Immunosuppressive Renal Transplantation: Present Status ......Renal Transplantation: Present Status...

Immunosuppressive Management:

Case-Based ApproachWilliam M. Bennett, MD, MACP, FASN

Professor of Medicine (Retired)Oregon Health Sciences University

Medical Director, Legacy Transplant ServicesLegacy Good Samaritan Medical Center

Portland, Oregon

Renal Transplantation: Present Status

• Mortality rates approximately 1% at 1 year• Short-term graft survival: 95% at 1 year• Acute rejection rates: 10-15%• Can optimize combination regimens for

individual patient comorbidities• Long-term graft survival still suboptimal

due to Ab-mediated rejection/CNI toxicity

0.1

1

10

0 106 183 244 365 548

Days Since Transplantation

Rel

ativ

e R

isk

of D

eath

Risk equal

Survival equal

0.1

1

10

0 106 183 244 365 548

Days Since Transplantation

Rel

ativ

e R

isk

of D

eath

Risk equal

Survival equal

Pre-transplant workup re:

comorbidities

Standard Protocols(2014)

InductionAntiCD 25, Thymoglobulin, or Alemtuzumab

MaintenanceCNI (Cyclosporine, Tacrolimus)Mycophenolate 1 gm bid or highest tolerated doseSteroid tapered to 0.1 mg/kg/day or steroid free

Immunosuppressants in Clinical Use in 2014

MaintenancePrednisoneAzathioprine

Mycophenolate mofetil/EC Mycophenolate sodium

CyclosporineTacrolimusBelatacept

Sirolimus/Everolimus

Belatacept

• Co-stimulatory pathway blocker• Must be given by IV infusion• Compared to CSA – better renal

function but more rejection (severe)• Black box warning about PTLD

Figure 3

FIGURE 3. Proposed model of the mechanism action of CTLA4-Ig.

Copyright © 2013 Transplantation. Published by Lippincott Williams & Wilkins.

Costimulation Blockade: Current Perspectives and Implications for Therapy

Kinnear, Gillian; Jones, Nick D.; Wood, Kathryn J.Transplantation. 95(4):527-535, February 27, 2013.doi: 10.1097/TP.0b013e31826d4672

Components of Most Maintenance Immunosuppressive Protocol

Class of Agent Options

Calcineurin inhibitor Cyclosporine, tacrolimus

Corticosteroids Dose and regimen

Antiproliferative Azathioprine, MMF, mTOR inhibitors

Decision Making on Immunosuppression

• Assess immunologic risk of recipients

• Assess non-immunologic risk of recipients

• Evaluate quality of organ

Immunologic High Risk

• Retransplant

• HLA sensitization > 80%

• Ethnicity

• Age

Determinants of Non-Immunologic Risk

• Native kidney disease (recurrence)

• Hepatitis status (C, B)

• BMI

• Diabetes

• Cardiovascular disease

• Skeletal disease

Determinants of Quality of Organ

• Is this an ECD kidney ie., age of donor?

• Risk of DGF ie., cold ischemic time/pump time

• Reduced nephron mass ie., size differential

Expanded Criteria Donors (ECD)• Expanded criteria donors (ECD) defined by

RR>1.7 at 5 years

• Offers of OMM ECD limited to ECD recipient list

• Organ Center has 2 hours to place OMM ECD

• OPO has 6 hours after cross-clamp to identify local recipients, then must offer regionally and nationally

• Informed consent expected

Age % on WL Top 20% EPTS

18-25 2.8 96.7%26-35 8.4 80.6%36-45 16.3 43.8%46-55 25.4 10.1%56-65 29.8 0%66-75 14.9 0%76+ 1.5 0%

Relationship Between EPTS and Age

Top 20% of nationalCut off set yearly

4 current sequences

PriorityLocalRegionalNational

Sequence order

Rankorder

SCD

81 7875 73 70 67 65 62

5853

41

0

10

20

30

40

50

60

70

80

90

1 10 20 30 40 50 60 70 80 90 99

5Y Graft Survival

KDPI

%

KDPI 0‐20

81 7875 73 70 67 65 62

5853

41

0

10

20

30

40

50

60

70

80

90

1 10 20 30 40 50 60 70 80 90 99

5Y Graft Survival

KDPI

%

KDPI 21‐34

81 7875 73 70 67 65 62

5853

41

0

10

20

30

40

50

60

70

80

90

1 10 20 30 40 50 60 70 80 90 99

5Y Graft Survival

KDPI

%

KDPI 35‐85 81 7875 73 70 67 65 62

5853

41

0

10

20

30

40

50

60

70

80

90

1 10 20 30 40 50 60 70 80 90 99

5Y Graft Survival

KDPI

%

KDPI 86‐100

0‐20 21‐34 35‐85 86‐100

Good Not as good

cPRA ≥980MM top 20%Prior LDPediatricTop 20%0MMLocalRegionalNational

cPRA ≥980MMPrior LDPediatricTop 20%

LocalRegionalNational





Split priority

CaseYou have a 65-year old Caucasian male with end-stage renal disease due to hypertensive nephrosclerosis with stage 5 CKD. He has comorbid type 2 diabetes, moderate obesity, hyperlipidemia, although his coronary angiogram has revealed no high-grade stenotic lesions. He has been cleared for the transplant program in your area. He has several potential living donors and is also willing to be placed on the deceased donor waiting list. The best choice of a donor for him would be

CaseA. Deceased donor with KDPI of 90

B. A living donor from his 69-year old spouse

C. A standard criteria deceased donor

D. A 21-year old grandson

E. Continue on dialysis without transplantation because of the risk of the transplant procedure and its complications

Induction Agents

Polyclonal Antibodies• Rabbit anti-thymocyte globulin (Thymoglobulin®)• ATGAM® horse gammaglobulin to human thymocytesHumanized Antibodies to IL-2 Receptors – CD25• Basiliximab (Simulect®)Alemtuzumab (Campath) Humanized Anti-CD52 Pan

Lymphocytic (B+ T cells) Monoclonal

Depleting Induction AgentsThymoglobulin® Campath®

Antibody Polyclonal Rabbit Humanized Murine

Administration Central Peripheral

Monitoring CD3 counts CD4 counts

“First” Dose Effects 1+ 3+

Efficacy in Rejection 3+ 3+

Infections 2+ 3+

Pharmacologic Considerationsof Basiliximab

Parameter Basiliximab

Recombinant technology Chimerized

Mechanism of action Block IL-2Rα

Saturation concentration 0.1 to 0.4 µg/mL

Immunogenicity0.4% anti-idiotype1.4% anti-isotype

Duration of IL-2 blockade 30 to 45 days

Half-life 7.2 ± 3.2 days

Dosing IV infusion of IV bolus 20 mg-dose (2 doses on days 0 and 4)

Antibody Side EffectsDepleting Agents• Cytokine release: Fever, cytopenias, flu-like

symptoms; Rare – “capillary leak syndrome” +/-renal dysfunction

• Serum sickness• Predisposition to infection: Viral (ie. CMV)• Predisposition to malignancy, PTLD, EBV

activationImmune Modulators• Virtually no side effects

CaseA 45-year old African American male is anticipating his second kidney transplant. His original renal disease was hypertensive nephrosclerosis. He lost his first graft after 5 years of function. There was no obvious acute rejection and his original allograft is still in place. He is now anticipating a live donor transplant from a friend. His tissue typing shows a 1A, 2B and 2DR mismatch. He is 50% sensitized versus the panel. His standard cross match against this particular donor is negative. You are asked to select an immunosuppressive regimen for this patient.

CaseA. Thymoglobulin induction followed by tacrolimus,

mycophenolate mofetil and prednisone

B. Basiliximab induction followed by tacrolimus, MMF and prednisone

C. Alemtuzumab induction followed by tacrolimus monotherapy and no corticosteroids

D. No induction with cyclosporine, mycophenolate mofetil and prednisone maintenance therapy

E. Plasma exchange plus IVIG pretransplant followed by thymoglobulin induction, tacrolimus, mycophenolate mofetil and prednisone

Alemtuzumab Induction in Renal Transplantation

Hanaway et al. N Engl J Med364:1909-1919, 2011

Calcineurin Inhibitors

• Cyclosporine or tacrolimus

• Chemically unrelated

• Complex with intracellular binding protein blocks calcineurins ability to phosphorylate nuclear transcription factors.

