- Email: [email protected]
Magnesium as a Janus-faced inhibitor of calcification
commentary
www.kidney-international.org
Magnesium as a Janus-faced inhibitor of calcification Yosuke Nakagawa1, Hirotaka Komaba1,2,3 and Masafumi Fukagawa1 Vascular calcification is a life-threatening complication in patients with chronic kidney disease. Magnesium is a potent inhibitor of calcification and attracting attention as a new therapeutic candidate. ter Braake and colleagues demonstrate that magnesium supplementation strikingly prevents vascular calcification in Klotho knockout mice. However, these mice also show osteomalacia, indicating that magnesium has a Janus face. Maximizing the beneficial effects of magnesium without causing bone mineralization defects is an important next challenge. Kidney International (2020) 97, 448–450; https://doi.org/10.1016/j.kint.2019.11.035 Copyright ª 2020, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 487
V
ascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD) and contributes to an increased risk of cardiovascular morbidity and mortality. The mechanism of VC is not just a passive precipitation of excess calcium and phosphorus but an active process of transformation from vascular smooth muscle cells into osteoblast-like cells. Accumulating data suggest an imbalance between vascular calcification inducers and inhibitors in the process of osteogenic smooth muscle cell transformation in CKD. One of such calcification inhibitors is Klotho, which was originally identified as a senescencerelated protein because Klotho-hypomorphic (kl/kl) mice develop complex phenotypes resembling human aging, including VC.1 1 Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; 2Interactive Translational Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan; and 3 The Institute of Medical Sciences, Tokai University, Isehara, Japan
Correspondence: Masafumi Fukagawa, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara 259-1193, Japan. E-mail: [email protected] 448
The principal role of transmembrane Klotho is to function as a coreceptor for fibroblast growth factor 23 (FGF23).2 Loss of Klotho hampers the classical, Klotho-mediated action of FGF23 and results in severe hyperphosphatemia and hypervitaminosis D. These alterations in mineral metabolism are considered to explain for the most part the premature aging and VC in kl/ kl mice, but recent studies suggest that the cleaved form of Klotho (soluble Klotho) could also directly inhibit VC.3 Despite recent progress in the treatment of CKD-mineral and bone disorder such as non–calcium-based phosphate binders and calcimimetics, preventing the development or progression of VC has been challenging. In this context, magnesium (Mg) has recently attracted attention as a new therapeutic candidate for VC. Experimental studies revealed that Mg inhibits calcification of vascular cells by preventing hydroxyapatite formation and osteogenic transformation.4 In support of these findings, observational studies showed an independent association between lower Mg concentrations and an elevated risk of all-cause and cardiovascular mortality in hemodialysis patients. Furthermore, a recent small randomized controlled trial demonstrated that oral Mg oxide suppressed the progression of
coronary artery calcification in patients with predialysis CKD.5 In this issue of Kidney International, ter Braake et al.6 explored the systemic effects of Mg supplementation in Klotho knockout (Klotho / ) mice, which show more severe VC compared to uremic animal models. The researchers demonstrated that 0.48% Mg diet compared with 0.05% Mg diet strikingly prevented VC in Klotho / mice. The protective effect of Mg against VC was accompanied by inhibition of aortic osteogenic signaling such as Runx2 and matrix Gla protein, and downregulation of pathways related to inflammation and extracellular matrix remodeling. In addition to the protective effect against VC, the investigators also observed a marked impairment of bone mineralization in Klotho / mice on high Mg diet, without evident changes in osteoblast and osteoclast activities. Clearly, the most noteworthy finding of the study by ter Braake et al. is that Mg supplementation could prevent the progression of VC in Klotho / mice. Although prior studies have already shown that high Mg diet inhibits the progression of VC in a 5/6 nephrectomy rat model,7 this paper