University:
Michigan State University
Course:
MED 615 | Gastroenterology Clerkship
Academic year:

2020
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327

Pages:

83
Author:

descorrer7yy

Renal transplantation (RT) Fall 2021 References: • DiPiro. Solid Organ Transplantation • Koda-Kimble. Solid Organ Transplantation • Guidelines on Renal Transplantation (European Association of Urology 2010). • KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney International advance online publication, 21 October 2009 EPIDEMIOLOGY & ETIOLOGY • RT is the preferred long-term therapeutic option for most pts with ESRD • the greatest improvement in QoL • HD catheter-related infections, PD-associated peritonitis & scheduled dialysis treatments are avoided • Dietary restrictions are fewer • DM, HTN, & glomerulonephritis are the most common causes of ESRD leading to RT (70% of pts) PHYSIOLOGIC CONSEQUENCES OF TRANSPLANTATION • Standard formulas used to predict drug dosing may be inaccurate immediately following transplantation • anemia, calcium & phosphate imbalance, & altered lipid profiles, need a few weeks to resolve • →continuation of calcitriol, calcium supplementation, &/or phosphate binders may be needed PHYSIOLOGIC CONSEQUENCES OF TRANSPLANTATION (cont’d) • Delayed graft function (DGF): need for dialysis in the first 7 postop days or failure of SrCr to ↓ by 30% of pretransplantation value • in primary cadaveric RT is 8-50% • Dif. ds: ureteral obstruction, thrombosis, or leak or vascular stenosis or thrombosis • Primary cause: acute tubular necrosis (ATN) • ↑ risk: prolonged ischemia in donor (e.g., cardiac arrest) • Cyclosporine & tacrolimus may be involved in prolongation of ATN • DGF predisposes patients to acute rejection, PATHOPHYSIOLOGY OF REJECTION • activation of alloreactive T cells & antigenpresenting cells (APC) (B cells, lymphocytes, macrophages, & dendritic cells). • Acute allograft rejection is caused primarily by infiltration of T cells into allograft → inflammatory & cytotoxic effects on graft • Chronic rejection: complex interactions between allograft & cellular cytokines, cell-to-cell interactions, CD4+ & CD8+ T cells, & B cells → graft loss if adequate immunosuppression is not maintained T cell activation & site of action of immunosuppressive drugs. Rejection mechanism • Antigen MHC II molecule complexes initiate activation of CD4 T cells: • A costimulatory signal is required for T-cell activation: CD80/CD86 (from APC) – CD28 interaction (from T-cell) - blocked by belatacept. • MHC-peptide complexes are recognized by Tcell recognition complex (TCR) → costimulatory signal → activation of 2nd messengers, e.g. calcineurin • Calcineurin is phosphatase [removes phosphates from nuclear factors (NFAT-P)] allowing them to enter nucleus→ nuclear factors bind to IL-2 promoter gene → IL-2 gene transcription • Cis (CYC & TAC) bind to immunophillins (cyclophilin & FKB, respectively) → complex (-) calcineurin & calcineurin-catalyzed dephosphorylation of NFAT into nucleus. [alpha][beta]-TCR mAb, [alpha] [beta]-T cell receptor monoclonal antibody; APC, antigen-presenting cells; ATG, antithymocyte globulin; IL-2, interleukin-2; IL-2R, interleukin-2 receptor; mAb, monoclonal antibody; MHC, major histocompatibility complex antigen; MMF, mycophenolate mofetil; NAFT, nuclear factor of activated T cells; TCR, T cell receptor T cell activation & site of action of immunosuppressive drugs. Rejection mechanism (cont’d) • Interaction of IL-2 with IL-IL-2R → cell proliferation & production of cytokines by T cell • Sirolimus (rapamycin) (& everolimus) work downstream of IL-2R, biding to FKBP → their complex binds to & inhibits mTOR, kinase involved in cell cycle progression (proliferation). • MPA & AZA (-) NA synthesis → (-) proliferation • Muromonab (OKT3) (-) TCR function via interaction with its CD3 component. • Daclizumab & baziliximab block IL-2 signaling by interacting with alpha-subunit of IL-2R complex (CD25). • Antibodies that block TNF effect ??? • Alemtuzumab binds to CD52, marks cells for destruction → depletes CD52+ cells. [alpha][beta]-TCR mAb, [alpha] [beta]-T