REJET AIGU et TRANSPLANTATION RENALE Christophe LEGENDRE Service de Transplantation Rénale Hôpital NECKER -PARIS Subclinical acute rejection. Mrs PLA, 46 year old female, APKD, anti-hla abs (36%), Received a first cavader kidney transplant from a 35 year old donor (normal biopsy) with 3 HLA mismatches (IB, 2DR), No DGF, screat at discharge = 130µmol/l under Simulect + Tac + Inh IMPDH + ste, At M3: screat = 80µmol/l, GRF = 64 ml/min/1.73m2, Pu < 0.10g/d, A first routine biopsy is performed: acute Banff IA RX + CAN I.
BR1 BR1
BR1 Subclinical acute rejection. She received 3 shots of methyprednisolone and oral steroids, At M6, screat = 70mol/l, Pu < 0.10g/d, A second biopsy is performed: acute Banff IA RX + CAN I.
Subclinical acute rejection. She received a course of Thymoglobuline and 3 shots of methylprednisolone. At one year, screat = 99 µmol/l, Pu < 0.10g/d A third biopsy is performed: CAN III + allograft glomerulopathy. C4d always remained negative. BR3
BR3 BR3
Graft survival at one year 100% 50% 100 80 60 40 20 CsA Control 1975 1985 1995 2005 Time Improved short-term graft survival % Hôpital Necker Mois
Post-RT mortality (6 months) Hôpital Necker 1959-2004 50 < 1% 1959 1969 1979 1989 Avoiding short term patients death 2004 Acute rejection (%) 50 45 40 35 30 25 20 15 10 5 0 Acute rejection incidence 36.7 22.5 21.4 43.7 33.9 27.4 17.9 15.3 14.6 6.1 7.26.1 6.7 7.4 5.8 5.2 Acute rejection 12-24 months 6-12 months 0-6 months Meier-Kriesche HU, 2004 Am J Transplant 6 2.9 1995 1996 1997 1998 1999 2000 Transplant year Decreasing the incidence of acute rejection
Meier-Kriesche HU, 2004 Am J Transplant 1995 1988 Very modest improvements! Causes of late allograft loss Allograft nephropathy Death with a functioning graft M. Pascual, N Engl J Med 2002
Natural history of a renal transplant Creat TR Natural history of a renal transplant Renal biopsy Creat Renal dysfunction TR
La biopsie rénale Insuffisance rénale: IRA initiale = reprise retardée de fonction, IRA secondaire = le diagnostic du rejet : hyperaigu retardé ou aigu accéléré (HUMORAL) aigu (CELLULAIRE) IRC = dégradation progressive de la fonction du greffon La biopsie rénale Protéinurie: Glomérulopathie d allogreffe, Récidive de la néphropathie initiale, Glomérulonéphrite de novo.
1. L approche clinique: insuffisance rénale + chronologie. Rejet hyperaigu Minutes à heures Rejet aigu Jours à semaines Rejet chronique Mois Hyperacute rejection Definition = irreversible antibody-mediated rejection that generally occurs within minutes or hours after transplantation.
Hyperacute rejection Which antibodies? 1. anti-hla antibodies +++ 2. anti-abo antibodies 3. miscellaneous: anti-monocyte antibodies, anti-endothelium antibodies, cold-reactive IgM agglutinins. Hyperacute rejection Anti-ABO antibodies
Hyperacute rejection: the X-match 1. L approche clinique: insuffisance rénale + chronologie. Rejet hyperaigu Minutes à heures Rejet aigu Jours à semaines
La «crise de rejet» J. Hamburger, Ann NY Acad Sci, 1962
Acute rejection «An immunologic process resulting in renal dysfunction (serum creatinine 0.4mg/dl), in the presence or absence of clinical signs (ie, decreased urine output, fever 38.5 C) and should include histological evidence characterized according to Banff criteria.» 1995 Efficacy Endpoints Conference, AJKD 1998 Banff
La lésion de tubulite La lésion d endothélite
Le rejet aigu Discussion «sémantique»: - sur l intensité du rejet = diffusion, - sur la sévérité du rejet = présence de lésions vasculaires. En pratique, opposition entre: - rejet aigu cellulaire, - rejet aigu vasculaire
Un nouveau marqueur: le C4d. Feucht HE, Clin Exp Immunol 1991 C4d et rejet aigu C4d présent dans 54% des cas des cas de dysfonction aiguë. Feucht HE et al, Kidney Int 1993 Lederer SR et al, Kidney Int 2001
Nouvelle définition du rejet aigu humoral. Nouvelles définitions du rejet aigu.
