Definition of anemia, screening, causes, iron profile, iron status, management Spectrum of mineral bone disease and management

1. Presentation by :
Dr Binay Kumar
2nd year PGT
Department of
Medicine
Management of Anemia and
Mineral Bone Disorders in CKD
Mentor:
Dr Pankaj Hans
Associate professor
Department of
Medicine
PMCH Patna
Unit Chief:
Dr Rajan Kumar
Associate professor
Department of Medicine
PMCH Patna

2. Definition of Anemia:
Anemia is defined by the World Health Organization (WHO) as
a hemoglobin (Hb) concentration <13.0 g/dL for adult males and
postmenopausal women and
a Hb <12.0g/dL for premenopausal women
Same definition was given by KDIGO guidelines for renal anemia

3. Causes of Anemia in CKD
1. Relative erythropoietin deficiency(most important)
2. Diminished red blood cells survival
3. Bleeding diathesis
4. Iron deficiency
5. Hyperparathyroidism/bone marrow fibrosis
6. Chronic inflammation
7. Vitamin B12 or Folate deficiency
8. Blood loss during dialysis
9. Comorbid conditions-Hypo/hyperthyroidism, pregnancy,HIV, Autoimmune
disease, immunosuppressive drugs

4. Treatment benefits of Anemia in CKD
Decrease mortality/morbidity
Reduce left ventricular hypertrophy
Increase exercise tolerance
Increase quality of life

5. Anemia work-up
Preliminary investigations
CBC with Red cell indices
PBS
Absolute reticulocyte count
Iron profile (%Transferrin saturation, Serum ferritin,TIBC)
Stool guaiac test
Serum Folate,Vit B12
Bone marrow aspiration/biopsy

6. Iron status
Presence or absence of storage iron -Serum ferritin
Availability of Iron to support ongoing erythropoiesis-TSAT(Serum
iron ×100/TIBC)

7. Treatment Options
Iron(intravenous/oral)
Erythropoiesis stimulating agents (ESA)
Blood transfusion
Folic acid and Vit B12

8. Use of iron to treat anemia in CKD
1. To treat Iron deficiency
2. To prevent development of iron deficiency in ESA treated patients
3. To raise Hb level in presence or absence of ESA treatment
4. Reduce ESA dosing in patients receiving ESA treatment

9. When to start iron therapy?
For adult CKD patients with anemia not on iron or ESA therapy,a trial of iv
iron (or in CKD ND patients alternatively a trial of 1-3 months of oral iron
therapy)if:
1. An increase in Hb concentration without ESA treatment is desired
2. TSAT is <30% and ferritin is <100mcg/L

10. For adult CKD patients with anemia on ESA therapy,who are not receiving
iron supplements ,a trial of iv iron (or in CKD ND patients alternatively a trial
of 1-3 months of oral iron therapy)if:
1. An increase in Hb concentration or a decrease in ESA dosing is desired
2. TSAT is <30% and ferritin is <100mcg/L

11. When should not to give iron?
Routine use of iron supplementation in patients with TSAT >30% or
serum ferritin>500mcg/L is not rrecommended

12. IV or Oral Iron
• Parenteral therapy is the recommended route for all CKD patients, because of
poor oral absorption in this state.
• Most CKD patients receiving ESA treatment require parenteral iron therapy to
meet increased requirements.
• Oral therapy is limited by poor absorption and non adherence with therapy due
to adverse effects.
• Consider oral iron supplements in ND or PD patients without iv access or
maintenance therapy in ND or PD patients.
• Oral route is not recommended in HD patients.

13. Oral iron is typically prescribed to provide approximately 200mg of
elemental iron daily
(for instance ferrous fumarate 300 mg twice daily ,each pill provide 98.6 mg
elemental iron)
Liposomal iron and citrate forms are newer formulations having better git
absorption and tolerance.

14. Iron Therapy
Oral formulations- sulphate, ascorbate, fumarate, polysaccharide
complex,liposomal iron,citrate (newer)
Parenteral(IV) formulations- dextran, gluconate, sucrose
Newer- ferric carboxymaltose, ferumoxytol, and iron
isomaltoside
In patients with CKD 5D,IV formulations are the only form to be used.
Newer formulations are associated with significantly fewer side effects.
IV iron therapy should be guided by the iron status of the patients rather than
the empirical treatment.Approx 1000mg of iron over 2-3 weeks is necessary to
overcome the deficiency.

