Immunology/Transplantation and Nephrology PRNs Focus Session Long-term Management of the Renal Transplant Recipient Activity No. 0217-0000-11-076-L01-P Monday, October 17 1:30 p.m. 3:30 p.m. Convention Center: Rooms 319 & 320 Moderators: Heather A. Nyman, Pharm.D., BCPS Clinical Pharmacist, Dialysis, University of Utah Dialysis Program, Salt Lake City, Utah and Angela Q. Maldonado, Pharm.D., BCPS Clinical Assistant Professor of Pharmacotherapy, Washington State University; Kidney Transplant Pharmacist, Providence Hospital, Spokane, Washington Agenda 1:30 p.m. Introduction and Welcome 1:40 p.m. Mineral and Bone Disorder in Chronic Kidney Disease and Kidney Transplantation Timothy M. Clifford, Pharm.D., BCPS Clinical Pharmacist Specialist Transplant/Critical Care; Assistant Adjunct Professor, Pharmacy and Surgery, University of Kentucky, Lexington, Kentucky 2:15 p.m. Anemia Pre- and Post-renal Transplant Shouldn t the Allograft Be the Cure? Joanna Q. Hudson, Pharm.D., FASN, BCPS Associate Professor, The University of Tennessee, Departments of Clinical Pharmacy & Medicine (Nephrology), Memphis, Tennessee 2:50 p.m. The Pharmacokinetics and Pharmacodynamics of Drug Dosing in the Renal Allograft Recipient Ali Olyaei, Pharm.D. Professor of Medicine, Director of Clinical Research, Division of Nephrology and Hypertension, Oregon State University/Oregon Health & Sciences University, Portland, Oregon 3:25 p.m. Closing Remarks Faculty Conflict of Interest Disclosures Timothy M. Clifford: no conflicts to disclose. Joanna Q. Hudson: speaker s bureau for Amgen. Ali Olyaei: no conflicts to disclose. Annual Meeting Long-term Management of the Renal Transplant Recipient 1
Learning Objectives 1. Discuss the pathophysiology of mineral and bone disorder (MBD)in the CKD patient. 2. Discuss the prevalence of MBD in the kidney transplant recipient. 3. Describe the methods of diagnosing MBD, goals of management and monitoring parameters. 4. Recommend non-pharmacological and pharmacological treatment of MBD. 5. Discuss the pathophysiology of anemia both pre- and post-renal transplant. 6. Describe the goals of therapy and pharmacological management of anemia. 7. Describe the conflicting data on target hemoglobin with the use of erythropoiesis stimulating agents. 8. Describe the various methods of estimating GFR in the renal allograft recipient. 9. Discuss the use of potentially nephrotoxic medications in the renal allograft recipient and how to minimize nephrotoxicity. 10. Discuss how the varying degree of renal insufficiency affects the pharmacokinetics and pharmacodynamics of the immunosuppressants. Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am Annual Meeting Long-term Management of the Renal Transplant Recipient 2
Anemia Pre- and dpost-renal tr Transplant Shouldn t the Allograft Be the Cure? Joanna Hudson, Pharm.D., BCPS, FASN Associate Professor Departments of Clinical Pharmacy & Medicine (Nephrology) The University of Tennessee Memphis, TN
Objectives Discuss the pathophysiology of anemia both pre- and post-renal transplant Describe the goals of therapy and pharmacological management of anemia Describe the conflicting data on target hemoglobin with the use of erythropoiesis stimulating agents
Erythropoiesis in CKD Bone Marrow Circulation Erythropoietin Iron Stem Cell BFU-E CFU-E Proerythroblast Reticulocyte RBCs 0 15 19 21 25 Time to Mature Cell Development (days) JH Brook et al. Iron Metabolism in Health and Disease. 1 st edition. London, England: W.B. Saunders; 1994.
Response to RBC Mass Plasm ma Erythr ropoietin (U/liter) Normal Kidney Function Patients with Anemia and Normal Blood Donors 10 5 Normal Blood Donors Patients with Anemia 10 4 10 3 10 2 10 1 (U/liter) Plasm ma Erythr ropoietin Kidney Disease Patients on Dialysis 10 5 Patients with Kidneys Patients without Kidneys 10 4 10 3 10 2 10 1 10 0 10 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0 0.1 0.2 0.3 0.4 0.5 0.6 Hematocrit Hematocrit Erslev AJ. N Engl J Med. 1991;324:1339-1344.