cell receptor monoclonal antibody; APC, antigen-presenting cells; ATG, antithymocyte globulin; IL-2, interleukin-2; IL-2R, interleukin-2 receptor; mAb, monoclonal antibody; MHC, major histocompatibility complex antigen; MMF, mycophenolate mofetil; NAFT, nuclear factor of activated T cells; TCR, T cell receptor PATHOPHYSIOLOGY OF REJECTION (cont’d) • To ↓rejection & ↑survival rates well-matched, according to HLA-A, -B, & -DR, kidneys are allocated • If pt has (+) panel reactive antibody [PRA] >1020%), (-) T-cell crossmatch is required prior to transplantation • Transplanted organs must be matched for ABO blood group compatibility with recipient to avoid hyperacute rejection. • Excessive cold ischemia time (>36 hrs) & donor age > 60 yrs also ↑chance of rejection HYPERACUTE REJECTION • May be evident within min. of transplantation if preformed donor-specific antibodies are present • antibody-dependent, cell-mediated cytotoxicity or activation of complement cascade • Ischemic damage to microvasculature → tissue necrosis • Now is uncommon because transplant donors are matched for ABO blood groups & crossmatch testing is done to determine presence of donor-specific lymphocytotoxic antibodies ACUTE CELLULAR REJECTION • Is most common in the first few months but can occur at any time • Is mediated by alloreactive T-lymphocytes that infiltrate allograft through vascular endothelium • Local release of lymphokines → attraction & stimulation of macrophages → tissue damage through delayed hypersensitivity-like mechanism • Nonspecific signs & symptoms (S&S): pain & tenderness over graft site, fever, & lethargy • Generally is reversible within 1-3 days, if treated ACUTE CELLULAR REJECTION (cont’d) • • • • May affect up to 20% of pts during first 6 mths Abrupt ↑ in SrCr ≥30% over baseline Diffuse infiltrate of lymphocytes on biopsy HTN often worsens & edema & weight gain are common • Symptomatic azotemia may develop in severe cases • Needs appropriate adjustments in pharmacotherapy due to ↓ renal function HUMORAL REJECTION (vascular rejection) • Antibody-mediated process directed against HLA antigens of donor vascular endothelium • Capillary deposition of Igs, complement, & fibrinogen • < common than cellular rejection • Occurs in the first 3 months after transplantation. • Is > common when antilymphocyte antibodies are used for rejection prophylaxis • ↑ risk: female gender, ↑ PRA, cytomegalovirus seropositivity, positive crossmatch, & prior sensitization to OKT3 (muromonab CD3). • HW: Treatment? CHRONIC REJECTION • Major cause of late graft loss - is not reversible with any of immunosuppressive agents currently available • May be slow & indolent form of acute cellular rejection • Involvement of humoral immune system & antibodies against vascular endothelium may play role • Is the most common cause of graft loss in late post-transplantation period (>1 year) • May present as early as 3 months • HTN, proteinuria, & progressive ↓ in renal function CHRONIC REJECTION (cont’d) • HW: Factors that contribute to development of chronic allograft nephropathy? TREATMENT OF REJECTION DESIRED OUTCOME • Immediately following surgery, to prevent hyperacute & acute rejection; • High doses of immunosuppressants → rapid dosage reductions are frequently used (to avoid nephrotoxicity, infection, thrombocytopenia, & drug-induced DM) GENERAL APPROACH TO TREATMENT Multidrug approach: 1. many agents have overlapping & potentially synergistic MoA 2. use of lower doses of individual agents →↓ severity of dose-related ADRs • usually, pts receive IV methylprednisolone during perioperative period • → maintenance immunosuppressive regimen • protocols generally combine drug from 2-3 of the following classes: calcineurin inhibitors + antimetabolites or sirolimus/everolimus + corticosteroids GENERAL APPROACH TO TREATMENT (cont’d) • If rejection is suspected, biopsy can be done for definitive diagnosis or pt may be empirically treated for rejection: • Usually methylprednisolone 500-1,000 mg IV for 1-3 doses. • If S&S of rejection are resolved → maintenance immunosuppressive regimen is generally modified • If rejection is confirmed by biopsy, treatment may be based on severity • Polyclonal or monoclonal antibodies are used for moderate to severe rejections or those which 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guideline: induction • starting combination of immunosuppressive medications before, or at the time of, kidney transplantation. • including induction therapy with biologic agent as part of the initial immunosuppressive regimen in KTRs. • IL2-RA be the first-line induction therapy. • using lymphocyte-depleting agent, rather than IL2-RA, for KTRs at high immunologic risk. Acute Rejection • Primary goal: minimize intensity of immune response & prevent irreversible injury to allograft Options: (a)↑ doses of current immunosuppressive drugs (b) “pulse” corticosteroids with subsequent dose taper – in most cases (c) addition of another immunosuppressant indefinitely (d) short-term treatment with polyclonal or monoclonal antibody • African Americans do not respond as well to corticosteroids as non– African Americans → antithymocyte globulin may be preferable Maintenance Therapy • Goal is to prevent acute & chronic rejection while minimizing drug-related toxicity • With time, risk of acute rejection ↓→ gradually ↓ doses of immunosuppressants or in some cases totally withdraw them over 6-12 months to ↓ADRs • Calcineurin inhibitors generally are central component in most maintenance regimens KDIGO guideline: maintenance therapy • using the lowest planned doses of maintenance immunosuppressive medications by 2–4 months after transplantation, if there has been no acute rejection. • CNIs be continued rather than withdrawn. • If prednisone is being used beyond the first week after transplantation, guideline suggests prednisone be continued rather than withdrawn. General approach to solid-organ transplant immunosuppression. (BUN, blood urea nitrogen; CI, calcineurin inhibitor; CSA, cyclosporine; IL2RA, interleukin-2 receptor antagonist; LFTs, liver function tests; MMF, mycophenolate mofetil; OKT3, muromonab CD3; RATG, rabbit antithymocyte immunoglobulin; Scr, serum creatinine; SRL, sirolimus; TAC, tacrolimus.) General approach to solid-organ transplant immunosuppression (cont’d) CALCINEURIN INHIBITORS (CIs) • Cyclosporine (CSA) & tacrolimus (TAC) are CIs currently used for most solid-organ transplant recipients • Today, TAC is used more commonly than CSA • CIs ↓incidence & severity of acute rejection, incidence of chronic rejection • But: long-term complications, e.g.,HTN & compromised kidney function, have not changed with use of CIs Pharmacology/MoA • (-) T-cell proliferation by (-) production of IL-2 & other cytokines by T cells • Bind to unique cytoplasmic immunophilins: CSA to cyclophilin & TAC to FK-binding protein-12 (FKBP12) • In both cases, drug–immunophilin complex inhibits action of calcineurin, enzyme that (+) NFAT (responsible for transcription of several key cytokines necessary for T-cell activity, including IL-2) • IL-2 is potent growth factor for T cells & is responsible for activation & clonal expansion Pharmacokinetics • low bioavailability of ~30% for both drugs (range: 5-60%) • CSA depends on bile for intestinal absorption→> interpatient & intrapatient variability • Microemulsion formulation (NEORAL)is selfemulsifying & forms microemulsion spontaneously with aqueous fluids in GIT → < dependent on bile for absorption than conventional CSA (SANDIMMUNE)→ > rate & extent of absorption & < intraindividual variability in pharmacokinetics • Microemulsion formulation is not bioequivalent to conventional & should not Efficacy • Significantly improved outcomes of solid-organ transplantation in terms of pt & graft survival • Equivalent efficacy of TAC with either formulation of CSA as primary immunosuppression • Primary advantage of CI monotherapy: avoidance of long-term corticosteroids • Primary disadvantage: higher incidence of rejection → are rarely used as monotherapy Adverse Effects • Nephrotoxicity: ↑ SrCr, ↓GFR, proteinuria, & hyperkalemia (TAC=CSA). • Neurotoxicity (TAC>CSA): tremors, HA, & peripheral neuropathy; occasionally, seizures • CSA: > HTN & hyperlipidemia compared to TAC • Hyperglycemia is > common with TAC than CSA • CSA: cosmetic changes (hirsutism & gingival hyperplasia) → convert to TAC or maintain proper hygiene in pts who cannot be switched to TAC • TAC: alopecia, usually self-limiting & reversible Comparison of Common Adverse Effects of Maintenance Immunosuppressants Hepatotoxicity Osteoporosis Acne Seizures CIs Nephrotoxicity Two types: • Acute is dose dependent & reversible, but chronic nephropathy is > common. • Clinical manifestations: ↑SrCr & BUN, hyperkalemia, hyperuricemia, mild proteinuria, & ↓ fractional excretion of Na • Predominant mechanism: renal vasoconstriction, primarily of afferent arteriole → renal vascular resistance, ↓ renal blood flow, ↓ GFR & ↑ proximal tubular Na reabsorption with ↓ urinary Na & K excretion CIs Nephrotoxicity (cont’d) Measures to ↓ CIs nephrotoxicity: 1. Delaying administration immediately postoperatively in patients at high risk for nephrotoxicity (using IL-2 receptor antagonist or antilymphocyte globulin for induction) 2. Monitoring CI trough blood levels & ↓dosage if excessive 3. Avoiding other nephrotoxins (e.g., aminoglycosides, amphotericin B, NSAIDs) when possible • It is often difficult to differentiate CIs nephrotoxicity from renal allograft rejection • Even biopsy findings may be similar Differential Diagnosis of Acute Rejection & Cyclosporine or Tacrolimus Nephrotoxicity Drug–Drug & Drug–Food Interactions • CIs are substrates for CYP3A4 & P-glycoprotein • Inhibitors of CYP3A4, such as diltiazem or erythromycin, can ↑ CI concentrations significantly • Some centers routinely prescribe CYP3A4 inhibitors to ↓ dosage & cost of CI therapy • Drugs that induce CYP3A4 activity (phenytoin or rifampin) can ↓ drug concentrations significantly • In vitro data: drugs that ↑ pH of GIT, such as Mg, Al-, or Ca- antacids, NaHCO3, & MgO, can cause a pH-mediated degradation of TAC → should be separated from TAC by at least 2 hrs Effect of Concomitant Drug Administration on Cyclosporine, Tacrolimus, & Sirolimus Drug–Drug & Drug–Food Interactions • CSA & (<)TAC are also inhibitors of CYP3A4 • ↑ risk of statins ADRs → pts should be monitored for S&S of myopathy when receiving statins in combination with CSA or TAC • Consistency in administration of CI with regard to food intake is important • High-fat meals can ↑ both plasma clearance & Vd of CSA by > 60% • Food ↓ rate & extent of TAC absorption & highfat meal may further delay gastric emptying & ↓ TAC conc. • Grapefruit juice ↑ both CSA & TAC conc. (furocoumarins, such as quercetin, naringin, & bergamottin are potent inhibitors of CYP3A4) Dosing & Administration • Initial oral CSA : 8-18 mg/kg/d BID Q 12 hrs • Oral TAC doses: 0.1-0.3 mg/kg/d BID Q 12 hrs • A recently-approved tacrolimus ER tablet (Envarsus®) has > bioavailability than IR formulation & lower recommended daily starting dose range of 0.11-0.17 mg/kg/day. • Astagraf XL® or Advagraf® (TAC extendedrelease capsule) may need ↓ dose • If oral administration is not possible, both drugs can be administered IV at 1/3 oral dosage (firstpass metabolism) Blood concentrations (cont’d) • Therapeutic range for Cpeak CSA levels is 1,500-2,000 ng/mL for the first few mths after transplant & 700-900 ng/mL after 6-12 mths. • Therapeutic range for TAC trough blood conc: 12-15 ng/mL (1-3 mth), 10-12 ng/mL (3-6 mths), 8-10 ng/mL (6-12 mths) & 6-8 ng/mL (>12 mth)after transplantation. • Drug conc should be measured frequently (daily or 3 t/wk) following initiation of drug & during stabilization period after transplantation • After some time, conc are measured usually monthly CORTICOSTEROIDS • Continue to be cornerstone of immunosuppression regimens • The most commonly used are methylprednisolone & prednisone Pharmacology/MoA • Block cytokine activation by binding to corticosteroid response elements, thereby inhibiting IL-1, IL-2, IL-3, IL-6, γ- Ifn, & TNF-α synthesis • Interfere with cell migration, recognition, & cytotoxic effector mechanisms Pharmacokinetics • Prednisone is converted to active prednisolone • Prednisone is very well absorbed from GIT & can be