- Email: [email protected]
Tissue protection by erythropoietin: new findings in a moving field
commentary
http://www.kidney-international.org & 2013 International Society of Nephrology
see basic research on pages 468 and 482
Tissue protection by erythropoietin: new findings in a moving field Masaomi Nangaku1 Two groups elucidate novel mechanisms of tissue protection by erythropoietin (EPO). Hu et al. demonstrate that Klotho’s protective effect against oxidant-induced cytotoxicity is partially mediated by an increase in the endogenous expression of the classical EPO receptor (EpoR). While erythropoiesis is stimulated by the canonical EpoR homodimer, the tissue-protective effects of EPO are mediated through a heterodimeric ‘tissue-protective’ receptor. Coldewey et al. demonstrate a protective role of the ‘tissue-protective’ EpoR against acute kidney injury. Kidney International (2013) 84, 427–429. doi:10.1038/ki.2013.140
Erythropoietin (EPO) is produced by neural crest-derived peritubular fibroblasts in the kidney in an oxygendependent manner.1 A decrease in oxygen tension stimulates EPO production via activation of hypoxiainducible factor-2. EPO receptor (EpoR) homodimerization is triggered by picomolar concentrations of EPO to stimulate erythropoiesis and provide adequate tissue oxygenation. Malfunctioning of EPO-producing cells in chronic kidney disease patients, at least in part due to uremic conditions, leads to deficiency of EPO and subsequent development of anemia as a major complication of CKD.2 Anemia results in a decrease in oxygen delivery to organs, and amelioration of anemia restores oxygen delivery with subsequent improvement of exercise tolerance and symptoms such as fatigue. Theoretically, a decrease in oxygen tensions in organs will also lead to damage to organs. In renal patients, it 1 Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan Correspondence: Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected]
Kidney International (2013) 84
will aggravate progression of kidney disease and promote cardiovascular complications. Recombinant human EPO and related reagents, the so-called erythropoiesis-stimulating agents (ESAs), have become indispensable drugs for the treatment of anemia in patients with chronic kidney disease. Darbepoetin alfa, a hyperglycosylated analog of EPO, and methoxy polyethylene glycol– epoetin beta are widely used as ESAs in the clinical setting today. Specific modification of ESAs may induce effects that are not obtained with EPO,3 but it is likely that ESAs work mainly by sharing the signaling pathway of EpoR. Darbepoetin alfa and methoxy polyethylene glycol–epoetin beta induce potent erythropoiesis via prolonged activation of EpoR due to their longer half-lives despite lower affinities for EpoR. While ESAs increase oxygen delivery to tissues by stimulation of erythropoiesis and improve quality of life, many unexpected non-hematopoietic protective functions of ESAs, such as antiapoptotic effects, have been identified over the past two decades. Direct effects of ESAs have been shown in immune cells, endothelial cells, neuronal cells, pancreatic b-cells, and a variety of endogenous kidney cells,
including podocytes.4 In this issue of Kidney International, two important studies shed new light on this subject. Hu et al.5 (this issue) investigated a mechanism of renoprotection by Klotho against oxidative kidney injury. Klotho was originally identified as an anti-aging protein but was subsequently discovered to have a multitude of biologic actions, including inhibition of renal tubular phosphate reabsorption and cytoprotection, which is mediated by antioxidation, antiapoptosis, protection of vasculature, promotion of angiogenesis, and inhibition of fibrogenesis. Hu et al. used transgenic mice overexpressing Klotho, Klotho hypomorphic mice, and administration of recombinant soluble Klotho and suggest that Klotho increases EpoR expression in the kidney. Klotho overexpression did not induce polycythemia in the animals, and EpoR regulation by Klotho may not be universal in all organs. The authors also confirmed regulation of EpoR expression by Klotho in vitro using cultured renal tubular cells and showed that Klotho protected these cells against oxidative injury via upregulation of EpoR. Previously, Elliott et al. pointed out that investigation of EpoR expression has been hampered by the lack of a reliable antibody that specifically detects EpoR.6 The same group extended their findings and reported that functional EpoR was undetectable in non-hematopoietic cells, mainly in endothelial cells, by quantitative PCR, immunoblots, isotope-labeled EPO surface binding, and examination of intracellular signaling.7 However, Hu et al.5 performed careful experiments to establish the presence of functional EpoR in the kidney: demonstration of EpoR transcript, protein labeling by multiple independent antisera, and activation of multiple signaling molecules downstream of EpoR upon addition of EPO, and reduction of EpoR protein and signaling by EpoR knock-down. While erythropoiesis is stimulated by the canonical EpoR homodimer, 427
commentary
Klotho
EPO
EPO βcR
EpoR
? Cytoprotection Nucleus
Figure 1 | Cytoprotection by EPO. Endogenous kidney cells are protected by EPO. The beneficial effect is mediated by the tissue-protective receptor composed of EpoR and bcR. The canonical receptor of a homodimer of EpoR may also be involved in tissue protection. Klotho, another important factor produced by the kidney, increases expression of EpoR and enforces tissue protection.
