Ckd mbd

medical affairs à concord biotech
15 Mar 2018

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Ckd mbd

  1. Chronic kidney disease-mineral bone disorder
  3. CKD-MBD Chronic kidney disease–mineral and bone disorder (CKD- MBD) is a common complication of chronic kidney disease and is a part of broad spectrum disorders of mineral metabolism.
  4. Pathogenesis of CKD MBD Reduced glomerular filtration of phosphate leads to phosphate retention Hyperphosphataemia as a result of phosphate retention usually becoming clinically evident at stage 4–5 CKD. Reduced renal mass leads to reduced activity of 1 -hydroxylase in the renal tubule and thus failure to increase calcitriol production when required. However, circulating calcitriol concentrations begin to fall at stage 3 CKD either as a direct result of phosphate retention or as a secondary effect via FGF-23 stimulation. Ann Clin Biochem 2012; 49: 432–440
  5. PATHOGENESIS OF CKD-MBD Lowered calcitriol leads to reduced calcium absorption from the gut and proximal tubule, thus causing a tendency to hypocalcaemia which is counteracted by increased PTH production and secretion. The net effect is secondary hyperparathyroidism (i.e. abnormally high PTH concentrations as an appropriate response to hypocalcaemia), which further aggravates hyperphosphataemia (positive feedback). Ann Clin Biochem 2012; 49: 432–440
  6. Consequences of CKD- MBD A. Renal osteodystrophy B. Hyperphosphatemia C. Cardiovascular calcification D. Extraskeletal calcification E. Endocrine disturbances F. Neurobehavioral changes G. Compromised immune system H. Altered erythropoiesis
  7. BONE FRACTURES DUE TO CKD MBD If left uncorrected, the secondary hyperparathyroidism leads to increased mobilization of calcium from bone with bone weakening and a tendency to fracture. The risk of fracture is increased in patients who have had longer exposure to dialysis. Ann Clin Biochem 2012; 49: 432–440
  8. BONE DISEASE DUE TO CKD HIGH BONE TURNOVER DISEASE: Osteitis fibrosa. LOW BONE TURNOVER DISEASE: Osteomalacia Adynamic bone disease Ann Clin Biochem 2012; 49: 432–440
  9. VASCULAR CALCIFICATIONS In CKD-MBD, there is a greater proportion of calcification in the arterial media which causes vascular stiffness and hypertension. Calciphylaxis is a condition where small cutaneous blood vessels become calcified, leading to acute, painful necrosis and ulceration of the skin. It is strongly associated with the presence of CKD-MBD Ann Clin Biochem 2012; 49: 432–440
  10. SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis.
  11. TERTIARY HYPERPARATHYROIDISM Parathyroid glands gradually undergo hypertrophy and become less responsive to modulatory influences. In late CKD, therefore, PTH production may become autonomous (so- called tertiary hyperparathyroidism) with acceleration of bone destruction and vascular calcification. Ann Clin Biochem 2012; 49: 432–440
  12. DIAGNOSIS OF CKD-MBD Biochemistry Serum calcium, phosphorus, alkaline phosphatase (ALP) Bone biopsy Radiology – x ray
  13. The KDOQI guidelines recommend against PTH levels below 150 pg/ml in CKD stage 5 in order to mitigate the risk of adynamic bone disease. Lower the PTH, greater the survival.
  14. HYPERPHOSPHATASEMIA High serum alkaline phosphatase level in CKD patients is usually (esp. if > 120 U/L) associated with poor survival in hemodialysis patients Whereas serum alkaline phosphatase used to be a traditional measure for the management of kidney bone disease, in recent years it appeared to have fallen out of favor, probably since the KDOQI guidelines did not include it in its recommendations, nor did they suggest any cutoff levels or target ranges for it Alkaline phosphatase can be effectively lowered by both active vitamin D products and calcimimetics Lower serum alkaline phosphatase the better is the response of dialysis patients to ESAs during anemia management. Kidney Int Suppl. 2010 August ; (117): S10–S21
  15. Martin K J , González E A JASN 2007;18:875-885
  16. Ann Clin Biochem 2012; 49: 432–440
  17. PHOSPHATE BINDERS The administration of agents to bind phosphate in food is usually required as CKD progresses. Agents containing calcium are inexpensive and well tolerated, but these may contribute to vascular calcification. Non-calcium-containing phosphate binders (lanthanum and sevelamer) have the advantage of reducing calcium intake and thus slowing vascular calcification.
  20. Sevelamer: Calcium-free, aluminium-free phosphate binders Sevelamer was approved by the US Food and Drug Administration (FDA) in 1998. Sevelamer is completely resistant to digestive degradation and, therefore, not absorbed from the GI tract. Sevelamer carbonate tablets are a phosphate binder indicated for the control of serum phosphorus in adults with chronic kidney disease on dialysis
  21. MECHANISM OF ACTION By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus).
