKD. In patients like this, prognosis is poor and management is difficult. Patients with CKD were older in most studies, which may be because of age-related decline in GFR; however, presence of CKD was associated with higher mortality when adjusted for age (5). In addition, a significant number of patients with heart failure also suffer from AKI resulting from a variety of conditions, such as sepsis, kidney hypoperfusion, and drug toxicity, with significant adverse outcomes (6). However, the worsening of eGFR because of initiation of renin-angiotensin-aldosterone system inhibitors (RAASis) does not bear the same long-term consequences as persistent AKI owing to sepsis or hypovolemia (7,8).

The Interdependence of the Heart and Kidney

The heart and the kidney are interlinked in physiologic states to maintain salt-water homeostasis and normal BP. In health, the crosstalk between the two organs helps the body to respond to changes in kidney perfusion resulting from volume depletion or overload, to maintain appropriate blood flow to vital organs and thereby avoid ischemia or hyperperfusion injury. In disease, the kidney and heart can adversely affect each other’s function (9). On the one hand, inability to excrete salt and water and abnormal renin secretion by the diseased kidney increases cardiac preload, afterload, and heart failure; on the other hand, poor kidney perfusion owing to low cardiac output, and renal venous congestion owing to right heart failure, causes kidney failure. When both organs are diseased, they adversely affect each other’s function, which poses significant challenges in the management of patients with compromised heart and kidney function. Common pathologic mechanisms may affect both organs and cause simultaneous dysfunction of the kidney and heart (10).

The neurohumoral interactions between the two organs are complex in disease states. The natriuretic peptides, which induce diuresis with cardiac volume overload, are upregulated with kidney disease so as to help with associated fluid retention; however, they can be elevated because of poor elimination of the peptide molecules by the kidneys themselves. During treatment of heart failure with diuretics, although congestive symptoms and brain natriuretic peptide (BNP) concentrations improve, kidney function may worsen because of a reduction in kidney plasma flow (11). Stopping of diuretics may improve kidney function but worsen cardiac volumes and levels of BNP.

In heart failure with reduced ejection fraction (HFrEF), the renin, angiotensin, and aldosterone levels increase with hypotension, in response to low kidney perfusion, to improve GFR by efferent arteriolar vasoconstriction and increase systemic BP. However, the excess fluid retention caused by increased levels of renin, angiotensin, and aldosterone may increase the volume overload of the heart and cause further deterioration of heart failure.

Treatment with angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) lowers intraglomerular pressure caused by efferent arteriolar vasodilation, presenting as apparent worsening of kidney function, which causes anxiety in treating physicians. However, with ACEis, eGFR decline up to 35% has been associated with improved heart failure hospitalization rates (12).

Progression of CKD in patients with heart failure is perhaps faster than in patients without heart failure in the absence of AKI; for example, in the recently completed EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR)-reduced trial, eGFR declined by 4.2 ml/min per 1.73 m² (95% CI, 3.1 to 5.3) in the placebo arm, over a median follow-up of 16 months, with most patients on ACEis and a baseline eGFR of 62±21 ml/min per 1.73 m² (13).

AKI in Patients with Heart Failure and CKD

The incidence of AKI is high in patients with heart failure. Incidence of AKI among acute heart failure admissions at St George’s Hospital was 17% in 1094 patients admitted with acute decompensated heart failure, and inpatient mortality was 21% with stage 1, 36% with stage 2, and 48% with stage 3 AKI (P<0.001) (6). In a meta-analysis of 28 trials with 49,890 patients, the incidence of AKI or worsening of kidney function was 23%, and the mortality was higher (odds ratio, 1.81; 95% CI, 1.55 to 2.12; P<0.001) over 488±569 days (2). In a unique situation in cardiology, when the kidney insult is known and preventive measures are used (i.e., with coronary angiogram), the incidence was 7.1% in 985,737 US patients undergoing percutaneous coronary interventions, and was higher with the presence of CKD and heart failure (14). The other causes of AKI in patients with heart failure are infection, sepsis, volume depletion, drug toxicity, and obstruction of the urinary tract in older men with enlarged prostate.

