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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 98% 96.5 Allograft Survival 1 yr LRD DD LRD DD 95% 96.5 5 yrs LRD 21 years 91 % 81 5 years LRD DD DD 13.8 years Allograft half-life LRD DD 76% 92% at 3 yrs Transplant survival Relative risk of death Transplanted in 1993 = 1.0 Transplanted in 1998 = 0.74 Currently on Wait list = 1.7 These Patients are the healthy ones! 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 6.3 % 10.8 % 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 Screen tests and colonoscopy 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 2 - 4 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 Surgical Transplantation 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? Surgical Transplantation 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! Surgical Transplantation 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 Surgical Transplantation Cold Storage limits for organs: Heart Lung Pancreas Liver Kidney Primary Tissue Bone, 6 hours 6 hours 12 hours 24 hours 72 hours + graft failure rate higher after 72 hrs. weeks to months! skin, cornea, dura mater, etc. Donors with AKI can still be used Surgical Transplantation 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 Deceased donor Recipient over 60 Donor over 60 Recipient race Lower Risk Living donor Recipient under 60 Donor under 60 Recipient race Black / Hispanic Long Cold Ischemic time Previous Txp High PRA 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: Kidney Txp: Islet cells Panc Txp alone SPK (K-P) $ 60,000 53,000 105,000 130,000 Each year on dialysis: $27,000 LOS for uncomplicated Kidney: 5-7 days Typical Kidney Course Creat 8 7 6 5 Typical 4 3 2 1 0 1 2 3 4 5 6 7 Days after Transplant 8 9 10 Delayed Graft Function Course Biologic agent used first 10-14 days Creat 8 7 6 5 4 Delayed 3 2 1 0 1 2 3 4 5 6 7 Days after Transplant 8 9 10 Rejection Clinical Diagnosis: 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) Relative frequency Pattern of Acute Renal Failure after Transplant 45 40 35 30 25 20 15 10 5 0 rejection Drug tox surgical ATN Recurrent 1st Month 2nd to 6th 6 to 12 after 12 Month after transplant Rejection 4 Types: Hyperacute (preformed antibody) 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 Most common Due to Antigen presentation to an awakened immune system Cellular or Vascular Delayed Must Type or Chronic Rejection be differentiated from drug nephrotoxicity Rejection and Complement Circulating Proteins in blood: #1 #2 #3 Albumin Immunoglobulin 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: 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 Antigen Presenting Cell Antigen plus HLA, coreceptors Humoral Cell Mediated T lymphocytes Fc receptor comp Cytotoxic Helper Suppressor Memory Pmn’s B cell C3b 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? 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 Bactrim SS MWF reduces bacteriuria 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 Bactrim SS MWF reduces bacteriuria What is Acyclovir used for after Txp? 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 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 Induction Immunosuppression 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 Induction Immunosuppression Biological Agents Expensive, complex to use Use in high risk patients: High PRA Second transplant African American recipient Delayed Graft function Induction Immunosuppression 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 Induction Immunosuppression New Biological Agents coming soon: CTL4 Ig stimulates to LEA a CTL4 coreceptor on T cell which leads Decreased activation Apoptosis of the activated cell line 29 Y second generation CTL4 Ig Regulation of T-Cell Activation IL-2 APC CD 40 CD 80/86 CD 25 CTL4 Negative stimulatory T-Cell Positive stimulation IL -2 Receptor Induction Immunosuppression 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 Cyclosporine, Tacrolimus, Prograf Adjuvant Agents Interfere signal modifiers 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 G2 G1 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 10 mg daily or every other day CyA 4-6 mg/Kg/day usually 100 - 150 BID Levels 1-6 months: 250 - 400 Level after 6 months: 100 – 250 Imuran 50 – 100 mg daily at bedtime Drug Dosages Prograf 0.1 – 0.2 mg/kg/day Usually about 5 mg BID Levels 5-15 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: Tac decrease steroid dose -> CyA may be helpful Hirsuitism: CyA -> Tac Gout: Azo -> MMF Gingival Hyperplasia: CyA -> Tac Stop dihydropyridines (procardia XL) Immunology of Rejection 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 Peripheral T- Cell deletion Thy – 1 cells lead to rejection 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 Complications of Transplant Surgical Wound infection, dehiscence Ureter stricture or leak Bladder rupture if atrophic Renal artery Stenosis Renal Vein thrombosis DVT UTI, Pneumonia Complications of Transplant Drug Side Effects Hypertension Diabetes Hirsuitism Tremor Renal Failure TTP Anemia/marrow suppression GI side effects N/V/D Complications of Transplant Infections Pattern First of infectious complications: 30 days Period from 1 – 6 months After 6 months Complications of Transplant Infections First 30 days Surgical complications UTI, wound, IV sites Pre-existing C-Dif, CMV, Herpes simplex Infection infections in recipient carried from donor CMV, West Nile Virus Complications of Transplant Infections Period Here from 1 – 6 months There be Monsters Could be anything Need to be aggressive and thorough in approach Complications of Transplant 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) Complications of Transplant Hypertension Correlates with Age Diabetes Race Graft Function CNI use Steroids Graft Survival reduced if hypertension + Complications of Transplant Hypertension Target SBP < 130 Chronic Allograft Nephropathy Proteinuria Target BP 125 / 75 Recommended B Drugs: blockers ACE inhibitors CCB’s and diuretics as needed. Complications of Transplant 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! Complications of Transplant 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. Complications of Transplant Post Transplant Bone Disease Osteoporosis in 40- 60 % of pts BMD decreases 6-10 % per year Fractures occurrence Rate Diabetics: Non diabetics: Contributing Renal 40-50 % 10-15 % Factors: osteodystrophy, Immunosuppressives PTH, Age, Gender, Gonadal Status Complications of Transplant Post Transplant Bone Disease Treatment Calcium 1200 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 Complications of Transplant 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 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 Kidney – Pancreas Transplant 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. Kidney – Pancreas Transplant Surgical Complication rate 10% at 1 yr. Immunologic Failure Rates: Type PAK PTA SPK of Txp % graft loss at 1 yr. 7% 8 2 Gruessner, Clinical Transplantation 2002, p 52 Kidney – Pancreas Transplant 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. Ethnic Disparities in Transplant 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 Ethnic Disparities in Transplant Insurance Impact on Transplant: Compared to pts of other ethnic groups with same insurance, 70-80 % of eligible AA pts get to transplant HMO rates 70-80 % of eligible pts get to transplant, evenly across races Example Military of Rationing by Inconvenience patients demonstrate NO disparity in rates of transplant or Graft survival. Ethnic Disparities in Transplant this may be changing… Immunologic Factors Once AA transplanted, AA pts fare worse 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 WY14643 ligand for PPAR Immunology of Rejection 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