represents an important addition to our knowledge as it confirms the protective effect of Mg against VC in a different animal model that develops more severe, lifethreatening VC. Furthermore, it should be acknowledged that Klotho / mice and uremic animal models share similar phenotypes including hyperphosphatemia, elevated FGF23, and Klotho deficiency, but differ in kidney function, calcium and vitamin D metabolism, and parathyroid function. Despite these differences, the present study reproduced the findings from 5/6 nephrectomized rats, which support the therapeutic potential of Mg supplementation against VC across diverse settings. There are several additional issues that should be addressed in this study. First, ter Braake et al. found that Klotho / mice on high Mg diet showed bone mineralization defects indicating osteomalacia. Because these mice did not have hypophosphatemia or low serum 1,25-dihydroxyvitamin D levels, Kidney International (2020) 97, 448–462
commentary
the observed osteomalacia is likely caused by a direct effect of high Mg levels to inhibit hydroxyapatite formation. Osteomalacia is a serious complication as it contributes to increased bone fragility, bone pain, and gait abnormalities. Indeed, in the present study, Klotho / mice on high Mg diet showed a more fragile appearance with lower body weight compared with Klotho / mice on low Mg diet. Interestingly, however, wild-type mice fed the same high Mg diet did not develop osteomalacia, suggesting that Klotho / mice are more susceptible to the skeletal effect of Mg supplementation. Klotho / mice are known to have a low bone turnover, which is mainly caused by suppressed parathyroid hormone levels owing to elevated 1,25-dihydroxyvitamin D levels and consequent hypercalcemia. It is possible that the low bone turnover state of Klotho / mice might have favored the mineralization-inhibiting effect of high Mg intake. Because patients with CKD display a wide spectrum of bone turnover, it is important to know whether the type of underlying bone metabolism changes the skeletal effect of oral Mg supplementation. Second, ter Braake et al. observed that serum levels of phosphorus and FGF23 were further increased by Mg supplementation in Klotho / mice. This finding was unexpected because Mg has the capacity to bind phosphate in the intestine. Although data on urinary phosphorus excretion were unavailable as metabolic cage experiments were impossible to conduct in the fragile Klotho / mice, the lack of differing in renal expression of Napi-2a and Napi-2c between Klotho / mice on high and low Mg diets suggests that urinary phosphorus excretion was comparable in the 2 groups. Thus, one can speculate that the paradoxical increase in serum phosphorus in Klotho / mice on high Mg diet is best explained by an increase in active intestinal phosphate transport, as suggested by the observed increase in Napi-2b expression. This possibility is in agreement with prior studies showing that administration of phosphate binders leads to a compensatory upregulation of Napi-2b expression and intestinal Kidney International (2020) 97, 448–462
phosphate absorption.8 However, it is difficult to imagine that the increased Napi-2b-dependent dietary phosphate absorption overwhelmed the phosphatebinding capacity of Mg. It appears more likely that the impaired bone mineralization in Klotho / mice on high Mg diet led to an increased phosphorus efflux from bone and thereby increased serum phosphorus levels. These changes in phosphate metabolism are largely different from those in patients with CKD treated with Mg, which necessitate careful interpretation of the results. Third, ter Braake et al. demonstrated that the inhibition of VC by Mg supplementation in Klotho / mice was accompanied by decreased expression of aortic osteogenic genes, suggesting that Mg prevented the process of osteogenic transformation in vascular smooth muscle cells. By contrast, Mg supplementation inhibited bone mineralization in these mice, but there was no decrease in the osteoblast surface. Likewise, Mg supplementation (2 mM) in Saos-2 osteoblasts reduced mineralization but did not affect osteogenic gene markers. It is, however, noteworthy that in a previous study of primary osteoblasts, supplementation with higher levels of Mg than the current study could suppress osteogenic differentiation.9 Thus, it could be