Monitoring Calcineurin and mTOR Inhibitors

Neoral/GenericsCo – does not predict AUC

C2 – better correlation with AUC but can be misleading

Tacrolimus/Generics Co – sufficient for monitoring

mTOR Inhibitors Timing does not matter for sirolimus but trough levels for everolimus

Side Effects of CNI

• Nephrotoxicity• Hypertension (CSA > Tacro)• Post-transplant diabetes (Tacro > CSA)• Neurological (Tacro)• Hirsuitism (CSA)/Alopecia (Tacro)• Hyperlipidemia (CSA > Tacro)

CNI Nephrotoxicity

RENAL

HEMODYNAMICS

Nitric oxide Catecholamines

AngiotensinEndothelin

Thromboxane/ Vasodilator prostaglandins

Ruggenenti et al: CsA-induced Renal Hypoperfusion

Side Effects of mTOR Inhibitors

• Acne/Rash• Mouth ulcers• Hyperlipidemia• Anemia, thrombocytopenia• Swelling – proteinuria (rare)• Pneumonitis (rare)

Is There a Difference Between Cyclosporine

and Tacrolimus?

Hemodynamic Effects of Tacrolimus vs. CSA in Normals

Klein et al. 2002GFR ERPF MABP

Baseline2

Weeks Baseline2

Weeks Baseline2

Weeks

CSA(100-200)

99 85 597 438 93 108

Tacro(5-15)

NC NC NC

8 patients crossover design

Renal Function Calculated GFR at Month 12

(Cockcroft-Gault)ITT GFR (ml/min)

n Median Mean SD

Normal-dose CsA 390 57.0 57.1 25.1

Low-dose CsA 399 61.0 59.4 25.1

Low-dose TAC 401 66.2 65.4 27.0

Low-dose SRL 399 57.5 56.7 26.9

p

Enterohepatic Circulation

time

[C]blood

Prolonged plasma concentration

CSA

Van Gelder et al. TDM 2001; 23:119

MMF: Practical Considerations

• More than 2 gms per day usually not tolerated

• Many centers use 500-750 mg BID• Hematologic effects common• Myfortic® 720 mg = 1 gm CellCept®

Myfortic®

• Enteric coated MMF – Na salt of MPA• “Presumed” less GI toxicity• Similar efficacy with CellCept®

Generic Prescribing

• “Bioequivalence” defined in normal volunteers (n=30)

• Few studies in complex transplant recipients

• Drug class substitutions by non-MDs common

• Pharmacists often do not appreciate kinetic differences between drugs in a single class

• Who gets the savings?

Generics in Transplant 2013Brand Name GenericImuran® AzathioprineNeoral®* At least 3 genericsPrograf® 2 genericsCellCept® 6 new genericsMyfortic® No genericSandimmune®* Multiple generics for

cyclosporine non-modifiedRapammune® No genericZortress® No genericDeltasone® Multiple generics*Not bioequivalent

CaseA 46-year old Asian female received a living related donor transplant from her haploidentical sister 6 months ago. She presents to you with fever, increasing allograft discomfort, elevation of blood pressure and slight peripheral edema. Her maintenance immunosuppressive regimen is prednisone 5 mg daily, cyclosporine microemulsion 100 mg bid, and mycophenolate mofetil 1 gm bid. She had received basiliximab induction therapy. Her last cyclosporine blood level 5 days ago was 100 nanograms/mL. Urinalysis shows 1+ protein, specific gravity of 1.015, 4-10 red cells and 6-10 white cells per high power field. Bacteria are not present. Her donor was CMV positive and she is CMV negative. She has received six months of valganciclovir prophylaxis. An ultrasound of her transplant reveals increased resistive indices but no evidence of hydronephrosis. Serum creatinine at the time of her cyclosporine blood level was 1.1 mg/dL and today’s value is 1.4 mg/dL. The most likely diagnosis in this patient is:

Case

A. Acute cellular allograft rejection

B. Primary CMV infection with renal involvement

C. Cyclosporine nephrotoxicity

D. Allograft pyelonephritis

E. Acute interstitial nephritis due to valganciclovir

Acute Cellular Rejection• Most common cause of renal dysfunction

1-3 months post-transplant

• Diagnosis by biopsy – “tubulitis”

• Can be subclinical ie. surveillance biopsy

• Rx – corticosteroid pulse followed by biologic if resistant

CaseYou are following a 36-year old Caucasian man with end-stage renal disease secondary to chronic IgA nephropathy. He received a renal transplant from his father six years ago. He is maintained on tacrolimus, mycophenolate mofetil, and low dose prednisone therapy. Early after transplant he had an acute rejection that was characterized by peritubular capillary neurophilic inflammation and C4D positivity.

On a routine visit in your office he is found to have an increased urinary protein/creatinine ratio and a rise in serum creatinine from a baseline of 1.3 mg/dL to 1.7 mg/dL. Blood pressure has gradually become more difficult to control and he is on metoprolol 50 mg bid and amlodipine 10 mg daily with marginal control. In addition to the proteinuria the urinalysis shows 0-3 red blood cells and 2-3 white blood cells per high power field. There are no casts present. Hemogram reveals a hemoglobin of 10.5 grams, white blood count of 4600 and a platelet count of 120,000. His last tacrolimus was 6 nanograms/mL. Ultrasound reveals no evidence of obstructive uropathy. Urine surveillance for polyoma virus shows 104 log copies of BK virus. Serum BK PCR is negative. A renal biopsy is performed. You would most likely observe:

CaseA. Interstitial nephritis with large viral inclusion bodies in

proximal tubule cells

B. Arteriolar hylanosis suggestive of calcineurin inhibitor nephrotoxicity

C. Recurrence of IgA nephropathy in the transplanted kidney

D. Chronic tubular interstitial fibrosis plus glomerular lesions suggesting splitting and reduplication of glomerular basement membrane

E. Acute interstitial nephritis with extensive tubulitis

Antibody Mediated Rejection• C4D deposition

• Donor specific antibodies

• Glomerular changes similar to MPGN “allograft glomerulopathy”

• Peritubular capillaritis-interstitial hemorrhage

Rx – Pheresis, IVIG, Rituximab, ?Bortezemib

?Eculizimab. Success related to time post-transplant

Chronic Allograft Loss

• Slow deterioration due to humoral immunologic processes

• Non-immunologic factors including patient death, donor changes

• Calcineurin-inhibitor nephrotoxicity

• Recurrent or de novo nephropathy

CaseA 64-year old Caucasian male received a deceased donor transplant six months ago. Kidney function has been excellent with baseline serum creatinines of 1-1.2 mg/dl. At the past several clinic visits he is noted to have 5-10 red blood cells per high power field. An ultrasound of his renal transplant reveals a very mild new hydronephrosis without any evidence of hemodynamic compromise. His urine to protein creatinine ratio is 0.1, and his serum creatinine on today’s visit is 1.4 mg/dl. Immunosuppression since the time of transplant has been mycophenolate mofetil 1 gm BID, tacrolimus maintaining a blood level of 8-10 ng/ml, and prednisone 5 mg daily. A renal biopsy shows some interstitial inflammatory cells. C4D staining is negative. You would next

CaseA. Insert an antigrade stent to bypass the ureteral

obstruction to see if renal function improves

B. Treat the patient with high dose steroids for acute rejection

C. Perform an allograft biopsy

D. Cystoscope the patient looking for bladder tumors

E. Examine urinary PCR for BK virus

Causes of Late Kidney Allograft Loss

Pascual M et al. N Engl J Med. 2002;346:580-590.

Causes of late allograft loss(>1 yr after transplantation)

Chronic renal allograft dysfunctionleading to graft failure in

50% of cases

Death of a patient with afunctioning graft in

50% of cases

Other diagnoses in10-20% of cases

Chronic allograft nephropathy in 30-40% of cases

True chronicrejection

(immunologic injury)

IF/TAof mixed origin (e.g., non-

specific interstitial fibrosis and tubular atrophy)

Chronic toxic effects of

calcineurin inhibitors

New diseases

Acute rejection

Recurrent diseases

Chronic ABMR

Jordan et al., Am J Transplant 2009; 88:2Copyright © 2009 Wolters Kluwer. Published by Lippincott Williams & Wilkins.

Jordan et al., Am J Transplant 2009; 88:5Copyright © 2009 Wolters Kluwer. Published by Lippincott Williams & Wilkins.

Emerging CS Sparing Regimens

• Rapid withdrawal (< 7 days after transplantation)

• Complete elimination

Advantages of Very Early Withdrawal or Complete Avoidance of Corticosteroids

in Renal Transplantation• Acute rejection may occur early and be readily

diagnosed and treated• The host’s immune response remains

unmodified by the effect of chronic steroid therapy– No interference by steroids of tolerogenic pathway– Lack of steroid dependency– Prevention of heightened immune response after

discontinuation of steroids• Prevention of steroid side effects

69

A Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

Comparing Early (7 Day) Corticosteroid Cessation Versus Long-Term, Low-Dose

Corticosteroid Therapy

Woodle ES, Fitzsimmons W, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldheisen P;

Astellas Corticosteroid Withdrawal Study GroupAnn Surg. 2008;248(4):564-577.

70

Primary Endpoint of Death, Graft Loss, or Moderate/Severe Acute Rejection:

Kaplan-Meier AnalysisPr

obab

ility

(%)

Years Posttransplant

83.3%

84.9%P=0.691

Chronic low-dose corticosteroid therapyEarly corticosteroid withdrawal

Woodle ES, et al. Ann Surg. 2008;248(4):564-577.

