Prof.said khamis ckd mbd 1 2019

CKD-MBD: Classifications and Diagnosis
Dr Said KhamisDr Said Khamis
MD, (MSc., KUL Belgium )MD, (MSc., KUL Belgium )
Prof. of Internal Medicine & NephrologyProf. of Internal Medicine & Nephrology

Agenda
The size of the problem (CKD-MBD)
Definitions & Classifications
Bone disease in CKD (B)
Vascular calcifications/CVD (V/C)
Role of Calcium and Phosphorus (L)
Importance of Vitamin D in CKD-MBD (L)
CKD & SHPT (L)
Frequency of Monitoring
 CKD-MBD 2017 Guidelines (Diagnosis of CKD-MBD & VC)

Disorders of mineral metabolism are major risk
factors in CKD-MBD
Moe SM, Chertow GMMoe SM, Chertow GM. Clin J Am Soc Nephrol. Clin J Am Soc Nephrol 2006.2006.
The risk associated with disorders of mineral metabolism is higher than that associated with inefficient dialysisThe risk associated with disorders of mineral metabolism is higher than that associated with inefficient dialysisThe risk associated with disorders of mineral metabolism is higher than that associated with inefficient dialysisThe risk associated with disorders of mineral metabolism is higher than that associated with inefficient dialysis
0
2
4
6
8
10
12
14
16
18
20
Low URR Anaemia High Pi High Ca High PTH All
mineral
Attributablemortalityrisk(%)
(5.1%)(5.1%)
(11.3%)(11.3%)
(6%)(6%)
(17.5%)(17.5%)

Blood Purif 2018;45:1–7
CKD-MBD:
Mortality

• However, we must keep in mind that all these
CKD-MBD players have a close connection & any
change in one could certainly affect the other
• Therefore, only an integrative approach for CKD-
MBD therapy will succeed

1970 1980 1990 2000 2010 2017
Aluminum
Binders
PO Calcitriol
Calcium
Binders
Vitamin D
Analogues
K/DOQI
IV Calcitriol
History of Treatment Strategies for
Secondary Hyperparathyroidism
Focus: Bone Disease,
Systemic effects of PTH,
High Ca was
thought to be good
Sevelamer
Cinacalcet HCl
KIDGO
Focus: Fractures, Mortality,
& Vascular Calcification
KIDGO
VIT K2

Definition of CKD-MBD And Renal
Osteodystrophy
 Definition of CKD-MBD
– A systemic disorder of mineral and bone metabolism due to CKD
manifested by either one or the combination of the following:
L/Abnormalities of calcium, Phosphorus, PTH, or Vitamin D
metabolism
 B/ Abnormalities in bone turnover, mineralization, volume, linear growth, or
strength.
V/C: Vascular or other soft-tissue calcification
 Definition of Renal Osteodystrophy
– Renal osteodystrophy is an alteration of bone morphology in patients
with CKD.
– It is one measure of the skeletal component of the systemic disorder of
CKD-MBD that is quantifiable by histomorphometry of bone biopsy.
– Uhlig et al, AJKD Vol 55, No 5, May 2010.
– KDIGO classification of CKD-MBD 2009

Framework for classification of CKD-MBD
MBD parameter Laboratory
abnormalities
Bone disease Calcification of
Vascular or other
soft tissue
L + - -
LB + + -
LC + - +
LBC/V + + +
Moe S et al. Kidney Int 2006;69:1945–
53.
L= laboratory abnormalities; B = bone disease; C/V = calcification of vascular or other soft tissue.L= laboratory abnormalities; B = bone disease; C/V = calcification of vascular or other soft tissue.

Definition of CKD-MBD And Renal
Osteodystrophy
 Definition of CKD-MBD
– A systemic disorder of mineral and bone metabolism due to CKD
manifested by either one or the combination of the following:
L/Abnormalities of calcium, Phosphorus, PTH, or Vitamin D
metabolism
 B/ Abnormalities in bone turnover, mineralization, volume, linear growth, or
strength.
V/C: Vascular or other soft-tissue calcification
 Definition of Renal Osteodystrophy
– Renal osteodystrophy is an alteration of bone morphology in patiens
with CKD.
– It is one measure of the skeletal component of the systemic disorder of
CKD-MBD that is quantifiable by histomorphometry of bone biopsy.
– Uhlig et al, AJKD Vol 55, No 5, May 2010.
– KDIGO classification of CKD-MBD 2009

