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Management of Anemia in Chronic Kidney Disease Dr. Overview CKD Anemia Anemia of CKD Consultant pharmacist challenges with MRR for dialysis patients Managing and treating patients on dialysis Cases for review Chronic Kidney Disease (CKD) in the U.S. National Kidney Foundation (NKF) classification system 2002 for staging CKD CKD previously called: Chronic renal failure Pre-ESRD Renal failure Renal damage Kidney disease KDOQI Defines CKD Stages of Chronic Kidney Disease NKF Kidney Disease Outcomes Quality Initiative (K/DOQI): CKD Stages1 Stage 1 Description GFR (mL/min/1.73 m2) Kidney damage with normal or ↑ GFR Kidney damage with mild ↓ GFR 60-89 3 Moderate ↓ GFR 30-59 4 Severe ↓ GFR 15-29 5 Kidney failure <15 (or dialysis) 2 Reference: 1. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S1-S266. ≥90 NKF-KDOQI Stages of CKD CKD Continuum ESRD Renal Insufficiency 1 2 3 4 5 Kidney Damage with normal or GFR Kidney Damage with Mild GFR Moderate GFR Severe GFR Kidney Failure 90 80 70 60 50 40 GFR (mL/min/1.73 m2) NKF-K/DOQI. Am J Kidney Dis. 2002;37:S1-S266. 30 20 <15 or Dialysis/ Transplantation (RRT) Markers of Renal Function Serum creatinine Cockcroft-Gault Equation eCrCl MDRD Equation eGFR Calculating Creatinine Clearance Cockcroft-Gault Equation CrCl men = (140 - Age) x LBW Scr x 72 CrCl women = CrCl men x 0.85 Modification of Diet in Renal Disease Equation (MDRD) CrCl men = (Scr) -1.154 x (age) -0.203 CrCl women = CrCl men x 0.742 CrCl African American = CrCl men x 1.210 http://www.mdrd.com/ USRDS: ESRD Incidence by Age Patients Age 65 Years or Older Are More Than Twice as Likely to Have ESRD as People Under Age 50 Years1 23% 11% 14% 1% 3% 30% 17% Adapted from the United States Renal Data System (USRDS).1 9 Reference: 1. United States Renal Data System. 2007 annual data report reference tables: incidence. Available at: http://www.usrds.org/2007/ref/A_incidence_07.pdf. 0-14 years 15-29 years 30-49 years 50-64 years 65-69 years 70-79 years 80+ years In LTC Residents, the Prevalence of CKD Increases With Age Age-Related Prevalence of Low GFR (%) 40% of the population had a GFR of <60 mL/min/1.73 m2 (MDRD) n=106 6 Men Women 5 n=671 n=3354 n=977 4 3 n=1061 n=2644 n=646 n=472 2 1 0 65-74 75-84 85-94 95+ Age in Years n=9931 MDRD=Modification of Diet in Renal Disease. Reference: Garg et al. Kidney Int. 2004;65:649-653. Almost One Half of All LTC Residents Have GFR <60 mL/min/1.73 m2 Residents with CKD (GFR <60 mL/min/1.73 m2) 44% 44% 56% Residents without CKD 56% N=4240 (residents with SCr, calculating GFR using MDRD) SCr=serum creatinine. Reference: Van Vleet et al. Poster presented at: American Geriatric Society Annual Meeting; May 11-15, 2005; Orlando, Fla. CKD Risk Factors Contributors to Renal Function Decline Decline in kidney weight, loss of nephrons Decline in renal perfusion Decline in GFR Est healthly adults lose 8-10ml/min of GFR every decade of life beginning around age 30 Decrease in ability to concentrate urine Decreased reabsorption of sodium Decreased bladder capacity Beck LH. Long-term Care Forum. 