Certain classes of drugs decrease kidney function at therapy initiation, which is distinguished from true AKI by the term “permissive AKI,” or “hemodynamic AKI.” ACEis and ARBs work by dilating the efferent arteriole, thereby lowering intraglomerular pressure and preventing long-term harmful effects of hyperfiltration in individual nephrons (e.g., glomerulosclerosis) in patients with CKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a recently introduced class of oral hypoglycemics, cause a drop in eGFR at therapy initiation. With canagliflozin, a SGLT2i in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) study (baseline eGFR of 56 ml/min per 1.73 m²), the initial drop of eGFR was followed by a slowing of progression of CKD and improvement in heart failure outcomes. The drop in eGFR at 3 weeks in the canagliflozin arm was 3.17 ml/min per 1.73 m² (95% CI, 3.87 to 2.47) more than in the placebo arm, yet the decline in eGFR was less over longer follow-up (15). The drop in eGFR in the first 4 weeks was similar with empagliflozin in the EMPEROR-reduced trial, where the baseline eGFR was 62±22 ml/min per 1.73 m² (13). The initial worsening of GFR is likely a result of increased delivery of salt and water to the distal tubule, which, in turn, decreases glomerular filtration pressure through the crosstalk between the distal tubule and efferent arteriole of the same nephron by a mechanism known as “tubuloglomerular feedback.”

Heart Failure Therapy in Patients with CKD

Management of chronic heart failure in the general population has changed over the past 3 decades. Novel agents such as ivabradine, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor inhibitors, and cardiac resynchronization therapy have improved survival. Many trials have included patients with mild-to-moderate CKD, and evidence has emerged for newer agents in the treatment of patients with heart failure and CKD, which is discussed below, and summarized in Figure 1 and Table 1 (1).

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Figure 1.

The figure shows level of evidence for heart failure management in patients with CKD with different levels of kidney function. Adapted from the Kidney Disease Improving Global Outcomes Consensus Conference report (1). The increasing levels of evidence for improved outcomes (mortality and hospitalizations) are shown for each therapy on the y axis, with increasing levels of GFR on the x axis. Evidence is strong for BBs, ACEis, ARBs, and MRAs and moderate for CRTs and ivabradine for eGFR>30 ml/min per 1.73 m². ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; CKD G3a–3b, chronic kidney disease grade 3a and 3b; CKD G4, chronic kidney disease grade 4; CKD G5D, chronic kidney disease GFR category 5 patient on dialysis; CKD G5 ND, chronic kidney disease GFR category 5 patient not on dialysis; CRT, cardiac resynchronization therapy; EF, ejection fraction; H-ISDN, hydralazine-isosorbide dinitrate; ICD, implantable cardioverter defibrillator; IV, intravenous; LBBB, left bundle branch block; MRA, mineralocorticoid receptor antagonist; PO, oral; QRS, QRS wave length in electrocardiogram.

Diuretic Therapy

As seen in the case in Box 1, water retention and lung congestion in patients with heart failure and CKD causes breathlessness, poor exercise tolerance, and multiple hospital admissions, resulting in poor quality of life. Diuretic therapy is challenging in these patients because of the need for higher doses, frequently causing transient worsening kidney function and electrolyte imbalances such as hyponatremia and hypokalemia (16). These challenges result in the patient needing to visit a variety of specialty doctors, each changing diuretic agents and diuretic doses, often to minimize adverse electrolyte and creatinine changes, and resulting in poor symptom control for the volume-overloaded patient. Renal venous congestion and consequent kidney dysfunction owing to elevated right heart pressure is an often mentioned, poorly understood, and difficult to manage condition, requiring careful escalation of diuretic doses with close monitoring of weight, electrolytes, and creatinine (17). With appropriate use of diuretic therapy, working on different segments of the nephron, symptoms can be controlled and survival may be better. Commonly used thiazide diuretics may not be effective, and loop diuretics are often used with metolazone, as necessary. Intravenous diuretics are used for admitted patients with acute decompensated heart failure. However, there is no significant difference between continuous infusion or bolus administration of intravenous diuretics (16). Spironolactone in patients with acute heart failure can be natriuretic and relieve congestion without significant adverse effect on serum potassium levels (18). A study by the National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network has demonstrated that in 360 patients with acute heart failure and CKD stages 3 and 4, rapid diuresis of 8425 ml (interquartile range 6341–10,528) over 72 hours, with 560 mg (interquartile range 300–815) of furosemide, was safe and was not associated with elevation of markers of tubular injury despite some worsening of creatinine (19). Aggressive diuresis may be useful, provided that the patient is adequately decongested, as evidenced by improvement of physical symptoms and decreased BNP and hemoconcentration, despite the rise in creatinine (20).

