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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.