15. Monitoring Therapy
Tests Recommended range
Serum ferritin 100-500 mcg/L
Transferrin saturation 20-40%
Hypochromic red cells <10%
Reticulocyte Hb content >29pg/cell
Markers of Iron status in CKD Patients

16. ESA THERAPY

17. Types of erythropoietin stimulating agents
First generation ESA
Erythropoietin alpha
Erythropoietin beta
Second generation ESA
Darbepoietin
Third generation ESA
CERA(continuous erythropoietin receptors activator)

18. Erythropoietin alpha and beta
Manufacture of rHuEPO is achieved by gene transfer into a suitable
mammalian cell line such as Chinese hamster ovary (CHO) cells.
EPO alpha is formulated with polysorbate 80 and EPO beta with
polysorbate 20 along with urea , calcium chloride and five amino acids as
excipients.
Having half life of 6-8 hours after iv administration,which is prolonged
after sc administration.

19. Darbepoietin alfa
 Supersialyted analogue of EPO with two extra N-linked glycosylation
chains
3× times longer half life(25 hours) and greater biological activities than
recombinant erythropoietin.
Once weekly or 2 weekly dose is sufficient.
Cera
Continuous erythropoiesis receptors activator
A pegylated form of recombinant human erythropoietin beta
Has the ability to repeatedly activate the erythropoiesis receptors
Elimination half life 130 hours
Once monthly dose may be sufficient

20. When to start ESA therapy
Exclude all correctable causes of Anemia prior to initiation of ESA therapy
Serum ferritin>100 mcg/L or failure of iron therapy
CKD ND
Hb > 10 gm/dl – ESA not to be initiated
Hb <10gm/dl- Initiation of ESA therapy be individualized
CKD 5D
ESA therapy should be initiated when the Hb is between 9-10 gm/dl

21. ESA dosing

22. Target Hb level
Objective of initial ESA therapy is to increase Hb level of 1.0-2.0gm/dl(10-
20gm/L) per month
Rise of Hb level >2 gm/dl (20gm/dl) over a 4-weeks period should be
avoided
Target Hb – not to exceed >11.5 gm/dl
Hb initially monitored weekly ,dose adjustment made every 4 weekly
Once stable Hb level achieved, monitor 4 weekly or monthly Or in between
any incurrent illness.

23. Dose modifications
If Hb level increases by >2gm%/month , decrease the dose of ESA by 25%
If Hb level not increases by >1gm%, increase the dose of ESA by 25%

24. Poor response to ESA therapy

25. Adverse events of rHuEPO
Hypertension-30%
Hypertensive encephalopathy
Increased risk of thromboembolic phenomena,like stroke,MI, venous
thromosis.
Seizure
Potential risk of cancer progression
Minor like infection,rashes, itching, headache

26. Chronic kidney disease-Mineral bone
diseases (CKD-MBD)

27. Definition of CKD-MBD
A systemic disorder of mineral and bone metabolism due to CKD manifested
by either one or the combination of the following..
Abnormalities of calcium, phosphorus,PTH,or vitamin D metabolism.
Abnormalities in bone turnover, mineralization, volume, linear growth or
strength
Vascular or other soft tissue calcification

28. Pathogenesis
Reduced glomerular filtration of phosphate leads to phosphate retention.
Renal failure leads to reduced activity of 1-alpha hydroxylase in the renal
tubule ,thus failure to increase calcitriol when required.
Calcitriol may fall secondary to FGF-23 stimulation by hyperphosphatemia.
Lowered calcitriol leads to reduced calcium absorption from GIT and
proximal tubule,thus causing a tendency to hypocalcemia which is
counteracted by increased PTH production and secretion.

29. The net effect is secondary hyperparathyroidism(i.e abnormally high PTH
concentration as an appropriate response to hypocalcemia)which further
aggravates hyperphosphatemia (by positive feedback).

30. Types of CKD-MBD
Traditionallyclassifiedaccording to abnormal boneturnover
High turnover
Osteitis fibrosa
Low turnover
Adynamic bone disease, Osteomalacia
Osteoporosis
Beta 2 microglobulin amyloidosis

32. High turnover bone disease
Due to excess PTH
 Increased bone turnover activity (Greater number of osteoclasts and
osteoblasts)and defective mineralization
Elevated levels of PTH in blood, hyperplasia of the parathyroid glands,
and elevations in FGF-23 are seen once eGFR declines below approximately
about 50 ml/min/1.73 m2.

33. Clinical features:
pain in the lower back, hips, and legs which areaggravated by weight
bearing.
acute periarthritis, which is associated with periarticular deposition of
calcium phosphate crystals, especially in patients with marked
hyperphosphatemia.
Deformities due to fractures, kyphoscoliosis,chest wall deformities
In the skin hyperparathyroidism can manifest as pruritus

34. Investigations:
Serum calcium, phosphate, intact-PTH
*iPTH levels above approximately 600 pg/ ml are characteristic of patients
with osteitis fibrosa.
Serum 25-hydroxyvitamin D
Markers of bone formation- Alkaline phosphatase,osteocalcin
Markers of bone resorption- Tartrate resistant acid phosphatase,collagen
degradation products
DEXA scan for bone density
Radiology
Biopsy- gold standard for diagnosis