Contributing Factors of Anemia Associated With CKD Erythropoietin deficiency & resistance Chronic blood loss Shortened RBC lifespan from 120 to ~60 days Iron losses (iron deficiency) GI bleeding Reduced intake & absorption Malnutrition Inflammatory conditions Hemodilution Secondary Hyperparathyroidism Other disease states (e.g. cancer, HIV)
Body Iron Distribution and Pathways: Hemodialysis i Patient t Reticuloendothelial th li l stores (low) ferritin 50 to 800 Gut Tissue Transferrin Absorption 0.5 mg/day 32 mg/day 200 mg 1.5 mg = 50 µg/% (20% sat) Erythroid marrow 36 mg/day Red blood cells 1500 mg (Hct 30) Adapted from Bothwell et al. Iron Metabolism in Man. 2nd ed. 1979. Loss: 1 mg/day Loss: 4 mg/day Net loss: 4.5 mg/day
Clinical and Economic Impact of Anemia Increased Mortality, Increased LVH 1-3 Decreased Quality of Life 4 Increased Hospitalization and Length of Stay 5 1. Harnett et al. Am J Kidney Dis. 1995;25(4 suppl 1):S3-S7. 2. Ma et al. J Am Soc Nephrol. 1999;10:610-619. 3. Levin et al. Am J Kidney Dis. 1996;27:347-354. 4. Strippoli et al. J Am Soc Nephrol. 2004;15:3154-3165. 5. Jones et al. Kidney Int. 2004;65:757-767.
Lower HCT Associated With Increased Mortality in ESRD Patients t k 1.4 1.2 1 1.33 1.25 1.12 1.11 1.00 All-cause death Cardiac-related related death 1.00 0.96 0.97 *Re elative Ris 0.8 0.6 0.4 02 0.2 0 < 27% 27% to < 30% 30% to < 33% 33% to < 36% *After adjustment for medical diseases. Ma et al. J Am Soc Nephrol.. 1999;10:610-619. 619. Hct N = 75,283
Anemia Post Transplant At time of kidney transplantation almost all patients have anemia of CKD Post-transplantation anemia (PTA) is estimated to occur in 30-40% of patients Anemia usually resolves by 3-6 months, but some patients have late PTA defined as anemia 6 to 12 months after transplant Use of ESAs in kidney transplant recipients is y p p relatively low
Mechanisms of PTA Decreased RBC Production Drug induced d (immunosuppressants, ACEIs/ARBs, antimicrobial agents) Allograft dysfunction and rejection Erythropoietin resistance (iron deficiency, infections, aplastic anemia) Loss of RBCs Surgical blood loss GI blood loss Frequent phlebotomy
Mechanisms of PTA Increased RBC destruction Immune-mediated d hemolysis (immunosuppression, i PTLD) Microangiopathic hemolytic anemia (tacrolimus, cyclosporine, sirolimus) Nonimmune hemolysis (G6PD deficiency dapsone, ti trim/sufla, hemoglobinopathies) Other factors Donor and recipient factors Limitations of iron indices in transplant population Elevated hepcidin levels
Immunosuppressive Medications and Anemia Antimetabolite medications (azathioprine, MMF, mycophenolic acid) bone marrow suppression mtor inhibitors (sirolimus, everolimus) myelosuppression ess o and other mechanisms s Hemolytic anemia with sirolimus and the Hemolytic anemia with sirolimus and the calcineurin inhibitors tacrolimus and cyclosporine
Role of Hepcidin in Iron Metabolism Hormone produced primarily in the liver Principal regulator or iron absorption and distribution into tissues hepcidin blocks iron absorption hepcidin increases iron absorption Iron deficiency, Increased erythropoiesis Inflammation, Increased iron stores Hepcidin Hepcidin
Prevalence of PTA Male Mild: Hb > 12-13 g/dl Moderate: Hb > 11-12 g/dl Severe: Hb 11 g/dl Female Hb > 11-12 g/dl Hb > 10-11 g/dl Hb 10 g/dl Vanrenterghem et al. Am J Transplant 2003;3:835.
