In accordance to the US Renal Data System, in 2016, the prevalence of HF in CKD patients aged 65 and older was close to 26%, compared to 6% among patients without CKD.8 When patients were stratified in types of HF based on the presence of reduced or preserved left ventricular ejection fraction (HFrEF and HFpEF, respectively), or unspecified the prevalence of all types of HF were more common among those with CKD than among non-CKD patients and increased with greater severity of CKD stage. In this regard, an estimated 44% of patients with end-stage renal disease (ESRD) have HF (10% with HFpEF, 13% with HFrEF, and 21% with unspecified) (Fig. 1A).

Fig. 1.

(Panel A) Heart failure (HF) in patients with and without chronic kidney disease (CKD). (HFrEF, HF with reduced ejection fraction; HFpEF, HF with preserved EF). (Panel B) Adjusted survival of patients by CKD and HF status, 2015–2016.

(0.13MB).

(Adapted with permission from Ref. 8).

Data on pre-transplant HF prevalence and prognosis are sparse, but the prevalence of left ventricular’LV’ systolic dysfunction/failure in patients carrying a renal transplant may be as high as 25%,9–11 despite that renal transplantation resulted in an increase in EF in more than 86% of recipients with HFrEF, and it was associated with an improvement in the New York Heart Association functional status in more than two-thirds of recipients.12

Whereas the worldwide incidence of de novo HF in the general population does not exceed of 1%,13 the incidence in known CKD is in the range of 17% to 21%.14 The cumulative probability to develop HF varies depending on the degree of CKD and the modality of renal replacement therapy (RRT), including transplantation. On the basis of Medicare billing claims data, the incidence of post-transplant de novo HF is ∼18% at 3 years.10

Of interest, in a study pooling participants without prevalent cardiovascular disease from 3 community-based cohorts from USA an estimated glomerular filtration rate (GFR) <60mL/min/1.73m2 (i.e., CKD stage 3a or higher) was found to be associated with an increased risk of HF that was similar in magnitude to ischemic heart disease and greater than stroke.15 However, the incidence of HF in renal transplant recipients has been reported to be considerably higher than that in the Framingham cohort, whereas the incidence of ischemic heart disease was not, suggesting that renal transplantation might correspond to a state of “accelerated HF”.16

The presence of HF reduces the probability of survival among patients both with and without CKD, but to a greater extent among those with CKD (p-value for interaction <0.0001) (Fig. 1B).8 Over a two year period, patients with both CKD and HF had an adjusted survival probability of 77.8%, as compared to 90.2% for those with CKD alone, and 93.7% for those without HF or CKD.8

CKD was more strongly associated with mortality and had more prognostic discrimination in patients with HFrEF than in patients with HFpEF.17 The association of CKD with mortality in HFrEF is independent of age, functional class, duration of HF, hemoglobin, or diabetes mellitus.17

The presence of HF at the time of renal transplantation is associated with a higher risk of mortality, cardiovascular events, and graft failure.9,10,18 The ongoing burden of HF after renal transplantation is illustrated by the fact that HF accounts for 16% of all hospitalizations.19

The data from the US Renal Data System on expenditures show the enhancer effect of HF on CKD.20 In the Medicare population aged 65 and older the per-person per-year costs in 2014 increased by 93% in patients with CKD and HF compared to patients with CKD alone. Data from Spain for the 2008–2010 period show that the direct and indirect health care costs related to HF are 58% higher in patients with estimated GFR values <60mL/min/1.73m2 than in patients with values ≥60mL/min/1.73m2 (14.868,2 euros per year vs 9.364,5 euros per year, respectively).21

In CKD, hemodynamic risk factors for chronic HF include excessive afterload due to long-standing hypertension and arterial stiffness, and excessive preload due to salt and water retention.22,23 In addition, there are non-hemodynamic CKD-specific factors such as neurohormonal activation, excess of reactive oxygen species, pro-inflammatory cytokines and pro-fibrotic factors, impaired iron utilization, anemia, vitamin D deficiency, and retained uremic toxins that may also facilitate HF.22,23

