commentary
secondary lymph vessels. Identification of molecular mechanisms of lymphangiogenesis by vascular endothelial growth factors9 has opened insights into interstitial fluid physiology that go beyond the classical model. We now learn that immune function is modulated by lymph capillary function, regulatory growth factors, interstitial electrolyte concentration, and interstitial pressure, which suddenly become components determining the resolution of inflammatory responses, immunological tolerance and tumor growth,10 autoimmunity, and systemic blood pressure. We do not know whether or not the increases in interstitial fluid content and fluid pressure observed in CDK patients trigger similar immune responses in the human interstitium. Ebah and colleagues have provided clinical news from a ‘black box’, which has been named the ‘interstitium’. Evidence suggests that a more critical look into the inner workings of this black box provides promising and novel information.
8.
volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 2009; 15: 545–552. Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev 1990; 70: 987–1028.
9.
10.
Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 2010; 140: 460–476. Randolph GJ, Angeli V, Swartz MA. Dendriticcell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 2005; 5: 617–628.
see clinical investigation on pages 989 and 998
Serum phosphorus in people with chronic kidney disease: you are what you eat Marcello Tonelli1 This issue of Kidney International includes two important articles about serum phosphorus and its treatment. The article by Cannata-Andı´ a and colleagues describes a rigorous observational study of the association between serum phosphorus level, phosphate binder use, and clinical outcomes including all-cause and cardiovascular mortality. The article by Mehrotra and colleagues addresses the association between serum phosphorus, socioeconomic status, and mortality among participants in the US-based KEEP program. Kidney International (2013) 84, 871–873. doi:10.1038/ki.2013.258
ACKNOWLEDGMENTS
The author receives grant support from the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Economics and Technology/German Aerospace Center, and the Interdisciplinary Center for Clinical Research/Friedrich-Alexander-University Erlangen/Nu¨rnberg. REFERENCES 1.
2.
3.
4.
5.
6.
7.
Ebah LM, Wiig H, Dawidowska I et al. Subcutaneous interstitial pressure and volume characteristics in renal impairment associated with edema. Kidney Int 2013; 84: 980–988. Wiig H, Swartz MA. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev 2012; 92: 1005–1060. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 1896; 19: 312–326. Guyton AC. Interstitial fluid pressure. II. Pressure-volume curves of interstitial space. Circ Res 1965; 16: 452–460. Reed RK, Rubin K, Wiig H et al. Blockade of beta 1-integrins in skin causes edema through lowering of interstitial fluid pressure. Circ Res 1992; 71: 978–983. Adamson RH, Lenz JF, Zhang X et al. Oncotic pressures opposing filtration across nonfenestrated rat microvessels. J Physiol 2004; 557: 889–907. Machnik A, Neuhofer W, Jantsch J et al. Macrophages regulate salt-dependent
Kidney International (2013) 84
Control of serum phosphorus has become an important clinical priority in contemporary nephrology practice. This development was preceded by increasing interest in the prognostic significance of hyperphosphatemia among patients with end-stage renal disease. Subsequently, there were concerted efforts to specify tighter targets for serum phosphorus level and (because of concerns about vascular calcification) to reduce use of calciumbased phosphate binders. Initial enthusiasm for non-calcium-based binders based on theoretical grounds and observational studies (some positive1 and some negative2) has been tempered by the disappointing results of randomized trials that 1
Alberta Kidney Disease Network, University of Alberta, Edmonton, Alberta, Canada Correspondence: Marcello Tonelli, Alberta Kidney Disease Network, 7-129 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2C3. E-mail: [email protected]
showed similar outcomes regardless of the type of binder that was used. More recently, observational data have shown that modest increments in serum phosphorus level are associated with adverse clinical outcomes in people with only mildly reduced glomerular filtration rate—or even without any evident kidney disease. This issue of Kidney International includes two important articles about serum phosphorus and its treatment. The article by Cannata-Andı´a and colleagues3 describes a rigorous observational study of the association between serum phosphorus level, phosphate binder use, and clinical outcomes including all-cause and cardiovascular mortality (Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS)). The cohort of 6797 prevalent hemodialysis patients was partially funded by Amgen and enrolled patients from 227 dialysis units in 20 European countries. COSMOS is 871