71

Biopsy-Confirmed Acute Rejection


27.3%

17.0%P=0.005

Prob

abili

ty (%

)

Years Posttransplant

Chronic low-dose corticosteroid therapyEarly corticosteroid withdrawal

72

Chronic Allograft Nephropathyat 5 Years

CCSN=195

CSWDN=191 P Value

Biopsy-confirmed CAN 8 (4.1%) 19 (9.9%) 0.028


CAN=chronic allograft nephropathy; CCS=chronic low-dose corticosteroid therapy; CSWD=early corticosteroid withdrawal

Summary

• Very early corticosteroid appears to be safe in low immunologic risk patients

• Longer-term follow-up is still required

Drugs in Pregnant Transplant Patients

• Prednisone – safe, perinatal dose for labor ‘stress’

• Azathioprine – safe

• Cyclosporine/tacrolimus – same blood concentration in fetus as mother, ? IGR or small for age babies

• Mycophenolate/sirolimus, everolimus – limited data

• BP drugs: methyldopa, hydralazine, labetolol

Bortezomib• Approved for myeloma• Acts early in B cell pathway (proteosome

inhibitor)• Given IV• Use for humoral rejection and

desensitization “off label”• Neurotoxicity and hematologic effects

Eculizimab

• Humanized monoclonal antibody against C5 protein

• Prevents C5b-C9 complex• Approved for PNH, atypical HUS• Off label – desensitization, AMR• EXPENSIVE!

Key Points• Kidney transplant is treatment of

choice for ESRD• Standard regimen: Triple drug – CNI,

MPA, steroid• Steroid withdrawal safe in short term• Antibody mediated processes major

cause of CAN• Drug interactions are frequent and

clinically important

Immunosuppressive Drugs: Mechanisms of Action

and Issues for Use

Douglas J. Norman, MDProfessor of Medicine

Oregon Health & Science University

D1

’60 ‘65 ‘70 ‘75 ’80 ‘85 ‘90 ‘95 ’00 ‘05

• Cyclosporine• OKT3

• Cyclosporine Emulsion• Tacrolimus

• MMF• Daclizumab• Basiliximab

• Thymoglobulin• Sirolimus

YearAdapted from Stewart F, Organ Transplantation, 1999

• Radiation• Prednisone• 6-MP

• AZA•ATGAM

• Rituximab• Alemtuzumab

• Leflunomide• Everolimus• Belatacept

Deceased Donor Renal Allograft Survival

The Phases of Immunosuppression

Acute Post-TransplantImmunosuppression

Chronic Allograft Dysfunction

Pre transplant Immuno-suppression

InductionTherapy

Early Acute Rejection

ImmuneAccommodation

Late Acute RejectionImmune Desensitization

MaintenanceImmunosuppression

Graft Failure

Adapted from Martin Zand, MD

Signal 2Costimulation

CD45 CD28

IL-2 mRNAIL-2R mRNA

Signal 3Proliferation

IL-2 R

M

G1 S

G2

P13-K

TOR

Cyclin/CDK

MMF AzathioprineLeflunamide

Sirolimus Everolimus

Signal 1Activation

TCR ComplexCD3 +CD4

Calcineurin promoter(IL-2)

NFATp

calcineurin

TacrolimusCyclosporine

ThymoglobulinAlemtuzumab

Basiliximab

T Cell Martin Zand, MD

Belatacept

ARS: Which drugs are blockers of signal 3 of the T cell activation cascade?

• 1. Cyclosporine, tacrolimus, everolimus• 2. MMF, Azathioprine, leflunamide• 3. Belatacept, MMF, sirolimus• 4. Basiliximab, tacrolimus, OKT3• 5. OKT3, cyclosporine, tacrolimus

Antilymphocyte Antibodies

• Polyclonal– Atgam (equine)– Thymoglobulin (rabbit)

• Monoclonal– Murine (100% mouse)

• OKT3 (anti CD3)– Human/Murine

• Chimeric (70% human)– Basiliximab (anti IL2R)– Rituximab (anti CD20)

• Humanized (90% human)– Alemtuzumab (anti CD52)

Mechanisms of Action of Antilymphocyte Antibodies

• Cell Depletion (most effective)– opsonization / phagocytosis– complement mediated lysis– apoptosis– antibody dependent cell mediated cytotoxicity

• Blocking function of T cells– removes functional molecules from cell surface– occupies functional molecule to prevent ligand

binding

ARS: What is a true statement about antilymphocyte antibodies?

• 1. Chimeric monoclonal antibodies are mostly murine• 2. Humanized monoclonal antibodies are 50% human• 3. Thymoglobulin and basiliximab are polyclonal antibodies• 4. Alemtuzumab is a 90% human monoclonal antibody• 5. Atgam is a rabbit polyclonal antibody

Important Additional Issues Regarding Immunosuppression

• Never use azathioprine with allopurinol• MMF may have selective lymphocyte activity

because it acts through the de novo pathway of purine synthesis

• OKT3, Thymoglobulin and Atgam can cause a cytokine release syndrome that can be significant

Key Board Review PointsMechanisms of action of

immunosuppressive drugs

• T cell signal 1 blockers have been the most important drugs used in kidney transplantation

• T cell signal 3 blockers have mostly been used as adjuvant treatments

• Antilymphocyte antibodies block the immune response mostly by depleting lymphocytes but some inactivate T cells by blocking a functional molecule on the cell surface

• Azathioprine should never be used with allopurinol (xanthine oxidase inhibitor)

Initial Immunosuppression Before and After Transplantation

Initial Immunosuppression

Acute Post-TransplantImmunosuppression

Pre-Transplant Immunosuppression

InductionTherapy

Immune Desensitization

PosttransplantPretransplant

Immune Desensitization

• Plasmapheresis• IVIG• Rituximab• Bortezomib

ARS: Why is strong immunosuppression used initially following kidney

transplantation?

• 1. The indirect pathway of T cell activation is prominent• 2. The direct pathway of T cell activation is prominent• 3. Infections are uncommon during the first 3 months

following transplantation• 4. Delayed graft function can be prevented using strong

immunosuppression• 5. Living donor kidneys are more immunogenetic than

deceased donor kidneys

Direct Allorecognition Induction Immunosuppression

• Antilymphocyte antibody• Methylprednisolone, 500mg IV on day 0• Antiproliferative drug (sirolimus should be

avoided because of wound healing problems)

Odds Ratios For Allograft Loss when ATG or OKT3 used for Induction

.1 0.2 0.5 1.0 2.0 5.0 10.0

Michael .63 (.18, 2.2)

Belitsky 1.57 (.56, 4.41)

Banhegyi .71 (.19, 2.65)

Abramowicz .50 (.19, 1.33)

Norman .56 (.28, 1.12)

Slakey .52 (.19, 1.42)

SMSG* .67 (.20, 2.33)

OVERALL .66 (.45, .96)

Szczech et al*Spanish monoclonal antibody study group

Meta-analysis of Randomized TrialsOf Anti-IL2R* in Kidney Transplantation:

8 trials involving 1816 Patients

.1 0.2 0.5 1.0 2.0 5.0 10.0

Acute Rejection .51 (.42, .62) (

No InductionOKT3AtGamThymoglobulinBasiliximabDaclizumabAlemtuzumab

Antibody Induction 2009

No Induction

Anti IL2 R

Anti IL2 R + T cellDepletingT cell Depleting

Antibody Induction 2011

Key Board Review PointsInduction Drugs and Protocols

• Strong immunosuppression must be used initially following kidney transplantation because the direct pathway of T cell activation is prominent

• Most induction protocols are currently including an antilymphocyte antibody.

• Immune desensitization might be necessary prior to kidney transplantation if donor specific antibodies are present

• The use of antilymphocyte antibodies increases the risk of infection and lymphoproliferative disease

Treatment of Rejection

When Rejections OccurEarly Acute Rejection

Late Acute Rejection

Acute Recognition of Chronic Rejection

Antibody MediatedRejection

HyperacuteRejection

Treatment of Cell Mediated Rejection

• Corticosteroids• Anti lymphocyte antibodies

• Thymoglobulin, OKT3• Increase maintenance drugs

• Signal 1 and signal 3 blockers

Treatment of Antibody Mediated Rejection

• B-cell inactivation• Thymoglobulin, Rituximab, IVIG,

Bortezomib• Alloantibody removal

• Plasmapheresis• Alloantibody neutralization/modulation

• IVIG

Rituximab (Rituxan®)

• Binds to CD20 on naïve and resting memory B cells

• Does not bind to plasma cells• No cytokine release syndrome• Used in immune desensitization protocols

for high PRA

Intravenous Immunoglobulin (IVIG)

• Down-regulates antibody production by plasma cells

• Induces apoptosis of B cells• Effective for treatment of acute humoral

rejection and immune desensitization protocols

Bortezomib (Velcade®)

• Protease inhibitor• Used to treat multiple myeloma• Purpose is to reduce antibody production by

plasma cells

Plasmapheresis

• Removes circulating antibodies• Used as temporizing measure while anti-B

cell/plasma cell therapies are started• Effective for treatment of acute humoral

rejection and immune desensitization protocols

ARS: What are possible treatments for cell mediated rejection?