Pathophysiologic mechanisms of ROD

Table 1. Pathology and Diagnosis of Bone Turnover in CKD
©© 2008 American Society for Bone and Mineral Research2008 American Society for Bone and Mineral Research
From theFrom the Primer on the Metabolic Bone Diseases andPrimer on the Metabolic Bone Diseases and
Disorders of Mineral Metabolism, 7th EditionDisorders of Mineral Metabolism, 7th Edition..
www.asbmrprimer.orgwww.asbmrprimer.org

Spectrum of ROD
Mixed LesionMixed Lesion
Osteitis FibrosaOsteitis Fibrosa
Normal BoneNormal Bone
FormationFormation
HighHigh
Low turnoverLow turnover High turnoverHigh turnover
AdynamicAdynamic
OsteomalaciaOsteomalacia
LowLow
PTHPTH
< 150 pg/ml< 150 pg/ml 150 – 300 pg/ml150 – 300 pg/ml > 300 pg/ml> 300 pg/ml

Imaging in Chronic Kidney Disease Metabolic Bone Disease‐
Seminars in Dialysis, Volume: 30, Issue: 4, Pages: 361-368, First published: 05 April 2017, DOI: (10.1111/sdi.12598)
26 year old male with hand radiograph‐ ‐
demonstrating mild periosteal reaction
along the metacarpal bones (arrows).

Imaging in Chronic Kidney Disease Metabolic Bone Disease‐
Seminars in Dialysis, Volume: 30, Issue: 4, Pages: 361-368, First published: 05 April 2017, DOI: (10.1111/sdi.12598)
(A,B) 39 year old male with lateral and AP radiographs of the elbow demonstrating well defined, lobular,‐ ‐
calcified mass in the soft tissues about the elbow (arrow) consistent with periarticular calcification. (C) 42‐
year old male with right hip radiograph demonstrating periarticular “tumoral” calcification adjacent to the right‐
femoral neck (arrow).

Amino terminal and carboxy-Amino terminal and carboxy-
terminal propeptides of type Iterminal propeptides of type I
collagen (PINP, PICP).collagen (PINP, PICP).

Bone Turnover:
Biomarkers and Images
Low bone turnover
J Am Soc Nephrol 2018, in press

Clin Exp Nephrol (2015) 19:543–555
Bone and Transplantation

Abnormal boneAbnormal bone
AgeAge
Oxidation (OxLDL)Oxidation (OxLDL)
DiabetesDiabetes
HTNHTN
Advanced glycationAdvanced glycation
end-productsend-products
SmokingSmoking
GeneticsGenetics
DyslipidemiaDyslipidemia
Carbonyl stressCarbonyl stress
Low fetuin-ALow fetuin-A
Traditional Risk FactorsTraditional Risk Factors Non-traditional Risk FactorsNon-traditional Risk Factors
Elevated IL-1, Il-6, TNFElevated IL-1, Il-6, TNFαα
HomocysteineHomocysteine
Abnormal mineral metabolismAbnormal mineral metabolism
FracturesFractures
Cardiovascular disease in CKDCardiovascular disease in CKD

Control of vascular calcifications
SMCSMC OsteoblastOsteoblast
InhibitorsInhibitors
FetuinFetuin
MGlaPMGlaP
OsteoprotegerinOsteoprotegerin
OsteopontinOsteopontin
PhytatePhytate
PyrophosphatePyrophosphate
BMPBMP
77
ActivatorsActivators
PhosphorusPhosphorus
Uremic toxinsUremic toxins
PTHPTH
FGF23FGF23
VitaminDVitaminD
OxLDLOxLDL
BMPBMP
22
SclerostinSclerostin
-- ++
Semin Dial. 2018 Jan;31(1):72-81.

•Two types of vascular calcification
• Intimal calcification leads to calcific plaques or circumferentially calcified atherosclerosis
• Medial calcification is nonocclusive and leads to vascular stiffening; it can cause local ischemia and also affect
the capacity of the vasculature to dampen increases in arterial pressure with each ventricular systole, leading to
left ventricular hypertrophy
•Traditionally, the CAC score obtained by electron beam CT is used to quantify calcification burden
•Other available techniques can provide semi-quantitative evidence of calcification, including duplex ultrasonography,

Types of Vascular Calcification in CKD
Uremic arteriopathyUremic arteriopathy AtherosclerosisAtherosclerosis

Review Series August 2015 mmunodiagnostic Systems Limited

Imaging techniques for V/C
The best diagnostic technique is unknown
Which bed?
– Coronary vs central vs peripheral
Which technique?
– Simplicity and accuracy
Which golden standard?
– CAC vs hard clinical outcomes

Ideally
Appropriate vascular bed
Simple, available, interpretable
Detects disease with reasonable sensitivity/specificty
Detects progression
Detects effect of treatment
Results correlate with hard clinical outcomesResults correlate with hard clinical outcomes

CAC
Plain
X-rays
Ultrasound
Echocardiography
Functional
Evolution of diagnostic techniques
Non-contrast CT
EBCT vs MSCT
Planar vs volumetric
Aortic (?level)
Peripheral (?which)
Which bed?
Which level?
Which valve?
Technique?
Score
Doppler?
MRI?

