Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015

Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015
Transplantation Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015

Transplantation Summary
Trends in Survival after transplant Donor and Recipient preparation HLA Matching Surgical Procedure Rejection diagnosis and treatment Immunosuppression Infectious complications after Transplant Other complications after Transplant Kidney Pancreas Update Immunology and Tolerance

Scope of problem 300,000 dialysis patients in US
55,000 patients on waiting List 17,000 recovered kidneys per year 11000 from “deceased donors” 6000 from living related donors 1000 kidneys not used after recovery Average waiting time 5 years !

History of Transplants
1950’s First attempted in Twins Still rejected due to minor antigen differences 1960’s First success Imuran and Prednisone, ATG 1983 Cyclosporine A introduced Dramatic improvement in graft survival Opened the era for success in Heart, lung, liver and other arenas.

Survival after Transplant
Patient Survival 1 yr LRD 98% DD 96.5 Allograft Survival 1 yr LRD 95% Allograft half-life LRD 21 years 5 yrs LRD 91 % DD 81 5 years LRD 76% DD 92% at 3 yrs DD 13.8 years

Transplant survival Relative risk of death Transplanted in 1993 = 1.0
Currently on Wait list = 1.7 These are the healthy ones! Patients not on wait list = 2.6

Trends in Transplantation
Overall Mortality is unchanged! Death with functioning graft increasing Donor Age older Recipient age is older Time on waiting list is longer Older, sicker patients are getting transplants

Transplant Update Annual Death Rates
Pts on list % Diabetic pts on list % Pts not on list 21 % Note that “death censored graft loss” is standard measure used in transplant outcome reports since this is desired outcome.

Donor Criteria Living related preferred Living unrelated next
Deceased Donor means longer wait Brain death required No Infection No malignancy (except CNS lymphoma) Preferrably under 60 years old Normal renal function

Recipient Preparation
Dialysis or near Dialysis GFR < 15 ml/min Compliant with meds and treatment Screen for infection, malignancy Blood tests and colonoscopy Screen for Heart Disease Higher risk for dialysis pts 25 y.o. on dialysis has same risk as 55 y.o. Risk for dialysis pt 10 fold higher at any age.

Surgical Transplantation
Procedure time hours Hernia incision to expose Iliac A and V, extend to expose bladder Retroperitoneal so recovery time from surgery is minimal Anastomose Artery and Vein Tunnel ureter into bladder Lich, Ledbetter

The native kidneys are left intact Unless problems with infection, HTN Allograft is easy to palpate, biopsy Ureter length is kept short Where does the ureter get its blood supply?

The native kidneys are left intact Unless problems with infection, HTN Allograft is easy to palpate, biopsy Ureter length is kept short Dual Blood supply from renal artery and from cystic artery. Ischemic ureter leads to stricture or leak. Warm ischemia time is kept to < 45 min Cold ischemia time up to 72 hours!

Typical Scenario: Multiple organ donor identified, blood typed Organ recovery team takes abdominal organs first, heart and lungs last. (bone skin corneas may be taken after heart stops). Organs are perfused and stored in preservative solution Mixture of high K, antioxidants Kept cold on ice. Lymph Nodes, spleen used for HLA typing

Cold Storage limits for organs: Heart 6 hours Lung 6 hours Pancreas 12 hours Liver 24 hours Kidney 72 hours + Primary graft failure rate higher after 72 hrs. Tissue weeks to months! Bone, skin, cornea, dura mater, etc.

Donors with AKI can still be used

UNOS master list used to determine where organs sent, which pts are best match Primary patient, plus a standby are called Crossmatch takes 6 hours Standby used if CM + or primary not available A single Txp team could then do SPK first (4-6 hours) Liver next (8-12 hours) Kidney last (2-4 hours)

Risk of Graft Loss Higher risk Lower Risk Deceased donor
Recipient over 60 Donor over 60 Recipient race Black / Hispanic Long Cold Ischemic time Previous Txp High PRA Lower Risk Living donor Recipient under 60 Donor under 60 Recipient race Asian Short cold ischemia Higher HLA match Low PRA

Expanded Donor Kidneys
Used when risk of Txp is better than life expectancy on dialysis Criteria Recipient/donor over 60 Diabetics over 40 Failing access for dialysis Patient with poor Quality of Life

HLA in transplantation
HLA Matching Main HLA groups A B C D C not important for transplant survival Host of minor antigens Most important antigens are B and D A and B are constitutive (always expressed) D antigen is inducible and responsible for more serious (vascular) rejections when it gets expressed.

