commentary
respective peritoneal membrane transport type;9 and a moderate dietary restriction of salt and water intake. The results of the recently published balANZ trial10 might indicate that the use of biocompatible peritoneal dialysis fluids containing low concentrations of glucose-degradation products may play an additional role in the preservation of both RRF and peritoneal membrane integrity. On the other hand, the potential benefits of icodextrin in augmenting peritoneal ultrafiltration must be tempered by the observation that icodextrin usage may risk hypovolemia, so possibly risking loss of RRF.6 Finally, as with most treatment paradigms in clinical practice, the proof of the pudding is in the eating. At the end of the day, prospective randomized controlled trials will be needed to confirm that the proposed strategy not only is intuitively attractive, but will actually lead to improved patient outcomes. However, in view of the different combinations of interventions to be tested, such a randomized controlled trial might not be realistic. A prospective observational cohort study, where the outcome of different treatment strategies is followed, might be a more realistic and achievable design. DISCLOSURE
Wim Van Biesen is the principal investigator of the European Body Composition Monitoring (EuroBCM) trial and the Initiative for Patient Outcomes in Dialysis in PD trial. He has received travel fees from Fresenius and Baxter. Achim Jo¨rres has received research support from Fresenius and speaker honoraria from Fresenius and Gambro. REFERENCES 1.
2.
3.
4.
Bargman JM, Thorpe KE, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001; 12: 2158–2162. Van Biesen W, Lameire N, Verbeke F et al. Residual renal function and volume status in peritoneal dialysis patients: a conflict of interest? J Nephrol 2008; 21: 299–304. Van Biesen W, Williams JD, Covic AC et al. Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort. PLoS One [online] 2011; 6: e17148. McCafferty K, Fan S, Davenport A. Extracellular volume expansion, measured by multifrequency bioimpedance, does not help preserve residual renal function in
Kidney International (2014) 85
5.
6.
7.
peritoneal dialysis patients. Kidney Int 2013; 85: 151–157. Davies SJ, Woodrow G, Donovan K et al. Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003; 14: 2338–2344. Konings CJ, Kooman JP, Gladziwa U et al. A decline in residual glomerular filtration during the use of icodextrin may be due to underhydration. Kidney Int 2005; 67: 1190–1191. Cianciaruso B, Bellizzi V, Minutolo R et al. Salt intake and renal outcome in patients with progressive renal disease. Miner Electrolyte Metab 1988; 24: 296–301.
8.
9.
10.
Davies SJ, Phillips L, Naish PF et al. Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001; 12: 1046–1051. van Biesen W, Heimburger O, Krediet R et al. Evaluation of peritoneal membrane characteristics: clinical advice for prescription management by the ERBP working group. Nephrol Dial Transplant 2010; 25: 2052–2062. Johnson DW, Brown FG, Clarke M et al. Effects of biocompatible versus standard fluid on peritoneal dialysis outcomes. J Am Soc Nephrol 2012; 23: 1097–1107.
see clinical investigation on page 174
Magnesium and the risk of all-cause and cardiac mortality in hemodialysis patients: agent provocateur or innocent bystander? Cecile Courivaud1 and Andrew Davenport2 There have been previous reports of hypomagnesemia associated with increased cardiovascular risk in hemodialysis patients. However, these reports were often confounded by hypomagnesemia linked to increased patient co-morbidity. Sakaguchi and colleagues now report increased patient survival, with both reduced all-cause and cardiovascular mortality for those with mild hypomagnesemia, compared to patients with both normal and low serum magnesium concentrations, and also those with moderate hypomagnesemia. Kidney International (2013) 85, 17–20. doi:10.1038/ki.2013.301
Sakaguchi and colleagues report an association between serum magnesium and both 1-year all-cause and cardiac mortality in a Japanese hemodialysis registry cohort of almost 150,000 patients,1 with 1-year mortality increased for both those in the lowest and highest 1 Department of Nephrology, Universite´ de Franche-Comte´, UMR645, INSERM, Besanc¸on, France and 2Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK Correspondence: Andrew Davenport, Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK. E-mail: [email protected]