Prevalence of PTA ESA therapy was used in 5.2% of patients overall and in 18% of patients with severe anemia. Vanrenterghem et al. Am J Transplant 2003;3:835.
Prevalence of PTA Mix et al. Am J Transplant 2003;3:1426. Among pts with Hct < 30% 36% had iron studies 46% received iron 40% ESA
Association with GFR Mix et al. Am J Transplant 2003;3:1426.
Consequences in Transplant? Anemia significantly associated with mortality (hazard ratio 1.69; 95% CI 1.15 2.5) 1 graft failure (hazard ratio 2.47; 95% CI 1.47-4.10) 1 Left ventricular growth 2 Anemia not related to all-cause mortality but associated with 25% risk of allograft loss (hazard ratio 1.25; 95% CI 1.02-1.59) 3 1 Molnar et al. Am J Transplant 2007;7:818. 2 Rigatto et al. J Am Soc Nephrol 2003;14:462. 3 Winkelmayer et al. Nephrol Dial Transplant 2006;21:3559.
Consequences in Transplant? Not a clear consensus than anemia is associated with increased mortality and adverse CV events in transplant population Anemia may not directly cause adverse outcomes in transplant population, but may be a marker for an underlying pathologic process
Goals in Transplant Patient QUALITY OF LIFE TRANSFUSIONS RISK OF ALLOGRAFT LOSS Balance goals while minimizing the risks of treatment.
Approach to Prevention and Treatment Perioperatively: Consider iron for patients with transferrin saturation < 20% and serum ferritin < 200 ng/ml Consider ESA therapy when benefit Consider ESA therapy when benefit outweighs risk
K/DOQI Guidelines for Anemia Management in the Transplant Population Recommend that treatment guidelines for anemia in the general CKD population be followed in the transplant population ESAs Early Post-transplantation Studies support that ESAs are effective in correcting anemia, although higher doses may be required compared to doses pre-transplant ESAs Late Post-transplantation spa a o ESAs are effective and do not likely accelerate a decline in renal function May contribute to hypertension Am J Kidney Dis. 2006;47(suppl 3):S1-S146.
Guidelines for Anemia of CKD CKD diagnosis Hb <12 g/dl (females) Hb <13.5 g/dl (males) Evaluate RBC, reticulocytes, iron parameters Iron deficient Correct iron deficiency (oral, parenteral) Normal Erythropoietic Stimulating Agent (ESA) No Anemia corrected Hb < 1 g/dl 4 weeks after dose change Increase doses by 25% Measure Hb every week until stable, then every 4 weeks Hb > 1 g/dl in 2 wk period Decrease doses dose by 25% Adapted from: National Kidney Foundation. Am J Kidney Dis. 2001;37(suppl 1):S182-S237, Am J Kidney Dis. 2006;47(suppl 3):S1-S146 and Epoetin PI June 2011.
What is known about ESAs in the transplant t population? ESA therapy post-transplanttransplant shortens time to achieve higher hematocrit and improves QOL 1,2 Observational studies in kidney transplant show evidence of increase mortality with Hb levels above 12.5 g/dl 3 Medicare e reimbursement e polices affect therapy 1 Van Loo et al. Nephrol Dial Transplant 1996;11:815. 2 McDevitt et al. Am J Transplant 2005;5:1948. 3 Heinze et al. BMJ 2009;339:b4018.
Questions about ESAs in the transplant population? Can we apply data from ESA studies in CKD population? When do we start treatment and how aggressive should we be? What is the target Hb?