Rejet aigu C4d - C4d + Médiation cellulaire Lymphocyte T Médiation humorale Lymphocyte B HLA Non-HLA Dragun D et al, New Engl J Med 2005
Exemple # 1 1000 2 750 500 250 1,5 1 0,5 Haptoglobine Créatinine LDH 0 J0 J1 J2 J3 J4 J5 J6 J7 0 TR IRA Date 14/10/2 25/6/3 28/09/3 8/10/3 10/10/3 13/10/3 15/10/3 4/11/3 µlymph 0 0 0 % 66 % 0 % 23 % 20 % 0 % ELISA Neg Pos Pos Pos Pos Pos Pos Pos Exemple # 2 Mr RAZ, Maladie de Berger 1ère TR 6/4/89. Retour en HD 1/3/98 Immunisation anti-hla (anti-a11) 2ème TR le 7/4/05 avec un greffon A11! X-match historique négatif mais X- match du jour positif en IgM. Présence d anti-a11 en Elisa. Décision d un traitement «lourd».
Exemple # 2 Anti-CD20 Anti-CD20 Exemple # 3 Mme DIO, 1ère TR Rein = conjoint. Pas d ac anti-hla (Elisa), 3G, 2AS, 2AP J3: créat = 98 µmol/l, J5: créat = 129µmol/L BR = rejet humoral C4d+ TT = Rejet + EP + anti-cd20 + IvIg Créat = 91µmol/L, BR M3 = normale Pas d Ac anti-hla +++
1. L approche clinique: insuffisance rénale + chronologie. Rejet hyperaigu Minutes à heures Rejet aigu Jours à semaines Rejet chronique Mois Chronic rejection Hume DM et al. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest, 1955 Hildemann WH et al. Chronic skin homograft rejection in the Syrian hamster. Ann N Y Acad Sci, 1960
Chronic rejection «Chronic rejection is a slow, gradual destruction of the graft which can extend over weeks or even months and usually occurs rather late after transplantation. Progressive increase of serum creatinine with or without proteinuria and elevated blood pressure, with tubular atrophy, interstitial fibrosis and fibrous intimal thickening.» Textbooks of nephrology
Causes of graft failure Progressive graft dysfunction Death with function M. Pascual, N Engl J Med 2002
Progressive graft dysfunction: an innovative approach. «Call for Revolution: A new Approach to Describing Allograft Deterioration». Philip F. Halloran «The four questions» 1. What is the state of the parenchyma? 2. Is the graft undergoing rejection? 3. Is a specific disease identifiable? 4. Are there accelerating factors?
Function 1. What is the state of the parenchyma? Reduced GFR with increased rate of nephron loss Pathology Interstitial fibrosis Tubular atrophy IF / TA 2. Is the graft undergoing rejection? Yes T-cell-mediated rejection: tubulitis, endothelialitis, interstitial infiltrate, «chronic allograft arteriopathy». Reassess immunosuppression + compliance
Yes 2. Is the graft undergoing rejection? Alloantibody-mediated rejection: C4d deposits, Anti-HLA antibodies, Glom. double contours or PCBM multilayering C4d+. Reassess immunosuppression + compliance
Glomérule Capillaire péritubulaire Exemple # 4 Mme THA, TR le 15/9/89 Créat à 10 ans = 95µmol/L, Pu < 1g/24h Lente dégradation de la fonction: 2000: créat = 99µmol/L, 2001: créat = 107µmol/L, 2002: créat = 116µmol/L, 2003: créat = 123µmol/L, 2004: créat = 122µmol/L.
Exemple # 4 C4d+ 2. Is the graft undergoing rejection? No No evidence that additional immunosuppression is useful No additional immunosuppression
3. Is a specific disease identifiable? Recurrent or de novo renal disease BK nephropathy CNI nephrotoxicity Hemolytic-uremic syndrome Hypertensive renal disease 4. Are there accelerating factors? Hypertension accelerating other disease CNI nephrotoxicity Diabetes Proteinuria Lipid abnormalities
1. L approche clinique: insuffisance rénale + chronologie. Rejet hyperaigu Rejet hyperaigu retardé Rejet aigu accéléré Rejection aigu Minutes à heures Jours Jours à semaines Rejet aigu tardif Mois (>3) Rejet chronique Mois Late acute rejection Definition = acute rejection occurring after 90 days post-transplantation. Poorer prognostic: JT Joseph, Clin Transplant 2001 YW Sijpkens, Transplantation 2003 Related to non compliance (LS Baines, Clin transplant 2001) Different pathogenesis: CMV-induced (P. Reinke, Lancet 1994) EBV-induced (N. Babel, Transplantation 2001)
Histoire naturelle d une TR Biopsie rénale Biopsie rénale Créat Dégradation de la fonction Créat TR La biopsie rénale Syatématique: précoce = déclampage après la transplantation.