serum magnesium ranges. Several other observational hemodialysis studies have similarly reported increased mortality for patient cohorts with the highest and lowest serum potassium and phosphate concentrations. As such, the question arises as to whether magnesium is a true agent provocateur or simply an innocent bystander. Magnesium along with potassium is the dominant intracellular cation. As magnesium acts as a catalyst or activator for many intracellular enzymatic reactions, particularly those which depend upon ATP, and the magnesium–ATP complex is a key intermediate 17
commentary
substrate, then both hypo- and hypomagnesemia could have detrimental effects on intracellular metabolism. Hypomagnesemia has been linked with increased co-morbidity and cardiovascular risk factors; including C-reactive protein (CRP), atherosclerosis, hypertension, and dyslipidemia. Epidemiological studies and clinical trials have demonstrated an inverse association between blood pressure and serum magnesium, as magnesium can act as a calcium channel antagonist, stimulating prostacyclins and nitric oxide, and altering the vascular response to vasoactive agonists.2 Hypomagnesemia exacerbates both atrial and ventricular arrhythmias associated with hypokalemia, and may increase the risk of sudden cardiac death, with a recent meta-analysis reporting a 30% increase in cardiovascular disease for every 0.49 mg/dl (0.2 mmol/l) decrease in serum magnesium within the normal range.3 In vitro, exposure of endothelial cells to low magnesium levels causes them to express an inflammatory phenotype, and in vivo hypomagnesemia is associated with increased CRP, leukocyte and macrophage activation, NFkB, cytokines, and platelet aggregation. Increased endothelial permeability increases lipid penetration into the vascular media, leading to foam cells, plaque formation and increased oxidative stress.4 Hypomagnesemia promotes hypercholesterolemia by increasing both the inactive forms of HMGCo-A reductase, and post receptor insulin resistance.5,6 Conversely, magnesium supplementation has been reported to reduce carotid intima medial thickness in dialysis patients.7 Magnesium is also well recognized to prevent soft tissue calcification and renal stone formation, by inhibiting hydroxyapatite formation and increasing natural inhibitors of calcification (fetuin A, osteoprotegerin, and undercarboxylated-matrix Gla protein).8 Sakaguchi and colleagues now report both higher all-cause and cardiovascular mortality in Japanese hemodialysis patients both in the lowest magnesium sextile (o2.3 mg/dl, o0.95 mmol/l), and also in the highest (X3.1 mg/dl, 41.27 mmol/l). 18
Serum magnesium reflects the balance between dietary intake and gastrointestinal absorption and renal regulation (reabsorption and excretion). Whereas calcium homeostasis is under hormonal control, to date, no specific magnesium regulating hormone has been identified. Hemodialysis patients have a tendency to become hypermagnesemic, whereas hypomagnesemia, defined as a serum level o1.8 mg/dl (o0.74 mmol/l), is relatively uncommon (o1%), and typically observed in association with hypokalemia and hypophosphatemia. It is unclear as to how many patients were frankly hypomagnesemic or simply had low-normal serum magnesium results, as the lowest sextile serum magnesium concentration was o2.3 mg/dl (o0.95 mmol/l). The inverse correlation reported between serum magnesium and deaths from infections is interesting. However, this effect was markedly reduced, when patients with elevated high sensitivity CRP values were excluded from analysis, with only an increased mortality remaining for the lowest sextile. Although there were no data presented on serum potassium, predialysis serum urea, albumin, and phosphate appeared to be least in the lowest magnesium sextile and higher with higher magnesium levels. Similarly there was a trend for more older patients, diabetics, and those with a medical history of ischemic heart disease, stroke, amputation, or hip fracture to be represented in the lowest sextile. This would suggest that dietary factors and patient co-morbidity have a major influence on serum magnesium, and may have accounted in part for the increased mortality reported. POTENTIAL ADVERSE EFFECTS OF HYPERMAGNESEMIA
Ten to fifteen percent of hemodialysis patients have been reported to have hypermagnesemia, defined as a serum magnesium X2.8 mg/dl (1.15 mmol/l). Although oral magnesium intake can be increased by ingestion of magnesium-containing antacids and laxatives, the dialysate magnesium concentration may affect magnesium balance in