some studies proposed that the tissueprotective effects of EPO are mediated through a ‘tissue-protective’ receptor with a lower affinity for EPO (Figure 1). This tissue-protective receptor is distinct from the classical hematopoietic EpoR and is supposed to be a heterocomplex composed of EpoR and the ubiquitous b-common receptor (bcR, CD131, colony-stimulating factor 2 receptor-b) that is also used for signaling by the type 1 cytokines, such as granulocyte– macrophage colony-stimulating factor, interleukin-3, or interleukin-5. Detailed signaling cascades downstream of the two EpoRs remain to be determined. However, accumulating evidence suggests that EPO at low concentrations activates the JAK2–STAT5 pathway via the canonical EpoR, while EPO at pharmacologically high concentrations activates the RAF–MEK–ERK pathway and the PI3K–Akt pathway, inhibiting GSK3b, via the tissue-protective receptor. The study by Hu et al.5 did not show whether EpoR protected the kidney as a homodimer or as a heterodimer. The molecular mechanism of upregulation of EpoR by Klotho should also be clarified in the future. These are among several questions that remain to be answered. 428
Coldewey et al.8 (this issue) elucidate a new role of the tissueprotective receptor in the kidney. They induced models of septic acute kidney injury (AKI) in wild-type and bcR knockout mice and treated the experimental animals with EPO. Notably, they used two murine models of sepsis, one induced by lipopolysaccharide and another produced by polymicrobial sepsis of cecal ligation and puncture. Furthermore, they administered EPO to the animals after development of the disease; that is, this is not a prevention study but a treatment study mimicking our clinical situations. They found that the activation of the bcR is essential for renoprotection by EPO in AKI. Previous studies suggested a protective role of bcR using reagents supposed to bind only to the heterodimer receptor, not to the homodimer receptor, such as carbamoylated EPO.9 The study by Coldewey et al.,8 for the first time, clearly shows an essential role of bcR using mouse molecular genetics. One question that remains to be answered is whether bcR of the resident kidney cells or of non-kidney cells was responsible for renoprotection by EPO. Another interesting question is
whether renoprotection via bcR is mediated by direct cytoprotection or by microcirculation. Recent studies showed that bcR activates Src, Akt, and JAK2 signaling to increase interaction with endothelial nitric oxide synthase (eNOS) and subsequent eNOS activation and nitric oxide production.10 In the current report,8 the authors show that EPO enhanced eNOS activity in the wild-type mice, while this effect was lost in bcR knockout mice. Thus, it is possible that activation of bcR may protect the kidney against AKI via improvement of microcirculation, as ischemia is a common pathway in a variety of AKI conditions, including septic AKI.11 In spite of successful demonstration of an essential role of bcR in renoprotection by EPO, it is likely but remains to be proven that other ESAs require bcR for tissue protection in the same manner. Hu et al.5 and Coldewey et al.8 used supraphysiologic doses of EPO. As described above, the putative tissueprotective receptor shows a lower affinity for EPO, and tissue protection requires a large amount of EPO, which may cause some adverse effects. This may be one reason for the discrepancy between successful prevention and treatment of animal models of ischemic organ damage by EPO and negative outcomes of clinical studies of human subjects.12 The majority of clinical studies did not show neuroprotective or cardioprotective effects under various conditions of hypoxia of these organs. Furthermore, large-scale randomized controlled studies in chronic kidney disease patients and hemodialysis patients failed to show benefits of normalization of hemoglobin by ESAs,13 making us suspicious about potential adverse effects to counterbalance benefits and a pathogenic role of EPO resistance in this population. However, a randomized controlled study of patients admitted to the intensive care unit examined the mortality rate as a secondary end point and suggested an increase in survival in patients treated with EPO compared with those given placebo, who had equivalent hemoglobin levels and Kidney International (2013) 84
commentary
received comparable units of blood transfusion.14 Although this clinical study strongly suggested a non-erythropoietic protective effect of EPO, there was a significantly higher occurrence of thrombotic and thromboembolic complications in the EPO group. A more detailed elucidation of the organ-protective mechanisms mediated by EpoR, canonical or not, may delineate both unwanted adverse effects and beneficial effects of ESA therapy and provide us with a useful clinical tool for organ protection in the future.