hypothesized that compared with skeletal osteoblasts, osteoblast-like vascular cells might be more susceptible to the anti-osteogenic effect of Mg. If so, this difference may provide a clue to maximize the protective effect against VC without causing bone mineralization defects, and additional studies are required to address this possibility. Finally, it is worth mentioning that the findings by ter Braake et al. have important implications for the design of future clinical trials of Mg supplementation. On the basis of their findings, it seems reasonable that future trials will focus on patients with progressive VC and exclude those who have a potential risk of osteomalacia, such as in the presence of hypophosphatemia, severe vitamin D deficiency, diabetes, and malnutrition. In conclusion, ter Braake et al. confirmed the therapeutic effects of Mg supplementation in Klotho / mice with rapidly progressing VC. Their findings support Mg supplementation as a promising therapeutic option even for advanced VC and provide an additional rationale for conducting clinical trials of Mg supplementation in CKD patients with VC. However, their study also highlights an adverse effect of Mg supplementation on bone mineralization, indicating that Mg supplementation has Pre-existing bone pathology
Mg supplementation
Inhibition of vascular calcification
Bone mineralization defects
Prevention of cardiovascular events
Osteomalacia
Better survival
Skeletal pain fractures
Figure 1 | The Janus face of magnesium (Mg). Mg supplementation inhibits vascular calcification, which will decrease the risk of cardiovascular disease and death. However, Mg supplementation also inhibits bone mineralization, which leads to osteomalacia and subsequent bone pain and increased fractures. The negative effect of Mg supplementation on bone might be enhanced in the presence of pre-existing bone pathology or other predisposing conditions. 449
commentary
a Janus face (Figure 1). Clearly, maximizing the beneficial effects of Mg while simultaneously minimizing the adverse effects is an important next challenge. DISCLOSURE
HK has received honoraria, consulting fees, and/or grant support from Bayer Yakuhin, Chugai Pharmaceutical, Japan Tobacco, Kyowa Kirin, Novartis, and Ono Pharmaceutical. MF has received honoraria, consulting fees, and/or grant support from Bayer Yakuhin, Fresenius Kabi, Kissei Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Torii Pharmaceutical. The other author declared no competing interests. REFERENCES 1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51. 2. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444: 770–774.
3. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124–136. 4. Kircelli F, Peter ME, Sevinc Ok E, et al. Magnesium reduces calcification in bovine vascular smooth muscle cells in a dosedependent manner. Nephrol Dial Transplant. 2012;27:514–521. 5. Sakaguchi Y, Hamano T, Obi Y, et al. A randomized trial of magnesium oxide and oral carbon adsorbent for coronary artery calcification in predialysis CKD. J Am Soc Nephrol. 2019;30:1073–1085. 6. ter Braake AD, Smit AE, Bos C, et al. Magnesium prevents vascular calcification in Klotho deficiency. Kidney Int. 2020;97: 487–501. 7. Diaz-Tocados JM, Peralta-Ramirez A, Rodríguez-Ortiz ME, et al. Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats. Kidney Int. 2017;92:1084–1099. 8. Schiavi SC, Tang W, Bracken C, et al. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol. 2012;23:1691–1700. 9. Lu WC, Pringa E, Chou L. Effect of magnesium on the osteogenesis of normal human osteoblasts. Magnes Res. 2017;30:42–52.
Dysfunctional HDL takes its Toll on the endothelial glycocalyx Matthew J. Butler1 Patients with end-stage renal disease have a high risk of dying from cardiovascular disease that cannot be explained solely by traditional cardiovascular disease risk factors. Hesse et al. suggest that dysfunctional high-density lipoprotein cholesterol generated in patients with end-stage renal disease causes endothelial glycocalyx degradation. Glycocalyx degradation may represent one of the earliest insults leading to atheroma formation, and so this work suggests a novel link between renal failure and cardiovascular disease. Kidney International (2020) 97, 450–452; https://doi.org/10.1016/j.kint.2019.11.017 Crown Copyright ª 2020, Published by Elsevier, Inc., on behalf of the International Society of Nephrology. All rights reserved.
