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[email protected] de référence des maladies rénales rares NéphrogonesHospices Civils de LyonUniversité de Lyon, France
Primary hyperoxalurias
Metabolic defect
Inborn error of glyoxylate metabolismRecessive autosomal inheritance
3 types- HP1 80% AGXT- HP2 5% GRHPR- HP3 15% HOGA1- HPx
Oxalosis: Systemic calcium oxalate storageCochat N Engl J Med 2013
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Representation of the AGT 3D structure
Cellini Biochim Biophys Acta 2011
PH1
1:120,000 live births
Alanine-glyoxylate aminotransferase deficiency
Healthy
Liver
Glyoxylate
GlycineGlycolate
Oxalate
Plasma
Glycolate OxalateUrine
AGT[B6]
PH1
Liver
Glyoxylate
GlycineGlycolate
Oxalate OxalateSkeleton
Plasma
Glycolate OxalateUrine
AGT[B6]X
Primary hyperoxaluria type 1
Plasmaoxalate
Urinaryoxalate
Oxalate productionfrom the liver
PH1 – Stage 1
Monohydrated calcium oxalate (whewellite)
Daudon N Engl J Med 2008
Courtesy JF Sabot
Orazi Skeletal Radiol 2009
Nephrocalcinosis: Pathology
Nephrocalcinosis: Imaging
Primary hyperoxaluria type 1
Slow
turnover
oxalate
Bone &
tissues
Oxalate productionfrom the liver
Miscibleoxalate
pool
Plasmaoxalate
Urinaryoxalate
GFR<30-40
x
PH1 – Stage 2
Systemic involvement
Tanriover Kidney Int 2010Cochat EMC 2009
Arteries Joints
Bone Eye LiverBone
Eye
Presentation
1. Infantile form 35%
2. Recurrent stones with progressive CKD 20%
3. Late adulthood onset 15%
4. Presymptomatic diagnosis from pedigree screening 15%
5. Diagnosis from post-renal Tx recurrence 10%
Diagnosis - 1
Presentation Urolithiasis/nephrocalcinosis + CKD
Urine crystals Monohydrated calcium oxalate
Urine oxalate > 0.5 mmol/1,73m² per dayUox/Ucr > 0.10 mmol/mmol
Plasma oxalate N < 5 µmol/LLimited value for diagnosisInterest in follow-up post-Tx
AGXT gene sequencing (>100 private mutations) Prenatal diagnosis
[Enzyme activity measurement (liver biopsy): limited indications]
Diagnostic - 2
Registry - 512 PH1 pts van Woerden IPNA 2010
Vision globale en europe
88%
44%
32%
22%Harambat Clin J Am Soc Nephrol 2012
Age at start of RRT in PH1 patients in Europe
Conservative treatment
As soon as a diagnosis of PH1 has been even suggested ++ High fluid intake ≥ 3 L/m² per 24 h Tube feeding for adequate hydration (infants) Vitamin B6 (pyridoxine)
Starting at a dose of 5 mg/kg per day, up to 20 mg/kg per day Aiming to decrease Uox by < 30% Discontinue in non-G170R non-P152L mutations
Calcium oxalate crystallization inhibition Alkalization with oral potassium citrate 0.10–0.15 g/kg BW per day as long as GFR is preserved
No special dietary interventions in the absence of CKD
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GFR at start: 92 mL/min per 1.73 m²Final GFR (N= 23, without ESRD): 110 19 pts: stable GFR 8 pts: progressive CKD 4 pts: progression to ESRD
Early conservative measures[Hydration – vitamin B6 – citrate]
Fargue Kidney Int 2009
N= 27Age at start: 4.1 yrsFollow-up: 7.7 yrs
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Good adherencePoor adherence
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Surgical management of urolithiases
Avoid any kind of surgical intervention in patients with uncomplicated urinary stone disease, except when there is obstruction, infection or multiple urolithiasis
Endoscopic procedure is the preferred strategy in patients who require intervention
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RRT: unadjusted 5-year patient survivalH
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Harambat Clin J Am Soc Nephrol 2012
Oxalate = small molecule, easy to clear
Systemic deposition as soon as Pox > 50 µmol/L
Dialysis
COOH
COOH
Oxalate clearance fromdialysis: 2 to 4 mmol/day
Tissue storage2 to 4 mmol/day
Oxalate production4 to 8 mmol/day
Dialysis procedures
Avoid any form of dialysis and consider pre-emptive Tx
High efficacy dialysis when pre-emptive Tx is not an option Daily HD Nocturnal dialysis Combination of HD and PD
Limited indications Infant wait for Tx Before/after isolated renal Tx Before/after combined liver-kidney Tx according to GFR
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Unadjusted 5-year kidney graft survivalH