12.
DISCLOSURE
Rosa M.A. Moyse´s1 and Maria E.F. Canziani2
Masaomi Nangaku has received honoraria as speaker from Kyowa Kirin. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Asada N, Takase M, Nakamura J et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J Clin Invest 2011; 121: 3981–3990. Chiang CK, Tanaka T, Inagi R et al. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest 2011; 91: 1564–1571. Yang WS, Chang JW, Han NJ et al. Darbepoetin alpha suppresses tumor necrosis factor-alphainduced endothelin-1 production through antioxidant action in human aortic endothelial cells: role of sialic acid residues. Free Radic Biol Med 2011; 50: 1242–1251. Eto N, Wada T, Inagi R et al. Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int 2007; 72: 455–463. Hu M-C, Shi M, Cho HJ et al. The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. Kidney Int 2013; 84: 468–481. Elliott S, Busse L, Bass MB et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006; 107: 1892–1895. Sinclair AM, Coxon A, McCaffery I et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood 2010; 115: 4264–4272. Coldewey SM, Khan AI, Kapoor A et al. Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the b-common receptor. Kidney Int 2013; 84: 482–490. Hand CC, Brines M. Promises and pitfalls in erythropoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J Investig Med 2011; 59: 1073–1082. Su KH, Shyue SK, Kou YR et al. b Common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J Cell Physiol 2011; 226: 3330–3339. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011; 121: 4210–4221.
Kidney International (2013) 84
13.
Tanaka T, Nangaku M. Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents. Exp Cell Res 2012; 318: 11068–11073. Pfeffer MA, Burdmann EA, Chen CY et al. A trial of darbepoetin alpha in type 2 diabetes
14.
and chronic kidney disease. N Engl J Med 2009; 361: 2019–2032. Corwin HL, Gettinger A, Fabian TC et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007; 357: 965–976.
see basic research on page 491
Sevelamer and CKD-associated cardiovascular disease: going further, but far from there Cardiovascular disease is a major complication of chronic kidney disease (CKD), and current data support its link to mineral metabolism disturbances. However, there is an intense debate over whether CKD–mineral and bone disorder therapy could change the cardiovascular burden in CKD. The study by Maizel and colleagues shows the benefits of a phosphate binder, sevelamer, for the progression of aortic stiffness and endothelial dysfunction as well as left ventricular dysfunction and hypertrophy in mice with CKD. Kidney International (2013) 84, 429–431. doi:10.1038/ki.2013.160
Cardiovascular disease is a major cause of mortality in patients with chronic kidney disease (CKD) and is not only characterized by a high prevalence but also has a unique aggressiveness, which is represented by the high mortality rate of CKD patients in comparison with general population. In recent years, several studies have confirmed the role of mineral metabolism disturbances in the physiopathology of CKD-associated cardiovascular disease.1 However, we are far from having a wide and definitive comprehension of the mechanisms by which CKD increases the progression not only of vascular calcification, but also of left ventricular hypertrophy (LVH). 1 Nephrology Division, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil and 2Nephrology Division, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Correspondence: Rosa M.A. Moyse´s, Nephrology Division, Universidade de Sa˜o Paulo, 690, Iperoig Street, 05016-000 Sa˜o Paulo, Brazil. E-mail: [email protected]
Arterial hypertension and hypervolemia are commonly found in CKD, and for many years LVH has been linked only to these two major causes. But it is becoming clear that other players, such as phosphate, calcium, parathyroid hormone, fibroblast growth factor 23 (FGF23), and vitamin D, are involved in the physiopathology of CKD-associated LVH. Almost a decade ago, Neves and colleagues showed that phosphate could induce myocardial hypertrophy in rats with CKD independently of serum parathyroid hormone levels or the presence of vascular calcification.2,3 However, animals with a high myocyte diameter also presented high serum levels of FGF23,4 preventing us from defining whether or not these effects of phosphate and FGF23 were direct. Since then, several clinical and experimental studies have shown the association of phosphate and FGF23 with LVH (Figure 1). The question that remains is what is just a biomarker and what directly induces this pathological 429
http://www.kidney-international.org & 2013 International Society of Nephrology
see basic research on pages 468 and 482