5(3) 1995. Risk Factors for ESRD 25 Year Follow-up Retrospective review of 177,570 individuals from large MCO (1964-’73) Followed for ESRD Tx (USRDS) 842 cases ESRD observed Goal: evaluate value of potential novel risk factors for ESRD vs established risk factors Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009; 169(4):342-350 Risk Factors for ESRD 25 Year Follow-up cont’d Established Risk Factors for ESRD: Gender (M) Age Proteinuria* DM HTN AA race Elevated SCr (or, decreased GFR) Obesity* Lower educational attainment *most potent risk factors Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009; 169(4):342-350 Risk Factors for ESRD 25 Year Follow-up cont’d Independent Risk Factors for ESRD: Lower Hgb Higher serum uric acid level (in females) Self-reported Hx of nocturia Family Hx of kidney disease Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009; 169(4):342-350 Complications of CKD CVD “All patients with chronic kidney disease should be considered in the ‘‘highest risk’’ group for cardiovascular disease, irrespective of levels of traditional CVD risk factors.” HTN (cause and complication) Protein energy malnutrition Central and peripheral neuropathy Anemia ESRD Bone disease/disorders of calcium and phosphorus National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39:S1-S266, 2002 (suppl 1) Anemia Defining Anemia (NKF) Group of diseases characterized by a decrease in either Hgb, Hct or red blood cells (RBC) that reduce the oxygen carrying capacity of the blood. Diagnose anemia if: - Hemoglobin < 12 g/dL (adult females) - Hemoglobin < 13.5 g/dL (adult males) In patients with CKD the hemoglobin should be 11 g/dL or greater KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3) World Health Organization WHO definition of anemia: Males Females Hgb< 13 gm/dL Hgb < 12 gm/dL World Health Organization: Nutritional anemia: report of a WHO Scientific Group. Geneva, Switzerland: World Health Organization, 1968. Common Causes of Anemia in Elderly Patients Anemia of Chronic Inflammation (inflammatory disease, infections, CKD) Iron Deficiency Anemia 30% - 40% Post Hemorrhagic Anemia Vitamin B-12 and Folate Deficiency Anemia Chronic Leukemia or Lymphoma Anemia 5% - 10% 5% - 10% No Identifiable Cause 15% - 25% 15% - 30% 5% Joosten E, et al, Prevalence and causes of anemia in a geriatric hospitalized population. Gerontology 1992; 38:111-117 Cause of Anemia in Long Term Care 13.2 Chronic disease Chronic kidney disease 15.9 Unknown Fe, B12, folate Other 4.0 65.6 LTC=long-term care. Reference: Chernetsky et al. Harefuah. 2002;141:591-594. 1.3 n=481 Signs and Symptoms of Anemia Are Nonspecific Central nervous system (CNS) • Fatigue • Headache • Dizziness • Syncope • Depression • Impaired cognition Vascular system • Cold intolerance • Edema • Pallor of skin, mucous membranes, and conjunctivae Cardiorespiratory system • Dyspnea • Tachycardia • Systolic ejection murmur • Palpitations • Cardiac enlargement • Hypertrophy • Wide pulse pressure • Hypotension • Orthostasis Gastrointestinal system • Anorexia • Nausea Genital tract • Impotence Reference: Morley et al. Ann Long-Term Care. 2003:S1-S21. Available at: http://www.annalsoflongtermcare.com/supplements.cfm. Accessed February 6, 2007. Laboratory Tests for Anemia Reticulocyte count (low indicates decreased RBC production; high count may be increased RBC destruction) Sedimentation rate (ESR): index of inflammation Stool for occult blood: evaluates GI loss Morphology by peripheral smear: size, color, shape of RBC Hepatic and renal function Thyroid-stimulating hormone (TSH) Medications That Can Cause Anemia Red blood cell production* Red blood cell loss (bleeding) Red blood cell survival Alcohol Anticoagulants High-dose penicillin H2 blockers Antiplatelet agents Sulfa agents Metformin Aspirin Phenobarbital Bisphosphonates Phenytoin Corticosteroids Proton pump inhibitors Nonsteroidal anti-inflammatory drugs Sulfa agents Chemotherapy agents *Can impair vitamin B12 and folate absorption or metabolism, which impairs red blood cell production. Reference: American Medical Directors Association. Clinical