Management of I have no disclosures Rejection (relevant or - PowerPoint PPT Presentation

9/30/2016 Disclosures Management of I have no disclosures Rejection (relevant or otherwise) Deborah B Adey, MD Professor of Medicine University of California, San Francisco Kidney and Pancreas Transplant Center Connie Frank Transplant Center Connie Frank Transplant Center Objectives Rejection: Definition • Recognize there are different types of rejection of a kidney transplant A directed cellular or humoral response • Describe the inherent differences of the recipient against the foreign tissue (allograft) from the donor between cellular and antibody mediated rejection • Understand the expected outcomes based on the type and severity of acute rejection Connie Frank Transplant Center Connie Frank Transplant Center 1

9/30/2016 Question #1 Question #1 Which of the following statements is NOT true Rejection is always a concern of the about rejection after transplant: transplant recipient, the primary care 1. The risk of rejection is always high, every bump provider, and the transplant care team. in creatinine is probably rejection – these patients are like time bombs. 2. There are different types of rejection and treatment is based on the type of rejection 3. Outcomes after treatment of rejection depend on the timing and severity of the rejection 4. Most patients will have a rejection episode after transplant Connie Frank Transplant Center Connie Frank Transplant Center Question #1 Types of Rejection Which of the following statements is NOT true • Cellular about rejection after transplant: • Antibody Medicated 1. The risk of rejection is always high, every bump in creatinine is a probably rejection – • Mixed Cellular and Antibody Mediated these patients are like time bombs. 2. There are different types of rejection and treatment is based on the type of rejection 3. Outcomes after treatment of rejection depend on the timing and severity of the rejection 4. Most patients will have a rejection episode after transplant Connie Frank Transplant Center Connie Frank Transplant Center 2

9/30/2016 Acute rejection within the first year post-transplant Timing of Rejection Figure 7.19 (Volume 2) • Immediate: First 2-6 weeks after transplant. • Early: First 6 weeks to 12 months after transplant. • Late: > 12 Months to years after transplant. Patients age 18 & older with a functioning graft at discharge. Connie Frank Transplant Center USRDS 2012 ADR Connie Frank Transplant Center Banff classification ACUTE REJECTION • Antibody-mediated rejection • Acute • Pathogenesis • C4d+ • Cell-mediated. • C4d- • Chronic – Chiefly T-cells but others may be involved. • C4d+ • C4d- • Clinical • Borderline changes – Rise in serum creatinine of 20%-25% over • T-cell-mediated rejection • Acute (1A, 1B, 2A, 2B, 3) baseline creatinine • Chronic active – Rarely do patients have fever, pain over the • Interstitial fibrosis and tubular atrophy allograft, hematuria, flu-like symptoms • No evidence of any specific etiology • Other Connie Frank Transplant Center Connie Frank Transplant Center 3

9/30/2016 Question #2 Question #2 The most likely diagnosis and outcome are: A 42 yo woman is s/p living donor transplant 10 weeks 1. Chronic rejection and she will lose the ago for kidney disease related to polycystic kidney allograft disease and is seen for routine follow-up at 3 months. Her baseline creatinine is 1.2 mg/dl and has been 2. Acute rejection and this will probably be stable for the past 5 weeks. She did have a flu like treatable with a decent outcome syndrome 2 weeks ago when other members of her household were also ill, but feels well now. 3. Recurrent disease and the kidney is not Her creatinine is noted to be 1.8 mg/dl from yesterday. going to work An ultrasound is done to rule out obstruction and is normal, and her labs repeated with a creatinine of 1.9 4. Acute rejection and the kidney is not mg/dl. Her immunosuppression drug level is within going to recover target range and she denies problems with missing any doses of medications. Arrangements are made to do a biopsy tomorrow. Connie Frank Transplant Center Connie Frank Transplant Center Question #2 Normal Kidney Biopsy The most likely diagnosis and outcome are: This image cannot currently be displayed. 1. Chronic rejection and she will lose the allograft 2. Acute rejection and this will probably be treatable with a decent outcome 3. Recurrent disease and the kidney is not going to work 4. Acute rejection and the kidney is not going to recover Connie Frank Transplant Center Connie Frank Transplant Center 4

9/30/2016 TOO MUCH BLUE!!! Patchy Inflammation Connie Frank Transplant Center Tubulitis??? Severe Interstitial Infiltrate with Lymphocytes Invading the tubules Patcy Infiltrate 5

