Academic Editor: Giuseppe Coppolino
Heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) are global diseases of increasing prevalence and are frequent co-diagnoses. The two conditions share common risk factors and CKD contributes to HFpEF development by a variety of mechanisms including systemic inflammation and myocardial fibrosis. HFpEF patients with CKD are generally older and have more advanced disease. CKD is a poor prognostic indicator in HFpEF, while the impact of HFpEF on CKD prognosis is not sufficiently investigated. Acute kidney injury (AKI) is common during admission with acute decompensated HFpEF, but short and long-term outcomes are not clear. Pharmacological treatment options for HFpEF are currently minimal, and even more so limited in the presence of CKD with hyperkalaemia being one of the main concerns encountered in clinical practice. Recent data on the role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of HFpEF are encouraging, especially in light of the abundance of evidence supporting improved renal outcomes. Herein, we review the pathophysiological links between HFpEF and CKD, the clinical picture of dual diagnosis, as well as concerns with regards to renal impairment in the context of HFpEF management.
Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent
across the world and comprises around half of all patients with clinical heart
failure . Diagnosis of HFpEF is considered in patients who are breathless, do
not have reduced left ventricular ejection fraction (LVEF) (commonly taken as
While common risk factors for HFpEF and CKD are clearly identified, including diabetes, hypertension and obesity, a number of pathophysiological processes contribute to the interplay between cardiac and renal dysfunction (Fig. 1), which are not completely understood.
Summary of pathophysiological processes linking heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). HFpEF and CKD share common risk factors including diabetes, hypertension and obesity, but also a number of pathophysiological processes contribute to the interplay between cardiac and renal dysfunction.
Myocardial fibrosis is the key pathology seen in HFpEF , with resulting cardiac structural and functional abnormalities which can potentially affect kidney function. Right ventricular (RV) dysfunction has been implicated in the development of renal impairment in patients with heart failure with a reduced ejection fraction (HFrEF) for some time . In HFpEF worse RV indices are seen in association with CKD, often with poorer prognoses [6, 7, 8]. Left ventricular (LV) hypertrophy without dilatation is a further cardinal feature of HFpEF, and increased LV mass predicts progression of renal disease in community cohorts at high risk for heart failure [9, 10]. Left atrial enlargement and diastolic dysfunction are common in HFpEF [11, 12, 13], and impaired left atrial function predicts renal function decline in patients seen in a tertiary cardiology clinic with dyspnoea  and left atrial strain predicts progression of renal disease in patients with CKD , although causality is uncertain.
Pulmonary hypertension is seen in the majority of patients with HFpEF , largely thanks to metabolic insult in addition to pressure-related injury . Haemodynamic markers of pulmonary hypertension (elevated transpulmonary gradient, pulmonary vascular resistance, and diastolic pulmonary gradient) were associated with increased mortality and increased cardiac hospitalisations in patients with HFpEF from a large cohort undergoing right-heart catheterisation . Pulmonary hypertension is recognised as increasing the risk of poorer outcomes after kidney transplantation [9, 10, 18, 19].
Furthermore, increased central venous pressure in HFpEF results in reduced glomerular capillary blood flow and raised interstitial and tubular pressures within the kidney . On top of that, patients with HFpEF commonly have chronotropic incompetence, which is independently associated with reduced glomerular filtration rate (GFR) , likely due to renal hypoperfusion. Novel haemodynamic parameters may offer insights into further pathophysiologic mechanisms .
In the opposite direction, renal impairment is an independent risk factor for development of HFpEF . Indeed, in a porcine model CKD via 5/6 nephrectomy induced development of HFpEF , while human data suggest that advanced CKD is associated with a variety of cardiac structural abnormalities . Patients with CKD have impaired sodium handling and fluid overload, directly contributing to venous congestion, which is more pronounced in the advanced stages of the disease. Up to date understanding makes central the importance of systemic inflammation in HFpEF pathophysiology, leading to coronary microvascular endothelial inflammation and dysfunction, and ultimately to stiff cardiomyocytes and diastolic LV stiffness via reduced nitric oxide signalling . Traditional HFpEF co-morbidities such as diabetes and hypertension contribute to the inflammation, and CKD itself is well-recognised as a pro-inflammatory state . Obesity is over-represented in older patients with HFpEF and adipose tissue contributes to a number of pathophysiological pathways increasing inflammation and oxidative stress, potentially leading to both cardiac and renal dysfunction . Further, there is some evidence that increased fibroblast growth factor 23 levels in CKD induce LV hypertrophy , while enhanced sympathetic activation in CKD can contribute to heart failure , with increased neurohormonal activation noted in both CKD and pulmonary hypertension being associated with vascular remodelling and worse outcomes .
