Anemia and Iron Management With CKD: The Challenge Connie Gilet, ANP UNC Healthcare/Kidney Center May 23, 2012

Outline Brief history of anemia management Guidelines: what they are and what they are not Research about anemia management Research about iron administration Gaps in the research anemia & iron research Information about ESA and Iron medications Using the new guidelines: case studies

Brief History Epogen approved for treatment of anemia of CKD, June 1989 Prior to 1989, blood transfusions used to treat anemia (about 15% received blood) >Blood transfusions increased the likelihood of developing antibodies that could make a kidney donor transplant difficult/impossible >Adverse effects, including vol. & iron overload

Comparing ESAs Chemical Structure Epotein alfa (Epogen, Procrit) Darbepoetin (Aranesp) Approved 9/2001 Peginesatide Synthesis Genetically engineered from Chinese hamster ovary cells Synthetic Route of administration IV/SC CKD-ND CKD-HD Initial Dosing Amounts 50-100 units/kg 0.45 mcg/kg 0.04 – 0.08 mg/kg Dosing Schedule Adapted from Dutka 2012 3 times/week Weekly – 2-8 wks Every 4 weeks

Peginesatide: New ESA Studied in USA/Europe. Mean f/u 67.4 weeks Studies funded by Affymax and Takeda Drug was approved by FDA 3/2012 >Greater than 25,000 received medication Pulled from the market 2/2013 >0.2% dialysis pts have severe allergic rx >0.02% fatal rx with first dose, 30 mins after administration (N = 3) >Reasons for reactions are unclear Emerald 1 & 2 (n=1626) = peginesatide and epogen for HD pts. Pearl 1 & 2 (n = 983) = peginestatide and aranesp for non dialysis pts. CV outcomes greater in peginestatide group than aranesp.

Definitions: KDOQI and KDIGO >Kidney Disease Outcomes Quality Initiatives >Created 1995 by National Kidney Foundation >Publish practice guidelines KDIGO >Kidney Disease Improving Global Outcomes >Created 2003 >Independent, non profit organization governed by multi-discipline international board and managed by the National Kidney Foundation

Brief History of Treatment Guidelines KDOQI/KDIGO Federal Drug Administration (FDA) Hemoglobin Goal Year Hemoglobin Goal Year 11-12 g/dl 1997 10-11 g/dl Year?- initial recommendation Up to 13 g/dl 2006 10-12 g/dl 1994 11-12 g/dl 2007 10-11 g/dl 1997 More complex (KDIGO) 2012 More complex guidelines: 2006 -Lowest dose to avoid PRBC -No epogen to treat anemia symptoms or QOL -Dec dose if Hgb inc > 1gm 2 wks No longer recommend 2011 Hgb range

Guidelines: What They Are And Are Not What They Are Not Provides information Not a standard of care Based on evidence and expert advice, helps with making informed decision Not suitable for all; can not account for all variations in people (age, co-morbidities, genetics), provider, and system variants Have been shown to improve quality of care for a population One size DOES NOT fits all , while a guideline can apply to the population, it may not apply to an individual

Consequences Of Using Treatment Guidelines Guidelines supported increasing Epogen doses >>> Hgb values increased… >Hgb 9.6 in 1991 >>>>> >Hgb 12.0 in 2006 (90% of those receiving epogen on dialysis) >Hypothesis: higher Hgb would decrease cardiovascular complications (e.g. LVH) >Improved quality of life (e.g. functional status) How did the research support the guidelines?

Evolution of Guidelines: Is More Better? Since Epogen successful to increase Hgb, why not treat anemia to targeted “normal” levels? >Women ~ 12 g/dl and men ~13 g/dl or Hct 30% vs 42% Larger doses of Epogen given to achieve these higher Hgb (without much research to support)

What Does the Research Tell Us How To Treat Anemia?

How Does One Interpret Research Data? Few important facts about research studies…. Randomized control trial (RCT) done prospectively with a large number of subjects followed for a long time produces the most reliable data. May want to base therapy on results. VS Observational study done retrospectively with a few subjects, may provide ‘food for thought’ but don’t want to base therapy on results Can not generalize research results to groups other than the one(s) studied

Normal Hematocrit Trial RCT, prospective study (1998) of 1233 people on HD with cardiac disease compared “low” Hct (30%) vs “normal” Hct (42%) >Average age 65 >Many with diabetes >Followed for average 14 months >Epogen doses 160u/kg/week for “low” group vs “normal” group 460u/kg/week Besarab, et al, 1998

Normal Hematocrit Trial Although difference did not meet statistical significance, greater mortality, MI and vascular clots in group with “normal” Hct values, trial was stopped before all enrolled No improvement in QOL with higher Hct levels Besarab, et al, 1998