see basic research on page 502 1 Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Correspondence: Matthew J. Butler, Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. E-mail: [email protected] 450
H
istorically, high-density lipoprotein (HDL) has been seen as the good cholesterol, following a number of observational studies demonstrating an inverse relationship between cardiovascular disease (CVD) risk and HDL levels.1 However, in
patients with end-stage renal disease (ESRD) on hemodialysis, Moradi et al. demonstrated that the relationship between HDL and CVD risk might be more complicated, finding a U-shaped relationship between HDL concentrations and CVD risk.2 In patients on hemodialysis, HDL levels above 60 mg/dL were associated with increased CVD and overall mortality.2 The composition of HDL was not examined in this study, but Moradi’s work and that of others helped shift the popular view that all HDL is good cholesterol. Previously, work by Speer et al. confirmed that HDL from patients with chronic kidney disease (CKD) had an altered structure.1 This altered HDL reduced endothelial nitric-oxide synthase–activating phosphorylation and nitric oxide production in cultured human aortic endothelial cells via Toll-like receptors 2 (TLR2).1 They suggested that symmetric dimethylarginine (SMDA) could transform healthy HDL to a dysfunctional HDL (d-HDL) form.1 SMDA is an enantiomer of asymmetric dimethylarginine. Both SMDA and asymmetric dimethylarginine (ADMA) are endogenously generated from L-arginine.3 Both are considered uremic toxins, and elevated plasma levels are considered an independent risk factor for the development of CVD and CKD progression.3,4 However, only SMDA (measured using mass spectrometry) was found within the HDL fraction taken from patients with CKD, suggesting that SMDA may contribute to the d-HDL phenotype.1 Hesse et al.5 now provide evidence, in this issue, that glycocalyx damage resulting from SMDA 2 mM (a concentration seen in dialysis patients) is dependent on its association with HDL. This dose of SMDA in the absence of HDL had no significant effect on the glycocalyx of cultured endothelial cells. It should be noted that Hesse et al.5 could not isolate SMDA within d-HDL from patients with ESRD. However, given the elevated plasma levels of SMDA in dialysis patients, its known ability to associate with apolipoprotein 1, and the data suggesting that the presence of HDL is necessary for the 2-mM SMDA to have a Kidney International (2020) 97, 448–462
www.kidney-international.org
Magnesium as a Janus-faced inhibitor of calcification Yosuke Nakagawa1, Hirotaka Komaba1,2,3 and Masafumi Fukagawa1 Vascular calcification is a life-threatening complication in patients with chronic kidney disease. Magnesium is a potent inhibitor of calcification and attracting attention as a new therapeutic candidate. ter Braake and colleagues demonstrate that magnesium supplementation strikingly prevents vascular calcification in Klotho knockout mice. However, these mice also show osteomalacia, indicating that magnesium has a Janus face. Maximizing the beneficial effects of magnesium without causing bone mineralization defects is an important next challenge. Kidney International (2020) 97, 448–450; https://doi.org/10.1016/j.kint.2019.11.035 Copyright ª 2020, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see basic research on page 487
V
ascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD) and contributes to an increased risk of cardiovascular morbidity and mortality. The mechanism of VC is not just a passive precipitation of excess calcium and phosphorus but an active process of transformation from vascular smooth muscle cells into osteoblast-like cells. Accumulating data suggest an imbalance between vascular calcification inducers and inhibitors in the process of osteogenic smooth muscle cell transformation in CKD. One of such calcification inhibitors is Klotho, which was originally identified as a senescencerelated protein because Klotho-hypomorphic (kl/kl) mice develop complex phenotypes resembling human aging, including VC.1 1 Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; 2Interactive Translational Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan; and 3 The Institute of Medical Sciences, Tokai University, Isehara, Japan
Correspondence: Masafumi Fukagawa, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara 259-1193, Japan. E-mail: [email protected] 448
