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Emerging role for fetuin-A as contributor to morbidity and mortality in chronic kidney disease

2007; Elsevier BV; Volume: 72; Issue: 2 Linguagem: Inglês

10.1038/sj.ki.5002355

1523-1755

Rajnish Mehrotra,

Iron Metabolism and Disorders

Vascular calcification (VC) is an important reason for the high burden of vascular disease among chronic dialysis patients. Chronic kidney disease (CKD) is associated with increased promoters and decreased inhibitors of VC. The circulating levels of fetuin-A, a well-described inhibitor of calcification, regulate the cell-dependent process of osteogenesis. It is not surprising that the low circulating fetuin-A levels are associated with a greater prevalence and/or severity of VC and increased risk for all-cause and cardiovascular mortality. However, high circulating fetuin-A levels appear to induce insulin resistance and, in non-dialyzed subjects with diabetic nephropathy, are directly related to VC burden. These findings underscore the need to further clarify the multiple, systemic effects of fetuin-A and its role in health and various stages of CKD. Vascular calcification (VC) is an important reason for the high burden of vascular disease among chronic dialysis patients. Chronic kidney disease (CKD) is associated with increased promoters and decreased inhibitors of VC. The circulating levels of fetuin-A, a well-described inhibitor of calcification, regulate the cell-dependent process of osteogenesis. It is not surprising that the low circulating fetuin-A levels are associated with a greater prevalence and/or severity of VC and increased risk for all-cause and cardiovascular mortality. However, high circulating fetuin-A levels appear to induce insulin resistance and, in non-dialyzed subjects with diabetic nephropathy, are directly related to VC burden. These findings underscore the need to further clarify the multiple, systemic effects of fetuin-A and its role in health and various stages of CKD. Maintenance dialysis patients experience considerable morbidity and have a high mortality rate, particularly from vascular diseases. Accelerated vascular calcification (VC) is but one of the several important pathobiologic mechanisms that contribute to the high burden of vascular disease in dialysis patients. In the setting of chronic kidney disease (CKD), VC is more severe and prevalent in both the intima and the media of the blood vessels — the former invariably occurs in the setting of atherosclerosis.1.Kalpakian M.A. Mehrotra R. Vascular calcification and disordered mineral metabolism in dialysis patients.Semin Dial. 2007; 20: 139-143Crossref PubMed Scopus (46) Google Scholar It should be noted that none of the currently available noninvasive tools for the assessment of VC can reliably distinguish intimal from medial calcification. Thus, in most human studies, the ascertained VC is a composite of intimal and medial calcification.1.Kalpakian M.A. Mehrotra R. Vascular calcification and disordered mineral metabolism in dialysis patients.Semin Dial. 2007; 20: 139-143Crossref PubMed Scopus (46) Google Scholar It had long been believed that the high prevalence and severity of VC in CKD were a result of passive precipitation of calcium phosphate, and this led to management algorithms that cautioned against exceeding predesignated calcium × phosphorus products. Research over the last 15 years has shown that VC is an active and regulated, cell-mediated process wherein vascular smooth muscle cells undergo a phenotypic change to osteoblasts or chondrocytes. These cells, in turn, deposit hydroxyapatite, possibly by the release of mineral-laden matrix vessels and apoptotic bodies.1.Kalpakian M.A. Mehrotra R. Vascular calcification and disordered mineral metabolism in dialysis patients.Semin Dial. 2007; 20: 139-143Crossref PubMed Scopus (46) Google Scholar Studies also indicate that the degree of VC probably reflects a balance between the promoters and the inhibitors of calcification. CKD appears to be associated with both an increased availability of promoters (hyperphosphatemia, hypercalcemia, increased oxidized low-density lipoprotein cholesterol, hyperleptinemia) and a decreased amount of inhibitors (matrix Gla protein, fetuin-A). This may explain the markedly high prevalence and severity of VC in maintenance dialysis patients. Hermans et al.