hemodialysis patients, with studies reporting a decrease in serum magnesium from 3.4–2.1 mg/dl (1.4–0.86 mmol/l) with 0.5 mEq/l (0.25 mmol/l) dialysate, whereas there was no change in serum magnesium using a 1.5 mEq/l (0.75 mmol/l) dialysate.9 The majority of patients used a dialysate concentration of 1 mEq/l (0.5 mmol/l, in this Japanese study, similar to the normal ionized serum magnesium of 0.5 mmol/l. Sakaguchi and colleagues report 32.4% of patients were hypermagnesemic, and used the sextile with serum magnesium concentrations of 2.8–o3.1 mg/dl (1.15–1.27 mmol/l) as the reference cohort for all analyses. The uppermost sextile had a serum magnesium 43.1 mg/dl (41.27 mmol/l), but it is unclear as to how many, if any patients had severe hypermagnesemia, which is a potentially serious condition leading to hypotension, nausea, vomiting, and facial flushing with serum magnesium values of 4–6 mg/dl (1.64–2.47 mmol/l). Higher magnesium concentrations can result in flaccid muscle paralysis, hyporeflexia, bradycardia, respiratory depression, coma, and cardiac arrest when values reach 10–20 mg/dl (4.1–8.2 mmol/l). Milder forms of hypermagnesemia inhibit PTH secretion, and predispose to adynamic bone disease, which is an important risk factor for soft tissue and vascular calcification, and mortality in hemodialysis patients. Reducing the dialysate magnesium concentration from 1.5–0.5 mEq/l (0.75–0.25 mmol/l) has been reported to decrease serum magnesium and increase serum PTH, whereas increasing the dialysate magnesium decreased PTH.10 So on one hand, magnesium can reduce soft tissue and vascular calcification, yet on the other, inhibiting PTH secretion increases the risk of low bone turnover by inhibiting osteoid mineralization and bone formation, and so in the longer term potentially affecting bone structure and also increasing the risk for soft tissue and vascular calcification in the dialysis patient. Although serum PTH appeared similar across the six serum magnesium Kidney International (2014) 85
commentary
Mortality HyperMg without low PTH
Vascular calcification
?
Serum PTH level Adynamic bone disease
All hyperMg HyperMg
Normal range 1.8 mg/dl < magnesemia < 2.8 mg/dl
Mg < 1.8
respective peritoneal membrane transport type;9 and a moderate dietary restriction of salt and water intake. The results of the recently published balANZ trial10 might indicate that the use of biocompatible peritoneal dialysis fluids containing low concentrations of glucose-degradation products may play an additional role in the preservation of both RRF and peritoneal membrane integrity. On the other hand, the potential benefits of icodextrin in augmenting peritoneal ultrafiltration must be tempered by the observation that icodextrin usage may risk hypovolemia, so possibly risking loss of RRF.6 Finally, as with most treatment paradigms in clinical practice, the proof of the pudding is in the eating. At the end of the day, prospective randomized controlled trials will be needed to confirm that the proposed strategy not only is intuitively attractive, but will actually lead to improved patient outcomes. However, in view of the different combinations of interventions to be tested, such a randomized controlled trial might not be realistic. A prospective observational cohort study, where the outcome of different treatment strategies is followed, might be a more realistic and achievable design. DISCLOSURE
Wim Van Biesen is the principal investigator of the European Body Composition Monitoring (EuroBCM) trial and the Initiative for Patient Outcomes in Dialysis in PD trial. He has received travel fees from Fresenius and Baxter. Achim Jo¨rres has received research support from Fresenius and speaker honoraria from Fresenius and Gambro. REFERENCES 1.
2.
3.
4.
Bargman JM, Thorpe KE, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001; 12: 2158–2162. Van Biesen W, Lameire N, Verbeke F et al. Residual renal function and volume status in peritoneal dialysis patients: a conflict of interest? J Nephrol 2008; 21: 299–304. Van Biesen W, Williams JD, Covic AC et al. Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort. PLoS One [online] 2011; 6: e17148. McCafferty K, Fan S, Davenport A. Extracellular volume expansion, measured by multifrequency bioimpedance, does not help preserve residual renal function in
Kidney International (2014) 85
5.
6.
7.
peritoneal dialysis patients. Kidney Int 2013; 85: 151–157. Davies SJ, Woodrow G, Donovan K et al. Icodextrin improves the fluid status of peritoneal dialysis patients: results of a double-blind randomized controlled trial. J Am Soc Nephrol 2003; 14: 2338–2344. Konings CJ, Kooman JP, Gladziwa U et al. A decline in residual glomerular filtration during the use of icodextrin may be due to underhydration. Kidney Int 2005; 67: 1190–1191. Cianciaruso B, Bellizzi V, Minutolo R et al. Salt intake and renal outcome in patients with progressive renal disease. Miner Electrolyte Metab 1988; 24: 296–301.