The principal role of transmembrane Klotho is to function as a coreceptor for fibroblast growth factor 23 (FGF23).2 Loss of Klotho hampers the classical, Klotho-mediated action of FGF23 and results in severe hyperphosphatemia and hypervitaminosis D. These alterations in mineral metabolism are considered to explain for the most part the premature aging and VC in kl/ kl mice, but recent studies suggest that the cleaved form of Klotho (soluble Klotho) could also directly inhibit VC.3 Despite recent progress in the treatment of CKD-mineral and bone disorder such as non–calcium-based phosphate binders and calcimimetics, preventing the development or progression of VC has been challenging. In this context, magnesium (Mg) has recently attracted attention as a new therapeutic candidate for VC. Experimental studies revealed that Mg inhibits calcification of vascular cells by preventing hydroxyapatite formation and osteogenic transformation.4 In support of these findings, observational studies showed an independent association between lower Mg concentrations and an elevated risk of all-cause and cardiovascular mortality in hemodialysis patients. Furthermore, a recent small randomized controlled trial demonstrated that oral Mg oxide suppressed the progression of
coronary artery calcification in patients with predialysis CKD.5 In this issue of Kidney International, ter Braake et al.6 explored the systemic effects of Mg supplementation in Klotho knockout (Klotho / ) mice, which show more severe VC compared to uremic animal models. The researchers demonstrated that 0.48% Mg diet compared with 0.05% Mg diet strikingly prevented VC in Klotho / mice. The protective effect of Mg against VC was accompanied by inhibition of aortic osteogenic signaling such as Runx2 and matrix Gla protein, and downregulation of pathways related to inflammation and extracellular matrix remodeling. In addition to the protective effect against VC, the investigators also observed a marked impairment of bone mineralization in Klotho / mice on high Mg diet, without evident changes in osteoblast and osteoclast activities. Clearly, the most noteworthy finding of the study by ter Braake et al. is that Mg supplementation could prevent the progression of VC in Klotho / mice. Although prior studies have already shown that high Mg diet inhibits the progression of VC in a 5/6 nephrectomy rat model,7 this paper represents an important addition to our knowledge as it confirms the protective effect of Mg against VC in a different animal model that develops more severe, lifethreatening VC. Furthermore, it should be acknowledged that Klotho / mice and uremic animal models share similar phenotypes including hyperphosphatemia, elevated FGF23, and Klotho deficiency, but differ in kidney function, calcium and vitamin D metabolism, and parathyroid function. Despite these differences, the present study reproduced the findings from 5/6 nephrectomized rats, which support the therapeutic potential of Mg supplementation against VC across diverse settings. There are several additional issues that should be addressed in this study. First, ter Braake et al. found that Klotho / mice on high Mg diet showed bone mineralization defects indicating osteomalacia. Because these mice did not have hypophosphatemia or low serum 1,25-dihydroxyvitamin D levels, Kidney International (2020) 97, 448–462
commentary
the observed osteomalacia is likely caused by a direct effect of high Mg levels to inhibit hydroxyapatite formation. Osteomalacia is a serious complication as it contributes to increased bone fragility, bone pain, and gait abnormalities. Indeed, in the present study, Klotho / mice on high Mg diet showed a more fragile appearance with lower body weight compared with Klotho / mice on low Mg diet. Interestingly, however, wild-type mice fed the same high Mg diet did not develop osteomalacia, suggesting that Klotho / mice are more susceptible to the skeletal effect of Mg supplementation. Klotho / mice are known to have a low bone turnover, which is mainly caused by suppressed parathyroid hormone levels owing to elevated 1,25-dihydroxyvitamin D levels and consequent hypercalcemia. It is possible that the low bone turnover state of Klotho / mice might have favored the mineralization-inhibiting effect of high Mg intake. Because patients with CKD display a wide spectrum of bone turnover, it is important to know whether the type of underlying bone metabolism changes the skeletal effect of oral Mg supplementation. Second, ter Braake et al. observed that serum levels of phosphorus and FGF23 were further increased by Mg supplementation in Klotho / mice. This finding was unexpected because Mg has the capacity to bind phosphate in the intestine. Although data on urinary phosphorus excretion were unavailable