Hemodialysis: slightly beyond basics Dialysate calcium and magnesium concentrations

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1 Dialysate calcium and magnesium concentrations Stefan Farese Department of Nephrology Bürgerspital Solothurn

2 Dialysate calcium and magnesium concentrations Do we know the optimal concentrations? NO Short overview Pathophysiologic considerations Guidelines/recommendations (if available) Personal suggestions (after review of the literature)

3 Dialysate calcium concentrations over time Evolution of dialysate Ca concentrations over time aluminium PB PTH suppression Calcitriol, Ca PB Adynamic bone disease Vascular calcification Recommandation without hard data 1.25 mmol/l 1.75 mmol/l mmol/l mmol/l 1.25 mmol/l 1960s 1970s 1980s, 1990s 2000 Messa P., NDT 2013 Toussaint et al. Hemodial Int 2006

4 Estimation of calcium balance in renal failure Vitamin D deficiency, phosphate binders dialysate Ca vascular calcification Hyper /Hypopara renal failure From Messa P. NDT 2013

5 Dialysate calcium concentrations hyperparathyreoidism increase Ca What is your goal? Treatment of... hypoparathyreoidism and adynamic bone disease hyper or hypocalciemia hemodynamic stability during dialysis decrease Ca decrease /increase Ca increase Ca hyperphosphatemia with calcium/noncalcium phosphate binders, calcitriol decrease /increase Ca

6 Dialysate calcium concentrations Ca dialysate 1.5 mmol/l Neutral Ca balance** Ca dialysate 1.75 mmol/l Positive Ca balance** Ca dialysate 1.25 mmol/l Negative Ca balance**..however, Ca transfer during dialysis depends also on the Ca gradient between serum and dialysate concentration and total calcium balance as well on vitamin D and Ca binder use Toussaint et al. Hemodial Int 2006

7 Dialysate calcium concentrations acute effects Hemodynamic stability on dialysis Intradialytic hypotension Preventive effect of high dca (1.75mmol/l) Increased cardiac contractility (+ increased peripheral resistence) synergistic effect with high dmg and high dhco 3 Maynard et al. Ann Intern Med 1986 Heinrich et al. NEJM 1984 Gabutti et al. NDT 2009 Gabutti et al. NDT 2009 Toussaint et al. Hemodila Int 2006

8 Dialysate calcium concentrations acute effects Hemodynamic stability on dialysis Calcium overload with chronic dca 1.75mmol/l?? dca profiling (n=18) dca 1.25 for 4h vs dca 1.25 for 2h then 1.75 for 2h vs dca 1.5 for 4h n=8 9 treatments with 1.25 vs 9 with 1.25/1.75 dca in random order Reduced intradialytic events Kyriazis et al. Kidney Int 2002

9 Dialysate calcium concentrations acute effects Cardiac arrhythmias N= HD patients, N=510 witnessed cardiac arrest vs 1560 matched controls Risk probably potentiated with concomitant hypokaliemia (or large dialysate serum K + gradient) Pun et al. CJASN 2013 Severi et al. NDT 2008

10 Dialysate calcium concentrations chronic effects Effects on bone Low turn over bone disease PTH (!) Reduction of dca from 1.75 to 1.25 mmol/l or from 1.5 to 1.25mmol/l PTH (+ others) Fiedler et al. Nephron Clin Pract 2004 Hamano et al. Bone 2005 High turn over bone disease Suppression of PTH with higher dca (1.75 mmol/l) Toussaint et al. Hemodial Int 2006

11 Dialysate calcium concentrations chronic effects Effects on vessels? Higher dca aortic puls wave velocity (=vascular stiffness) over time (6 mts) Hypercalciemia..however Acute effects of dca variations on PWV observed LeBoeuf et al. NDT 2011 Charitaki et al. BMC Nephrology 2013 LeBoeuf et al. NDT 2011 Kim et al. Korean J Int Med 2011 Davenport et al. Blood Purif 2010 vascular stiffness = vascular calcification??

12 Summary dialysate calcium concentrations Dialysate Calcium Advantages Disadvantages Low ( mmol/l) Risk for Hypercalciemia Potential for negative Ca balance and PTH Greater use of Vitamin D and Ca containing phosphate binders allowed Intra dialytic hypotension Benefit in adynamic bones Cardiac arrhythmias High ( mmol/l) hemodynamic stability Risk of hypercalciemia Benefit on bone protection in nocturnal HD Limited use of vitamin D and calcium based binders PTH Risk of vascular calcification adapted from Toussaint et al. Hemodial Int 2006

13 Dialysate magnesium Magnesium in ESRD Vascular tone ( ) Heart contractility ( ) Arrhythmias ( ) LV Hypertrophy ( ) PTH ( ) Osteoporosis ( ) Insulin Resistance ( ) Inflammation ( ) Vascular calcification ( ) Mortality ( )

14 Dialysate Magnesium: Mg kinetics during high efficiency dialysis HD Session with 0 mmol/l Mg removal 486 +/ 44mg HD Session with 0.25 mmol/l Mg removal 306 +/ 69 mg HD Session with 0.75 mmol/l Mg removal 56 +/ 50m Plasma Mg concentrations constant with 0.75mmol/l

