Recent years have seen remarkable progress in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) with approved regimens, many of which include vascular endothelial growth factor (VEGF) inhibitors (1). Management of adverse events including hypertension and proteinuria caused by VEGF inhibitors is critical for improving patient safety and treatment outcomes (2).

ARNI, a combination of sacubitril and valsartan in a 1:1 molar ratio, has demonstrated significant efficacy in managing hypertension (3,4). In spontaneously hypertensive rats (5), ARNI showed a stronger antihypertensive effect than valsartan, an angiotensin receptor blocker (ARB). In hypertensive patients, ARNI showed a significantly stronger antihypertensive effect than placebo (6) and a stronger antihypertensive effect than valsartan (7). It was approved for the additional indication of hypertension (8).

In the PARADIGM-HF study, angiotensin-converting enzyme inhibitors (ACEI) suppressed the decline in the estimated glomerular filtration rate (eGFR) over time in patients with heart failure (9). A sub-analysis of the PARAMOUNT trial reported that it also prevented secular decline in eGFR better than valsartan (9). These findings indicate that ARNI may help reduce urinary albumin levels in patients receiving atezolizumab plus bevacizumab (Atez/Bev) for HCC. However, its efficacy in this specific population has not been previously reported.

In this study, we aimed to investigate the effects of ARNI on antihypertensive control and urinary albumin levels in patients with hypertension undergoing Atez/Bev treatment for HCC.

Patient selection and data collection. Of the 57 patients with unresectable HCC treated with Atez/Bev, ten patients with unresectable HCC who had poorly controlled hypertension by ARB during treatment with Atez/Bev combination therapy were included in the study. The effects of ARNI on antihypertensive control and urinary protein levels were retrospectively examined in these patients. Proteinuria was evaluated by the urine protein/ creatinine ratio (UPCR). Brain natriuretic peptide (BNP), eGFR, and UPCR were compared before switch and 3 months after switching from ARB to ARNI.

Ethics approval and informed consent. The study protocols were approved by the Institutional Review Board of Saiseikai Niigata Hospital (approval no.: E05-13) and were conducted in accordance with the principles of the Declaration of Helsinki (as revised in 2013). Prior to participation in this study, written informed consent was obtained from all patients.

Statistical analysis. Categorical variables were expressed as numbers, and continuous variables as means and standard deviation. Differences in quantitative values were analyzed using a Mann-Whitney U-test. All statistical analyses were performed using EZR (Saitama Medical Centre, Jichi Medical University, Shimotsuke, Japan), a graphical user interface for R version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria) (10). All p-values were derived from two-tailed tests, with statistical significance set at p<0.05.

Ten of 57 patients during Atez/Bev therapy for unresectable HCC (uHCC) developed hypertension and proteinuria. Five males and five females, mean age 76.6 years. One patient had a background of hepatitis B virus (HBV), 4 patients had hepatitis C virus (HCV), and 5 patients were non-HBV/non-HCV infected (Table I). Blood pressure remained poorly controlled despite ARB use during Atez/Bev therapy, with an average treatment duration of 18.8 courses (Table I). Following the switch to ARNI, eGFR significantly improved from a mean of 52.87 to 59.46 ml/min/1.73 m² (p=0.006), and UPCR decreased from a mean of 2.31 to 0.79 (p=0.025) (Table II).

Among these 10 patients, five switched to ARNI after UPCR exceeded 2, including two males and three females. The mean age of these patients was 78.6 years, and they had a background of HBV (n=1), HCV (n=3), non-HBV/non-HCV (n=1) (Table III). In this subgroup, eGFR improved significantly from a mean of 50.54 to 58.62 ml/min/1.73 m² (p=0.026) and UPCR decreased from a mean of 3.99 to 1.13 (p=0.025), allowing continuation of treatment with Bev (Table III and Table IV).

As a representative case, a 76-year-old woman presented with HBV-related HCC in September 2021; it was her first occurrence of HCC. Intrahepatic tumors were controlled using transarterial chemoembolization (TACE)/radiofrequency ablation (RFA), and Atez/Bev therapy was initiated. During Atez/Bev therapy, the UPCR exceeded 2.0 between courses 9 and 11 and for this reason the patient skipped Bev during these courses. Similarly, the UPCR exceeded 2.0 and the patient was skipped again Bev in courses 14 and 15. However, after her medication changed from ARB to ARNI for hypertension and proteinuria control, UPCR fell below 2.0 and Atez/Bev combination therapy continued from 16^th course onwards (Figure 1).

In this study, switching from a standard-dose ARB to ARNI improved eGFR and significantly reduced UPCR in patients with hypertension undergoing Atez/Bev treatment for HCC, enabling continued Bev therapy. The major adverse events reported in the IMrave150 study for Atez/Bev therapy included hypertension (29.8%), proteinuria (20.1%), fatigue (20.4%), increased AST (19.5%), pruritus (19.5%), infusion reaction (11.2%), diarrhea (18.8%), and increased ALT (14.0%) (11).

Several mechanisms contribute to anti-VEGF-induced hypertension, including inhibition of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, increased endothelin-1 levels, salt sensitivity of tissue macrophages, reduced skin capillary density, and renal dysfunction (12,13). Currently, there are no standardized recommendations for hypertension or proteinuria management in anti-VEGF therapy. ARBs and other renin-angiotensin system inhibitors have superior antiproteinuric effects; in an observational study of colorectal cancer patients, treatment with ARBs with Bev was associated with a better prognosis and higher antitumor effects compared to treatment only with Bev (14). In animal experiments, anti-VEGF agents were associated with better prognosis and higher antitumor effects with ARB (15). Cardiac dysfunction induced by anti-VEGF agents was suppressed by renin-angiotensin system inhibitors (15).

