This document discusses chronic kidney disease-mineral and bone disorder (CKD-MBD). It notes that abnormalities in mineral metabolism are common even in early stages of CKD and accelerate with worsening kidney function. The factors involved in secondary hyperparathyroidism pathogenesis are described. Different types of renal osteodystrophy are defined based on laboratory abnormalities and presence of bone disease and soft tissue calcification. The document also outlines clinical manifestations of renal osteodystrophy including bone pain, fractures, and tendon ruptures.

1. Magdy ElSharkawy
Prof. of Internal Medicine and
Nephrology
Ain Shams University

2. KI (2007) 71, 31-38. Levin et. al.
Prevalence of Abnormal Mineral Metabolism in CKD
>4.6

3. •
• CKDComplications
Evolution and Acceleration by Stage
•CKDStage
•1 •2 •3 •4
•Affected pts
•(%)
•0
•20
•40
•60
•80
•100
•Hypertension
•Hyperparathyroidism
•Anemia (Hgb < 12 g/dl)
•Phosphorus > 4.5 mEq/L
•Fail quartermile walk
•Hypoalbuminemia
•(Alb < 3.5 g/dl)

4. Evolutionof CKD-MBD
Bone changes in renal failure patients, mainly
hyperparathyroidism, begin early in the natural history of
the disease.
About 50% of the patients have histological evidences of
bone disease when GFR is halved.
Almost all patients with CRF on regular heamodialysis
has evidance of ROD

5. Renal Bone Disease
This disorder is often subclinical, and its
presence is suggested from abnormal laboratory
tests such as;
hyperphosphatemia, high circulatory levels of
PTH, and low levels of 1,25(OH)2D3.
In other patients, however, renal osteodystrophy is
a cause of great morbidity.

6. Population Attributable Risk of All
Cause Mortality in CKD 5D
• 17.5% Mineral metabolism abnormalities
(Phosphorus > 5.0 mg/dl, Calcium > 10 %
mg/dl, intact PTH > 600 pg/ml)
• 11.3% Anemia (hgb < 11 g/dl)
• 5.1% Inefficient Dialysis (URR < 65%)
Corollary: We should be able to significantly improve
mortality of CKD patients by improving control of
mineral metabolism
•Block et al JASN 2004Block et al JASN 2004

7. Akmal M et al. Kidney Int. 1995;47:158-163.
Drüeke TB. Nephrol Dial Transplant. 1996;11(suppl 3):37-42.
Hsu CH. Am J Kidney Dis. 1997;29:641-649. .
Soft-Tissue Calcification
Type of Calcification Morbid Effects
Myocardiam and valves Atrioventricular block, cardiac failure,
pulmonary hypertension, arrhythmia, left and
right ventricular hypertrophy, sudden death
Peripheral arteries Bone and soft tissue necrosis, amputation
Skin arterioles Calcific uremic arteriolopathy (calciphylaxis)
Pulmonary Cough, dyspnea, restrictive defects,
decreased diffusion, hypoxia

8. *P=0.01 vs Ca × P product 43-52 mg2
/dL2
.
Block GA et al. Am J Kidney Dis. 1998;31:607-617.
The Importance of Ca × P Product:
A Key Determinant of Mortality Risk
1.06
1.00
1.08
1.13
1.34*
1.00
1.25
1.50
1.1-3.4 40-45 50-55 56-65 66-780
RelativeMortalityRisk(RR)
n=2669
Ca × P Product Quintile (mg2
/L2
)

9. *P=0.03 vs phosphorus 4.6-5.5 mg/dL.
†
P<0.0001 vs phosphorus 4.6-5.5 mg/dL.
Block GA et al. Am J Kidney Dis. 1998;31:607-617.
Elevated Serum Phosphorus Increases
Mortality Risk
1.00
1.25
1.50
0.40-1.45 1.46-1.80 1.81-2.10 2.11-2.55 2.56-5.50
RelativeMortalityRisk(RR)
Serum Phosphorus Quintile (mmol/L)
1.00 1.00
1.02
1.18*
1.39†N=6407

10. Coronary-artery calcificationsCoronary-artery calcifications
increase with years of dialysisincrease with years of dialysis
1.0
0
Years of dialysis
Proportionwith
calcification
0.8
0.6
0.4
0.2
0.0
4 8 12 16 20 24
Patients with coronary-
artery calcification (n = 39)
Estimates by logistic
regression analysis
Goodman WG et al. N Engl J Med 2000;342:1478–83.

