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

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Steven Van Laecke

Calcium, phosphor and magnesium:

pathophysiology, diagnosis, clinical management

S. Van Laecke

Ghent University Hospital BVN Core Curriculum Course 2013

Steven Van Laecke

What is it and how did it disappear?

Miyamoto M et al. Urology 2012

Steven Van Laecke

What is it and how did it not disappear?

Patel G et al. BMJ 2006

X

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Steven Van Laecke

Arterial media calcification: outcome in ESRD

London GM et al. NDT 2003

Steven Van Laecke

Vascular calcification: a complex interplay

Schroff R et al. JASN 2013

Steven Van Laecke

Target values of the culprits in CKD-MBD

Cunningham J et al. NDT 2011

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Steven Van Laecke

Phosphorus: distribution

Serum phosphorus 2.5- 4.5mg/dL Total-body stores 700g

Steven Van Laecke

Phosphate metabolism in health/ESRD

Tonelli M et al NEJM 2010

Steven Van Laecke

Response to high phosphorus diet

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Steven Van Laecke

Alterations in CKD-MBD

John GB et al. AJKD 2011

Steven Van Laecke

Hypophosphatemia: etiology and symptoms

Felsenfeld AJ et al. AJKD 2012

Severe acute hypophosphatemia <1mg/dL

Steven Van Laecke

Hypophosphatemia after transplantation

Barros X et al. Transplantation 2012

* p<0.05

FIRST PHASE:

FGF23 SECOND PHASE:

PTH

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Steven Van Laecke

Approach to hypophosphatemia

Bachhetta J et al. AJKD 2012

Steven Van Laecke

Phosphorus and cardiovascular risk

Steven Van Laecke

Phosphorus in the general population

Tonelli M et al. Circulation 2005 HR per 1 mg/dL P of 1.27 (95% CI 1.02–1.58)

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Steven Van Laecke

Phosphorus in ESRD

Block GA et al. JASN 2004 n=40,538

Steven Van Laecke

Phosphate and CKD progression

Zoccalli C et al. JASN 2011

Steven Van Laecke

Phosphorus: nutrition status as confounder

Lopez AA et al. AJKD 2012

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Steven Van Laecke

Novel determinants of serum phosphorus

Gutierrez OM, Wolf M et al. JASN 2010 -

SOCIO-ECONOMICAL STATUS HORMONAL STATUS

Ix JH et al. AJKD 2011

Steven Van Laecke

PHOSPHATE RESTRICTION PROTEIN RESTRICTION

Phosphorus lowering and diet

Steven Van Laecke Calvo et al. Seminars in Dialysis 2013

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Steven Van Laecke

Phosphorus containing drugs in CKD

Calvo et al. Seminars in Dialysis 2013

Steven Van Laecke

Phosphorus lowering and dialysis

Daugirdas JT et al JASN 2012

DAILY TRIAL

NOCTURNAL TRIAL

CAVEAT no significant changes in Calcium and PTH

Steven Van Laecke

Ca vs. non-Ca phosphorus binders

Frazao JM et al. Nephron Clin Pract 2012

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Steven Van Laecke

Pleiotropic effects sevelamer

Evenepoel P. KI 2007

Steven Van Laecke

Sevelamer in Diabetic Kidney Disease

Vlassara H et al. cJASN 2012

Steven Van Laecke

Lanthanum prevents atherosclerosis

Nikolov IG et al. NDT 2012

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Steven Van Laecke

Phosphate binders and mortality

Steven Van Laecke

Mortality and phosphorus binders:RCT

Suki WN et al. cJASN 2007

DCOR n=2103

Prevalent HD patients

Steven Van Laecke

Mortality and sevelamer vs CaCarbonate

n=212 CKD 3 CKD 4

Di Iorio B et al. cJASN 2012

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Steven Van Laecke

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 calcium- containing 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

Steven Van Laecke

Phosphorus binders in moderate CKD?

Block et al JASN 2012

A FALSE NOTE?

Steven Van Laecke

Calcium

Bolland MJ et al. BMJ 2011

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Steven Van Laecke

Calcium physiology

Serum calcium 8.5- 10.5mg/dL

Total-body stores 1000g (99%bone, 0.1% extracellular)

Steven Van Laecke

Calcium physiology: a role of CaSR/PTH

Ferre S et al. KI 2012

Steven Van Laecke

Key regulators of PTH expression/excretion

Ferre S et al. KI 2012

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Steven Van Laecke

A rationale for PTH lowering

Torres et al. KI 2012

Steven Van Laecke

A rationale for calcimimetics

Torres et al. KI 2012

Steven Van Laecke

Overlapping effects Ca/P on VSMC

Shanahan CM et al. Circulation Research 2011

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Steven Van Laecke

Calcimimetics and vascular calcification

n=360

Raggi P et al NDT 2011

Steven Van Laecke

The paradigm shift in CKD-MBD

John GB et al. AJKD 2011

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Steven Van Laecke

FGF23 is increased early in CKD

Isakova et al. KI 2011

Steven Van Laecke

FGF23 and outcome in general population

Ix JH et al. JACC 2012

P=0.001 log rank

FGF23 and outcome in CKD

Isakova et al JAMA 2011 –Kendrick J et al JASN 2011

CKD 2-4 ESRD

n=3879

n=1099

Is LVH the pathophysiological link?