Impact of Race on Allograft Survival
Registry data show that African American allograft survival now matches the white population for DDKT or LDKT since 2012. Reasons for the improvement: Change in UNOS scoring that eliminated the HLA B matching bias Shorter time on dialysis (which may be one of the biggest risk factors for allograft and pt survival) Improved insurance coverage for Txp meds.

UNOS Waiting list Update 2015
candidate Kidney Allocation Score (KAS): 1. Life Years from Transplant (LYFT): Determines the estimated survival that a recipient of a specific donor kidney may expect to receive versus remaining on dialysis. LYFT is primarily a measure of utility.  2. Dialysis Time (DT): Time spent on dialysis allows candidates to gain priority over the period they receive this treatment, adding the essential element of justice into the allocation system.  3. Donor Profile Index (DPI): Provides a continuous measure of organ quality based on clinical information. DPI increases individual autonomy by providing a better metric for deciding which organs are appropriate for which candidates. LYFT, DPI, and DT are incorporated so that kidneys are matched to candidates based on the expected survival of both the kidney and the recipient.

Transplant Costs Cost: Each year on dialysis: $27,000
Kidney Txp: $ 60,000 Islet cells ,000 Panc Txp alone ,000 SPK (K-P) ,000 Each year on dialysis: $27,000 LOS for uncomplicated Kidney: 5-7 days

Typical Kidney Course Creat Days after Transplant

Delayed Graft Function Course
Biologic agent used first days Creat Days after Transplant

Rejection Clinical Diagnosis: Biopsy findings: Hypertension
Increased Creatinine Decreased urine output Biopsy findings: Tubulitis – usual Vasculitis - bad Interstitial infiltration Fixing of C 4 d

Rejection Biopsy findings
Normal Cellular Rejection

Rejection Differential Diagnosis Not all ARF is rejection!
Drug toxicity Ureter complication Renal Artery Stenosis Contrast, Aminoglycoside toxicity Tubulo-interstitial Nephritis Pre or Post renal causes Recurrent disease (late)

Pattern of Acute Renal Failure after Transplant
Relative frequency Month after transplant

Rejection 4 Types: Hyperacute (preformed antibody) ADCC
Screened for with Lymphocyte crossmatch Immediate/on the OR table Rare due to testing ADCC Antibody dependent cellular cytotoxicity 1-4 days post op Rare occurance.

Rejection 4 Types: Acute Delayed Type or Chronic Rejection Most common
Due to Antigen presentation to an awakened immune system Cellular or Vascular Delayed Type or Chronic Rejection Must be differentiated from drug nephrotoxicity

Rejection and Complement
Circulating Proteins in blood: #1 Albumin #2 Immunoglobulin #3 Complement, esp C 3. Triggers of Complement fixation Ischemia reperfusion injury (IP - 10) Brain injury in donor Dialysis after transplant Infection

Basic Immunology Antigen presenting cells Macrophages Mesangial cells
Dendritic/Kupfer cells Reticuloendothelial system (RES) Endothelial cells and others once injured D antigen expression

Basic Immunology Cell mediated Immunity Antigens: T cell lymphocytes
Viruses, fungi, parasites, intracellular organisms T cell lymphocytes Cytotoxic Directly attack and kill APC, Organism usually Helper/ inducer cells Recruit more immune cells to respond IL-1 and IL-2 Suppressor cells Feedback to modulate immune response Important for tolerance.

Basic Immunology Humoral / Neutrophil system
Parallel to Cell mediated system Antigens: Usually bacterial cell polysaccharide Antibodies Produced by B lymphocytes May be specific or nonspecific IgG, IgM, others

Basic Immunology Humoral / Neutrophil system Immune complex formation
Occurs when Antigen fixed by antibody Specificity of ab for ag determines size and solubility of Immune complex formed Immune complex fixes complement Complement activation increases clearance of I-C by spleen, etc C3b chemotactic factor for PMN’s PMN’s attack with lysozyme

Basic Immunology comp Humoral Cell Mediated C3b
Antigen Presenting Cell Antigen plus HLA, coreceptors Humoral Cell Mediated T lymphocytes B cell Fc receptor comp C3b Cytotoxic Helper Suppressor Memory Pmn’s

Memory cell formation

Immunology of Rejection
HLA A and B are constitutive antigens HLA D is inducible antigen Infection, ischemia induce D antigen expression D antigen expression leads to vascular rejection which is worst type How does Bactrim SS MWF help?

