The Role of Activin: The Other Side of Chronic Kidney Disease–mineral Bone Disorder?

Giuseppe Cianciolo; Gaetano La Manna; Irene Capelli; Lorenzo Gasperoni; Andrea Galassi; Paola Ciceri; Mario Cozzolino

Disclosures

Nephrol Dial Transplant. 2021;36(6):966-974. 

In This Article

Abstract and Introduction

Abstract

Chronic kidney disease–mineral bone disorder (CKD-MBD) plays a pivotal role in the excess of cardiovascular morbidity and mortality associated with CKD. There is now a growing awareness that pathways involved in CKD-MBD, like canonical Wnt signalling, are activated from the earliest stages of CKD, playing a role in the development of adynamic bone disease with unknown consequences on vasculature. These changes occur before the classic changes in mineral metabolism: secondary hyperparathyroidism, calcitriol deficiency and hyperphosphataemia. Furthermore, vascular calcification is frequently associated and evolves with decreased bone mineral density and deranged bone turnover, while bone and arterial mineralization share common pathways. Therefore, results of clinical trials focused on mineral bone disorder, aimed at preserving bone and cardiovascular health, are considered unsatisfactory. In order to identify more effective therapeutic strategies, it is necessary to clarify the pathways modulating the cross-talk between bone and vasculature and identify new mediators involved in the pathogenesis of CKD-MBD. Much attention has been paid recently to the role of the transforming growth factor-beta superfamily members in renal disease, and in particular of activin A (ActA). Preclinical studies demonstrate an upgrade of ActA signalling in kidney, skeleton, vasculature and heart during CKD. This supports the idea that an endocrine factor produced in the kidney during renal disease, in addition to promoting the progression of kidney damage, deranges other organs' homoeostasis and participates in CKD-MBD. In this review, we analyse the contribution of ActA to kidney fibrosis and inflammation as well as its role in the development of CKD-MBD.

Introduction

Chronic kidney disease–mineral bone disorder (CKD-MBD) is characterized by changes in mineral metabolism, a high risk of bone fractures, cardiovascular calcification and left ventricular hypertrophy (LVH). CKD-MBD plays a pivotal role in the excess of cardiovascular morbidity and mortality associated with CKD either directly or indirectly, when the single component of this syndrome interacts with several traditional and renal-related cardiovascular risk factors, such as diabetes, inflammation, anaemia, renin–angiotensin–aldosterone system and fluid overload.[1–4]

In recent years, our increasing knowledge of the pathways involved in the onset and progression of CKD-MBD has highlighted that they are rapidly regulated by soluble inhibitors sclerostin and dickkopf-related protein 1 (DKK-1), which could play a pathogenetic role in the development of adynamic bone disease, with unknown consequences on the vascular wall. The expression of sclerostin and DKK-1 is not restricted to the bone but, to varying degrees between the two molecules, takes place in other organs, in particular in the kidney (DKK-1), calcifying vascular smooth muscle cells and aortic valves (sclerostin).[5]

The number of osteocytes expressing sclerostin and circulating sclerostin levels decrease in parallel with the severity of the developing hyperparathyroidism.[5,6]

These phenomena not only help to supersede the old 'intact nephron hypothesis', but they also occur well before the development of the well-known 'triad' of CKD-MBD: secondary hyperparathyroidism, calcitriol deficiency and hyperphosphataemia. However, the puzzle is still incomplete: what is lacking is a common pathogenetic pathway capable of binding together the early alterations previously described. Not surprisingly, the results of clinical trials aimed at preserving bone health and reducing the cardiovascular burden related to mineral and bone disorders are considered unsatisfactory, with possible unfavourable consequences for cardiovascular health. It is largely debated that some features make CKD-MBD even more complex: vascular calcification (VC) is frequently associated and evolves in parallel with decreased bone mineral density (BMD) and deranged bone turnover, while bone and vessel mineralization share common pathways.

In light of this, and in order to identify more effective therapeutic strategies, it is necessary to clarify the pathways modulating this cross-talk between bone and vasculature, as well as to identify new mediators acting in the early stages of CKD and involved in the pathogenesis of CKD-MBD.

Much attention has been paid recently to the role of the transforming growth factor-beta (TGF-β) superfamily members in renal disease, and in particular of activin A (ActA).[7] ActA is an important regulator of the normal development of foetal kidneys. While it is not expressed in healthy adult kidneys, it seems to be involved in the progression of several renal diseases and related complications. Indeed, ActA is an important contributor to fibrosis and inflammation in CKD, also promoting mineral bone disorders, VC and LVH[7,8] Recent studies also support the hypothesis of activin involvement in cardiac hypertrophy,[9] although it is likely that this effect can be mediated by other ligands of the TGF-β superfamily able to cross-link activin receptor Type IIA (ActRIIA) (see below).

Like other members of TGF-β superfamily, activin signalling follows the binding with specific receptors belonging to a serine/threonine kinase family. These receptors were distinguished on the basis of their molecular weights and identified as Type I, of low molecular weight, and Type II, of high molecular weight, designed as ActRIIA and ActRIIB.[10]

Preclinical studies demonstrate activation of ActRIIA signalling in the kidney, skeleton, vasculature and heart during CKD.[11–13] This supports the idea that an endocrine factor produced in the kidney during renal disease, in addition to promoting the progression of kidney damage, also deranges other organs' homoeostasis and participates in the pathogenesis of CKD-MBD. During kidney disease, there is a reactivation of those nephrogenic pathways that we usually encounter in the foetus, during early kidney development. Clearly, the activation of the ActA signalling and Wnt pathway is part of this process. More specifically, TGF-β1 induces the secretion of ActA in renal fibroblasts, mesangial and tubular cells. The following activation of ActRIIA signalling lowers klotho levels and increases both renal and circulating DKK-1, thus proving that Wnt activation happens downstream of the ActRIIA signalling.[11] In preclinical studies, inhibition of ActRIIA signalling is effective in reducing the features of CKD-MBD as well as the Wnt signalling that follows the upregulation of activin in the kidney during the renal repair.[11–13]

In this review, we analyse the contribution of ActA to kidney fibrosis and inflammation as well as its role in the development of CKD-MBD. Furthermore, we analyse experimental studies that show how ActA inhibition, using a ligand trap for the receptor RAP-011, is protective against CKD progression as well as the markers of CKD-MBD in mice models of kidney disease.

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