commentary
notable because of its careful use of time-varying analysis and its matching of treatment and control participants on the propensity to receive phosphate binders. Like prior studies done in other settings, COSMOS found a significant association between prescription of phosphate binders and lower mortality. There were no convincing differences in mortality between the specific phosphate binders prescribed. Because patients were selected from participating dialysis units (rather than all eligible patients in each center being included) and the underlying hypotheses were known, skeptics will point out the potential for biased selection of treatment and control subjects. Those who persevere and read how the study was done (despite Kidney International’s odd practice of placing Methods after the Discussion) will note other potential limitations—including the focus on prevalent patients (introducing the possibility of survivor bias), the use of stratification to account for center effects (rather than more robust statistical methods), and the use of an ‘open-cohort’ design, where patients who died or received a transplant were replaced in the cohort by other patients drawn from the same dialysis facility. The latter is not necessarily inappropriate but might complicate interpretation of absolute mortality rates. As the COSMOS investigators point out, observational studies of treatments should not be used as the basis for treatment decisions—and additional randomized trials are clearly needed. Consideration should be given to a randomized trial that compares tight and liberal strategies for phosphorus control in end-stage renal disease patients—perhaps with serum phosphorus targets of o1.6 and o2.5 mmol/l. As phosphate binders can cause harm, such a trial should collect information on quality of life and side effects as well as mortality and cardiovascular events. The article by Mehrotra and colleagues4 (this issue) addresses the association between serum phosphorus, socioeconomic status, and mortality 872
among 10,672 participants in the USbased Kidney Early Evaluation Program (KEEP). KEEP is a large case-finding program that seeks to identify unrecognized chronic kidney disease among people with one or more risk factors. Since previous studies suggest that higher serum phosphorus is associated with lower socioeconomic status, Mehrotra et al. hypothesized that the latter characteristic would confound the association between serum phosphorus and adverse outcomes in KEEP. However, higher levels of serum phosphorus did not correlate with increased mortality among KEEP participants. This finding is worth reporting because
several prior studies have shown an association between higher levels of serum phosphorus and increased mortality in populations with non-dialysisdependent chronic kidney disease, as well as in the general population.5–8 Differences between the populations studied appear to be the most likely explanation for the discrepant findings in KEEP. Other possibilities might include random error in the KEEP serum phosphorus measurements (due to failure to account for fasting status and/or differences in assays between the two KEEP laboratories) or the relatively short follow-up in KEEP. Regardless of the explanation, the findings of this
Figure 1 | The FoodSwitch smartphone app (developed by the George Institute for Global Health and Bupa) allows consumers to scan the barcode of a food product and view its sodium, fat, sugar, and gluten content, rated on a three-category traffic-light scale (red, yellow, green). Alternative products with lower sodium and glycemic content or gluten-free status can also be displayed below the product being viewed. If better information were available on the phosphorus content of processed foods, a similar app could be developed to help kidney patients to control their serum phosphorus levels. The FoodSwitch app is available at www.bupa.com.au/foodswitch. Kidney International (2013) 84
commentary