HLA A and B are constitutive antigens HLA D is inducible antigen Infection, ischemia induce D antigen expression D antigen expression leads to vascular rejection which is worst type Bactrim SS MWF reduces bacteriuria

HLA A and B are constitutive antigens HLA D is inducible antigen Infection, ischemia induce D antigen expression D antigen expression leads to vascular rejection which is worst type Bactrim SS MWF reduces bacteriuria What is Acyclovir used for after Txp?

HLA A and B are constitutive antigens HLA D is inducible antigen Infection, ischemia induce D antigen expression D antigen expression leads to vascular rejection which is worst type Bactrim SS MWF reduces bacteriuria Acyclovir reduces shedding of Herpes Simplex virus in urine

Induction Immunosuppression
Biological Agents Steroid use vs steroid sparing Cellcept used in place of Imuran Calcineurin Inhibitors / Sirolimus

Biological Agents OKT-3 rarely used Thymoglobulin (rabbit) ATG (polyclonal) Basiliximab (Simulect) Chimeric Anti CD 25/ anti IL-2 receptor monoclonal Daclizumab (Zenapax) Humanized Anti CD 25 Monoclonal

Biological Agents Expensive, complex to use Use in high risk patients: High PRA Second transplant African American recipient Delayed Graft function

Biological Agents Basiliximab and Daclizumab Anti CD 25 monoclonals Do not deplete lymphocytes Will not stop ongoing rejection Other immunosuppression (CNI, steroid, MMF) should continue during use OKT-3, ATG Deplete lymphocytes, stop rejection, reduce or withhold other immunosuppression while in use

New Biological Agents coming soon: CTL4 Ig stimulates CTL4 coreceptor on T cell which leads to Decreased activation Apoptosis of the activated cell line LEA 29 Y a second generation CTL4 Ig

Regulation of T-Cell Activation
IL-2 APC CD 40 CD 80/86 CTL4 CD 25 T-Cell Negative stimulatory Positive stimulation IL -2 Receptor

Biological Agents recommendations Low risk patient: IL-2 receptor antibody, consider steroid sparing regimen High Risk patient Thymoglobulin plus 3 drug regimen CNI, Steroids, MMF

Maintenance Immunosuppression
Categories of Agents: Steroids Calcineurin Inhibitors Intracellular signal modifiers Cyclosporine, Tacrolimus, Prograf Adjuvant Agents Interfere with cell cycling Sirolimus, Rapamicin Cellcept (MMF) Imuran (azothioprine)

Where the drugs work Steroids: Toxic to lymphocytes Stops rejection
Inhibits release of IL-1 and IL-2 Inhibits chemotaxis

Where the drugs work Cyclosporin A, Tacrilimus Neoral, Prograf
Calcineurin Inhibitors (CNI) Multiple effects on proliferating immune cells Inhibits m-RNA producing IL-2 Negligible effect on pre-sensitized cells Does not stop ongoing rejection

Where the drugs work Imuran, Cellcept
Antimetabolite – blocks purine synthesis Interupt cell cycling/proliferation S Phase G 2 G 1 Mitosis

Where the drugs work Rapamicin Sirolimus
Calcineurin inhibitor with novel effects Receptor is called TOR Similar side effects to CYA and TAC May be used in conjunction with TAC and CYA.

Maintenance Immunosuppression
Three Drug Regimen: Steroid - prednisone Calcineurin Inhibitor Cyclosporine, Tacrolimus (Prograf) Adjuvant Agent Cellcept (MMF) Steroid Sparing Regimen: Prograf + MMF or Rapamicin

Drug Dosages Steroid CyA Imuran 10 mg daily or every other day
4-6 mg/Kg/day usually BID Levels 1-6 months: Level after 6 months: 100 – 250 Imuran 50 – 100 mg daily at bedtime

Drug Dosages Prograf Rapamicin Cellcept (MMF) 0.1 – 0.2 mg/kg/day
Usually about 5 mg BID Levels by ELISA Rapamicin 6 mg po load then 2 mg po daily Cellcept (MMF) 1000 mg BID, taper if low WBC or anemia, GI intolerance.