It is also worth considering that in a minority of patients HFpEF may be caused by specific diseases, some of which, such as amyloidosis, may affect the kidneys concurrently.
The European Society of Cardiology 2019 consensus statement on the diagnostic
criteria for HFpEF includes the definition of a “preserved” LVEF as
|Trial (intervention)||HFpEF LVEF criteria||Mean LVEF of HFpEF participants||Relevant sub-group analysis|
|CHARM-Preserved (candesartan)||Not specified, but 35.5% of participants had LVEF 41–49%||Specific consideration of group with LVEF 40–49% showed benefit of treatment with regard to primary outcome: HR 0.76 (95% CI 0.61–0.96; p = 0.02)|
|TOPCAT (spironolactone)||57.10%||Interaction between continuous LVEF and treatment for primary outcome: p = 0.046; Interaction between continuous LVEF and treatment for HF hospitalisations: p = 0.039|
|PARAGON-HF (sacubitril-valsartan)||57.60%||HR for events in sacubitril-valsartan arm in group with LVEF |
|HR in group with LVEF |
|RELAX (sildenafil)||61.3% (calculated from presented data)||-|
|EMPEROR-Preserved (empagliflozin)||54.30%||Treatment benefit with respect to primary composite in groups with lower LVEF:|
CKD is commonly seen in HFpEF, although estimated prevalence varies. Most
studies report CKD as estimated GFR (eGFR)
Multiple studies have shown that HFpEF patients with CKD have higher rates of traditional cardiovascular risk factors such as hypertension and diabetes than those without [6, 7, 33, 37], and the clinical picture of patients with HFpEF and co-existing CKD is generally that of more advanced disease.
HFpEF encompasses a broad range of clinical characteristics, possibly resulting from the multiple pathophysiological mechanisms, making understanding and prediction of renal involvement somewhat challenging. Phenomapping has allowed for distinct clusters of HFpEF patients to be classified. The first published study found that the cluster more likely to have CKD are older and have most severe electrical and myocardial remodelling, pulmonary hypertension, and RV dysfunction .
The cohort with CKD (eGFR 20–60 mL/min/1.73 m
A prospective study of 299 HFpEF patients (with LVEF
HFpEF is also common in patients with end-stage renal disease (ESRD) managed
with maintenance haemodialysis (HD) or peritoneal dialysis (PD). Antlanger
et al.  reviewed a cohort of 105 ESRD patients undergoing regular HD
in Vienna, Austria, and found that 57% fulfilled the definition criteria of
HFpEF (including LVEF
In a Chinese cohort of ‘advanced CKD’ patients – in practice a mix of CKD stage
4 and ESRD, including those on HD and PD – the HFpEF group (inclusion LVEF
Overall, patients with concomitant HFpEF and CKD appear to be characterised by a more severe disease burden as a result of both the presence of shared for the two conditions risk factors as well as the added impact of the two conditions.
It has been recognised for some time that prognosis is worse for HFpEF patients with concomitant renal dysfunction. Studies of patients admitted with acute decompensation of HFpEF report rates of baseline CKD far higher than those seen in the general HFpEF population, of up to 82% .
In a cohort of 397 patients identified post-discharge following hospital
admission with symptomatic HFpEF, the pheno-group with higher rates of CKD had
increased mortality and hospitalisation rate than those without . The
diagnostic cut-off for LVEF was
The Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved
Ejection Fraction (PARAGON-HF) trial compared treatment with sacubitril/valsartan
versus valsartan in 4796 patients with HFpEF over a median follow-up period of 34
months. Participants were all aged
In line with PARAGON-HF findings, the analysis of the 1767 patients in the
Americas group in the Treatment of Preserved Cardiac Function Heart Failure with
an Aldosterone Antagonist Trial (TOPCAT) study highlighted an independent inverse
relationship between eGFR and many clinical outcomes, including all-cause
mortality and heart failure hospitalisations . Again, patients with an eGFR
Proteinuria or albuminuria are signs of abnormal kidney function and can often
be present before GFR drops. As such, a proportion of patients with CKD may be
overlooked if the only criteria used to identify them is eGFR
Information regarding prognosis in patients with concomitant ESRD and HFpEF is
limited. In one small study of patients on regular HD, the presence of HFrEF was
strongly associated with a higher risk of cardiac death and/or hospitalisation
for cardiovascular reason adjusted hazard ratio (HR) 3.24; 95% CI 1.08–9.75;
p = 0.037) but for HFpEF (including LVEF
Overall, renal impairment appears to be associated with a worse prognosis in HFpEF patients. There is not specific data regarding the prognostic implications of HFpEF on CKD progression or mortality; nevertheless, a number of echocardiographic features typically seen in HFpEF have been associated with poorer renal outcomes and/or mortality in CKD .
