Renal Allograft Rejection
(Treatment)
Hussein A. Sheashaa
Professor of Nephrology, Urology and Nephrology Center and Director of
Medical E-Learning Unit, Mansoura University , Egypt. Executive
Director of ESNT Virtual Academy (http://lms.mans.edu.eg/esnt/)
Cell Mediated Rejection
KDIGO: Chapter 6: Treatment of Acute
Cellular Rejection
American Journal of Transplantation 2009, Volume 9, suppl 3
Response of ACMR to Anti rejection
treatment
Wu et al. Transplantation 2014;97: 1146-1154
Late Acute Cellular Rejection (after 90 days):
355 episodes in a cohort of 5758 patients
A total of 215 patients had 1 episode, 57 had 2 episodes, and
13 had 3 episodes of LAR.
The prevalence and recurrence of LAR are considerable and
associated with increased incidence of graft loss.
Rodrigues et al. Transplantation 2014 May 12
Impact of the presence of a Humoral
Component with Acute Cellular Rejection
(147 Cases: Pure ACR/Mixed 92 /55)
Willicombe et al. Transplantation 2014;97: 433-439
Antibody Mediated Rejection
Antibody Mediated Rejection
Worsens graft Survival
Lefaucheur, et al. Lancet 2013; 381: 313–19
Strategies to prevent AMR
The ideal regimen for the prevention of ABMR in sensitized
patients remains unknown.
Djamali et al American Journal of Transplantation 2014; 14: 255–271
Strategies to prevent AMR
 Strategies to minimize the risk for de novo DSA should be a
mandatory part of clinical management:
o Allocation points for class II matching,
o Avoiding drug minimization in patients at risk for de novo
DSA [i.e. class II mismatch, or early TCMR],
o Early recognition of nonadherence
 Desensitization
Mengel et al. American Journal of Transplantation 2014; 14: 524–530.
Prevention of AMR
Vo et al. Transplantation 2014 Aug 15;98(3):312-9.
Prevention of Chronic AMR
 Prevention, rather than treatment appears to be a more
effective option for reducing the incidence of C-AMR
 Plasmapheresis, IVIG, and Rituximab seems the most effective
of current desensitization protocols
Strategies to prevent AMR:
Why Donor Exchange?
Nephrology Self-Assessment Program - Vol 10, No 6, November 2011
Therapy options for Acute AMR
 The suppression of the T-cell–dependent antibody response
(steroids, cyclosporine, tacrolimus, and sirolimus).
 The removal of donor reactive antibody (plasmapheresis).
 The blockade of the residual allo-antibody (IvIg).
 The depletion of naive and memory B cells (rituximab).
 Inactivation of plasma cells (bortezomib).
 The blockade of complement component C5 by monoclonal
antibodies (eculizumab).
Kidney International (2012) 81, 628–639
Treatment of Acute AMR:
KDIGO Guidelines
2C
American Journal of Transplantation 2009; 9 (Suppl 3): S14–S15
Treatment of Acute AMR
Djamali et al American Journal of Transplantation 2014; 14: 255–271
Treatment of Acute AMR
Kim et al. Pharmacotherapy 2014 Jul;34(7):733-44.
Hepatitis B Reactivation and
Rituximab
 It is recommended that those patients with HBsAg or
HBsAg/anti-HBc be administered antiviral prophylaxis
immediately prior to the initiation of Rituximab and upward of
6 months after the cessation of therapy.
 Vaccination to HBV prior to transplantation remains the most
efficacious and cost effective strategy to preventing HBV
infection in the solid organ transplantation.
Martin et al American Journal of Transplantation 2014; 14: 788–796.
Treatment of Acute AMR:
Mansoura UNC Protocol
• IV methyl prednisolone, PP and Rituximab ( IV
infusion of a single dose of 375 mg/m2)
Treatment of Refractory Acute AMR:
Splenectomy
Tzvetanov et al. Transplantation 2012;94: 255-262
Late Antibody Mediated Rejection
(After 6 Months)
Non adherence or reduction of immunosuppression
are predictors of late AMR
These data demonstrate an inadequate response of
late AMR to current therapies
Gupta et al. Transplantation 2014 Jun 27;97(12):1240-6
Treatment of Chronic AMR (CAMR)
Combination therapy for CAMR might be effective,
even in patients with relatively late-stage CAMR
Kim et al. Nephrology 18 (2013) 820–826
Treatment of CAMR in Children
The decrease of GFR could be significantly reduced
over 2 years by this combination treatment
Pape L, et al. Pediatr Nephrol 2014 , May 28.
Antibody Mediated Rejection:
Unmet Needs
• Further improve the understanding of the
regulation of B cell maturation and antibody
response
• More precise diagnostics of ABMR are needed for
risk stratification and monitoring of treatment
effects by molecular pathology and sensitive
antibody testing
• Multicenter trials with enhanced power
Mengel et al. American Journal of Transplantation 2014; 14: 524–530.
Mixed Antibody and Cell
Mediated rejection
Treatment of Mixed Rejection:
Bortezomib
• 6 cases
Everly et al. Transplantation 2008;86: 1754–1761
Treatment of Mixed Rejection:
Bortezomib Mechanisms
Nephrol Dial Transplant (2010) 25: 3480–3489
Remmember!
Specimen Adequacy
 2 cores of cortex or 2 separate cortical areas.
 Adequate: > 10 glomeruli and > 2 arteries
Minimal : 7 glomeruli and 1 artery
 Slide preparation: 7 slides (multiple sequential sections.
Hematoxylin and eosin (HE): 3 slides
Periodic acid –Schiff (PAS) or silver: 3 slides
 Trichrome: 1 slide
The Banff 97 working clas. . Kidney Int 1999; 55: 713–723.
Case Scenario:
Urology and Nephrology Center, Mansoura, Egypt
Case Scenario
 A- 47- year old male patient
 Chronic renal failure and hemodialysis 1990
 First transplant; August 1992:
– Triple (pred, CsA and Aza)
– Two acute rejection episodes (2nd month and after 2 years)
– Returned to dialysis on June 2003
Case Scenario
 Second transplant; Feb 2004
 Early graft loss due to severe vascular rejection
Day 17
Case Scenario
Prepared for the 3rd transplantation:
Unrelated donor:
35 year old male
Same blood group
 Mismatch: 3/6
 PRA class I :0 %.
 PRA class II : 29 % ( DNS )
Case Scenario
• Plasmapheresis and MMF were initiated 2 weeks prior
to transplantation
• Renal transplantation (November 2007):
Ischemia time was 60 minutes
Immediate diuresis
• Immunosuppression: Basiliximab+pred+tac+MMF
Third Transplant Early Course
Day 0
Urine volume (L)
S.Creatinine
(mg/dl)
Day 1
7
0.5
10 to 4.1
4.6
Third Transplant Course
• Complete phenotype acute AMR (DSA, ATN, c4d)
Immediate therapy: Plasmapheresis, Rituximab (IV
infusion of 375 mg/m2) and hemodialysis
Response
Current Status (September 2014)
 Perfect graft function: Serum creatinine
1.0 mg/dl
Daily immunosuppression: prednisone 5
mg, MMF 1.5 g and 4 mg tacrolimus
Case Scenario: Teaching Points:
a. Multidisciplinary Care is Crucial
Immunology Lab
Radiologist
Successful Transplant
Program
Pathology
Lab
b. Early Detection and Management of acute AMR
make a big difference
Transplant
Nephrologist
Transplant
Surgeon
Thank You
• “ It is better to look ahead and
prepare, than to look back and regret”
(Jackie Joyner-Kersee)