Review of Rituximab and renal transplantation. Dr.E Nemati. Professor of Nephrology

Review of Rituximab and renal transplantation Dr.E Nemati Professor of Nephrology

Introductio n Rituximab is a chimeric anti-cd20 monoclonal antibody. The CD20 antigen is a transmembrane nonglycosylated phosphoprotein, expressed on immature and mature B cells. 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd 26 (2013) 563 575

Rituximab is a chimeric anti-cd20 monoclonal antibody

Rituximab causes a reduction in B cells in the peripheral blood within 1 3 days of administration, and complete B cell depletion in the majority of patients within 1 6 weeks. It does not have a direct effect on plasma cells. 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd 26 (2013) 563 575

Clinical use of rituximab in renal transplantation A) Desensitization protocols for highly sensitized recipients prior to or concurrent with kidney transplantation, ABO incompatible kidney transplantation B) Induction therapy C) Treatment of Acute and Chronic Antibody Mediated Rejection D) Treatment of Recurrent and de novo Glomerular Diseases after kidney transplant, E) Treatment of Post transplant Lymphoproliferative Disorder (PTLD). Transplantation. 2018 Jan; Anti-CD20 Blocker Rituximab in Kidney Transplantation. Sood P1, Hariharan S1.

Clinical use of rituximab in renal transplantation A) Desensitization protocols for highly sensitized recipients prior to or concurrent with kidney transplantation, ABO incompatible kidney transplantation B) Induction therapy B) Treatment of Acute and Chronic Antibody Mediated Rejection C) Treatment of Recurrent and de novo Glomerular Diseases after kidney transplant, D) Treatment of Post transplant Lymphoproliferative Disorder (PTLD). Transplantation. 2018 Jan; Anti-CD20 Blocker Rituximab in Kidney Transplantation. Sood P1, Hariharan S1.

Conclusions These findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. Larger and longer trials are needed to evaluate the clinical efficacy and safety of this approach.

Clinical use of rituximab in renal transplantation induction therapy B cells play a central role in the formation of Tertiary Lymphoid Organs (TLOs) and the modulation of chronic rejection. Rituximab leads to a reduction in B cells within allografts when given as induction therapy, and also when given as treatment for rejection. An association between improvement in allograft function and reduction in B cells after rituximab treatment for rejection has been described. 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd 26 (2013) 563 575

In conclusion we demonstrated that pretransplantation induction with rituximab could significantly decrease AMR and increase graft survival rates in sensitized patients undergoing kidney transplantation.

Acute rejection with or without de novo DSA : impact upon kidney allograft survival If DSA does appear at the time of acute rejection Allograft survival p= 0,001 Rapid decrease in DSA following specific therapy Improvement in allograft survival -24- Everly MJ & al. Am J Transplant. 2009;9:1063-1071

AMR Acute antibody-mediated rejection (AMR) is characterized by acute graft dysfunction, histologic evidence of acute tissue injury, deposition of C4d in peritubular capillaries, and the presence of donor-specific antibodies (DSAs). Acute AMR can be arbitrarily divided into early (occurring within 6 months of renal transplantation) or late (occurring after 6 months of renal transplantation).

AMR Acute ABMR, has been reported to occur in up to 7% of patients but can be as high as 50% in patients with HLA incompatible transplants. It can have over a four-fold risk of graft loss compared to matched controls and many of these patients go on to develop transplant glomerulopathy or other features of chronic antibody-mediated rejection (cabmr). http://dx.doi.org/10.1016/j.trre.2016.10.004 0955-470X/ 2016 Elsevier Inc. All rights

Types of Antibody-Mediated Rejection (AMR) Hyperacute AMR. It occurs due to preformed donor specific antibodies (DSA) present in high titers and presents as graft failure that can occur within minutes (but sometimes may be delayed for a few days) after transplantation.

Hyperacute AMR The histopathology is characterized by features of severe endothelial and arterial injury manifested as arteritis (often transmural), interstitial edema, and severe cortical necrosis, with almost all cases requiring allograft nephrectomy. Most of the initial cases were reported in patients with a history of previous transplantation or in multiparous women, suggesting the role of sensitization and preformed antibodies.

Acute AMR It is characterized by graft dysfunction manifesting over days and is a result of DSAs, that may either be preformed or develop denovo after transplantation. Acute AMR occurs in about 5 7% of all kidney transplants and is responsible for 20 48% of acute rejection episodes among presensitized positive crossmatch patients. Histopathology in these patients is again related to endothelial injury mediated by antibodies but is less severe than that seen in hyperacute rejections.

