Kidney Dysfunction and Pulmonary Vascular Disease in Heart Failure with preserved Ejection Fraction

AIMS: Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. METHODS: Consecutively evaluated patients with HFpEF undergoing invasive hemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, hemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. RESULTS: Of 925 patients with HFpEF, 319 (34.5%) had eGFR < 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension.. At rest, reduced kidney function was associated with lower hemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR < 30, p<0.001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR < 30, p<0.001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01-5.59) for eGFR 60-90 to HR 16.77 (95% CI 6.65-42.28) for eGFR < 30 (vs. reference eGFR ≥ 90)]. CONCLUSIONS: Kidney dysfunction in patients with HFpEF is characterized by more severe pulmonary vascular disease at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.