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

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Connie Frank Transplant Center Deborah B Adey, MD Professor of Medicine University of California, San Francisco Kidney and Pancreas Transplant Center

Management of Rejection

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Disclosures

I have no disclosures (relevant or otherwise)

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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

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Rejection: Definition

A directed cellular or humoral response

f the recipient against the foreign tissue

(allograft) from the donor

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Question #1

Rejection is always a concern of the transplant recipient, the primary care provider, and the transplant care team.

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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
n the timing and severity of the rejection
4. Most patients will have a rejection episode

after transplant

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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
n the timing and severity of the rejection
4. Most patients will have a rejection episode

after transplant

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Types of Rejection

Cellular
Antibody Medicated
Mixed Cellular and Antibody Mediated

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Timing of Rejection

Immediate: First 2-6 weeks after transplant.
Early: First 6 weeks to 12 months after

transplant.

Late: > 12 Months to years after transplant.

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USRDS 2012 ADR

Acute rejection within the first year post-transplant

Figure 7.19 (Volume 2)

Patients age 18 &

lder with a

functioning graft at discharge.

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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

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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

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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.

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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

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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

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This image cannot currently be displayed.

Normal Kidney Biopsy

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

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Fibrinoid Necrosis Connie Frank Transplant Center Interstitial Hemorrhage Connie Frank Transplant Center

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Acute T cell-mediated Rejection, Type 3

Fibrinoid necrosis Connie Frank Transplant Center

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

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Treatment of Acute Rejection

Depends on:
Timing post-transplant
Severity of rejection
Previous rejection episodes
Comorbid illnesses

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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

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Graft survival in patients with and without early acute renal rejection

El Ters, AJT 2013 Connie Frank Transplant Center

Patients with no late rejection (%)

Primary vs repeat episodes of late acute rejection

70 75 80 85 90 95 100 1 2 3 4 5 6 7 8 9 10 Primary Repeat

Time post-transplant (years)

Patients continued

n MMF or AZA

Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl 3):148. Abstract 43.

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Acute Rejections after the 1st yr

May be triggered by an infection

– Viral – Bacterial

Inadequate immunosuppression

– Patient non-adherence – Under immunosuppressed

Potentially impacts long term outcome
f renal function

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<0.0001 1.74-2.26 1.98 Donor age 60-69 <0.0001 1.82-2.05 1.93 AA recipient <0.0001 1.57-1.75 1.66 Previous acute rejection 0.01 0.83-0.98 0.90 CMV neg→neg <0.0001 0.88-0.91 0.90 Tx year (per yr) <0.0001 0.66-0.80 0.72 Living donor <0.0001 0.27-0.45 0.35 MMF

p value 95% CI RR Variable

Late acute rejection after 12 months

Cox regression of selected protective & risk factors

Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl 3):148. Abstract 43.

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Chronic Cellular Rejection

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

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Relative risk for chronic allograft failure by Cox Proportional Hazard

1 2 3 4 5 6 96-97 94-95 92-93 90-91 88-89 1.53 1.37 1.31 1.14 1 5.2 4.98 3.4 2.35 1.67

Relative risk Year No acute rejection Acute rejection

Meier-Kriesche H-U et al. Transplantation 2000; 70:375-379.

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CHRONIC TRANSPLANT NEPHROPATHY- PATHOGENESIS

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

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CHRONIC TRANSPLANT NEPHROPATHY- PATHOLOGY

Tubular atrophy
Interstitial fibrosis
Intimal thickening
Glomerulosclerosis

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Interstital Fibrosis Obsolescent Glomeruli Intimal Thickening Tubular Atrophy Dilated Tubules

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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

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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.

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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

utcome

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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

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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

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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)

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ACUTE HUMORAL REJECTION PATHOLOGY

Neutrophils in glomerular and peritubular

capillaries

Fibrin thrombi
May see only edema by LM
C4d by IF staining peritubular capillaries

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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)

Peritubular capillary staining for C4d Connie Frank Transplant Center

Treatment of Acute AMR

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

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Reversibility of acute AMR (C4d)

pre-treatment 1 month post-treatment

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JASN 2002;13:2371-2380

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

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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)

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Chronic Rejection

Cell Mediated
Antibody Mediated

This territory is a bit like the wild wild west ………….

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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

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Risks with increased immunosuppression

Infection

– Viral

BK
CMV
Malignancy