analysis from KEEP are important because they highlight broader uncertainties about the clinical and publichealth significance of levels of serum phosphorus that are higher than average but do not represent overt hyperphosphatemia. A recent conference sponsored by the National Kidney Foundation focused on the public-health implications of higher serum phosphorus levels in early chronic kidney disease.9 Attendees highlighted uncertainties about how best to measure exposure to phosphorus, the potential for differential absorption of plant- versus animalbased sources of dietary protein, the weak data linking dietary phosphorus intake to serum phosphorus levels in people without kidney failure, and (relevant to the study by Mehrotra et al.4) the need to confirm in a broader range of populations the apparent link between higher levels of serum phosphorus and adverse outcome. An especially interesting discussion highlighted the potential importance of secular changes in the use of food additives for exposure to dietary phosphorus—and, by extension, for serum phosphorus levels. Phosphoruscontaining additives are now ubiquitous in food, can increase the phosphorus content of food by as much as 80%, and are much better absorbed than phosphorus from dietary protein. The presence of these additives makes traditional estimates of food phosphorus content completely inaccurate—and food labels in North America do not include quantitative estimates of phosphorus content. These observations lead to two important conclusions for nephrologists. First, our current approach to control of serum phosphorus is unfair and irrational. We nag our dialysis patients to eat less phosphorus but generally do
Kidney International (2013) 84
not provide them with the information they need to achieve this goal. When patients fail to achieve the unilaterally determined phosphorus targets, we then prescribe phosphate binders, which may not improve patient-important outcomes but which often lead to side effects. As a community, we should either de-emphasize phosphorus targets until more is known about their benefits, increase our focus on controlling serum phosphorus through diet, or perhaps both. Structured counseling about the potential merits of avoiding foods with phosphorus-based additives,10 and emphasizing of the merits of plant-based proteins (rather than those from meat or dairy sources11), may help to achieve this goal. In addition, the renal community should work toward the development of a patient tool (similar to the FoodSwitch app developed by the George Institute;12 Figure 1). Such a tool could provide patients with suggestions for alternative products that contain less total phosphorus (inclusive of additives). This initiative would require a comprehensive effort to document the total phosphorus content of available foods. Second, phosphorus-based additives are ‘generally regarded as safe’ by the US Food and Drug Administration, meaning that any regulatory oversight is very light. Current evidence does not permit a firm conclusion about whether these additives contribute to the putative association between higher levels of serum phosphorus and adverse outcomes. On the other hand, it has been known for thousands of years that poor diet can cause disease. The liberal use of phosphorus-based chemicals in our food despite their uncertain implications for health should make us think about the broader implications of all food additives—for ourselves and our families as well as our patients.
DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
Dr Tonelli is supported by an AHFMR Population Health Scholar award and a Government of Canada Research Chair in the optimal care of people with chronic kidney disease. He holds a peer-reviewed operating grant from the Canadian Institutes of Health Research through the Industry-Partnered Operating Grant Competition, with partnered funding provided by Abbott Laboratories. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Isakova T, Gutie´rrez OM, Chang Y et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009; 20: 388–396. Winkelmayer WC, Liu J, Kestenbaum B. Comparative effectiveness of calciumcontaining phosphate binders in incident U.S. dialysis patients. Clin J Am Soc Nephrol 2001; 6: 175–183. Cannata-Andı´a JB, Ferna´ndez-Martı´n JL, Locatelli F et al. Use of phosphate-binding agents is associated with a lower risk of mortality. Kidney Int 2013; 84: 998–1008. Mehrohta R, Peralta CA, Chen S-C et al. No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease. Kidney Int 2013; 84: 989–997. Kestenbaum B. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16: 520–528. Dhingra R, Sullivan LM, Fox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007; 167: 879–885. Tonelli M, Sacks F, Pfeffer M et al. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005; 112: 2627–2633. Foley RN. Phosphate levels and cardiovascular disease in the general population. Clin J Am Soc Nephrol 2009; 4: 1136–1139. The Public Health Impact of Phosphate Homeostasis in Early CKD [conference]. 17–18 February 2012; Miami, FL. Sullivan C, Sayre SS, Leon JB et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial. JAMA 2009; 301: 629–635. Moe SM, Zidehsarai MP, Chambers MA et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6: 257–264. FoodSwitch. Bupa. owww.bupa.com.au/ health-and-wellness/tools-and-apps/mobileapps/foodswitch-app4.
