Mechanisms of impaired renal function in heart failure with preserved ejection fraction
Pathophysiologic mechanisms of cardiorenal interactions
Traditional cardiovascular risk factors | Smoking Obesity Hypertension Diabetes Dyslipidaemia |
Neurohumoral factors | Sympathetic nervous system Renin-angiotensin-aldosterone system |
Inflammation-mediated pathways | Endothelial dysfunction Immune-mediated damage Oxidative stress Coagulation imbalance |
Hemodynamic factors | Ventriculo-arterial uncoupling Elevated central venous pressure Sodium and water retention Hypertension |
Other factors | Natriuretic peptides Anemia Uremic solute retention Calcium and phosphate abnormality Electrolyte and acid-base imbalances |
Neurohumoral mechanisms drive salt and water avidity in HFrEF and consist of activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) [36, 37]. Although both systems are presumed to be operational in HFpEF, there is only modest evidence to support this hypothesis [22, 38].
Chronic inflammation plays an especially important role in CKD and likely leads to the promotion and progression of HFpEF. Many factors contribute to the induction and maintenance of chronic inflammation in CKD, such as SNS activation, oxidative stress, venous congestion, uremic toxins, obesity, and diabetes, as well as nutritional, environmental and genetic factors. Increased inflammation and oxidative stress lead to fibrosis and remodeling in both organs, as well as endothelial dysfunction [36, 37]. High levels of reactive oxygen species (ROS) induce several molecules, such as transforming growth factor (TGF)-β, nuclear factor (NF)-kB and galectin-3, which are involved in inflammation and interstitial fibrosis though upregulation and proliferation of fibroblasts and production of procollagen [36, 37]. Many other conditions common to the patient with CKD, such as Anemia, metabolic changes, hyperphosphatemia, insulin resistance, hyper-homocysteinemia and dyslipidemia may also play important roles in myocardial dysfunction characteristic of HFpEF [3, 30, 35, 39].
Comorbidities in HFpEF and CKD
The term “cardio-metabolic syndrome” describes the clustering of several cardiovascular and renal risk factors, including type 2 diabetes, central obesity, hypertension, and dyslipidemia. Approximately 34% of the adult US population have cardio-metabolic syndrome, which significantly increases the risk for both HFpEF and CKD [40].
The prevalence of diastolic dysfunction in the patients with cardio-metabolic syndrome is reported to be significantly higher compared with the general population [41, 42]. However, the progressive transition into clinical HFpEF remains to be fully studied. Cardiac insulin resistance and impaired insulin signaling are the main molecular mechanisms leading to diastolic dysfunction and clinical HFpEF in patients with CMS [43]. In the early stage, altered substrate use, endothelium-related dysregulation of myocardial perfusion and impaired calcium handling leads to decreased myocardial ATP generation; the consequent repetitive intermittent energy supply and demand mismatch results in diastolic dysfunction. The progression to remodeling processes include myocellular hypertrophy, altered titin, collagen and fibrosis metabolism, accumulation of triglycerides, and advanced glycemic end-products. The subsequent activation of the RAAS and SNS leads to further myocardial cell damage, contractile dysfunction and clinical HFpEF [44, 45].
Numerous studies have also confirmed CMS as an independent risk factor for the development of CKD. Multiple abnormalities that can lead to kidney injury have been identified in CMS patients including insulin resistance, compensatory hyperinsulinemia, inappropriate activation of the RAAS and increased oxidative stress, endoplasmic reticulum stress, coagulability, and impaired fibrinolysis. The combined effects of these conditions in the kidney lead to pressure natriuresis, glomerular hypertension, endothelial dysfunction, and vasoconstriction, as well as matrix proliferation and expansion, which culminate in clinical CKD [46].
Diabetes
Diabetes is a leading cause of CKD and end-stage renal disease; about 50% of patients with diabetes will develop CKD [47, 48]. The prevalence of heart failure in patients with diabetes is high (27–50%) and mostly of the HFpEF phenotype [49, 50]. The rising prevalence of diabetes in young individuals and increasing longevity characterize the changes in the epidemiology of CKD and HFpEF in the United States and worldwide [51].
