Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin–angiotensin–aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio‐ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio‐ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non‐neutralizing ADM‐binding antibody with a half‐life of 15 days. Adrecizumab binds at the N‐terminal epitope of ADM, leaving the C‐terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM‐binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

Kidney transplant recipients (KTR) may be at increased risk of adverse COVID‐19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID‐19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID‐19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID‐19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID‐19. Random‐effects meta‐analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID‐19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%–27%), and AKI, 50% (95% CI: 44%–56%), is high among KTR with COVID‐19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR.

Background Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active (bio‐) ADM in heart failure (HF) are a counteracting response to vascular leakage and tissue oedema. This study aimed to establish the value of plasma bio‐ADM as a marker of congestion in patients with worsening HF. Methods and results The association of plasma bio‐ADM with clinical markers of congestion, as well as its prognostic value was studied in 2179 patients with new‐onset or worsening HF enrolled in BIOSTAT‐CHF. Data were validated in a separate cohort of 1703 patients. Patients with higher plasma bio‐ADM levels were older, had more severe HF and more signs and symptoms of congestion (all P < 0.001). Amongst 20 biomarkers, bio‐ADM was the strongest predictor of a clinical congestion score (r2 = 0.198). In multivariable regression analysis, higher bio‐ADM was associated with higher body mass index, more oedema, and higher fibroblast growth factor 23. In hierarchical cluster analysis, bio‐ADM clustered with oedema, orthopnoea, rales, hepatomegaly and jugular venous pressure. Higher bio‐ADM was independently associated with impaired up‐titration of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers after 3 months, but not of beta‐blockers. Higher bio‐ADM levels were independently associated with an increased risk of all‐cause mortality and HF hospitalization (hazard ratio 1.16, 95% confidence interval 1.06–1.27, P = 0.002, per log increase). Analyses in the validation cohort yielded comparable findings. Conclusions Plasma bio‐ADM in patients with new‐onset and worsening HF is associated with more severe HF and more oedema, orthopnoea, hepatomegaly and jugular venous pressure. We therefore postulate bio‐ADM as a congestion marker, which might become useful to guide decongestive therapy.

No abstract