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CKD - MBD MODIFIED.pptx
1. CKD - MBD
SPEAKER : DR. MOHAMMED DAANISH
MODERATOR : DR. SUBHASH GIRI
2. KDIGO CLASSIFICATION OF CKD-
MBD
DEFINTION OF CKD- MBD :
A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a
combination of the following :
1. Abnormalities of calcium, phosphorus, PTH or Vitamin D metabolism
2. Abnormalities in bone turnover, mineralization, volume, linear growth, strength.
3. Vascular or other soft tissue calcification
8. ELEVATED PTH LEVELS
Secondary hyperparathyroidism begins early in the course of CKD and prevalence increases as the
kidney function declines ( eGFR < 60ml/min/1.73m2
Almost all elements of MBD are present below a eGFR of <40
9. Abnormalities that contribute to secondary hyperparathyroidism are:
1. PO4 retention
2. Decreased calcitriol
3. Decreased ionized calcium
4. Increased FGF-23
5. Reduced expression of Vitamin D receptors(VDRs), Calcium sensing receptors(CaSRs), Fibroblast
growth factor receptors and Klotho receptors
10. High circulating levels of PTH downregulate the PTH receptors hence, skeletal resistance to the
calcemic action of PTH is seen
Both Calcitriol deficiency and hyperphosphatemia contribute
Can lead to tertiary hyperparathyroidism – reflects severe parathyroid hyperplasia with autonomous
secretion of PTH which no longer is responsive to plasma calcium concentration
11. In Patients with tertiary hyperparathyroidism , decreased expression of CaSR and VDR result in a
lack of suppression of PTH.
Nodular hyperplasia of parathyroid gland does not resolve even with resolution of some triggering
mechanism
Therefore, CKD patients with post renal transplant status still show persisting high PTH and
hypercalcemia
12. HYPERPHOSPHATEMIA
3 MAJOR THEORIES PROPOSED EXPLAINING HYPERPHOSPHATEMIA CAUSING
INCREASED PTH RELEASE:
1. By Inducing hypocalcemia
2. Decreased formation / activity of calcitriol
3. Increased PTH gene expression
13. Bone changes occurs as early as stage 2
The initial increase in PTH levels is appropriate since it results in phosphate excretion and lowers
the plasma phosphate concentration towards normal.
<30 eGFR the phosphaturic action of FGF 23 and PTH fails
14. In ESRD patients, PTH inhibits proximal tubular phosphate reabsorption from the normal 80 to 95 %
to as low as 15% of the total filtered phosphate
PTH induces phosphate release from bone resulting in hyperphosphatemia
Increased PTH levels tends to correct both the hypocalcemia (by bone resorption) and calcitriol
deficiency (by stimulating 1 alpha hydroxylase in proximal tubule)
15. DECREASED CALCITRIOL ACTIVITY
Plasma calcitriol levels fall below normal levels when eGFR< 60ml/min/1.73m2
Mechanism of decrease in calcitriol levels :
1. Early CKD : increase FGF -23 levels(inhibits 1 alpha hydroxylase activity)
2. Advanced CKD : hyperphosphatemia and loss of renal mass
16. Low calcitriol levels increase PTH release by;
1. Indirectly : low calcitriol --- low intestinal absorption of calcium and calcium release from bone ---
hypocalcemia----CaSR stimulated on parathyroid gland------ PTH release
2. Directly : calcitriol normally acts on VDR in parathyroid gland to suppress PTH transcription but not
on PTH secretion
17. HYPOCALCEMIA AND CALCIUM SENSING
RECEPTOR (CaSR)
Calcium is a major regulator of PTH secretion
Minute changes in serum ionized calcium are sensed by the specific membrane receptor CaSR,
expressed on the chief cell of parathyroid glands, tightly regulating PTH secretion
18. Total serum calcium concentration decreases during the course of CKD due to :
1. Phosphate retention
2. Decreased calcitriol concentration
3. Resistance to calcemic actions of PTH on bone
19. In CKD, number of CaSR are reduced in hypertrophied parathyroid gland, in areas of nodular
hypertrophy
The decrease in receptor levels can lead to inadequate suppression of PTH secretion by calcium ,
therefore the inappropriately high PTH levels in the setting of normal or high calcium levels
20.
21. When do we call it ‘RENAL
OSTEODYSTROPHY’?
Renal osteodystrophy is alteration bone morphology in patients with CKD based upon bone biopsy.
KDIGO recommends 3 parameters be used to assess bone pathology : (TMV system)
1. Bone turnover
2. Bone Mineralisation
3. Bone Volume
22. TMV CHARACTERISTICS OF MAJOR CKD
RELATED BONE DISEASES :
1. OSTEITIS FIBROSA CYSTICA
2. ADYNAMIC BONE DISEASE
3. OSTEOMALACIA
4. MIXED UREMIC OSTEODYSTROPHY
5. UREMIC BONE DISEASE TYPE
24. ADYNAMIC BONE DISEASE
Low bone turnover
Results from excessive suppression of the parathyroid gland induced by the relatively high doses of
vitamin D analogs, calcium based phosphate binders, and/or calcimimetic agents or resistance to
PTH actions on bone.
Major bone lesion found in females, Caucasians, diabetics, peritoneal dialysis and hemodialysis
patients.
25. OSTEOMALACIA
Low bone turnover + abnormal mineralization
Normal mineralization lag time is <35days , this is prolonged to >100days in osteomalacia.
Earlier increased prevalence was due to aluminium deposition in bone when aluminium containing
antacids were used as phosphate binders.