La biopsie rénale Biopsie de déclampage: aide au choix du donneur, biopsie de référence, élément prédictif. A «marginal» donor! A 64 year old female. Past history: hypertension, type 2 diabetes mellitus (Diamicron, Glucophage ). Serum creatinine at time of procurement = 135µmol/l. Adrenaline = 6mg/h.
A «marginal» donor? «Zero-hour biopsy» A «marginal» donor? M3 post-tr No DGF Screat = 131μmol/l GFR = 74ml/min/1.73m 2
An «ideal» donor? A 60 year old male. Cause of death: stroke. Serum creatinine at time of procurement = 100µmol/l. Adrenaline = 0mg/h. An «ideal» donor? Primary non function
La biopsie rénale Biopsie après la transplantation: le rejet infraclinique, la néphropathie chronique d allogreffe. Rejet infra-clinique et TR Définition: Présence de lésions histologiques attribuées à du rejet sans altération simultanée de la fonction du greffon.
Un peu d histoire! Jean Crosnier. Société Française de Transplantation 1972 Concept de «rejet histologique» or «crise latente de rejet». Ratnet ML et al, Vestn Akad Med Nauk SSSR 1973 «Subclinical crises of kidney allotransplant rejection» Winnipeg
Subclinical acute rejection. The Winnipeg experience: Rush D et al, Transplantation 1994 29 biopsies performed in «stable» patients during the first 3 months post-transplantation. 9/29 patients had a Banff grade I acute rejection. Concept of subclinical rejection Rejet infra-clinique et TR Définition: Présence de lésions histologiques attribuées à du rejet sans altération simultanée de la fonction du greffon.
Tubulite Tubulitis rejection Adaptation does occur and may involve cells encountering the graft. Tubulitis is nonspecific in itself. Tubulitis may indicate a damaging process but may not be damaging in itself. The effect of treatment of asymptomatic infiltrates is unknown.
Créat Quelle est la fonction optimale d un greffon?? Temps? Rejet infra-clinique et TR. Définitions. Epidémiologie
Subclinical acute rejection. The Winnipeg experience: Rush D et al, Transplantation 1994 29 biopsies performed in «stable» patients during the first 3 months post-transplantation. 9/29 patients had a Banff grade I acute rejection. Concept of subclinical rejection Subclinical acute rejection Gloor JM et al, Transplantation 2002 Diagnosis n % Subclinical rejection 3 2.6% Borderline 12 10.6% Normal 99 86.8% M3 biopsy (MMF-Tac-Ste) 114 100
Subclinical rejection Moreso F et al, Transplant Proc 2004 CsA+MMF+P TAC+MMF+P n 111 49 Normal 44.0 55.2 Borderline + AR 19.8 8.2 CAN 36.0 36.8 p = 0.01 Acute rejection incidence Acute rejection Acute rejection (%) 50 45 40 35 30 25 20 15 10 5 0 12-24 months 43.7 6-12 months 36.7 33.9 0-6 months 22.5 27.4 21.4 17.9 15.3 14.6 6.1 7.26.1 6.7 7.4 5.8 5.2 6 2.9 1995 1996 1997 1998 1999 2000 Transplantation year Meier-Kriesche HU, Am J Transplant 2004
Nankivell BJ et al, Transplantation 2004 Nankivell BJ et al, N Engl J Med 2004
Nankivell BJ et al, Transplantation 2004 Subclinical acute rejection. The Pittsburgh experience: Shapiro R et al, Am J T 2001 28 stable patients underwent a routine renal biopsy a mean of 8 ± 2 days after transplantation: 6 (21%) had Banff borderline lesions, 7 (25%) had acute tubulitis. The true incidence of rejection may be higher than clinically appreciated!
Rejet infra-clinique et TR Facteurs de risque: Degré d incompatibilité HLA: 0 inc DR: 20, 25 et 0% 1 inc DR: 30, 32, 32% 2 inc DR: 63, 37, 30% Cross-match FACS positif. Rejet infra-clinique et TR. Définition. Epidémiologie. Influence pronostique
Subclinical acute rejection The Necker experience: Girardin C et al, ATC 2002 Routine biopsies at 3-6 months, 2 and 10 years post-tr in 154 renal transplant recipients (1975-89). Results: group 1: >25% interstitial fibrosis at 10years (n=114), group 2: < 25% (n=40), renal function at 2 and 10 years lower in group 2, mononuclear infiltrates were significantly more frequent in group 1 at M3, fibrosis at 10 years correlated with mononuclear infiltrates at M3. Nankivell BJ et al, Transplantation 2004
Nankivell BJ et al, Transplantation 2004 Subclinical acute rejection. The Winnipeg experience: Rush D et al, Transplantation 1995 Screatinine at one year in patients with routine biopsies at 1, 2, 3, 6 and 12 months post-transplantation: screat = 106 ± 26µmol/l in case of normal renal biopsy, screat = 166 ± 40µmol/l if subclinical rejection on renal biopsy, screat = 157 ± 45µmol/l in case of treated acute rejection.