LVH is the principal initial cardiac structural perturbation in patients with CKD and the strongest independent predictor of cardiovascular mortality in these patients.23,24 Key histologic myocardial features underlying LVH include cardiomyocyte hypertrophy, thickening of intramyocardial arterioles, reduction of capillary density, and interstitial fibrosis (Fig. 2).25 Recently, it has been proposed that myocardial interstitial fibrosis, an almost constant finding in autopsy studies from patients at different stages of CKD, may be the major driver of cardiac dysfunction and failure in CKD patients.26 Initially, myocardial fibrosis enhances LV stiffness thus decreasing passive relaxation and impairing diastolic filling, and in advanced stages alters the alignment of cardiomyocytes thus impairing contractility and leading to systolic incompetence.27 It is plausible that pro-fibrotic mechanisms specific for CKD exist, among them an excess of fibroblast growth factor 23 that may serve as a biomarker and/or a therapeutic target of the cardiac involvement in CKD patients.28 There is strong evidence that abnormalities of LV structure and function, and the development of myocardial interstitial fibrosis are present in early stages of CKD, prompting the term CKD-associated cardiomyopathy instead of uremic cardiomyopathy.23,24

Fig. 2.

Myocardial interstitial fibrosis in four patients with arterial hypertension and with (+) or without (−) chronic kidney disease (CKD) and/or heart failure (HF) (Picro-sirius red staining, 20×).

(0.27MB).

Cumulative evidence supports that when chronic HF develops in the context of CKD both renal hypoperfusion due to low cardiac output and renal congestion due to elevation in cardiac pressures and preload act as major hemodynamic determinants of facilitating the progression of CKD.29 In addition, it is emerging the notion that the failing heart releases cardiokines, which can strongly impact various peripheral organs, as the kidney. For instance, cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family produced and secreted in excess by the failing heart,30,31 has been shown to induce renal fibrosis and dysfunction through direct actions on the kidney.32 Of interest, an inverse association between plasm CT-1 and the estimated GFR has been reported in HF patients, and plasma CT-1 levels were significantly higher in patients with estimated GFR values <60mL/min/1.73m2 than patients with estimated GFR values ≥60mL/min/1.73m2.33

Although nearly a third of patients with stable chronic HF admitted for acute decompensated HF experience worsening renal function during the acute and post-hospitalization phases, its clinical impact in patients already presenting previous CKD has been scarcely evaluated and thus is currently unknown.34 Venous congestion instead of arterial underfilling, plus concomitant exacerbations of neurohormonal activation and inflammation are considered the main drivers of worsening renal function in the setting of acute decompensated HF.35

Almost all patients with ESRD who do not receive RRT develop signs and symptoms consistent with HF, including dyspnea and edema due to inability of the severely diseased kidneys to excrete sodium and water. In addition, the severity of dyspnea in patients on intermittent hemodialysis changes with volume removal. Therefore, the definition of HF by the ESC has limitations when applied to patients with advanced CKD, namely those with ESRD undergoing hemodialysis. To address this gap, the Acute Dialysis Quality Initiative (ADQI) XI Workgroup proposed a functional classification of HF in ESRD, considering the timing of the assessment and periodicity of dialysis to classify HF symptoms in a patient on dialysis (Table 1).37

As recently shown, only systemic congestion related to cardiac dysfunction and not overhydration per se is associated with higher mortality in ESRD patients undergoing hemodialysis.38 Therefore, the dissection of overhydration in cardiac and non-cardiac components in the individual ESRD patient is of primary clinical relevance since it provides prognostic information and might implicate different treatments. Although bioimpedance analysis is a popular tool in the assessment of overhydration in ESRD patients undergoing hemodialysis and the use of lung ultrasound for the detection of pulmonary congestion in HF is growing fastly in clinical practice, the two methodologies present limitations that challenge their ability to distinguish the underlying organ origin of overhydratation.

On the other hand, structural heart disease, for instance LVH, is highly prevalent in patients with CKD, the prevalence increasing progressively with the loss of renal function and thus being present in more than 80% of patients with ESRD. Hence, the ADQI XI Workgroup proposed a new definition of structural cardiac disease in HF for patients with CKD, namely for patients with ESRD, according to the presence of at least one of eight echocardiographic alterations (Table 2).37 In all patients meeting one or more of those echocardiographic criteria, HF class is subsequently defined by the degree of dyspnea and by the response of congestive symptoms to diuretic therapy or dialysis and ultrafiltration (Table 1).37

However, as recently reported,39 echocardiographic criteria proposed by ADQI XI workgroup as a precondition for the clinical staging of HF (Table 2) are virtually omnipresent among CKD patients.11 By labeling a majority of CKD patients as having HF, application of ADQI criteria fails to specifically identify patients at high risk for future cardiac events. Therefore, it seems reasonable to assume the definition of HF proposed either by the ESC until the validity and utility of ADQI criteria have been shown in independent prospective studies.