Diabetes has been shown to be an independent predictor of adverse outcomes in HFpEF patients. Analyses of the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial showed that HFpEF patients with diabetes had more signs of congestion, worse quality of life, and a higher risk of cardiovascular mortality and hospitalization [52]. Similarly, in the Candesartan in Heart failure – Assessment of mortality and Morbidity (CHARM) study, diabetes was associated with an adjusted two-fold increase in cardiovascular death or hospitalization for heart failure and a 80% increase in the hazard of all-cause mortality [53]. The Digital Intervention Group (DIG) trial enrolled patients with a left ventricular ejection fraction >45% and showed that patients with diabetes had an adjusted hazard of 1.68 for heart failure death or hospitalization [54]. An ancillary study of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial showed that apart from a worse clinical presentation, more frequent hospitalizations and less exercise capacity, HFpEF patients with diabetes had more LV hypertrophy and greater LV stiffness [55].
Evidence indicates that the cardio-renal interaction is aggravated by diabetes and this combination is sometimes referred as a “triple threat” [56]. Recently, an analysis of the National Health and Nutrition Examination Survey (NHANES) data revealed that the prevalence of primary renal failure that progressively leads to cardiac dysfunction was significantly higher among individuals with diabetes as compared to those without diabetes after controlling for medical and demographic risk factors [56]. Furthermore, studies have shown the presence of diabetes as an independent risk factor for WRF among HFpEF patients during hospitalization and after 1 year follow up period [13].
Anemia
Anemia is more frequent in HFpEF patients than in HFrEF patients [57–60] and is a common complication of CKD. In the Get with The Guidelines Registry, there was an association between higher ejection fraction and increased prevalence of Anemia [60]. These findings were confirmed in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE–HF) registry and CHARM studies [61, 62]. Several studies have shown Anemia as an independent predictor of mortality in HFpEF [18, 63–65]. Persistent Anemia has also been associated with ventricular hypertrophy and myocyte dysfunction, as well as activation of the RAAS, renal vasoconstriction and diminished eGFR [64–66]. Recently, a post-hoc analysis of the Treatment Of Preserved Cardiac function heart failure with an Aldosterone Antagonist (TOPCAT) study revealed Anemia as an independent predictor of hyperkalemia among HFpEF patients that received spironolactone [67]. The combination of HFpEF, CKD, Anemia, and/or iron deficiency is associated with the progression of CKD and HFpEF and an unfavorable prognosis [3, 68, 69]. Analysis of a large Medicare database did note that the relative risk of death at 2 years was increased by a factor of 1.6 in anemic patients with HFpEF who also had CKD [70].
Several studies have shown CKD as one of the strongest predictors of Anemia in HFpEF patients [64, 71–73]. Inadequate production of erythropoietin has been suggested as one of the main mechanisms of Anemia in the patients with HFpEF with concomitant CKD [73, 74]. Also, 50–70% of HFpEF patients have iron deficiency, which is exacerbated by CKD [9, 66, 72, 75, 76]. Chronic inflammation in HFpEF and CKD may also lead to functional iron deficiency, erythropoietin resistance and bone marrow unresponsiveness to erythropoietin due to intrinsic bone marrow defects [77–79]. Low vitamin D levels are common in CKD patients, and associated with the development of myocardial dysfunction, heart failure, and sudden cardiac death [80–83].
Heart Failure Assessment in a Patient with CKD
Interpretation of various cardiovascular biomarkers in the presence of CKD is complicated by the near ubiquitous presence of concomitant cardiovascular disease. However, heart failure biomarkers such as B-type natriuretic peptide (BNP), N-terminal of the prohormone of BNP (NT-proBNP) and troponin T (TnT) appear to have good predictive value for cardiovascular outcomes in patients with CKD [84–86]. Elevated TnT and NT-proBNP levels correlate with hypervolemia and identify a subgroup of asymptomatic CKD patients with increased cardiovascular mortality [84, 87–90]. A detailed baseline echocardiographic assessment with focus on parameters of diastolic dysfunction should therefore be obtained.
Renal tubular biomarkers are available primarily for research purposes, and have not been generally incorporated into clinical practice. Urinary N-acetyl glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) may reflect tubular injury that may not be apparent from assessments of blood urea nitrogen (BUN), eGFR, or sodium excretion. NGAL seems to play an important role in limiting oxidative damage in acute kidney injury and CKD, and it represents the earliest kidney biomarker of ischemic damage. KIM-1 is a transmembrane glycoprotein, normally undetected in urinary samples, that can be found in the urine after an ischemic or nephrotoxic insult to proximal tubular cells; urinary KIM-1 levels seem to be highly specific for acute tubular necrosis. Such biomarkers may have diagnostic and prognostic value for cardiovascular outcomes in CKD patients [91, 92].