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar (this issue) now further expand our knowledge of the possible role of a long-known calcification inhibitor, fetuin-A. Fetuin-A, a 62-kilodalton glycoprotein, is a member of the cystatin superfamily of proteins. In humans, the 349-amino acid protein, as secreted from the liver, consists of two chains: a heavy and a light chain joined by a connecting segment and linked by disulfide bonds.3.Szweras M. Liu D. Partridge E.A. et al.α2-HS glycoprotein/fetuin, a transforming growth factor β/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling.J Biol Chem. 2002; 277: 19991-19997Crossref PubMed Scopus (183) Google Scholar The N-terminal of the heavy chain consists of two cystatin domains, D1 and D2; the acidic amino acids in the D1 domain appear to account for fetuin's ability to inhibit precipitation of calcium and phosphorus.3.Szweras M. Liu D. Partridge E.A. et al.α2-HS glycoprotein/fetuin, a transforming growth factor β/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling.J Biol Chem. 2002; 277: 19991-19997Crossref PubMed Scopus (183) Google Scholar Indeed, fetuin-A accounts for up to one-half of the in vitro capacity of the serum to prevent the precipitation of calcium and phosphorus. It is now recognized that fetuin-A can actively regulate the cell-mediated process of osteogenesis in the vessel wall. In the presence of calcium, fetuin-A binds to cell surface proteins, annexins II and VI.4.Kundranda M.N. Ray S. Saria M. et al.Annexins expressed on the cell surface serve as receptors for adhesion to immobilized fetuin-A.Biochim Biophys Acta. 2004; 1693: 111-123Crossref PubMed Scopus (42) Google Scholar This binding facilitates the flow-mediated entry of fetuin-A into the endosomes within the vascular smooth muscle cells.5.Chen N.X. O'Neill K.D. Chen Z. et al.Fetuin-A uptake in bovine vascular smooth muscle cells is calcium dependent and mediated by annexins.Am J Physiol Renal Physiol. 2007; 292: F599-F606Crossref PubMed Scopus (53) Google Scholar Intracellular fetuin-A inhibits apoptosis of vascular smooth muscle cells.6.Reynolds J.L. Skepper J.N. McNair R. et al.Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification.J Am Soc Nephrol. 2005; 16: 2920-2930Crossref PubMed Scopus (266) Google Scholar It is also incorporated into the secreted matrix vesicles and apoptotic bodies and therein inhibits mineralization in a concentration-dependent manner. Furthermore, it enhances the phagocytosis of apoptotic bodies by viable vascular smooth muscle cells, limiting their ability to nucleate calcium phosphate.6.Reynolds J.L. Skepper J.N. McNair R. et al.Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification.J Am Soc Nephrol. 2005; 16: 2920-2930Crossref PubMed Scopus (266) Google Scholar Finally, fetuin-A antagonizes the action of bone morphogenetic protein-2, an important osteogenic protein that stimulates the first step in VC — the transdifferentiation of calcifying vascular cells.3.Szweras M. Liu D. Partridge E.A. et al.α2-HS glycoprotein/fetuin, a transforming growth factor β/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling.J Biol Chem. 2002; 277: 19991-19997Crossref PubMed Scopus (183) Google Scholar Several studies have demonstrated that maintenance dialysis patients have relatively low circulating fetuin-A levels. Fetuin-A is a negative acute-phase reactant, and various cytokines, particularly interleukin-1β, decrease the synthesis of this glycoprotein. It is, thus, likely that the inflammatory state associated with uremia is an important reason for low fetuin-A levels in dialysis patients (Figure 1). The magnitude of the decrease in serum fetuin-A in the presence of inflammation may be modulated by genetic predisposition (Figure 1).7.Stenvinkel P. Wang K. Qureshi A.R. et al.Low fetuin-A levels are associated with cardiovascular death: impact of variations in genes encoding fetuin.Kidney Int. 2005; 67: 2383-2392Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Furthermore, it is possible, though not consistently demonstrated, that genetic polymorphisms may determine fetuin-A levels independently of inflammation. Finally, it is conceivable that the pro-calcification milieu associated with uremia consumes circulating fetuin-A; this hypothesis, however, remains speculative. As is discussed above, fetuin-A has the capacity to actively regulate the cell-mediated process of VC. The importance of fetuin-A deficiency in the accelerated VC observed in dialysis patients is underscored by the inverse relationship between serum fetuin-A levels and the presence of valvular calcification or the severity of coronary artery calcification.8.Wang A.Y.M. Woo J. Lam C.W.K. et al.Associations of serum fetuin-A with malnutrition, atherosclerosis, and valvular calcification syndrome and outcome in peritoneal dialysis patients.Nephrol Dial Transplant. 