Managing Anemia and Bone/MIneral Abnormalities in CKD

1. Connie Gilet, ANP UNC Kidney Center/ UNC Healthcare September 2011

2. Objectives  Discuss lab values related to anemia management >Interpret CBC results, including H/H, RDW (red cell distribution width), MCV (mean corpuscular volume) and MCHC (mean corpuscular hemoglobin concentration) >Examine iron study results, focusing on iron saturation and ferritin

3. Objectives  Discuss the complex relationship between calcium, phosphorus, vitamin D and PTH >Review bone and mineral pathophysiology >Discuss why interventions involve thinking about all four of the above lab values >Outline when lab values are “only” abnormal vswhen theyare alarming >Discuss treatment of bone and mineral abnormalities with medications and surgery

4. Objectives  Discuss how dialysis adequacy is determined and used in a clinical setting >Discuss URR, Kt/V and PET, how to calculate these measures and how to interpret the results >Discuss the advantages and disadvantages of URR (Urea Reduction Ratio) vs Kt/V >Examine when, why and how the dialysis prescription should be adjusted

5. Plan  Briefly present basic information for each topic  Hopefully, present new information for each topic  Case studies will help to enhance understanding of information presented

6. Anemia  Anemia is defined as a decrease in red blood cells (RBC’s)

7. Anemia  Decrease in RBC’s can be due to a variety of factors….. >Abnormal destruction of red blood cells (e.g. hemolytic anemia, sickle cell disease) >Lack/decreased cell production from bone marrow (e.g. aplastic anemia, myeloproliferativedisorders) >Blood loss (e.g. GI Bleed) >Lack of substances needed to produced RBC’s >All of the above seen in people with CKD

8. Substances Needed for RBC Formation NECESSARY RELATED INFORMATION SUBSTANCE/STRUCTURE Erythropoietin (hormone) Stimulates bone marrow to produce RBC’s Need adequate nutrients—e.g. Iron, Vitamin B12, Folic acid To produce hemoglobin DNA Chronic inflammation 2/2 infection and/or autoimmune disorders (e.g. Lupus) impairs DNA synthesis => anemia Bone marrow Reticulocyte count reflects ability of bone marrow to produce RBC’s. Retic ulocyte = immature RBC’s Anemia in ESRD, can see decreased RBC production (lack of substances to make cells) and increased retic count. Avery elevated reticcount pointsto increase RBC destruction or hemolysis as a potential cause of anemia. Images from www.google.com/bonemarrow

9. Anemia Management  Current practice >If Hgb less than 10 g/dl x 2, start Epogen/Aranesp >Hgb levels checked at least monthly (KDOQI) >Goal: maintain Hgb between 10 and 12 g/dl >CREATE and CHOIR study >Do not know optimal Hgb for people with CKD >If Hgb exceeds upper limit (12 g/dl) or increases more than 1 g/dl in 2 wks: >Hold the dose (per FDA) >No benefits to hemoglobin > 13 g/dl. In fact, increases the risk of clots, vascular events (heart attack and stroke) and death

10. Anemia Management  “New?” >TREAT--Trial to Reduce Cardiovascular Events with Aranesp Therapy (people not on dialysis) >Study completed in 2009 >Recommends Hgb >10 and <11 g/dl >Reduce risk of clots, heart attacks, stroke and death >Several other studies currently underway >Will guidelines for people on dialysis also change?

11. Anemia  Let’s define lab values reported in a CBC results: >Red blood cells >Hemoglobin >Hematocrit >Reticulocyte count >MCV (mean corpuscular volume) >MCHC (mean corpuscular hemoglobin concentration) >RDW (red cell distribution width)

12. Red Blood Cells and Hemoglobin  Red blood cells (RBC) >Normal life span 120 days/80-90 days if on dialysis >Decreased life span due to toxic, uremic environment* >Composed of mostly water and hemoglobin  Hemoglobin >Hgb molecule made of iron and protein >The predominant protein in RBC >Carries oxygen *Ly, et al (200$)

13. Hemoglobin  CKD abnormal H/H; what are critical Hgbvalues?  Hgbvalues below 5 g/dl can cause heart failure  Hgbvalues above 13 g/dl can cause CV events/death* KDOQI Anemia Guidelines: 2007 Update

14. Hematocrit  Hematocrit >% of RBC in plasma (liquid part of the blood) >Increase/decrease of plasma volume affects the hematocrit values >Decrease occurs with over hydration (diluted) >Increase occurs with under hydration (concentrated blood volume) >How would Hct change before/after dialysis? >What lab value used to dose epo? Why? >If RBC and Hgb are normal, estimate Hct by multiplying the Hgb times 3. (10 x 3 = 36)

15. Reticulocyte Count  Reticulocytes are immature forms of erythrocytes (also called RBC’s) >Up to 1.5% “normal” in men >Up to 2.5% “normal” in women >Low retic count seen with folic acid deficiency >High retic count seen when the bone marrow is responding to an increase need for RBC’s. Bone marrow can’t produce enough mature RBC’s fast enough, so it does the next best “thing”, increases the production of immature RBC’s >What would you expect a reticcount to be in a person with ESRD on dialysis?

