6-2. Primary hyperoxaluria. Pierre Cochat (eng)

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pierre.cochat@chu-lyon.frCentre 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

1:120,000 live births

Alanine-glyoxylate aminotransferase deficiency

Healthy

Glyoxylate

GlycineGlycolate

Oxalate

Plasma

Glycolate OxalateUrine

AGT[B6]

Glyoxylate

GlycineGlycolate

Oxalate OxalateSkeleton

Plasma

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

turnover

oxalate

Bone &

tissues

Oxalate productionfrom the liver

Miscibleoxalate

Plasmaoxalate

Urinaryoxalate

GFR<30-40

PH1 – Stage 2

Systemic involvement

Tanriover Kidney Int 2010Cochat EMC 2009

Arteries Joints

Bone Eye LiverBone

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

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

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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Glyoxylate

GlycineGlycolate

Plasma

AGT[B6]X

PH1 after liver Tx

« New » liver

Glyoxylate

GlycineGlycolate

Plasma

« New» kidney

AGT[B6]

Therapeutic goalsH

ité C

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

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 !

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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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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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Aluminum citrate to prevent oxalate-induced tubular injuryBesenhofer J Am Soc Nephrol 2013

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Wistar rat modelAcute high-dose ethylene glycol

IL-1b blockade to prevent inflammasome damage induced by nephrocalcinosis

Mulay J Clin Invest 2013

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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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6-2. Primary hyperoxaluria. Pierre Cochat (eng)

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