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Harambat Clin J Am Soc Nephrol 2012
Transplantation strategy
Plan preemptive organ Tx at CKD Stage 3b to avoid the complications of systemic oxalosis
Avoid isolated kidney Tx unless there is no other option
Combined liver–kidney Tx is recommended in most patients, either simultaneously or sequentially
Avoid preemptive isolated liver Tx unless in very well-defined and selected patients
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PH1
Liver
Glyoxylate
GlycineGlycolate
Oxalate OxalateSkeleton
Plasma
Glycolate OxalateUrine
AGT[B6]X
PH1 after liver Tx
« New » liver
Glyoxylate
GlycineGlycolate
Oxalate OxalateSkeleton
Plasma
Glycolate OxalateUrine
« New» kidney
AGT[B6]
Therapeutic goalsH
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Treatment Conservative Dialysis Transplantation
Urine oxalate< 0.4 mmol/L
B6 response if ↓ 30% --- < 0.4 mmol/L
Plasma oxalate --- < 40-50 µmol/L < 20 mmol/L
Urine calcium < 4 mmol/L --- < 4 mmol/L
Urine crystal volume < 200 /mm3 --- < 200 /mm3
PH2
Unknown incidence ~ 50 case reports Higher in Asian populations Clinical phenotype: less severe than PH1 Biochemical phenotype: hyperoxaluria + hyperglyceraturia Deficit: D-glycerate dehydrogenase:glyoxylate reductase Gène GRHPR (glyoxylate reductase/hydroxypyruvate reductase) Treatment: hydration + cristallization inhibitor ± Tx?
PH3 – Experience in Lyon
Origin Age at first symptoms Presentation Clinical
outcomeGFR at last
examination
Brasil 0.4UTI
UrolithiasisNephrocalcinosis
Recurrent stones 64
China 2.4 UrolithiasisObstruction Recurrent stones 77
China 5.0 Urolithiasis Recurrent stones 151
France 9.8 Urolithiasis Recurrent stones 108
Algeria 1.8 UTIUrolithiasis Recurrent stones 151
France 1.0 UTIUrolithiasis No recurrence 127
France 0.5 UTINephroclacinosis No recurrence 103
Conclusions
Priorities: Think of PH - Identification of PH type Early conservative measures asap Patient information regarding lifelong management
Management of PH requires technical and ethical resources
Reference to large databases and multicenter RCT
Various treatment options may help in the future
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Thank you for your attention !
Hos
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1 Suggested Tx options according to residual GFR, systemic involvement and local facilities
Tx strategy Simultaneous liver + kidney
Sequential liver–kidney Isolated kidney Isolated liver
CKD Stage 3(30 < GFR < 59)
CKD Stage 4 (15 < GFR < 29)
CKD Stage 5 (GFR < 15)
Infantile form (ESRD < 2 years)
HD strategyPerop + postop
according toPOx and GFR
Standard HD following liver Tx
aiming at POx < 20 µmol/L
Preop + perop Sometimes peroperative
Future options for treatment - 1
New trial with Oxalobacter formigenesOxabact® OxThera 2013
Aluminum citrate to prevent oxalate-induced tubular injuryBesenhofer J Am Soc Nephrol 2013
Guo Am J Nephrol 2013
IL-1b blockade to prevent inflammasome damage induced by nephrocalcinosis
Mulay J Clin Invest 2013
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Future options for treatment - 2
Animal models for PH1, PH2, PH3
Cell [hepatocyte transplantation] therapyJiang Transplantation 2008
Beck Nephrol Dial Transplant 2012
Somatic gene therapy using adenovirus-associated vector2013 OXALgTHER Project
Identification of chaperones to restore correct protein folding may be applicable to some genotypes
Hopper J Biol Chem 2008
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Future options for treatment - 1
Aluminum citrate to prevent oxalate-induced tubular injuryBesenhofer J Am Soc Nephrol 2013
Hos
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Wistar rat modelAcute high-dose ethylene glycol
Future options for treatment - 1
IL-1b blockade to prevent inflammasome damage induced by nephrocalcinosis
Mulay J Clin Invest 2013
Hos
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Future options for treatment - 2
Animal models for PH1, PH2, PH3The problem in PH is not the lack of enzyme per se but the accumulation of precursors requiring sufficient replacement to overcome residual enzyme inactivity.
Cell [hepatocyte transplantation] therapyJiang Transplantation 2008
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