Treatment Options in HFpEF and CKD
Management of heart failure patients with preserved ejection fraction and chronic kidney disease
Initial assessment | Collaborative relationship between cardiologist and nephrologist A detailed patient history and physical examination Baseline electrocardiogram and echocardiogram Renal ultrasound Urinalysis Consider renal biomarkers |
Preventive measures | Blood pressure, cholesterol and glucose management Physical activity Smoking cessation |
Treatment options | Diuretics to achieve euvolemia in patients with volume overload Strong consideration to mineralocorticoid receptor antagonists Consider sacubitril/valsartan Consider pulmonary artery pressure–guided management Statins according to current guidelines Comorbidity management |
Preventative Measures
Primary prevention cannot be overemphasized for both renal and cardiac disease as they share common risk factors. Aggressive and early treatment of comorbidities, such as hypertension, diabetes, and lipids with lifestyle changes and pharmacologic therapies form the cornerstone of prevention. Although there is evidence that inhibition of a stimulated RAAS by angiotensin II receptor blockers (ARB) in CKD patients has cardioprotective effects, the specific impact of such agents on preventing HFpEF in CKD is not clear [93–96].
Clinical trial evidence suggests that drugs that impact sodium excretion reduce incident HFpEF among CKD patents. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the diuretic chlorthalidone, was associated with less incident HFpEF over time in comparison with lisinopril, amlodipine, or doxazosin [97]. It also is notable that spironolactone, a diuretic, lowered the risk of the secondary end-point of heart failure hospitalizations (predominantly attributable to volume overload) in the landmark HFpEF trial, TOPCAT [98].
Dyslipidemia represents another fundamental target to achieve in managing cardiovascular complications in CKD patients. The Study of Heart and Renal Protection (SHARP) represents the largest study of statin therapy in CKD patients and has demonstrated a significant benefit of the combination simvastatin/ezetimibe on major atherosclerotic events, although all-cause mortality was unaffected [99].
Treatment of the complications of CKD may also impact on the development of heart failure, although data for HFpEF in particular are not clear. Cinacalcet is a calcimimetic that is used to treat hypercalcemia and hyperparathyroidism. In the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, a reduction in the number of first heart failure episodes was reported in the cinacalcet group [103]. Hyperphosphatemia, through FGF-23, may also be operational in predisposing CKD patients to heart failure. Di Lullo et al. found that treating pre-dialysis patients with sevelamer hydrochloride, a calcium-free phosphate binder, reduced cardiac valve calcifications and attenuated the decline in kidney function [104]. Gut-derived uremic toxins, such as indoxyl sulphate, a metabolite of dietary tryptophan, may also contribute to vascular stiffness in heart failure; oral charcoal has been used to decrease indoxyl sulphate levels and decrease cardiovascular complications in animal models.
Treatment of the cardiometabolic syndrome may be instrumental in preventing the consequences (e.g. HFpEF) of diabetes, CKD, and obesity. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Canagliflozin Cardiovascular Assessment Study (CANVAS) have revealed a marked reduction in deaths from cardiovascular causes, heart failure hospitalizations, and deaths from any cause when empagliflozin and canagliflozin, respectively, were added to the standard care of patients with diabetes [105, 106]. Similar findings were observed in Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study [107]. Multiple planned and ongoing trials are testing the hypothesis that this class of diabetes agents can be used to treat patients with established HFpEF or HFrEF.
Treatment Options in the Patients with Cardiorenal Syndrome
Treatment of Volume Overload
For the patients presenting with volume overload and not requiring dialysis, diuretics should be used for relief of symptoms. The dose should be adjusted according to the patient’s body weight, symptoms, and electrolyte status. Intermittent use of a thiazide-like diuretic such as metolazone, administered before the dose of a loop diuretic, may be helpful in outpatients with volume overload that is refractory to higher doses of loop diuretics. A careful monitoring is required because of the risk of hypokalaemia, hyponatremia, and WRF. Persistent diuretic resistance may result from impaired diuretic absorption, necessitating intravenous administration of loop diuretics. In the light of the TOPCAT trial, strong consideration should be given to mineralocorticoid receptor antagonists if the eGFR and serum potassium levels are acceptable (e.g. serum creatinine <2.5 mg/dL and serum potassium level <5.0 mmol/L). In cases of diuretic-refractory volume overload, dialysis may be required for relief of patient symptoms. Lowering of extremely elevated central venous pressures (e.g., >15 mmHg) with direct volume removal may in fact improve renal function to the point that dialysis can be discontinued in favor of traditional diuretic management.