“CHOIR” Study Correction of Hemoglobin and Outcomes in Renal Insufficiency RCT study (2006) looked at 1432 patients with CKD, stage 3 and 4 >Compared Hgb >= 13 to 11.3 gm/d: Group with Hgb >= 13 had increased risk of MI, hospitalization, stroke, and death. >Terminated early >Similar improvements in quality of life After the study, goal Hgb reverted 11-12 g/dl Singh, et al 2006

“CREATE” Study CV Risk Reduction by Early Anemia Treatment with Epoetin Beta RCT (2006) of 603 CKD-ND (c/s diabetes) people >Compared Hgb 13-15 to 10.5 to 11.5: risk of CV events not lowered by correcting the anemia >Epogen doses 5,000 VS 2,000 units per week >After about 3 years, Hgb 13-15 group 22% greater first CV event (not statistically significant) >Renal function declined faster >Higher QOL scores Drueke, et al, 2006

“Treat” Study Trial to Reduce CV Events with Aranesp Therapy RCT study (2009) of 4, 038 CKD 3 & 4 with diabetes. Compared treatment with placebo with Aranesp to achieve a Hgb of 13 gm/d >No difference death or progression to ESRD >Greater doses increased risk for stroke, venous clots and possibly, malignancy. >Reported a small improvement in fatigue and QOL >54% of those had Hgb of 13 >49% of those receiving placebo also reported improvements in fatigue and QOL Pfeffer, et al, 2009

Children/PD And Anemia Studies? None

Research About Anemia Management And Transplant? Retrospective study (2009), non randomized. >1794 transplant recipients >Hgb > 12.5 g/dl associated with increased mortality

What Are The Outcomes If Hgb Is High Without ESA? DOPPS study >DOPPS = Dialysis Outcomes and Practice Patterns Study >Prospective, observational with 20 counties >545 of 29,796 (1.8%) folks on HD maintained a Hgb >12.0 g/dl for 4 months without ESA >No increase in mortality noted Goodwin, et al, 2009

Anemia Management With ESA Resistance? About 15% of ESRD are ESA resistance “Choir” Study >High dose Epogen associated with 57% increased risk death, MI, HF and stroke “Treat” Study >Poor response to Aranesp >>increase risk of CV adverse events

Summary Of Research Findings For Anemia Management Most research done on adults with CKD-ND and some with those receiving HD “Reasonable” dose of ESA probably has some benefits Do not want Hgb >= 13 with ESA dosing Individualize epogen therapy balancing the pros (feeling better/dec blood transfusions) vs the cons (inc chance MI, stroke and death)

Summary Of Research Findings Those who are ESA resistant and treated with high ESA doses may have more adverse outcomes (e.g CV and death). Naturally occurring high Hgb probably less risky than a high Hgb achieved with ESA

Gaps In Research Data Most of the research done on those with CKD, not on dialysis, older than 60 years with many comorbitities (e.g. DM, HTN) >Apply findings to groups not studied with caution. For example, how much Epogen do you give to a 25 year old who was started on HD due to IgA nephropathy and has no comorbidities? Little info on PD, children or those transplanted

Gaps In Research Data What is the optimal Epogen dose frequency; one a week, twice a week, three times per week? While research demonstrates Hgb > 13.0 are associated with adverse outcomes, no data on the benefits vs. adverse outcomes of Hgb between 11.5 and 13.0 g/dl

Gaps In Research Data Doses of Epogen varied widely to obtain Hgb values greater than 13. >ESA resistant patients received the highest Epogen doses? How do we better ID those who are resistant? How much Epogen is too much? How does one decide how much Epogen to administer in this group?

Most Recent KDIGO Guidelines: CKD-ND Individualize dose; use the lowest dose that reduces need for blood transfusion >Target Hgb range not provided >Consider starting ESA when Hgb below 10 and reduce or stop ESA when Hgb above 10

Most Recent FDA Guidelines: CKD-ND Consider ESA when Hgb < 10 g/dl. If Hgb > 10, reduce or interrupt dose

UNC CKD-ND Anemia Guidelines Outpatient anemia clinic guidelines for CKD III to V >Start Aranesp at 50mg/kg >Goal Hgb between 9.5 and 10.4 >If Hgb >= 11.0 hold Ananesp

Most Recent KDIGO Guidelines: CKD-HD Use ESA therapy to avoid Hgb below 9.0 Start ESA between 9 & 10. Initiate therapy less than 10 and reduce or interrupt if Hgb exceeds 11.5