  22. NEFROLOGIA 2015; 35(2):207-217
  23. SEVELAMER HYDROCHLORIDE VS. SEVELAMER CARBONATE Sevelamer hydrochloride is an ion-exchange resin that reduces serum phosphorus concentrations. & produces favorable lipid profile effects and does not cause hypercalcemia. However, reported drawbacks of this agent are metabolic acidosis, high pill burden, and a relatively low affinity and selectivity for phosphate anions.
  24. SEVELAMER HYDROCHLORIDE VS. SEVELAMER CARBONATE Sevelamer carbonate is a new buffered formulation that does not increase the risk of metabolic acidosis. It does not decrease serum bicarbonate levels, it may be more appropriate for patients at risk for metabolic acidosis who require phosphate binders that do not contain calcium or aluminum.
  25. INDICATIONS For the control of serum phosphorus in adults with chronic kidney disease on dialysis
  26. DOSAGE AND ADMINISTRATION Starting dose of sevelamer carbonate tablets is 800 mg (if serum phosphorus level > 5.5 and < 7.5 mg/dL) or 1600 mg (> 7.5 mg/dl) administered orally three times per day with meals. Titrate by 800 mg per meal in two week intervals for adult patients as needed to obtain serum phosphorus target. For adult patients switching from Sevelamer Hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose.
  28. SUMMARY It does not increase calcium load and is associated with fewer hypercalcaemic episodes than calcium-based agents. Reduces the tendency to soft tissue calcification and renal damage Attenuates the progression of coronary and aortic calcification in haemodialysis patients. Nephron Clin Pract 2005;99:c1–c7
  29. SUMMARY Reduces total and LDL, while increasing HDL, cholesterol. Sevelamer is commonly initially used over lanthanum, although equally effective in lowering Phosphate, as the long-term data on safety of Lanthanum are more limited. Nephron Clin Pract 2005;99:c1–c7
  30. CALCINOMIMETIC AGENTS Calcium-sensing receptor (CaSR) is a G protein–coupled receptor identified as an essential molecule for the regulation of PTH secretion by extracellular calcium (Ca). Binding of extracellular Ca inhibits PTH secretion Calcimimetics are agents that increase the sensitivity of the calcium- sensing receptor (CaSR) in the parathyroid gland to calcium, regulating PTH secretion and the gland hyperplasia.
  31. Cinacalcet: mechanism of action The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor(CaSR) to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
  32. INDICATIONS Cinacalcet is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis.
  33. DOSAGE AND ADMINISTRATION 30 mg once daily with food or shortly after a meal. Serum calcium and serum phosphorus should be measured within 1 week and PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Cinacalcet. Cinacalcet should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH consistent with the NKF-K/DOQI recommendation for CKD patients on dialysis of 150-300 pg/mL. PTH levels should be assessed no earlier than 12 hours after dosing with Cinacalcet.
  34. ADJUVANT WITH VITAMIN D ANALOGUES Treatment is associated with hypocalcaemia, hyperphosphataemia and an increased requirement for calcium supplements. The long-term consequences of these effects are unknown, thus the use of cinacalcet is recommended only in patients with CKD stage 5. They generally used to adjunct treatment with vitamin D analogues where the latter have not sufficiently suppressed PTH production
  35. SUMMARY Lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with sHPT. 40-50% (250-350 pg/ml) serum PTH, a 5-8% (0.5-0.8 mg/dl) serum calcium and 5- 10% (0.2-1.0 mg/dl) serum phosphorous reduction is expected when cinacalcet is administered Reduces the rate of parathyroidectomy, fracture, and hospitalization due to cardiovascular events Cinacalcet HCl and Concurrent Low-dose Vitamin D Improves Treatment of Secondary Hyperparathyroidism in Dialysis Patients Compared with Vitamin D Alone

Notes de l'éditeur

  1. FGF-23 is a circulating peptide that plays a key role in the control of serum phosphate concentrations.
  2. FGF-23 is a circulating peptide that plays a key role in the control of serum phosphate concentrations. Similar to PTH, FGF-23 has phosphaturic properties, but it also inhibits 1-α hydroxylation and, hence, may aggravate calcitriol deficiency leading to further PTH production and release.
  3. FGF-23 is a circulating peptide that plays a key role in the control of serum phosphate concentrations. Klotho, a transmembrane protein produced by osteocytes, is required for FGF-23 receptor activation
  4. Fetuin-A has been noted as a vascular calcification inhibitor and is associated with mortality in HD patients. a prospective study including 57 HD patients [28]. After phosphate binder was changed from calcium-containing binder to Sevelamer hydrochloride, serum fetuin-A level significantly increased (+21%).