This document discusses primary hyperoxalurias (PH), which are inborn errors of glyoxylate metabolism. There are three main types - PH1, PH2, and PH3 - caused by deficiencies in different enzymes involved in glyoxylate processing. PH1 is the most severe and results from alanine-glyoxylate aminotransferase deficiency. The standard treatment involves conservative measures like hydration and medication, but the only cure is liver or combined liver-kidney transplantation due to ongoing oxalate overproduction in the liver. New treatments under investigation include probiotics to break down oxalate, medications to prevent kidney damage, and gene or cell therapies to replace the missing enzyme function.

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. 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. 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. Healthy
Plasma
Liver
Glyoxylate
Oxalate
AGT
[B6]
Glycine
Glycolate
Urine
Glycolate Oxalate

5. PH1
Plasma
Liver
Skeleton
Glyoxylate
Oxalate
AGT
[B6]
X
Glycine
Glycolate
Urine
Glycolate Oxalate
Oxalate

6. PH1 – Stage 1
Primary hyperoxaluria type 1
Oxalate production
from the liver
Plasma
oxalate
Urinary
oxalate

7. Monohydrated calcium oxalate (whewellite)
Courtesy JF Sabot
Daudon N Engl J Med 2008
Orazi Skeletal Radiol 2009

8. Nephrocalcinosis: Pathology

9. Nephrocalcinosis: Imaging

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. Systemic involvement
Arteries
Joints
Bone
Bone
Cochat EMC 2009
Eye
Eye
Liver
Tanriover Kidney Int 2010

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. 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. Diagnostic - 2
 AGXT gene sequencing (>100 private mutations)
 Prenatal diagnosis
 [Enzyme activity measurement (liver biopsy): limited indications]

15. Registry - 512 PH1 pts
van Woerden IPNA 2010

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

18. 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

19. 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

20. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1

21. 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

22. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
RRT: unadjusted 5-year patient survival
Harambat Clin J Am Soc Nephrol 2012

23. 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

24. 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

25. Hospices Civils de Lyon & Université Claude-Bernard Lyon 1
Unadjusted 5-year kidney graft survival
Harambat Clin J Am Soc Nephrol 2012

26. 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

27. PH1
Plasma
Liver
Skeleton
Glyoxylate
Oxalate
AGT
[B6]
X
Glycine
Glycolate
Urine
Glycolate Oxalate
Oxalate

28. PH1 after liver Tx
Plasma
« New » liver
Skeleton
Glyoxylate
Oxalate
AGT
[B6]
Glycine
Glycolate
« New» kidney
Urine
Glycolate Oxalate
Oxalate

29. 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

30. 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?

31. 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

32. 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

33. Thank you for
your attention !

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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