Most Recent FDA Guidelines: CKD-HD CKD-D: start ESA when Hgb < 10. >Reduce or interrupt when Hbg > 11.0

Recent KDIGO Guidelines For Both CKD-ND and CKD-HD Base dosing decision/initiation of ESA >How rapidly Hgb decreasing >Response to Iron administration >Risks of transfusion and ESA therapy >Symptoms due to anemia Don’t use ESA to maintain Hgb > 11.5, unless willing to take the risk Don’t use ESA to inc Hgb > 13 g/dl

Recent KDIGO Guidelines For Both CKD-ND and CKD-HD Prefer decreasing dose vs holding dose ESA Use ESA’s with GREAT caution in people with CKD if malignancy, past or current, or history of stroke Blood transfusions may be preferred if > Hemoglobinopathies, ESA resistance, Malignancy, Stroke Address all correctable causes of anemia before starting ESA

Guidelines For Anemia Management With ESA Resistance FDA-inadequate response to ESA over 12 week escalation period, no further dose increases Per KDOQI: Evaluate “for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered.”

KDIGO Guidelines For ESA Hyporesponsiveness Initial >No inc Hgb from baseline after 1 month of weight-based dosing = hyporesponsive > If hyporesponsive, suggest no inc dose beyond doubling initial weight-based dose (50 to 100 u/kg) Subsequent (acquired) >If previously stable Hgb, may inc 50% beyond dose at which stable (no data to support) >Avoid inc dose beyond 2 x dose at which Hgb had been stable

KDIGO Guidelines For ESA Hyporesponsiveness Management >Treat cause of poor ESA response >If poor response remains, balance benefits/ burden of >Decrease in Hgb >Continuing ESA >Blood transfusions (All 2D = Suggest and very low quality evidence)

Correctable Vs Not Correctable Causes of Anemia “Easily” Correctable Potentially Correctable Not Correctable Non-adherence Hyperparathyroidsm PRCA (pure red cell aplasia) Malignancy Malnutrition Hemoglobinopathies (group of disorders affecting the red blood cells) B12/Folate deficiency Under dialyzed Bone Marrow Disorders Hypothyroidism Hemolysis ACE-inhibitors Bleeding Iron deficiency Infection/inflammation Adapted from Drueki & Parfrey 2012 PRCA-red cells don’t form normally in the bone marrow

Oral Iron Medications Dose Elemental Iron Side Effects Ferrous Fumarate (buy on-line: 100 pills for about $30) 325 mg 108 mg iron Upset stomach, constipation Ferrous Sulfate 65 mg iron Ferrous Gluconate Vitamin C increases absorption of iron. Take between meals with 8 oz water. 35 mg iron

IV Iron Medications Elemental Iron Dosing Side Effects Ferrlecit (Sodium ferric gluconate) 62.5 mg/ml 125 mg for 8 doses Flushing, HA, fever, chills, dec BP Venofer (Iron sucrose) 20 mg/ml 100 mg for 10 doses Ferraheme (Ferumoxytol) 39 mg/ml 510 mg; 2 doses 3 to 8 days apart INFed (Dextran) 50 mg/ml Use formula Test dose used. Can cause severe allergic reactions Ferrlecit and Venofer had the lowest reported adverse events of this group. Dailie 2012

Anemia Management and Iron FDA Black Box warning is 2007 >> decreased Epogen doses >As Epogen doses decreased, IV iron usage increased >% dialysis patients receiving IV iron increased from 57% to 71% between 8/2010 to 8/2011.* *Pisoni, et al 2011

Iron: Where It’s Found And How It’s Measured Most iron found in liver and red blood cells. Also present in bone marrow, spleen and in all cells >Body hoards and recycles iron Two tests used to estimate iron stores, ferritin and transferrin saturation (TSAT) >Ferritin: measures protein inside cells that store iron > TSAT: % serum iron and total iron binding capacity. 20% sats = 20% of the binding sites of transferrin occupied by iron

Why We Care About How to Measure Iron Stores Can have too much of a good thing >>> iron toxicity Iron toxicity >> organ damage >Lungs - fluid >Liver failure - n/v and bleeding >CV - hypotension >Neuro - drowiness, seizures and coma >Death

What Do Iron Tests Tell You? If sats <30% and ferritin <500 = iron deficiency If sats 25% and ferritin 650 ??? >Increase in ferritin can be due neoplasm, inflammatory (including autoimmune dx) or infectious state OR >Iron overload Should iron be given if sats low and ferritin high?