Practice Guideline. Columbia, MD: American Medical Directors Association; 2007. Treating Anemia B-12 Deficiency B-12 replacement Oral, sublingual, intranasal, IM Folic Acid Deficiency Folic acid replacement Oral, subcutaneous, IM Iron Deficiency Iron replacement (several salt forms/dose forms) Oral, IV, IM Anemia of Chronic Kidney Disease (CKD) Erythropoietic Stimulating Agents Epoetin Alfa (Epogen™/Procrit™), Darbepoetin Alfa (Aranesp™) KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3) Assessing Anemia JM 84 yo female Dx: anemia, DM, dementia, incontinence, osteoarthritis, osteoporosis Recurrent falls CNAs report “she won’t use the call light” What action, in general, should the CP take when requested to review resident for falls for an interim MRR? Iron Products and Drug Interactions Avoid administration with calcium, antacids, levothyroxine, levodopa, fluoroquinolones, PPIs, H-2 blockers Iron and the State Operations Manual (SOM) Iron does not stimulate rbc production Iron does not correct anemia that is not caused by iron deficiency Document chronic use Document doses > once daily Documentation for “clinical rationale” may include use of an ESA When is “Enough” Iron “Too Much”? F329 Unnecessary Drugs Table 1 “Iron therapy is not indicated in anemia of chronic disease when iron stores and transferrin levels are normal or elevated” “Clinical rationale should be documented for long-term use (> 2 months) or > 1 daily > 1 week because of side effects and risk of iron accumulation in tissues” Adverse Outcomes Associated With Anemia in Older Adults Decreased muscle strength and physical function1 Increased risk of stroke10 Increased heart disease2 Anemia Increased frequency of hospital admission7,8 and death7-9 Increased falls3 and fall-related injuries4 Cognitive impairment5,6 References: 1. Penninx et al. J Am Geriatr Soc. 2004;52:719-724. 2. Zeidman et al. Isr Med Assoc J. 2004;6:16-18. 3. Guse et al. WMJ. 2003;102:37-42. 4. Herndon et al. J Am Geriatr Soc. 1997;45:739-743. 5. Zuccala et al. Am J Med. 2005;118:496-502. 6. Arygyriadou et al. BMC Fam Pract. 2001;2:5. 7. Felker et al. J Cardiol. 2003;92:625-628. 8. Li et al. Kidney Int. 2004;65:1864-1869. 9. van Dijk et al. J Am Geriatr Soc. 2005;53:660-665. 10. Abramson et al. Kidney Int. 2003;64:610-615. Impact of Anemia on QIs Incidence of new fractures Prevalence of falls Prevalence of behavioral symptoms Prevalence of symptoms of depression Incidence of cognitive impairment Prevalence of weight loss Prevalence of dehydration Incidence of decline in ADLs Prevalence of little or no activity Prevalence of psychoactive medication use Anemia of CKD Anemia Worsens as Kidney Function Declines Prevalence of Anemia (%) 100 90 80 70 60 Hb Levels Hb=11-12 g/dL (n=181) Hb=10-11 g/dL (n=105) Hb=<10 g/dL (n=315) 50 10 15 15 8 40 17 62 30 20 10 9 5 14 8 43 20 0 <2 2.0-2.9 3.0-3.9 Serum Creatinine Level (mg/dL) Reference: Adapted from Kausz et al. Dis Manage Health Outcomes. 2002;10:505-513. >4 Etiology of CKD Anemia Decreased rbc production due to lack of erythropoietin; kidneys responsible for 90% of epo production Increased rbc destruction due to hemolysis Increased blood loss due to multiple venipunctures Decreased rbc production is present in CKD anemia and anemia of chronic disease, and both are normochromic, normocytic anemias Anemia of Chronic Disease and Renal Failure. http://emedicine.medscape.com Accessed Sept 12, 2009 Renal Anaemia damaged kidney impaired production of erythropoietin reduced number of red blood cells anaemia Erythropoietin Deficiency Iron Erythroid marrow X Erythropoietin