Disclosures Management of Rejection - UCSF CME€¦ · Management of Rejection Connie Frank...

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Connie Frank Transplant Center

Deborah B Adey, MDProfessor of Medicine

University of California, San FranciscoKidney and Pancreas Transplant Center

Management of Rejection


Disclosures I have no disclosures (relevant or otherwise)


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: DefinitionA directed cellular or humoral response of the recipient against the foreign tissue (allograft) from the donor

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Question #1Rejection 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

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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.

Connie Frank Transplant Center USRDS 2012 ADR

Acute rejection within the first year post-transplantFigure 7.19 (Volume 2)

Patients age 18 & older with a functioning graft at discharge.


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

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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.


Question #2The most likely diagnosis and outcome are:1. Chronic rejection and she will lose the

allograft2. Acute rejection and this will probably be

treatable with a decent outcome 3. Recurrent disease and the kidney is not

going to work4. Acute rejection and the kidney is not

going to recover


Question #2The most likely diagnosis and outcome are:1. Chronic rejection and she will lose the

allograft2. Acute rejection and this will probably

be treatable with a decent outcome 3. Recurrent disease and the kidney is not

going to work4. Acute rejection and the kidney is not

going to recover


This image cannot currently be displayed.

Normal Kidney Biopsy

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TOO MUCH BLUE!!!


Patchy Inflammation

Patcy Infiltrate

Tubulitis???

Severe Interstitial Infiltrate with Lymphocytes Invading the tubules

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Fibrinoid Necrosis


Interstitial Hemorrhage


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Acute T cell-mediated Rejection, Type 3

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


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

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Graft survival in patients with and without

early acute renal

rejection

El Ters, AJT 2013 Connie Frank Transplant Center

Patie

nts w

ith no

late

rejec

tion (

%)

Primary vs repeat episodes of lateacute rejection

70

75

80

85

90

95

100

0 1 2 3 4 5 6 7 8 9 10

Primary

Repeat

Time post-transplant (years)

Patie

nts c

ontin

ued

on M

MF o

r AZA

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


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 of renal function


<0.00011.74-2.261.98Donor age 60-69<0.00011.82-2.051.93AA recipient

<0.00011.57-1.751.66Previous acute rejection

0.010.83-0.980.90CMV neg→neg<0.00010.88-0.910.90Tx year (per yr)<0.00010.66-0.800.72Living donor<0.00010.27-0.450.35MMFp value95% CIRRVariable

Late acute rejection after 12 monthsCox regression of selected protective & risk factors

Meier-Kriesche H-U et al. Am J Transplant 2002; 2 (Suppl3):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


Relative risk for chronic allograft failure by Cox Proportional Hazard

0

1

2

3

4

5

6

96-97 94-95 92-93 90-91 88-89

1.53 1.37 1.311.14 1

5.2 4.98

3.4

2.351.67

Relat

ive ris

k

Year

No acute rejection

Acuterejection

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


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


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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Connie Frank Transplant Center Connie Frank Transplant Center

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

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Question #3You 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 #3You 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)Connie Frank Transplant Center

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


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 Connie Frank Transplant Center 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


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)


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 – Post-transplant Lymphoproliferative

disorders – Skin Cancers

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