2005; 20: 1676-1685Crossref PubMed Scopus (267) Google Scholar Fetuin-A levels are also particularly low among patients with calcific uremic arteriolopathy. Moreover, three previous studies have demonstrated an inverse association between serum fetuin-A levels and survival of dialysis patients (Table 1), presumably as a result of accelerated VC (Figure 1).7.Stenvinkel P. Wang K. Qureshi A.R. et al.Low fetuin-A levels are associated with cardiovascular death: impact of variations in genes encoding fetuin.Kidney Int. 2005; 67: 2383-2392Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 8.Wang A.Y.M. Woo J. Lam C.W.K. et al.Associations of serum fetuin-A with malnutrition, atherosclerosis, and valvular calcification syndrome and outcome in peritoneal dialysis patients.Nephrol Dial Transplant. 2005; 20: 1676-1685Crossref PubMed Scopus (267) Google Scholar, 9.Ketteler M. Bongartz P. Westenfeld R. et al.Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.Lancet. 2003; 361: 827-833Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar and This association of low fetuin-A levels and all-cause mortality is confirmed in the study by Hermans and colleagues.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar In 987 incident dialysis patients (664 hemodialysis and 323 peritoneal dialysis), an increase of serum fetuin-A by 0.1 g per liter was associated with a 9% lower adjusted risk for death during a median follow-up of 2.8 years.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar In this study, the association of fetuin-A with all-cause mortality was independent of serum C-reactive protein levels — a finding consistent with the only other study of incident dialysis patients.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar,7.Stenvinkel P. Wang K. Qureshi A.R. et al.Low fetuin-A levels are associated with cardiovascular death: impact of variations in genes encoding fetuin.Kidney Int. 2005; 67: 2383-2392Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar On the other hand, in the two reports of prevalent dialysis patients, fetuin-A levels lost their prognostic value when serum C-reactive protein levels were entered in multivariate models.8.Wang A.Y.M. Woo J. Lam C.W.K. et al.Associations of serum fetuin-A with malnutrition, atherosclerosis, and valvular calcification syndrome and outcome in peritoneal dialysis patients.Nephrol Dial Transplant. 2005; 20: 1676-1685Crossref PubMed Scopus (267) Google Scholar,9.Ketteler M. Bongartz P. Westenfeld R. et al.Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.Lancet. 2003; 361: 827-833Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar These apparently disparate findings regarding the dependence of the association of fetuin-A and mortality on inflammation may have several possible explanations. First, the study by Hermans et al.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar is substantially larger than those reported previously and thus has greater statistical power. Second, serum C-reactive protein levels may be an imprecise measure of the link between fetuin-A levels and inflammation. Third, risk factors, including serum fetuin-A and inflammatory markers, were ascertained only on one occasion in all these studies. Thus, none of the studies could capture the dynamic state of cardiovascular risk of the study subjects. Fourth, there may be heretofore unknown, inflammation-independent mechanisms that may lead to low serum fetuin-A levels in dialysis patients. Notwithstanding these apparent inconsistencies, the preponderance of in vitro, animal, and human studies support the notion that low serum fetuin-A levels in dialysis patients are associated with increased risk for death, possibly secondary to accelerated VC (Figure 1).Table 1Key findings from the studies that have evaluated the association of serum fetuin-A and mortality in patients undergoing maintenance dialysisAuthor, year [ref.]nRaceHD/PDFollow-up, monthsRelationship of serum fetuin-A to all-cause/CV mortalityRelationship of serum fetuin-A to non-CV mortalityKetteler et al., 2003 [9]312WhitePrevalent HD33Significant association with all-cause/CV mortality non-significant on entering serum CRP in multivariate modelsNot studiedStenvinkel et al., 2005 [7]25897% White118 incident HD 136 incident PD42 (mean)Fetuin-A levels below median for group significantly associated with all-cause (adjusted hazards, 2.58) and CV mortality (adjusted hazards, 2.63), independent of serum CRPNot studiedWang et al., 2005 [8]238ChinesePrevalent PD32 (mean)Significant association with all-cause and CV mortality non-significant on