15 Dialysate Magnesium: acute effects Blood pressure and myocardial contractility n=8, in randomized order, 4 h HD Group I Mg 0.75, Ca 1.75 Group II Mg 0.25, Ca 1.75 Group III Mg 0.75, Ca 1.25 Group IV Mg 0.25, Ca 1.25 Group I and III: smg +2% Low Ca, low Mg Group II and IV:s Mg 35% Group IV: CI, stroke Index, MAP Kyriazis et al. Kidney Int 2004

16 Dialysate Magnesium: acute effects Blood pressure and myocardial contractility n=14 (ca 1.25mmol/l) 4 weeks with 0.5mmol/l 4 weeks with 0.25 mmol/l 4 weeks with 0.75 mmol/l dmg 0.75mmol/l significant reduction in intradialytic morbidity and improved BD stability Intradialytic changes of serum Mg correlation with hypotensive episodes Elsharkawy et al. Hemodial Int 2006 Kyriazis et al. Kidney Int 2004

17 Dialysate magnesium: acute effects Muscle cramps n=15 Switch from 0.75 to 0 mmol/l dmg + oral MgCO 3 for 2 weeks and dmg 0.25 mmol/l for 2 weeks Severe muscle cramps (n=8) not associated with changes in blood pressure Immediate relief after switch to 0.75 mmol/l and dmg oral Mg CO 3 mmol/l for 2 weeks Well tolerated Kelber et al. AJKD 1994

18 Dialysate magnesium: which one to choose? Optimal dmg concentration 0.75 mmol/l for blood pressure and muscle cramps (...if no Mg phosphate binder is used) Information from guidelines? EBPG on HD (2007) in patients with frequent episodes of IHD, low (0.25mmol/l) dmg should be avoided, especially in in combination with low calcium dialysate CARI (2000) mmol/l will maintain normomagnesemia...but levels in some case may have to be individualised

19 Dialysate magnesium: chronic effects Evidence from animal studies supporting use of higher dmg Mg supplemented diet prevents/retards VC Gorgels et al. J Mol Med 2010 Mg CO3 phosphate binder vs Lanthanum prevents VC Li et al. Clin Transl Sci 2009 by unclear, probably multiple mechanisms (direct inhibition of hydroxyapatite formation, cellular effects, expression of anti calcification proteins...) Massy et al. Clin Kidney J 2012

20 Dialysate Magnesium: chronic effects Evidence from human studies supporting the use of higher dmg Tissue calcification Low serum Mg in HD patients vascular calcification (VC) (independent of Ca, Ph, and PTH) Ishimura et al. Clin Nephrol 2007 Mitral annular calcifications Tzanakis et al. NDT 1997 Increased carotid intima media thickness oral Mg supplementation reduces thickness Turgut et al. Int Urol Nephrol 2008 Dietary Mg (MgCO 3 / Mg citrate) supplementation prevents/retards (VC) Turgut et al. Int Urol Nephrol 2008 Spiegel et al. Hemodial Int 2009

21 Dialysate magnesium: chronic effects Evidence from human studies supporting the use of higher dmg Outcome n= 515 HD patients, mean follow up 51 months, observational prospective Higher Mg group >1.1.4mmol/l Lower Mg group < 1.14mmol/l Serum Mg at 0 and 1 year correlates strongly Serum Mg = independent significant predictor overall mortality (OR 0.48 per 0.41 mmol/l Mg) Ishimura et al. Magnes Res 2007

22 Dialysate magnesium: chronic effects Evidence from human studies supporting the use of higher dmg Outcome n= (FMC North America facilities) retrospecitve Results Compared to mid normal values ( mmol/l) drop of hazard ratio at smg 0.95 mmol/l to as low as 0.68 at smg > 1.15 mmol/l Linear trend lower mortality with increasing serum Mg concentrations Lacson et al. Poster at the Renal Week 2009 in San Diego, US Passlick Deetjen, oral presentation at the ERA/EDTA Congress 2012 in Munich, Germany

23 Dialysate magnesium: chronic effects Evidence from human studies supportin the use of higher dmg Effects on serum calcification propensity JASN 2012 N =45 chronic HD patients, crossover design Assessment of calcification propensity with a 0.5mmol/l dmg vs 0.75mmol/l dmg JASN 2013 Preliminary Results 0.75mmol/l dmg improves calcification propensity in serum of HD Patients under preparation for publication Effect on outcome?

24 Dialysate calcium: Summary Optimal dca concentration Guidelines (KDOQI): mmol/l Compromise between the need for personal suggestion (after review of literature) cardiovascular stability during HD the goal to maintain normal (?) bone turnover and tissue mineralization

25 Dialysate magnesium: Summary Optimal dmg concentration No or few comments in major guidelines dmg 0.75 (or higher?) favorable for personal suggestion (after review of literature) cardiovascular stability during dialysis probable positive effect on vascular calcification no major side effects reported (without concomitant use of Mgphosphate binders)