11. Definition, Evaluation and Classification
of Renal Osteodystrophy:
ApositionstatementfromKidneyDisease
ImprovingGlobalOutcomes (KDIGO)
April, 2006

12. •www.kdigo.org

13. Definition of CKD-MBD
A systemic disorder of mineral and bone
metabolism due to CKD manifested by
either one or a combination of the
following:
– Abnormalities of calcium, phosphorus, PTH, or
vitamin D metabolism
– Abnormalities in bone turnover, mineralization,
volume, linear growth, or strength
– Vascular or other soft tissue calcification
• Moe et al Kidney International June 2006

14. Standardization of Terms
• The term renal osteodystrophy (ROD) should
be used exclusively to define the bone
pathology associated with CKD.
• The clinical, biochemical, and imaging
abnormalities should be defined more broadly
as a clinical entity or syndrome called Chronic
Kidney Disease-Mineral and Bone Disorder
(CKD-MBD).

15. A Framework for Classification of CKD-MBD
Type*
Laboratory
Abnormalities
Bone Disease
Calcification of
Vascular or Other
Soft Tissue
L + - -
LB + + -
LC + - +
LBC + + +
* L = laboratory abnormalities (of calcium, phosphorus, PTH,
alkaline phosphatase or vitamin D metabolism); B = bone disease
(abnormalities in bone turnover, mineralization, volume, linear
growth, or strength); C = calcification of vascular or other soft
tissue.
•KidneyInternationalJune2006

16. KI (2007) 71, 31-38. Levin et. al.
Prevalence of Abnormal Mineral Metabolism in CKD
•>4.6

20. The factors involved in the pathogenesis of secondary hyperparathyroidism.
Kevin J. Martin, and Esther A. González JASN 2007;18:875-885

21. ROD and Bone Remodeling

25. Consequences of HyperphosphatemiaConsequences of Hyperphosphatemia
P
Mortality
Risk of
Calcification
Parathyroid
Cell Growth
PTH Secretion
PTH Resistance
Ca++
Calcitriol Resistance
Calcitriol

26. VDR = vitamin D receptor; CaR = Ca-Sensing receptor.
Adapted from Murayama A et al. Endocrinology. 1999;140:2224-2231. Satomura K et al. Kidney Int. 1988;34:712–716
CKD ProgressionCKD Progression
Normal Diffuse Early
nodular
Nodular
hyperplasia
Single nodule
Monoclonal nodules
Decline in
receptor density
of VDR, CaR
Cells with lower density of VDR
proliferate vigorously to form
several monoclonal nodules
Progression of PTH Gland Hyperplasia
in CKD

28. Increased FGF23 develops earlier than
increased phosphate or PTH
Isakova T et al., Kidney Int 2011

30. Pathogenesis of Different Types of ROD
There are five components in the pathogenesis of renal
osteodystrophy:
1- Secondary hyperparathyroidism (HTO) due to:
-Phosphate retention. - An abnormal set point for calcium.
- Altered metabolism of vit.D. - Skeletal resistance to PTH.
- Impaired degradation of PTH.
- Altered feed back regulation of PTH by calcium.
2- Adynamic bone disease: (Defective meniralization of bone (LTO)
- Altered vitamin D metabolism. - Acidosis.
- Altered synthesis and maturation of collagen.
- Retention of aluminum. - Retention of iron.
- Skeletal accumulation of magnesium, fluoride,pyrophosphate, and
oxalately stranchium..
3- MUD.
4 - Osteosclerosis.
5- -Osteoporosis .

