7-1 Transplantation short lecture

Recent progress in kidney transplantation

Kosuke Masutani, MD, PhD

Department of Medicine and Clinical Science, Graduate School of Medical Sciences,

Kyushu University, Fukuoka, Japan

APSN-CME Course (6/4/2015, Nagoya, Japan)

Statement of Disclosure

The author does not have a financial conflict of interest relevant to any of the material presented in this presentation.

The number of patients with ESKD is expandingPatients receiving renal replacement therapy (RRT) in 2010

Estimated number of receiving RRT from 2010-2030 by region.

Liyanage T et al. Lancet 2015[Epub ahead of print]

Livingdonors

Actual deceased

donors

Worldwide deceased & living organ donors 2012 (%)

Malaysia

Japan

Hong Kong

South Korea

Australia

New Zealand

Taiwan

Philippines

Gomez MP et al. Transplant Proc 46, 2014

USA

FranceSpainItaly

UK

Canada

Germany

Organ donation from deceased persons is the most important, but difficult by various reasons

- Ethical considerationsprioritydefinition of deathconsent and incentive

- Social misconceptionsdelays in funeralsunwilling organ procurementsuppressed lifesaving efforts etc.

- Religious perspectivesfamily as the moral basis of societyintegrity of spirit and bodydying process taking hoursonly God makes decision about body’s fate etc.

Robson NZ et al. Asia Pac J Public Health 22, 2010

Awareness of benefit of transplantation, legal definition of brain death to the society…

Transplant surgeons have spent great efforts

Hand-assisted laparoscopic surgery (Living donor nephrectomy)

Novel strong and specific immunosuppressive agents

Expanding living donor source: ABO-I KTx

Countermeasure for rejection and infection

Long-term management of KT recipient

Recent progress in kidney transplantation

Karran P and Attard N. Nat Rev Cancer 8, 2008

1986~ (Japan)1993~

1999~

Anti IL-2R mAbBasiliximab

2002~

2006~ Heart2011~ Kidney

History of immunosuppressive agents used for KTx

Improved outcomes in both living/deceased donor KTxLiving-donor KTx Deceased-donor KTx

Living-donor KTx（2001～） Deceased-donor KTx, brain dead5Y graft survival 92.7% 5Y graft survival 89.1%5Y patient survival 96.5% 5Y patient survival 93.5%

Deceased-donor KTx, cardiac dead5Y graft survival 80.3%5Y patient survival 89.3%

Data from the registry of Japanese Society for Clinical Renal Transplantation 2013

Novel strong and specific immunosuppressive agents

Expanding living donor source: ABO-I KTx

Countermeasure for rejection and infection

Long-term management of KT recipient

Recent progress in kidney transplantation

The mean age of the ESKD patients who start on dialysis is 68.4 years old in Japan

Data from the registry of Japanese Society for Dialysis Therapy 2013

Male

Female

Expanding living donor source: ABO-I KTx

Takahashi K et al. Clin Exp Nephrol 11, 2007

- Acute antibody-mediated rejection (AMR) due to blood-type

related antigens

- Critical period of AMR in 1-2 weeks post-transplant

- Accomodation (B-cell tolerance) is induced after the period

- Desensitization and prevention of infection

0.0

20.0

40.0

60.0

80.0

100.0

Preoperative desensitization in ABO-I KTx

Plasmapheresis

Splenectomy

Immunoadsorption IVIG

（%）

94.0%

62.8%

3.7%

9.9%

0.0%7.2%

9.3%

Data from the registry of the Japanese Society for Clinical Renal Transplantation

84.2%

Anti-CD20 antibody retuximab

Incompatible

Compatible

Minormismatch

Match

Data from the registry of the Japanese Society for Clinical Renal Transplantation

ABO-I KTx is increasing in Japan（%）

66.4 61.7 59.4 55.3 56.2 52.3 53.3 51.5 48.0 50.4 46.5

18.8 20.4 19.7

21.4 20.3 23.5 20.2 22.1 20.9 21.0

22.0

14.8 17.8 20.9 23.3 23.5 24.2 26.4 26.3 31.0 28.5 31.5

0.0

20.0

40.0

60.0

80.0

100.0

Comparable medium-term outcomes between ABO-C and ABO-I KTx

Opelz G et al. Transplantation 99, 2015

Controversy: complications in ABO-I KTx

Opelz G et al. Transplantation 99, 2015

Muramatsu M et al. World J Transplant 4, 2014

Shirakawa H et al. Clin Transplant 25, 2011

Group 1: Rituximab 500mg/bodyGroup 2: Rituximab 200mg/body

The safety and efficacy of low dose rituximab ABO-I KTx

Controversiy: Complications after living donation- Comparable to the general population (previous)- High risk as compared with matched cohort (recent)- Selection criteria, follow-up, and management

Ibrahim HN et al. N Engl J Med 360, 2009

Controversiy: Complications after living donation- Comparable to the general population (previous)- High risk as compared with matched cohort (recent)- Selection criteria, follow-up, and management

Ibrahim HN et al. N Engl J Med 360, 2009Abimereki AD et al. JAMA 311, 2014

Controversiy: Complications after living donation- Comparable to the general population (previous)- High risk as compared with matched cohort (recent)- Selection criteria, follow-up, and management

Ibrahim HN et al. N Engl J Med 360, 2009Lam NN et al. Am J Kidney Dis [Epub ahead of print]

Garg AX et al. N Engl J Med 372, 2015

Controversiy: Complications after living donation- Comparable to the general population (previous)- High risk as compared with matched cohort (recent)- Selection criteria, follow-up, and management

Novel strong and specific immunosuppressive agents

Expanding living donor source: ABO-I KTx

Countermeasure for rejection and infection

Long-term management of KT recipient

Recent progress in kidney transplantation

Understanding the pathological features and diagnostic approaches for allograft rejection

Revised AMR criteria (Banff 2013)

Haas M et al. Am J Transplant 14, 2014

Double contour of GBM

PTCBM multilayering

Treatment: rituximab, IVIG, Bortezomib, Ecrulizumab…

(not enough evidence)

- Establishment the international criteria for allograft pathology- The first Banff classification in 1993- Conference is held every 2 years, and the classification

has been modified.