CKD is one among the numerous causes of elevated NPs that may weaken their diagnostic utility in HF.40 Current data suggest that the cause of elevated NP concentrations in advanced CKD is multifactorial, representing in part a true counter-regulatory response from the heart to the kidney, and not only diminished passive renal clearance, as only 25% clearance of NPs is related to renal filtration.41 Indeed, two recent studies showed that patients with advanced CKD and HF with elevated brain natriuretic peptide (BNP) have very low neprilysin activity and postulated that BNP is a potent endogenous neprilysin inhibitor.42,43

To maintain optimal diagnostic performance, the cut-off concentrations for detecting HF may need to be raised when estimated GFR is <60mL/min/1.73m2.44 Due to the strong correlation between renal dysfunction and age, no additional adjustment seems necessary for N-terminal pro-brain natriuretic peptide (NT-proBNP) once using age-adjusted rule-in cut-offs. For BNP, the effect of renal dysfunction overall is smaller, and increasing the rule-out cut-off to 200pg/mL rather than 100pg/mL seems sufficient. Due to incomplete data, NP testing for HF should be discouraged in patients on dialysis.

High-quality data on prevention of HF in CKD are scarce. Intensive antihypertensive treatment aimed to a tight control of blood pressure has been shown to reduce incident HF in hypertensive patients with CKD.46,47 However, none of the 2 studies was specifically designed to investigate this effect. In patients with CKD and diabetes, treatment with the angiotensin II antagonist (AIIA) losartan,48 or with one sodium glucose cotransporter 2 inhibitor (SGLT2) reduce the risk of first hospitalizations for HF.49–54 However, as AIIAs and SGLT2s exert favorable effects on both blood pressure and glycemia, slow the progression of CKD, and display direct cardioprotective actions, the precise mechanism involved in HF prevention is actually unclear.

In the last 2 decades between half and two-thirds of cardiovascular trials excluded patients with renal dysfunction as assessed by variable degrees of increase in serum creatinine or decrease in estimated GFR.55–57 In particular, patients with stages 4 and 5 CKD were usually excluded from HF trials, often because of concern that the study drug might cause complications (Fig. 3).58 As a consequence, little evidence exists in support of treatment with beta-blockers, renin–angiotensin–aldosterone inhibitors, and sacubitril/valsartan in patients with advanced CKD. Accordingly, and in line with the caution expressed by contemporary HF guidelines regarding the treatment of patients with concomitant advanced CKD with HF drugs, this group of patients is mostly undertreated.

Fig. 3.

Summary of data from published systematic reviews reporting the percent of cardiovascular trials that excluded renal patients (thresholds applied for the exclusion: serum creatinine ≥1.5mg/dL or ≥2.3mg/dL or ≥3mg/dL, or estimated glomerular filtration rate <30mL/min/1.73m2).

(0.1MB).

(Adapted with permission from Ref. 58).

The current evidence on treatment of patients with CKD and HFrEF has been reviewed in detail elsewhere.59,60 In particular, as regards the treatment of patients with advanced CKD and HFrEF, it seems that beta-blockers, angiotensin converting enzyme inhibitors, and sacubitril/valsartan may be used in these patients under surveillance to avoid hemodynamic deterioration, worsening renal function and hyperkalemia. On the contrary, mineralocorticoid receptor antagonists are generally contraindicated in patients with an estimated GFR of <30mL/min/1.73m2 as its use is associated with higher rates of all-cause mortality. As patients with advanced CKD and HF with high BNP levels exhibit very low neprilysin activity,42,43 the use of sacubitril/valsartan to treat these patents is questionable. Similar as for non-CKD patients with HFpEF no evidence-based treatment to reduce mortality outcomes exists for advanced CKD patients with HFpEF.61 To date, only weight reduction, exercise training, and diuretics have been shown to improve exercise tolerance and morbidity in HFpEF patients with or without advanced CKD.61 There are limited controlled data on the optimal pharmacotherapy of HF specific to renal transplant recipients. Management of HF in the context of renal transplant involves integrating available evidence-based therapies for HF in CKD (based on the degree of allograft function) as well as transplant-specific factors such as immunosuppressive agents.62

