1. Management of disease recurrence after renal transplantation
Patrick Niaudet
Néphrologie Pédiatrique
Centre de référence des maladies rénales génétiques
Hôpital Necker-Enfants Malades, Paris
ESPN, September 2008

2. Recurrence of primary disease
Recurrence frequency
Graft loss
SRNS with FSGS
30%
40-50%
MPGN
Type I
20-30%
30-40%
Type II
80-100%
20%
Membranous nephropathy
10%
40%
IgA nephropathy
15-30%
SHP nephritis
<1%
Systemic vasculitis
10-20%
<5%
SLE
< 2%
rare
Anti-GBM disease
< 5%
50%
D+HUS
exceptionnal
Atypical HUS
30-50%
>50%
Amyloidosis
25 %
Primary hyperoxaluria
100%
80%

3. Recurrence of nephrotic syndrome after renal transplantation
Occurs in about 30% of patients with SRNS and FSGS
Extremely low rate of recurrence in genetic forms of the disease
Proteinuria is most often of rapid onset

4. Recurrence of nephrotic syndrome after renal transplantation
Risk factors for recurrence :
duration of disease shorter than 3 years
disease starting after the age of 6 years
diffuse mesangial proliferation on initial biopsy
recurrence on a previous graft
Graft failure occurs in 60% of patients with recurrence
CsA does not prevent recurrence but improves graft survival

5. Recurrence of nephrotic syndrome according to the age at onset of disease
% with recurrence
age > 6 years 54
age < 6 years
22 (p < 0.01)
age < 3 years (n=41) 7
age < 1 year (n=15)
Enfants Malades

6. Removal of circulating factor lowers protein excretion in recurrent NSh a n g e 1 Pu P r o t e i n a b s o r p t i o n 8 6 4 2
Prett Tt
Day 7
Day 15
Dantal et al, NEJM 1994, 330: 7

7. Prophylactic plasma exchanges
Recurrence in 4 of 6 pts in the non prophylactic group
Recurrence in 5 of 15 pts in the prophylactic group
7 recurrent pts received PE with remission in 6
(Ohta et al, Transplantation, 2001)

8. Plasma exchanges plus cyclophosphamide
Dall’Amico et al (AJKD, 1999)
Sucessfull in 9 of 11 children
Persistent remission in 7 with a follow-up of 32 months
Cheong et al (NDT, 2000)
Complete remission in 3/6
Partial remission in 3/6

9. Rituximab failed to improve nephrotic syndrome in four adult renal transplant patients with early recurrent FSGS refractory or dependent on plasmapheresis
Yabu JM et al AJT 2008; 8: 222-7

10. Intravenous CsA for recurrent nephrotic syndrome after RT
Between March 1991 and July 2007, recurrence has occurred in 22 grafts in 21 children
CsA was immediately administered IV, at an initial dose of 3 mg/kg/d and the dose was adjusted in order to maintain whole blood levels above 250 ng/ml
Plasma exchanges, 2 to 10 sessions, in 9 patients
Enfants Malades

11. Intravenous CsA for recurrent nephrotic syndrome after RT
One pt with delayed recurrence (day 18) did not respond to IV CsA + PE
Among the 21 early recurrences (within the first week) :
1 pt did not respond to IV CsA + PE
3 pts showed partial remission (proteinuria without nephrotic syndrome) after IV CsA + ACEI
17 pts (77%) entered into complete remission within 20 days (D12 to D40)
with CsA alone in 11 cases
with CsA + PE in 7 cases
11 of the 17 pts are still in CR 1 to 14 years later

12. Recurrence of NS after RT
Seems to be mediated by a circulating 50-kD plasma protein, which is bound to Ig
Identification of the protein ?
Clinical usefullness of the presence of the « permeability » factor ?
Living donor or cadaveric donor ?
Best therapy
Plasma exchanges ± cyclophosphamide
IV cyclosporine ± plasma exchanges
Others ?

