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

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

  1. 1. pierre.cochat@chu-lyon.fr Centre de référence des maladies rénales rares Néphrogones Hospices Civils de Lyon Université de Lyon, France Primary hyperoxalurias
  2. 2. Metabolic defect Inborn error of glyoxylate metabolism Recessive autosomal inheritance 3 types - HP1 - HP2 - HP3 - HPx 80% 5% 15% AGXT GRHPR HOGA1 Cochat N Engl J Med 2013 Oxalosis: Systemic calcium oxalate storage
  3. 3. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Representation of the AGT 3D structure PH1 1:120,000 live births Alanine-glyoxylate aminotransferase deficiency Cellini Biochim Biophys Acta 2011
  4. 4. Healthy Plasma Liver Glyoxylate Oxalate AGT [B6] Glycine Glycolate Urine Glycolate Oxalate
  5. 5. PH1 Plasma Liver Skeleton Glyoxylate Oxalate AGT [B6] X Glycine Glycolate Urine Glycolate Oxalate Oxalate
  6. 6. PH1 – Stage 1 Primary hyperoxaluria type 1 Oxalate production from the liver Plasma oxalate Urinary oxalate
  7. 7. Monohydrated calcium oxalate (whewellite) Courtesy JF Sabot Daudon N Engl J Med 2008 Orazi Skeletal Radiol 2009
  8. 8. Nephrocalcinosis: Pathology
  9. 9. Nephrocalcinosis: Imaging
  10. 10. PH1 – Stage 2 Primary hyperoxaluria type 1 Oxalate production from the liver Slow GFR<30-40 turnover oxalate Bone & tissues Miscible oxalate pool Plasma oxalate x Urinary oxalate
  11. 11. Systemic involvement Arteries Joints Bone Bone Cochat EMC 2009 Eye Eye Liver Tanriover Kidney Int 2010
  12. 12. 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%
  13. 13. Diagnosis - 1  Presentation Urolithiasis/nephrocalcinosis + CKD  Urine crystals Monohydrated calcium oxalate  Urine oxalate > 0.5 mmol/1,73m² per day Uox/Ucr > 0.10 mmol/mmol  Plasma oxalate N < 5 µmol/L Limited value for diagnosis Interest in follow-up post-Tx
  14. 14. Diagnostic - 2  AGXT gene sequencing (>100 private mutations)  Prenatal diagnosis  [Enzyme activity measurement (liver biopsy): limited indications]
  15. 15. Registry - 512 PH1 pts van Woerden IPNA 2010
  16. 16. Vision globale en europe Age at start of RRT in PH1 patients in Europe 88% 32% 44% 22% Harambat Clin J Am Soc Nephrol 2012
  17. 17. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 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
  18. 18. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Early conservative measures [Hydration – vitamin B6 – citrate] N= 27 Age at start: 4.1 yrs Follow-up: 7.7 yrs Good adherence Poor adherence GFR at start: 92 mL/min per 1.73 m² Final GFR (N= 23, without ESRD): 110  19 pts: stable GFR  8 pts: progressive CKD  4 pts: progression to ESRD Fargue Kidney Int 2009
  19. 19. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
  20. 20. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 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
  21. 21. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 RRT: unadjusted 5-year patient survival Harambat Clin J Am Soc Nephrol 2012
  22. 22. Dialysis Oxalate = small molecule, easy to clear COOH COOH Systemic deposition as soon as Pox > 50 µmol/L Tissue storage 2 to 4 mmol/day Oxalate production 4 to 8 mmol/day Oxalate clearance from dialysis: 2 to 4 mmol/day
  23. 23. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 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
  24. 24. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Unadjusted 5-year kidney graft survival Harambat Clin J Am Soc Nephrol 2012
  25. 25. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 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 welldefined and selected patients
  26. 26. PH1 Plasma Liver Skeleton Glyoxylate Oxalate AGT [B6] X Glycine Glycolate Urine Glycolate Oxalate Oxalate
  27. 27. PH1 after liver Tx Plasma « New » liver Skeleton Glyoxylate Oxalate AGT [B6] Glycine Glycolate « New» kidney Urine Glycolate Oxalate Oxalate
  28. 28. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Therapeutic goals Treatment Conservative Dialysis Transplantation < 0.4 mmol/L B6 response if ↓ 30% --- < 0.4 mmol/L --- < 40-50 µmol/L < 20 mmol/L Urine calcium < 4 mmol/L --- < 4 mmol/L Urine crystal volume < 200 /mm3 --- < 200 /mm3 Urine oxalate Plasma oxalate
  29. 29. 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?
  30. 30. PH3 – Experience in Lyon Age at first symptoms Presentation Clinical outcome GFR at last examination Brasil 0.4 UTI Urolithiasis Nephrocalcinosis Recurrent stones 64 China 2.4 Urolithiasis Obstruction Recurrent stones 77 China 5.0 Urolithiasis Recurrent stones 151 France 9.8 Urolithiasis Recurrent stones 108 Algeria 1.8 UTI Urolithiasis Recurrent stones 151 France 1.0 UTI Urolithiasis No recurrence 127 France 0.5 UTI Nephroclacinosis No recurrence 103 Origin
  31. 31. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 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
  32. 32. Thank you for your attention !
  33. 33. Hospices Civils de Lyon & Université Claude-Bernard Lyon 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 Perop + postop according to POx and GFR Standard HD following liver Tx aiming at POx < 20 µmol/L Preop + perop Sometimes peroperative CKD Stage 3 (30 < GFR < 59) CKD Stage 4 (15 < GFR < 29) CKD Stage 5 (GFR < 15) Infantile form (ESRD < 2 years) HD strategy
  34. 34. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Future options for treatment - 1  New trial with Oxalobacter formigenes Oxabact® OxThera 2013  Aluminum citrate to prevent oxalate-induced tubular injury Besenhofer 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
  35. 35. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Future options for treatment - 2 Animal models for PH1, PH2, PH3  Cell [hepatocyte transplantation] therapy Jiang Transplantation 2008 Beck Nephrol Dial Transplant 2012  Somatic gene therapy using adenovirus-associated vector 2013 OXALgTHER Project  Identification of chaperones to restore correct protein folding may be applicable to some genotypes Hopper J Biol Chem 2008
  36. 36. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Future options for treatment - 1  Aluminum citrate to prevent oxalate-induced tubular injury Besenhofer J Am Soc Nephrol 2013 Wistar rat model Acute high-dose ethylene glycol
  37. 37. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Future options for treatment - 1  IL-1b blockade to prevent inflammasome damage induced by nephrocalcinosis Mulay J Clin Invest 2013
  38. 38. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1 Future options for treatment - 2 Animal models for PH1, PH2, PH3 The 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] therapy Jiang Transplantation 2008

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