8.
9.
10.
Davies SJ, Phillips L, Naish PF et al. Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001; 12: 1046–1051. van Biesen W, Heimburger O, Krediet R et al. Evaluation of peritoneal membrane characteristics: clinical advice for prescription management by the ERBP working group. Nephrol Dial Transplant 2010; 25: 2052–2062. Johnson DW, Brown FG, Clarke M et al. Effects of biocompatible versus standard fluid on peritoneal dialysis outcomes. J Am Soc Nephrol 2012; 23: 1097–1107.
see clinical investigation on page 174
Magnesium and the risk of all-cause and cardiac mortality in hemodialysis patients: agent provocateur or innocent bystander? Cecile Courivaud1 and Andrew Davenport2 There have been previous reports of hypomagnesemia associated with increased cardiovascular risk in hemodialysis patients. However, these reports were often confounded by hypomagnesemia linked to increased patient co-morbidity. Sakaguchi and colleagues now report increased patient survival, with both reduced all-cause and cardiovascular mortality for those with mild hypomagnesemia, compared to patients with both normal and low serum magnesium concentrations, and also those with moderate hypomagnesemia. Kidney International (2013) 85, 17–20. doi:10.1038/ki.2013.301
Sakaguchi and colleagues report an association between serum magnesium and both 1-year all-cause and cardiac mortality in a Japanese hemodialysis registry cohort of almost 150,000 patients,1 with 1-year mortality increased for both those in the lowest and highest 1 Department of Nephrology, Universite´ de Franche-Comte´, UMR645, INSERM, Besanc¸on, France and 2Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK Correspondence: Andrew Davenport, Centre for Nephrology, Royal Free Hospital, University College London Medical School, London, UK. E-mail: [email protected]
serum magnesium ranges. Several other observational hemodialysis studies have similarly reported increased mortality for patient cohorts with the highest and lowest serum potassium and phosphate concentrations. As such, the question arises as to whether magnesium is a true agent provocateur or simply an innocent bystander. Magnesium along with potassium is the dominant intracellular cation. As magnesium acts as a catalyst or activator for many intracellular enzymatic reactions, particularly those which depend upon ATP, and the magnesium–ATP complex is a key intermediate 17
commentary
substrate, then both hypo- and hypomagnesemia could have detrimental effects on intracellular metabolism. Hypomagnesemia has been linked with increased co-morbidity and cardiovascular risk factors; including C-reactive protein (CRP), atherosclerosis, hypertension, and dyslipidemia. Epidemiological studies and clinical trials have demonstrated an inverse association between blood pressure and serum magnesium, as magnesium can act as a calcium channel antagonist, stimulating prostacyclins and nitric oxide, and altering the vascular response to vasoactive agonists.2 Hypomagnesemia exacerbates both atrial and ventricular arrhythmias associated with hypokalemia, and may increase the risk of sudden cardiac death, with a recent meta-analysis reporting a 30% increase in cardiovascular disease for every 0.49 mg/dl (0.2 mmol/l) decrease in serum magnesium within the normal range.3 In vitro, exposure of endothelial cells to low magnesium levels causes them to express an inflammatory phenotype, and in vivo hypomagnesemia is associated with increased CRP, leukocyte and macrophage activation, NFkB, cytokines, and platelet aggregation. Increased endothelial permeability increases lipid penetration into the vascular media, leading to foam cells, plaque formation and increased oxidative stress.4 Hypomagnesemia promotes hypercholesterolemia by increasing both the inactive forms of HMGCo-A reductase, and post receptor insulin resistance.5,6 Conversely, magnesium supplementation has been reported to reduce carotid intima medial thickness in dialysis patients.7 Magnesium is also well recognized to prevent soft tissue calcification and renal stone formation, by inhibiting hydroxyapatite formation and increasing natural inhibitors of calcification (fetuin A, osteoprotegerin, and undercarboxylated-matrix Gla protein).8 Sakaguchi and colleagues now report both higher all-cause and cardiovascular mortality in Japanese hemodialysis patients both in the lowest magnesium sextile (o2.3 mg/dl, o0.95 mmol/l), and also in the highest (X3.1 mg/dl, 41.27 mmol/l). 18