RE cells Red blood cells O2 delivery RE=reticuloendothelial Adapted from: Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine. 1998; 334. Factors That Cause or Contribute to Anemia in CKD • • • • • • • • α Erythropoietin deficiency (insufficient production of endogenous erythropoietin) Iron deficiency Acute/chronic inflammatory conditions Severe hyperparathyroidism Aluminum toxicity Folate deficiency Decreased RBC survival Hemoglobinopathies (eg, alpha-thalassemia, sickle-cell anemia) KDOQI. Am J Kidney Dis. 2001;37(1 Suppl 1):S182-238. Agarwal AK. J Am Med Dir Assoc. 2006;7(9 Suppl):S7-S12. Key goals in managing anaemia of CKD increase exercise capacity improve cognitive function regulate and/or prevent left ventricular hypertrophy prevent progression of renal disease reduce risk of hospitalisation decrease mortality What the recommendations cover Diagnosis of anaemia of CKD Management of anaemia of CKD Assessment and optimisation of erythropoiesis Maintaining stable haemoglobin Monitoring of ACKD treatment Assessment of Anemia in CKD Test Hb at least annually in all patients, regardless of stage or cause of CKD Hct is a derived value, affected by plasma water, and, therefore, can be imprecise as a direct assessment of erythropoiesis. In contrast to Hct, Hb values are absolute and directly impacted by decreased erythropoietin production by the kidney1 Assessment should include the following tests: A complete blood count Absolute reticulocyte count Serum ferritin to assess iron stores Serum transferrin saturation (TSAT) or content of Hb in reticulocytes to assess adequacy of iron for erythropoiesis Stool for occult blood2 References: 1. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S145. 2. National Kidney Foundation. Available at: http://www.kidney.org/professionals/kdoqi/ guidelines_updates/doqiupan_i.html. Treatment for Anemia of CKD Replete iron stores to maintain: TSAT > 20% and Serum ferritin >100ng/ml Consider erythropoiesis-stimulating agent (ESA) Continue to evaluate responsiveness to treatment When treating with ESA, avoid Hgb > 12 gm/dL Anemia of CKD Management Supplement iron; most patients should receive oral iron supplement to prevent the development of iron deficiency even if iron studies are normal at initiation of therapy* Select ESA therapy Epoetin alfa Darbepoetin alfa Monitor Hgb, adjust dose by 25% no more frequently than monthly to reach and maintain target *Wish JB, Coyne DW. May Clin Proc.2007;82:1371-80. Hgb Target and ESAs Consider risk to benefit Hgb targets 11-12 g/dL per 2007 NKF KDOQI guidelines 10-12 g/dL per FDA package inserts Do not exceed Hgb >12 g/dL; adjust dose as “Hgb approaches 12 gm/dL” Monitor Hgb: Weekly: darbepoetin Twice weekly: epoetin Black Box Warning Renal Failure: Patients experienced greater risk for death and serious cardiovascular events when administered ESAs to a target higher versus lower hemoglobin level in two clinical studies. Individualize dosing to achieve and maintain a target hemoglobin within the range of 10 to 12 g/dL. Nov 07 Aranesp [package insert]. November 2007. Epogen [package insert]. November 2007. Procrit [package insert]. November 2007 Diagnosis of anaemia of CKD in adults Treat and repeat Hb eGFR < 60ml/min/1.73m2 AND Hb ≤ 11 g/dl Yes No Non renal and haematinic deficiency excluded? No Consider other causes Yes No See sections 1.2 & 1.3 See initial management algorithm Patient on haemodialysis? Yes Initial management algorithm Yes Ferritin < 500 µg/l? No Ferritin < 200 µg/l? TSAT < 20% Or %HRC > 6% No Yes No Yes – functional iron deficiency Assess Hb Hb > 9 g/dl Hb < 