ledvina foto MUDr. J.Svojanovský Kidney transplantation I I . i n t e r n í k l i n i k a F N u s v. A n n y v B r n ě FN u sv Anny oficiální průhledné Renal replacement therapy excrect. function metabolic/ endocrin.f. availability 1. EXTRACORPORAL 1.1. hemodialysis 1.2. hemofiltration 1.3. hemodiafiltration + – immediat. 2. INTRACORPORAL 2.1. CAPD 2.2. APD (cycler) + – weeks 3. KIDNEY TRANSPLANTATION + + month- years Kidney transplantation (Tx) •best option for patient with chronic renal failure (recovery of both excrectory and metabolic/endocrine functions) •not a life-saving transplant (Tx is one of three options of renal replacement therapy) •hardest available (necessity of waiting or searching for suitable donor) •most improves the quality of life •most cost-saving Comparison of costs (in CZK) TRANSPLANT DONORS 1.LIVING DONORS A) GENETICALLY RELATED (parents, sibling, children) B) GENETICALLY NON-RELATED (spouse, friends, altruistic) Advantages: 1. no waiting for Tx ( avoidance of prolonged dialysis – time on dialysis may be a risk factor for poorer transplant outcome ) 2. the best organ quality (minimal ischaemic damage of graft, which can cause delayed graft function) 3. better graft and patient survival than cadaveric transplantation – regardless of genetic relationship and HLA mismatch (genetically non-relat. living donor is better than cadaveric HLA well-matched donor) Pre- emptive transplantation (prior to dialysis) – best outcome of all • 1. • 1.CADAVERIC DONORS organ obtained from someone who has died TRANSPLANT DONORS • •CADAVERIC (deceased) DONORS organ obtained from someone who has died • •Czech republic: 88% cadaveric Tx, 12% living donor Tx •Western countries: 50% cadaveric, 50% living donor • CADAVERIC ORGAN DONATION 1.VOLUNTARY individual has consented to donate his/her organs after the death (donor´s card, record in driving licence) 2.PRESUMED CONSENT it is presumed that ALL ADULT individuals AGREE to donate their organs after the death UNLESS they have registered an objection (Czech Rep., Austria, France, Portugal) 3.PRESUMED OBJECTION it is presumed that ALL ADULT individuals DON´T AGREE to donate their organs after the death CONSENT IS REQUIRED FROM FAMILY CADAVERIC DONOR (part I ) 1.PEOPLE WHO ARE BRAINSTEM DEAD 2.BRAIN DEATH = DEATH OF ORGANISM 3.The patient has irreversible BRAIN DAMAGE OF KNOWN CAUSE (head injury, brain haemorrhage, after long resuscitation, drowned people) 4.All efforts have been made to treat the patient condition and any associated problems CADAVERIC DONOR (part II ) • CRITERIA OF BRAIN DEATH 1.DEEP COMA with no signs of reactivity 2.MUSCLE ATONIA 3.AREFLEXIA OVER C1 4.NO SPONTANEOUS BREATHING 5.NO SIGNS OF BRAINSTEM IN BRAIN CAVITY BY BRAIN PANANGIOGRAPHY CONTRAINDICATIONS OF ORGAN TAKING 1.WRITTEN OBJECTION DURING THE LIFE 2.THE CAUSE OF DEATH IS NOT KNOWN 3.DONOR HAS: hepatitis B/C, HIV +, generalised infection, malignancy, disease of unknown cause ESSENTIAL CONDITION OF RENAL TRANSPLANTATION 1.DONOR 2.FINDING OF SUITABLE COUPLE RECIPIENT – DONOR 3.MAINTENANCE IMMUNOSUPPRESSION TO PREVENT REJECTION RECIPIENTS OF KIDNEY GRAFT •Patient with severe deterioration of renal function (prior to dialysis - pre-emptive living donor or cadaveric Tx) or patient on renal replacement therapy (dialysis method) due chronic renal failure •without contraindications •being on waiting list Chronic renal failure – renal replacement therapies Hemodialysis Peritoneal dialysis Cadaveric (deceased) donor kidney Tx Chronic renal failure Preemptive living-donor kidney Tx CONTRAINDICATIONS •1. PERMANENT (CONTINUING) •non-treatable chronic inflammatory disease •active chronic liver disease •malignancy (min. 2 years desease-free) •non-solvable abnormalities of distal urinary tract (urinary bladder, and urethra) •serious disease of other systems (e.g. cardiovascular) •diabetics with progressive foot necrosis § 2. TRANSIENT (TEMPORARY) •acute infection of various origin •disturbances of haemocoagulation •acute disease of gastrointestinal tract •any treatable temporary disease (cardiovascular complications, fracture,..) •obesity (BMI > 35) • • WAITING LIST •number of identification •personally dates (name etc) •blood group •HLA antigens •Panel Reactivity Antibodies (PRA = antileukocytes ab) (scale: 0 – 100 %) • WL TC Brno ASSESMENT