32. Clinical Manifestations of Renal
Osteodystrophy
The symptoms of renal osteodystrophy usually
appear when renal failure is advanced and
thus appear in dialysis patients, except in some
etiologies of renal failure when there is
prolonged course of disease before the need of
dialysis, as in
– analgesic induced renal disease, or
– when the patient present late in-spite of advanced
renal failure
– Renal transplant patients.

33. These manifestations include:
Bone pains
Muscle pain and weakness
Skeletal deformities
Pseudogout
Calcefic periartheritis
 Vascular calcification
Fractures.
Tendon rupture
Pruritus
-Calciphelaxis

34. Bone Pains
Causes are: osteitis fibrosa cystica,
osteomalacia, osteoarthritis, β2-
microglobulin amyloidosis.
Fibromyalgia induces more diffuse
muscle and soft tissue pain.
Radiography may reveal
pseudofractures of the pelvis, femurs,
metatarsals, or lateral margins of the
scapulae.
Therapy of chronic pain has to be
adapted to the individual patient with
special regard to the presence of a high
or low bone turnover osteopathy.

35. •PeriarticularCalcification

36. UREMIC MYOPATHY
MUSCLE WEEKNESS
The development of a myopathy in CKD causes
proximal muscle weakness and wasting, predominantly
in the muscles of the lower limbs.
Uremic myopathy typically develops with glomerular
filtration rates of <25 ml/min, and has been associated
with fatigability and reduced exercise capacity.
Electromyography and creatine kinase levels are
generally normal, and the diagnosis is, therefore, made
largely on clinical grounds.
 Campistol,. Kidney Int. 62, 1901-1913 (2002).

37. Waddling gate

38. Bone Fractures
Worldwide, one in three women and one in five
men over the age of 50 will have a fracture
This is very different from what is known in men
and women with chronic kidney disease (CKD).
Data from a large cohort of patients of (NHANES
III) in USA demonstrate that compared with those
with (eGFR) of greater than or equal to 60 ml/min,
those with an eGFR less than 60 ml/min had a
twofold increased risk of hip fractures.

39. Bone Fractures
On the other hand, the prevalence
of vertebral fractures in CKD
patients is similar to that in the
general population.
– Fusaro et al., Calcif Tissue Int 2013
There are data indicating that impaired
neuromuscular function, probably
resulting in increased incidence
of falls, is assciated with fractures in
patients with CKD.
– Barreto, Kidney Int 2008

40. Yearly incidence of hip fracture
Reference Country HD General population with simil
USA 1% 0.22%
2012 DOPPS 2 countries 0.89% 0.47–1.57% 0.07–0.22%*
↵*References available in [2].
Michel Jadoul, NDT, 2012

41. Pseudogout
Calcium pyrophosphate dihydrate deposition disease is a crystal
arthritis, crystal deposition in the articular cartilage or synovium.
In chronic kidney disease patients, the major causes of crystal
arthritis are calcium oxalate crystals and basic calcium
phosphate crystals.
Although considered uncommon, pseudogout may cause acute
arthritis in chronic renal failure more often than previously
suspected.
Joint aspiration and identification of CPPD crystals with
compensated polarized light microscopy will establish the diagnosis of
pseudogout.
– Michael et al., Arch Intern Med .1979.

