Management of disease recurrence after renal transplantation Patrick Niaudet Néphrologie...
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Transcript of Management of disease recurrence after renal transplantation Patrick Niaudet Néphrologie...
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