AMR According to the Banff 2013 classification,all of the following 3 features are required for the diagnosis of acute AMR: Histologic evidence of acute tissue injury defined by the presence of one or more of the following: 1. a. Glomerulitis (g >0) or peritubular capillaritis (ptc >0) b. Intimal or transmural arteritis (v >0) c. Acute thrombotic microangiopathy (TMA) of no other obvious cause d. Acute tubular injury of no other obvious cause Ochsner Journal 17:46 55, 2017 Academic Division of Ochsner Clinic Foundation

AMR 2. Histologic evidence of current/recent antibody interaction with vascular endothelium, defined by at least one of the following: a. Linear C4d staining in the peritubular capillaries b. Moderate microvascular inflammation c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-hla) in the serum Ochsner Journal 17:46 55, 2017 Academic Division of Ochsner Clinic

Diagnosis of AMR Based on the histopathology, AMR can be classified into three subtypes as below. Class I: Presence of acute tubular necrosis (ATN) only, with minimal inflammation. Class II: glomerulitis, peritubular capillaritis, and microthrombosis. Class III: Arteritis.

Chronic AMR Acute AMR has been shown to be a major risk factor for the development of chronic AMR. According to the revised Banff 2013 classification,the diagnosis of chronic, active AMR requires 3 features: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy b. b. Severe peritubular capillary basement membrane multilayering identified by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology Ochsner Journal 17:46 55, 2017 Academic Division of Ochsner Clinic Foundation

Chronic AMR 2. Histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in the peritubular capillaries b. Moderate microvascular inflammation c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Detection of DSAs (HLA or non-hla) in the serum Ochsner Journal 17:46 55, 2017 Academic Division of Ochsner Clinic Foundation

Chronic AMR It is now well recognized that antibodies can mediate chronic allograft injury which is characteristically seen as transplant glomerulopathy (TG) on kidney biopsies. TG (also known as or chronic allograft glomerulopathy) is characterized by : glomerular mesangial expansion capillary basement membrane (BM) duplication, seen as basement membrane double contouring or splitting. Similarly,the peritubular capillary (PTC) basement membrane also shows changes, but these are seen mostly on electron microscopy sections as basement membrane multilayering.

Chronic AMR Clinically, the manifestations : Asymptomatic Nephrotic range proteinuria, Hypertension, Allograft dysfunction Progression can sometimes be fairly rapid, especially with ongoing acute AMR, resulting in graft failure Within months. The prevalence of TG in protocol biopsies has varied between 5% at 1 yr to 20% at 5 years.

Treatment The primary goal in AMR treatment : Reduction/ removal of DSAs Elimination of the B-cell/plasma cell population responsible for the production of these antibodies.

Prevention and treatment of antibody-mediated rejection after kidney transplantation Anti-humoral treatment concepts: most protocols combine two major therapeutic principles: (a) apheresis for antibody depletion and (b) modulation of B cell immunity and other components of adaptive and innate immunity. -38- Bartel G et al. Transplant Int, 2011;24:1142-1155

Conclusion This meta-analysis of 10 studies, including 249 patients, suggests that treatment with RTX is associated with improved graft out come in patients with AMR of the transplanted kidney.

Treatment Rituximab. The mechanism of action of Rituximab in AMR is not clear, given that the plasma cells do not express CD20 on their surface. The depletion of CD20-positive subset of B-cells may attenuate the antibody generation process. The standard dosing of Rituximab is 375 mg/m2/wk for 2 4 weeks.

Clinical use of rituximab in renal transplantation A) Desensitization protocols for highly sensitized recipients prior to or concurrent with kidney transplantation, ABO incompatible kidney transplantation B) Induction therapy C) Treatment of Acute and Chronic Antibody Mediated Rejection D) Treatment of Recurrent and de novo Glomerular Diseases after kidney transplant E) Treatment of Post transplant Lymphoproliferative Disorder (PTLD). Transplantation. 2018 Jan; Anti-CD20 Blocker Rituximab in Kidney Transplantation. Sood P1, Hariharan S1.

Kidney International (2017) 92, 461 469

Results & Conclusions The incidence of recurrent imn was 44%, and recurrences occurred at a median time of 13.6 months after transplantation. Two patterns of recurrence were identified: Early and late. No predictors of recurrence or disease progression could be identified. Treatment with rituximab was effective in four of four patients in stabilizing or reducing proteinuria and stabilizing renal function. Recurrence of imn is common even in the era of modern immunosuppression. Rituximab seems to be a valuable treatment option for these patients, although larger studies are needed to confirm our data. Clin J Am Soc Nephrol 5: 790 797, 2010. doi: 10.2215/CJN.04120609

Clinical use of rituximab in renal transplantation A) Desensitization protocols for highly sensitized recipients prior to or concurrent with kidney transplantation, B) ABO incompatible kidney transplantation C) Treatment of Acute and Chronic Antibody Mediated Rejection D) Treatment of Recurrent and de novo Glomerular Diseases after kidney transplant, E) Treatment of Post transplant Lymphoproliferative Disorder (PTLD). Transplantation. 2018 Jan; Anti-CD20 Blocker Rituximab in Kidney Transplantation. Sood P1, Hariharan S1.

In conclusion Monotherapy with monoclonal antibody rituximab is a safe and effective treatment for patients with PTLD following solid organ transplantation. The efficacy of monotherapy with rituximab in PTLD patients is superior to that achieved in non-transplanted patients with aggressive B-cell lymphomas. Rituximab proved to be well tolerated and effective in the treatment of PTLD.

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