dosed once daily Adverse Effects • Occur in >10% of patients: ↑ appetite, insomnia, indigestion (bitter taste), & mood changes. • < often but seen with high doses or prolonged therapy: cataracts, hyperglycemia, hirsutism, bruising, acne, sodium & water retention, HTN, bone growth suppression, & ulcerative esophagitis • Best to take with food • Drug Interactions: Barbiturates, phenytoin, & rifampin induce hepatic metabolism of prednisone →↓ effectiveness • Prednisone ↓ effectiveness of vaccines & toxoids Dosing & Administration • Frst-line therapy for acute graft rejection is highdose IV methylprednisolone (250-1,000 mg) daily for 3 days or oral prednisone (200 mg) • Doses of oral prednisone are then tapered over 5 days to 20 mg/day • Prednisone doses are tapered progressively over time, depending on type of additional immunosuppression & organ function. As doses are tapered, it is preferable to administer corticosteroids every other day & between 7 AM & 8 AM to mimic body’s diurnal release of cortisol • Corticosteroids often are continued for entire life of functional graft ANTIMETABOLITES • Mycophenolic acid (MPA) has two formulations: 1. mycophenolate mofetil (MMF) is morpholinoethyl ester of MPA, 2. mycophenolate sodium is enteric-coated formulation of sodium salt of MPA. Pharmacology/Mechanism of Action • Noncompetitive binding to inosine monophosphate dehydrogenase (key enzyme in guanosine nucleotide synthesis via de novo pathway) →↓nucleotide synthesis & ↓ DNA polymerase activity →↓lymphocyte proliferation • > specific for T & B cells, which use only de novo pathway for nucleotide synthesis • may downregulate activation of lymphocytes MMF • MPA is unstable in acidic environment → MMF acts as prodrug • Mycophenolate sodium protects MPA from gastric acidity & allows release in small intestine • MMF is effective in treatment of acute rejection in addition to maintenance therapy • Patients converted to MMF after 1st acute rejection episode had < subsequent rejections than patients who continued with AZAafter rejection treatment • MMF is key component of CI-sparing protocols • Combination of MMF with sirolimus → improved renal function with no change in acute rejection & patient & graft survival MMF (cont’d) Adverse Effects • GI are the most common : N&V, diarrhea, abdominal pain - may be alleviated by ↓ dose, dividing total daily dose into 3-4 doses, administration with food, or titrating upward from lower doses during initial therapy • Hematologic: leukopenia & anemia • Peripheral IV administration may cause local edema & inflammation → central venous administration may be preferred route. MMF (cont’d) Drug–Drug & Drug–Food Interactions • Food delays absorption & ↓ MPA Cmax • Administration with Al- & Mg-containing antacids or cholestyramine significantly ↓ AUC of MPA & should be avoided • Acyclovir competes with MPAG for renal tubular secretion • MMF(but not mycophenolate sodium) + pantoprazole ↓MPA levels • CSA ↓ MPA trough concentrations (CSA interferes with enterohepatic recycling of MPAG) MMF (cont’d) Dosing & Administration • MMF is used as both oral & IV formulations • Mycophenolate sodium: only oral. • AUC monitoring has been proposed as the most appropriate measure of MPA drug exposure to predict therapeutic outcomes Azathioprine • • Prodrug for 6-mercaptopurine (6-MP) Converts rapidly to 6-MP in blood→metabolized by 3 enzymes: 1. Xanthine oxidase in liver & GI tract→6-thiouric acid (inactive) 2. Thiopurine S-methyltransferase in hematopoietic tissues & RBCs→methylation to methylmercaptopurine (inactive) 3. Hypoxanthine-guanine phosphoribosyltransferase→to 6-thioguanine nucleotides (6-TGNs) (active) metabolites →incorporated into Nas → disruption of both salvage & de novo pathways of DNA, RNA & protein synthesis → cell are unable to proliferate. • 6-TGNs eventually are catabolized by xanthine oxidase & thiopurine S-methyltransferase to inactive products Azathioprine (cont’d) • AZA use is ↓ Adverse Effects • Dose-limiting – blood ADRs (leukopenia, anemia & thrombocytopenia) can be managed by dose ↓ or discontinuation of azathioprine. • HW: relation