Serum magnesium reflects the balance between dietary intake and gastrointestinal absorption and renal regulation (reabsorption and excretion). Whereas calcium homeostasis is under hormonal control, to date, no specific magnesium regulating hormone has been identified. Hemodialysis patients have a tendency to become hypermagnesemic, whereas hypomagnesemia, defined as a serum level o1.8 mg/dl (o0.74 mmol/l), is relatively uncommon (o1%), and typically observed in association with hypokalemia and hypophosphatemia. It is unclear as to how many patients were frankly hypomagnesemic or simply had low-normal serum magnesium results, as the lowest sextile serum magnesium concentration was o2.3 mg/dl (o0.95 mmol/l). The inverse correlation reported between serum magnesium and deaths from infections is interesting. However, this effect was markedly reduced, when patients with elevated high sensitivity CRP values were excluded from analysis, with only an increased mortality remaining for the lowest sextile. Although there were no data presented on serum potassium, predialysis serum urea, albumin, and phosphate appeared to be least in the lowest magnesium sextile and higher with higher magnesium levels. Similarly there was a trend for more older patients, diabetics, and those with a medical history of ischemic heart disease, stroke, amputation, or hip fracture to be represented in the lowest sextile. This would suggest that dietary factors and patient co-morbidity have a major influence on serum magnesium, and may have accounted in part for the increased mortality reported. POTENTIAL ADVERSE EFFECTS OF HYPERMAGNESEMIA
Ten to fifteen percent of hemodialysis patients have been reported to have hypermagnesemia, defined as a serum magnesium X2.8 mg/dl (1.15 mmol/l). Although oral magnesium intake can be increased by ingestion of magnesium-containing antacids and laxatives, the dialysate magnesium concentration may affect magnesium balance in
hemodialysis patients, with studies reporting a decrease in serum magnesium from 3.4–2.1 mg/dl (1.4–0.86 mmol/l) with 0.5 mEq/l (0.25 mmol/l) dialysate, whereas there was no change in serum magnesium using a 1.5 mEq/l (0.75 mmol/l) dialysate.9 The majority of patients used a dialysate concentration of 1 mEq/l (0.5 mmol/l, in this Japanese study, similar to the normal ionized serum magnesium of 0.5 mmol/l. Sakaguchi and colleagues report 32.4% of patients were hypermagnesemic, and used the sextile with serum magnesium concentrations of 2.8–o3.1 mg/dl (1.15–1.27 mmol/l) as the reference cohort for all analyses. The uppermost sextile had a serum magnesium 43.1 mg/dl (41.27 mmol/l), but it is unclear as to how many, if any patients had severe hypermagnesemia, which is a potentially serious condition leading to hypotension, nausea, vomiting, and facial flushing with serum magnesium values of 4–6 mg/dl (1.64–2.47 mmol/l). Higher magnesium concentrations can result in flaccid muscle paralysis, hyporeflexia, bradycardia, respiratory depression, coma, and cardiac arrest when values reach 10–20 mg/dl (4.1–8.2 mmol/l). Milder forms of hypermagnesemia inhibit PTH secretion, and predispose to adynamic bone disease, which is an important risk factor for soft tissue and vascular calcification, and mortality in hemodialysis patients. Reducing the dialysate magnesium concentration from 1.5–0.5 mEq/l (0.75–0.25 mmol/l) has been reported to decrease serum magnesium and increase serum PTH, whereas increasing the dialysate magnesium decreased PTH.10 So on one hand, magnesium can reduce soft tissue and vascular calcification, yet on the other, inhibiting PTH secretion increases the risk of low bone turnover by inhibiting osteoid mineralization and bone formation, and so in the longer term potentially affecting bone structure and also increasing the risk for soft tissue and vascular calcification in the dialysis patient. Although serum PTH appeared similar across the six serum magnesium Kidney International (2014) 85
commentary
Mortality HyperMg without low PTH
Vascular calcification
?
Serum PTH level Adynamic bone disease
All hyperMg HyperMg
Normal range 1.8 mg/dl < magnesemia < 2.8 mg/dl
Mg < 1.8