• 1. Corticosteroids, rituximab, plasmapheresis• 2. Corticosteroids, thymoglobulin, IVIG• 3. Corticosteroids, thymoglobulin, bortezomib• 4. Corticosteroids, thymoglobulin, increase signal 1

blockers

Key Board Review PointsTreatment of rejection

• Mild or moderate cell mediated rejection should be treated with corticosteroids first

• Severe cell mediated rejection should be treated with an antilymphocyte antibody first ± corticosteroids

• Early antibody mediated rejection can be treated successfully

• Treatment of chronic rejection, acutely recognized, is usually unsuccessful

Key Update PointsTreatment of rejection

• Some kidney transplant programs use surveillance biopsies at one or more time points in the first two years after transplant

• Surveillance biopsies clearly demonstrate that rejection can occur in the absence of clinical manifestations (stable, normal creatinine)

THE END

Friday, August

Post-Transplant Non-Infectious Complications

Donald E. Hricik, MD

9:30 a.m. - 11:00 a.m.

Noninfectious Complications of Kidney Transplantation

Donald E. Hricik, M.D.

Professor of Medicine and Chief,Division of Nephrology and Hypertension

Director, Transplant InstituteUniversity Hospitals Case Medical Center

Overview: Complications of TransplantationOverview: Complications of Transplantation

Early Complications– Surgical complications

Early Complications– Surgical complications

Later Complications– Cardiovascular disease

• Hypertension• Hyperlipidemia• Diabetes mellitus• Anemia/erythrocytosis

– Chronic allograft dysfunction

– Malignancy– Bone diseaseManaging the failed transplant

Later Complications– Cardiovascular disease

• Hypertension• Hyperlipidemia• Diabetes mellitus• Anemia/erythrocytosis

– Chronic allograft dysfunction

– Malignancy– Bone diseaseManaging the failed transplant

Surgical Complications – Kidney Transplantation

Surgical Complications – Kidney Transplantation

Wound infections Fluid Collections – Vascular

– Seromas– Hematomas

• Mycotic aneurysm (rare; > 50% mortality)• Renal rupture (acute rejection; rare)• Management: variable

– Lymphocele (5-15% of cases; more common with TOR inhibitors)

• Management: conservative when non-obstructing, or:– Percutaneous drainage– 30% require surgical repair

Wound infections Fluid Collections – Vascular

– Seromas– Hematomas

• Mycotic aneurysm (rare; > 50% mortality)• Renal rupture (acute rejection; rare)• Management: variable

– Lymphocele (5-15% of cases; more common with TOR inhibitors)

• Management: conservative when non-obstructing, or:– Percutaneous drainage– 30% require surgical repair

Surgical Complications – Kidney Transplantation, continued


Fluid Collections – Urologic– Urine Leaks (1-3% of cases)

• Diagnosis: Creatinine ratio – fluid collection: serum; nuclear scans

• Management:–Prolonged bladder drainage +/- ureteral

stenting–Surgical repair:

• Repeat implantation into bladder• Ureter-ureter reconstruction

Fluid Collections – Urologic– Urine Leaks (1-3% of cases)

• Diagnosis: Creatinine ratio – fluid collection: serum; nuclear scans

• Management:–Prolonged bladder drainage +/- ureteral

stenting–Surgical repair:

• Repeat implantation into bladder• Ureter-ureter reconstruction



Decreased diuresis – urologic– Compression of the ureter– Urine leak– Obstruction of the urinary tract an any level

• Ureteral blood clot/tissue/stone/kink• Bladder outlet obstruction• (Later cases of obstructive uropathy more often

related to ischemic strictures or BK polyoma infection)

Decreased diuresis – vascular– Arterial or venous thrombosis 1-2% of cases

• Diagnosis – Doppler ultrasound (no flow)• Management – immediate surgical exploration

Decreased diuresis – urologic– Compression of the ureter– Urine leak– Obstruction of the urinary tract an any level

• Ureteral blood clot/tissue/stone/kink• Bladder outlet obstruction• (Later cases of obstructive uropathy more often

related to ischemic strictures or BK polyoma infection)

Decreased diuresis – vascular– Arterial or venous thrombosis 1-2% of cases

• Diagnosis – Doppler ultrasound (no flow)• Management – immediate surgical exploration

‘60 ‘65 ‘70 ‘75 ‘80 ‘85 ‘90 ‘95 ‘00

• CY-A• OKT3

• Cyclosporine Emulsion• Tacrolimus

• MMF• Dicluzimab• Basiliximab

• Thymoglobulin• Sirolimus

Year

Cadaveric Renal Allograft Survival

Adapted from Stewart F, Organ Transplantation, 1999

• Radiation• Prednisone• 6-MP

• AZA•ATGAM

Meier-Kriesche, Schold, Kaplan, AJT 2004;4:1289

Long term allograft survival: Progress or time to rethink strategies ? Causes of Late Kidney Allograft Loss

Late allograft loss(>1 yr after

transplantation)

50%Chronic renal allograft

dysfunction

40%Death with

functioning graft

50%Cardiovascular

disease

10%–20%Other diagnoses

Chronic rejectionNon-specific fibrosis,

tubular atrophy

Drug toxicity

New diseases

Recurrent diseases

Acute rejection

Pascual M et al. N Engl J Med. 2002;346:580-590.

30%–40%Chronic allograft

nephropathy

Interim SummaryInterim Summary

Board Review Points– Incidence of acute

rejection in first posttransplant year < 20%

– Improvement in rates of acute rejection not paralleled by improvements in long-term graft survival

– Death with a functioning graft accounts for ~ 40% of late graft losses

Board Review Points– Incidence of acute

rejection in first posttransplant year < 20%

– Improvement in rates of acute rejection not paralleled by improvements in long-term graft survival

– Death with a functioning graft accounts for ~ 40% of late graft losses

Update Points– Wound healing is

impaired by and lymphoceles are more common with TOR inhibitors

Update Points– Wound healing is

impaired by and lymphoceles are more common with TOR inhibitors

Which of the following is the most common cause of mortality after kidney transplantation?

Which of the following is the most common cause of mortality after kidney transplantation?

A. Posttransplant lymphoproliferative disease B. Myocardial infarction C. Opportunistic infection D. Squamous cell carcinoma

A. Posttransplant lymphoproliferative disease B. Myocardial infarction C. Opportunistic infection D. Squamous cell carcinoma

Cardiovascular Mortality in Renal Transplant RecipientsCardiovascular Mortality in

Renal Transplant Recipients

USRDS databaseFoley, et al. J Am Soc Nephrol. 1998;9(suppl):S16.Foley, et al. Am J Kidney Dis. 1998;32(suppl 3):S112.

USRDS databaseFoley, et al. J Am Soc Nephrol. 1998;9(suppl):S16.Foley, et al. Am J Kidney Dis. 1998;32(suppl 3):S112.

Cardiovascular Annual Mortality

General 0.28 %

Hemodialysis 9.12%

Peritoneal dialysis 9.24 %

Renal transplant 0.54 %

Cardiovascular Annual Mortality

General 0.28 %

Hemodialysis 9.12%

Peritoneal dialysis 9.24 %

Renal transplant 0.54 %

Other23%

Other23%

Cerebrovasculardisease

7%


7%

Infection20%

Infection20%

Malignancy13%

Malignancy13%

Cardiovasculardisease

37%


37%N = 47,581N = 47,581

All Patients


48%


48%

Malignancy6%

Malignancy6%

Infection17%

Infection17%


10%


10%

OtherOther19%19%

N = 16,231N = 16,231

Diabetic Patients

Kidney Transplantation Reduces CVD Risk in Patients With ESRD

Meier-Kriesche HU et al. Am J Transplant. 2004;4:1662-1668.

Rat

es p

er 1

000

pati

ent

year

s

0-3 3-6

Months

6-12 12-24 24-36 36-48 48-60 60+

jkimSticky Noteoverlapping text

Independent Risk Factors forPost-transplant Cardiovascular Events

Independent Risk Factors forPost-transplant Cardiovascular Events

*P < 0.0001; †P < 0.01; ‡P < 0.05Error bars represent 95% CISingle-center retrospective study (N = 427)Aker S et al. Int Urol Nephrol. 1998;30:777–788.

*P < 0.0001; †P < 0.01; ‡P < 0.05Error bars represent 95% CISingle-center retrospective study (N = 427)Aker S et al. Int Urol Nephrol. 1998;30:777–788.

