Nefropatía crónica del injerto Aspectos clínicos y terapeúticos

1. Nefropatía crónica del injertoAspectos clínicos y terapeúticos Pablo U. Massari Programa de Trasplantes Renales Hospital Privado Centro Médico de Córdoba Carrera de Postgrado en Nefrología Universidad Católica de Córdoba Armenia, Septiembre 2008

2. Hospital Privado- Centro Medico de Cordoba Supervivencia del injerto y paciente en serie completa n: 850 PACIENTES 1 ,8 ,6 Supervivencia acumulada Paciente Injerto ,4 ,2 0 0 10 20 30 40 50 60 Tiempo (meses)

3. Hospital Privado- Centro Medico de Cordoba Supervivencia del injerto 1 ,8 ,6 Logrank: p= 0.6 Supervivencia Acumulada No DBT DBT ,4 ,2 0 0 10 20 30 40 50 60 No DBT 488 375 306 258 209 171 138 DBT 35 24 21 13 11 9 8 Tiempo (meses)

4. Era n t 1/2 90-94 11,712 12.8 95-99 18,137 15.3 00-04 26,543 18.6 Long-term Patient and Graft Survival Rates during 3 Eras for Living Donor Transplants 100 Patient 80 80 78 60 58 Graft 57 Percent Survival 40 20 0 0 2 4 6 8 10 Years Posttransplant Cecka, Clinical Transplants 2005 (p.3)

5. Long-term Patient and Graft Survival Rates during3 Eras for Standard Criteria Donor Transplants 100 Patient 80 80 78 Graft 60 Percent Survival 46 40 Era n t 1/2 42 90-94 26,614 9.0 20 95-99 27,707 10.3 00-04 29,609 10.9 0 0 2 4 6 8 10 Years Posttransplant Cecka, Clinical Transplants 2005 (p.3)

6. Late allograft loss Death with functioning graft 40 % Chronic allograft nephropathy 50 % Recurrence of original disease 10 %

7. DISFUNCION TARDIA DEL INJERTO • Perdida de filtrado glomerular • Proteinuria • Hipertensión arterial

8. 100 SCr (mg/dl) 0.5-1.0 1.1-1.5 1.6-2.0 2.1-2.5 2.5-3.0 3.1-4.0 4.1-5.0 80 60 Percent Graft Survival 40 20 5 Year 10 Year 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Years Posttransplant Graft Survival by Serum Creatinine Level at 5 and 10 Years Mizutani, Clinical Transplants 2004 (p.346)

9. DISFUNCION TARDIA DEL INJERTO 4. Anemia 5. Insuficiencia renal 6. Morbimortalidad CV

12. Late allograft loss Death with functioning graft 40 % Chronic allograft nephropathy 50 % Recurrence of original disease 10 %

13. DISFUNCION TARDIA DEL INJERTO ( + de 3 meses ) Diagnostico diferencial • Uropatia obstructiva • Estenosis arteria renal • Recurrencia enf. glomerular original • Microangiopatia-HUS • Enfermedad glomerular de novo • Nefritis tubulo intersticial cronica • Nefroesclerosis • Nefropatia cronica del injerto

14. NEFROPATIA CRÓNICA DEL INJERTO • Rechazo cronico • Nefroesclerosis-senescencia • Nefrotoxicidad por drogas

15. La nefropatía crónica del injerto (CAN) se desarrolla precozmente después del trasplante 100 pacientes Tx renal CsA/TAC + AZA/MMF + esteroides Leve (6–25%) 100 Moderada (26–50%) 75 Severa (>50 %) Pacientes (%) 50 % área cortical afectada 25 0 0 2 4 6 8 10 Años postrasplante 1Nankivell BJ et al. N Engl J Med 2003; 349: 2326–33; 2Racusen LC et al. Kidney Int 1999; 55: 713–23.

17. Lower doses of CNI are associated to less nephrotoxicity 7 P< 0.0001 HR: 1.71 6 CsA (mg/kg/día) with CNI toxicity 5 Without CNI toxicity 4 0 0 1 2 3 4 5 years post- transplant Nankivell BJ et al. Transplantation 2004; 78: 557–65

19. Tx Glomerular Sclerosis Arteriosclerosis Arteriolar Hyalinosis TubularAtrophy Interstitial Fibrosis GRAFT LOSS Rising Creatinine Chronic Donor Disease Acute Donor Disease CNI Toxicity AcuteRejection Subclinical Rejection/Chronic Humoral Rejection Ischaemia The timeline for destruction of a kidney Chapman JR et al. J Am Soc Nephrol 2005; 16: 3015–3026.