Treatment of Hypertension
Hypertension may exacerbate heart failure and predispose patients to other adverse outcomes. The 2017 Joint National Committee recommend target blood pressures of less than 130/80 mmHg in persons with CKD. In those with stage 3 or higher CKD or stage 1 or 2 CKD with albuminuria (>300 mg/day), treatment with an angiotensin-converting enzyme inhibitor is reasonable to slow progression of kidney disease. An angiotensin receptor blocker is reasonable if an angiotensin-converting enzyme inhibitor is not tolerated [108]. The choice of additional agents to achieve blood pressure control should be guided by the presence of coexisting conditions, the patient’s ability to receive the agent without adverse effects, and the effect of the agent on blood pressure.
Treatment of Comorbidities
Patients should be treated with statins according to the usual criteria. Patients with coronary artery disease should receive medical therapies according to current guidelines. Atrial fibrillation should be managed according to current guidelines, which recommend rate control and anticoagulation initially; a trial of rhythm control should be considered if symptoms persist despite adequate rate control [109]. Parenteral iron therapy in iron-deficient HFpEF patients improves symptoms, exercise tolerance, quality of life and reduces readmissions [110]. Observational studies, including a propensity-score–matched analysis and a large meta-analysis have shown lower mortality among patients with HFpEF who have received statins [100–102].
Pulmonary Artery Pressure-Guided Management
In a subgroup analysis from the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial, pulmonary artery pressure–guided management in patients with heart failure showed to reduce hospitalizations for both HFrEF and HFpEF. However, the effect of remote monitoring strategies in the patients with CKD and HFpEF needs to be further explored [111].
Targeting Natriuresis in HFpEF
Modulation of the natriuretic peptide system in patients with HFpEF is appealing. The natriuretic peptide activity appears to be relevant in both HFpEF and HFrEF; elevated BNP levels predict adverse clinical outcomes in both groups of patients [112]. In addition, data suggests that the natriuretic peptide system may also modulate cardiomyocyte stiffness and resting passive tension [113].
Neprilysin Inhibition
Neprilysin is responsible for the breakdown of multiple endogenous vasoactive peptides including bradykinin, natriuretic peptides, and adrenomedullin. The Prospective comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection fraction (PARAMOUNT) study provides phase 2 clinical trial data for the use of sacubitril/valsartan in HFpEF patients. The sacubitril/valsartan group demonstrated a greater decline in NT-proBNP levels, greater improvement in left atrial volumes, no increase in clinical adverse events, and lower levels of high-sensitivity troponin. Furthermore, treatment with sacubitril/valsartan as compared to valsartan resulted in significantly less decline in eGFR and fewer episodes of elevated creatinine or serum potassium [114–116]. In aggregate, these data suggest that ARNIs could potentially slow the progression of CKD, lower NT-proBNP and decrease left atrial volume in HFpEF. The Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial is the subsequent ongoing phase 3 trial of sacubitril/valsartan use in HFpEF. It is aimed to compare the rate of cardiovascular death and heart failure hospitalizations among subjects with New York Heart Association functional class II–IV HFpEF with an ejection fraction ≥45% who are treated with sacubitril/valsartan versus valsartan.
Sodium-Glucose Transporter-2 Inhibitors
The role of sodium-glucose transporter-2 (SGLT-2) inhibitors is also being explored in a number of HFpEF trials, which include patients with and without diabetes. Dapagliflozin in Type 2 Diabetes or Pre-diabetes, and Preserved Ejection Fraction Heart Failure (PRESERVED-HF) is assessing the role of dapagliflozin in lowering NT-proBNP levels in HFpEF without diabetes and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER-HF) is testing the hypothesis that dapagliflozin will lower clinically relevant outcomes and is powered for cardiovascular mortality and heart failure hospitalizations as a primary end-point.
Treatment Pearls for the Case Vignette
The cornerstone of management is the prevention of insidious salt and water overload, e.g. avoidance of TZDs, NSAIDs, and other agents that may stimulate volume overload. Ambulatory hemodynamic monitoring (e.g. CARDIOMEMS) may also be useful in this regard. The use of SGLT2i should also be considered in light of their known natriuretic effects, ability to slow renal insufficiency, and the observed reduction in HF events in randomized trials. Spironolactone has also been associated with a reduction in HF hospitalizations, which may reflect its pleiotropic cardiovascular effects as well as its diuretic action. Weight loss, exercise, and dietary management should be addressed as well.
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