Kidney transplantation 2016: current status and potential challenges

Transcription

1 Kidney transplantation 2016: current status and potential challenges 15/12/2016 BVN-SBN : State-of-the-Art on Kidney Transplantation Patrick Peeters Ghent University Hospital, Belgium Challenges in 2016 and beyond Challenge N 1 2 native kidneys are still better than 1 transplanted kidney 1

2 Challenges in 2016 and beyond Challenge N 2 Less/older/worse donors Longer waiting times Older/sicker receptors About solid organ transplantions done in 2014: 1.8% increase over

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4 Donation from deceased donors pmp Deceased donors in ET pmp 4

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6 Living donor transplants 2015 in Belgium Kidney Liver Annual adjusted graft loss rates per 1,000 patients Cadaveric Living > <6 Pre-emptive Meier-Kriesche HU, et al. Transplantation 2002;74:

7 Effective DCD Euthanasie DCD IV DCD III DCD II n= 106 Median age of deceased donor in ET 7

8 Evolution of donor age in ET Age of effective donors in Belgium % 90% 80% 29,7 70% 60% 50% 40% 47, < 20 30% 20% 10% 0% ,7 4,4 Note number of donors 1994: 230 vs 2015: 315 8

9 Kidney waiting list 2015 Belgium Active WL Kidney waiting list 2015 Belgium Kidney en bloc Kidney Tx Active WL

10 = n 11/01/2017 Kidney waiting list 2015 Belgium Mortality Kidney en bloc Kidney Tx Active WL Removals from the ET waiting list 10

11 Challenges in 2016 and beyond CHALLENGE N 4 Graft function/loss Death with a functioning graft THE AXIS OF EVIL Cardiovascular disease Cancer Infections Causes of death and death rates in renal transplant patients United States Renal Data System. USRDS 2012 Annual Data Report 11

12 Freedom from BPAR (%) 11/01/2017 Individualized therapy progress Chapman Tx 2013 Freedom from BPAR at 12 months SYMPHONY trial 30 Standard-dose CsA (n=390) 20 Low-dose CsA (n=399) Low-dose tacrolimus (n=401) 10 CNI free (low-dose sirolimus; n=399) Months BPAR, biopsy-proven acute rejection; CsA, cyclosporin; CNI, calcineurin inhibitor Ekberg H et al. N Engl J Med 2007;357:

13 Do we do better?? ANZA data 2013 Chronic allograft dysfunction Pascual NEJM

14 Graft survival (%) 11/01/2017 egfr at 1 year post-transplant is a strong predictor of 5-year graft survival 5-year graft survival among patients with graft function at 1 year by egfr (ml/min/1.73 m 2 ) <90 45 <60 30 <45 15 <30 < Time post-transplant (months) Kidney-only transplant recipients, aged >18 years United States Renal Data System Annual Data Report egfr, estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) 2009, vol. 2, ch. 7, Association between CV death and serum creatinine at 1 year post-transplant Meier-Kriesche HU, et al. Transplantation 2003;75:

15 Death rate (per 100 patient-years) 11/01/2017 Adjusted patient survival for patients with a transplant and for patients after transplant loss Kaplan B, et al. Am J Transplant 2002;2:970 4 CVD is a leading cause of death with a functioning graft Retrospective analysis of ANZDATA between 1980 and ,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 1,8 1,7 1,2 1,1 1 0,9 0,8 0,7 0,7 0,7 0,6 0,6 0,7 0,7 0,5 0,4 0,4 0,4 0,4 0,4 0,4 0,3 0,3 0,3 Cardiovascular Malignancy Infection Other CVD, cardiovascular Pilmore disease HL et al. Transplantation 2010;89:

16 Death rate 11/01/2017 CVD death: time from transplant CVD death rates/100 patient-years according to time from transplant RR RR * * ** * * ** ** * RR 0.32 ** *** *** *p<0.05; **p<0.01; ***p<0.001 CVD, cardiovascular disease; RR, relative risk Time post-transplant (years) Pilmore HL et al. Transplantation 2010;89:851 7 Cardiovascular risk factors in transplant recipients Diabetes Hypertension Dyslipidaemia Smoking Pre-transplant low GFR proteinuria phosphate, calcium, PTH LVH, arterial stiffness anaemia Post-transplant NODAT low GFR Hypertension proteinuria Dyslipidaemia LVH Smoking Anaemia Increased age Inflammation Vascular disease GFR, glomerular filtration rate; PTH, parathyroid hormone; LVH, left ventricular hypertrophy; NODAT, new-onset diabetes after transplantation Rigatto C et al. J Am Soc Nephrol 2003;14:462 8; Ojo AO. Transplantation 2006;82:

17 RR a for ischaemic heart disease events >1 year post-kidney transplant 11/01/2017 Diabetes is a key risk factor for cardiovascular events after kidney transplantation Retrospective analysis of ischaemic heart disease in 1500 renal transplant patients between 1963 and 1997 at a single centre n= Diabetes Cholesterol BP 140/ mg/dl 159/99 mmhg Smoking a Compared to Framingham Heart Study database RR, relative risk; BP, blood pressure Kasiske BL et al. J Am Soc Nephrol 2000;11: NODAT is associated with 2-fold increase in death after kidney transplant Prospective 8-year analysis of 201 consecutive renal transplant ( ) patients at a single centre 100 Patient survival (%) a No diabetes (n=138) NODAT (n=35) Time since baseline (months) a Kaplan-Meier estimates NODAT, new-onset diabetes after transplantation Adapted from Hjelmesaeth J et al. Kidney Int 2006;69:

18 Patients free of 11/01/2017 NODAT has a strong impact on long-term CV outcomes: 3-fold increase in major cardiac events after kidney transplant Prospective 8-year analysis of 201 consecutive renal transplant ( ) patients at a single centre 100 cardiac events (%) a No diabetes (n=138) NODAT (n=35) Time since baseline (months) a Kaplan-Meier estimates NODAT, new-onset diabetes after transplantation; CV, cardiovascular Adapted from Hjelmesaeth J et al. Kidney Int 2006;69: The negative impact of post transplant cancer 2nd most common cause of death with a functioning graft AJT 2008; 8: Survival with cancer is extremely poor < 10% survival / 5 y CJASN 2008; 3:S P Peeters, M.D. Dept Nephrology - Ghent University Hospital, B Kuwait 18

19 Cumulative incidence skin cancer (%) 11/01/2017 Relative tumor risk after renal transplantation Cancer risk Cancer site RR All malignancy RR = 4.3 Small (RR > 2) Lung Bladder, urothel. Sarcoma Liver CNS Melanoma Cervix, vulva,vagina Intermediate (RR > 5) Thyroid Multiple myeloma PTLD (vs. NHL) Farynx, larynx High (RR > 15) Kidney Skin (non-melanotic) Kaposi sarcoma P Peeters, M.D. Dept Nephrology - Ghent University Hospital, B Kuwait Adapted from Wimmer CD et al, Kidney Int 2007; 71: 1271 Incidence of skin cancer increases over time Cumulative incidence of skin cancer in patients from Australia and the Netherlands CA in the Netherlands SCC in the Netherlands BCC in the Netherlands CA in Queensland SCC in Queensland BCC in Queensland Cumulative incidence of NMSCs ranges from 2 14% after 5 years 7 33% after 10 years Years of immunosuppression NMSC, non-melanomatous skin cancer; CA, all skin cancer; SCC, squamous-cell carcinoma; BCC, basal-cell carcinoma de Fijter JW. Nephrol Dial Transplant 2007;22(Suppl 1):i P Peeters, M.D. Dept Nephrology - Ghent University Hospital, B Kuwait 19

20 Risk factors associated with post-transplant malignancy Conventional Increasing age 1,2 Exposure to UV light 1 Previous exposure to carcinogens 1 Genetic predisposition 1,2 History of malignancy 1 Cigarette smoking 2 Analgesic abuse 2 Immunosuppressive regimen, eg CsA 3 or tacrolimus 6 Chronic viral infection 2 Previous treatment with cytotoxic agents, e.g. cyclophosphamide 2 Transmission of malignancy from donor 2 Levels of immune system components, eg high regulatory T-cells 4 MMP-26 and MMP-9 levels 5 Time after transplant 6 Duration of haemodialysis 6 Race 6 Transplant specific Age at time of transplant 6 UV, ultraviolet; CsA, cyclosporin; MMP, matrix metalloproteinase 1. Valantine H. J Heart Lung Transplant 2007;26:557 64; 2. Morath C et al. J Am Soc Nephrol 2004;15:1582 8; 3. Hojo M et al. Nature 1999;397:530 4; 4. Carroll RP et al. J Am Soc Nephrol 2010;21:713 22; 5. Kuivanen T et al. J Cutan Pathol 2009;36:929 36; 6. Imao T et al. Cancer 2007;109: P Peeters, M.D. Dept Nephrology - Ghent University Hospital, B Kuwait Infection risk Symphony Study Opportunistic infection p=0.03 CMV-infection p=0.003 Ekberg NEJM

21 Risk of Infectious Death Post Transplant: Impact of Allograft Function Meier-Kriesche Transplantation 2003 Challenges in 2016 and beyond CHALLENGE N 5 AMBR Common cause of death censored graft failure Dyscompliance vs. minimization 21

22 Post-transplant biopsy diagnosis Sellares AJT 2012;12: Causes of kidney transplant failure Sellares AJT 2012;12:

23 Wiebe AJT 2012;12: De novo DSA Wiebe AJT 2012;12:

24 Causes of kidney transplant failure Sellares AJT 2012;12: Early (< 3 m) vs. late acute ABMR after KTx Dörje Transplantation 2013; 94:

25 Challenges in 2016 and beyond CHALLENGE N 6 Biomarkers Biomarkers prediction of Acute Rejection AlloMap assay 20 genes mrna (NEJM 2014 Teuteberg) ksort assay 17 genes mrna (Plos Med 2014) Trugraf assay 200 transgenomic transscripts (AJT 2014) AlloSure donor derived free DNA (PNAS 2014 De Vlaminck) AUC 0.9 severe 0.83 moderate AR CXCL9-CXCL10 (Loupy JASN 2015) AUC 0.9 AR DSA + CXCL9-CXCL10 (Loupy JASN 2016) : better AUC 25

26 Challenges in 2016 and beyond CHALLENGE N 7 Tolerance Boston/Chicago/Stanford One-Study 26

27 Cause of death donors 2015 DBD vs. DCD 13% 10% 2% 3% 7% 18% 6% 6% 15% 11% 2% 1% 2% 2% 1% 2% 2% 24% 47% 19% 7% Anoxia / Strangulation Cerebral Ischemia Intoxication (suicide) Other Trauma (other) Cardiovascular ICB Meningitis Suicide (gunshot) Trauma (road accident) Anoxia / Strangulation Cerebral Ischemia Intoxication (suicide) Other Trauma (road accident) Euthanasie Cardiovascular ICB Meningitis Trauma (other) Tumor At least kidney transplantations done in 2014 performed in 99 countries 27

28 Kidney transplant waiting list ET 28