as metabolic cage experiments were impossible to conduct in the fragile Klotho / mice, the lack of differing in renal expression of Napi-2a and Napi-2c between Klotho / mice on high and low Mg diets suggests that urinary phosphorus excretion was comparable in the 2 groups. Thus, one can speculate that the paradoxical increase in serum phosphorus in Klotho / mice on high Mg diet is best explained by an increase in active intestinal phosphate transport, as suggested by the observed increase in Napi-2b expression. This possibility is in agreement with prior studies showing that administration of phosphate binders leads to a compensatory upregulation of Napi-2b expression and intestinal Kidney International (2020) 97, 448–462
phosphate absorption.8 However, it is difficult to imagine that the increased Napi-2b-dependent dietary phosphate absorption overwhelmed the phosphatebinding capacity of Mg. It appears more likely that the impaired bone mineralization in Klotho / mice on high Mg diet led to an increased phosphorus efflux from bone and thereby increased serum phosphorus levels. These changes in phosphate metabolism are largely different from those in patients with CKD treated with Mg, which necessitate careful interpretation of the results. Third, ter Braake et al. demonstrated that the inhibition of VC by Mg supplementation in Klotho / mice was accompanied by decreased expression of aortic osteogenic genes, suggesting that Mg prevented the process of osteogenic transformation in vascular smooth muscle cells. By contrast, Mg supplementation inhibited bone mineralization in these mice, but there was no decrease in the osteoblast surface. Likewise, Mg supplementation (2 mM) in Saos-2 osteoblasts reduced mineralization but did not affect osteogenic gene markers. It is, however, noteworthy that in a previous study of primary osteoblasts, supplementation with higher levels of Mg than the current study could suppress osteogenic differentiation.9 Thus, it could be
hypothesized that compared with skeletal osteoblasts, osteoblast-like vascular cells might be more susceptible to the anti-osteogenic effect of Mg. If so, this difference may provide a clue to maximize the protective effect against VC without causing bone mineralization defects, and additional studies are required to address this possibility. Finally, it is worth mentioning that the findings by ter Braake et al. have important implications for the design of future clinical trials of Mg supplementation. On the basis of their findings, it seems reasonable that future trials will focus on patients with progressive VC and exclude those who have a potential risk of osteomalacia, such as in the presence of hypophosphatemia, severe vitamin D deficiency, diabetes, and malnutrition. In conclusion, ter Braake et al. confirmed the therapeutic effects of Mg supplementation in Klotho / mice with rapidly progressing VC. Their findings support Mg supplementation as a promising therapeutic option even for advanced VC and provide an additional rationale for conducting clinical trials of Mg supplementation in CKD patients with VC. However, their study also highlights an adverse effect of Mg supplementation on bone mineralization, indicating that Mg supplementation has Pre-existing bone pathology
Mg supplementation
Inhibition of vascular calcification
Bone mineralization defects
Prevention of cardiovascular events
Osteomalacia
Better survival
Skeletal pain fractures
Figure 1 | The Janus face of magnesium (Mg). Mg supplementation inhibits vascular calcification, which will decrease the risk of cardiovascular disease and death. However, Mg supplementation also inhibits bone mineralization, which leads to osteomalacia and subsequent bone pain and increased fractures. The negative effect of Mg supplementation on bone might be enhanced in the presence of pre-existing bone pathology or other predisposing conditions. 449
commentary
a Janus face (Figure 1). Clearly, maximizing the beneficial effects of Mg while simultaneously minimizing the adverse effects is an important next challenge. DISCLOSURE
HK has received honoraria, consulting fees, and/or grant support from Bayer Yakuhin, Chugai Pharmaceutical, Japan Tobacco, Kyowa Kirin, Novartis, and Ono Pharmaceutical. MF has received honoraria, consulting fees, and/or grant support from Bayer Yakuhin, Fresenius Kabi, Kissei Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Torii Pharmaceutical. The other author declared no competing interests. REFERENCES 1. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51. 2. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444: 770–774.
3. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124–136. 4. Kircelli F, Peter ME, Sevinc Ok E, et al. Magnesium reduces calcification in bovine vascular smooth muscle cells in a dosedependent manner. Nephrol Dial Transplant. 2012;27:514–521. 5. Sakaguchi Y, Hamano T, Obi Y, et al. A randomized trial of magnesium oxide and oral carbon adsorbent for coronary artery calcification in predialysis CKD. J Am Soc Nephrol. 2019;30:1073–1085. 6. ter Braake AD, Smit AE, Bos C, et al. Magnesium prevents vascular calcification in Klotho deficiency. Kidney Int. 2020;97: 487–501. 7. Diaz-Tocados JM, Peralta-Ramirez A, Rodríguez-Ortiz ME, et al. Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats. Kidney Int. 2017;92:1084–1099. 8. Schiavi SC, Tang W, Bracken C, et al. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J Am Soc Nephrol. 2012;23:1691–1700. 9. Lu WC, Pringa E, Chou L. Effect of magnesium on the osteogenesis of normal human osteoblasts. Magnes Res. 2017;30:42–52.
Dysfunctional HDL takes its Toll on the endothelial glycocalyx Matthew J. Butler1 Patients with end-stage renal disease have a high risk of dying from cardiovascular disease that cannot be explained solely by traditional cardiovascular disease risk factors. Hesse et al. suggest that dysfunctional high-density lipoprotein cholesterol generated in patients with end-stage renal disease causes endothelial glycocalyx degradation. Glycocalyx degradation may represent one of the earliest insults leading to atheroma formation, and so this work suggests a novel link between renal failure and cardiovascular disease. Kidney International (2020) 97, 450–452; https://doi.org/10.1016/j.kint.2019.11.017 Crown Copyright ª 2020, Published by Elsevier, Inc., on behalf of the International Society of Nephrology. All rights reserved.
see basic research on page 502 1 Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Correspondence: Matthew J. Butler, Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. E-mail: [email protected] 450
H
istorically, high-density lipoprotein (HDL) has been seen as the good cholesterol, following a number of observational studies demonstrating an inverse relationship between cardiovascular disease (CVD) risk and HDL levels.1 However, in
patients with end-stage renal disease (ESRD) on hemodialysis, Moradi et al. demonstrated that the relationship between HDL and CVD risk might be more complicated, finding a U-shaped relationship between HDL concentrations and CVD risk.2 In patients on hemodialysis, HDL levels above 60 mg/dL were associated with increased CVD and overall mortality.2 The composition of HDL was not examined in this study, but Moradi’s work and that of others helped shift the popular view that all HDL is good cholesterol. Previously, work by Speer et al. confirmed that HDL from patients with chronic kidney disease (CKD) had an altered structure.1 This altered HDL reduced endothelial nitric-oxide synthase–activating phosphorylation and nitric oxide production in cultured human aortic endothelial cells via Toll-like receptors 2 (TLR2).1 They suggested that symmetric dimethylarginine (SMDA) could transform healthy HDL to a dysfunctional HDL (d-HDL) form.1 SMDA is an enantiomer of asymmetric dimethylarginine. Both SMDA and asymmetric dimethylarginine (ADMA) are endogenously generated from L-arginine.3 Both are considered uremic toxins, and elevated plasma levels are considered an independent risk factor for the development of CVD and CKD progression.3,4 However, only SMDA (measured using mass spectrometry) was found within the HDL fraction taken from patients with CKD, suggesting that SMDA may contribute to the d-HDL phenotype.1 Hesse et al.5 now provide evidence, in this issue, that glycocalyx damage resulting from SMDA 2 mM (a concentration seen in dialysis patients) is dependent on its association with HDL. This dose of SMDA in the absence of HDL had no significant effect on the glycocalyx of cultured endothelial cells. It should be noted that Hesse et al.5 could not isolate SMDA within d-HDL from patients with ESRD. However, given the elevated plasma levels of SMDA in dialysis patients, its known ability to associate with apolipoprotein 1, and the data suggesting that the presence of HDL is necessary for the 2-mM SMDA to have a Kidney International (2020) 97, 448–462