20/03/2013. What is it and how did it disappear? What is it and how did it not disappear?

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1 Calcium, phosphor and magnesium: pathophysiology, diagnosis, clinical management S. Van Laecke Ghent University Hospital BVN Core Curriculum Course 2013 What is it and how did it disappear? Miyamoto M et al. Urology 2012 What is it and how did it not disappear? X Patel G et al. BMJ

2 Arterial media calcification: outcome in ESRD London GM et al. NDT 2003 Vascular calcification: a complex interplay Schroff R et al. JASN 2013 Target values of the culprits in CKD-MBD Cunningham J et al. NDT

3 Phosphorus: distribution Serum phosphorus mg/dL Total-body stores 700g Phosphate metabolism in health/esrd Tonelli M et al NEJM 2010 Response to high phosphorus diet 3

4 Alterations in CKD-MBD John GB et al. AJKD 2011 Hypophosphatemia: etiology and symptoms Severe acute hypophosphatemia <1mg/dL Felsenfeld AJ et al. AJKD 2012 Hypophosphatemia after transplantation FIRST SECOND PHASE: FGF23 PTH * p<0.05 Barros X et al. Transplantation

5 Approach to hypophosphatemia Bachhetta J et al. AJKD 2012 Phosphorus and cardiovascular risk Tonelli M et al NEJM 2010 Phosphorus in the general population HR per 1 mg/dl P of 1.27 (95% CI ) Tonelli M et al. Circulation

6 Phosphorus in ESRD n=40,538 Block GA et al. JASN 2004 Phosphate and CKD progression Zoccalli C et al. JASN 2011 Phosphorus: nutrition status as confounder Lopez AA et al. AJKD

7 Novel determinants of serum phosphorus SOCIO-ECONOMICAL STATUS HORMONAL STATUS Gutierrez OM, Wolf M et al. JASN Ix JH et al. AJKD 2011 Phosphorus lowering and diet PROTEIN RESTRICTION PHOSPHATE RESTRICTION Calvo et al. Seminars in Dialysis

8 Phosphorus containing drugs in CKD Calvo et al. Seminars in Dialysis 2013 Phosphorus lowering and dialysis DAILY TRIAL NOCTURNAL TRIAL CAVEAT no significant changes in Calcium and PTH Daugirdas JT et al JASN 2012 Ca vs. non-ca phosphorus binders Frazao JM et al. Nephron Clin Pract

9 Pleiotropic effects sevelamer Evenepoel P. KI 2007 Sevelamer in Diabetic Kidney Disease Vlassara H et al. cjasn 2012 Lanthanum prevents atherosclerosis Nikolov IG et al. NDT

10 Phosphate binders and mortality Tonelli M et al NEJM 2010 Mortality and phosphorus binders:rct DCOR n=2103 Prevalent HD patients Suki WN et al. cjasn 2007 Mortality and sevelamer vs CaCarbonate n=212 CKD 3 CKD 4 Di Iorio B et al. cjasn

11 Conclusion phosphorus binders CKD3-5 Available phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calciumcontaining phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD. Navaneethan SD et al. Cochrane Database Syst Rev 2011 Phosphorus binders in moderate CKD? A FALSE NOTE? Block et al JASN 2012 Calcium Bolland MJ et al. BMJ

12 Calcium physiology Serum calcium mg/dL Total-body stores 1000g (99%bone, 0.1% extracellular) Calcium physiology: a role of CaSR/PTH Ferre S et al. KI 2012 Key regulators of PTH expression/excretion Ferre S et al. KI

13 A rationale for PTH lowering Torres et al. KI 2012 A rationale for calcimimetics Torres et al. KI 2012 Overlapping effects Ca/P on VSMC Shanahan CM et al. Circulation Research

14 Calcimimetics and vascular calcification n=360 Raggi P et al NDT 2011 The paradigm shift in CKD-MBD John GB et al. AJKD

15 FGF23 is increased early in CKD Isakova et al. KI 2011 FGF23 and outcome in general population Ix JH et al. JACC 2012 FGF23 and outcome in CKD Is LVH the pathophysiological link? CKD 2-4 ESRD n=3879 n=1099 P=0.001 log rank Isakova et al JAMA 2011 Kendrick J et al JASN

16 FGF23 and phosphate restriction in CKD Isakova et al cjasn 2013 FGF23 neutralization: useful in CKD-MBD? Shalhoub et al JCI