Concerns with ESAs and Target Hb in CKD
Mean monthly hemoglobin & mean EPO dose per week United States Renal Data System (USRDS) 2006 Annual Data Report
Safety Information on ESAs: Supporting Studies WARNINGS: Increased Mortality and Serious Cardiovascular Events Study Patients Sponsor Published Target Hb (g/dl) Besarab et al 1 Epoetin alfa Cardiac disease on hemodialysis Amgen 1998 14 ± 1 * vs 10 ± 1 CHOIR 2 Epoetin alfa Anemia associated with CKD not on dialysis Ortho Biotech/ J & J 2006 13.5 * vs 11.3 F. CREATE 3 Anemia associated with CKD not on Hoffmann Epoetin beta dialysis La Roche. 2006 13-15 g/dl vs 10.5-11.5 g/dl 1. Besarab A, et al. NE Engl ljm Med. 1998;339:584-590. 590 CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency i 2. Singh AK, et al. N Engl J Med. 2006;355:2085-2098. CREATE = Cardiovascular Risk Reduction by Early Anemia Treatment 3. Drüke, et al. N Eng J Med 2006:355:2071-84. with Epoetin Beta
CHOIR Trial Primary endpoints: time to composite death, MI, stroke, death, CHF hospitalization 1432 patients enrolled 715 assigned to high-hb group (13.5 g/dl) 717 assigned to low-hb group (11.3 g/dl) 312 completed 36 months or withdrew at study termination without having primary event 125 had a primary event 278 withdrew before early termination of study 131 required renal replacement therapy (RRT) 147 withdrew for other reasons 349 completed 36 months or withdrew at study termination without having primary event 97 had a primary event 271 withdrew before early termination of study 111 required RRT 160 withdrew for other reasons Singh AK, et al. N Engl J Med. 2006;355:2085-98.
CHOIR Study Singh AK, et al N Engl J Med. 2006;355(20):2085-2098. Primary Composite End Point N = 1432 30 High-hemoglobin hemoglobin group y of Event robability mposite E Pr Com 20 10 Low-hemoglobin group 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Month 222 composite events (death, MI, hospitalization for CHF, stroke) High-Hb (13.5 g/dl): 125 events (18%) Low-Hb (11.3 g/dl): 97 events (14%) Hazard ratio (HR) = 1.34; 95% Confidence Interval (CI), 1.03 to 1.74 (P = 0.03)
CREATE Study 603 patients with CKD stage 3 or 4 randomly assigned to 1 of 2 groups: Epoetin beta therapy targeted to Hb 13.0-15.0 g/dl Epoetin beta therapy targeted to Hb 10.5-11.5 g/dl Primary endpoint was time to first cardiovascular event Secondary endpoints were LVMI, QOL, and progression of CKD Drüeke TB, et al, for the CREATE Investigators. N Engl J Med. 2006;355(20):2071-2084.
Median Hemoglobin Levels in the Intention-to-Treat Population During the Study (g/dl) oglobin Hem 16 15 14 13 12 11 10 9 8 Group 1 (n=301) Group 2 (n=302) 0 0 6 12 18 24 30 36 42 48 Months Drüeke, T. et al., N Engl J Med 2006;355:2071-84.
ee Survi val (%) Event-Fr 100 90 80 70 60 50 40 30 20 10 0 Time to Primary End Point of First Cardiovascular Event Group 2 Lower Hb Group 1 Higher Hb 58 events in group 1 vs. 47 events in group 2 Hazard ratio 0.78; 95% CI 0.53 to 1.14; 14; P = 0.20 0 6 12 18 24 30 36 42 48 Month Drüeke, T. et al., N Engl J Med 2006;355:2071-84.
CREATE Study There was no difference between the groups in the primary endpoint, LVMI, or progression of CKD QOL increased significantly in both groups, but was significantly better in the higher Hb group compared with the lower Hb group at yr 1 Drüeke TB, et al, for the CREATE Investigators. N Engl J Med. 2006;355(20):2071-2084.
Meta-Analysis of CKD Trials p= 0.031 Phrommintiku, Haas, Elsik, Krum. Lancet 2007; 369:381-388.
FDA Reaction to Safety Information on ESAs FDA issued warning in late 2006 regarding g new risks associated with use of ESAs FDA changed labeling for ESA on March 9, 2007 The use of ESAs may increase the risk for death and for serious cardiovascular events when dosed to achieve a target hemoglobin of >12 g/dl FDA recommends using the lowest dose of ESAs that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion FDA Web page. Information for healthcare professionals: erythropoiesis stimulating agents (ESA). Available at: http://www.fda.gov/cder/drug/infosheets/hcp/rhe2007hcp.htm. Accessed April 5, 2007.
Black Box Warning for ESAs in CKD Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesisstimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dl; 14 vs. 10 g/dl) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dl. Epogen PI, Amgen Inc. - August 2008
K/DOQI- 2007 Update of Hb Target Adequate Hb Lower limit of Hb (Recommendation) In dialysis and nondialysis CKD patients receiving i ESA therapy, the selected Hb target should generally be in the range of 11-12 g/dl Upper limit of Hb (Guideline) In dialysis and nondialysis CKD patients receiving ESA therapy, the Hb target should not be above 13 g/dl Strength of evidence = moderate KDOQI. Am J Kidney Dis. 2007;50:471-530.
