MINERAL AND BONE DISORDERS IN CHRONIC KIDNEY DISEASE PEDRAM.AHMADPOOR SHAHID BEHESHTI MEDICAL UNIVERSITY

Normal Bone Metabolic Unit Low turn over bone disease High turn over bone disease mixed

TMV classification OM=Osteomalacia OF=Osteitis fibrosa AD= Adynamic bone disease MUD=Mixed

Mechanism for 2 HPT in CRF Increased intracellular P in remaining proximal tubules  suppression of 1-alpha OHase Increased intracellular P in remaining proximal tubules  suppression of 1-alpha OHase Decreased level of 1,25 D3 starts with GFR<80 Decreased level of 1,25 D3 starts with GFR<80 Increased intracellular P starts earlier than changes in serum P Increased intracellular P starts earlier than changes in serum P

Consequences of 1,25( OH )D3 deficiency Increase in PTH level Increase in PTH level Parathyroid cell proliferation ( VDR) Parathyroid cell proliferation ( VDR) Decreased bone calcemic response to PTH Decreased bone calcemic response to PTH Increased PTH set point,Decreased CaSR Increased PTH set point,Decreased CaSR Hypocalcemia Hypocalcemia

PTH - Calcium set point PTH Ionised Calcium 1.25 mmol/l Normal Uraemia 50%

Causes of decreased 1,25(OH)D3 synthesis in renal failure Phosphate retention and Hyperphosphatemia Phosphate retention and Hyperphosphatemia Renal tissue loss Renal tissue loss Uremic toxins(GSA,Uric acid) Uremic toxins(GSA,Uric acid) FGF-23 FGF-23

Clinical Manifestation of Renal Osteodystrophy Bone pain Bone pain Myopathy and muscle weakness Myopathy and muscle weakness Pruritis Pruritis Metastatic and extraskeletal calcification (vascular –soft tissue) Metastatic and extraskeletal calcification (vascular –soft tissue) Arthritis and Periarthritis Arthritis and Periarthritis Spontaneous tendon rupture Spontaneous tendon rupture

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sub-periosteal resorption

AP view looser’s zone frogleg view looser’s zone

Vascular Calcification in ESRD Reprinted from: London, et al. Nephrol Transpl Dial. 2003;18: (London, 2003 p fig.1)

Increased Death Risk in CKD Stage 5 with Elevated Serum Calcium Adapted from Block GA et al. J Am Soc Nephrol. 2004;15:

K/DOQI™ Clinical Practice Guidelines on Bone Metabolism Target Levels CKD Stage 3 CKD Stage 4 CKD Stage 5 (on dialysis) P(mg/dL) * Ca(mg/dL)“Normal”“Normal” ; Hypercalcemia = >10.2 Intact PTH (pg/mL) *

Prevention and Treatment of Renal Osteodystrophy Prevention of Phosphate retention and Hyperphosphatemia Prevention of Phosphate retention and Hyperphosphatemia Treatment of Hypocalcemia Treatment of Hypocalcemia Vit. D analogs Vit. D analogs Calcimimetics Calcimimetics Parathyroidectomy Parathyroidectomy

Phosphate binders Calcium containing Calcium containing CaCO3 CaCO3 Ca acetate (Phoslo) Ca acetate (Phoslo) non calcium containing non calcium containing Renagel,Renvela Renagel,Renvela lanthanum carbonate (Fosrenol) lanthanum carbonate (Fosrenol) Mg Mg Al Al

Al based phosphate binders Aluminium toxicities Aluminium toxicities Bone Bone Neurologic Neurologic hematologic hematologic Calcium based phosphate binders Calcium based phosphate binders

P<5.5 Ca<9.5  Ca containing P binder P<5.5 Ca<9.5  Ca containing P binder P 9.5 no P binder P 9.5 no P binder ( if vascular calc.  non calcium containing P binder) ( if vascular calc.  non calcium containing P binder) P>5.5 Ca 5.5 Ca <9.5  Ca containing P binder if Ca x P <55 if Ca x P <55 P>5.5 Ca >9.5  non Ca containting P binder P>5.5 Ca >9.5  non Ca containting P binder Ca containing P binders must not be used if: Ca containing P binders must not be used if: PTH <150 PTH <150 corrected Ca >10.2 corrected Ca >10.2 P binder elemental Ca >1500 P binder elemental Ca >1500 total elemental Ca >2000 total elemental Ca >2000

A 45 years old man under hemodialysis for 6 years due to chronic GN ( wt =70 kg) A 45 years old man under hemodialysis for 6 years due to chronic GN ( wt =70 kg) Ca = 9.8 mg% Ca = 9.8 mg% P = 5.7 mg% P = 5.7 mg% intact PTH = 600 pg/ml intact PTH = 600 pg/ml albumin =3.7 gr/dl albumin =3.7 gr/dl dialysis 3 x4 h/wk dialysis 3 x4 h/wk What type of bone disease ? How do you manage it How do you manage it

Diet  mg P /d Diet  mg P /d Phosphate binder? Phosphate binder? Types of Phosphate binder? Types of Phosphate binder? Calcium containing Calcium containing CaCO3 CaCO3 Ca acetate (Phoslo) Ca acetate (Phoslo) non calcium containing non calcium containing Renagel,Renvela Renagel,Renvela lanthanum carbonate (Fosrenol) lanthanum carbonate (Fosrenol) Mg Mg Al Al

P>5.5 Ca >9.5  non Ca containting P binder Dose? Dose? Depends on P blood level Depends on P blood level daily removal daily removal daily intake /absorption daily intake /absorption binder potency binder potency