Tissue protection by erythropoietin: new findings in a moving field Masaomi Nangaku1 Two groups elucidate novel mechanisms of tissue protection by erythropoietin (EPO). Hu et al. demonstrate that Klotho’s protective effect against oxidant-induced cytotoxicity is partially mediated by an increase in the endogenous expression of the classical EPO receptor (EpoR). While erythropoiesis is stimulated by the canonical EpoR homodimer, the tissue-protective effects of EPO are mediated through a heterodimeric ‘tissue-protective’ receptor. Coldewey et al. demonstrate a protective role of the ‘tissue-protective’ EpoR against acute kidney injury. Kidney International (2013) 84, 427–429. doi:10.1038/ki.2013.140
Erythropoietin (EPO) is produced by neural crest-derived peritubular fibroblasts in the kidney in an oxygendependent manner.1 A decrease in oxygen tension stimulates EPO production via activation of hypoxiainducible factor-2. EPO receptor (EpoR) homodimerization is triggered by picomolar concentrations of EPO to stimulate erythropoiesis and provide adequate tissue oxygenation. Malfunctioning of EPO-producing cells in chronic kidney disease patients, at least in part due to uremic conditions, leads to deficiency of EPO and subsequent development of anemia as a major complication of CKD.2 Anemia results in a decrease in oxygen delivery to organs, and amelioration of anemia restores oxygen delivery with subsequent improvement of exercise tolerance and symptoms such as fatigue. Theoretically, a decrease in oxygen tensions in organs will also lead to damage to organs. In renal patients, it 1 Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan Correspondence: Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected]
Kidney International (2013) 84
will aggravate progression of kidney disease and promote cardiovascular complications. Recombinant human EPO and related reagents, the so-called erythropoiesis-stimulating agents (ESAs), have become indispensable drugs for the treatment of anemia in patients with chronic kidney disease. Darbepoetin alfa, a hyperglycosylated analog of EPO, and methoxy polyethylene glycol– epoetin beta are widely used as ESAs in the clinical setting today. Specific modification of ESAs may induce effects that are not obtained with EPO,3 but it is likely that ESAs work mainly by sharing the signaling pathway of EpoR. Darbepoetin alfa and methoxy polyethylene glycol–epoetin beta induce potent erythropoiesis via prolonged activation of EpoR due to their longer half-lives despite lower affinities for EpoR. While ESAs increase oxygen delivery to tissues by stimulation of erythropoiesis and improve quality of life, many unexpected non-hematopoietic protective functions of ESAs, such as antiapoptotic effects, have been identified over the past two decades. Direct effects of ESAs have been shown in immune cells, endothelial cells, neuronal cells, pancreatic b-cells, and a variety of endogenous kidney cells,
including podocytes.4 In this issue of Kidney International, two important studies shed new light on this subject. Hu et al.5 (this issue) investigated a mechanism of renoprotection by Klotho against oxidative kidney injury. Klotho was originally identified as an anti-aging protein but was subsequently discovered to have a multitude of biologic actions, including inhibition of renal tubular phosphate reabsorption and cytoprotection, which is mediated by antioxidation, antiapoptosis, protection of vasculature, promotion of angiogenesis, and inhibition of fibrogenesis. Hu et al. used transgenic mice overexpressing Klotho, Klotho hypomorphic mice, and administration of recombinant soluble Klotho and suggest that Klotho increases EpoR expression in the kidney. Klotho overexpression did not induce polycythemia in the animals, and EpoR regulation by Klotho may not be universal in all organs. The authors also confirmed regulation of EpoR expression by Klotho in vitro using cultured renal tubular cells and showed that Klotho protected these cells against oxidative injury via upregulation of EpoR. Previously, Elliott et al. pointed out that investigation of EpoR expression has been hampered by the lack of a reliable antibody that specifically detects EpoR.6 The same group extended their findings and reported that functional EpoR was undetectable in non-hematopoietic cells, mainly in endothelial cells, by quantitative PCR, immunoblots, isotope-labeled EPO surface binding, and examination of intracellular signaling.7 However, Hu et al.5 performed careful experiments to establish the presence of functional EpoR in the kidney: demonstration of EpoR transcript, protein labeling by multiple independent antisera, and activation of multiple signaling molecules downstream of EpoR upon addition of EPO, and reduction of EpoR protein and signaling by EpoR knock-down. While erythropoiesis is stimulated by the canonical EpoR homodimer, 427
commentary
Klotho
EPO
EPO βcR
EpoR
? Cytoprotection Nucleus
Figure 1 | Cytoprotection by EPO. Endogenous kidney cells are protected by EPO. The beneficial effect is mediated by the tissue-protective receptor composed of EpoR and bcR. The canonical receptor of a homodimer of EpoR may also be involved in tissue protection. Klotho, another important factor produced by the kidney, increases expression of EpoR and enforces tissue protection.