Diagnosis of co-existing HFpEF and CKD can proceed along usual pathways, although in a community setting without access to echocardiography, then N-terminal-pro brain natriuretic peptide (NT-proBNP) is commonly used in cases of suspected heart failure, and a higher threshold is needed for diagnosis in patients with CKD .
Clinicians caring for patients in the advanced stages of CKD will be mindful that typical symptoms and signs such as shortness of breath, fatigue and peripheral oedema commonly occur in either condition, or distinguishing the underlying cause with dual pathology can be challenging. They should also be aware that the creation and use of upper limb arteriovenous fistulae and grafts (for dialysis in end stage renal disease) is associated with the development of right ventricular remodelling and dysfunction , potentially contributing to HFpEF.
There are similarities in the management of patients with HFpEF and CKD, including iron replacement in deficiency, optimal treatment of associated co-morbidities (particularly weight management, and control of diabetes and hypertension), and diuretics to treat fluid overload. Loop diuretics are the treatment of choice for troublesome peripheral oedema in both conditions, but the threshold dose is typically higher in CKD than in patients with normal renal function. Diuretic use in CKD may be associated with greater decline in renal function, even after other variables including hydration status and baseline eGFR are taken into account , and a careful balance is often needed.
Co-existing major coronary artery disease and atrial fibrillation should be
managed, but specific treatment options for HFpEF are limited, especially in
comparison to HFrEF. Treatments that are effective in HFrEF such as
renin-angiotensin-aldosterone system (RAAS) inhibitors and vasodilators have not
shown the same benefit, e.g., in the HFpEF I-PRESERVE and CHARM-Preserved trials
[53, 54, 55, 56], likely reflecting the differing underlying pathophysiologies. A
re-analysis of CHARM participants with LVEF 40–49% suggested outcome benefits
for candesartan in this range, but not when LVEF
|Class of agent||Effect on HFpEF||Renal considerations|
|Loop diuretics||Symptomatic benefit when treating fluid overload||Possible association with greater decline in renal function|
|Renin-angiotensin-aldosterone system inhibitors||Prognostic benefit not demonstrated [54, 55]||Can potentially slow CKD progression via blood pressure control and reduction of proteinuria;|
|May precipitate renal hypoperfusion;|
|Risk of hyperkalaemia|
|Mineralocorticoid receptor antagonists (MRAs)||Mortality benefit not demonstrated ||Reduction of albuminuria ;|
|Lower risk of composite endpoint of cardiovascular mortality, heart failure hospitalisation or aborted cardiac arrest in those with estimated GFR 30–60 mL/min/1.73 m|
|May be associated with reduced hospitalisations for heart failure ||Risk of adverse events including hyperkalaemia and worsening renal function |
|Sacubitril-valsartan||No reduction in composite endpoint of death from cardiovascular causes or hospitalisations for heart failure ||No differing treatment effect between those with eGFR 30–60 or |
|Reduction in renal composite endpoint (|
|Phosphodiesterase-5 inhibitors||No clinical benefit ||Associated with worsening renal function |
|Sodium zirconium cyclosilicate Patiromer||No specific benefits||Effective treatment for hyperkalaemia [74, 75]|
|Heart failure patients included in trial [72, 73]|
|May allow other medications to be tolerated|
|Sodium-glucose cotransporter 2 inhibitors||Reduction in cardiovascular mortality and hospitalisations for heart failure ||Promising results in CKD without heart failure ;|
|DELIVER trial ongoing|
|eGFR, estimated glomerular filtration rate; MRA, mineralocorticoid receptor antagonist; CKD, chronic kidney disease.|
MRAs improve prognosis in HFrEF. Initial results of the (Treatment of Preserved
Cardiac Function Heart Failure With an Aldosterone Antagonist) TOPCAT study of
3445 patients with symptomatic HFpEF (LVEF
Treatment with MRAs may be problematic for patients with CKD because of adverse
events, particularly hyperkalaemia; a quarter of the Americas cohort enrolled in
TOPCAT developed a potassium
A later analysis of the 1175 TOPCAT participants with a recorded baseline urine
albumin: creatinine ratio (uACR) showed that increased uACR was associated with
worse clinical outcomes, with no difference between the spironolactone and
placebo arms. However, the group treated with spironolactone had reduced
albuminuria after one year, and reduction in albumin excretion was associated
with a reduction in heart failure hospitalisation and all-cause mortality .
