Management of disease recurrence after renal

transplantation

Patrick NiaudetNéphrologie Pédiatrique

Centre de référence des maladies rénales génétiques

Hôpital Necker-Enfants Malades, Paris

ESPN, September 2008

Recurrence of primary disease

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 30% 15-30%

SHP nephritis <1% <1%

Systemic vasculitis 10-20% <5%

SLE < 2% rare

Anti-GBM disease < 5% 50%

D+HUS exceptionnal

Atypical HUS 30-50% >50%

Amyloidosis 25 % rare

Primary hyperoxaluria 100% 80%

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

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

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

Removal of circulating factor lowers protein

excretion in recurrent NS

20

40

60

80

100 Plasma exchangeProtein absorption

Prett Tt Day 7 Day 15Dantal et al, NEJM 1994, 330: 7

Pu

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)

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

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

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

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

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 ?

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

Atypical HUS : French Pediatric Registry

CFH IF MCP No

N (46) 10 (22%)

6 (13%)

7 (15%)

22 (48%)

Outcome

Death 2 1 0 1

ESRD 6 2 2 6

Mutation

(Sellier-Leclerc et al, JASN 2007)

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)

Atypical HUS : recurrence after RT

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

Mutation

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)

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

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

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

0

20

40

60

80

100

120

140

160

180

200

0 24 48 72 96 120 144 168 192 216 240

time (months)

GFR (Schwartz formula) mL/mn/1.73m2

Evolution of GFR in children with PH1 under conservative

treatment

GFR at initiation : 92 ml/mnAt last examination• Stable GFR 19/27pts• Decreased GFR 8/27pts• ESRF 4/27pts

(Société de Néphrologie Pédiatrique)

Extra renal complications in PH1

• bone disease

• retinal deposits with amblyopia

• conduction system abnormalities

• cardiomyopathy

• artery calcifications and ischemia

• livedo reticularis , gangrene

• polyneuritis

Oxalate accumulates in tissues when plasma oxalate reaches 50mol/l

4 to 8 mmol of oxalate are produced every day

Liver + kidney

Liver then kidney

Kidney Liver

Infantile (ESRF<2yr)

Second choice

First choice X X

GFR 40 to 60 mL/min

X X X ?

GFR 20 to 40 mL/min

First choice X

? If Vit B is active and G170R mutation

X

GFR<20 mL/min Second

choiceFirst choice X X

Transplantation strategy (P. Cochat)

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

24 h Oxaluria in 3 children after liver/ kidney transplantation

2000200015001500100010005005000000

250250

500500

750750

10001000

12501250

15001500

17501750

20002000

Days post Days post graftinggrafting

µmol/ dayµmol/ day

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

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