Research About Iron and CKD Observational study (2004) >No relationship between IV iron & mortality >Subjects had depleted iron stores and no systemic inflammation * Several studies claim people on dialysis have iron overload per labs, yet no clinical symptoms of iron overload ** *Feldman, et al, 2004 **Conavese, et al, 2004. Ferrari, et al, 2001. Rostocker, et al, 2012

More Research About Iron and CKD: Drive I (2007) RCT, prospective study of CKD-hemodialysis >Low sats (<=25%) and high ferritin (500- 1200) >Hgb <= 11 and Epogen >= 225u/kg/week Group Intervention Outcomes One 1 gm ferric gluconate + 25% increase epogen 1.6 g/dl inc Hgb Two 25% inc epogen and no iron 1.1 g/dl inc Hgb

DRIVE I and II Drive I >Showed no adverse effect when ferritin levels high (up to 1200) and sats low >Only followed 134 people for 6 wks Drive II >Observational study: Those who received iron maintained Hgb for 12 weeks despite lower Epogen doses

Other Iron Studies Study (2011), prospective study with 25 people with CKD III to VI found, after infusion of IV iron, increases of iron in liver don’t correlate with increases in serum ferritin or TSATs Little data on long-term clinical benefit of iron administration other than increasing Hgb Ferrari 2011

Summary of Iron Research Data If the sats are low (< = 30) and ferritin < = 500, ok to give oral or IV iron If the sats are low and ferritin > 500, unclear status of iron stores >>> dosing??? >Individualize care: balance pros and cons of giving IV iron

KDIGO Guidelines For Iron Administration Balance potential benefits with risks of harm For adults with CKD-ND, trial of iron if TSAT is <=30% & ferritin is <=500 ng/ml CKD-HD: If Hb increase or Epogen dose decrease desired, try iron. Avoid administering IV iron to patients with active systemic infections. (Not Graded)

KDIGO Guidelines For Iron Administration For CKD ND patients who require iron supplementation, select route of iron administration based on severity of iron deficiency, availability of venous access, response to prior oral iron, side effects with prior oral or IV iron therapy, patient compliance, and cost. (Not Graded) Guide subsequent iron administration in CKD patients based on Hb responses to recent iron therapy, as well as ongoing blood losses, iron status tests (TSAT and ferritin), Hb concentration, ESA responsiveness and ESA dose in ESA treated patients, trends in each parameter, and the patient’s clinical status. (Not Graded)

Iron Management And Children For all pediatric CKD patients with anemia not on iron or ESA therapy, we recommend oral iron (or IV iron in CKD HD patients) administration when TSAT is <=20% and ferritin is <=100 ng/ml 100 ug/l). (1D) For all pediatric CKD patients on ESA therapy who are not receiving iron supplementation, we recommend oral iron (or IV iron in CKD HD patients) administration to maintain TSAT >20% and ferritin >100 ng/ml. (1D) (1D = Recommended but very low quality of evidence)

Anemia Management And Children Data lacking for adults/very little data, if any, for children. KDIGO = Hgb between 11 & 12 UNC Kidney Center: Goal = Hgb 10-12 HD PD/CKD Children < 5yrs 200-300 units/kg/week 100-150 units/kg/week Children > 5 yrs 150 units/kg/week 100 units/kg/week Iron goals (give enough iron to achieve values) Ferritin > 100 ng TSAT > 20%

Case Study #1 Mr. C.C. is a 70 year old male with >Hx: CKD IV, IDDM, CAD with two stents, TIA >Meds = 3 HTN, Zocor, oral iron bid, ASA, insulin >VS/Labs: BP 135/82, Creatinine 2.6, GFR 25 ml Hgb 9.4, Ferritin 110 ng, Saturation 19% Weight = 70 kg Should Mr. C.C. receive an ESA? IV iron?

Case Study #1 Mr. C.C. receives IV iron, repeat labs are… >Ferritin 350, Sats 35%, Hgb 9.5 Should Mr. C.C. receive epogen ? >When Hgb below 10, consider… >Rate of Hgb decrease >Prior response to iron >Risk of needing transfusion >Symptoms 2/2 anemia

Case Study #1 Mr. C.C. was started on Aranesp 40 mcg. Labs drawn 2 weeks after dose given: >Hgb inc from 9.5 to 9.6 >Ferritin inc from 350 to 500 , >Sats dec from 35 to 31% >No c/o SOB or change in energy level >With a history of TIA, CAD, do you want to increase the Aranesp dose?