00

22

44

66

88

1010

DiabetesmellitusDiabetesmellitus

Rel

ativ

e ris

kR

elat

ive

risk

Age attransplant

(> 50 y)

Age attransplant

(> 50 y)

Body massindex

(> 25 kg/m2)

Body massindex

(> 25 kg/m2)

SmokingSmoking LDL-C(> 180 mg/dL)

LDL-C(> 180 mg/dL)

Uric acid(> 6.5 mg/dL)

Uric acid(> 6.5 mg/dL)

‡‡††

**

‡‡ ‡‡‡‡

Cardiovascular Death by sCr at 1 Year Posttranplant

Cardiovascular Death by sCr at 1 Year Posttranplant

Serum Creatinine @ 1 Year 5 Year CV death-free survival rate

< 1.3 97%

1.3-1.4 96%

1.5-1.6 95.5

1.7-1.8 94

1.9-2.1 93.5

2.2-2.5 93

2.6-4.0 91Meier-Kriesche at al. Transplantation 2003; 75: 1291

CyA Tac SRL Ster MMFHypertension ++ + ++ Hyperglycemia + ++ + +++ Renal insufficiency ++ ++ Hyperlipidemia ++ + ++ ++

Hyperkalemia +++ +++ Tremor + Hirsutism + Gingival hyperplasia + Hypophosphatemia ++ ++ + Osteoporosis ± ± +++ Malignancy + + ? +

CyA Tac SRL Ster MMFHypertension ++ + ++ Hyperglycemia + ++ + +++ Renal insufficiency ++ ++ Hyperlipidemia ++ + ++ ++

Hyperkalemia +++ +++ Tremor + Hirsutism + Gingival hyperplasia + Hypophosphatemia ++ ++ + Osteoporosis ± ± +++ Malignancy + + ? +

Immunosuppression Long-Term Side Effect Profiles Immunosuppression Long-Term Side Effect Profiles

CyA = cyclosporine; Tac = tacrolimus; SRL = sirolimus+++ = severe; – = opposite; + = mild; ++ = moderate; = none; ? = unknownCyA = cyclosporine; Tac = tacrolimus; SRL = sirolimus+++ = severe; – = opposite; + = mild; ++ = moderate; = none; ? = unknown

Incidence of Hypertension at 1 Year Post-transplantation (N = 29,751)

Incidence of Hypertension at 1 Year Post-transplantation (N = 29,751)

SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.

9.5%9.5%

SBP values (mm Hg) < 120120–129130–139140–149150–159160–169170–179 180

SBP values (mm Hg) < 120120–129130–139140–149150–159160–169170–179 180

15.2%15.2%

20.2%20.2%22.6%22.6%15.0%

9.8%9.8%

4.1%4.1% 4.2%4.2%

Association of Hypertension at 1 YearWith Decreased Graft Survival

Association of Hypertension at 1 YearWith Decreased Graft Survival

SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.

% g

rafts

sur

vivi

ng%

gra

fts s

urvi

ving

5050

6060

7070

8080

9090

100100

0000 11 22 33 44 55 66 77

Years post-transplantationYears post-transplantation

SBP No. pts

< 120 2,805120–129 4,488130–139 5,961

SBP No. pts

< 120 2,805120–129 4,488130–139 5,961140–149 6,670140–149 6,670150–159 4,443150–159 4,443160–169 2,925160–169 2,925170–179 1,217170–179 1,217

180 1,242 180 1,242

Pathogenesis of Hypertensionin Renal Transplant RecipientsPathogenesis of Hypertensionin Renal Transplant Recipients

Mailloux LU et al. Am J Kidney Dis. 1998;32(suppl 3):S120–S141.Kew CE II et al. J Renal Nutrition. 2000;10:3–6.Mailloux LU et al. Am J Kidney Dis. 1998;32(suppl 3):S120–S141.Kew CE II et al. J Renal Nutrition. 2000;10:3–6.

• Pre-existing essential hypertension• General-population risk factors

(obesity, alcohol, excessive salt intake) • Renal dysfunction/rejection• Renal-transplant artery stenosis • Effects of native kidneys• Hypertensive donor• Immunosuppressive drugs

• Steroids; CNIs (CsA>FK)

• Pre-existing essential hypertension• General-population risk factors

(obesity, alcohol, excessive salt intake) • Renal dysfunction/rejection• Renal-transplant artery stenosis • Effects of native kidneys• Hypertensive donor• Immunosuppressive drugs

• Steroids; CNIs (CsA>FK)
jkimText Box

Transplant Renal Artery StenosisTransplant Renal Artery Stenosis• Prevalence 5-25%• Highest rates between 3 months and 2 years• Pathophysiology: Anastomotic strictures (more

common after live donor transplantation), arterial kinks, rejection, proximal stenoses in the recipient’s aorto-iliac arterial tree

• Clinical presentation: Worsening hypertension, “creatinine creep”

• Diagnosis: Doppler US, MRA, gold standard is arteriogrpahy

• Treatment: PTA, surgery

• Prevalence 5-25%• Highest rates between 3 months and 2 years• Pathophysiology: Anastomotic strictures (more

common after live donor transplantation), arterial kinks, rejection, proximal stenoses in the recipient’s aorto-iliac arterial tree

• Clinical presentation: Worsening hypertension, “creatinine creep”

• Diagnosis: Doppler US, MRA, gold standard is arteriogrpahy

• Treatment: PTA, surgery

Posttransplant Hypertension: TreatmentPosttransplant Hypertension: Treatment

• All antihypertensive drugs work!• No established algorithm, but consider:

– Interactions between immunosuppressive meds and BP meds (diltiazem, verapamil increase CNI and TORilevels)

– Side effects of BP meds– Cost and number of medications!– HTN is a side effect of IS medications

• All antihypertensive drugs work!• No established algorithm, but consider:

– Interactions between immunosuppressive meds and BP meds (diltiazem, verapamil increase CNI and TORilevels)

– Side effects of BP meds– Cost and number of medications!– HTN is a side effect of IS medications

ACEIs and ARBs in Kidney Transplantation

Antiproteinuric

? Renal Protection

Hyperkalemia

Acute Renal Failure (rare)

Anemia

Kaplan-Meier estimates of patient survival

ACEIs/ARBs Do not Influence Graft or Patient Survival

Opelz G, et al. J Am Soc Nephrol 2006;17:3257-3262

Losartan vs Placebo in Kidney Transplant Recipients

• Prospective randomized double blind placebo controlled• Randomization at 3 months to losartan (n=77) vs

placebo (n=76)• 5 year follow-up• Composite endpoint of doubling of interstitial volume

on serial biopsies or ESRD attributed to IFTA• Results: No statistically significant benefit of losartan

Ibrahim HN, et al. JASN 24: 320-327

Pathogenesis of Hyperlipidemiain Renal Transplant Recipients (prevalence of 60-90%

depending on immunosuppressive regimen*)

Pathogenesis of Hyperlipidemiain Renal Transplant Recipients (prevalence of 60-90%

depending on immunosuppressive regimen*)• High prevalence of predisposing factors1

– Age– Diabetes– Obesity

• Impaired renal function2– Renal insufficiency– Proteinuria

• Drugs3– Diuretics, beta-blockers– Immunosuppressive agents*

Steroids, CNIs, TOR inhibitors

• High prevalence of predisposing factors1– Age– Diabetes– Obesity

• Impaired renal function2– Renal insufficiency– Proteinuria

• Drugs3– Diuretics, beta-blockers– Immunosuppressive agents*

Steroids, CNIs, TOR inhibitors 1. Keane WF. Miner Electrolyte Metab. 1997;23:166–169.2. Kasiske BL. Am J Kidney Dis. 1998;32(suppl 3):S142–S156.3. Aakhus S et al. J Intern Med. 1996;239:407–415.

1. Keane WF. Miner Electrolyte Metab. 1997;23:166–169.2. Kasiske BL. Am J Kidney Dis. 1998;32(suppl 3):S142–S156.3. Aakhus S et al. J Intern Med. 1996;239:407–415.

240240

220220

200200

180180

160160

140140Mea

n to

tal c

hole

ster

ol (m

g/dL

)M

ean

tota

l cho

lest

erol

(mg/

dL)

Cyclosporine vs TacrolimusCyclosporine vs Tacrolimus

Randomized, multicenter trial with traditional formulation of cyclosporinePirsch JD et al. Presented at Transplant 2000; Chicago, Illinois; May 13–17, 2000.Randomized, multicenter trial with traditional formulation of cyclosporinePirsch JD et al. Presented at Transplant 2000; Chicago, Illinois; May 13–17, 2000.