9 g/dl ESA (s.c.or i.v.) and iron Hb < 11 g/dl i.v. iron Assess Hb at 6 weeks Hb > 11 g/dl ESA (s.c.or i.v.) If Hb increase < 1g/dl after 4 weeks, increase ESA using dose schedule Continue monitoring Hb and iron status Assess and optimise erythropoiesis Iron supplements should be given to maintain serum ferritin levels ESA therapy is appropriate in iron-replete patients where existing comorbidities or prognosis do not negate its effect Benefits of ESA therapy include improved quality of life and physical functioning There is no evidence to distinguish between ESAs in terms of efficacy Hb maintenance algorithm (assumes ESA therapy and maintenance i.v. iron) Measure Hb Hb < 11 g/dl If Hb is persistently low see poor response algorithm ↑ ESA dose/ frequency as per schedule unless Hb rising by 1/g/dl/month. Check Hb as per Schedule. Hb 11–12 g/dl No change unless Hb rising by 1g/dl/month in which case consider ESA dose adjustment Hb 12–15 g/dl Hb > 15 g/dl Consider stopping i.v. iron. ↓ ESA dose/frequency as per schedule unless Hb falling by more than 1g/dl/month. Check Hb as per schedule. Stop i.v. iron. Consider stopping ESA or halve dose/frequency. Check Hb in 2 weeks. Ferritin < 200 µg/l? Iron dosage schedule Hb monitoring Monitor treatment Iron status: not earlier than 1 week after i.v. iron routinely at intervals of between 4 weeks and 3 months Haemoglobin: induction phase of ESAs every 2–4 weeks maintenance phase of ESAs every 1–3 months more actively after ESA dose adjustment Epoetin Alfa Darbepoetin Alfa Indications • Anemia of CKD • • Anemia of CKD Chemotherapy induced anemia • Chemotherapy induced • HIV induced anemia anemia • elective, noncardiac,nonvascular surgery Dosing Starting: 50 to 100 Units/kg TIW Starting: 0.45 ug/kg Initial: 1 dose/week or .75mcg/kg qow Target Hgb 10-12gm/dL Hgb 10-12gm/dL Dose Response 2 to 6 weeks 2 to 6 weeks Adapted from Package Inserts Data on File. Amgen, In; Thousand Oaks, CA ESA Adverse Events Hypertension, or worsening of control Headache, arthralgias, nausea Rarely: seizures, MI, stroke, antibody-induced pure red cell aplasia (PRCA) Adverse events from SQ administration Stinging Necrotic tissue lesions Subcutaneous nodules Hypo-responsiveness to ESAs POTENTIAL CAUSES1-4 Missed doses Inadequate iron stores Iron deficiency is present in 25-37.5% of patients and is a common cause of hyporesponse1 Drug/disease interactions Remember, iron needs an acidic environment to be maximally absorbed B12 or folate deficiencies Protein deficiencies Occult blood loss Infection/inflammation processes Coexisting medical conditions Malignancies, hematological disorders Hemolysis 1. Agarwal AK. J Am Med Dir Assoc. 2006 Nov;7(9 Suppl):S7-S12. 2. KDOQI. Am J Kidney Dis. 2001;37(1 Suppl 1):S182-238. 3. Procrit [package insert]. November 2007. 4. Aranesp [package insert]. November 2007. ESA Monitoring “at regular intervals” once stabilized1,2 CBC with differential and platelet count regularly1,2 Blood pressure should be controlled adequately before initiation of therapy1,2 Fe studies (TSAT, ferritin) prior to and during therapy1,2 Serum chemistry should be checked regularly (BUN, creatinine, phosphorus, uric acid, K+)1 Hgb References: 1. Procrit [package insert]. Raritan, NJ: Ortho Biotech Products, LP; 2008. Available at: www.procrit.com/procrit/. Accessed October 23, 2008. 2. Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; 2008. Available at: www.aranesp.com/. Accessed October 23, 2008. The Role of the Consultant Pharmacist in the Management of the Dialysis Patient CM 77yo male resident of short-stay facility Rehab s/p laminectomy; spinal stenosis, gout, DM, HTN, CAD, COPD, RA, renal failure Dialysis TIW Weight Pre-dialysis Post-dialysis 79.6 kg 77.5 kg Blood pressure Pre-dialysis Post-dialysis 192/76 163/74 Additional Information Continuous oxygen at 2L/min Renal diet Fluid restriction 1000cc qd Labs: Hgb 9.9 gm/dL Glucose 86 mg/dL SCr 6.1; eGFR 10ml/min K+ 4.7 mEq/L Calcium 9.1 mg/dL Current Medications Zyloprim 300mg qd Colchicine .6mg qd Glipizide 10mg qd Simvastatin 80mg qhs Diovan 320mg bid Clonidine .1mg q12h Hydralazine 50mg bid Metoprolol 25mg bid Furosemide 40mg qd Phos-Lo 667mg qd w/meal Nephrocaps qd Docusate 100mg bid Chemsticks ac & hs Fosrenal 2000mg w/ each meal What’s a Consultant to do??? The Role of the Consultant Pharmacist in the Management of the Dialysis Patient CM 77yo male resident of short-stay facility Rehab s/p laminectomy; spinal stenosis, gout, DM, HTN, CAD, COPD, RA, renal failure Dialysis TIW Weight Pre-dialysis Post-dialysis 79.6 kg 77.5 kg Blood pressure Pre-dialysis Post-dialysis 192/76 163/74 Additional Information Continuous oxygen at 2L/min Renal diet Fluid restriction 1000cc qd Labs: Hgb 9.9 gm/dL Glucose 86 mg/dL SCr 6.1; eGFR 10ml/min K+ 4.7 mEq/L Calcium 9.1 mg/dL Current Medications Zyloprim 300mg qd Colchicine .6mg qd Glipizide 10mg qd Simvastatin 80mg qhs Diovan 320mg bid Clonidine .1mg q12h Hydralazine 50mg bid Metoprolol 25mg bid Furosemide 40mg qd Phos-Lo 667mg qd w/meal Nephrocaps qd Docusate 100mg bid Chemsticks ac & hs Fosrenal 2000mg w/ each meal Case Studies The Role of the Consultant Pharmacist in the Management of Anemia of CKD Case 1 RB is an 85yo male resident of a LTCF Two months ago he was started on ferrous sulfate 325mg bid for “anemia” Follow-up labs Hgb 8.1 g/dl Hct 32% Iron 45 mcg/dl Recent hospital return on epoetin alfa 30,000 units TIW (wt 75kg) Case 1 cont’d CP recommends lab Hgb 8.9 g/dl Hct 35% TSAT 18% Ferritin 92 ng/ml Hgb has not increased significantly over 4 weeks TSAT should be >= 20% Ferritin >= 100ng/ml Case 1 cont’d Consider possible causes for lack of rise in Hgb Appropriate dosing? 30,000 units TIW for 75 kg patient; the recommended starting dose for epo is 50-100 units/kg TIW, IV or SC The starting dose range based on weight would be 37,500 – 75,000 units TIW If Hgb does not increase by 1g/dl after 4 weeks and iron stores are adequate, increase dose by 25% Case 1 cont’d Are iron stores adequate in this resident? No, based on reported labs CP discusses administration of iron with nurses PRN antacid is frequently given with the iron to reduce c/o of GI upset; or, doses are held For optimal absorption, iron should be given 1 hr before or 2 hrs after meals, but may be given with food to reduce GI irritation Case 1 cont’d What action should be taken by the CP? Educate staff on proper administration of iron Recommend to prescriber to increase epo dose to 40,000 units TIW Check iron, ferritin, TSAT in about a month Hgb should be checked at least weekly x 4 after a dosage change (then monthly, when stabilized) Clinically significant improvements may not be seen for 2-6 weeks, but do not adjust dose any more frequently than once per month Case 2 JC is an 80yo female resident of a LTCF Primary Dx: HTN, anemia of CKD Hgb 8.7 g/dl Taking 45,000 units erythropoietin TIW x 4 weeks, Hgb results: Week 1 Week 2 Week 3 9.1 g/dl 10.1 g/dl 11.9 g/dl Case 2 If there is a rapid increase in Hgb (>1g/dl in any 2 week period) OR The Hgb is increasing and approaching 12 Reduce weekly dose by approximately 25% Rapid rise increases risk of exacerbation of HTN ESAs should not be used in patients with uncontrolled HTN