16. RDW (RBC Distribution Width)  RDW >Indicator of variation in the size of red blood cells >Values > 14.5% = RBC vary a lot in size >Immature red cells usually larger >RDW increased in those with ESRD Why? Bone marrow working hard to produce enough red blood cells but can’t produce enough mature cells to keep up with demand.

17. MCV and MCHC Results  MCV (mean corpuscular volume) >Measures average size of RBC  MCHC (mean corpuscular hemoglobin concentration) >Measures % of hemoglobin in the RBC >Hgb/Hct x 100  Why should I care about the MCV and MCHC values?

18. What the MCV and MCHC Tells You Test Normal Range Value Below Range (Microcytic = small than normal) Value Above Range (Macrocytic = larger than normal) Value Within Range MCV (mean corpuscular volume) (size of RBC) 80-100 femoliters < 80 = Iron deficiency anemia, congenital anemias > 100 = Folic acid deficiency, B12 deficiency, myelodysplastic, leukemias 80-100 = Anemia due to blood loss or a chronic disease MCHC (mean corpuscular hemoglobin concentration) (% RBC in fluid) 32-35% < 32% = Iron deficiency anemia > 35% = same as above 32-35% = Anemia due to blood loss or a chronic disease

19. Anemia  Case study >E.R. is a 39 y/o Hispanic female. Separated with 3 children, ages 12, 13 and 19 years old. >ESRD of unknown etiology; transplant in 2003. Kidney was from her sister. >Rejection (per renal biopsy) August 2010; restarted dialysis in August 2010. >Receives dialysis via ED every 4-5 days. >Receives Aranespevery 2-3 weeks with dialysis.

20. Putting It All Together  Before looking at lab values, you should be asking…. >What are normal vs. abnormal values? >What information does the abnormal lab values “tell” you? >Are there any alarming/critical lab values?

21. CBC Results Test Range Patient = E.R. RBC (red cell count) 4.00-5.20 2.99 million HGB (hemoglobin) 12-16 g/dl 9.2 g/dl HCT (hematocrit) 36-46 % 26.9 % Retic count (reticulocyte count) 0.5% - 1.5%/2.5% 3.0% MCV (mean corpuscular volume) 80-100 90.0-------------75% MCHC (mean corpuscular hemoglobin concentration) 31-37 34.0%-----------28% RDW 12-15 % 18.0% B12 193-900 pg/ml 843 pg/ml Folic Acid 2.7 – 20.0 ng/ml > 20 ng/ml

22. Anemia  Case Study >32 year old male, T.A., mentally challenge >Lives with his mother >ESRD on hemodialysis 2/2 neurogenic bladder and >Gout >HTN >Sickle cell trait

23. CBC Results Range Test Patient = T.A. RBC (red cell count) 4.00-5.20 3.52 HGB (hemoglobin) 12-16 g/dl 10.8 g/dl HCT (hematocrit) 36-46 % 32.2 % Retic count (reticulocyte count) 0.5% - 1.5%/2.5% Not reported MCV (mean corpuscular volume) 80-100 FL 91 FL MCHC (mean corpuscular hemoglobin concentration) 31-37 g/dl 34 g/dl RDW 12-15 % 16.4%

24. Measuring Iron  Where iron is found  Two tests used to estimate iron stores: Ferritin and Saturation >Ferritin >Is a protein that binds to iron; helps to transport iron in the body >Most ferritin is found in the liver, spleen, muscle and bone marrow with a small amount found in the blood >Normally, 1 ng of ferritin (in blood) = 10 ng of iron stores (in liver, spleen, muscle and bone marrow) >Ferritin is a proxy measure for iron stores and has it ‘s limitations. Image retrieved August 11, 2011 from http://www.google.com/imgres?q=diagram+iron+stores+body&um...