873
secondary lymph vessels. Identification of molecular mechanisms of lymphangiogenesis by vascular endothelial growth factors9 has opened insights into interstitial fluid physiology that go beyond the classical model. We now learn that immune function is modulated by lymph capillary function, regulatory growth factors, interstitial electrolyte concentration, and interstitial pressure, which suddenly become components determining the resolution of inflammatory responses, immunological tolerance and tumor growth,10 autoimmunity, and systemic blood pressure. We do not know whether or not the increases in interstitial fluid content and fluid pressure observed in CDK patients trigger similar immune responses in the human interstitium. Ebah and colleagues have provided clinical news from a ‘black box’, which has been named the ‘interstitium’. Evidence suggests that a more critical look into the inner workings of this black box provides promising and novel information.
8.
volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 2009; 15: 545–552. Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev 1990; 70: 987–1028.
9.
10.
Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 2010; 140: 460–476. Randolph GJ, Angeli V, Swartz MA. Dendriticcell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol 2005; 5: 617–628.
see clinical investigation on pages 989 and 998
Serum phosphorus in people with chronic kidney disease: you are what you eat Marcello Tonelli1 This issue of Kidney International includes two important articles about serum phosphorus and its treatment. The article by Cannata-Andı´ a and colleagues describes a rigorous observational study of the association between serum phosphorus level, phosphate binder use, and clinical outcomes including all-cause and cardiovascular mortality. The article by Mehrotra and colleagues addresses the association between serum phosphorus, socioeconomic status, and mortality among participants in the US-based KEEP program. Kidney International (2013) 84, 871–873. doi:10.1038/ki.2013.258
ACKNOWLEDGMENTS
The author receives grant support from the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Economics and Technology/German Aerospace Center, and the Interdisciplinary Center for Clinical Research/Friedrich-Alexander-University Erlangen/Nu¨rnberg. REFERENCES 1.
2.
3.
4.
5.
6.
7.
Ebah LM, Wiig H, Dawidowska I et al. Subcutaneous interstitial pressure and volume characteristics in renal impairment associated with edema. Kidney Int 2013; 84: 980–988. Wiig H, Swartz MA. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev 2012; 92: 1005–1060. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 1896; 19: 312–326. Guyton AC. Interstitial fluid pressure. II. Pressure-volume curves of interstitial space. Circ Res 1965; 16: 452–460. Reed RK, Rubin K, Wiig H et al. Blockade of beta 1-integrins in skin causes edema through lowering of interstitial fluid pressure. Circ Res 1992; 71: 978–983. Adamson RH, Lenz JF, Zhang X et al. Oncotic pressures opposing filtration across nonfenestrated rat microvessels. J Physiol 2004; 557: 889–907. Machnik A, Neuhofer W, Jantsch J et al. Macrophages regulate salt-dependent
Kidney International (2013) 84
Control of serum phosphorus has become an important clinical priority in contemporary nephrology practice. This development was preceded by increasing interest in the prognostic significance of hyperphosphatemia among patients with end-stage renal disease. Subsequently, there were concerted efforts to specify tighter targets for serum phosphorus level and (because of concerns about vascular calcification) to reduce use of calciumbased phosphate binders. Initial enthusiasm for non-calcium-based binders based on theoretical grounds and observational studies (some positive1 and some negative2) has been tempered by the disappointing results of randomized trials that 1
Alberta Kidney Disease Network, University of Alberta, Edmonton, Alberta, Canada Correspondence: Marcello Tonelli, Alberta Kidney Disease Network, 7-129 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2C3. E-mail: [email protected]
showed similar outcomes regardless of the type of binder that was used. More recently, observational data have shown that modest increments in serum phosphorus level are associated with adverse clinical outcomes in people with only mildly reduced glomerular filtration rate—or even without any evident kidney disease. This issue of Kidney International includes two important articles about serum phosphorus and its treatment. The article by Cannata-Andı´a and colleagues3 describes a rigorous observational study of the association between serum phosphorus level, phosphate binder use, and clinical outcomes including all-cause and cardiovascular mortality (Current Management of Secondary Hyperparathyroidism: A Multicenter Observational Study (COSMOS)). The cohort of 6797 prevalent hemodialysis patients was partially funded by Amgen and enrolled patients from 227 dialysis units in 20 European countries. COSMOS is 871