Naturally there was an association between increased albuminuria and CKD.
Analysis of the same cohort by kidney function (eGFR 30–45, 45–60,
The primary outcome in the PARAGON-HF trial comparing sacubitril-valsartan with
valsartan alone in 4796 patients with HFpEF was a composite of total
hospitalisations for heart failure and death from cardiovascular causes, and
rates were not significantly different between the two groups . A pooled
analysis with data from the PARADIGM-HF trial (inclusion LVEF
The rate ratio in PARAGON-HF appeared to favour sacubitril-valsartan in
participants with a baseline eGFR
A sub-group analysis of PARAGON-HF looked at the findings according to
background of MRA therapy. Jering et al.  found potential value in
combining treatment with MRA and sacubitril/valsartan in patients with HFpEF. The
proportion of patients reaching the secondary outcome renal composite endpoint
Another treatment that has been considered is sildenafil, a phosphodiesterase-5
inhibitor. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and
Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial
compared sildenafil with placebo in 212 HFpEF patients (with LVEF
Ultrafiltration has been considered for management of advanced heart failure without ESRD. Grossekettler et al.  have shown symptomatic improvement and reduced hospitalisations in patients with undifferentiated (but mean EF 31%) heart failure and non-end-stage CKD treated with peritoneal ultrafiltration. Subsequent sub-group analysis demonstrated that the beneficial effects were greater among those with HFpEF than HFrEF . The CARESS-HF trial investigated venous ultrafiltration as treatment for acute decompensated heart failure (any EF) with worsened renal failure and found no benefits but increased adverse events compared to standard diuretic treatment .
Maintaining safe potassium levels is a particular concern for patients with
HFpEF and CKD, and use of various treatments under consideration has had to be
tempered as a result. Interestingly, potassium abnormalities appear to pose a
greater threat for patients with HFpEF than HFrEF . Hyperkalaemia is common
in advanced CKD, and extreme abnormalities of potassium in either direction can
cause arrhythmias. There appears to be a U-shaped relationship between potassium
and mortality, with normokalaemia offering the best prognosis. Ferriera
et al. , conducting a post-hoc analysis of the PARAGON-HF
trial, observed that in patients with HFpEF taking either valsartan or
sacubitril/valsartan those with potassium outside the range 4–5 mmol/L had
higher rates of heart failure hospitalisations. Hypokalaemia carried a greater
risk than hyperkalaemia, and was also associated with increased risk of death
within the follow-up period for patients with CKD. Patients with potassium
The recent emergence of patiromer and sodium zirconium cyclosilicate (SZC), as effective treatment strategies for hyperkalaemia, should allow more patients to start or remain on medications such as RAAS inhibitors or MRAs. These are newer potassium binders with improved efficacy and safety profile, compared to their predecessor sodium polystyrene sulfonate. The two work at different sites in the gastrointestinal tract resulting in increased potassium faecal excretion and, hence, reduced serum potassium levels. Given their individual characteristics it has been proposed that patiromer might be preferable for the management of chronic hyperkalaemia with SZC a better option for the acute management of hyperkalaemia .
Both agents appear efficacious and reasonably well tolerated in patients with heart failure (with any EF) and though there is no available evidence in relation to HFpEF specifically, there is no reason that their effects would be compromised [72, 73, 74].
Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer hope to improve
prognosis for many patients with HFpEF and CKD, especially those with diabetes.