42. Tendon Rupture
• Spontaneous tendon
rupture is a rare complication
which severely disables
patient's activity.
• It generally occurs in
association with different
chronic metabolic disorders,
chronic renal failure, gout and
obesity.
• Especially rare are
simultaneous, spontaneous,
(the quadriceps femoris,
Achilles and patellar tendon).
• Nikolina KIDNEY AND BLOOD PRESSURE RESEARCH ·
2009

43. Pruritus
A terrible symptom that may be related to
PTH
Persistent uremic pruritus of patients with
secondary hyperparathyroidism decreased
after parathyroidectomy
Intradermal application of parathormone did
not cause a significant skin reaction in
humans.
Itching can occur in patients with accepted
PTH serum level.
Kleeman CR et al. Trans Assoc Am Physicians. 1968;81:203–212.
Massry SG et al. N Engl J Med. 1968;279(13):697–700.
Ståhle-Bäckdahl M et al. J Intern Med. 1989;225(6):411–415.
7

44. Chou FF et al. J Am Coll Surg 2000; 190:65.
6

45. Chou FF et al. J Am Coll Surg 2000; 190:65.
6

46. Extra-skeletal manifestations
It is a systemic disorder affecting soft tissues, particularly
vessels, heart valves and skin.
Coronary artery and vascular calcifications occur
frequently in CKD 5 (and increase each year on dialysis)
CVD accounts for around half
of all deaths of dialysis patients.

47. “If we X-Ray most of our patients, they’ve got “tram tracks” – we hardly
need an angiogram!”

48. Types of calcification
1. Focal calcification associated
with lipid laden atherosclerotic plaques
• Increases fragility and risk of plaque rupture
1. Diffuse calcification
• not in atherosclerotic plaques and occurs in media of vessels
• Called “Monckeberg’s sclerosis”
• Increases blood vessel stiffness and reduces vascular
compliance
 Results in widened pulse pressure
 Increased afterload
 LVH
• Contributing to CVD morbidity

52. Extra-skeletal manifestations
• Important to recognize
disordered bone and mineral
metabolism is a systemic
disorder affecting soft tissues,
particularly vessels, heart
valves and skin.
• CVD accounts for around half
of all deaths of dialysis
patients.
• Coronary artery and vascular
calcifications occur frequently
in CKD 5 (and increase each
year on dialysis)

53. Calciphylaxis or calcemic uremic arteriolopathy (CUA)
–Seen primarily in CKD 5
–Occurs in 1-4% of dialysis
patients
–Presents with extensive
calcification of the skin,
muscles and SC tissues.
 Extensive medial calcification of
small arteries, arterioles, capillaries
and venules.
 Clinically they may have skin
nodules, skin firmness, eschars,
livedo reticularis and painful
hyperaesthesia of the skin.
 May lead to non healing ulcers and
gangrene
Brandenburg et al., Journal of nephrology 2011

54. Calciphylaxis
• A, Confluent calf plaques (borders
shown with arrows).
Parts of the skin are erythematous,
which is easily confused with simple
cellulitis.
• B, Gross ulceration in the same patient
3 months later. The black escharhas
been surgically débrided.
• C, Calciphylactic plaques, a few of
which are beginning to ulcerate.
• (Photographs courtesy of Dr. Adrian Fine. Up To
Date)

55. Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of the eschar.

56. Amyloidosis
Pts on dialysis for 7- 10 years can develop osteoarticular amyloid
deposits.
May present with carpel tunnel syndrome and arthritis

57. Amyloidosis

58. Management of ROD
• Detection of the type of ROD
• Define goals of therapy
• Follow the guidelines (KDOQI)
• Prevent ROD in predialysis patient
(CKD III, IV)

59. Management of ROD
• Diagnosis of ROD
• Biochemical Markers
• Radiology
• Histology and Pathology

60. Biochemical Markers of Renal
Osteodystrophy
• Total Calcium (8.5-10mg/dl)
• Phosphorus ( 3.5-5.2mg/dl).
• PTH assays (150-300pg/dl KDOQI).
• PTH assays (150-700pg/dl KDIGO)
• Alkaline phosphatase (age related).
• Aluminum.

61. X-Ray studies:
Traditional X-ray cannot help in defining the existent
histologic pattern of osteodystrophy and the rate of bone
turnover.
Bone densitometric studies:
It is probably safe to state that densitometric techniques
in renal disease are mainly useful in the follow up control
of renal bone diseases.

