Paediatric Renal Transplantation Dr Heather Maxwell Consultant Paediatric

Paediatric Renal Transplantation Dr Heather Maxwell Consultant Paediatric Nephrologist Royal Hospital for Sick Children Glasgow

Paediatric Renal Transplantation • • Background information Outcome of transplantation Work up for transplantation Access to transplantation

Renal Transplantation • First human to human renal transplant was in 1933 • The first successful adult renal transplant was performed in Boston in 1954 in twins • First paediatric renal transplant performed in 1959 from identical twin sister • First in Yorkhill was 1977 and 204 transplants have now been performed since

Paediatric Renal Transplant Outcome • • • Patient survival Graft survival Parameters of Growth BP Haemoglobin • Factors affecting outcome • RHSC Audits • NHSBT ODT (UKT) – Centre-specific data – Cohort studies – 20 year review of paediatric renal Tx • Renal Registry

Paediatric Renal Transplant Program RHSC Glasgow

Results of Audit from 1990’s • High incidence of vascular thromboses • Lower graft survival data than expected • Change in practice • Joint adult transplant and paediatric urologists • Multi-disciplinary team approach • Transplant work-up and protocol

Paediatric Renal Transplant Program RHSC Glasgow

UK Paediatric Renal Transplant Data DECEASED DONOR LIVING DONOR Patient Survival 1 yr 99% (97 -100) Graft Survival 1 yr 94% (90 -96) 97% (94 -98) Patient Survival 5 yrs 99% (97 -100) 97% (94 -99) Graft Survival 5 yrs 81% (77 -85) 91% (86 -94) Jan 2005 – Dec 2009 Jan 2001 – Dec 2005 NHSBT www. uktransplant. org. uk

RHSC Glasgow Data NHSBT www. uktransplant. org. uk

RHSC Audit 1998 -2007 37 LRD (46%) 43 DD (54%) Male 63% Female 37%

Cause of Renal Failure

RHSC Audit 1998 -2007

1998 -2007 RHSC Audit - Outcome 79 children 42 (53%) RHSC 2 Dialysis 1 Creatinine>200 (3%) Died 35 (44%) Arnold Chiari Malformation Lymphoproliferative disease Adult Services 2 39 Well 3 Dialysis 1 2 nd transplant 31 Well

Audit 2008 -2011 • Higher incidence of graft thrombosis and vascular complications than expected • Particularly with LRD transplants • M&M reviews – Small number of transplants – High risk patients

RHSC Audit Surgical Complications 1998 -2003 N=52 2003 -2007 N=28 2008 -2011 N=29 Haematoma 4 (8%) 2 (7%) 1 (3%) Lymphocoele 3 (6%) 1 (2%) 0 Ureteric Problems 3 (6%) 2 (7%) 4 (14%) AV Fistula 1 (2%) 0 0 1 (2%) 4 (14%)* 1 (2%) 0 6 (21%) 8 (28%) Thrombosis Kinked Renal vein Re-exploration 6 (12%) * 3 grafts lost

RHSC Audit Medical Complications 1998 -2003 N=52 2003 -2007 N=28 2008 -2011 N=29 Rejection Episodes 18 (35%) 8 (29%) 3 (10%) * Infections 14 (27%) 3 (11%) 5 (17%) PTLD 6 (12%) 0 0 Diabetes 5 (10%) 0 1 CAN 1 (4%) 0 Recurrence of FSGS 1 (4%) 0 * 16 (55%) biopsied

Current Immunosuppression • Tacrolimus • Mycophenolate Mofitil • Treatment Arm – Daclizumab – Prednisolone for 5 days • Control Arm – Standard prednisolone Treatment Arm Control Graft Survival 97% BPAR 10% 7% Growth 0. 17 SD 0. 04 SD Adverse Glucose Metabolism 3% 16% Grenda et al, 2010

Rejection Rate Probability of First Rejection at 12 Months Transplant Year LIVING DONOR DECEASED DONOR % SE 1987 -90 54. 1 1. 7 69. 3 1. 4 1991 -94 45. 8 1. 5 61. 0 1. 5 1995 -98 33. 6 1. 3 42. 5 1. 6 1999 -02 22. 9 1. 3 26. 9 1. 7 2003 -06 13. 7 1. 5 17. 9 1. 7 NAPRTCS Report 2007

2008 -2011 RHSC Audit - Outcome 29 children 23 (79%) RHSC 1 CKD 3 grafts lost -1 Re-graft -2 PD No Deaths 19 Good function 6 (21%) Adult Services 6 Good function

Audit 2008 -2011 • Higher incidence of graft thrombosis and vascular complications than expected • Particularly with LRD transplants • M&M reviews – Small number of transplants – High risk patients • Internal and external review • Change in practice – smaller group of surgeons involved

Factors Affecting Outcome of Paediatric Renal Transplantation

Factors Affecting Outcome of Paediatric Renal Transplantation • An analysis of deceased donor paediatric renal transplants performed in the UK between 1986 and 1995 found that extremes of donor age, young recipient age and poor HLA matching were the major factors which adversely affected transplant outcome • Avoided transplants in the very young • Only used donors aged 5 -50 years • Better matching Postlethwaite et al, 2002