commentary
notable because of its careful use of time-varying analysis and its matching of treatment and control participants on the propensity to receive phosphate binders. Like prior studies done in other settings, COSMOS found a significant association between prescription of phosphate binders and lower mortality. There were no convincing differences in mortality between the specific phosphate binders prescribed. Because patients were selected from participating dialysis units (rather than all eligible patients in each center being included) and the underlying hypotheses were known, skeptics will point out the potential for biased selection of treatment and control subjects. Those who persevere and read how the study was done (despite Kidney International’s odd practice of placing Methods after the Discussion) will note other potential limitations—including the focus on prevalent patients (introducing the possibility of survivor bias), the use of stratification to account for center effects (rather than more robust statistical methods), and the use of an ‘open-cohort’ design, where patients who died or received a transplant were replaced in the cohort by other patients drawn from the same dialysis facility. The latter is not necessarily inappropriate but might complicate interpretation of absolute mortality rates. As the COSMOS investigators point out, observational studies of treatments should not be used as the basis for treatment decisions—and additional randomized trials are clearly needed. Consideration should be given to a randomized trial that compares tight and liberal strategies for phosphorus control in end-stage renal disease patients—perhaps with serum phosphorus targets of o1.6 and o2.5 mmol/l. As phosphate binders can cause harm, such a trial should collect information on quality of life and side effects as well as mortality and cardiovascular events. The article by Mehrotra and colleagues4 (this issue) addresses the association between serum phosphorus, socioeconomic status, and mortality 872
among 10,672 participants in the USbased Kidney Early Evaluation Program (KEEP). KEEP is a large case-finding program that seeks to identify unrecognized chronic kidney disease among people with one or more risk factors. Since previous studies suggest that higher serum phosphorus is associated with lower socioeconomic status, Mehrotra et al. hypothesized that the latter characteristic would confound the association between serum phosphorus and adverse outcomes in KEEP. However, higher levels of serum phosphorus did not correlate with increased mortality among KEEP participants. This finding is worth reporting because
several prior studies have shown an association between higher levels of serum phosphorus and increased mortality in populations with non-dialysisdependent chronic kidney disease, as well as in the general population.5–8 Differences between the populations studied appear to be the most likely explanation for the discrepant findings in KEEP. Other possibilities might include random error in the KEEP serum phosphorus measurements (due to failure to account for fasting status and/or differences in assays between the two KEEP laboratories) or the relatively short follow-up in KEEP. Regardless of the explanation, the findings of this
Figure 1 | The FoodSwitch smartphone app (developed by the George Institute for Global Health and Bupa) allows consumers to scan the barcode of a food product and view its sodium, fat, sugar, and gluten content, rated on a three-category traffic-light scale (red, yellow, green). Alternative products with lower sodium and glycemic content or gluten-free status can also be displayed below the product being viewed. If better information were available on the phosphorus content of processed foods, a similar app could be developed to help kidney patients to control their serum phosphorus levels. The FoodSwitch app is available at www.bupa.com.au/foodswitch. Kidney International (2013) 84
commentary
