Management of Rejection

Transcription

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

2 Question #1 Rejection is always a concern of the transplant recipient, the primary care provider, and the transplant care team. Question #1 Which of the following statements is NOT true about rejection after transplant: 1. The risk of rejection is always high, every bump 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 Question #1 Which of the following statements is NOT true about rejection after transplant: 1. The risk of rejection is always high, every bump in creatinine is a 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 Types of Rejection Cellular Antibody Medicated Mixed Cellular and Antibody Mediated 2

3 Timing of Rejection Acute rejection within the first year post-transplant 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. USRDS 2012 ADR ACUTE REJECTION Pathogenesis Cell-mediated. Chiefly T-cells but others may be involved. Clinical Rise in serum creatinine of 20%-25% over baseline creatinine Rarely do patients have fever, pain over the allograft, hematuria, flu-like symptoms Banff classification Antibody-mediated rejection Acute C4d+ C4d- Chronic C4d+ C4d- Borderline changes T-cell-mediated rejection Acute (1A, 1B, 2A, 2B, 3) Chronic active Interstitial fibrosis and tubular atrophy No evidence of any specific etiology Other 3

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

5 TOO MUCH BLUE!!! Patchy Inflammation Tubulitis??? Severe Interstitial Infiltrate with Lymphocytes Invading the tubules Patcy Infiltrate 5

6 Fibrinoid Necrosis Interstitial Hemorrhage 6

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

8 Primary vs repeat episodes of late acute rejection Graft survival in patients with and without early acute renal rejection El Ters, AJT 2013 Patients with no late rejection (%) Patients continued on MMF or AZA Primary Repeat Time post-transplant (years) Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl 3):148. Abstract 43. Acute Rejections after the 1 st yr Late acute rejection after 12 months Cox regression of selected protective & risk factors May be triggered by an infection Viral Bacterial Inadequate immunosuppression Patient non-adherence Under immunosuppressed Potentially impacts long term outcome of renal function Variable MMF Living donor Tx year (per yr) CMV neg neg Previous acute rejection AA recipient Donor age RR % CI p value < < < < < < Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl 3):148. Abstract 43. 8

9 Chronic Cellular Rejection Relative risk for chronic allograft failure by Cox Proportional Hazard Often insidious Presents with creatinine creep Treatment depends on the biopsy findings Oral or IV pulse of steroids Switch to a mtori from calcineurin inhibitor Relative risk Year Meier-Kriesche H-U et al. Transplantation 2000; 70: Acute rejection No acute rejection CHRONIC TRANSPLANT NEPHROPATHY- PATHOGENESIS CHRONIC TRANSPLANT NEPHROPATHY- PATHOLOGY Drug toxicity Repeated acute rejection (clinical and/or subclinical) Loss of renal mass (e.g. size mismatch) Recurrent or de novo glomerular disease Combination of all or some of these factors Tubular atrophy Interstitial fibrosis Intimal thickening Glomerulosclerosis 9

10 Obsolescent Glomeruli Interstital Fibrosis Tubular Atrophy Dilated Tubules Intimal Thickening 10

11 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 Question #3 A 56 yo woman with ESRD due to lupus received a LRRT from her son 6 years ago. She was known to donor specific antibodies to her son but was desensitized prior to transplant. She has been followed every 6 months and recently noted to have an increase in her proteinuria (UPC 4.6) over the past 6 months. Her creatinine has crept up from 1.5 mg/dl to 2.0 mg/dl over the past 3 months. Question #3 You evaluate with an ultrasound which is unremarkable, lupus serologies are negative. Her donor specific antibodies are rechecked and she has developed an increase in the number and intensity of antibodies against her kidney. You discuss performing a biopsy and she asks about what you expect will be the outcome 11

12 Question #3 You advise her that based on what you are seeing 1. She has developed diabetes that explains the protein in her urine 2. Not to worry about it, her kidney function is still pretty decent, a lot of people spill protein in the urine 3. She likely has developed transplant glomerulopathy related to injury from the antibodies directed towards the kidney from her son. 4. You have no idea and need to call a transplant Nephrologist immediately Question #3 You advise her that based on what you are seeing 1. She has developed diabetes that explains the protein in her urine 2. Not to worry about it, her kidney function is still pretty decent, a lot of people spill protein in the urine 3. She likely has developed transplant glomerulopathy related to injury from the antibodies directed towards the kidney from her son. 4. You have no idea and need to call a transplant Nephrologist immediately Early Acute Antibody Mediated Rejections Highest risk in those with known donor specific antibodies (DSA) Patients with high levels of antibodies to human leukocyte antigens (HLA) high panel reactive antibodies Prior transplants Underlying autoimmune diseases (eg Lupus) ACUTE HUMORAL REJECTION PATHOLOGY Neutrophils in glomerular and peritubular capillaries Fibrin thrombi May see only edema by LM C4d by IF staining peritubular capillaries 12

13 Acute/Active AMR Tissue injury (x1) Microvascular inflammation (g>0 and/or ptc>0) Intimal or transmural arteritis Thrombotic microangiopathy Acute tubular necrosis Evidence of Antibody/endothelial interaction (x1) Linear C4d along tubulo-interstitial space capillaries At least moderate microvascular inflammation Increased expression of endothelial injury genes DSA+ (HLA or other) Treatment of Acute AMR Peritubular capillary staining for C4d Depends on Biopsy findings Level of antibody (MFI) Prior treatment for antibody mediated rejection Treatment Plasmapheresis remove the antibody IVIG Rituximab to block the B cells Increase baseline immunosuppression Sometimes eculizumab to block complement Bortezomib to block plasma cells 13

14 Reversibility of acute AMR (C4d) cumulative frequency of continuously TxGP-free patients after the early biopsy (until the index biopsy) and after the index biopsy (until the late follow-up biopsy) according to the absence or presence of C4d pre-treatment 1 month post-treatment JASN 2002;13: Chronic Active AMR Morphologic evidence of chronic injury (x1) Transplant glomerulopathy Transplant capillaropathy New onset fibrous intimal thickening of arteries Evidence of Ab/endothelial interaction (x1) Linear C4d along tubulo-interstital capillaries, or At least moderate microvascular inflammation Increased expression of endothelial injury genes DSA+(HLA or other) Cell Mediated Chronic Rejection Antibody Mediated This territory is a bit like the wild wild west. 14

15 Chronic Antibody Mediated Rejection Often presents with proteinuria and possible creatinine creep Treatment depends on the biopsy findings Rarely do plasmapheresis for chronic AMR IVIG Possible Riuximab 15

16 Risks with increased immunosuppression Infection Viral BK CMV Malignancy Post-transplant Lymphoproliferative disorders Skin Cancers 16