Chronic kidney disease - mineral bone disease

Chronic kidney disease - mineral bone disease

1. CKD-Progression CKD-MBD CKD-ANEMIA Presented by: Dr. Solomon (IMR2) Moderator: Dr. Nebiyou ( consultant internist and nephrologist) 1

2. CKD-MBD Introduction Definition Pathogenesis Diagnosis Treatment CKD-ANEMIA PATHOGENESIS DIAGNOSIS TREATMENT CKD-MBD-ANEMIA 2 Outlines

3. Definition CKD-MBD is a systemic disorder of mineral and bone metabolism due to CKD . manifested by either one or a combination of the following three components: Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism. Abn o rmalities in bone turnover, mineralization, volume linear growth, or strength. Extraskeletal (Vascular or other soft tissue calcification) calcification. 3

4. PATHOGENESIS Several biochemical and hormonal abnormalities associated with CKD contribute to renal osteodystrophy and can be affected by efforts at prevention and treatment. T he two major entities: high and low-turnover osteodystrophy

5. HIGH-TURNOVER RENAL BONE DISEASE Elevated levels of PTH, hyperplasia of the parathyroid glands, and elevations in FGF-23 are seen once eGFR declines below 50 ml/min/1.73 m2. The level of free calcium in blood is normally the principal determinant of PTH secretion.

6. Abnormalities of Calcium Metabolism

7. Abnormalities of Phosphate Metabolism

8. Abnormalities of Vitamin D Metabolism

9. CKD-MBD-ANEMIA 9

10. Abnormalities of Parathyroid Gland Function CKD is associated with intrinsic abnormalities in parathyroid gland function, in addition to those caused by hypocalcemia , low levels of calcitriol , and skeletal resistance to the actions of PTH.

11. Clinical manifestation Usually nonspecific and often preceded by biochemical or imaging abnormalities. Nonspecific aches and pains are common. The gradual onset of muscle weakness is also common in patients with ESRD.

12. Bone abnormalities, deformities because of fracture. Extra-skeletal calcifications most commonly, vascular calcifications In the skin, hyperparathyroidism can manifest as pruritus. CKD-MBD-ANEMIA 12

13. CKD-MBD-ANEMIA 13

14. Calciphylaxis (Calcific uremic arteriolopathy) is a rare and serious disorder characterized by systemic medial calcification of the arterioles that leads to ischemia and subcutaneous necrosis. Calciphylaxis most commonly occurs in patients with ESRD who are on hemodialysis or who have recently received a renal transplant, but may also occur in non-ESRD patients 14

15. calcific uremic arteriolopathy calcific Aortic valve 15

16. Diagnosis serum Biochemistry Ca and phosphate Parathyroid Hormone Vitamin D Metabolites Markers of Bone Formation & Bone Resorption ( Alk phos ) Radiology of the Skeleton Measurements of Bone Density Bone Biopsy, gold standard, TMV classification

17. 17

18. Radiology of the Skeleton 18

19. Bone Biopsy Bone biopsy is the gold standard for the diagnosis and classification for renal osteodystrophy. Its done when biochemistry is not conclusive and when treatment decisions depend on bone histology. KDIGO CKD-MBD work group proposed the TMV classification, an assessment of turnover (T), mineralization (M), and bone volume (V). 19

20. Treatment Prevention is the primary goal in management of renal osteodystrophy . The successful approach involves the integration of a variety of measures directed toward the suppression of PTH secretion and prevention of parathyroid hyperplasia.

21. Treatment of Hypocalcemia Hypocalcaemia, should be corrected because it is a potent stimulus for PTH secretion . The initial approach to therapy for hypocalcaemia in patients with mild to moderate CKD is the administration of calcium supplements .

22. Assessment of 25-hydroxyvitamin D status should be done, and corrected if it is below 30 ng/ml . Adjunctive therapy with active vitamin D sterols should be considered if hyperparathyroidism or hypocalcemia persists. CKD-MBD-ANEMIA 23

23. Vitamin D Metabolites Calcitriol , alfacalcidol , doxercalciferol , and paricalcitol They Lower PTH levels and improves bone histology . Early in CKD, parathyroid glands are more sensitive to such therapy. Calcitrol = 0.25mig three times/week (adjust the dose to maintain PTH<150pg/ml Calcidiol =30mcg/day (maintenance dose should target 25(OH)D level 30-1oong/ml) Concerns : hypercalcemia and ABD 24

24. Hyperphosphatemia Initial treatment principally involves Dietary phosphate restriction Phosphate binders (either calcium or non-calcium containing binders) to remove the phosphate-mediated stimulus for hyperparathyroidism Its control is cornerstone for effective management of secondary hyperparathyroidism

25. Dietary Phosphate Restriction Restriction of dietary phosphate intake might be considered in patients with CKD stage 2 or 3. Phosphate-protein restriction increases the serum levels of calcitriol in patients with mild to moderate CKD. moderate restriction of phosphate intake (approximately 900 mg/day), provided that this can be done without compromising nutritional status CKD-MBD-ANEMIA 26