All this with
NO consensus on diagnostic technique

The Parathyroids, Third Edition, 2015
CKD-MBD:
Laboratory Profile

CKD-M(B/V)DCKD-M(B/V)D Key PlayersKey Players
Complex interdependence of calcium, phosphorus, vitamin D, FGF23 &Complex interdependence of calcium, phosphorus, vitamin D, FGF23 &
PTHPTH
PP
PTHPTH
CaCa
Vit.DVit.D
FGF23FGF23
Bone and Mineral Balance

Consequences of Phosphorus
Dysregulation

CKD-MBD: Dysregulation and Clinical Manifestations
of an Increasingly Compromised System

Serum Phosphorus Levels and Mortality in
CKD Non-Dialysis Patients
Mortality risk increases as phosphorus levels rise, even within normal range
Each 0.5 mg/dL increase in serum phosphorus was associated with increased mortality
Statistically significant increases in mortality were noted when phosphorus levels reached 3.5 mg/dL
or above
Adapted from Kestenbaum B, Sampson JN, Rudser KD, et al. J Am Soc Nephrol. 2005;16:520-528.
1.00
1.15
1.32 1.34
1.83
1.90
1.00
1.20
1.40
1.60
1.80
2.00
2.5-2.99 3.0-3.49 3.5-3.99 4.0-4.49 4.5-4.99 >5.0
Phosphorus (mg/dL)
Adjustedhazardratio(HR)
Mortality rates by phosphate category
72% of patients
(n=3,289)

*Multivariable adjusted
With permission from Block GA, Klassen PS, Lazarus JM, et al. J Am Soc Nephrol. 2004;15:2208-2218.
Elevated Serum Phosphorus
and Mortality Risk in Dialysis Patients
Relativeriskofdeath*
<3 3-4 4-5 5-6 6-7 7-8 8-9 >9
Serum phosphorous concentration (mg/dL)
0.00
1.0
1.4
1.6
2.0
2.2
0.08
1.2
1.8
N = 40,538
Referent
Range

KDIGO Focus: Normal Treatment Target
Ranges for Phosphorous and Calcium
Stage Target PO4
1,2
Target Ca1,2
3
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDOQI: Normal for Lab
4-5
KDOQI: Normal for Lab
5D
KDIGO: Towards Normal
Emphasis on individual levels of serum calcium and phosphorus
rather than Ca x P product
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline
for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)
Kidney Int. 2009;76(suppl 113):S1-S130.
2. National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic
kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

Summary Slide
Despite early phosphate retention, many patients have
serum phosphorus levels within normal range
Mortality risk increases as phosphorus levels rise,
even when levels remain within normal range
Increased serum phosphorus levels are associated
with CV events and mortality
Adequate dialysis may have an additive role in
controlling hyperphosphatemia

Importance of Vitamin D
in CKD-MBD

Calcium and
Phosphorus
Homeostasis
Bone Health
Cardiovascular
Effects
Renin-Angiotensin
Regulation
Decreased Risk for:
Hypertension
Type II Diabetes
(via stimulation of pancreatic
insulin production)
Heart Failure
Immunomodulatory
Effects
Multiple Sclerosis
Type 1 Diabetes
(via ß-islet cell
destruction)
Psoriasis
Rheumatoid Arthritis
Inflammatory Bowel
Disease
Periodontal Disease
Growth & Regulation
Antiproliferation
Prodifferentiation
Apoptotic
Anti-angiogenic
Prostate,
Colon,
Breast Cancers etc.
Neuromuscular
Effects
Muscle Mass
Muscle Strength
Better Balance
25(OH)D
Major Circulating Metabolite
1,25(OH)2D
Biologically Active
Keratinocytes
M
acrophages
Colon
Prostate
Breast, etc.
Kidney
Physiologic Effects of Vitamin D
Throughout the Body
Adapted from: Holick MF. Mayo Clin Proc. 2006;81:353-373.