Renin-Angiotensin-Aldosterone System Inhibitor Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

Randomized controlled trials have shown improvement of survival in patients with heart failure with use of ACEis (or ARBs) and mineralocorticoid receptor antagonists. Most of these studies included patients with mild-to-moderate (i.e., stages 1–3) CKD (21). Patients with severe CKD have been excluded from most ACEi studies (Figure 1, Tables 1 and 2).

Mineralocorticoid receptor antagonist therapy has been associated with improved survival of patients with symptomatic heart failure; in a randomized controlled trial of spironolactone, 50% of patients had a GFR of <60 ml/min per 1.73 m², hence the benefits of the trial extended in CKD patients. Similarly, eplerenone was beneficial in patients with postmyocardial infarction heart failure and CKD. However, hyperkalemia was not infrequent and was associated with discontinuation of the therapy.

The use of ACEis and mineralocorticoid receptor antagonists, particularly in patients with CKD, is often associated with hyperkalemia and rising creatinine. Rising creatinine of up to 40% has been observed in ACEi trials, without significant effects on long-term outcomes (12,22). A rise of up to 30% can be viewed as resulting from hemodynamic changes owing to RAASis (23). In fact, such a change may be beneficial and is named permissive AKI as opposed to true AKI due to other reasons in patients with HFrEF, which requires careful history taking and physical examination (7). RAASis should be stopped when kidney blood flow autoregulation is necessary in the patient, e.g., with diarrhea causing volume depletion.

Patients are referred back and forth, between nephrologists and cardiologists, with RAASi-induced changes in creatinine and potassium, resulting in multiple hospital attendances and, often, discontinuation of the RAASi. Analysis of 194,456 patient records showed increasing frequency of hyperkalemia of up to 30% in patients with CKD stages 4 and 5 if measured more than four times a year, and discontinuation of ACEis/ARBs in 24% of patients (24). Nephrologists traditionally have managed hyperkalemia with judicious use of diuretics and correction of acidosis, but oral potassium binders such as patiromer or sodium zirconium cyclosilicate may be useful (25). Randomized controlled studies of new potassium binders for maximization of RAASi therapy in patients with advanced CKD and heart failure are necessary. A close collaboration between nephrologists and cardiologists is necessary for successful initiation and continuation of RAASi in patients with CKD and heart failure.

Angiotensin Receptor and Neprilysin Inhibitor Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

A large randomized controlled trial of dual angiotensin receptor and neprilysin inhibitor therapy excluded patients with eGFR<30 ml/min per 1.73 m² (see Figure 1, Tables 1 and 2), but included patients with only mild CKD (26). A randomized controlled trial of angiotensin receptor neprilysin inhibitors, including patients with eGFR as low as 20 ml/min per 1.73 m², demonstrated safety and efficacy similar to irbesartan (27). More recently, angiotensin receptor and neprilysin inhibitor therapy has been shown to slow the progression of CKD in patients with heart failure with preserved ejection fraction (HFpEF) more effectively than valsartan (28). The recommended starting dosage for patients with eGFR<60 ml/min per 1.73 m² is 24 mg sacubitril and 26 mg valsartan, administered twice per day, at least 36 hours after stopping ACEis or ARBs; the dose is then increased, with careful monitoring of creatinine, potassium, and BP.

Ivabradine and β-Blocker Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

β-Blockers are beneficial in patients with HFrEF and CKD, as evidenced in studies of CKD and the general population (Figures 1 and 2, Tables 1 and 2) (29⇓⇓⇓–33). Carvedilol has been shown to be beneficial in patients with heart failure with CKD stage 5 who are receiving dialysis (34).

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Figure 2.