some studies proposed that the tissueprotective effects of EPO are mediated through a ‘tissue-protective’ receptor with a lower affinity for EPO (Figure 1). This tissue-protective receptor is distinct from the classical hematopoietic EpoR and is supposed to be a heterocomplex composed of EpoR and the ubiquitous b-common receptor (bcR, CD131, colony-stimulating factor 2 receptor-b) that is also used for signaling by the type 1 cytokines, such as granulocyte– macrophage colony-stimulating factor, interleukin-3, or interleukin-5. Detailed signaling cascades downstream of the two EpoRs remain to be determined. However, accumulating evidence suggests that EPO at low concentrations activates the JAK2–STAT5 pathway via the canonical EpoR, while EPO at pharmacologically high concentrations activates the RAF–MEK–ERK pathway and the PI3K–Akt pathway, inhibiting GSK3b, via the tissue-protective receptor. The study by Hu et al.5 did not show whether EpoR protected the kidney as a homodimer or as a heterodimer. The molecular mechanism of upregulation of EpoR by Klotho should also be clarified in the future. These are among several questions that remain to be answered. 428
Coldewey et al.8 (this issue) elucidate a new role of the tissueprotective receptor in the kidney. They induced models of septic acute kidney injury (AKI) in wild-type and bcR knockout mice and treated the experimental animals with EPO. Notably, they used two murine models of sepsis, one induced by lipopolysaccharide and another produced by polymicrobial sepsis of cecal ligation and puncture. Furthermore, they administered EPO to the animals after development of the disease; that is, this is not a prevention study but a treatment study mimicking our clinical situations. They found that the activation of the bcR is essential for renoprotection by EPO in AKI. Previous studies suggested a protective role of bcR using reagents supposed to bind only to the heterodimer receptor, not to the homodimer receptor, such as carbamoylated EPO.9 The study by Coldewey et al.,8 for the first time, clearly shows an essential role of bcR using mouse molecular genetics. One question that remains to be answered is whether bcR of the resident kidney cells or of non-kidney cells was responsible for renoprotection by EPO. Another interesting question is
whether renoprotection via bcR is mediated by direct cytoprotection or by microcirculation. Recent studies showed that bcR activates Src, Akt, and JAK2 signaling to increase interaction with endothelial nitric oxide synthase (eNOS) and subsequent eNOS activation and nitric oxide production.10 In the current report,8 the authors show that EPO enhanced eNOS activity in the wild-type mice, while this effect was lost in bcR knockout mice. Thus, it is possible that activation of bcR may protect the kidney against AKI via improvement of microcirculation, as ischemia is a common pathway in a variety of AKI conditions, including septic AKI.11 In spite of successful demonstration of an essential role of bcR in renoprotection by EPO, it is likely but remains to be proven that other ESAs require bcR for tissue protection in the same manner. Hu et al.5 and Coldewey et al.8 used supraphysiologic doses of EPO. As described above, the putative tissueprotective receptor shows a lower affinity for EPO, and tissue protection requires a large amount of EPO, which may cause some adverse effects. This may be one reason for the discrepancy between successful prevention and treatment of animal models of ischemic organ damage by EPO and negative outcomes of clinical studies of human subjects.12 The majority of clinical studies did not show neuroprotective or cardioprotective effects under various conditions of hypoxia of these organs. Furthermore, large-scale randomized controlled studies in chronic kidney disease patients and hemodialysis patients failed to show benefits of normalization of hemoglobin by ESAs,13 making us suspicious about potential adverse effects to counterbalance benefits and a pathogenic role of EPO resistance in this population. However, a randomized controlled study of patients admitted to the intensive care unit examined the mortality rate as a secondary end point and suggested an increase in survival in patients treated with EPO compared with those given placebo, who had equivalent hemoglobin levels and Kidney International (2013) 84
commentary
received comparable units of blood transfusion.14 Although this clinical study strongly suggested a non-erythropoietic protective effect of EPO, there was a significantly higher occurrence of thrombotic and thromboembolic complications in the EPO group. A more detailed elucidation of the organ-protective mechanisms mediated by EpoR, canonical or not, may delineate both unwanted adverse effects and beneficial effects of ESA therapy and provide us with a useful clinical tool for organ protection in the future.