13. Atypical HUS Mutations in genes of the complement pathway (50%)
Anti-CFH antibodies
Von Willebrand factor cleaving protease deficiency (ADAMTS13 gene mutation)
Defects of vitamine B12 metabolism
Idiopathic autosomal recessive disease
Idiopathic autosomal dominant disease

14. Atypical HUS : French Pediatric Registry
Mutation
CFH IF
MCP No
N (46)
10 (22%)
6 (13%)
7 (15%)
22 (48%)
Outcome
Death 2 1
ESRD 6
(Sellier-Leclerc et al, JASN 2007)

15. Atypical HUS : posttransplant course
24 grafts in 15 patients
12 graft failures during the first year (50%)
8 from thrombosis
3 from recurrence
1 from CMV
4 graft failures later (recurrence in 2, rejection in 2)
2 functioning grafts at 2yr despite recurrence
6 grafts with good outcome 5 to 15 yr later
(Sellier-Leclerc, JASN 2007)

16. Atypical HUS : recurrence after RT
Mutation
CFH IF
MCP No
Nb pts 34 8 10 20
Recurrence
76%
88%
20%
30%
Graft loss (from recurrence at 1yr)
81%
100%
1/2
83%
Richards 2003 ; Fremeaux-Bacchi 2004, 2006, 2007 ; Kavanagh 2005 ; Bresin 2005 ;
Caprioli 2006 ; Heinen 2006 ; Venables 2006 ; Nilsson 2007 ; Geelen 2007 ; Sellier-Leclerc 2007

17. Possible therapy FFP ± PE Eculizumab (monoclonal antibody)
Binds to C5, inhibiting its clivage to C5a and C5b
Prevents the release of C5a and the formation of C5b-C9
Reduces transfusion requirements in paroxysmal noctural hemoglobinuria (lack of GPI-linked-proteins that protect cells from complement-mediated attack)

18. Atypical HUS with CFH mutation : results of liver transplantation
Initial experience with combined L+K (2) or L (1) but no plasma therapy : 2 deaths and 1 with neurological sequellae (Remuzzi, Cheong)
Combined L+K with extensive plasma therapy : children with excellent outcome and no recurrence (Saland, Jalanko)
PE with FFP before surgery
FFP ± PE during surgery
Anticoagulation after surgery

19. Consensus Conference (Bergame, Dec 2007) Indications for combined liver-renal or isolated liver transplantation
CFH mutation
First graft lost from recurrence
Another family member with the same mutation and who lost a graft from recurrence
Patient with a mutation reported to be associated with graft loss from recurrence
Not enough data for HUS associated with other complement mutations

20. Conservative treatment of primary hyperoxaluria
High fluid intake over 24h : 3l/m2
Solubilization of calcium oxalate : potassium citrate
AGT coenzyme : Pyridoxine [G170R]
Avoid surgical removal of calculs
Low oxalate diet
Oxalobacter formigenes (OxabactTM : 2 x 107 UFC/d) : ongoing trial

21. Evolution of GFR in children with PH1 under conservative treatment
200
180
160
140
120
100
GFR (Schwartz formula) mL/mn/1.73m2 80
GFR at initiation : 92 ml/mn
At last examination
Stable GFR 19/27pts
Decreased GFR 8/27pts
ESRF 4/27pts 60 40 20 24 48 72 96
120
144
168
192
216
240
time (months)
(Société de Néphrologie Pédiatrique)

22. Extra renal complications in PH1
Oxalate accumulates in tissues when plasma oxalate reaches 50mol/l
4 to 8 mmol of oxalate are produced every day
bone disease
retinal deposits with amblyopia
conduction system abnormalities
cardiomyopathy
artery calcifications and ischemia
livedo reticularis , gangrene
polyneuritis

23. Transplantation strategy (P. Cochat)
Liver + kidney
Liver then kidney
Kidney
Liver
Infantile (ESRF<2yr)
Second choice
First choice X
GFR to 60 mL/min ?
GFR to 40 mL/min
? If Vit B is active and G170R mutation
GFR<20 mL/min

24. Management of primary hyperoxaluria
The best treatment of oxalosis is conservative and preventive when possible
A careful protocol must be applied and maintained for preventing recurrence on the graft
The most important point is to maintain high urine output after renal transplantation (low oxalate concentration)
Dialysis is indicated only in case of oliguria

25. 24 h Oxaluria in 3 children after liver/ kidney transplantation
µmol/ day
250
500
750
1000
1250
1500
1750
2000
2000
1500
1000
500
Days post grafting

26. Evolution of extra renal complications after liver-kidney transplantation
Bone disease improves very slowly but complete healing was reported after several years
Toussaint et al Am J Kidney Dis
Conduction system abnormalities and cardiomyopathy may rapidly be reversed after some weeks
Rodby et al. Am J Med
Fyfe et al. Am J Cardiol

27. Conclusion
Recurrent disease in a renal transplant remains an important cause of chronic allograft dysfunction and graft failure
Patients and their families should be informed of the recurrence risk, potential therapeutic options and prognosis
The indication of retransplantation when a primary graft has been lost to recurrence is a difficult issue