25. Ferritin  Low ferritin levels usually indicates iron deficiency  High ferritin levels, however….. >Does not necessarily indicate adequate iron stores >Many factors can increase ferritin levels, e.g. recent iron infusion, infection, inflammation, e.g. autoimmune disorders, malignancy, blood transfusions (250 mg of iron/1 unit packed red cells) >Wait two weeks before measuring iron stores after giving iron load (more than 125 mg/week) >Can become iron toxic (ferritin greater than 1000) >High levels can be due to inherited disorders or too much iron administration >Toxic levels of iron can cause organ failure and death

26. DRIVE STUDY  Dialysis Patients’ Response to IV iron with elevated ferritin Study (DRIVE) >Provided some clarification for safe upper limits of ferritin levels in hemodialysis patients. >Ferric gluconate (ferrlecit) administration is superior to no iron therapy in anemic dialysis patients receiving epogen and ferritin levels of 500 to 1200 ng/ml and Tsats of <or=25%. Retrieved August 11, 2011 from http://www.ncbi.nlm.nih.gov/pubmed/17267740?dopt=Abstract

27. Iron Saturation  Complete name = transferrin iron saturation or Tsat >Estimates ability to bind iron and transport it to various sites in the body >Serum iron / total iron binding capacity X 100  More sensitive than ferritin; not affected by inflammation/infection

28. Goal for Iron Stores* HD-CKD ND-CKD/PD-CKD* Ferritin > 200 ng/ml Sats > 20% Ferritin > 100 ng/ml Sats > 20% From KDOQI Anemia Guidelines *No RCT to support recommendation

29. Iron Deficiency  Many causes… >Blood loss >Celiac disease (decreases absorption of iron) >Hemolysis (RBC breaks apart) >Gastric bypass (decreases absorption) >Epogen administration, etc.  Must identify cause of iron deficiency before treating

30. Look at Entire Picture  Decreasing ferritin/stable sats/decreasing Hgb = iron deficit >? external iron loss >Need more iron  Decreasing ferritin and increasing Hgb = iron moving from storage to hemoglobin (e.g. in response to epogen administration)  Increasing ferritin and decreasing satsand decreasing Hgb = inflammation >Increase ESA dose

31. Case Study  Case Study >F.L. 86 yo female who attends the anemia/CKD clinic. History significant for…. >HTN >CKD IV >Anemia >Unable to tolerate po iron supplements due to GI upset

32. Case Study TEST/ INTERVENTION DATE = 11/8/2010 DATE = 12/22/2010 DATE = 1/17/2011 Hemoglobin 8.8 (decreasing) 7.7 9.5 Hematocrit 28.4 25.3 30.9 Saturation none 10% none Ferritin none 33 none BUN 54 (increasing) 55 39 Creatinine 2.4 (increasing) 2.35 2.04 GFR 23 ml/min 24 ml/min 28 ml/min Aranesp dose Increased to 200 mcg 200 mcg 200 mcg

33. Take Home Points for Anemia and Iron Administration  Look at hemoglobin trends >If Hgb is decreasing >Don’t miss other causes of anemia >Increase epogen  Look at iron sats and ferritin >If iron sats and ferritin both low, give iron >Remember iron is stored in places we don’t measure, so look at the entire clinical picture

34. Bone and Mineral Balance  Briefly discuss the four primary “players”: >Vitamin D >Calcium >Phosphorus >PTH  Discuss the complex interdependence amongst calcium, phosphorus, vitamin D and PTH

35. Vitamin D2-3  Vitamin D comes from sun, food and our body  25-hydroxyvitamin D2 produced in the liver  Normally kidneys produce an enyzme that converts D2 to D3 (1,25 dihydroxyvitamin = calcitriol)

36. Vitamin D  A complex group of fat-soluble substances (D1-D5) >D2 = ergocalfciferol >Sources >Food—only found in seafood, mushrooms, egg yolks and fortified foods >OTC: Generic Vitamin D >Prescription: Drisdoll >Changed in the liver to 25-hydroxycholecalciferol (25-OH) >Measured in those with CKD Stages 3-5 >25-OH changed in normal kidneys to 1,25 dihydroxycholecalciferol >Measured in those with CKD Stage 3-6

37. Vitamin D3  D3 = cholecalciferol >D3 = 1,25 dihydroxycholecalciferol >Decreased amounts produced in CKD >Also referred to as active Vitamin D >Sources: Calcitriol (Rocaltrol) Hectoral (doxercalciferol) Zemplar (paricalcitrol) Sunlight (converted to Vitamin D3 in the skin)

38. Vitamin D  Lab ranges >25OH = < 30/32 >1,25 = 18-78 >Controversy on what level is normal & too high  What does Vitamin D do? >Helps maintain serum calcium and phosphorus levels/regulates release of calcium and phosphorus from the bone >Increases calcium absorption from the intestines >Suppresses PTH synthesis