35. Radiological findings in hyperparathyroidism
Ruger jersey spine Salt and pepper skull(Pepper pot skull)

36. Brown tumor

37. Treatment of high turnover bone disease
Directed towards normalising the serum
calcium, phosphate and PTH level while
minimising the risks associated with treatment.
1. Dietary phosphorus restrictions
2. Calcium and non-calcium phosphate binders
3. Calcitriol or vitamin D analogues
4. Calcimimetics
5. Parathyroidectomy

38. Dietary phosphorus restrictions
 Prevent excessive PTH synthesis and secretion
Prevent parathyroid cell proliferation.
It is suggested to limit dietary phosphate intake to 900mg/day
Protein restriction and avoidance of dairy products (especially processed
foods containing high amounts of added phosphate) are the mainstays
of the regimen.

39. Phosphate Binders
Calcium containing
Calcium carbonate- 1gm binds 40mg phosphate
Calcium acetate- 1 gm binds 45 mg phosphate
Non-calcium containing
Sevelamer- 1gm binds 36mg phosphate
Lanthanum carbonate- 1gm binds 93 mg phosphate
Aluminium hydroxide- 1 gm binds 60-65 mg phosphate
Magnesium carbonate
Newer phosphate binders
Ferric citrate
Sucroferric oxyhydroxide

40. Phosphate balance and phosphate binders used in
hemodialysis patients.

41. Aluminum containing antacids are effective phosphate binders,but their
long term use can cause Aluminum toxicity,thus not recommended.
Hypercalcemia and calcium loading are the major potentially serious side
effects, hence recommendations are to limit the ingestion of elementary
calcium to 1500 mg/day.
Sevelamer- Non-absorbable, calcium free polymer,dose range 2.4-4.8
gm/day, decreased progression of vascular calcification.
Lanthanum carbonate is also effective ,but appears to accumulate in
bone,liver and gastric mucosa

42. Calcitriol and Vitamin D analogues
Calcitriol and other 1α-hydroxylated vitamin D sterols, such as
alfacalcidol, doxercalciferol and paricalcitol are effective in the control of
secondary hyperparathyroidism.
In severe hyperparathyroidism with markedly enlarged glands and severe
nodular hyperplasia, effectiveness of calcitriol is low, because of
decreased vitamin D receptors in such tissues.
Adverse effects- Hypercalcemia, Hyperphosphatemia, Metastatic
calcification, Adynamic bone disease

43. Calcimimetics
Cinacalcet
Targets the calcium-sensing receptor and increases its sensitivity to
calcium
Additional approach for treating hyperparathyroidism in ESRD.
Started when serum iPTH exceeds 300 pg/ml.
Side effects- Nausea and vomiting ,hypocalcemia
Not to be used in CKD ND patients
Etelcalcetide
Newer calcimimetic
Potent, parenteral peptide based.

44. Parathyroidectomy
Last option
Considered when other methods fail to decrease PTH.
Two types-
1.subtotal removal
2. total removal of the parathyroid glands with reimplantation of
parathyroid tissue in the forearm.
 Recurrence- 10% of patients.
Before parathyroidectomy, coexisting aluminum accumulation should
be ruled out with deferoxamine testing and bone biopsy , because of
the risk of osteomalacia after Sx.

45. Indications of Parathyroidectomy
Severe hyperparathyroidism with..
1. Persistent Hyperphosphatemia
2. Unresponsive to calcitriol and calcium
3. Hypercalcemia
4. Unresposive or intolerance to calcimimetics
5. Transplantation candidates
6. Metastatic calcification
7. Calciphylaxis

46. Adynamic bone disease
Characterised by low osteoblastic and osteoclastic activities.
Seen in up to 40 % HD and 50% PD patients.
Bone develops a relative resistance of the PTH-1 receptor to its ligand
PTH as CKD progresses,
May be due to excessive suppression of parathyroid gland with therapies,
particularly calcium containing phosphate binders and vitamin D
analogues.
Represent a state of relative hypoparathyroidism.

47. Clinical features- unexplained fractures, bone pain, progressive extraosseous
calcifications, hypercalcemia.
Diagnosis- Low iPTH levels (<100 to 150 pg/ml) are almost always indicative of
low bone turnover in CKD stage 5D.
Bone biopsy- gold standard for ABD
TMV classification- low turnover, normal mineralization, and low bone volume.

48. Treatment:
AIM- avoid PTH overexpression and restore adequate PTH levels
Avoid calcimimetics
Reduction or withdrawal of active vitamin D metabolites
Reduction or withdrawal of calcium-containing phosphate binders.
Any aluminumshould be withdrawn.
PTH,calcium,phosphate,alkaline phosphatase,and especially BAP should be
monitored more frequently than usual.

49. 🙏 Thank You 🙏