Nankivell BJ et al, Transplantation 2004 Rejet infra-clinique et TR Lipman ML et al, Transplantation 1998
Rejet infra-clinique et TR Anil Kumar SL et al, Transplantation 2005 Rejet infra-clinique et TR. Définition. Epidémiologie. Influence pronostique et traitement
Subclinical acute rejection. The Winnipeg experience: Rush D et al, JASN 1998 A prospective study comparing: group 1 (n=36): routine biopsy at 1, 2 and 3 months. Subclinical rejection treated with steroids, group 2 (n=36): no routine biopsy during the first 3 months, in both groups: biopsy at 6 months and 2 years of follow-up. Subclinical acute rejection. The Winnipeg experience: Rush D et al, JASN 1998 Results: reduction in early and late clinical rejections in group 1, lower chronic tubulo-interstitial score at 6 months in group 1, better renal function at 2 years in group 1. Treatment of subclinical rejection is beneficial
Subclinical acute rejection. The Canadian experience: Rush D et al, WTC 2006 2 groups of patients on FK-MMF: 120 patients: RB at D0, M1, M2,M3, M6 and M24, 120 patients: RB at D0, M6 and M24. At 6 months: no difference in the 2 groups! Incidence of subclinical rejection was: 5,7% (M1), 0% (M2), 8,2% (M3) and 8.9% at M6. Rejet infra-clinique et TR. Définition. Epidémiologie. Influence pronostique et traitement. Limites
1. L erreur d échantillonage
2. La variabilité des données. Furness P et al, Kidney Int 2001
Inter-observateur Le cas de la tubulite 100% 90% 80% 70% 60% 50% 40% 30% Grade 3 Grade 2 Grade 1 Grade 0 20% 10% 0% 1 2 3 4 5 6 7 8 9 10 N des observateurs Furness PN et al. Kidney Int 2001 Variabilité inter-observateur Gough J P et al, NDT 2002
Rejet infra-clinique et TR. Définition. Epidémiologie. Influence pronostique et traitement. Limites et complications Safety of routine biopsies In Wilczek s experience, there was a lower risk of complications in case of routine biopsy: 4 out of 340 = 1.2% routine biopsy 28 out of 789 = 3.5% non-routine biopsy (p<0.05) The Franklin-Silverman (14G) needle has a higher complication rate than the 18G automated core biopsy needle (Kolb LG et al, Transplantation 1994). The 16G needle appears to be the best compromise between diagnostic usefulness and patient acceptability (Nicholson ML, Kidney Int 2000).
Safety of routine biopsies In the experience of 4 european centers (Furness P et al, Transplantation 2003), a total of 2127 biopsies were assessed for major complications and 1486 for minor ones. There were no death, one kidney loss, 3 episodes of hemorrhage requiring surgical intervention, 3 cases of blood transfusion and 1 cases of peritonitis = 8 cases. All serious complications occurred within 4hr of biopsy. Safety of routine biopsies In our group (Capote Fereira L et al, Transplantation 2003), the incidence of serious complications was 2.7% ( out of 251 routine biopsies over 2 years). It implied a 6.5 day hospitalization without deleterious consequence on renal function: Serum creatinine before = 138 ± 36µmol/l, Serum creatinine after = 143 ± 25µmol/l. No kidney was lost and one patient required a blood transfusion. All biopsies were performed in a day care unit: all complications occurred within 4hr of biopsy.
Jean Hamburger, Société Médicale des Hôpitaux de Paris 1963. «Sur les biopsies tardives, l infiltrat cellulaire est moins riche, mais on observe le développement d une sclérose interstitielle, qui s accompagne de zones d atrophie tubulaire. Fait remarquable, en dépit de ces lésions, l évolution fonctionnelle du transplant est loin de se faire obligatoirement vers une aggravation progressive.» Allograft nephropathy The Necker experience: Legendre Ch et al, Transplantation 1998 31 stable cadaver renal transplant recipients with a normal renal function and without any rejection Chronic Allograft Nephropathy 50 M3 Y2
Les leçons des BR systématiques Aggravation histologique TR Rejet infraclinique Dégradation de la fonction rénale
Icebe g d oit devant! Fonction Histologie Alloréactivité Qu attend le clinicien du pathologiste? Tout! Et de plus en plus DIU de pathologie rénale Paris, 5-7 mars 2007