26. Experiment in animals with mild CKD N.B: low phosphate diet doesn’t exactly reduce the GFR progression rather it Keeps the PTH lower through out the course 2/15/2024 27

27. Phosphate Binders Calcium containing: - Used in hypocalcemic or normocalcemic patients with no evidence of vascular calcification. Non Calcium containing: - Used in hypercalcemic patients & patients with adynamic bone disease or vascular calcification . 28

28. Cont Calcium containing salts Calcium carbonate , calcium acetate, calcium citrate They are effective phosphate binders in 60% to 70% of patients on hemodialysis. Current recommendations are to limit the ingestion of elementary calcium to 1500 mg/day Magnesium salts Magnesium carbonate For patients who become hypercalcemic with calcium-containing phosphate binders Should be administered with caution in patients not on dialysis because hypermagnesemia may have serious adverse effects. 29

29. Cont. Nonabsorbable polymers Sevelamer hydrochloride, sevelamer carbonate and Lanthanum carbonate provides effective phosphate control without hypercalcemia and also produces a significant reduction in total and low-density lipoprotein cholesterol. sevelamer is associated with decreased progression of vascular calcification Drawback: Their availability and Cost 30

30. Non dialysis chronic kidney disease patients maintain the serum phosphate level in the normal range ( ie , <4.5 mg/ dL [1.45 mmol /L]) with dietary modification phosphate binders ; if persistently elevated >5.5 mg/ dL despite dietary restriction . Those present with very high phosphate ( >6 mg/ dL ), start phosphate binders concurrently with dietary restriction. CKD-MBD-ANEMIA 31

31. Dialysis patients Serum phosphate >5.5 mg/ dL (1.78 mmol /L) is an indication for treatment . A target phosphate goal between 3.5 and 5.5 mg/ dL (1.13 and 1.78 mmol /L) The initial therapy dietary restriction first and only use a phosphate binder if the phosphate is persistently and progressively elevated after one or two months CKD-MBD-ANEMIA 32

32. CKD-MBD-ANEMIA 33

33. Calcimimetics ( cinacalcet) Targets the calcium-sensing receptor and increases its sensitivity to calcium. Useful in patients with marginal or frank hypercalcemia or with hyperphosphatemia. 34

34. In dialysis patients, the goal is to achieve levels of iPTH that are two to nine times above the upper limit of the assay used . Therapeutic decisions be based on trends rather than on a single laboratory value

35. Role of Parathyroidectomy CKD-MBD-ANEMIA 36

36. ADYNAMIC BONE DISEASE ABD is increasingly important in CKD-MBD because of the high percentage of affected individuals (>40% in CKD stage 5) and because of its association with CV calcification and mortality. It is a consequence of inadequately low PTH levels, which cause suppression or cessation of both osteoblast and osteoclast activities, 2/15/2024 37

37. D iagnosis Fractures and hypercalcemia can occur Low levels of PTH (<100-150pg/ml) are almost always indicative of low bone turnover in CKD stage 5D. A lkaline phosphatase are usually normal or low, serum Ca and pi can be normal or high. 2/15/2024 39

38. I ncreased incidence of fracture and bone pain and an association with increased vascular and cardiac calcification. Occasionally, the calcium will precipitate in the soft tissues into large concretions termed tumoral calcinosis . 2/15/2024 40

39. The gold standard for diagnosis of ABD is bone biopsy . According to the TMV classification ABD is characterized by low turnover, normal mineralization and low bone volume. There are no typical features of ABD in conventional bone radiographs or DEXA. 2/15/2024 41

40. Treatment of Adynamic Bone Disease The key therapeutic approaches in the treatment of ABD are to avoid PTH overexpression . I ncludes avoidance of calcimimetics , R eduction or withdrawal of active vitamin D metabolites , Reduction or withdrawal of calcium-containing phosphate binders, and R eduction of the dialysate calcium concentration. Any aluminum should be withdrawn.

41. ANEMIA-CKD

42. Anemia in Chronic Kidney Disease Anemia is an almost universal complication of CKD. It contributes considerably to reduced quality of life of patients with CKD. H as been associated with a number of adverse clinical outcomes . CKD-MBD-ANEMIA 44

43. EPIDEMIOLOGY T here is a progressive increase in the incidence and severity of anemia with declining renal function. CKD-MBD-ANEMIA 45

44. It occurs independent of the cause of kidney disease, with exceptions of Diabetic patients --->at earlier stages of CKD, and more severely at a given level of renal impairment. PKD  Hb is on average higher than in other patients with similar degrees of renal failure, and polycythemia may occasionally develop.