OF SIUTABLE COUPLE RECIPIENT - DONOR 1.compatibility in blood group 2.negative result of cross – match 3.matching in HLA antigens on locusi A, B, DR best matching = full house = 000 MM (rare, e.g. siblings) • worst matching = none conformity = 2,2,2,MM • requirement depends on the titr of PRA (the highest titr of PRA the better matching is desirable) e.g. : PRA 80 – 100 % min. requirement : matching in 3 of HLA antigens (2 of them on DR locus ) BLOOD GROUP COMPATIBILITY •1. „0“ = UNIVERSAL DONOR „AB“ = UNIVERSAL RECIPIENT used in living kidney transplant •2. BLOOD GROUP COMPATIBILITY used in cadaveric kidney transplant BG donor recipient 0 ð 0 AB ð AB A ð A B ð B PANNEL REACTIVE ANTIBODIES (PRA) - detection of anti-HLA antibodies • Patient serum is incubated with lymphocytes from a panel of representative donors and complement. PRA is expressed as the percentage of donor wells with cell lysis (PRA 0% means no antibodies , PRA 60% should imply recipient antibodies against 60% of most commonly occuring antigens in that population). • Performed each 3 month whilst on waiting list • The higher a patient´s PRA, the higher a risk of hyperacute rejection after Tx •Sensitization events : previous transplant, pregnancy, blood transfusion, infection •. SYRINGE2 CROSS MATCH TEST (CM) •Lymphocytes from the donor (taking from spleen or lymphatic node) are incubated with serum from recipient in the present of complement. If the cells are killed, specific anti-donor antibodies are present. Positive CM is contraindication to Tx, because hyperacute rejection could occur. •Cross-match is performed before transplantations. SYRINGE2 ASSESMENT OF SIUTABLE COUPLE RECIPIENT - DONOR 1.compatibility in blood group 2.negative result of cross – match 3.matching in HLA antigens on locusi A, B, DR best matching = full house = 000 MM worst matching = none conformity = 2,2,2,MM • requirement depends on the titr of PRA (the higher titr of PRA the better matching is desirable) e.g. : PRA 80 – 100 % min. requirement : matching in 3 of HLA antigens (2 of them on DR locus ) IK 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 A No. of mismatche 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 B 0 0 0 1 1 1 2 2 2 0 0 0 1 1 1 2 2 2 0 0 0 1 1 1 2 2 2 DR 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 H L A S Y S T E M I. class ANTIGENS II. class ê A XX B XX LOCUS DR XX (=6Ag) ê number and position of o mismatches in A/B/DR represent so called COMPATIBILITY INDEX CI < 7 when anti HLA-Ab > 80% CI < 15 (= PRA) 20-79% CI no limitation 0-19% PRESERVATION OF CADAVERIC KIDNEYS I. •Simple cold preservation (at 4 st C) •(the vasculature of the kidney is flushed with a cold solution, which has the similar electrolyte content as intracellular fluid) •each kidney is then placed in a sterile plastic bag •a and finally in container surrounded with ice • •Warm ischemia (in minutes) period between circulatory arrest and start of cold storage (should be close to zero - the procedure takes only sec) LEDVINA PRESERVATION OF CADAVERIC KIDNEYS II. •Cold Ischemia (in hours) time from removing the kidney out of donor´s body to removing it from the box to perform the surgery most often is 18 – 20 hours •Time of manipulation ( in minutes) time from removing the preserved kidney from the box to termination of vascular anastomosis and restarting the blood stem in kidney in the recipient´s body most often 18 – 20 min • LEDVINA History of Tx • 23.12.1954 monozygotic twins • 21. 3.1959 dizygotic twins • 5. 4.1962 cadaveric • 23.11.1961 living donor (unsuccessful) • 21. 3.1966 living donor (successful) • 1972 cadaveric program • 30.11.1972 cadaveric logofnusa 1. successful Tx •23.12.1954 Boston •Joseph Murray a Hartwel Harrison • •Herrick´s twins •(Richard lived with functional graft 8 •years, Ronald died in 79 years with •normal kidney function) • ANd9GcSU844Puwug7moefAoMfKAKAeYVvbyVabnzqSjv40bY4Fiu1Sd3 SURGICAL TRANSPLANTATION PROCEDURE •Kidney graft is placed extraperitoneally in the right or left iliac fossa of the recipients. •Renal arteria and vein are anastomosed to external or internal iliac vessels. •After the vascular anastomosis is completed, the ureter is implanted into recipient´s urinary bladder. A sub-mucosal tunnel prevents reflux. TL - anastomoza • EARLY COURSE AFTER KIDNEY