Management of disease recurrence after renal transplantation

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

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) 0 Enfants Malades

6. Removal of circulating factor lowers protein excretion in recurrent NS P l a s m a e x c h a n g e 1 0 0 Pu P r o t e i n a b s o r p t i o n 8 0 6 0 4 0 2 0 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. Mutation Atypical HUS : French Pediatric Registry (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 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 : 4 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 0 0 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)

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. 2000 1750 1500 1250 1000 750 500 250 0 0 500 1000 1500 2000 24 h Oxaluria in 3 children after liver/ kidney transplantation µmol/ day 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 1993 21 54 • Conduction system abnormalities and cardiomyopathy may rapidly be reversed after some weeks Rodby et al. Am J Med 1991 90 498 Fyfe et al. Am J Cardiol 1995 75 210

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