1,25-dihydroxyvitamin D levels and 90-day all-cause (A) and CV mortality (B) in hemodialysis
patients according to whether patients received active vitamin D therapy
With permission from Wolf M, et al. Kidney Int. 2007;72:1004-1013.
1,25(OH)2D3 Levels and
Mortality in Dialysis Patients
1,25-dihydroxyvitamin D (pg/mL)
Oddsratioofall-causemortality
10
8
6
4
2
0
<5 6–13 >13
*
*
OddsratioofCVmortality
10
8
6
4
2
0
<5 6–13 >13
*
A B
RR
No active vitamin D therapy
Active vitamin D therapy
*P<0.05 for the comparison of the individual vitamin D level―vitamin D treatment groups with the corresponding referent groups.
R=subjects treated with active vitamin D and 1,25-dihydroxyvitamin D levels ≥13 pg/mL.
No active vitamin D therapy
Active vitamin D therapy

Summary
Patients with CKD have a high prevalence of both
25(OH)D and 1,25(OH)2D deficiency
As kidney function declines, patients lose the ability
to convert 25(OH)D to 1,25(OH)D
Patients with lower levels of 1,25(OH)2D had a higher
risk of mortality

Chronic Kidney Disease
and
Secondary Hyperparathyroidism (SHPT)

Compensatory Mechanism of PTH During
Disturbances in Mineral Metabolism
With permission from Levin A, et al. Kidney Int. 2007;71:31-38.
1.25-dihydroxyvitaminD(pg/mL)
25HydroxyvitaminD(ng/mL)
IntactPTH(pg/mL)
Median values of 1,25-dihydroxyvitamin D, 25 Hydroxyvitamin D,
and intact PTH by GFR levels
GFR level (mL/min)
50
45
40
35
30
25
20
15
10
5
0
>80 79-70 69-60 59-50 49-40 39-30 29-20 <20
50
0
100
150
25 Hydroxyvitamin D (ng/mL)
Intact PTH (pg/mL)

Elevated PTH Levels and Cardiovascular Disease
in Patients with CKD Stages 3 and 4
37
41
49
30
35
40
45
50
<35 35-70 >70
Rateofcardiovasculardisease,%
Parathyroid hormone level, pg/mL
With permission from Bhuriya R, et al. Am J Kidney Dis. 2009;53 (4 suppl 4):S3-S10.
P<0.001

Clin J Am Soc Nephrol 2018, in press
PTH in Focus

PTH Assays
•First-generation assays
• Radioimmunoassay using an antibody against the mid-region or carboxy-terminal end
• Detects full-length PTH as well as the multiple carboxy- and amino-terminal fragments
• Unreliable
•Second-generation assay/intact PTH assays/two-step first generation immunoradiometric assays
(IRMA)
• Involve two antibodies, one that detects the amino terminus and the other the carboxy terminus
• Most commonly used assay in clinical practice
• However, in addition to detecting full-length PTH, it also detects fragments commonly referred to
as 7-84 PTH
• This 7-84 PTH may have antagonistic effects to full-length PTH on bone
•Third generation assays/whole PTH assays/Biointact PTH assays only detect 1-84 PTH
•Poor correlation between any of the PTH assays and bone histology in CKD

Nat Rev Nephrol. 2017 Jul;13(7):429-442
Alkaline Phosphatase:
A Novel Target

KDIGO Focus: Consider Normal
Limit for PTH
Stage Treatment Target Range
3
KDIGO: Upper Limit of Normal* (2C)
KDOQI: 35-70 pg/mL
4
KDOQI: 70-110 pg/mL
5
KDOQI: 150-300 pg/mL
5D
KDIGO: 2 to 9 times Upper Limit of Normal (2C)
KDOQI: 150-300 pg/mL
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline
for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)
Kidney Int. 2009;76(suppl 113):S1-S130.
2. Adapted from National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in
chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
*In patients with CKD stages 3-5*In patients with CKD stages 3-5 not on dialysis,not on dialysis, in whom serum PTH is progressively rising and remainsin whom serum PTH is progressively rising and remains
persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment withpersistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with
calcitriol or vitamin D analogs is suggested.calcitriol or vitamin D analogs is suggested. (2C)(2C)

Summary
Elevated PTH levels are a compensatory mechanism
for 1,25D depletion — both are prominent and
progressive across the CKD continuum
Elevated PTH levels and 1,25D depletion have each
been independently associated with higher mortality
Vitamin D when appropriate without inducing what
is overtly oversuppressed parathyroid hormone
High calcium and high phosphorus with or without
vitamin D is a required objective

Conclusions:
After switching the frequency of routine blood work from 4- to 6-week intervals, performance on
anemia and CKD-MBD targets did not change and the reduction in blood work was associated
with laboratory cost savings.