39 mg P will bind to 1 gr CaCO3 39 mg P will bind to 1 gr CaCO3 45 mg P will bind to 1 gr Ca acetate 45 mg P will bind to 1 gr Ca acetate 32 mg to each 400 mg renagel 32 mg to each 400 mg renagel 64 mg to each 800 mg renagel tab 64 mg to each 800 mg renagel tab 15.3 mg to each Al tab 15.3 mg to each Al tab 22.3 mg to 5 ml AlOH mg to 5 ml AlOH3

For each gr protein intake consider 10-12mg P intake For each gr protein intake consider 10-12mg P intake Recommended protein intake in HD=1-1.2 g/kg Recommended protein intake in HD=1-1.2 g/kg 70 x 1.2 = 840 mg /d 70 x 1.2 = 840 mg /d 840 x 60% = 504 mg /d  accumulation 840 x 60% = 504 mg /d  accumulation each dialysis P removal  mg each dialysis P removal  mg CAPD  300 mg/d CAPD  300 mg/d 800 x 3= 2400 mg 800 x 3= 2400 mg 504 x 7 = x 7 = – 2400 = 1128 /7= 160 mg /d ( amount of P that must be bound) 3528 – 2400 = 1128 /7= 160 mg /d ( amount of P that must be bound) 64 mg to each 800 mg renagel tab 64 mg to each 800 mg renagel tab about 3 renagel tab /d about 3 renagel tab /d Ca-P recheck within 1-4 wks PTH q 1-3 months

How many Ca CO3 pills ? 160 mg/39= 4 gr CaCO3 ( 8 tab /d) 160 mg/39= 4 gr CaCO3 ( 8 tab /d) elemental Ca = 4000 mg x40%=1600 mg elemental Ca = 4000 mg x40%=1600 mg Ca containing P binders must not be used if: Ca containing P binders must not be used if: PTH <150 PTH <150 corrected Ca >10.2 corrected Ca >10.2 P binder elemental Ca >1500 P binder elemental Ca >1500 total elemental Ca >2000 total elemental Ca >2000 COMBINATION POLICY COMBINATION POLICY

P<5.5 Ca<9.5  Ca containing P binder P<5.5 Ca<9.5  Ca containing P binder P 9.5 no P binder P 9.5 no P binder ( if vascular calc.  non calcium containing P binder) ( if vascular calc.  non calcium containing P binder) P>5.5 Ca 5.5 Ca <9.5  Ca containing P binder P>5.5 Ca >9.5  non Ca containting P binder P>5.5 Ca >9.5  non Ca containting P binder

Vit D derivatives Vit D derivatives if intact PTH >300 & Ca 300 & Ca <9.5 & P<5.5 & Ca x P <55 Ca x P <55 Corrected Ca >10.2  stop Corrected Ca >10.2  stop Corrected Ca  50% dose reduction Corrected Ca  50% dose reduction corrected Ca rising  dose reduction corrected Ca rising  dose reduction Role of low dose active vitamin D irrespective of parathyroid suppression on overall mortality Role of low dose active vitamin D irrespective of parathyroid suppression on overall mortality

Vitamin D analogs 25(OH) D3 ( calcifediol) 1,25 (OH) D3 (calcitriol, rocaltrol) 1 alpha (OH) D3 ( alphacalcidiol,one alpha) 1alpha (OH) D2 (doxercalciferol, hectoral) 22 oxa 1,25 (OH) D3 (22 oxacalcitriol,maxacalcitol) 19 nor 1,25( OH) D2 (paricalcitol, zemplar) 24,25(OH)D3

Cinacalcet Cinacalcet indicated in all pts with intact PTH >300 and Ca >8.4 indicated in all pts with intact PTH >300 and Ca >8.4 (decrease parathyroidectomy,cardivascular hospitalizations,Fx) (decrease parathyroidectomy,cardivascular hospitalizations,Fx) Hyperphosphatemia is not containdication starting dose 30 mg/d  180 q4wks starting dose 30 mg/d  180 q4wks cinacalcet must not be started if Ca<8.4 cinacalcet must not be started if Ca<8.4 during Tx  Ca <7.4  stop during Tx  Ca <7.4  stop  adding vit d and /calcium if P <  adding vit d and /calcium if P <5.5 So if Ca 300  start with vit.D derivative

28 cinacalcet = 400,000 toman 28 cinacalcet = 400,000 toman Renagel 400 mg= 1980 toman Renagel 400 mg= 1980 toman AlOH3 AlOH3 Increasing dialysis Increasing dialysis parathyroidectomy parathyroidectomy

How can we calculate daily protein intake CRF= 6.25 ( urine urea nitrogen + nonurea nitrogen) + proteinuria if > 5 gr/d CRF= 6.25 ( urine urea nitrogen + nonurea nitrogen) + proteinuria if > 5 gr/d nonurea nitrogen =30mg/kg nonurea nitrogen =30mg/kg

How can we calculate daily protein intake HD (anuric ) HD (anuric ) PCR = x delta BUN PCR = x delta BUN Interval Interval BUN before dialysis = 70 BUN before dialysis = 70 BUN after diaysis = 30 BUN after diaysis = 30 interval =44 interval = x 40= 34/44= 0.78 gr/kg/d 0.86 x 40= 34/44= 0.78 gr/kg/d

Urinary urea nitrogen (g) x 150 anuric PCR+ ——————————————— ID interval (hrs) x weight (kg) Urinary urea nitrogen (g) x 150 anuric PCR+ ——————————————— ID interval (hrs) x weight (kg) PD: PCR = 6.25 x (Urea appearance [0.031x lean body weight, kg]) PD: PCR = 6.25 x (Urea appearance [0.031x lean body weight, kg])