There is robust evidence supporting a prognostic benefit from SGLT2 inhibition in
HFrEF which is independent of the presence of diabetes [78, 79, 80], and as a result
empagliflozin and dapagliflozin have recently been endorsed in the management of
HFrEF by international organisations [81, 82]. At the same time, SGLT2 inhibitors
have been associated with improved renal outcomes in both high cardiovascular
risk and CKD cohorts, an effect which, again, extends to non-diabetic populations
[83, 84, 85]. Recently, the results of EMPEROR PRESERVED were published  making
empagliflozin the first pharmacological agent ever reported to confer a
prognostic benefit in HFpEF. This trial enrolled 5988 patients with NYHA class
II–IV heart failure and an EF of more than 40%, assigned to receive
empagliflozin or placebo on top of standard therapy. Patients on empagliflozin
had a lower risk of the primary outcome of cardiovascular death or
hospitalisation for heart failure with a HR of 0.79 (95% CI 0.69–0.90;
Other potential pharmacological agents to be explored include growth hormone-releasing agonists, which appear to improve diastolic function in a swine model of CKD-induced HFpEF . The current Optimize-HFpEF trial is exploring the impact of systematically screening for and treating co-morbidities seen commonly in HFpEF, working from the hypothesis that these co-morbidities, including renal, contribute to the widespread pro-inflammatory state that leads to development on HFpEF . Unfortunately, specific treatments for CKD caused by the most common aetiologies (hypertension and diabetes) are lacking, although of course the underlying conditions may be optimally managed. There may also be potential for future development of treatment options that specifically target inflammation and the subsequent pathways to fibrosis , or the various pathways by which CKD leads to coronary microvascular dysfunction . Further, as noted when considering specific treatments above, trials have been undertaken adopting a range of LVEF thresholds, and as such results must be interpreted with a degree of caution when extrapolating to specific patient populations. Stark dichotomisation of HFpEF and HFrEF may not necessarily be helpful, especially given HFpEF phenotype heterogeneity.
Acute Kidney Injury (AKI) is defined by a sudden deterioration in renal function with rapid increase in serum creatinine or decrease in urine output , and is common in patients admitted to hospital for treatment of acute decompensation of heart failure (ADHF). A large registry study in the USA found that AKI complicated 20% of two million admissions with ADHF patients without underlying CKD , and slightly more commonly seen in HFrEF than in HFpEF.
In a pooled analysis of four studies of HFpEF patients admitted to hospital with
ADHF, baseline renal dysfunction, defined as eGFR
It is difficult to be sure whether transient creatinine changes during diuresis reflect changing haemodynamics within the glomerulus or true organ damage. An analysis of undifferentiated (i.e., both HFrEF and HFpEF) patients undergoing aggressive diuresis during ADHF did not find associations between worsening renal function and recognised markers of renal tubular injury including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) . Worsening renal function during ADHF is associated with echocardiographic signs of increased right ventricular free wall thickness and right ventricular dysfunction .
AKI in general is associated with future development of CKD , although
long-term prognosis following AKI in HFpEF is not yet demonstrated. While in an
undifferentiated cohort admitted with ADHF worsening renal function was
associated with significantly worse in hospital mortality, complication rate and
length of stay , in a pure HFpEF cohort of 332 patients (including with and
without CKD) 30 day outcomes were not affected by development of AKI .
Patients with HFpEF with normal baseline renal function admitted with ADHF who
developed AKI had an increased in-hospital mortality: 4.9% vs. 1.6%, adjusted
odds ratio (OR) 3.21, p
Cardiac catheterization, commonly used for diagnostic and therapeutic reasons, carries a risk of post-procedure AKI. While there are clear recommendations for pre-procedure hydration to mitigate AKI risk in patients without heart failure, and at a lower rate for those with HFrEF, the little evidence available to date suggests that over-hydration is not helpful for those with HFpEF .
HFpEF and kidney dysfunction commonly co-exist, and cardiologists, nephrologists and community physicians will care for patients with both with increasing frequency. They commonly share multiple risk factors and specific pathophysiological features of each contribute to the development and progression of the other, to the extent that they may often be seen as different manifestations of the same disease spectrum. Patients with a dual diagnosis of HFpEF and CKD appear to bear a more severe clinical picture and a worse prognosis. Neither CKD as caused by diabetes/hypertension/obesity nor HFpEF currently have proven treatments beyond control of co-morbidities and management of symptoms, and prevention and limitation of progression are key. The emerging evidence of a potential promising role of SGLT2 inhibitors in the management of HFpEF, on the background of their already demonstrated renal prognostic benefit may significantly add to the limited existing strategies, and possibly provide valuable insights on disease pathophysiology, should targeted research be taken forward.
JJ wrote the draft. EL conceived the idea and edited. EA edited the final version of the manuscript. All authors read and approved the final version of the manuscript.
This study received no external funding.
The authors declare no conflict of interest. Eirini Lioudaki and Emmanuel Androulakis are serving as the Guest editor of this journal. We declare that Eirini Lioudaki had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Giuseppe Coppolino.