Case Study #2 Ms. A.A. is a 52 year old on HD with >Hx: DM, HTN, CAD, PVD and SVC syndrome >Meds: 4 HTN, ASA, Warfarin, Lantus >VS/Labs: BP 150/90, Weight 60 kg Hgb 9.6, Ferritin 750, Sats 29% >Receiving Epogen 3,000 units 3 x per wk Just completed 1000 mg of ferrlecit IV

Case Study #2 Ms. A.A. is a 52 year old on HD with >Hx: DM, HTN, CAD, PVD and SVC syndrome >Hgb 9.6, Ferritin 750, Sats 29% Do the guidelines support giving additional iron? Do the guidelines support increasing the Epogen dose?

Unanswered Questions Is there a maximum or toxic dose of ESA? What makes someone ESA resistant? How does one manage ESA resistance? Does dosing frequency matter? >Is it better to give 2,000 units 3 x per week or 6,000 units once per week? How does Hgb variability due to ESA dosing changes affect outcomes?

What Is The Optimal Hgb Goal? Is this the question we should be asking? Our patients are all different; different genes, comorbidities, functional abilities, needs and expectations >Should the question not be ?…. >For each individual, at what Hgb level are the risks minimized (e.g. CV) and the benefits maximized (less fatigue, feel “better”) >Intern’l task force examining this question

Stay Tuned…

References Bailie, G.R. (2012). Comparison of rates of reported adverse events associated with I.V. iron products in the United States. American Journal of Health-System Pharmacy, 69,(4), 310-320. Besarab, A., Bolton, W.K., Browne, J.K., Egrie, J.C., Nissenson, A.R., Okamoto, D.M., Schwab, S.J., & Goodkin, D.A. (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin (Normalized Hct). New England Journal of Medicine, 339, (9), 584-590.

References Cavanese, C., et al. (2004). Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney International, 65, 1091-1098. Coyne, D.W. et al. (2007). Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results from the dialysis patients’ response to IV iron with elevated ferrin (DRIVE) study. Journal of American Society of Nephrology, 18, 975-984.

References Drueke, T.B., Locatelli, F., & Clyne, N. (2006). Normalization of hemoglobin level in patients with chronic kidney disease and anemia(CREATE). New England Journal of Medicine, 355, 2071-2084. Drueke, T.B., Parfrey, P.S. (2012). Summary of the KDIGO guideline on anemia and comment: reading between the guideline(s). Kidney International, 82, 952-960. Dutka, P. (2012). Erythorpoiesis-stimulating agents for the management of anemia of chronic kidney disease: Past Advancements and Current Innovations. Nephrology Nursing Journal, 39 (6), 447-457.

References Feldman, H., et al. (2004). Administration of parenteral iron and mortality among hemodialysis patients. Journal of American Society of Nephrology, 15, 1623-1632. Ferrari, P, et al. (2011). Serum iron markers are inadequate for guiding iron depletion in chronic kidney disease. Clinical Journal of American Society of Nephrology, 6, 77-83. Goodkin, D.A. et al. (2011). Naturally occurring higher hemoglobin concentration does not increase mortality among hemodialysis patients. Journal of American Society of Nephrology, 20, 358-365.

References Heinz, G., Kainz, A., Horl, W., & Oberbauer, R. (2009). Mortality in renal transplant recipients given erythropoietins to increase haemoglobin concentration: cohort study. British Medical Journal, 339, 4081. Kalantar-Zadeh, K. et al (2006). The fascinating but deceptive ferritin: to measure of not to measure it in chronic kidney disease. Clinical Journal of American Society of Nephrology, 1 (Supple 1), S9-S18.

References Kapalon, T. et al (2008). Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Journal of American Society of Nephrology, 19, 372-379. Pisoni, R.L. et al (2011). The DOPPS practice monitor for US dialysis care: trends throught August 2011. The American Journal of Kidney Diseases, 60, 160-165,

References Pfeffer, M. A., Burdmann,E.A., Chen, C.Y., Cooper, M.E., de Zeeuw, D., Eckardt, K., Ivanovich, P., Kewalramani, R., Levey, A.S., Lewis, E.F., McGill, J., McMurray, J., Parfrey, P., Parving, H., Remuzzi, G., Singh, A.K., Solomon, S.D., Toto, R., Uno, H. (2009). Baseline characteristics in the trial to reduce cardiovascular events with aranesp therapy (TREAT). American Journal of Kidney Diseases, 54 (1), 59-69.

References Rostocker, G. et al. (2012). Hemodialysis-associated hemosiderosis in the era of erythropoisis-stimulating agents. American Journal of Medicine, 125, 991-999. Singh, A.K., Szczech, L., Tang, K.L., Burnhart, H., Sapp, S., Wolfson, M., Reddan, D. (2006). Correction of anemia with epoetin alfa in chronic kidney disease, New England Journal of Medicine, 355, 2085-2098.