12.
DISCLOSURE
Rosa M.A. Moyse´s1 and Maria E.F. Canziani2
Masaomi Nangaku has received honoraria as speaker from Kyowa Kirin. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Asada N, Takase M, Nakamura J et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J Clin Invest 2011; 121: 3981–3990. Chiang CK, Tanaka T, Inagi R et al. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest 2011; 91: 1564–1571. Yang WS, Chang JW, Han NJ et al. Darbepoetin alpha suppresses tumor necrosis factor-alphainduced endothelin-1 production through antioxidant action in human aortic endothelial cells: role of sialic acid residues. Free Radic Biol Med 2011; 50: 1242–1251. Eto N, Wada T, Inagi R et al. Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int 2007; 72: 455–463. Hu M-C, Shi M, Cho HJ et al. The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. Kidney Int 2013; 84: 468–481. Elliott S, Busse L, Bass MB et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006; 107: 1892–1895. Sinclair AM, Coxon A, McCaffery I et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood 2010; 115: 4264–4272. Coldewey SM, Khan AI, Kapoor A et al. Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the b-common receptor. Kidney Int 2013; 84: 482–490. Hand CC, Brines M. Promises and pitfalls in erythropoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J Investig Med 2011; 59: 1073–1082. Su KH, Shyue SK, Kou YR et al. b Common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J Cell Physiol 2011; 226: 3330–3339. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011; 121: 4210–4221.
Kidney International (2013) 84
13.
Tanaka T, Nangaku M. Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents. Exp Cell Res 2012; 318: 11068–11073. Pfeffer MA, Burdmann EA, Chen CY et al. A trial of darbepoetin alpha in type 2 diabetes
14.
and chronic kidney disease. N Engl J Med 2009; 361: 2019–2032. Corwin HL, Gettinger A, Fabian TC et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007; 357: 965–976.
see basic research on page 491
Sevelamer and CKD-associated cardiovascular disease: going further, but far from there Cardiovascular disease is a major complication of chronic kidney disease (CKD), and current data support its link to mineral metabolism disturbances. However, there is an intense debate over whether CKD–mineral and bone disorder therapy could change the cardiovascular burden in CKD. The study by Maizel and colleagues shows the benefits of a phosphate binder, sevelamer, for the progression of aortic stiffness and endothelial dysfunction as well as left ventricular dysfunction and hypertrophy in mice with CKD. Kidney International (2013) 84, 429–431. doi:10.1038/ki.2013.160
Cardiovascular disease is a major cause of mortality in patients with chronic kidney disease (CKD) and is not only characterized by a high prevalence but also has a unique aggressiveness, which is represented by the high mortality rate of CKD patients in comparison with general population. In recent years, several studies have confirmed the role of mineral metabolism disturbances in the physiopathology of CKD-associated cardiovascular disease.1 However, we are far from having a wide and definitive comprehension of the mechanisms by which CKD increases the progression not only of vascular calcification, but also of left ventricular hypertrophy (LVH). 1 Nephrology Division, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil and 2Nephrology Division, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil Correspondence: Rosa M.A. Moyse´s, Nephrology Division, Universidade de Sa˜o Paulo, 690, Iperoig Street, 05016-000 Sa˜o Paulo, Brazil. E-mail: [email protected]
Arterial hypertension and hypervolemia are commonly found in CKD, and for many years LVH has been linked only to these two major causes. But it is becoming clear that other players, such as phosphate, calcium, parathyroid hormone, fibroblast growth factor 23 (FGF23), and vitamin D, are involved in the physiopathology of CKD-associated LVH. Almost a decade ago, Neves and colleagues showed that phosphate could induce myocardial hypertrophy in rats with CKD independently of serum parathyroid hormone levels or the presence of vascular calcification.2,3 However, animals with a high myocyte diameter also presented high serum levels of FGF23,4 preventing us from defining whether or not these effects of phosphate and FGF23 were direct. Since then, several clinical and experimental studies have shown the association of phosphate and FGF23 with LVH (Figure 1). The question that remains is what is just a biomarker and what directly induces this pathological 429