9/30/2016 Fibrinoid Necrosis Connie Frank Transplant Center Interstitial Hemorrhage Connie Frank Transplant Center 6

9/30/2016 Fibrinoid necrosis Basic Premise: If someone has an acute rejection episode ….. Something needs to change. • The medications were not working • The patient was under immunosuppressed • The patient was not taking the medications as prescribed • Something stimulated the immune system Acute T cell-mediated Rejection, Type 3 Connie Frank Transplant Center Acute Cellular Rejections: Treatment of Acute Rejection Treatment • Depends on: • Increase immunosuppression • Timing post-transplant – Thymoglobulin – Steroids • Severity of rejection – Increase the maintenance • Previous rejection episodes immunosuppression • Comorbid illnesses • Early acute rejection has less impact on long term graft function than late acute rejections Connie Frank Transplant Center Connie Frank Transplant Center 7

9/30/2016 Primary vs repeat episodes of late acute rejection 100 Patients with no late rejection (%) Graft 95 survival in Patients continued on MMF or AZA Primary patients 90 with and 85 without Repeat early acute 80 renal 75 rejection 70 0 1 2 3 4 5 6 7 8 9 10 Time post-transplant (years) El Ters, AJT 2013 Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl 3):148. Abstract 43 . Connie Frank Transplant Center Connie Frank Transplant Center Late acute rejection after 12 months Acute Rejections after the 1 st yr Cox regression of selected protective & risk factors • May be triggered by an infection Variable RR 95% CI p value – Viral MMF 0.35 0.27-0.45 <0.0001 – Bacterial Living donor 0.72 0.66-0.80 <0.0001 Tx year (per yr) 0.90 0.88-0.91 <0.0001 • Inadequate immunosuppression CMV neg → neg 0.90 0.83-0.98 0.01 – Patient non-adherence – Under immunosuppressed Previous acute 1.66 1.57-1.75 <0.0001 rejection • Potentially impacts long term outcome AA recipient 1.93 1.82-2.05 <0.0001 of renal function Donor age 60-69 1.98 1.74-2.26 <0.0001 Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl Connie Frank Transplant Center Connie Frank Transplant Center 3):148. Abstract 43. 8

9/30/2016 Relative risk for chronic allograft failure Chronic Cellular Rejection by Cox Proportional Hazard • Often insidious 5.2 4.98 Acute • Presents with creatinine creep rejection 3.4 6 • Treatment – depends on the biopsy 2.35 1.67 5 Relative risk findings 4 – Oral or IV pulse of steroids 3 1.53 1.37 1.31 2 1.14 1 – Switch to a mTORi from calcineurin 1 inhibitor 0 No acute 96-97 94-95 92-93 90-91 88-89 rejection Year Meier-Kriesche H-U et al. Transplantation 2000; 70:375-379. Connie Frank Transplant Center Connie Frank Transplant Center CHRONIC TRANSPLANT NEPHROPATHY- CHRONIC TRANSPLANT NEPHROPATHY- PATHOLOGY PATHOGENESIS • Drug toxicity • Tubular atrophy • Repeated acute rejection (clinical and/or • Interstitial fibrosis subclinical) • Intimal thickening • Loss of renal mass (e.g. size mismatch) • Glomerulosclerosis • Recurrent or de novo glomerular disease • Combination of all or some of these factors Connie Frank Transplant Center Connie Frank Transplant Center 9

9/30/2016 Obsolescent Glomeruli Interstital Fibrosis Tubular Atrophy Dilated Tubules Intimal Thickening 10

9/30/2016 Treatment Depends on – How much scarring is noted on the biopsy – Intensity of Rejection – Type of Rejection – How much immunosuppression the patient has already seen – Often no more than minor adjustments in immunosuppression Connie Frank Transplant Center Connie Frank Transplant Center Question #3 Question #3 • A 56 yo woman with ESRD due to lupus You evaluate with an ultrasound which is received a LRRT from her son 6 years ago. unremarkable, lupus serologies are She was known to donor specific antibodies negative. Her donor specific antibodies to her son but was desensitized prior to are rechecked and she has developed an transplant. She has been followed every 6 increase in the number and intensity of months and recently noted to have an antibodies against her kidney. You increase in her proteinuria (UPC 4.6) over discuss performing a biopsy and she asks the past 6 months. Her creatinine has crept up from 1.5 mg/dl to 2.0 mg/dl over the about what you expect will be the past 3 months. outcome Connie Frank Transplant Center Connie Frank Transplant Center 11