Drug Conversion for Cause
Refractory Rejection: CyA -> Tac Cardiovasc Dz: CyA -> Tac Rapa -> MMF Diabetes: decrease steroid dose Tac -> CyA may be helpful Hirsuitism: CyA -> Tac Gout: Azo -> MMF Gingival Hyperplasia: CyA -> Tac Stop dihydropyridines (procardia XL)

Tolerance is the best immunosuppression Has been known for years First seen in pts treated with Steroids/Imuran Patients present off all IS with stable renal function, normal biopsy. Cyclosporine seems to impair development of tolerance Has lead to research about T-Cell coreceptors

Tolerance Inducing Mechanisms
T- Cell deletion in Thymus Thy – 1 cells lead to rejection Peripheral T- Cell deletion IL-2 dependent FAS dependent Veto Cells So immune system activation is required but apoptosis is favored over rejection Peripheral Non-deletional mechanism Anergy – loss of response to antigen Thy 2 cells – regulatory/suppressor cell

Tolerance in Practice Today
For high PRA and Positive Crossmatch pts: IVIG/plasmapheresis before and after TXP Leads to decrease % Anti-donor antibody After Txp, Antidonor Ab returns but does not lead to rejection Anergy Increase in Bcl - 2

Tolerance “Tolerogenic Immunosuppression”
Rapamicin, Tacrilimus seem to be OK Cyclosporine blocks tolerance pathway Starzl Lancet 2003 Sayegh Annals of Surgery 2003

Complications of Transplant
Surgical Drug Side Effects Infections Malignancies Cardiovascular Bone Disease/hypercalcemia Polycythemia When to remove the allograft

Surgical Wound infection, dehiscence Ureter stricture or leak Bladder rupture if atrophic Renal artery Stenosis Renal Vein thrombosis DVT UTI, Pneumonia

Drug Side Effects Hypertension Diabetes Hirsuitism Tremor Renal Failure TTP Anemia/marrow suppression GI side effects N/V/D

Infections Pattern of infectious complications: First 30 days Period from 1 – 6 months After 6 months

Infections First 30 days Surgical complications UTI, wound, IV sites Pre-existing infections in recipient C-Dif, CMV, Herpes simplex Infection carried from donor CMV, West Nile Virus

Infections Period from 1 – 6 months Here There be Monsters Could be anything Need to be aggressive and thorough in approach

Infections After 6 months, again divides into 3 groups: Low risk group Low IS load, no serious rejection or infection Will mirror general population for the most part. High risk group Serious or recurrent bouts of rejection More prone to fungal, CMV infections Chronic infection group Need to consider withdrawal of Immunosuppression Hepatitis B, C, Difficult CMV, Virus associated Malignancy.

Complications after Transplant
Malignancy Due to reduced immune Surveillance, chronic virus affects Most common is ?

Complications after Transplant
Malignancy Due to reduced immune Surveillance, chronic virus affects Most common is ? Skin followed by Colon Lymphoma (Burkitt’s) Hepatoma (Hep B)

Hypertension Correlates with Age Diabetes Race Graft Function CNI use Steroids Graft Survival reduced if hypertension +

Hypertension Target SBP < 130 Chronic Allograft Nephropathy Proteinuria Target BP 125 / 75 Recommended Drugs: B blockers ACE inhibitors CCB’s and diuretics as needed.

New Onset Diabetes after Txp NODAT Decrease steroids if possible Consider Change from TAC to CyA. Cardiovascular Risk of a 25 y.o. recipient Equal to the risk for a 55 y.o. without renal disease. 10 fold higher at any age!

Hyperlipidemia Assume CV risk is present LDL target < 100 Consider decreasing Steroids Recommend changing CyA or Rapa to TAC. Thrombin Activatable Fibrinolysis Inhibitor TAFI levels are increased in Txp and Diabetes Increase risk of DVT, Unstable Angina.