TRANSPLANTATION I. •IMMEDIATE FUNCTION •satisfactory urine output + blood concentration of nitrogen metabolities (urea, cretainine) continues to decrease + no supportive dialysis method is necessary. • •DELAYED FUNCTION •blood concentration of N-metabolities are still raising + supportive hemo- or peritoneal dialysis is therefore inevitable the urine output fluctuates from anuria to 1 L, sometimes even more. The cause is ATN (injure of ischemic origin). Renal function usually recovers after 2 weeks. LEDVINA EARLY COURSE AFTER KIDNEY TRANSPLANTATION II. •NON-VIABLE KIDNEY •afunction takes place •none signs of blood perfusion in the graft by Doppler sonography cause: irreversible ischeamic injury of the graft early trombosis of the main graft- vessels hyperacute rejection •GRAFT HAS TO BEEN REMOVED ledvina - dobře prokrvená transplanted kidney – proper blood perfusion transplanted kidney – hyperacute rejection ledvina - zabitá rejekcí IMMUNOSUPPRESSIVE THERAPY • • INDUCTION • • MAINTENANCE 1. • PILLS IMMUNOSUPPRESSIVE THERAPY •INDUCTION THERAPY •polyclonal Ab: Anti-thymocyte globulin •monoclonal Ab : antiCD3,anti CD52, antiCD25 • (anti-IL- 2 receptor´s Ab:Simulect, Zenapax) •Indication: 1) immunologically high - risk patients (high level of PRA, second /third grafting) • 2) treatment of severe acute rejection • PILLS PILLS MAINTENANCE IMMUNOSUPPRESSION •combination of 1.CORTICOSTEROIDS 2.CALCINEURIN INHIBITORS (cyklosporin A, tacrolimus) 3.ANTIPROLIFERATIVE AGENTS azathioprine (blocks salvage pathways of purine synthesis) mycophenolate (blocks de novo synthesis of purines) 4.„mTOR“ INHIBITORS (sirolimus, everolimus) • MAIN EFFECTS OF IMMUNOSUPPRESSANTS •CORTICOSTEROIDS inhibit signals of APCs to Th lymphocytes •CALCINEURIN INHIBITORS inhibit IL-2 synthesis by blocking the IL-2 gene transcription (pre–receptor IL-2 effect) •„mTOR“ INHIBITORS inhibit post-receptor IL-2 activation of Th lymphocytes •ANTIPROLIFERATIVE AGENTS inhibit proliferation (dividing) of effectory cells PILLS Most common adverse effects of IS • ALL OF THEM predisposition to infections, risk of malignancy (skin, breast..) PREDNISON MEDROL osteoporosis, Cushing habitus, GI problems, DM IMURAN bone marrow suppression, hepatotoxicity !!! MUST NOT BE TAKEN TOGETHER WITH ALLOPURINOL !!! – risk of BM suppresssion CELLCEPT nauzea, vomiting, diarrhoea, leukopenia, trombocytopenia, hepatotoxicity (can be taken with allopurinol) MYFORTIC leukopenie, trombocytopenie, hepatotoxicita (can be taken with allopurinol) SANDIMMUN NEORAL CONSUPREN, EQUORAL 3 H: hypertension + hirsutismus + hyperplastic gingivitis !!! NEPHROTOXICITY, neurotoxicity PROGRAF hypertension, allopecia, DM !!! NEFROTOXICITY, neurotoxicity RAPAMUNE, CERTICAN dyslipidemia, anemia, proteinuria Gingivitis hypertrofie dásní hrozná hypertrofie dásní slabší hirsutismus2 hirsutismus1 Hirsutismus Most common complication after kidney transplantation Treatment of hypertension after kidney transplantation •1. Ca-CHANNEL BLOCKERS renoprotective effect in regimes with CNI ( dilatation of art. afferens in glomerulus) •2. ACE-I a AIIA renoprotective, antiproteinuric and antiproliferative effect •3. BETABLOCKERS •4. RILMENIDIN, MOXONIDIN •5. OTHERS TARGET BLOOD PRESSURE 135/80 Treatment of hyperlipidemia after kidney transplantation •STATINS: (esp. fluvastatin, atorvastatin – no metabolization through cP450) •FIBRATS TARGET: total cholesterol < 5mmol/L LDL-cholesterol < 2mmol/L TAG < 2mmol/L Risk of drug interactions •During treatment with CyA or Tacrolimus (metabolization through cP450) •A. Increase level of CyA / Tacrolimus syst. antimycotics (Keto / Flukonazol) Diltiazem Verapamil Erytromycin, Claritromycin Amiodaron •B. Decrease level of CyA / Tacrolimus Phenytoin Rifampicin Carbamazepin Result of Tx •10-years survival: •recipients: 70-80% •grafts: 50-70% •both is better more than 20% in living donor Tx • •The most common cause of graft failure is death of recipient and chronic allograft nephropathy (CAN, or „chronic rejection“) •The most common causes of death of recipient are cardiovascular complications, infections and malignancy. • Comparison of graft survival from living donor and cadaveric donor • I I . i n t e r n í k l i n i k a F N u s v . A n n y v B r n ě Cause of death in patients with functioning graft Thank you for your attention