45. PATHOGENESIS CKD-MBD-ANEMIA 47

46. DIAGNOSIS The diagnosis of anemia and the assessment of its severity are best made by measuring the Hb concentration than the Hct . A nemia should be diagnosed at Hb concentrations of less than 13.0 g/dl in men and less than 12.0 g/dl in women. CKD-MBD-ANEMIA 50

47. The measurement of serum EPO concentrations is usually not helpful in the diagnosis of renal anemia because there is relative rather than absolute deficiency. CKD-MBD-ANEMIA 51

48. Frequency of testing for anemia CKD-MBD-ANEMIA 52

49. TREATMENT Erythropoiesis-Stimulating Agents CKD-MBD-ANEMIA 53

50. Erythropoiesis-Stimulating Agents EPO alpha/beta >90% of patients show a significant increase in Hb concentration. -25 to 50 IU/kg (e.g., 2000 IU two or three times weekly( for Dialysis) 4000-10,000iu sc weekly(ND) -IV dosages should be 20-30% higher than SC IV epoetin half life (6–8 hours) Darbepoetin alpha -20 to 30 mcg once weekly elimination half life is 25.3 hours dosage same for IV and SQ administration(CF is200:1) C.E.R.A ( Methoxypolyethylene Glycol Epoetin Beta/continuous erythropoietin receptor activator ) -30 to 60 mcg once every 2 weeks elimination half-life 130 hrs ( IVor SQ. CKD-MBD-ANEMIA 54

51. Within 3 to 4 days of initiation , an increase in the reticulocyte count is seen, and W ithin 1 to 2 weeks , there is a significant rise in the Hb , ( 0.25 to 0.5 g/dl/ wk ). O ver the course of 1 month , increase of 1 to 2 g/dl in Hb is usually achieved If a patient fails to respond, upward titrations of 25% to 50%, and if still an inadequate response, causes of resistance to ESA therapy should be investigated. CKD-MBD-ANEMIA 55

52. I t is recommended that the Hb level should not be intentionally increased to 13 g/dl or higher and should generally not be maintained above 11.5 g/dl CKD-MBD-ANEMIA 56

53. ESA Hypo responsiveness N o increase in Hgb from baseline after the 1st month of ESA treatment on appropriate weight-based dosing. Patients who are hyporesponsive have a worse prognosis than those who do respond . CKD-MBD-ANEMIA 57

54. CKD-MBD-ANEMIA 59

55. Adverse Effects of ESAs Due to Increase in Hb concentration A moderate increase in BP An increased rate of thromboembolic events, including vascular access thrombosis Independent of Hb concentrations Enhance thrombogenicity & tumor growth in pts with malignancies Exacerbate vascular events Avoid in patients with active malignancy particularly when cure is anticipated, history of stroke, or history of malignancy 60

56. Hypoxia-Inducible Factor Stabilizers roxadustat , daprodustat , and vadadustat

57. IRON MANAGEMENT Multiple factors induce a negative iron balance in patients with CKD, including Reduced intake and absorption, Chronic losses due to occult and overt blood loss , Iron losses in patients with CKD can be up to 5-6 mg daily ( 1 mg iron daily in normal subjects) Reduced bioavailability of iron due to the chronic inflammatory state and increased hepcidin production Iron losses cannot be adequately compensated with oral iron supplements because GI absorption is limited by the chronic inflammatory state and hepcidin 62

58. A bsolute vs Functional iron deficiency Absolute iron deficiency – Among CKD patients For ND-CKD/stages G3 and G4: Ferritin < 100 ng/ml and TSAT < 20% usually indicate absolute iron deficiency. For dialysis patients: Ferritin < 200 ng/ml and TSAT < 20% usually indicate absolute iron deficiency 63

59. The sensitivity for ruling out iron deficiency was reported to be 90% for a ferritin cutoff of 300 μg /L and 100% for 500 μg /L IV iron is not recommended if ferritin is above 500 μg /L, b/c of Concerns about iron toxicity and overload Functional iron deficiency TSAT that is commonly ≤20 percent and elevated ferritin levels (as high as 800 ng /mL or even higher ).

60. Intravenous Iron Therapy There is significant associations of IV iron therapy with Increased Hgb, ferritin, and transferrin saturation values, & Reduced ESA requirements 23% dose reduction in ESA with the use of IV iron Oral vs IV iron therapy The Hgb response is much more potent with IV iron than with oral iron, with this effect being more substantial in patients on dialysis Oral iron may be effective with ND-CKD patients 65

61. Preparations of IV iron Lower Molecular Weight Iron Dextran It has a significant better tolerability and fewer side effects than the higher molecular weight product Iron Sucrose It is used worldwide for the treatment of renal anemia and is the most used parenteral iron preparation in the United States Ferric Gluconate Ferric Carboxymaltose A significant advantage of this preparation is the possibility of infusing up to 750 mg of iron in a short time (15 minutes), with minimal side effects Transient hypophosphatemia has been reported Ferumoxytol Ferric Isomaltoside 66

62. BLOOD TRANSFUSION - Avoid when possible CKD-MBD-ANEMIA 67

63. REFERENCES Comprehensive clinical nephrology 7 th edition 2023-KDIGO Clinical Practice Guideline for the evaluation and management Harrison 21 th edition Uptodate , online

64. THANK YOU