Post Transplant Bone Disease Osteoporosis in % of pts BMD decreases 6-10 % per year Fractures occurrence Rate Diabetics: % Non diabetics: % Contributing Factors: Renal osteodystrophy, Immunosuppressives PTH, Age, Gender, Gonadal Status

Post Transplant Bone Disease Treatment Calcium mg Daily Vit D 400 – 800 mcg daily Exercise, Tai Chi Quit smoking! Fosamax 70 mg week or 5 mg daily for 6-12 months. Hypercalcemia also common

Polycythemia Due to extra erythropoietin production High Hct, hypertensive Treatment Phlebotomy ACE inhibitor use

When to remove Allograft
Allograft Nephrectomy is indicated: Unusual – some pts have more than one allograft! For refractory infection Most commonly for terminal rejection, after graft has failed and pt is back on dialysis FUO, FTT, may thrombose or rupture.

Transplantation Summary
Trends in Survival after transplant Donor and Recipient preparation HLA Matching Surgical Procedure Rejection diagnosis and treatment Immunosuppression Infectious complications after Transplant Other complications after Transplant Kidney Pancreas Update Immunology and Tolerance

Kidney – Pancreas Transplant

Rejection Diagnosis: Hyperglycemia May also occur in face of high steroids, sepsis Increased serum amylase level Decreased urine amylase level in bladder anastomosis patients. Maintenance immunosuppression Tacrolimus/Cellcept preferred combo Avoid steroids if possible

Rejection rates improved Options for pancreas placement: Attach to bladder Dumps lots of bicarb, Cystitis Easy to identify rejection by measuring urine amylase Attach to intestine (enteric anastomosis) Eliminates problems with acidosis and cystitis Rejection harder to identify early.

Surgical Complication rate 10% at 1 yr. Immunologic Failure Rates: Type of Txp % graft loss at 1 yr. PAK 7 % PTA 8 SPK 2 Gruessner, Clinical Transplantation 2002, p 52

Effect of Pancreas Txp on outcomes No significant QOL improvement compared to kidney alone Insulin free for diabetics 50 – 90 % Neuropathy improves Microvasculature improves Retinopathy – no improvement Survival improved compared to wait list pts May be slightly better than kidney alone.

Ethnic Disparities in Transplant
Rate of transplantation for AA lower than any other ethnic group % of AA patients hearing about the option of transplant is only about 70% of other groups Rate of referral once they hear about transplant is only about 70% of other groups.

Socioeconomic Factors: 70% of AA children born into single parent homes Less likely to have insurance Barriers to travelling to appts Less likely to be available when called No phone or won’t answer due to debtors Higher PRA, fewer AA donors Mistrust of system

Insurance Impact on Transplant: Compared to pts of other ethnic groups with same insurance, % of eligible AA pts get to transplant HMO rates % of eligible pts get to transplant, evenly across races Example of Rationing by Inconvenience Military patients demonstrate NO disparity in rates of transplant or Graft survival.

Ethnic Disparities in Transplant this may be changing…
Immunologic Factors Once transplanted, AA pts fare worse AA with 0 MM does about as well as Caucasian with 6 MM and 1 rejection episode in first year. Require higher doses of Immunosuppression Don’t tolerate steroid or other drug withdrawal nearly as well as other groups Higher levels of IL-6, CD-80, TGF-B, Endothelin, Renin. More Hypertensive, which worsens overall survival

Immunology of Rejection The Future
Protein Tyrosine Kinases Src FAK Paxillin Akt PPARS peroxisome proliferator activated receptors Ligands for PPARs tend to decrease inflammatory response Include Piaglitizone, Lopid

Immunology of Rejection The Future
Chemokine receptors: CXC R3 antibody prolongs graft survival in monkey models Also in clinical trials: CCR-1, CCR-5 which bind CK’s and prevent activation of receptor. Soluble Complement Receptor CR-1 Trypriline decreases synthesis of complement WY ligand for PPAR

Chemoattractant Cytokines (chemokines) Leukocyte recruitment Most important CK is CXC Receptor is CXC-R3 Transmembrane protein Activation of CXC R3 activates rejection pathway IP-10 Activates CXC R3 Both CXC R3 and IP-10 are present in urine of pts who are rejecting

Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015

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Jeffrey J. Kaufhold, MD FACP Nephrology Associates July 2015

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