métabolisme des phosphates en dialyse - hÔpital...
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Métabolisme des phosphates en dialyse
Pr Laurent Juillard,
Dr Sandrine Lemoine
Nephrology department, Lyon.
Inserm CARMEN 1060, Univ Lyon1
CERMEP, Lyon
Conflicts of interest
Clinical research: Alexion, Bayer, GSK, Otsuka
Advisory Boards : Amgen, Baxter, Fresenius, GE Healthcare, Hemotech, Roche, Vifor,
Lectures : Bbraun, Genzyme, GE Heathcare, Vifor, Roche
Research support : Baxter, Fresenius, Genzyme
Compliance issues
All …..
Oral intake
900-1200 mg
490 mg/ 24h
350 mg /24h
Bone = 600-700g
Cells
Porg = 57g
Pi = 3g
Kidney
Interstitial area
Plasma
85%
14%
700mg
Phosphate flux between compartments
Oral intake
900-1200 mg
490 mg/ 24h
350 mg /24h
Bone = 600-700g
Cells
Porg = 57g
Pi = 3g
Kidney
Interstitial area
Plasma
85%
14%
700mg
Phosphate flux between compartments
Plasma Pi :
< 1 % overall phosphorus
= 90 mg
Oral intake
900-1200 mg
490 mg/ 24h
350 mg /24h
Bone = 600-700g
Cells
Porg = 57g
Pi = 3g
Kidney
Interstitial area
Plasma
85%
14%
700mg
Phosphate flux between compartments
Plasma Pi:
< 1 % overall phosphorus
= 90 mg
During dialysis:
= 600 to 700 mg removed
Oral intake
900-1200 mg
490 mg/ 24h
350 mg /24h
Bone = 600-700g
Cells
Porg = 57g
Pi = 3g
Kidney
Interstitial area
Plasma
85%
14%
700mg
Phosphate flux between compartments
Plasma:
< 1 % overall phosphorus
= 90 mg
During dialysis:
= 600 to 700 mg removed
Where does the depurated (Pi) come from ?
Spalding et al, Kidney Int 2002
Time, minutes
Dialysis end
Evolution of plasma Pi
Goals of Pi modeling during dialysis
- Prediction of plasma Pi concentration after changes in dialysis prescriptions (duration, frequency)
Pragmatic, urea type 2 compartments modeling
Description of Pi transfers during dialysis with multicompartimental modeling
TWO POOLS MODELING
Spalding et al, Kidney Int 2002
Evolution of plasma Pi
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 2 pools
2/3 TBW
1/3 TBW
350 mL/min
Spalding et al, Kidney Int 2002
Evolution of plasma Urea
Excellent Fit
Short Long
Spalding et al, Kidney Int 2002
Evolution of plasma bicarbonates
No plateau
Spalding et al, Kidney Int 2002
Evolution of plasma Pi
2 pools modeling
No plateau prediction
Underestimate final Pi
Spalding et al, Kidney Int 2002
Sugisaki et al,Trans Am Soc Artif Intern Organs 1982
Heaf et al, Scand J Urol Nephrol 1998
Evolution of plasma Pi
Spalding conclusion :
Pi prediction impossible with a 2 pools modeling
Confirm Sugisaki and Heaf
AJUSTED TWO POOLS MODELING
Leypoldt et al, Kidney Int 2013
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 2 pools
Distal volume infinite Fixed Km
Infinite pool volume
1/3 TBW
Fixed patient specific Km
Leypoldt et al, Kidney Int 2013
Effet Km
Evolution of plasma Pi 2 pools
Distal volume infinite Fixed Km
Leypoldt et al, Nephrol Dial Transplant 2014
Evolution of plasma Pi 2 pools
Distal volume infinite Fixed Km
Long noctural
Predialysis P
Short daily
Leypoldt et al, Nephrol Dial Transplant 2014
Long noctural
Predialysis P (%)
Short daily
Evolution of plasma Pi 2 pools
Distal volume infinite Fixed Km
Leypoldt et al, Nephrol Dial Transplant 2014
Evolution of plasma Pi 2 pools
Distal volume infinite Fixed Km
Predialysis P (%) 4, 5, 6 Jours
Spalding et al, Kidney Int 2002
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
3 TBW
1/3 TBW
Kc variable
0,97 m/L
Kc Vaviable selon Pi EC
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
BLOOD
DIALYSATE
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
Pi reduction
ratio Mean % error
Training set
Data
Training set
Data
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
Correct
prediction
Training set
Daugerdas et al, Nephrol Dial Transplant 2016
Evolution of plasma Pi 2 pools Kc Variable
Correct
prediction
Data
COMPLEX COMPARTMENTAL MODELING
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 2 pools
2/3 TBW
1/3 TBW
350 mL/min
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 3 pools
No plateau
Constant gain
Similar parameters
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 3 pools
Constant gain if Pi decreases
Reduced hysteresis
BLOOD CELL
DIALYSATE
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 4 pools
Spalding et al, Kidney Int 2002
Dialysis end
Evolution of plasma Pi 4 pools
Time, minutes
Constant gain if Pi decreases
Pulses from 4th pool
Plateau predicted
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 4 pools
4 pools only predicts adequately
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 4 pools
4 pools allows predictions of treatment change
MR SPECTROSCOPY FOR INTRACELLULAR PI IN HD PATIENTS
BLOOD CELL
DIALYSATE
Hypothesis
EC Pi = IC Pi
Spalding et al, Kidney Int 2002
Evolution of plasma Pi 4 pools
BLOOD CELL
DIALYSATE
Study of Pi transfers is restricted by the lack of direct intracellular Pi measurement
Rational
IC Pi ??