Mean Total Cholesterol Level Over TimeMean Total Cholesterol Level Over TimeCyclosporineTacrolimusCyclosporineTacrolimus

(n = 189)(n = 189)

150150

(n = 192)(n = 192)

144144

BaselineBaseline

230230

(n = 104)(n = 104)

194194

1 Year1 Year

226226

(n = 129)(n = 129)

199199

3 Years3 Years

210210

(n = 94)(n = 94)

198198

5 Years5 Years(n = 98)(n = 98) (n = 93)(n = 93) (n = 64)(n = 64)

P < 0.001P < 0.001 P < 0.001P < 0.001

P = 0.07P = 0.07

Characterization of Hyperlipidemia Associated With Sirolimus

Characterization of Hyperlipidemia Associated With Sirolimus

1. Hoogeveen RC et al. Transplantation. 2001;72:1244–1250.2. Zimmerman JJ et al. Presented at 10th Congress of European Society for Organ Transplantation; Lisbon, Portugal; October 6–10, 2001.

1. Hoogeveen RC et al. Transplantation. 2001;72:1244–1250.2. Zimmerman JJ et al. Presented at 10th Congress of European Society for Organ Transplantation; Lisbon, Portugal; October 6–10, 2001.

• Total-C and TG (increase LDL, VLDL, and HDL)• Mechanism: catabolism of apoB-100–containing

lipoproteins1

• Dose dependent• Generally reversible upon cessation• Responsive to lipid-reducing agents No clinically significant interaction with

atorvastatin2

• Total-C and TG (increase LDL, VLDL, and HDL)• Mechanism: catabolism of apoB-100–containing

lipoproteins1

• Dose dependent• Generally reversible upon cessation• Responsive to lipid-reducing agents No clinically significant interaction with

atorvastatin2

Adelman SJ et al. Presented at Transplant 2001; Chicago, Illinois: May 11–16, 2001.Adelman SJ et al. Presented at Transplant 2001; Chicago, Illinois: May 11–16, 2001.

ControlControl

Effect of Sirolimus on Aortic Atherosclerosis in ApoE-Deficient Mice

Effect of Sirolimus on Aortic Atherosclerosis in ApoE-Deficient Mice

8 mg/kg/d x 2 d8 mg/kg/d x 2 d

ALERT Trial (n=2102)*Cumulative Incidence of Cardiac Death or

Nonfatal definite MI - Core Study

Holdaas et al Lancet 2003;361:2024

Years since randomization1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

15

10

5

0

Placebo

Fluvastatin

0.50.0

P = 0.00535%

Proportion of patients with event

(%)

*Fluvastatin 40-80 mg/day

Mean follow-up 5 years

Total cardiac events not reduced significantly


Board Review Points– Cardiovascular disease

most common cause of death

– ACEIs and ARBs have been associated with posttransplant anemia (and used to treat erythrocytosis)

– Hyperlipidemia more common with CsA than with tacrolimus

Board Review Points– Cardiovascular disease

most common cause of death

– ACEIs and ARBs have been associated with posttransplant anemia (and used to treat erythrocytosis)

– Hyperlipidemia more common with CsA than with tacrolimus

Update Points– Cardiovascular disease

linked to renal impairment after transplantation

– Incidence of cardiovascular events decrease after transplantation

– TOR inhibitors may be anti-atherogenic

– Has been difficult to prove any renoprotective effect of ACEIs or ARBs in kidney transplantation

Update Points– Cardiovascular disease

linked to renal impairment after transplantation

– Incidence of cardiovascular events decrease after transplantation

– TOR inhibitors may be anti-atherogenic

– Has been difficult to prove any renoprotective effect of ACEIs or ARBs in kidney transplantation

Which of the following factors is most strongly associated with new onset of diabetes mellitus

after kidney transplantation?

Which of the following factors is most strongly associated with new onset of diabetes mellitus

after kidney transplantation? A. Hepatitis C B. Obesity C. Advanced recipient age D. Use of tacrolimus E. Advanced donor recipient age

A. Hepatitis C B. Obesity C. Advanced recipient age D. Use of tacrolimus E. Advanced donor recipient age

Classification of Diabetes MellitusClassification of Diabetes MellitusCategory ADA 2004 WHO 1999

Normal 200

FPG > 126 or2h PPG > 200

Survival Free of Posttransplant DiabetesBased on Medicare Claims

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30 33 36

3 months (9.1%) 12 months (16%) 36 months (24

Adapted from Kasiske B, et al Am J Transplantation 2003; 3:178-85

PTDM (NODAT)*Older age

Black/Hispanic

Immunosuppression

• Corticosteroids

• CNI

• Sirolimus

Family Hx of DM

Obesity

Insulin resistance / low GFR

Hepatitis C

Risk factors for the development of post-transplant hyperglycemia

*PTDM = Posttransplant Diabetes Mellitus

NODAT = New Onset Diabetes Mellitus

After Transplantation

APKD? Hypomagnesemia; Statins

PTDM: Independent Risk Factors

Clinical Factor Relative RiskAge > 60 2.60Age 49-59 1.90BMI > 30 1.73African American 1.68Tacrolimus 1.35Hepatitis C Antibodies 1.33

Kasiske et al. AJT 2003 3: 178

Tacrolimus is more diabetogenic than cyclosporine

(Kasiske et al. AJT 3:178, 2003)

22%

14%

Cumulative incidence of cardiovascular events five years posttransplant in patients classified according to fasting glycemia at 1 year

Cosio FG, et al. Kidney Int 2005; 67: 2415

Diabetes (pre or post-transplant) has a profound impact on recipient survival

No DM

NODM

DM

Adapted from Cosio et al. K Int 2002:62:1440

Nonpharmacologic Therapy

(Weight Loss; Exercise)

Oral Hypoglycemic Agent Monotherapy

Combination of Oral Agents

Insulin Plus Oral Agents

Insulin Monotherapy

? Manipulation of Immunosuppression

STEPWISE APPROACH TO

TREATMENT OF NODAT

Which of the following factors is most strongly associated with posttransplant anemia?

Which of the following factors is most strongly associated with posttransplant anemia?

A. Impaired allograft function B. Use of TOR inhibitors C. Use of ACE inhibitors or ARBs D. Number of acute rejection episodes

A. Impaired allograft function B. Use of TOR inhibitors C. Use of ACE inhibitors or ARBs D. Number of acute rejection episodes

Changes in Hematocrit after Kidney Transplantation (Christian T, et al: Am J Transplant 2003; 3: 1426)

Changes in Hematocrit after Kidney Transplantation (Christian T, et al: Am J Transplant 2003; 3: 1426)

0%10%20%30%40%50%60%70%80%90%

100%

0 1 3 6 12 24 36 48 60

Proportion of patients

Time Posttransplantation (months)

< 33%

33-36%

> 36%

Hematocrit

Hematocrit levels at different levels of kidney function (Christian T, et al, Am J Transplant 2003; 3: 1426)

Hematocrit levels at different levels of kidney function (Christian T, et al, Am J Transplant 2003; 3: 1426)

0%10%20%30%40%50%60%70%80%90%

100%

< 30 30-60 60-90 > 90

Prop

rtio

n of

pat

ient

s

GFR (ml/min)

< 33%33- 36%> 36 %

Hematocrit

Independent Risk Factors for Anemia in 4263 Kidney Transplant Recipients (Vanrenterghem Y, et al.

Am J Transplant 2003; 7: 835)

Independent Risk Factors for Anemia in 4263 Kidney Transplant Recipients (Vanrenterghem Y, et al.

Am J Transplant 2003; 7: 835)

Impaired renal function Use of ACEIs or ARBs (after excluding ~ 5-10% of

patients with post-transplantation erythrocytosis) Use of mycophenolate mofetil or azathioprine (no

patients on sirolimus included in analysis)

Sirolimus and Post-Transplant Anemia

p70s6k

PI 3kinase

mTOR

• SRL inhibits erythropoiesis at level of EPO receptor• Binding of EPO to receptor activates phosphorylating

enzymes including PI 3-kinase which is responsible for controlling cell survival and cell cycle progression

• SRL inhibits kinasep70S6k, a downstreamenzyme

Protein synthesis

EPO

R

Freedom from Cardiovascular Events in Type 1 Diabetics based on Anemia in the First 6 Months

(Djamali A, et al: 2003; 76:816)

Freedom from Cardiovascular Events in Type 1 Diabetics based on Anemia in the First 6 Months

(Djamali A, et al: 2003; 76:816)

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Hct < 30Hct > 30

P < 0.002

Cardiovascular event = CV death, MI, or hospitalization for CHF or angina,

Time post-transplantation (months)

Renal function at inclusion

Follow-up

150

140

110

100

90

80

120

70

130

Hem

oglo

bin

(g/l)

T0 M1 M6 M12M2 M24

Evolution of serum Hb level during the study

M3 M9 M18

59.0 %37.7 %

55.0 %36.2 %

54.5 %39.1 %Iron treatment

AB

Blood transfusion 1 (1.6 %) in A, and 5 (8.1 %) in B

89 %5600 ± 2700 UI/s

94 %6100 ± 3600 UI/s

92 %6500 ± 4400 UI/s

61 %4600 ± 3600 UI/s

41 %3600 ± 2100 UI/s

64 %4600 ± 3800 UI/s

Group A (red line): target Hb 130-150 g/L; group 2 (blue line): 105-115 g/l

Choukroun G eta l JASN 2011

B M6 M12 M24M-2M-4M-6

50

45

40

35

30

0

eGFR

(ml/m

in)