entering serum CRP and valvular calcification in multivariate modelsNot studiedHermans et al., 2007 [2]98793% White664 incident HD 323 incident PD34 (median)An increase of serum fetuin-A of 0.1 g per liter significantly associated with lower all-cause mortality (adjusted hazards, 0.91), independent of serum CRP. Trend toward increased CV mortalityAn increase of serum fetuin-A of 0.1 g per liter associated with lower non-CV mortality (adjusted hazards, 0.89), independent of serum CRPHD, hemodialysis; PD, peritoneal dialysis; CV, cardiovascular; CRP, C-reactive protein. Open table in a new tab HD, hemodialysis; PD, peritoneal dialysis; CV, cardiovascular; CRP, C-reactive protein. However, the relationship of fetuin-A to vascular disease is far more complex than is suggested by the above discussion. In patients with early CKD, fetuin-A levels are not low and, among subjects with diabetic nephropathy, may be higher than in diabetics without CKD.10.Mehrotra R. Westenfeld R. Christenson P. et al.Serum fetuin-A in non-dialyzed patients with diabetic nephropathy: relationship with coronary artery calcification.Kidney Int. 2005; 67: 1070-1077Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Fetuin-A inhibits the insulin-stimulated autophosphorylation of the insulin receptor. Consistent with these findings, serum fetuin-A levels are directly associated with insulin resistance and with dyslipidemia, particularly hypertriglyceridemia.10.Mehrotra R. Westenfeld R. Christenson P. et al.Serum fetuin-A in non-dialyzed patients with diabetic nephropathy: relationship with coronary artery calcification.Kidney Int. 2005; 67: 1070-1077Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar,11.Stefan N. Hennige A.M. Staiger H. et al.α2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans.Diabetes Care. 2006; 29: 853-857Crossref PubMed Scopus (372) Google Scholar Finally, in non-dialysis-dependent CKD patients with diabetic nephropathy, serum fetuin-A levels are directly, not inversely, related to calcification burden.10.Mehrotra R. Westenfeld R. Christenson P. et al.Serum fetuin-A in non-dialyzed patients with diabetic nephropathy: relationship with coronary artery calcification.Kidney Int. 2005; 67: 1070-1077Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar These findings may make the job of defining 'optimal' serum fetuin-A levels particularly challenging. It should be noted that most of these studies are cross-sectional, and longitudinal evaluation of fetuin-A levels may shed greater light on this issue. A novel finding in the study reported by Hermans et al.2.Hermans M.M.H. Brandenburg V. Ketteler M. et al.Association of serum fetuin-A levels with mortality in dialysis patients.Kidney Int. 2007; 72: 202-207Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar is the association of low serum fetuin-A levels with non-cardiovascular mortality. Non-cardiovascular causes of death represent a heterogeneous mixture of biologic processes — infectious causes constitute the single largest subgroup. The study had too few events in each subgroup of patients to meaningfully dissect the association of low serum fetuin-A with non-cardiovascular causes of death. Moreover, the biologic processes underlying this association are also not very well understood. Animal studies suggest that fetuin-A may promote phagocytic activity of macrophages, and thus, low fetuin-A levels may increase the risk of infection.12.Jersmann H.P. Dransfiled I. Hart S.P. Fetuin/α2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages.Clin Sci. 2003; 105: 273-278Crossref PubMed Scopus (84) Google Scholar Additional studies should be designed to further understand the nonvascular effects of fetuin-A. To conclude, the available evidence seems to suggest that the low fetuin-A levels often observed in dialysis patients increase the risk for both cardiovascular and non-cardiovascular mortality. There are currently no well-determined methods to change the levels of circulating fetuin-A. Nevertheless, upregulating fetuin-A levels may be a desirable goal; however, it should await our understanding of the deleterious vascular effects of high serum fetuin-A, particularly arising from its role in inducing insulin resistance and dyslipidemia. The author serves as a consultant to Novartis and Shire Pharmaceuticals, has received grant support from Shire and Amgen, and has received honoraria from Baxter Healthcare, Genzyme, and Shire. The author is supported by a K23 grant from the National Center for Research Resources (RR18298) of the National Institutes of Health and a Norman Caplan grant from Satellite Health.