This document contains several case studies related to anemia management in chronic kidney disease (CKD) patients: Case 1 describes a hemodialysis patient with pancytopenia due to secondary hyperparathyroidism causing bone marrow fibrosis. Case 2 involves a CKD patient who developed pure red cell aplasia due to erythropoietin antibodies. Case 3 is a patient with occult colon cancer presenting as iron deficiency anemia. Cases 4 and 5 discuss evaluating and treating iron deficiency anemia in CKD patients. The document also reviews causes of erythropoiesis-stimulating agent resistance and options for treating anemia in CKD.

1. Professor Salwa Ibrahim, MD FRCP(Edin)
Cairo University
Case Studies
Anemia management in CKD
4th CKD course, 15-17 May 2016

2. Case 1
• A 45-year-old man with end-stage renal disease on
hemodialysis
• The patient was pancytopenic (white blood cell count 2.3,
hemoglobin 10.3 g/dL, and platelets 85 KU/L)
• He had no history of malignancy or exposure to marrow-
suppressing agents
• His liver function test result was normal except for a high
alkaline phosphatase of 900 IU/L but normal GGT

3. Laboratory Findings
• His intact parathyroid hormone was 1786 pg/mL (normal 50-
60 pg/mL)
• Serum calcium was 7.2 mg/dL (normal 8.5-10.2 mg/Dl)
• Phosphorous was 4.9 mg/dL (normal 2.5-4.5 mg/dL)

4. Definition of Pancytopenia
• Anemia: hemoglobin < 13.5 g/dL (male) or 12 g/dL (female)
• leukopenia: total white cell count < 4.0 x 109/L
• Decrease in all types of white blood cells (revealed by doing a
differential count)
• Thrombocytopenia: platelet count < 150×109/L.

5. Causes
• Aplastic anemia
• Multiple myeloma
• Overwhelming infections
• Lymphoma
• Myelofibrosis
• Myelodysplastic syndrome
• Leukemia
• Severe Folate or vitamin B12 deficiency
• Systemic lupus erythematosus
• Paroxysmal nocturnal hemoglobinuria
• Viral infections
• Medication
• Hypersplenism

6. Bone Marrow Biopsy
• Bone marrow biopsy revealed fibrotic bone with bony
remodeling, most consistent with renal osteodystrophy

7. Secondary Hyperparathyroidism
• Increased PTH has a direct toxic effect on erythropoietin
synthesis and bone marrow erythroid progenitors
• High PTH promotes the release of cytokines (interleukin-6 and
tumor necrosis factor-α) that stimulate marrow fibroblasts,
resulting in myelofibrosis
• Myelofibrosis has been seen in primary hyperparathyroidism,
so uremic toxin and other factors associated with end-stage
renal disease may play a minor role in marrow fibrosis

8. Treatment of secondary hyperparathyroidism
• Treatment of secondary hyperparathyroidism consists of tight
control of phosphate and administration of active vitamin D, which
inhibits parathyroid cell hyperplasia, suppresses parathyroid
hormone, and increases calcium absorption
• Improvement of hematologic findings often observed after
parathyroidectomy
• However, marrow fibrosis associated with secondary
hyperparathyroidism in patients on dialysis may be irreversible

9. CASE II
• 78-year-old woman had CKD (eGFR 13 ml/min/1.73 m2)
• Was not on dialysis
• Her hemoglobin was 7.7 g/dl
• Eprex dose (4000 U weekly)

10. Follow up
• Her hemoglobin had decreased to 6 g/dl with an
unmeasurable reticulocyte count
• Bone marrow biopsy revealed normal myeloid and
megakaryocyte lines with absent red cell lines
• Positive serum erythropoietin antibody levels

11. Differential Diagnosis
• Pure red cell aplasia
• Thymoma
• Infections
• SLE
• Hemolytic anemia with aplastic crisis

12. Treatment of PRCA
• Eprex was discontinued
• Immunosuppressive therapy was initiated with prednisone
60 mg daily and cyclophosphamide 100 mg daily
• PRBC transfusion

13. • PRCA is a rare syndrome of anaemia associated with low
reticulocyte count, absent bone marrow erythroblasts,
resistance to epoetin therapy and anti-erythropoietin
antibodies
• It has been attributed to the induction of an IgG antibody
directed against the protein moiety of the glycosylated
erythropoietin polypeptide
• PRCA markedly increased after 1998, peaked in 2001 and
then slowly declined thereafter
• 200 cases were described between January 1998 and March
2003