62. Radiographic signs in hand skeletons of haemodialysis
patients with severe secondary hyperparathyroidism
•)b) periostal new bone formation
)periostal neostosis) )arrow);
• )c) subperiostal resorption zones )arrow).
• Both )b) and )c) show cortical thinning, cortical striation, and fluffy trabecular
structure.

63. Resorptive defects of diploë (pepper-pot aspect) in the skull of a
haemodialysis patient with severe hyperparathyroidism.

64. Increased density of ground plates of vertebrae contrasting with
radiolucency of the central vertebral slices (rugger jersey spine) in a
haemodialysis patient with severe hyperparathyroidism. Note the severe
aortic calcification.

65. Bone Biopsy and Histomorphometry
Bone biopsy can be taken either by needle
and is satisfactory for clinical purposes, or by
using electrical drill.
Bone dynamic studies:
The administration of tetracycline, that
localizes at the mineralizing surface and
whose fluorescence can be detected by
ultraviolet microscopy, is able to provide
dynamic information’s about bone turnover.

67. Therapeutic Modalities of Renal
Osteodystrophy:
•I-Control of calcium:
•Calcium supplementation.
•Vitamin D analogues.
•Choice of dialysate calcium
concentration.
•II-Control of phosphorus:
•Dietary phosphate restriction.
•Removal of phosphorus by
dialysis
•Phosphate-binding.

68. •III-Control of Parathyroid glands:
•Control of phosphorus
•Control of calcium
•Vit D Analogues
•Calcimimetics
•Parathyroidectomy.
•V-Removal of aluminum: disferrioxamine.

69. The new vitamin D analogues
Paricalcitol (Zemplar), or 19-nor-1alpha,25-
dihydroxyvitamin D2. .
• It binds specifically with vitamin D receptors on the
parathyroid gland, where it suppress the secretion of
PTH by about 60%,,and at the same time it does not
increase the intestinal absorption of calcium or
phosphorus.
Paricalcitol results in 10 times less elevation of serum
calcium than calcitriol It is 10 times less effective in
mobilising calcium and phosphorus from bone side
effect includes: fever, chills, feeling unwell.
Block GA. Clin Nephrol. 2000;54:318-324.

70. The new vitamin D analogues
Doxercalciferol (Hectorol), is a synthetic vitamin D2
undergoes metabolic activation in vivo to form 1a,25-
dihydroxyvitamin D2 (1a,25-(OH)2D2)
• Doxercalciferol is absorbed from the gastrointestinal
tract and activated by CYP 27 in the liver to form 1 ,25-
(OH)2D2 (major metabolite) and 1 ,24-
dihydroxyvitamin D2 (minor metabolite)..
• Precautions in:
• liver disease
• Pregnancy
• breast-feeding
Block GA. Clin Nephrol. 2000;54:318-324.

71. Summary
Calcium
In hypocalcemic patients
Calcium supplement
Calcium
Calcium containing PO
binders
In hyercalcemic patients
Calcium restrictions
Avoid Calcium Containing
PO binders
Dialysate calcium
Phosphorus
• Dietary Phosphate
Restriction
• Dialysis
• Phosphate Binding
Agents
• Ca containing
• Non Ca
Containing
• Metal based
• Ferric citrate
Parathyroid Gland
• Phosphorus
• Calcium
• Vitamin D analogues
• Parathyroidectomy
• Local Parathyroid gland
injection
• Alcohol
• Vitamin D
• Calcimimetics

72. Recommendations
• Aim for long-term serum phosphorus 3.0-
5.5 mg/dL
• Aim for long-term Ca × P product of <55
mg2
/dL2
• Monitor PTH level.
• Monitor calcium intake.
• Avoid agents that accumulate and cause
metal toxicity (aluminum)
• Avoid unneeded use of Vit. D analogues
Block GA. Clin Nephrol. 2000;54:318-324.
Llach F. Am J Kidney Dis. 1998;32:514-518.