Group A Hb 13 – 15 g/dl

Group B 10.5 – 11.5 g/dl

Time after randomization

Renal functioneGFR (MDRD)

*

p < 0.025A GFR value of 8 ml/min were attributed to patients who reach ESRD between M12 and M24

A n 63 61 60 58B n 62 61 58 59

M9

*


Board Review Points– Risk Factors for

NODAT: Age, BMI, ethnicity, hepatitis C

– Tacrolimus more diabetogenic than cyclosporine

– Anemia related to antiproliferative immunosuppressants –MMF, AZA, and especially sirolimus

Board Review Points– Risk Factors for

NODAT: Age, BMI, ethnicity, hepatitis C

– Tacrolimus more diabetogenic than cyclosporine

– Anemia related to antiproliferative immunosuppressants –MMF, AZA, and especially sirolimus

Update Points– Sirolimus can be

diabetogenic– NODAT associated with

increased risk of cardiovascular disease and death

– Anemia linked to cardiovascular death and decreased patient survival after transplantation

– CAPRIT study suggests correction of anemia improves allograft function

Update Points– Sirolimus can be

diabetogenic– NODAT associated with

increased risk of cardiovascular disease and death

– Anemia linked to cardiovascular death and decreased patient survival after transplantation

– CAPRIT study suggests correction of anemia improves allograft function

Differential Diagnosis of Late Renal Allograft Dysfunction

Differential Diagnosis of Late Renal Allograft Dysfunction

↓ Immunosuppression– Calcineurin inhibitor

toxicity– BK virus nephropathy

↑ Immunosuppression– Late acute rejection– Chronic humoral

rejection– Recurrence of original

renal disease– De-novo renal disease

↓ Immunosuppression– Calcineurin inhibitor

toxicity– BK virus nephropathy

↑ Immunosuppression– Late acute rejection– Chronic humoral

rejection– Recurrence of original

renal disease– De-novo renal disease

Other Intervention– Medication effect

(NSAID)– Renal artery stenosis– Obstructive uropathy– Interstitial nephritis– Pre-renal (CHF,

cirrhosis)

Other Intervention– Medication effect

(NSAID)– Renal artery stenosis– Obstructive uropathy– Interstitial nephritis– Pre-renal (CHF,

cirrhosis)

Recurrence of Primary Renal Disease in the Transplanted Kidney

Recurrence of Primary Renal Disease in the Transplanted Kidney

Kasiske. In: Danovitch, ed. Handbook of Kidney Transplantation. 3rd ed. 2001.Kasiske. In: Danovitch, ed. Handbook of Kidney Transplantation. 3rd ed. 2001.

Frequency of Graft LossType Recurrence (%) Rate (%)

Focal glomerulosclerosis 23–43 11–50Membranoproliferative type I 20–40 33Membranoproliferative type II 88–100 50Membranous (recurrence) 10 < 1Membranous (de novo) 4–9IgA nephropathy 8–50 1Henoch-Schonlein purpura 75–88 20–40Anti-GBM nephritis 12 < 1Hemolytic-uremic syndrome 13–25 40–50Lupus nephritis < 1 NoneThrombotic microangiopathy 30–45 10–25

Frequency of Graft LossType Recurrence (%) Rate (%)

Focal glomerulosclerosis 23–43 11–50Membranoproliferative type I 20–40 33Membranoproliferative type II 88–100 50Membranous (recurrence) 10 < 1Membranous (de novo) 4–9IgA nephropathy 8–50 1Henoch-Schonlein purpura 75–88 20–40Anti-GBM nephritis 12 < 1Hemolytic-uremic syndrome 13–25 40–50Lupus nephritis < 1 NoneThrombotic microangiopathy 30–45 10–25

Chronic Allograft Nephropathy

IFTA Transplant Glomerulopathy

Chronic Allograft NephropathyChronic Allograft Nephropathy

Transplant Glomerulopathy

Chronic Allograft NephropathyChronic Allograft Nephropathy

• Proteinuria (1–3 g/24 h; but can be nephrotic with transplant glomerulopathy)

• Hypertension

• Elevated serum creatinine level

• Renal biopsy pathology– Vascular occlusive change– Interstitial fibrosis and tubular

atrophy (IFTA)– Transplant Glomerulopathy

• Proteinuria (1–3 g/24 h; but can be nephrotic with transplant glomerulopathy)

• Hypertension

• Elevated serum creatinine level

• Renal biopsy pathology– Vascular occlusive change– Interstitial fibrosis and tubular

atrophy (IFTA)– Transplant Glomerulopathy

Renal Toxicity of Calcineurin InhibitorRenal Toxicity of Calcineurin Inhibitor• Acute toxicity

• Chronic toxicity

• Occurs in native kidneys

Nephrotoxicity of calcineurin inhibitors: native kidneys

(Ojo AO et al NEJM 349:10, 2003)

Inflammation and Graft Survival Retrospective analysis of long-term

outcome of kidney grafts related to biopsy at 1 yr (N = 292)

6 patients with inflammation and no fibrosis

Pathologic diagnoses

– Acute rejection (n = 3)

– BK nephropathy (n = 1)

– Pyelonephritis (n = 1)

– Nonspecific findings (n = 1)

In patients with fibrosis, level of inflammation associated with worse outcome

No fibrosis or inflammation (n = 87)Fibrosis only (i score = 0, n = 131)

Fibrosis + moderate/severe inflammation (I score > 1, n = 19)

Fibrosis + mild inflammation (i score = 1, n = 34)

Cosio F, et al. Am J Transplant. 2005;5:2464-2472.

Gra

ft Su

rviv

al

12 24 600.3

0.6

0.7

0.8

0.9

1.0

36 48

0.5

0.4

Mos Post Transplant

NormalFibrosisFib + i=1Fib + i>1

861223216

182893

751072612

4055126

HLA Antibodies Predict Kidney Graft Failure

Terasaki PI, Ozawa M. Am J Transplant. 2004;4:438-443.

Gra

ft Fa

ilure

; 1-Y

ear F

ollo

w

Up

(% o

f Pat

ient

s)

*p=.007 vs. Ab-; †p=.05 vs. Ab-; ‡p=.00003 vs. Ab-.

n=2278 Patients in 23 Centers

58

Prediction of graft survival by molecularly diagnosed ABMR

Training set 112 patients

Validation set 154 patients

Cum

ulat

ive

surv

ival

Post biopsy time (days)

No DSA

DSA+ with no DARC

DSA+ with DARC+, C4d-

DSA+ with DARC, C4d+

p=0.32

p

Chronic Humoral Rejection (Transplant Glomerulopathy):

Treatment

Chronic Humoral Rejection (Transplant Glomerulopathy):

Treatment Treatment of accompanying cellular rejection ? Plasmapheresis ? IVIg ?Proteasome Inhibitors (eg Bortezemib) ? Complement Inhibitors (eg Ecalizumab)

Treatment of accompanying cellular rejection ? Plasmapheresis ? IVIg ?Proteasome Inhibitors (eg Bortezemib) ? Complement Inhibitors (eg Ecalizumab)

Renal Function Improves With Sirolimus After Early Cyclosporine Withdrawal

Renal Function Improves With Sirolimus After Early Cyclosporine Withdrawal

N = 525CyA = cyclosporine; SRL = sirolimus; Pred = prednisone Johnson, et al. Transplantation. 2001;72:777.

N = 525CyA = cyclosporine; SRL = sirolimus; Pred = prednisone Johnson, et al. Transplantation. 2001;72:777.

CONVERT Trial - Treatment RegimensSRL Conversion vs CNI Continuation

SRL Conversion• Day 1: Stop CNI; SRL, 12-20 mg x1• Day 2: SRL 4-8 mg/day • Days 5-7: Adjust to 8-20 ng/mL • MMF or AZA: Continue or stop • Continue corticosteroids

CNI Continuation•Continue CsA or tacrolimus(can switch CsA tacro)

•MMF or AZA: Continue or stop•Continue corticosteroids

Pre-Randomization:• Corticosteroids• MMF or AZA• CsA or Tacrolimus

Screening

2:1 Randomization

Routine follow-up per protocol

Schena FP, et al. Transplantation 2009; 87: 233.

(n=555) (n=275)

Summary

At 1 Year, conversion to SRL was associated with: Significantly higher GFR in patients remaining on therapy

with baseline GFR >40 mL/min Greater improvement in GFR in patients with less proteinuria

at baseline Significantly fewer malignancies No increase in acute rejection Excellent patient and graft survival Adverse events consistent with known SRL safety profile.