14. CAUSES
• Substitution of polysorbate 80 and glycine for human serum
albumin as stabilizer
• The use of exposed rubber plungers and silicone oil lubricant
in pre-filled syringes
• The shift from the intravenous (i.v.) to the s.c. route of
administration

16. EVALUATION FOR PURE RED CELL APLASIA
(PRCA)

17. Peginesatide
• It was approved by the U.S. Food and Drug Administration for
treatment of anemia associated with chronic kidney disease
(CKD) in adult patients on dialysis
• On February 2013, Takeda issued a press release indicating
that they were recalling all batches of peginesatide from the
market
• The safety endpoint of cardiovascular events and death was
worse for peginesatide than for darbepoetin

18. Case III
• Male patient, Age 60
• eGFR 55 ml/min, creat 1.5 mg/dl
• Hb 8 g/dl
• Iron studies; TSAT 12% Ferritin 100 mcg/l

19. • Iron deficient BUT anaemia unlikely related to
renal failure (anaemia usually once eGFR < 40)
• DD for other causes
– ? Malignancy
– GIT bleeding

20. Malignancy
• Upper GIT endoscopy was requested, revealed NAD
• Colonoscopy revealed Cancer colon

21. Case IV
• 30 female
• ESRD on HDx
• Aranesp 20 mcg SC weekly
• eGFR 5, creat 7 mg/dl
• Hb 8 g/dl MCV 70
• Iron studies: TSAT % 11 Ferritin 100 mcg/l

22. Diagnosis
• Microcytic Anaemia
• Iron deficient
• Rule out other causes then
– Correct Iron with IV Iron infusion
– Re-check bloods. Once iron OK, may need to increase EPO

23. Iron preparations in the market

24. Iron studies
• Ferritin
– Iron storage protein, giving an indirect measurement of
stored iron
– ↓ ferritin always Iron def, but high in inflammation
(inflammatory marker)
• Transferrin
– Transports iron from stores to the bone marrow.
• Transferrin saturation
– Gives a measure of the iron available to bone marow
– Useful to detect functional iron deficiency

25. Iron studies
• Reticulocyte hemoglobin content: less than 29-32 pg/cell is
indicative of iron deficiency
• The percentage of hypochromic red cells: < 6% is indicative of
iron deficiency

27. Ferric citrate
• Oral phosphate binder containing iron

28. Iron added to dialysis solution
• Ferric pyrophosphate citrate (triferic)
• Phase III results showed reduction in ESA doses

29. Iron sucrose (Venofer)
• A popular option, the typical
dosing for Venofer is 100mg iv
dialysis x 10 doses
• Venofer offer fairly rapid release
of iron

30. low-molecular weight iron dextran (CosmoFer)
• Risk of adverse events is so
much lower
• Is given as an intravenous
infusion containing any dose up
to 2000 mg of iron depending
upon the patients’ calculated
iron deficit

31. Ferric carboxymaltose
• Is administered as an
intravenous bolus (containing
500 mg elemental iron) or
intravenous infusion over 30
minutes (containing 1 g of
elemental iron)

33. The increase in haemoglobin concentration
was significantly greater in both IS and FCM compared
with ID (P = 0.04 and <0.01, resp.).

34. Safety of IV iron
• Anaphylaxis
• Infections: iron is vital for growth of microorganisms
• Oxidation: iron is highly oxidative substance that can
promote atherosclerosis

35. Case V
• 54 year-old Male ESRD patient on regular HDx
• Hemoglobin level is 6.7 g/dl
• Serum ferritin 74 mcg/l, TSAT 7%
• Received IV iron 1000 mg

36. • On follow up : hemoglobin level 8 g/dl, TSAT 35 % and serum
ferritin 350 mcg/l
• EPO given 4000 u sc thrice weekly
• After one month Hb was 8.3 g/dl, so EPO dose increased by
50% to 6000u thrice weekly
• Still on follow up, hemoglobin level did not reach the target
despite reaching EPO dose 10.000 U thrice weekly

37. ESA resistance
• 300 IU/Kg/week SC Epo
• 450 IU/Kg/week IV Epo
• 1.5 mcg/Kg/ week darbepoetin

38. Causes of EPO not working
• Iron deficiency ** most common **
• B12 & Folate deficiency
• Inflammation
• ACE inhibitors
• Hyperparathyroidism – bone marrow fibrosis
• Aluminium toxicity
• Inadequate dialysis
• Malignancies, including multiple myeloma

39. Transfuse or not
• In CKD patients wishing to go for renal transplant,
PRBCs transfusion should be avoided
• Given only in severe symptomatic anemia