20. RISK FACTORS FOR LONG-TERM GRAFT LOSSIN RENAL TRANSPLANTATION P. Arenas, J. Bittar, C. Chiurchiu, J. de la Fuente, W. Douthat, J. de Arteaga, P.U. Massari Renal Transplant Program, Hospital Privado - Centro Médico de Cordoba. Postgraduate School of Nephrology, Catholic University of Cordoba, Argentina

21. INTRODUCTION Despite marked improvements in the short term outcome, chronic survival of kidney grafts has improved modestly. Until now, few data about long term survival and its associated factorsare available for Latin American patients with kidney transplant.

22. OBJETIVES To identify factors associated with long-term graft survival (LTGS) -over 8 years- and to determinate the causes of graft loss To compare this data with a control group (CG) matched for time of transplantation.

23. RESULTS

24. RESULTS

25. RESULTS

26. SOBREVIDA DE PACIENTES EN LA POBLACION TOTAL 100 80 60 Sobrevida acumulada % 40 20 0 TIEMPO EN MESES 0 25 50 75 100 125 150 175 200 POB. TOTAL 521 351 278 275 125 66 36 22 13 TIEMPO MEDIO DE SEGUIMIENTO HASTA LA MUERTE 73,6 ± 57,4

27. Log Rank < 0,0001 GRUPO CONTROL SV PROLONGADA SOBREVIDA DEL INJERTO DESPUES DE LOS 8 AÑOS 100 80 Sobrevida acumulada % 60 40 20 0 0 25 50 75 100 125 150 175 200 TIEMPO EN MESES SV PROLONGADA 127 127 127 127 88 63 41 30 26 CONTROLES 394 337 296 269 204 204 204 204 204 Arenas et al, 2007

28. SOBREVIDA DE PACIENTES EN CADA POBLACION 100 Log Rank < 0,0001 80 60 Log Rank < 0,0001 Sobrevida acumulada % SV PROLONGADA 40 SV injerto en grupo control GRUPO CONTROL 20 SV injerto en SV prolongada 0 TIEMPO EN MESES 0 25 50 75 100 125 150 175 200 SV PROLONGADA 127 127 127 127 127 125 124 123 122 CONTROLES 394 329 314 309 305 305 305 305 305

29. Cox Multivariate Analysis for factors associated with graft survival beyond 8 years (RR 1 = survival > 1 year and not reaching 8) SCr 1 year, mg/dl PreTx Hypertension CAN Post Tx diabetes Acute rejection 0 0,5 1,5 2 2,5 37

30. Trasplante cadavérico 2,9 (1,21-7,00) Creatinina 1º año mg/dl 2,00 (1,4-2,8) HTA pretx 1,68 (1,19 -1,87) CAN 1,77 (1,56 -1,89) Diabetes de novo 1,66 (1,22 - 1,85) 0 0,25 0,5 0,75 1 2 3 4 7 FACTORES DE RIESGO PARA PÉRDIDA DEL INJERTO EN LA POBLACIÓN TOTAL Arenas et al, 2007

31. ANALISIS MULTIVARIADO DE COX PARA SOBREVIDA EN LA POBLACION SOBREVIDA PROLONGADA DEL INJERTO RENAL Arenas et al, 2007

32. CAUSAS DE PERDIDA DEL INJERTO EN EL GRUPO CONTROL Y EN LOS PACIENTES SOBREVIDA PROLONGADA p=0,1 CONTROLES SV PROLONGADA % p=0,0002 p=0,0004 p=0,008 p=0,01 Arenas et al, 2007 SVP n=26 Controles n=229

33. CAUSAS DE MUERTE EN EL GRUPO CONTROL Y EN LOS PACIENTES CON SOBREVIDA PROLONGADA P< 0,0001 %

34. CAUSAS DE MUERTE EN PACIENTES EN EL GRUPO DE SOBREVIDA PROLONGADA

35. Conclussions This series suggest that long term graft survival is not related to immunological factors and underscore the importance of CAN and post-transplant diabetes in long termoutcomes.