TREAT: Trial to Reduce Cardiovascular Events with Aranesp (Darbepoetin alfa) Therapy Hypothesis: Treatment of anemia with darbepoetin reduces the risk of mortality and cardiovascular events and ESRD in patients with CKD and type 2 diabetes N = 2012 Darbepoetin Group (Target Hb 13 g/dl) Study Population Hb 11 g/dl GFR 20-60 ml/min Type 2 DM TSat 15% N = 4038 Design randomized (1:1), double blind, controlled N = 2026 Control Group Placebo group subjects could receive darbepoetin when Hb < 9 g/dl Pfeffer et al. N Eng J Med 2009;361:2019-32. 32.
Primary Endpoints Time to: TREAT Endpoints Composite outcome of death from any cause or a CV event defined as: Nonfatal myocardial infarction Congestive heart failure Stroke Hospitalization for myocardial ischemia Composite of death or ESRD Secondary Endpoints Time to: Death Death from CV causes Rate of decline in egfr Change in patient reported fatigue (FACT-fatigue) Pfeffer et al. N Eng J Med 2009;361:2019-32. 32.
TREAT End Points Pfeffer et al. N Eng J Med 2009;361:2019-32. 32. Median Hb 12.5 (12-12.8) 12.8) in darbepoetin group; 10.6 (9.9-11.3) in placebo group (p<0.0001).
TREAT TREAT failed to meet its primary objectives of demonstrating a reduction in all-cause mortality, CV morbidity, or ESRD and in time to all-cause mortality or ESRD. There was an almost two-fold increase in risk of stroke (5% in treatment arm vs. 2.6% in placebo arm) Among darbepoetin treated subjects with a past history g p j p y of cancer, there were more deaths due to all causes and due to cancer compared with the control group
FDA Urges Lower Doses of Anemia Drugs Reported that the FDA "said that three drugs that had been widely used to treat anemia in both kidney and cancer patients were so dangerous to the heart that doctors should consider avoiding the medicines altogether in some patients and using less of them in others." The FDA "concluded that there were no risk-free doses of Epogen (epoetin alfa), Aranesp (darbepoetin alfa) and Procrit (epoetin alfa), and that doctors should use the medicines only in patients suffering from severe anemia. New York Times (6/24/2011)
Most Recent Black Box Warning for ESAs in CKD Chronic Kidney Disease: In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesisstimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dl. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events. Epogen PI, Amgen Inc. June 2011
Labeling of ESAs For patients with CKD on dialysis: Initiate Epogen treatment when the hemoglobin level is less than 10 g/dl. If the hemoglobin level approaches or exceeds 11 g/dl, reduce or interrupt the dose For patients with CKD not on dialysis: Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dl and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal If the hemoglobin level exceeds 10 g/dl, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions. Epogen PI, Amgen Inc. June 2011
Questions Are negative outcomes associated with ESAs specifically or Hb level l or both? What is the Hb level at which QOL is maximixed, yet risk is minimized? Is iron a contributing factor or would increased use be supported to achieve target Hb without increased use of ESAs? What to do with conflicting FDA warnings and K/DOQI anemia guidelines?
Considerations in the Transplant Population Consider the risk of CV events and stroke in transplant recipients before initiating an ESA If blood transfusions are likely to be needed given the decline in Hb consider potential benefit of ESAs at low Hb (< 10 g/dl?) Until further guidance is available in the transplant population consider recommendations for ESA use in CKD patients not on dialysis
Summary Anemia of CKD is prevalent in patients post-kidney transplant and a problem many practitioners will be faced with given the increase in the population with ESRD. Iron supplementation and ESAs are essential for treatment of anemia of CKD; however, practitioners need to be cognizant of the limitations in using these agents. Recent evidence of mortality risk associated with higher Hb in select populations has raised many questions about the current strategies for anemia management. Whether the same risks of ESA use observed in the CKD population apply to kidney transplant patients has not been determined; however, there is enough information on ESAs to justify caution when making treatment t t decisions i for individuals with anemia post transplant.