analysis from KEEP are important because they highlight broader uncertainties about the clinical and publichealth significance of levels of serum phosphorus that are higher than average but do not represent overt hyperphosphatemia. A recent conference sponsored by the National Kidney Foundation focused on the public-health implications of higher serum phosphorus levels in early chronic kidney disease.9 Attendees highlighted uncertainties about how best to measure exposure to phosphorus, the potential for differential absorption of plant- versus animalbased sources of dietary protein, the weak data linking dietary phosphorus intake to serum phosphorus levels in people without kidney failure, and (relevant to the study by Mehrotra et al.4) the need to confirm in a broader range of populations the apparent link between higher levels of serum phosphorus and adverse outcome. An especially interesting discussion highlighted the potential importance of secular changes in the use of food additives for exposure to dietary phosphorus—and, by extension, for serum phosphorus levels. Phosphoruscontaining additives are now ubiquitous in food, can increase the phosphorus content of food by as much as 80%, and are much better absorbed than phosphorus from dietary protein. The presence of these additives makes traditional estimates of food phosphorus content completely inaccurate—and food labels in North America do not include quantitative estimates of phosphorus content. These observations lead to two important conclusions for nephrologists. First, our current approach to control of serum phosphorus is unfair and irrational. We nag our dialysis patients to eat less phosphorus but generally do
Kidney International (2013) 84
not provide them with the information they need to achieve this goal. When patients fail to achieve the unilaterally determined phosphorus targets, we then prescribe phosphate binders, which may not improve patient-important outcomes but which often lead to side effects. As a community, we should either de-emphasize phosphorus targets until more is known about their benefits, increase our focus on controlling serum phosphorus through diet, or perhaps both. Structured counseling about the potential merits of avoiding foods with phosphorus-based additives,10 and emphasizing of the merits of plant-based proteins (rather than those from meat or dairy sources11), may help to achieve this goal. In addition, the renal community should work toward the development of a patient tool (similar to the FoodSwitch app developed by the George Institute;12 Figure 1). Such a tool could provide patients with suggestions for alternative products that contain less total phosphorus (inclusive of additives). This initiative would require a comprehensive effort to document the total phosphorus content of available foods. Second, phosphorus-based additives are ‘generally regarded as safe’ by the US Food and Drug Administration, meaning that any regulatory oversight is very light. Current evidence does not permit a firm conclusion about whether these additives contribute to the putative association between higher levels of serum phosphorus and adverse outcomes. On the other hand, it has been known for thousands of years that poor diet can cause disease. The liberal use of phosphorus-based chemicals in our food despite their uncertain implications for health should make us think about the broader implications of all food additives—for ourselves and our families as well as our patients.
DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
Dr Tonelli is supported by an AHFMR Population Health Scholar award and a Government of Canada Research Chair in the optimal care of people with chronic kidney disease. He holds a peer-reviewed operating grant from the Canadian Institutes of Health Research through the Industry-Partnered Operating Grant Competition, with partnered funding provided by Abbott Laboratories. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Isakova T, Gutie´rrez OM, Chang Y et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009; 20: 388–396. Winkelmayer WC, Liu J, Kestenbaum B. Comparative effectiveness of calciumcontaining phosphate binders in incident U.S. dialysis patients. Clin J Am Soc Nephrol 2001; 6: 175–183. Cannata-Andı´a JB, Ferna´ndez-Martı´n JL, Locatelli F et al. Use of phosphate-binding agents is associated with a lower risk of mortality. Kidney Int 2013; 84: 998–1008. Mehrohta R, Peralta CA, Chen S-C et al. No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease. Kidney Int 2013; 84: 989–997. Kestenbaum B. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005; 16: 520–528. Dhingra R, Sullivan LM, Fox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 2007; 167: 879–885. Tonelli M, Sacks F, Pfeffer M et al. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 2005; 112: 2627–2633. Foley RN. Phosphate levels and cardiovascular disease in the general population. Clin J Am Soc Nephrol 2009; 4: 1136–1139. The Public Health Impact of Phosphate Homeostasis in Early CKD [conference]. 17–18 February 2012; Miami, FL. Sullivan C, Sayre SS, Leon JB et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial. JAMA 2009; 301: 629–635. Moe SM, Zidehsarai MP, Chambers MA et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6: 257–264. FoodSwitch. Bupa. owww.bupa.com.au/ health-and-wellness/tools-and-apps/mobileapps/foodswitch-app4.
873