Schena FP, et al. Transplantation 2009; 87: 233.


Board Review Points– “Chronic allograft

nephropathy” is not s single histologic entity

– IFTA and Transplant Glomerulopathy can appear together or alone

– Conversion from CNIs to TOR inhibitors is not very successful in patients with even moderate renal impairment or preexisting proteinuria

Board Review Points– “Chronic allograft

nephropathy” is not s single histologic entity

– IFTA and Transplant Glomerulopathy can appear together or alone

– Conversion from CNIs to TOR inhibitors is not very successful in patients with even moderate renal impairment or preexisting proteinuria

Update Points– In the absence of

associated inflammation, fibrosis alone is not a strong harbinger of graft loss

– The late development of donor specific antibodies is now recognized as an important cause of graft loss; treatment options are suboptimal

Update Points– In the absence of

associated inflammation, fibrosis alone is not a strong harbinger of graft loss

– The late development of donor specific antibodies is now recognized as an important cause of graft loss; treatment options are suboptimal

Compared to the general population, which malignancy occurs after transplantation

with the highest relative risk?

Compared to the general population, which malignancy occurs after transplantation

with the highest relative risk?

A. Lymphoma B. Nonmelanoma skin cancer C. Kaposi’s sarcoma D. Lung cancer

A. Lymphoma B. Nonmelanoma skin cancer C. Kaposi’s sarcoma D. Lung cancer

Cancers that Are Increased Compared to the General Population

Much higher:- Skin*- Kaposi's*- Vulvovaginal*- Lymphoma*- Kidney

Not different:- Breast- Prostate- Testicular- Ovarian- Lung- Colon

Higher:- Uterine cervix*- Esophagus- Liver*

* Viral etiology known or suspected in most cases

Risk factors for SCC/BCC

Age at transplantation: 12x increase if >55y versus liver

Presence of AKs and viral warts or ‘keratotic’ lesions

Sirolimus in non-melanoma skin cancer

Baseline 12 months later

Euvard S, et al. NEJM 2012 367: 329

Sirolimus for Kaposi’s Sarcoma

Stallone G, et al. New Engl J Med 2005;352:1317

15 kidney transplant recipients Biopsy-proven Kaposi’s Sarcoma Treatment:

CsA was discontinued Sirolimus was begun

Outcome: No lesions at 3 months Confirmed by biopsy

Before After

Post-Transplant Lymphoproliferative Disease (PTLD)

Post-Transplant Lymphoproliferative Disease (PTLD)

Lymphoma occurring post-transplant related to immunosuppression– EBV mediated (80% of cases) polyclonal,

monoclonal)– Non-EBV mediated

Most within 2 years post-transplant– Increased risk with high immunosuppression

Lesions within transplanted organ are common Treatment: lower immunosuppression, anti-

CD20 therapy (rituximab), chemotherapy

Lymphoma occurring post-transplant related to immunosuppression– EBV mediated (80% of cases) polyclonal,

monoclonal)– Non-EBV mediated

Most within 2 years post-transplant– Increased risk with high immunosuppression

Lesions within transplanted organ are common Treatment: lower immunosuppression, anti-

CD20 therapy (rituximab), chemotherapy

Posttransplant Bone Disease:

1) Avascular necrosis

2) Osteopenia

Gradient Risk of Osteoporosis Fracture

Osteoporosis -2.5T

Compared to osteopenic patients in the general population, osteopenic transplant

recipients demonstrate

Compared to osteopenic patients in the general population, osteopenic transplant

recipients demonstrate

A. Better response to bisphosphonates B. More appendicular fractures than spinal

fractures C. Reduction in the frequency of fractures over

time D. Improvement after menopause

A. Better response to bisphosphonates B. More appendicular fractures than spinal

fractures C. Reduction in the frequency of fractures over

time D. Improvement after menopause

Answer: B

Bone Loss Posttransplant• Bone mass decreases 6-10% in first year• Bone loss continues after that but at a slower

rate• In long term renal transplants, 40-60% have

osteoporosis• Fractures occur in 8% within 8 years (more

common in diabetics)• Foot is the most common fracture site

0 6 18

0

-3

-6

-9

-12

Cha

nge

in B

one

Den

sity

(%)

Months after Transplantation

Percent change in lumbar spine density

Female

Male

All

Adapted from Julian BA et al. N Engl J Med 1991;325:544-50.

*

*

*

*

**

WHO Definitions

OSTEOPENIA

T score = -1 and -2.5

T = number of SD a BMD value deviates from sex & age matched controls

OSTEOPOROSIS

T < -2.5

0102030405060708090

100

Hip Hip Spine Wrist

Perc

enta

ge

(Femoral Neck) (Total Femur)

Percentage of patients with osteoporosis or osteopeniaaccording to region

Adapted from Cayco AV et al. Transplantation 2000;70:1722-8.

OsteoporosisOsteopenia

Contributing FactorsUnderlying renal osteodystrophyImmunosuppressants (steroids and ? calcineurin

inhibitors)Persistent hyperparathyroidismGonadal statusAgeGenderSmokingGenetic predisposition

Post transplantbone loss

Post menopausalosteoporosis

HyperparathyroidismAdynamic boneOsteomalaciaOsteoporosis

Appendicular>> spine and hip

Spine and hipLocation of fracture

Predictive value of BMD

Predicts risk of fracture

?? Predicts risk of fracture

Osteoporosis BMDOsteopeniaT= -1 to -2.5 OsteoporosisT= < -2.5

1200 mg Ca2+/day400-800mcg vit D/dayExercise?hormone replacement?vitamin D analogs

Check bone turnoverstatus and considerbiphosphonate therapy

Yearly BMDT= -1 to -2.5

Treatment

Bisphosphonates for Posttransplant Osteopenia

• Effective in increasing bone density• Little evidence for reducing risk of fractures• High incidence of inducing aydnamic bone

disease


Board Review Points– Nonimmune factors

associated with CAN: IR injury, CNI therapy, Hypertension

– Most common posttransplant malignancies related to viral infection

– Most common posttransplant cancer –nonmelanoma skin ca (squamous cell > basal)

– Rapid bone loss (within 6 months of transplantation - multifactorial

Board Review Points– Nonimmune factors

associated with CAN: IR injury, CNI therapy, Hypertension

– Most common posttransplant malignancies related to viral infection

– Most common posttransplant cancer –nonmelanoma skin ca (squamous cell > basal)

– Rapid bone loss (within 6 months of transplantation - multifactorial

Update Points– Conversion from CNI to

sirolimus for CAN may not be effective with pre-existing proteinuria or GFR < 40

– TOR inhibitors effective in treatment of Kaposi’s sarcoma, RCC, and nonmelanoma skin cancer

– Pre-existing or denovo anti-HLA antibodies increase the risk of graft loss

Update Points– Conversion from CNI to

sirolimus for CAN may not be effective with pre-existing proteinuria or GFR < 40

– TOR inhibitors effective in treatment of Kaposi’s sarcoma, RCC, and nonmelanoma skin cancer

– Pre-existing or denovo anti-HLA antibodies increase the risk of graft loss

Relisting for Transplant and Transplant RatesRelisting for Transplant and Transplant Rates

• Historically, around 40% of patients with failed transplants are relisted

• Kidney retransplantation shows similar survival benefits as the original transplant

• However, less than half of those relisted go on to receive new kidney transplants within 5 years

• Historically, around 40% of patients with failed transplants are relisted

• Kidney retransplantation shows similar survival benefits as the original transplant

• However, less than half of those relisted go on to receive new kidney transplants within 5 years

Ojo A et al. Transplantation 66: 1651-9, 1998

Increased Mortality after Allograft Failure

Kaplan B. et al. Am J Transplant 2: 970-4, 2002

●USRDS data●78564 Kidney Transplant Recipients from 1988 to 1998 ●Analyzed if survived > 1 month after allograft failure●Two fold higher death rate than patients on waiting list●Four fold higher risk of infection-related mortality

Risk of Continuing Immunosuppressive Therapy after a Failed Kidney Transplant

Risk of Continuing Immunosuppressive Therapy after a Failed Kidney Transplant

Smak Gregoor PJH et al. Clin Transplant 15: 297-401, 2001

Group A – early discontinuation

Group B – late discontinuation

Post-transplant inflammation and effect of transplant nephrectomy

Epo resistance index

CRP

(Lopez-Gomez JM et al. J Am Soc Nephrol 15: 2494-2501; 2004)

Nephrectomy after Kidney Transplant Failure

● USRDS; 10,951 patients with failed kidney transplants returning to dialysis b/w 1/94 and 12/04; 3451 (31.5%) received transplant nephrectomies● 32% reduction in relative risk of all cause mortality in the nephrectomy group● Retransplantation rate

• Nephrectomy group 10%• Non-nephrectomy group 4.1%

Ayus J.C. et al. J Am Soc Nephrol 21: 374-80, 2010

p

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