immunosuppressive renal transplantation: present status ......renal transplantation: present status...
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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
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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
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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
cPRA ≥980MMPrior LDPediatricTop 20%
LocalRegionalNational
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
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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.
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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)
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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
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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
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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
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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.
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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
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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.
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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.
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Biopsy-Confirmed Acute Rejection
Woodle ES, et al. Ann Surg. 2008;248(4):564-577.
27.3%
17.0%P=0.005
Prob
abili
ty (%
)
Years Posttransplant
Chronic low-dose corticosteroid therapyEarly corticosteroid withdrawal
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Chronic Allograft Nephropathyat 5 Years
CCSN=195
CSWDN=191 P Value
Biopsy-confirmed CAN 8 (4.1%) 19 (9.9%) 0.028
Woodle ES, et al. Ann Surg. 2008;248(4):564-577.
CAN=chronic allograft nephropathy; CCS=chronic low-dose corticosteroid therapy; CSWD=early corticosteroid withdrawal
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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
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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)
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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
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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) (
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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
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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
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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
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Friday, August
Post-Transplant Non-Infectious Complications
Donald E. Hricik, MD
9:30 a.m. - 11:00 a.m.
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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
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
Surgical Complications – Kidney Transplantation, continued
Surgical Complications – Kidney Transplantation, continued
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%
Cerebrovasculardisease
7%
Infection20%
Infection20%
Malignancy13%
Malignancy13%
Cardiovasculardisease
37%
Cardiovasculardisease
37%N = 47,581N = 47,581
All Patients
Cardiovasculardisease
48%
Cardiovasculardisease
48%
Malignancy6%
Malignancy6%
Infection17%
Infection17%
Cerebrovasculardisease
10%
Cerebrovasculardisease
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
Interim SummaryInterim Summary
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
*
Interim SummaryInterim Summary
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.
Interim SummaryInterim Summary
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
Interim SummaryInterim Summary
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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