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FGF23 and phosphate restriction in CKD

Isakova et al cJASN 2013

Steven Van Laecke

FGF23 neutralization: useful in CKD-MBD?

Shalhoub et al JCI 2012

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Steven Van Laecke

..neutralization of FGF23 increases mortality

Shalhoub et al JCI 2012

Steven Van Laecke 21 december 2012

Magnesium

CaMg(CO

3

)

2

C

55

H

72

O

5

N

4

Mg

: an ubiquitous element

Steven Van Laecke 8 februari 2013 Rosanov A et al. Nutr Rev 2012

Insufficient Mg intake (general population)

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Steven Van Laecke 8 februari 2013 Jahnen-Dechent W; De Baaij JH et al. CKJ 2012

Magnesium balance

Normal serum magnesium: 0.65-1.05mM (1.7-2.5mg/dL)

Steven Van Laecke 8 februari 2013

Magnesium physiology

De Baaij JH et al. CKJ 2012

TAL HENLE DISTAL CONVOLUTED TUBULE

Steven Van Laecke 8 februari 2013 Dewitte K et al. Diabetes Care 2004

Hypermagnesemia: kidney disease

from Coburn JW et al. Arch Int Med 1969

Hypermagnesemia: >1.05mM (2.5mg/dL)

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Hypomagnesemia-magnesium deficiency

Hypomagnesemia: <0.65mM (1.7mg/dL)

Barbagallo M et al. JECM 1997

HYPOMAGNESEMIA

MAGNESIUM DEFICIENCY IC Mg (µM)

* P<0.05 vs. diabetes

#P<0.05 vs. healthy

*

# #

Prevalence of hypomagnesemia

Ethiology of hypomagnesemia

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Drug-induced hypomagnesemia

Lameris A et al. Clin Science 2012

Ethiology of hypomagnesemia

RENAL Mg wasting:

24 hour urine Mg>10 to 30mg OR FE

Mg

>2% AND normal renal function EXTRARENAL Mg loss (gastro-intestinal):

24 hour urine Mg<10mg OR FE

Mg

>2%

Steven Van Laecke 8 februari 2013 Peacock JM et al. Am J Cardiology 2010

Hypomagnesemia and outcome

0 0,2 0,4 0,6 0,8 1 1,2

Q1: Mg < 0.75mM Q2 Q3 Q4: Mg >0.9mM

AHR*

AHR Q4 vs. Q1: 0.62; 95%CI 0.42-0.93; p=0.006

38% ↓ risk

N=14232

*adjusted for age, race, sex, lipids, K, QT, physical activity, smoking, alcohol intake, education, diabetes, hypertension an d diuretics 30% ↓ risk

Sudden cardiac death

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Magnesium and hypertension

Ma J et al. J Clin Epidemiol 1995

adjusted for age and BMI adjusted for age and BMI; patients without CVD

Magnesium and diabetes

Kao WH et al. Arch Int Med 1999

Adjustment for age, sex, education, family history of diabetes, body mass index, waist-to- hip ratio, physical activity, alcohol use, diuretics, serum calcium and potassium levels.

‘High’ Mg intake:

23% ↓risk of diabetes AHR diabetes 0.77 (95%CI 0.72-0.84) Q1Q5 (n=271,869)

(Schulze MB et al. Arch Intern Med 2007)

Magnesium and inflammation

Sugimoto J et al. J Immunol 2012

*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.

From Chacko SA et al. Diabetes Care 2010 n=1,047

P for trend:0 .001

n=2,666 P for trend: 0.17

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Steven Van Laecke 21 december 2012

Magnesium and endothelial function

0 2 4 6 8 10 12 14 16

Baseline month 6

%FMD

placebo Mg

From Shechter M et al. Circulation 2000 P=0.02

Maier JA . Clin Science 2012

Magnesium and outcome in CKD

Van Laecke S et al. Am J Med 2013 (in press) 20

25 30 35 40 45 50 55 60 65

0 1 2 3 4 5 6 7 8 9 10

eGFR (ml/min)

Time (years)

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)

after adjustment for age, sex, diabetes and hypertension

AHR mortality: 0.930 per 0.1mg/dL increase;

95%CI 0.887-0.974; p=0.002

n=1650

Magnesium and calcification in aortic VSMC

Louvet L et al. NDT 2012; Salem S et al. Am J Nephrol 2012

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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 2012

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