Spalding et al, Kidney Int 2002
PCr = phosphocreatine
α β
γ
ATP
PCr
Pi
Nuclear Magnetic Resonance Spectroscopy Spectrum of 31 phosphorus
- Several peaks like inorganic phosphate (Pi) or phosphocreatin.
- Intracellular concentration assessment of each molecule by repeating acquisitions.
-- Non invasive, non radiant, usable in animals as well as in humans.
Spectrum of 31 phosphorus by NMR spectroscopy
Materials and methods : How to measure intracellular Pi/ IP?
Feasibility of intracellular Pi measurement with spectroRMN during hemodialysis.
Measurement of intracellular Pi and ATP concentration during a hemodialysis session.
Test Spalding’s hypothesis on the diffuse transfert of Pi during hypothesis
Aims of this study
Animal model
•6 anephric pigs, 3 months old, about 30kg.
• Intubated, ventilated, spectroRMN during HD
•Because of the magnetic environment, we performed an adaptation of:
•Blood lines
•Ventilator lines
•Diet = for end stage renal disease, low in potassium, water intake control (500ml/day).
•Dialysis modality:
- Haemodialysis using a PrismaFlex® dialyser.
- Blood flow 100 to 150 mL/min
- Dialysate flow 100 mL/min.
Dialysis modality
Design
Day 1 Day 2 Day 4
Bilateral nephrectomy
HD catheter
Dialysis
31P spectroscopy
Measurements of intracellular and plasma Pi
3H
31P spectroscopy
3H Surgery
0 2000 4000 6000 80000.0
0.2
0.4
0.6
0.8
1.0
Time (s)
Pi/P
CR
Sham pig
Results: Pi kinetic
Times (s)
Pi/P
cr High reproducibility
Lemoine et al, unpublished
Results
Lemoine et al, J Am Soc Nephrol 2016
Results : urea and bicarbonates kinetic
Lemoine et al, J Am Soc Nephrol 2016
Expected evolution of Urea and Bicarbonates
Lemoine et al, J Am Soc Nephrol 2016
Stable calcemia
Calcium balance almost null
Results: Calcium kinetic
Results: Extra and Intracellular Pi kinetic
Lemoine et al, J Am Soc Nephrol 2016
Expected evolution of EC Pi
Unexpected evolution of IC Pi
Constant
depuration of Pi
Results: Intracellular ATP and pH kinetic
Lemoine et al, J Am Soc Nephrol 2016
Unexpected evolution of ATP
Discussion
1. Validation and safety of the model.
2. Opportunity to measure Pi during hemodialysis.
3. Unexpected results :
a. Pi increased in the intra-cellular compartment.
b. ATP decreases
4. Pi origin : intracellular / Bone ?
5. Acute model : to be confirmed in chronic HD patients
BLOOD CELL
DIALYSATE
Adaptation to Spalding 4 pools model
No
Spalding et al, Kidney Int 2002
Yes
EC Pi sensor ??
MR spectroscopy in HD patients
Durozard et al, Kidney Int 1993
MR spectroscopy 4,5 T
Muscle metabolism in 6 normal and HD patients
Day without dialysis
BLOOD
DIALYSATE
Exercise Pcr drop
Pi increase
Durozard et al, Kidney Int 1993
MR spectroscopy in HD patients
Durozard et al, Kidney Int 1993
MR spectroscopy in HD patients
HD
HD
Reduced work load in HD patients
BLOOD
DIALYSATE
EC Pi = IC Pi
Durozard et al, Kidney Int 1993
MR spectroscopy in HD patients
BLOOD
DIALYSATE
Durozard et al, Kidney Int 1993
MR spectroscopy in HD patients
HD
Reduced work load in HD patients
HD
CIPHEMO
12 patients
Dialyse conventionnelle 4 heures
Mesure Pi IC par spectro MR en continu IRM 3T
Evaluation métabolisme osseux
Conclusions
During a hemodialysis:
- Extra-cellular Pi decreased with a plateau as described previously.
- Intra-cellular Pi increased
- Origin of production
- Intra-cellular ATP decreased
- Cell impact ? Fatigue ?
- Spalding model rejected
- Adapted 2 pools modeling may predict Pi after prescription changes
Many thanks to :
Sandrine Lemoine
Amélie Belloi
Thomas Fournier
CERMEP: Gabriel Kocevar, Danielle Ibarola, Dominique Sappey Marinier
HOSPAL