Managing congestion is a critical point in the treatment of patients with CKD and HF, as it has been demonstrated that a close link exits between congestion and both worsening renal function,63,64 and HF events.65,66 Although diuretics are widely used to counteract sodium and water retention and reduce systemic congestion in HF, their use in patients with CKD requires particular considerations.67 Indeed, an excessive diuretic dose may lead to intravascular volume depletion and add pre-renal insults to established CKD. On the other hand, a diuretic-resistant state, defined as the inability to reduce congestion despite the use of high-dose intravenous loop diuretics, sequential nephron blockade and adequate fluid and sodium restriction may occur more frequently in patients with advanced CKD, than in patients with pre-existing normal kidney function. Therefore, the use of ultrafiltration may be considered.

The findings of a number of trials (Ultrafiltration Versus Intravenous Diuretics in Decompensated Heart Failure [UNLOAD], Continuous Ultrafiltration for Congestive Heart Failure [CUORE], Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure [AVOID-HF] and Cardiorenal Rescue Study in Acute Decompensated Heart Failure [CARRESS-HF]) demonstrate more effective decongestion with ultrafiltration than with pharmacological therapies.68–71 Whereas the UNLOAD, AVOID-HF and CUORE trials consistently showed greater reductions in HF events without greater increases in serum creatinine in the ultrafiltration compared to the diuretic arm, the CARRESS-HF trial showed no differences in 60-day outcomes between the ultrafiltration arm and the pharmacological arm, as well as a higher increase in serum creatinine in the former than in the later.71 Nevertheless, these data from the CARRESS-HF trial must be considered with awareness due to the inherent limitations of any per-protocol analysis as the one performed in this trial.

A meta-analysis on the effect of peritoneal dialysis to relief congestion in patients with CKD and refractory HF showed that in patients with CKD stages 1–4 the treatment was associated with reduction in body weight, improvement in cardiac function, maintenance of eGFR, and no changes in diuretic requirements.72 Thus, peritoneal dialysis can be an option to treat congestion in CKD stages 1–4 patients with refractory HF.

Intradialytic hypotension complicates the management of volume status in ESRD patients undergoing hemodialysis. Intradialytic hypotension may be caused by aggressive ultrafiltration in response to interdialytic weight gain, and can lead to cardiac arrhythmias and myocardial stunning (Fig. 4).73 Myocardial stunning is characterized by delayed recovery of ischemia-induced regional myocardial contractile function after reperfusion despite the absence of irreversible damage and despite restoration of normal flow.74 Myocardial stunning over time is associated with permanent regional LV systolic dysfunction and HF,75 and an increased risk for cardiovascular death.76,77

Fig. 4.

Sequence of events involved in the pathogenesis of myocardial stunning in patients submitted to hemodialysis (ROS, reactive oxygen species; Ca2+, calcium; LV, left ventricular).

(0.2MB).

There is evidence that in patients undergoing hemodialysis and in patients with a kidney transplant the vascular access may be a risk factor for HF as a high arteriovenous fistula flow is associated with LVH, LV dilatation and reduction of LV ejection fraction, as well as with development of pulmonary hypertension and right ventricular dysfunction.78–80 In addition, through its effect as a left-to-right extracardiac shunt, the arteriovenous fistula can increase cardiac workload substantially, and, in certain patients, leads to a high-output state and resultant HF over time.81

In renal transplantation mammalian targets of rapamycin (mTOR) inhibitors, are commonly used to offset the adverse effects of calcineurin inhibitor (CNI). A recent study showed that the supplementary administration of the mTOR inhibitor everolimus combined with a reduced-exposure CNI can reduce cardiac systolic function (i.e., reductions in LV fractional shortening) with no effect on diastolic function in the long term after renal transplantation.82 Whether this implies that the supplementary administration of everolymus for maintenance immunosuppression after renal transplantation should be avoided in recipients with HFrEF before transplantation deserves further study.