17 ..neutralization of FGF23 increases mortality Shalhoub et al JCI 2012 Magnesium : an ubiquitous element CaMg(CO 3 ) 2 C 55 H 72 O 5 N 4 Mg 21 december 2012 Insufficient Mg intake (general population) Rosanov A et al. Nutr Rev februari

18 Magnesium balance Normal serum magnesium: mM ( mg/dL) Jahnen-Dechent W; De Baaij JH et al. CKJ februari 2013 Magnesium physiology TAL HENLE DISTAL CONVOLUTED TUBULE De Baaij JH et al. CKJ februari 2013 Hypermagnesemia: kidney disease Hypermagnesemia: >1.05mM (2.5mg/dL) from Coburn JW et al. Arch Int Med 1969 Dewitte K et al. Diabetes Care februari

19 Hypomagnesemia-magnesium deficiency Hypomagnesemia: <0.65mM (1.7mg/dL) IC Mg (µm) HYPOMAGNESEMIA * # # * P<0.05 vs. diabetes #P<0.05 vs. healthy MAGNESIUM DEFICIENCY Barbagallo M et al. JECM februari 2013 Prevalence of hypomagnesemia 8 februari 2013 Ethiology of hypomagnesemia 8 februari

20 Drug-induced hypomagnesemia Lameris A et al. Clin Science februari 2013 Ethiology of hypomagnesemia RENAL Mg wasting: 24 hour urine Mg>10 to 30mg OR FEMg >2% AND normal renal function EXTRARENAL Mg loss (gastro-intestinal): 24 hour urine Mg<10mg OR FEMg >2% 8 februari 2013 Hypomagnesemia and outcome AHR* 1,2 Sudden cardiac death 1 0,8 30% risk 38% risk 0,6 0,4 0,2 0 Q1: Mg < 0.75mM Q2 Q3 Q4: Mg >0.9mM AHR Q4 vs. Q1: 0.62; 95%CI ; p=0.006 N=14232 *adjusted for age, race, sex, lipids, K, QT, physical activity, smoking, alcohol intake, education, diabetes, hypertension and diuretics Peacock JM et al. Am J Cardiology februari

21 Magnesium and hypertension adjusted for age and BMI adjusted for age and BMI; patients without CVD Ma J et al. J Clin Epidemiol februari 2013 Magnesium and diabetes High Mg intake: 23% risk of diabetes AHR diabetes 0.77 (95%CI ) Q1Q5 (n=271,869) (Schulze MB et al. Arch Intern Med 2007) Adjustment for age, sex, education, family history of diabetes, body mass index, waist-tohip ratio, physical activity, alcohol use, diuretics, serum calcium and potassium levels. Kao WH et al. Arch Int Med februari 2013 Magnesium and inflammation P for trend:0.001 P for trend: 0.17 n=1,047 n=2,666 From Chacko SA et al. Diabetes Care 2010 *Adjustment for age, race/ethnicity, smoking, alcohol, total energy expenditure/week, total energy intake, BMI, type 2 diabetes, dietary fiber intake, fruit and vegetable intake, folate intake, trans and saturated fat intake. Sugimoto J et al. J Immunol februari

22 egfr (ml/min) %FMD 20/03/2013 Magnesium and endothelial function Baseline month 6 placebo Mg P=0.02 From Shechter M et al. Circulation 2000 Maier JA. Clin Science december 2012 Magnesium and outcome in CKD 65 AHR mortality: per 0.1mg/dL increase; 95%CI ; p= n= High Mg (+1mg/dL) High Mg (+0.3mg/dL) High Mg (+0.1mg/dL) Mean Mg Low Mg (-0.1mg/dL) LowMg (-0.3mg/dL) Low Mg (-1mg/dL) Time (years) after adjustment for age, sex, diabetes and hypertension Van Laecke S et al. Am J Med 2013 (in press) 8 februari 2013 Magnesium and calcification in aortic VSMC Louvet L et al. NDT 2012; Salem S et al. Am J Nephrol

23 Magnesium and vascular calcification Qiaoli L et al. Clin Transl Sci 2009 Magnesium and vascular calcification Massy Z et al. CKJ 2012 Magnesium, renal injury and CVD Van Laecke S et al. NDT februari

24 Conclusions Observational studies or effects on surrogate end-points vs. poor evidence <RCT Farmaco-economical issues CKD-MBD policy CKD 3-4: inclarity FGF-23: translation into clinical practice? Pleiotropic effects magnesium: to be explored 8 februari