The figure shows m anagement strategy for patients with heart failure and CKD, including KRT. Adapted from the Kidney Disease Improving Global Outcomes Consensus Conference report (1). Stepwise, evidence-based drug therapy (increasing levels of evidence from the top to bottom of the pyramid) is shown in the middle. The bars on either side of the pyramid show relevant supportive treatment. AF, atrial fibrillation; ARNI, angiotensin receptor neprilysin inhibitor; CKD-MBD, CKD with mineral and bone disorder; CRRT, continuous KRT; i.v., intravenous; NSAID, nonsteroidal anti-inflammatory drug; RAASi, renin-angiotensin-aldosterone system inhibitor.

The Ivabradine and outcomes in chronic heart failure (SHIFT) study demonstrated improved hospitalization and deaths owing to heart failure with ivabradine treatment in patients with HFrEF with a heart rate >70 beats per minute despite β-blocker therapy, which included patients with creatinine <2.5 mg/dl. The study included 1589 patients with CKD stage 3, and benefits in patients with CKD were similar to patients without CKD (35). Ivabradine is metabolized by the CYP3A4 enzyme in the liver and gut, and elimination by kidneys is minimal. The dosage is 2.5–7.5 mg twice per day and does not require dose adjustment with creatinine clearance of >15 ml/min.

Sodium-Glucose Cotransporter 2 Inhibitor Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

SGLT2i therapy in patients with heart failure has been recently shown to reduce mortality and hospitalizations. The recently completed dapagliflozin study included 1926 patients with CKD stage 3 and was able to achieve a risk reduction for composite end points of 28% versus 24% in patients with eGFR>60 ml/min per 1.73 m² (see Box 1, Table 1). Adverse kidney events with dapagliflozin was not higher compared with placebo (36). More recently, empagliflozin was shown to reduce heart failure hospitalization and eGFR decline, including in patients with eGFR as low as 20 ml/min per 1.73 m² (48% had eGFR<60 ml/min per 1.73 m²) (13). The Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD) trial has reported lower heart failure admissions in patients with CKD (eGFR >25 but <75 ml/min per 1.73 m²) and proteinuria.

Management of Iron Deficiency and Anemia in Patients with Heart Failure with Reduced Ejection Fraction and CKD

Nephrologists have been using intravenous iron for the past 3 decades to treat anemia in patients with CKD, both before and during dialysis. In the United Kingdom, a recent study in patients receiving dialysis has shown benefits of high-dose intravenous iron in reducing mortality and morbidity, together with heart failure hospitalizations by 44% (37). A previous trial of benefits of intravenous iron in patients with HFrEF included patients with early stages of CKD (38). A collaboration between cardiologists and nephrologists may assist the management of iron deficiency in patients with HFrEF and CKD.

KRT

CKD is a progressive disease with declining kidney function over time, causing frequent episodes of fluid overload and hyperkalemia, further complicated by episodes of AKI. With eGFR<20 ml/min per 1.73 m², decisions need to be made, in discussion with the patient, about indications, appropriateness, and modality of KRT. Careful consideration of patient expectations, comorbidities, frailty, and quality of life are necessary factors to consider when starting KRT. Patients with heart failure on dialysis have very poor prognosis, with a 5-year survival rate of 12.5% (39). There may be symptomatic relief and fewer hospitalizations with peritoneal dialysis in carefully selected patients (40). In a study of 118 patients with heart failure and CKD, peritoneal dialysis was associated with improvement in quality of life and New York Heart Association class (41). A meta-analysis of 23 studies demonstrated benefits of peritoneal dialysis in patients with heart failure and CKD, with improved hospitalization rates and heart function (42). In patients with refractory heart failure, overnight ultrafiltration with icodextrin solution improved quality of life, heart function, and New York Heart Association class (43). Hemodialysis may be tricky in patients with low BP, but more frequent dialysis and longer nocturnal dialysis may be useful for fluid removal. However, creation of arteriovenous fistula or graft for hemodialysis may cause dilation of left atrium and right ventricle, and associated heart failure (44). For patients with acute heart failure and low BP, slow ultrafiltration with continuous KRT may be useful.

