The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes

Abstract

Background and aims: The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes.

Methods: Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A-C), HVPG (6-9 mmHg, 10-15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD.

Results: With increasing PH, hyperdynamic state was indicated by higher heart rates (6-9 mmHg: median 71.0 [IQR 18.0] bpm, 10-15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6-9 mmHg: 103.0 [13.5] mmHg, 10-15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6-9 mmHg: 139.0 [3.0] mmol/L, 10-15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6-9 mmHg vs. 10-15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07-2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70-5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01-2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27-26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36-7.95; p = 0.008). ProBNP levels did not predict clinical outcomes.

Conclusions: The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients.

Keywords: Arginine vasopressin; Ascites; Cirrhosis; Copeptin; Decompensation; Hyperdynamic circulation; Natriuretic peptide; Renin; Renin/angiotensin/aldosterone system; brain; proBNP.

Conflict of interest statement

L.H., M.J., C.D., D.S., R.P., G.S., E.E., R.M., T.S. and S.K. declare no conflict of interest. B.Simbrunner received travel support from AbbVie and Gilead. P.S. received speaking honoraria from Bristol-Myers Squibb and Boehringer-Ingelheim, consulting fees from PharmaIN, and travel support from Falk. D.B. has received travel support from AbbVie and Gilead. B.Scheiner received travel support from Gilead, AbbVie and Ipsen. T.B. received travel support from AbbVie, Bristol-Myers Squibb, and Medis, as well as speaker fees from Bristol-Myers Squibb. M.P.-R. served as investigator for Abbott, Arqle-Daiichi, Bayer, BMS, Boehringer-Ingelheim, Gilead, Imclone, Ipsen, Novartis and Roche, as a speaker and/or advisor for Abbott, Bayer, BMS, Boehringer-Ingelheim, Eisai, Gilead, Ipsen, MSD and Roche, received grant support from Abbott, Bayer, Gilead, MSD and Roche; data and safety monitoring board: BMS, Lilly-Imclone, ONXEO. M.T. received grant support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda, honoraria for consulting from Albireo, Boehringer Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, and 3Regulus, speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept and MSD, as well as travel support from AbbVie, FalkGilead and Intercept. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. T.R. received grant support from AbbVie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche.

© 2021. The Author(s).

Figures

Fig. 1

Plasma levels of renin, proBNP and copeptin stratified for HVPG (a–c) and CTP stage (d–f). a, d–f The borders of the whiskers are the 10th and the 90th percentile. b, c Depiction of plasma levels after outlier exclusion, the borders of the whiskers are the minimum and maximum. HVPG hepatic venous pressure gradient, CTP Child–Turcotte–Pugh, proBNP probrain-type natriuretic peptide; *p < 0.050; **p < 0.010; ***p < 0.001

Fig. 2

Incidence of first decompensation in a–c cACLD patients binary for elevated/non-elevated renin, proBNP and copeptin plasma levels. d–f Incidence of further decompensation in dACLD patients. Time to any first/further decompensation event (development/worsening of ascites or HE, or development of variceal bleeding), death or end of follow-up. Log-rank test is used to determine differences between the groups. proBNP probrain-type natriuretic peptide, ULN upper limit of normal

Fig. 3

a-c Transplant-free mortality in ACLD binary for elevated/non-elevated renin, proBNP and copeptin plasma levels. Transplant-free mortality in d-f cACLD patients and in g-i dACLD patients. Time to death, liver transplantation or end of follow-up. Log-rank test is used to determine differences between the groups. proBNP probrain-type natriuretic peptide, ULN upper limit of normal