CKD-MBD is a systemic disorder of mineral and bone metabolism due to chronic kidney disease. It is characterized by abnormalities in calcium, phosphorus, PTH, or vitamin D levels and bone abnormalities. The pathogenesis involves elevated PTH levels, hyperphosphatemia, decreased calcitriol activity, and hypocalcemia. Treatment focuses on controlling phosphate levels through diet, phosphate binders, and dialysis; maintaining normal calcium levels; and treating secondary hyperparathyroidism through calcimimetics and vitamin D analogues. The goal is to prevent skeletal and extraskeletal complications like fractures, vascular calcification, and calciphylaxis.

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

4. PATHOGENESIS

7. PATHOGENESIS
 EXPLAINED UNDER 4 HEADINGS :
1. Elevated PTH
2. Hyperphosphatemia
3. Decreased calcitriol activity
4. Hypocalcemia and calcium sensing receptor functions

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

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

23. OSTEITIS FIBROSA CYSTICA
 High bone turnover due to secondary hyperparathyroidism

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

26. MIXED UREMIC OSTEODYSTROPHY
 High or low bone turnover + abnormal mineralisation

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

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

40. TREATMENT

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

47. PHOSPHATE BINDERS
 NON CALCIUM CONTAINING
1. Sevelamer
2. Lanthanum
3. Ferric citrate
4. Sucroferric oxyhydroxide
5. Nicotinamide
6. Tenapavor
 CALCIUM CONTAINING
1. Calcium carbonate
2. Calcium acetate

48.  Sevelamer – phosphate levels – 5.5 – 7.5 mg/dl – 800mg TDS
> 7.5 mg/dl – 1600mg TDS

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

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

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

63.  Reference-
 Uptodate
 Kdigo guidelines

64. THANKYOU