Device Therapy

Rate of CKD progression to dialysis, associated blood stream infection, patient’s age, and general health determine the benefits of other treatments, such as use of cardiac resynchronization therapy and implantation of defibrillators. Cardiac synchronization therapy was beneficial in patients with CKD stage 3 in a Canadian study, of which more than half of patients had eGFR<60 ml/min per 1.73 m² (45). In a meta-analysis of five retrospective studies, defibrillator therapy was associated with improvement in mortality of patients at high risk of sudden cardiac death (46). Defibrillator therapy in dialysis was associated with high infection rates, and a recent randomized trial in patients on hemodialysis has failed to show any significant benefit (47,48).

Heart Failure with Preserved Ejection Fraction in Patients with CKD

The diagnosis of HFpEF in patients with CKD may be challenging. The BNP levels may be elevated because of the CKD and may not be diagnostic. The fluid overload may be a result of CKD itself. These patients have similar risk of poor outcomes and suffer frequent hospital admissions because of fluid overload, similar to patients with heart failure with reduced ejection function (49). Careful use of diuretics is necessary to control the symptoms of volume overload. Nonsteroidal anti-inflammatory drugs should be avoided because they can cause AKI and fluid retention in patients with CKD, and mimic HFpEF. There is no compelling evidence for effective therapy in HFpEF to improve outcomes such as cardiovascular mortality or heart failure hospitalizations. However, large trials are underway, such as FINEARTS-HF (ClinicalTrials.gov identifier NCT04435626) [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%], a randomized controlled trial of finerenone (a nonsteroidal mineralocorticoid receptor antagonist) in patients with CKD and HFpEF.

Multidisciplinary Care

Patients with CKD and heart failure need multidisciplinary care to minimize the number of health care visits. A close working relationship between nephrologists and cardiologists is the key to controlling symptoms and prolonging life where possible; treating with diuretics, ACEis, and mineralocorticoid receptor antagonists, while avoiding electrolyte abnormalities and AKI; and advising appropriately for dialysis and device therapy (Figure 2) (1). In a recent study in St George’s Hospital, multidisciplinary care was associated with improvement in iron stores and RAASi use in 124 patients with CKD and heart failure (50). A multidisciplinary cardiology-nephrology service with doctors and specialist nurses in the United Kingdom has demonstrated better utilization of evidence-based therapy and health care resources (51). A similar multidisciplinary meeting for prekidney transplant patients, with cardiologists, nephrologists, transplant surgeons, and specialist nurses, showed that high-cardiac-risk patients can be safely transplanted (52).

The Way Forward

To achieve appropriate therapy and the best possible outcome, combined cardiology-nephrology clinics are necessary, as demonstrated by the success of the kidney and heart failure clinic at St George’s Hospital, which manages kidney and heart care, together with intravenous iron and advice on dialysis therapy (50). Patients appreciate the multiple benefits from a single visit and provide excellent feedback. The multidisciplinary “one-stop shop” clinic is very patient centered and helps with decision making regarding RAASi, device therapy, and intravenous iron administration, but requires proper resources, including the presence of a nephrologist, cardiologist, anemia nurse, and appropriate space. However, once economic and outcome benefits of a combined clinic are established, such clinics need to be replicated in other institutions. With improved knowledge among cardiologists and nephrologists, multidisciplinary approach, evidenced-based therapy can be implemented in patients with early-to-moderate CKD. However, we recognize that more studies are necessary to strengthen the evidence base in patients with advanced CKD.

Disclosures

D. Banerjee reports receiving lecture fees from Pfizer and ViforPharma; grants and lecture fees from AstraZeneca; and grants from BHF, KRUK, and Wellcome Trust, outside the submitted work. C.A. Herzog reports receiving honoraria from UpToDate; receiving consultation fees from Abbvie, Amgen, Corvidia, Diamedica, Fibrogen, Janssen, NxStage, Pfizer, Relypsa, Sanifit, and University of Oxford; receiving grants from Amgen, National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Relapsa, and University of British Columbia; being a stockholder of Boston Scientific, Bristol-Myers Squibb, General Electric, Johnson & Johnson, and Merck; and being an employee of Hennepin Healthcare, outside the submitted work. The remaining author has nothing to disclose.

Funding

None.