Diagnosis and Management of Acute and Chronic Humoral Rejection. Lars Pape
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1 Diagnosis and Management of Acute and Chronic Humoral Rejection Lars Pape
2 Immunosuppression Acute rejection Chronic rejection Side effects Infections Nephrotoxicity
3 Adult population Nearly all late rejection-related graft losses involved antibody mediated rejections (Sellares et al., AJT 2012) Younger age seems to be associated with higher risk to develop donor specific antibodies (Everly et al., Transplantation 2013)
4 Diagnosis of humoral rejection - Transplant kidney biopsy - Detection of Donor Specific Antibodies (DSA) - Cross-match donor/recipient (living donation)
5 BANFF-Classification of transplant biopsy
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7 IVIG
8 Acute humoral rejection
9 Therapy of acute humoral rejection 6 (?) Steroid pulses IVIG-Administration 3-6 Plasmaphereses or Immunoadsorptions, Discuss Ritxuimab Increase underlying immuosuppressive therapy Monitor DSA
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14 Special cases Transplantation against forbidden antigens desensitatation protocols (i.e. Ritxuimab /Immunoadsorption / IgG / immunosuppression prior to Tx / Induction therapy) High Panel reactive antibodies prior to Tx ABO incompatible Tx (antigen specific immunoadsorption / Rituximab / IgG / Immunosuppression before Tx) Non-HLA-antibodies
15 Chronic humoral rejection
16 Chronic changes in protocol biopsy ah IF/TA GS 1 mo 12 mo early: tubulointersitial damage Nankivell et al, NEJM 349: 2326, 2003 Birk et al, Transplantation 15: 334, 2010 late: microvascular / Glomerular damage
17 Increasing Prevalence of IF/TA (Pediatric Recipients, Antibody/Tac/MMF/Pred) 100% 80% 60% 40% 20% 0% % Biopsies Grade III IF/TA Grade II IF/TA Grade I IF/TA No IF/TA Months Post-Transplant Birk et al, Transplantation 89: 334, 2010
18 Meaning of fibrosis and inflammation In late biopsies all infiltrates were associated with increased future graft loss. The impact of inflammation on survival reflects the association of progressing disease with inflammation. Sellarés et al, AJT 2011
19 Meaning of fibrosis and inflammation 1-yr protocol biopsies 1.) normal histology (n=86) 2.) fibrosis (n=45) 3.) fibrosis und inflammation (n=20) Park et al, JASN 2010
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24 Association of de novo DSA with late graft failure Hidalgo et al., Am J Transplant. 2009
25 Association of DSA positivity with graft survival DSA - DSA + p = 0.002, log-rank test 4 year graft survival DSA + 45% DSA - 87% Courtesy of Alexander Fichter, Heidelberg - Germany
26 Association of C1q-binding DSA with graft survival DSA - DSA+ / C1q - p = p < 0.001, log-rank test DSA+ / C1q + 4 year graft survival DSA + / C1q + 11% DSA + / C1q - 82% DSA - 87% Courtesy of Alexander Fichter, Heidelberg - Germany
27 JASN 2014
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33 Immune Response of Pediatric Renal Transplant Recipients challenged by Sensitization, Vaccination or Non- Adherence: Cross-Sectional and Prospective Analyses of the International CERTAIN Registry Cohort
34 Design Nested case-control study Identification of cases and controls from CERTAIN Statistical analysis of nested casecontrol study 10/14 01/15 03/15 6/15 9/15 40 cases controls Blood/urine collection and analysis at 1 time-point Identification of controls locally and via CERTAIN registry
35 Design Prospective longitudinal study Renal Tx (7/15-12/16) 7d 30d 6mo 1y 2y blood + urine collection (analysis at marked time points and in case of indication biopsy) 180 patients to be followed
36 Marker - Cytokines (Falk) - Senescence markers (Melk) - Urinary Proteomics (Pape) - Complement in Urine and Plasma (Heindl-Rusai) - Free DNA (Schütz) - Complement fixing DSA (Fichtner) - Virus-specific T cells (Pape)
37 Conclusions I Diagnosis of humoral rejection is a combination of detection of circulating DSA and histology. Complement fixing DSA might be the future diagnostic mean. Acute humoral rejection is a rare condition in pediatric renal transplantation and can be treated sucesfully in most cases. Fibrosis is a scar and stable; inflammation with fibrosis is signalling progressive disease and bad prognosis.
38 Conclusions II Chronic humoral rejection is the main cause for long-term graft loss. Chronic humoral rejection might be treated successfully if detected early enough. Treatment consists of IgG, Rituximab, increase of underlying immunosuppression and eventually Immunoadsorption / Plasmapehresis. The role of Bortezomib is to be determined.
Management of Rejection
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