of genetic polymorphism to this ADR? • Other common ADRs: N&V, which can be ↓ by taking with food • Alopecia, hepatotoxicity & pancreatitis are < common; they generally are reversible on dose ↓or discontinuation Azathioprine (cont’d) Drug–Drug & Drug–Food Interactions • Allopurinol & febuxostat (-) xanthine oxidase → metabolic pathways shift to favor production of 6-TGNs → can ↑ AZA & 6-MP conc. by 4-fold → ↑ BM suppression & pancytopenia Dosing & Administration • Initial doses are 3-5 mg/kg/d IV or PO • It is better to take in evening when initiating or titrating therapy to allow for morning determinations of WBC • Doses should be↓ by 50-75% when allopurinol is added Proliferation signal inhibitors (PSIs) (mTOR inhibitors) • Sirolimus (rapamycin) is immunosuppressive macrolide antibiotic • structurally similar to TAC • is effective in ↓ risk of acute rejection • Everolimus: shorter t1/2 than sirolimus Pharmacology/MoA • Bind to FKBP12 → sirolimus-FKBP12 complex binds to mTOR → (-) response to cytokines • IL-2 (+) mTOR → (+) kinases that advance cell cycle from G1 to S phase → mTOR inhibitors (-) T-cell proliferation by (-) cellular response to IL-2 & progression of cell cycle mTOR INHIBITORS (cont’d) Pharmacokinetics • Bioavailability is low (15%) Efficacy • SIR is only approved for prevention of rejection when given in combination with corticosteroids & CSA or after withdrawal of CSA in pts with low to moderate immunologic risk. • Is effective in combination with TAC or mycophenolate • Combination of sirolimus & mycophenolate can be used to avoid use of CIs & ↓ risk of nephrotoxicity • Everolimus was approved in combination with basiliximab, cyclosporine, TAC & corticosteroids. mTOR INHIBITORS (cont’d) ADRs • High sirolimus serum concentrations: thrombocytopenia & leukopenia. • Hypercholesterolemia & hypertriglyceridemia usually ↓ after 1 yr of therapy - can be managed by ↓ dose, discontinuing sirolimus, or by statin or fibrate • Delayed wound healing (should be avoided early (< 3mo) postoperatively) • Mouth ulcers • Reversible interstitial pneumonitis • Other: ↑ liver enzymes, HTN, rash, acne, diarrhea, & arthralgia mTOR INHIBITORS (cont’d) • Drug–Drug & Drug–Food Interactions • CYP3A4 enzyme-mediated - similar to those seen with CSA & TAC • Microemulsion (but not standard) formulation of CSA + sirolimus → ↑ AUC & trough sirolimus levels • CSA conc. & AUC are ↑ when it is given with sirolimus • Mechanism: competitive binding to CYP3A4 & P-glycoprotein • Pts should separate dose of sirolimus & CSA by 4 hrs to ↓ interaction • Grapefruit juice ↑ sirolimus levels HW • Belatacept DEPLETING ANTIBODIES POLYCLONAL ANTIBODIES (ANTITHYMOCYTE GLOBULINS) 1. ATG (Atgam, Pfizer), equine polyclonal antibody 2. RATG (Thymoglobulin, Genzyme), a rabbit polyclonal antibody (< immunogenic) Pharmacology/Mechanism of Action • binding to lymphocyte receptors, including CD2, CD3, CD4, CD8, CD25, & CD45 • → complement-mediated lysis → lymphocyte depletion • T cells are major target; POLYCLONAL ANTIBODIES (ANTITHYMOCYTE GLOBULINS) (cont’d) Efficacy • Used most commonly for treatment of acute allograft rejection or as induction therapy to prevent acute rejection • ATG is currently approved for both indications in kidney transplants • RATG is approved only for treatment of acute allograft rejection in kidney transplantations POLYCLONAL ANTIBODIES (ANTITHYMOCYTE GLOBULINS) (cont’d) ADRs • Dose-limiting myelosuppression • Anaphylaxis, hypotension, HTN, tachycardia, dyspnea, urticaria, rash • Serum sickness > frequently with ATG than RATG • Rare nephrotoxicity • Infusion-related febrile reactions can be managed by premedicating pt with acetaminophen, diphenhydramine, & corticosteroids • ↑ risk of infections, particularly viral, & malignancy. POLYCLONAL ANTIBODIES (ANTITHYMOCYTE GLOBULINS) (cont’d) Dosing & Administration • ATG: single dose for 7-14 d • RATG: single dose for 7-14 d for acute rejection or for 5-10 days for induction of immunosuppression • Both ATG & RATG should be administered through central line or through high-flow vein with filter over at least 4 hrs to minimize phlebitis & thrombosis Depleting antibody: Alemtuzumab • Is approved for use in B-cell chronic lymphocytic leukemia • Effects on depleting both T & B lymphocytes make it useful in solid-organ transplants Pharmacology/MoA • Is humanized monoclonal antibody directed at cells that express CD52 surface antigen (found on both T & B lymphocytes & other immune cells) • → antibody-dependent lysis → removal of both T & B lymphocytes from blood, bone marrow, & organs→ complete lymphocyte depletion Alemtuzumab (cont’d) Efficacy • as induction therapy for prevention of acute rejection & for treatment of acute rejection including corticosteroid- & antibody-resistant rejection ADRs • Infusion-related reactions, BM suppression, & infections NONDEPLETING ANTIBODIES Interleukin-2 Receptor Antagonists • Basiliximab: chimeric monoclonal antibody (25% murine) - higher affinity to epitope Pharmacology/MoA • specifically binds to α-chain (CD25) on surface of activated T lymphocytes • Binding to IL-2 receptor prevents IL-2-mediated activation & proliferation of T cells • approved for use in RT in combination with cyclosporine & corticosteroids • ↓ risk of rejection with no ↑ in graft loss, infectious complications, malignancy, or death IL-2 Receptor Antagonists (cont’d) • Basiliximab is part of CI- or corticosteroidsparing protocols • →↓ nephrotoxicity in early post-transplantation period ADRs • ↑ number of hypersensitivity reactions • ↑ mortality due to ↑ severe infections Drug–Drug & Drug–Food Interactions • ↑CSA & TAC levels • Dosing & Administration • 2 IV doses: intraoperatively & on postoperative day 4 (either centrally or peripherally over 20-30 minutes in 50 mL NS or dextrose) HW • Pregnancy in RT patients (European Association of Urology Guidelines) EVALUATION OF THERAPEUTIC OUTCOMES • The greatest risk to short-term graft survival is acute rejection. • daily to weekly check for first 1-3 months after transplantation) of CBC, electrolytes, BUN, SrCr & serum drug concentrations is important • Starting 3 months after transplantation, monitoring of these parameters can be ↓ to biweekly or monthly for most pts • Long-term graft survival is limited by chronic rejection • Estimated half-lives for kidneys are 26.9 years for HLAidentical grafts while markedly lower value of 7.8 years with mismatched kidneys Factors Negatively Affecting Allograft & Patient Survival Laboratory Monitoring after Transplantation as a Function of Time Post-Transplant Immunosuppression-related complications • • Comorbidities: Infections due to immunosuppression cardiovascular disease malignancy, recurrent disease, drug toxicities (namely nephrotoxicity), chronic rejection are primary causes of mortality in patients who have functioning graft 5 or > years after transplantation CARDIOVASCULAR (CV) DISEASE • Leading cause of morbidity & mortality in transplant pts • Preexisting CV disease is common in ESRD; not reversed with transplantation • HTN, hyperlipidemia, & DM are common complications in transplantation recipients • Chronic rejection has been linked to HTN & hyperlipidemia HYPERTENSION • Causes posttranslant: corticosteroids, CSA, TAC, & impaired kidney graft function • CIs cause peripheral vasoconstriction, promote Na retention→ extracellular fluid volume expansion • TAC < CSA • CCBs are 1st-line agents to treat HTN after transplantation - may < nephrotoxic effects of CSA & improve renal hemodynamics • CCBs may contribute to gingival hyperplasia often associated with CSA • CYP3A4 interactions with CSA & TAC, particularly with diltiazem, verapamil, & nicardipine HTN (cont’d) • ACEIs & ARBs are now considered to be equivalent alternative to CCBs • If ↑SrCr is > 30% within 1-2 wks after starting ACEIs or ARBs, drug should be discontinued & other measures used to control BP • addition of β-blocker, diuretic, or centrally acting agent is usually necessary • β-Blockers may worsen metabolic disturbances caused by immunosuppressants, such as hyperkalemia & dyslipidemia • CI-induced HTN is often salt-sensitive, making it very responsive to diuretics HYPERLIPIDEMIA • May be exacerbated by corticosteroids, CIs, sirolimus, diuretics, & β-b • TAC CSA • Other possible risk factors: ethnicity (African American or Hispanic), age (>40 years), pretransplant diabetes status, family history, & weight • Up to 40% of pts with PTDM will require insulin therapy POST-TRANSPLANTATION DM (cont’d) • In pts who can be managed with OHA, glipizide (metabolized extensively by liver), may be preferred over glyburide (renally eliminated) • Metformin should be used with extreme caution • Frequent blood glucose monitoring is needed in early postop phase to improve glucose control + to identify those with PTDM • Changes in renal function affect elimination of hypoglycemic agents, including insulin • Dose changes of immunosuppressant drugs also affect glycemic control INFECTION • Risk is greatest during the first 3 postop months, & following treatment of acute rejection • Bacterial infections: most frequently within the 1st month after transplantation & generally affect urinary tract, wound, or vascular access sites • Viral infections are caused most commonly by HSV (early transplantation), HZV (late posttransplantation), or CMV Prevention of Infection in RT (cont’d) • Surgical infection prophylaxis, e.g. with cefazolin started perioperatively & continued for <24 hrs. • Prophylactic TMP-SMX: inexpensive & well tolerated; FQs also have been evaluated. • HW: duration of UTI prophylaxis? (KDIGO 2009) • Transplant patients should receive pneumococcal vaccine once & influenza vaccine yearly; however, immunologic responses to these vaccines may be blunted by immunosuppressive therapy. Polyomavirus-associated nephropathy (PVAN) • specific polyomavirus that infects kidney allografts is the BK virus. • primary infection with BK virus occurs in childhood as asymptomatic infection in 50-90% of general population. • Transmission: possibly via oral or respiratory routes. • BK viremia if it develops may progress to allograft nephropathy in 50% of patients. • BK virus nephropathy may results in graft loss in ~46% of affected patients Polyomavirus-associated nephropathy (PVAN) • all KT recipients should be screened for urinary BK virus replication monthly for the first 3-6 months after transplant & every 3 months thereafter for the 1st year. • screening for BK virus should also occur any time CrSr is elevated without known cause & after treatment of acute rejection. • treatment should be initiated when plasma concentrations persist>10,000 copies/mL. • Treatment: ↓immunosuppressants. • other treatments: cidofovir, leflunomide, & FQs Prevention of Infection in RT (cont’d) • CMV-seronegative patients should not receive organs or blood products from seropositive donors if possible. • Prophylactic ganciclovir (IV) or oral valganciclovir ↓both primary & reactivated CMV disease in solid-organ transplantation. • HW: duration? (KDIGO guideline) • Ganciclovir prophylaxis also may ↓ reactivation of CMV disease in seropositive patients receiving antithymocyte globulin or muromonab for treatment of acute rejection. Prevention of Infection in RT (cont’d) • Prophylaxis with CMV IG has been strongly recommended for CMV-seronegative transplant recipients receiving organs from seropositive donors • (but benefits relative to other therapies, e.g., prophylactic or preemptive ganciclovir are not well known) • Some recommend use of CMV IG in combination with ganciclovir for treatment of severe, life-threatening CMV pneumonitis in RT • Acyclovir is used at some centers for HSV infection prevention because of high incidence of clinical HSV infection, including pneumonias, after transplantation. MALIGNANCY • Risk of malignancy in transplantation recipients is ↑ 3- to 4-fold • cancers that occur with > prevalence in transplantation recipients: lymphomas & lymphoproliferative disorders (PTLD), Kaposi sarcoma, renal carcinoma, in situ carcinomas of uterine cervix, hepatobiliary tumors, & anogenital carcinomas • Skin cancers are the most common tumors (38%) • Factors that may predispose to skin cancers: sun exposure & azathioprine (metabolite nitroimidazole with photosensitivity) • MMF:

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