Understanding the pathological features and diagnostic approaches for allograft rejection

Solez K et al. Am J Transplant 8, 2008

T-cell mediated rejection (TCMR) criteria (Banff 2007 update)

Active tubulointerstitial nephritis

Moderate intimal arteritisTreatment: mPSL pulse therapy with ATG (TCMR IIB)

Capillary C4d deposition

Understanding the pathological features and diagnostic approaches for allograft rejection

Revised AMR criteria (Banff 2013)

Haas M et al. Am J Transplant 14, 2014

Microvascular inflammation

Recent topic: AMR without evident C4d deposition

Treatment: mPSL followed by plasmapheresis and rituximab

Understanding the pathological features and diagnostic approaches for allograft rejection

Revised AMR criteria (Banff 2013)

Haas M et al. Am J Transplant 14, 2014

Double contour of GBM

PTCBM multilayering

Treatment: rituximab, IVIG, Bortezomib, Ecrulizumab…

(not enough evidence)

The 13th Banff Conference on Allograft PathologyBanff Working Groups 2011- C4d - ABMR- Fibrosis- Glomerular Lesion- Isolated v-lesion- Implantation biopsy- Polyomavirus- Banff initiative for quality assurance in

transplantation (BIFQUIT)

New Banff Working Groups 2013- T cell-mediated rejection (TCMR)- Clinical and laboratory assessment of

highly sensitized patients- Evaluation of adjunctive diagnostics in

renal allograft biopsy interpretation

Risk factors of preformed donor specific antibody (DSA)- Blood transfusion- Pregnancy- Kidney or other organ transplantation

Poor graft survival in highly-sensitized KT patients

Susal C et al. Hum Immunol 70, 2009

Sensitive DSA detection techniques

Cell based assays- CDC crossmatch and FCXM- Reduced hyperacute rejection

by CDC crossmatch- Inability to identify the antigen

causing positive

Negative crossmatch

Positive crossmatch

Solid phase assays- ELISA and Bead-based assays

(Flow-PRA & LABScreen)- More sensitive- Ability to identify the antigens

causing positive

Capable of quantifying anti-HLA Ab level(mean fluorescence intensity: MFI)

Desensitization consist of IVIG, Rituximab and Plasmapheresis

(not enough evidence)

Sensitive DSA detection techniques

Prediction of AMR using flow-PRA testing- 59-year-old male who had received HD for 10 years- Having the history of blood transfusion- KTx candidate from the cardiac dead donor

mPSL

Basilixmab

02.04.06.08.0

sCr(

mg/

dl)

0500

100015002000250030003500

Urine （

ml/

day）

HD PEX HD PEX

TacMMF

Rituximab

PSL

Basilixmab

Infectious complication: Cytomegalovirus (CMV)

Suggested algorism for preemptive therapy

Razonable RR et al. Am J Transplant 13, 2013

Infectious complication: Polyomavirus BK

- Firstly reported in 1995- Tubulointerstitial nephritis- Intranuclear inclusion- SV 40 large-T Ag staining

- Graft loss 20% after 3Y, and 50% after 5Y - No specific antiviral therapy- Reduction of immunosuppression

SV40 large T antigen immunostaining

Hirsch HH et al. Am J Transplant 13 (Suppl 4), 2013

Screening strategy 1PCR for BKV DNA in plasmaMonthly for 6M, then every 3M until 2Y posttransplant

Screening strategy 2Urine cytology + PCRBiweekly for 3M, monthly 3M-6M, every 3M until 2Y. Add PCR if positive decoy cells

Reduce immunosuppression in viremiaGraft biopsy if viremia or Cr increase

Novel strong and specific immunosuppressive agents

Expanding living donor source: ABO-I KTx

Countermeasure for rejection and infection

Long-term management of KT recipient

Recent progress in kidney transplantation

DWFG, one of the major causes of graft loss

El-Zoghby ZM et al. Am J Transplant 9, 2009

- Analysis of 1317 KTx between 1996 and 2006- Follow-up period 50.3 ± 32.6 months- Death with functioning graft (DWFG): 138

Living donor KTx

Deceased donor KTx

Management of the lifestyle diseases to prevent CVD after KTx

Japanese Society for Clinical Renal Transplantation, “Guidelines for medical and pediatric complications after kidney transplantation 2011” - Hypertension- Diabetes- Dyslipidemia- Hyperuricemia- Obesity- Metabolic syndrome- Short statue in children

Post-transplant malignancyCommon cancers & Cancers having High SIR

KDIGO Clinical Practice Guidelines for the Care of Kidney Transplant Recipients. Am J Transplant 9 (Suppl 3), 2009

Recurrent and de novo kidney diseases after KTx

El-Zoghby ZM et al. Am J Transplant 9, 2009

- Analysis of 1317 KTx between 1996 and 2006- Follow-up period 50.3 ± 32.6 months- Death with functioning graft (DWFG): 138- Graft loss during the period: 153

Summary- Current status of organ donation and KTx worldwide

- Living donor KTx: ABO-I KTx and donors’ outcome

- Allograft pathology and highly sensitized recipients

- Importance of cardiovascular diseases, cancer cancerscreening etc.