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.
5.
6.
7.
8. 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
9. 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
10. 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
11. 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
12. 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
13.
14. 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
15. 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.
16.
17. 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
21. 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.
22. 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
23. Martin K J , González E A JASN 2007;18:875-885
28. 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.
31. 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
32. MECHANISM OF ACTION
By binding phosphate in the gastrointestinal tract and decreasing
absorption, sevelamer carbonate lowers the phosphate concentration
in the serum (serum phosphorus).
35. 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.
36. 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.
38. 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.
40. 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
41. 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
42. 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.
43. 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.
45. 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.
46. 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
47.
48. 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
Editor's Notes
FGF-23 is a circulating peptide that plays a key role in the control of serum phosphate concentrations.
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.
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
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%).