Now aluminium containing phosphate binders have been banned from use, hence decreased cases
27. UREMIC BONE DISEASE TYPE
Unique pathogenesis
Occurs in patients on long term dialysis and presents as bone cysts which results from beta 2
macroglobulin associated deposits -----dialysis related amyloidosis
28.
29. CLINICAL FEATURES – SKELETAL
MANIFESTATIONS
BONE DISEASE
Can be asymptomatic
Can result in weakness, fractures, bone and muscle pain, avascular necrosis (dialysis)
Bone pain predominant in adynamic bone disease ---- low bone turnover leads to an impaired ability
to repair microdamage
30. EXTRASKELETAL MANIFESTATIONS
VASCULAR CALCIFICATIONS
Intimal and medial calcification are associated with increased mortality
Intimal calcification is marker for advanced atherosclerotic plaque and has been used for screening
for coronary disease
Medial calcification results in arterial distensibility loss ----- systolic hypertension, left ventricular
hypertrophy and impaired coronary artery perfusion
31. EXTRASKELETAL MANIFESTATION
CALCIPHYLAXIS ( CALCIFIC UREMIC ARTERIOLOPATHY)
Rare and serious disorder
Systemic medial calcification of arterioles ---- ischemia and subcutaneous necrosis
Occurs in ESRD who are on hemodialysis or who have received a renal transplant or also in non
ESRD patients
42. TREATMENT OF HYPERPHOSPHATEMIA
NONDIALYSABLE
Target <4.5mg/dl
Requires dietary modification
Use phosphate binders when levels >5.5mg/dl despite diet modification
When phosphate > 6mg/dl start diet modification with binders (diet alone not effective)
Phosphate intake restriction upto 900mg/day
43. DIALYSIS PATIENTS:
In dialysis patients maintain phosphate between 3.5 to 5.5 mg/dl
>5.5 mg/dl requires treatment
Hyperphosphatemia has increased risk for mortality – hence treatment is necessary
Start with phosphate restriction and binder
44. Limiting phosphate intake is difficult to achieve unless protein intake is limited which can contribute to protein
malnutrition, therefore high biologic value food should be used (meat and eggs)
Phosphate restriction to 900mg/day (avoid nutritional compromise)
Ensure protein intake in malnourished patients but restrict phosphate intake
Adequate dialysis (one average session removes 900mg of phosphate
Pt education regarding diet
49. Hypocalcemia – use calcium containing phosphate binders ( less likely to become hypercalcemic
with their use )
Normocalcemic – use calcium containing phosphate binders ( patients with no evidence of vascular
calcification or adynamic bone disease )
Hypercalcemia / adynamic bone disease / vascular calcification – use non calcium containing
phosphate binders
50. Start with lowest effective dose
If using calcium containing buffers total elemental calcium should not exceed 2000 mg/day
(including dietary sources)
The amount of elemental calcium contained in the phosphate binder should not exceed
1500mg/day
Phosphate binders effective only when taken with meals
51. REFRACTORY HYPERPHOSPHATEMIA
Not controlled by diet, phosphate binders and patient unwilling for hemodialysis --- reduce PTH
levels (CINACALCET)
52. MAINTAIN NORMOCALCEMIA
Corrected Ca >7.5(Asymptomatic and mild hypocal)-no rx as there is increased risk of
hypercalcemia
Maintain <9.5
53. VITAMIN D REPLENISHMENT
Vitamin D replacement in deficient pts (Sr. Calcium <10.2 and P<5.5)
Vitamin D levels : <12 ng/ml – 50000 IU ( vitamin D2 or D3 )weekly for 6 to 8 weeks followed by 800
IU (vitamin D2 or D3 ) daily
12 to 20-800 to 1000IU daily(repeat levels after 3 months)
20 to 30-600 to 800IU daily
54.
55.
56. INCREASED PTH Rx
Treatment initiation-pth>2.3 to 3 times ULN assay range
Calcimimetics-Widely available calcimimetics include cinacalcet (oral)
and etelcalcetide (intravenous)
Calcitriol /Synthetic Vitamin D analogues – should be avoided , given at a low dose or stopped if
P>5.5 or Ca >10.2
Any out of the two can be used as a monotherapy or in combination
57. Treat patients with phosphate <5.5 mg/dL (<1.78 mmol/L) and calcium <9.5 mg/dL (<2.37 mmol/L)
with calcitriol monotherapy
Among patients with serum phosphate ≥5.5 mg/dL (≥1.78 mmol/L) or serum calcium level ≥9.5 mg/dL (≥2.37
mmol/L) and persistently elevated PTH, despite maximal therapies to reduce phosphate, we initiate therapy
with a calcimimetic(used only in dialysis pts) rather than calcitriol or a synthetic vitamin D analog.
Among patients who do not sufficiently reduce PTH with cinacalcet alone, we add calcitriol or a synthetic
vitamin D analog, providing the phosphate <5.5 mg/dL (<1.78 mmol/L) and calcium <9.5 mg/dL (<2.37
mmol/L).
Calcitriol-0.25 microgram thrice per week(preferred dose)-titrate maintain pth <150
58. In general, the starting dose of calcitriol, whether oral or IV, or of the vitamin D analog
should be low (eg, 0.25 mcg thrice weekly). Dose adjustments may be made at four-
to eight-week intervals. Patients who are responsive to therapy typically show
significant reductions in PTH levels within the first three to six months of therapy
59.
60.
61. REFRACTORY HYPERPARATHYROIDISM-We define refractory hyperparathyroidism as persistent
and progressive elevations of serum parathyroid hormone (PTH) that cannot be lowered to levels
<600 pg/mL despite treatment with vitamin D derivatives and cinacalcet and without causing
significant hyperphosphatemia or hypercalcemia. Patients with severe disease may require
parathyroidectomy