UKT Study 1995 - 2001 • To investigate the influence of a variety of factors on five-year renal transplant survival in a more recent cohort of paediatric recipients 1995 -2001 • To compare risk-adjusted outcome of adult and paediatric recipients at five years post-transplant • 7946 transplants (596 paediatric & 7350 adult) WTC 2006 Maxwell et al, 2006

Methods • Cox regression analysis of factors influencing five-year transplant survival (time from transplant to earlier of graft failure or patient death) • Factors considered in the analysis: Donor factors Recipient factors Other factors Age Age match Cause of death Primary renal disease HLA Ethnicity Registration waiting time Shipping Gender Ethnicity Kidney damage CMV Gender Graft year CMV Sensitisation Residual sensitisation

Methods • Cox regression analysis of factors influencing five-year transplant survival (time from transplant to earlier of graft failure or patient death) • Factors considered in the analysis: Donor factors Recipient factors Other factors Age Age match Cause of death Primary renal disease HLA Ethnicity Registration waiting time Shipping Gender Ethnicity Kidney damage CMV Gender Graft year CMV Sensitisation Residual sensitisation

Summary • Significant year-on-year improvement in transplant outcome of paediatric patients

5 -year transplant survival of paediatric patients by year of transplant

Improved Acute Graft Survival • Better pre-transplant management • Improved anaesthetic and operative care • Better organ selection – Size – Matching • Use of more living donors • Organ preservation and reduced cold ischaemia time (<20 hours) • Reduced acute rejection • Reduced incidence of infection

Summary • Significant year-on-year improvement in transplant outcome of paediatric patients • Very young donors (0 – 10 years) and donors aged over 40 years confer the greatest risk of transplant failure in paediatric patients

5 -year transplant survival of paediatric patients by donor age group

Summary • Significant year-on-year improvement in transplant outcome of paediatric patients • Very young donors (0 – 10 years) and donors aged over 40 years confer the greatest risk of transplant failure in paediatric patients • Glomerulonephritis is associated with poorer outcome than other primary renal diseases

5 -year transplant survival of paediatric patients by primary renal disease group

Summary • Significant year-on-year improvement in transplant outcome of paediatric patients • Very young donors (0 – 10 years) and donors aged over 40 years confer the greatest risk of transplant failure in paediatric patients • Glomerulonephritis is associated with poorer outcome than other primary renal diseases • Risk of transplant failure associated with adolescents (14 – 17 years) similar to that for recipients aged over 60 years

5 -year transplant survival by recipient age – all patients

5 -year transplant survival by recipient age

2006 Allocation Scheme • Increased availability of well-matched organs for children • Improved access for long waiters • Increased access for homozygous patients • Reduce shipping times • Still use deceased donors 5 -50 yrs • Paediatric donors would no longer preferentially given to paediatric recipients • Avoid very small recipients

UK PAEDIATRIC KIDNEY TRANSPLANTATION: A 20 -YEAR REVIEW Lisa Mumford, Jane Tizard On behalf of the Kidney Advisory Group Paediatric Subgroup

Number of transplants Deceased and living paediatric kidney only transplants Year of graft

Number of donors Deceased donors aged between 5 and 50 years Year of donation

Donor age of deceased paediatric kidney only transplants Year of graft

Proportion of transplants HLA mismatch levels of deceased paediatric kidney only transplant patients Year of graft

HLA mismatch levels of deceased paediatric kidney only transplant patients

Waiting time (days) Waiting times of UK deceased paediatric kidney only transplants Year of graft

Waiting Times for Listed Patients • 2000 – 2002: • 2003 – 2005 2006 – 2008 median 153 days (95% CI: 119 -187) median 264 days (95% CI: 201 -327) median 374 days (95% CI: 285 -463) • In terms of the impact of the 2006 scheme on equity for paediatric patients, the number on the transplant list and the median waiting time have remained unchanged while the number of transplants for long-waiting patients has increased as a result of a change made in April 2008 such that only 3% of listed patients have been waiting in excess of 3 years compared to 12% in December 2005.

Waiting times of deceased paediatric kidney only transplants

Proportion of transplants Recipient ethnicity of deceased paediatric kidney only transplant patients Year of graft 2010 34% ethnic minority patients registered on transplant list

Proportion of transplants Sensitisation (c. RF) of first deceased paediatric kidney only transplant patients Year of graft 2010 48% patients with c. RF 11 -100 registered on transplant list

Sensitisation (c. RF) of first deceased paediatric kidney only transplant patients

Cold ischaemia time (hours) of DBD paediatric kidney only transplants Year of graft

Cold ischaemia time (hours) of DBD paediatric kidney only transplants

Proportion of transplants Reported immunosuppression following deceased paediatric kidney only transplant (3 mth) S=Steroid A=Azathioprine M=Mycophenolate C=Cyclosporin T=Tacrolimus Year of graft