39. Calcium  Functions >Maintains bone structure >Plays a major role in nerve conduction >Assists with muscle contraction/relaxation  Most calcium found in bone  Serum calcium binds to albumin >Serum calcium = 6.5 Albumin = 2.5 >0.8 x (4.0-2.5) + 6.5 = 7.7 >Corrected serum calcium more accurate >Corrected total calcium 8.4 to 9.5 mg/dl

40. Hypercalcemia  Long term consequences for those with CKD >Increased risk CV calcifications (larger arteries) >Calciphylaxis (soft tissue)  Serum calcium > 13.0  Causes >Medications (calcium acetate, zemplar)  S/S of hypercalcemia >Depression, anxiety, muscle weakness, cognitive dysfunction, fatigue, hypertension, constipation >ECG changes/arrhythmias

41. Hypocalcemia  Serum calcium < 6.5 >Numbness/tingling in perioral area, fingers, toes >Muscle cramps or tetany (muscle spasm or tremors) >Seizures http://morningreporttgh.blogspot.com/2010/03/h ypocalcemia.html community.wegohealth.com

42. Hypocalcemia  Causes >CKD (usually CKD Stages 5 & 6) >Medications (e.g. Cinacalcet, Hectoral) >Rapid correction of acidemia (CO2 low) during hemodialysis can trigger tetany and seizures >”Hungry Bone Syndrome” after parathyroidectomy >Severe decrease in serum calcium due to abrupt decreased in PTH release; change upsets balance of calcium moving to and from the bones

43. Phosphorus  85% of phosphorus is found in bone and teeth  Has many functions >Helps maintain health bone and teeth >Essential for storage of energy (ATP) >Helps maintain tissues, cells, DNA, and RNA  Phosphate = 3.5 to 5.5 mg/dl

44. Hyperphosphatemia  Serum levels greater than 12  May be asymptomatic  Signs and symptoms, if present >Pruritus, rash, bone and joint pain

45. Elevated Phosphorus  What is the role of dietary restriction in decreasing serum phosphorus levels? >Much phosphorus is found in high quality protein foods >Need high protein intake to prevent muscle wasting but can limit dairy, some vegetables, processed foods and colas >Goal protein intake = 1 gm protein per kg of body weight per day

46. Phosphorus and Protein  70 kg person = 70 gms prot  Breakfast >Two eggs >Two pieces toast  Lunch >Grilled chicken-4 oz >Garden salad-2 cups  Dinner >Steak-4oz >Green beans-1cup >Apple-medium, fresh FOOD PHOS* PROTEIN* Eggs 170 mg 12 gms Bread 60 mg 4 gms Chicken 265 mg 36 gms Garden Salad 340 mg 2 gms Steak 265 mg 32 gms Gr. Beans 25 mg 1 gms Apple 40 mg 0 gms 1355 mg 88 gms *www.davita.com

47. Calculating Phosphorus Balance  Intake = 1000 mg per day X 7 days = 7000 mg per week  GI tract absorbs 60% of what is consumed >7000 mg X 0.6 = 4200 mg phosphorus/wk  800 mg eliminated/HD treatment = 2400 mg/wk 4200 – 2400 = 1800 mg  Net + phosphorus balance 1800 mg per week >1 Renagel binds about 100 mg phosphorus 1 pill/meal X 100 = 300 x 7 days = 2100 mg/wk 1800 mg – 2100 mg = 300 mg negative balance/wk

48. Hypophosphatemia  Serum levels less than 2.5  May be asymptomatic  Causes >Not eating =>> malnutrition  Symptoms, when present >Muscle weakness (e.g. diplopia, dysphagia) >Ventricular arrhythmias >Neuro manifestions (e.g. confusion, coma, seizures) >Poor oxygenation (phosphorus and ATP)

49. Changes During Progression of CKD  Kidneys’ excretion of phosphorus decreases, causing the serum phosphorus to increase  Kidney does not reabsorb calcium and vitamin D is not activated, causing decreased serum calcium levels  Vitamin D is not activated, causing parathyroid gland hypertrophy and hyperplasia >Decreased serum calcium and increased serum phosphorus levels caused increased secretion of PTH

50. Changes During Progression of CKD  Kidney dysfunction results in >Calcitriol (Vitamin D) deficiency >Hyperphosphatemia –kidneys no longer excrete phosphate >Decreased Vitamin D and increased phosphorus causes hypocalcemia  Major factors responsible for stimulating PTH are >Hypocalcemia (sensed by receptors on parathyroid gland => increased secretion of PTH) >Decreased vitamin D levels (1,25 dihydroxyvitamin D = calcitriol) >Hyperphosphatemia