36. The Change in Allograft Function among Long-Term Kidney Transplant RecipientsGill et al, JASN 14: 1636, 2003 • Analysis of USRDS n: 40963 pts (1987-1996) • Survival of at least 2 yr • Mean eGFR: 49.6 ml/m/1.73 m2 at 6 mo • Mean follow-up 5.7 yr • 30 % improvement in eGFR • 20 % no change in eGFR • 50 % had decline of eGFR • Mean decline in eGFR: 1.66 ml/m/1.73 m2

37. Disease progression and outcomes in chronic kidney diease and renal transplantationDjamali et al, KI 64: 1800, 2003 • Retrospective, single center, n:1762 pts (1985-2001), sCr >1.3 mg/dl • CKD n: 872 RTR n: 890 • Cockcroft-Gault • 80 % had K/DOQI Stages 3 and 4 • eCrCl declined – 6.6 ml/min/y in CKD • eCrCl declined – 1.9 ml/min/y in RTR • Similar mortality rate

38. Progression and Outcomes in Renal Transplantation • The transplant patients as a high risk group • Long-term survival of grafts and patients • How to detect progression • Proteinuria and outcome • Renal function and outcome • GFR in transplant patients • What to do ?

39. Progression and Outcomes in Renal Transplantation • The transplant patients as a high risk group • Long-term survival of grafts and patients • How to detect progression • Proteinuria and outcome • Renal function and outcome • GFR in transplant patients • What to do ?

40. How to detect progression in RTP ? • Proteinuria • sCreatinine and GFR • Graft volume • Graft biopsy

41. PROTEINURIA IN TRANSPLANT PATIENTS • Early, transient, associated to DGF • Acute rejection • Recurrence of primary renal disease • De novo glomerular disease (HVC) • 5. Chronic allograft nephropaty

42. PROTEINURIA IN TRANSPLANT: PREVALENCE 36.6 % during first 3 monhs Perez Fontan et al, 1999 25 % at 6 months Hohage et al, 1997

43. PREVALENCE OF PROTEINURIA IN CADAVERIC TRASPLANTS, % 12 24 Month 60 225 168 84 n: 64,8 Ur. Prot/Creat < 0,5 68,4 54,7 20,2 26,6 Ur. Prot/Creat 0,5 – 1,5 19,0 11,3 26,2 8,4 Ur. Prot/Creat > 1,5 De la Fuente et al, 2006

44. IMPACT OF PROTEINURIA ON GRAFT SURVIVAL 1 80.1% ,8 ,6 58.0% Proteinuria < 1 gr/ 24 hs % sobrevida ,4 Proteinuria > 1 gr/ 24 hs Obs. Events Prot < 1 gr/ 24 hs 126 6 Logrank p 0,0001 ,2 25 9 Prot > 1 gr/ 24 hs Total 151 15 0 0 10 20 30 40 50 60 70 Month post TX 2006

45. Proteinuria < 0,5 Proteinuria 0,5-1,5 PROTEINURIA AND GRAFT SURVIVAL IN CADAVERIC TRANSPLANT 1 n:146 n: 60 n:19 .8 n: 55 n:17 .6 Cum. Survival n: 5 .4 .2 Proteinuria > 1,5 Logrank (Mantel-Cox)p= 0.0004 0 0 20 40 60 80 100 120 Time 2006

46. THE RISK OF CARDIOVASCULAR DISEASE ASSOCIATED WIT PROTEINURIA IN RENAL TRANSPLANT PATIENTS Fernandez-Fresnedo et al, Transplantation 73: 1345, 2002

47. How to detect progression in RTP ? • Proteinuria • sCreatinine and GFR • Graft volume • Graft biopsy

48. Renal function in long term graft survival n: 278 250 200 150 100 MDRD ml/min 50 0 1 2 3 4 5 8 years Bittar et al, 2007

49. Estimated GFR to post Cimetidine Creatinine Clearance rate 1,7 1,6 1,5 1,4 1,3 1,2 1,1 1 ,9 2 h Jellife1 MDRD Walser Jellife2 Cockro Nankiv Mawer Mayo Bittat et al, 2007

50. Measured GFR and estimated GFR by different formulas 67,3 70 66,2 63,5 61,6 59,9 54,9 55,6 60 51,6 53,1 50,1 50 40 ml/min/1,73 m2 30 20 10 0 Iothal 3Hora Jellif1 Walser MDRD Jellif2 Cockro Nankiv Mawer Mayo Bittar et al 2007