Graft survival following first DBD paediatric kidney only transplant 2006 -2010 1 yr survival 95% (92 -97) N=308 2001 -2005 5 yr survival 81% (77 -85) N=360 1996 -2000 10 yr survival 63% (58 -68) N=411 1991 -1995 15 yr survival 45% (41 -50) N=488 1986 -1990 20 yr survival 27% (23 -31) N=442 p<0. 0001

Graft survival following first DBD paediatric kidney only transplant excluding failures within the first year 2001 -2005 5 yr survival 88% (84 -91) N=328 1996 -2000 10 yr survival 73% (68 -78) N=345 1991 -1995 15 yr survival 55% (50 -60) N=392 1986 -1990 20 yr survival 38% (32 -44) N=310 p<0. 01 p=0. 5 (1991 – 2005)

Graft survival following first living paediatric kidney only transplant 2006 -2010 1 yr survival 97% (94 -98) N=286 2001 -2005 5 yr survival 91% (86 -95) N=198 1996 -2000 10 yr survival 74% (64 -81) N=116 1991 -1995 15 yr survival 45% (32 -58) N=67 1986 -1990 20 yr survival 35% (20 -50) N=47 p=0. 008

Graft survival following first living paediatric kidney only transplant excluding failures within the first year 2001 -2005 5 yr survival 95% (90 -97) N=173 1996 -2000 10 yr survival 78. 0% (68 -85) N=107 1991 -1995 15 yr survival 49% (34 -62) N=60 1986 -1990 20 yr survival 37% (22 -53) N=42 p=0. 009

Graft survival following first paediatric kidney only transplant 5 yr survival Living 10 yr survival 20 yr survival (n=714) 88 (85 - 91) p<0. 0001 71 (65 - 76) p<0. 0001 48 (38 - 58) p<0. 0001 DBD 72 (70 - 74) 59 (57 - 61) 37 (33 - 40) (n=2009)

Graft survival following first paediatric kidney only transplant 5 yr survival Living 10 yr survival 20 yr survival (n=714) 88 (85 - 91) p<0. 0001 71 (65 - 76) p<0. 0001 48 (38 - 58) p<0. 0001 DBD 72 (70 - 74) 59 (57 - 61) 37 (33 - 40) (n=2009)

Graft survival following first DBD paediatric kidney only transplant <6 years 6 -11 years 12 -17 years

UK Renal Registry Paediatric Data

UK Paediatric Renal Registry UK Renal Registry Report 2010

UK Paediatric Renal Registry Current RRT treatment used by prevalent <16 s in 2009 Treatment modality at 90 days after start of RRT by 5 year time period UK Renal Registry Report 2010

Pre-emptive Transplantation NHSBT Transplant Activity in the UK, 2010 -11

UK Paediatric Renal Registry UK Renal Registry Report 2010

UK Paediatric Renal Registry Median systolic BP SDS in transplant pts in 2009 Median Ht. SDS in pts receiving RRT from 1999 -2009 with % receiving rh. GH UK Renal Registry Report 2010

UK Paediatric Renal Registry Hb standard by MMF use 1999 -2009 % Patients achieving the haemoglobin standard in 2009 Hb standard by GFR 1999 -2009 UK Renal Registry Report 2010

Transplant Work Up

The Transplant Team Psychologists Radiologist Transplant Co-ordinator Surgeon Nephrologist Specialist renal nurses Teacher Tissue Typing Dietitian Social worker

Pre-Transplant Management • Attention to nutrition, growth, BP, proteinuria • Pre-transplant work-up – Blood vessels – Echocardiogram – Virology (CMV, EBV, Varicella) – Bladder – Psychology, education – HLA antibodies • Plan for operation

Transplant Procedure • Transplant surgeon and paediatric urologist • Anaesthetist • Paediatric nephrologist • Patient data easily accessible to all staff • Patient well hydrated • Early doppler USS if concerns re thrombosis • Close monitoring in ITU

Current Immunosuppression • Tacrolimus • Mycophenolate Mofitil • Treatment Arm – Daclizumab – Prednisolone for 5 days • Control Arm – Standard prednisolone Treatment Arm Control Graft Survival 97% BPAR 10% 7% Growth 0. 17 SD 0. 04 SD Adverse Glucose Metabolism 3% 16% Grenda et al, 2010

Access to Transplantation

Access to transplantation • Criteria for suitable recipient • Age / size • Sensitisation • Pre-emptive transplantation • Virtual cross-match • ABO Incompatibility • Paired donation

HLA Match

% donors HLA-A phenotype frequencies in 10 000 UK cadaver kidney donors UK Transplant 09/03

ABOi Transplants • • Group A consists of 2 types – A 1 and A 2 is less antigenic than A 1>B>A 2 Group O patients have higher titres of antibodies Anti-A titres are higher than anti-B titres Titres of 1 in 8 or 1 in 16 are low No additional treatment necessary for low titre antibodies which do not appear to pose an additional risk

ABOi Transplants

ABOi Transplants Recipient Donor O A B AB Yes Yes* - Yes - - Yes* O A B - - - Yes AB Donor O A B AB Yes Yes* Yes No Yes* Yes