Although the mechanism of VEGF-associated proteinuria has not been clarified, VEGF is involved in the maintenance of renal glomerular capillary endothelial cell function (16). VEGF inhibitors may cause swelling and loss of glomerular endothelial cells, resulting in impaired capillary repair, reduced filtering function, and protein migration in the urine. VEGF also induces the production of vasodilating nitric oxide (NO) and prostaglandin I2 (PGI2) in vascular endothelial cells, and the use of VEGF inhibitors is thought to cause hypertension and glomerular dysfunction, resulting in proteinuria (17).

In hypertensive patients, ARNI has been reported to have a significant antihypertensive effect compared to placebo and a stronger antihypertensive effect compared to valsartan. ARNI inhibits natriuretic peptide degradation while acting as a natriuretic and vasodilator (6,7). It also causes sympathetic nervous system suppression (18), which may lead to stronger antihypertensive effects. ARNI has also been reported to be more effective in reducing eGFR levels in patients with heart failure, compared to ACEIs and ARBs (8,9). Atrial natriuretic peptide (ANP) increases renal blood flow through vasodilation in the kidneys, which may contribute to the suppression of eGFR decline (19).

In this study, we report for the first time that switching from ARB to ARNI reduced UPCR in patients with HCC and hypertension from Atez/Bev treatment. Switching from a standard-dose ARB to an ARNI (sacubitril/valsartan) results in a reduction in blood pressure, which may be one of the reasons behind the reduction in UPCR. ARNI influences intraglomerular pressure and eGFR by increasing renal blood flow by dilating afferent arterioles (20) and efferent arterioles are dilating to counteract flow (20). Natriuretic peptides angiotensin II activity suppresses the increase in intraglomerular pressure, which is assumed to be renoprotective (21). In addition, natriuretic peptides relax mesangial cells that constitute the glomerulus, increasing the surface area of vascular filtration, which is assumed to expand the range of filtration and increase eGFR. These mechanisms indicate that it would be highly effective for the treatment of hypertension-associated renal dysfunction and proteinuria. However, evidence on the association of hypertension and proteinuria with pharmacotherapy for HCC is insufficient, and further case accumulation and analysis are important. Though the underlying mechanism has not yet been identified, ARNI may be an option for lowering blood pressure in patients with HCC and Atez/Bev hypertension, considering its ability to reduce UPCR. HCC patients are now also aging, therefore the number of cases with impaired renal function is increasing. In chronic kidney disease (CKD) patients, ARNI has also been shown to reduce proteinuria, and this effect is more pronounced in patients with poorly controlled blood pressure (22). Furthermore, in hypertensive patients on dialysis (especially hemo-dialysis), ARNI was more effective than ARB and had a similar safety profile (23).

Switching from ARBs to ARNI is a treatment option that can safely intensify 24-hour antihypertensive therapy (24). An inverse correlation between reactive hyperuricemia index and UPCR during Atez/Bev has also been reported (25). In clinical practice, the most common adverse effect is proteinuria, followed by hypertension (26). Management of proteinuria and hypertension is important to perform long-term treatment with Atez/Bev. The continuation of Bev therapy may also contribute to the efficacy of Atez/Bev therapy, improving patient prognoses. This study suggests that ARNI may be the first choice for controlling hypertension and proteinuria during Atez/Bev HCC.

Study limitations. First, this is a retrospective study with inherent unmeasured bias. Second, the sample size was small from a single center. It should be noted that the possibility of antihypertensive effects as a mechanism of reduction in UPCR could not be ruled out. The effect of age on UPCR also could not be examined in this study due to the small number of patients. Further long-term investigations are required to evaluate the effects of concomitant medications, involving broader patient groups across multiple research centers.

In patients with HCC and hypertension receiving Atez/Bev therapy, switching to ARNI demonstrated effective blood pressure control, eGFR preservation, and UPCR reduction. These findings suggest that ARNI may serve as a superior antihypertensive agent compared to conventional ARBs for patients with HCC experiencing hypertension due to Atez/Bev treatment.

The Authors declare no conflicts of interest related to this study.

Conceptualization: Toru Ishikawa; Data Curation: Toru Ishikawa; Formal Analysis: Toru Ishikawa; Investigation: Toru Ishikawa, Ryo Sato, Hiroki Natsui, Takahiro Iwasawa, Masahiro Ogawa, Yuji Kobayashi, Toshifumi Sato, Junji Yokoyama and Terasu Honma; Methodology: Toru Ishikawa; Project Administration: Toru Ishikawa; Resources: Toru Ishikawa; Software: Toru Ishikawa; Visualization: Toru Ishikawa; Writing - Original Draft: Toru Ishikawa; Writing - Review & Editing: Toru Ishikawa, Ryo Sato, Hiroki Natsui, Takahiro Iwasawa, Masahiro Ogawa, Yuji Kobayashi, Toshifumi Sato, Junji Yokoyama, and Terasu Honma.

The Authors would like to thank Editage (www.editage.com) for providing English language editing services.

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.