CKD-MBD:
2017 KDIGO Guidelines
Revision of 15
recommendations
7March 2018

Kidney Disease: Improving Global Outcomes
CHAPTER 3.1:
DIAGNOSIS OF CKD-MBD:
BIOCHEMICAL
ABNORMALITIES

ASSESSMENT
3.1.1: We recommend monitoring serum levels of calcium,
phosphate, PTH, and alkaline phosphatase activity beginning in
CKD G3a (1C). In children, we suggest such monitoring beginning
in CKD G2 (2D).
3.1.2: In patients with CKD G3a–G5D, it is reasonable to base the
frequency of monitoring serum calcium, phosphate, and PTH on
the presence and magnitude of abnormalities, and the rate of
progression of CKD (Not Graded).

ASSESSMENT
3.1.2 (cont’d.): Reasonable monitoring intervals would be:
o In CKD G3a–G3b: for serum calcium and phosphate, every 6–12 months; and
for PTH, based on baseline level and CKD progression.
o In CKD G4: for serum calcium and phosphate, every 3–6 months; and for PTH,
every 6–12 months.
o In CKD G5, including G5D: for serum calcium and phosphate, every 1–3
months; and for PTH, every 3–6 months.
o In CKD G4–G5D: for alkaline phosphatase activity, every 12 months, or more
frequently in the presence of elevated PTH (see Chapter 3.2).
In CKD patients receiving treatments for CKD-MBD, or in whom
biochemical abnormalities are identified, it is reasonable to increase the
frequency of measurements to monitor for trends and treatment efficacy
and side effects (Not Graded).

ASSESSMENT
3.1.3: In patients with CKD G3a–G5D, we suggest that 25(OH)D
(calcidiol) levels might be measured, and repeated testing
determined by baseline values and therapeutic interventions
(2C).
We suggest that vitamin D deficiency and insufficiency be
corrected using treatment strategies recommended for the
general population (2C).
3.1.4: In patients with CKD G3a–G5D, we recommend that
therapeutic decisions be based on trends rather than on a single
laboratory value, taking into account all available CKD-MBD
assessments (1C).

ASSESSMENT
3.1.5: In patients with CKD G3a–G5D, we suggest that individual
values of serum calcium and phosphate, evaluated together, be
used to guide clinical practice rather than the mathematical
construct of calcium-phosphate product (Ca x P) (2D).
3.1.6: In reports of laboratory tests for patients with CKD G3a–
G5D, we recommend that clinical laboratories inform clinicians
of the actual assay method in use and report any change in
methods, sample source (plasma or serum), or handling
specifications to facilitate the appropriate interpretation of
biochemistry data (1B).

CHAPTER 3.2:
DIAGNOSIS OF CKD-MBD:
BONE

TESTING FOR CKD-MBD
3.2.1: In patients with CKD G3a-G5D with evidence of CKD-MBD
and/or risk factors for osteoporosis, we suggest bone mineral
density (BMD) testing to assess fracture risk if results will impact
treatment decisions (2B).
3.2.2: In patients with CKD G3a-G5D, it is reasonable to perform a
bone biopsy if knowledge of the type of renal osteodystrophy will
impact treatment decisions (Not Graded).

ASSESSMENT
3.2.3: In patients with CKD G3a–G5D, we suggest that measurements of
serum PTH or bone-specific alkaline phosphatase can be used to
evaluate bone disease because markedly high or low values predict
underlying bone turnover (2B).
3.2.4: In patients with CKD G3a–G5D, we suggest not routinely
measuring bone-derived turnover markers of collagen synthesis (such as
procollagen type I C-terminal propeptide) and breakdown (such as
type I collagen cross-linked telopeptide, cross-laps, pyridinoline, or
deoxypyridinoline) (2C).
3.2.5: We recommend that infants with CKD G2–G5D have their length
measured at least quarterly, while children with CKD G2–G5D should be
assessed for linear growth at least annually (1B).

CHAPTER 3.3:
DIAGNOSIS OF CKD–MBD:
VASCULAR CALCIFICATION

ASSESSMENT
3.3.1: In patients with CKD G3a–G5D, we suggest that a lateral
abdominal radiograph can be used to detect the presence or
absence of vascular calcification, and an echocardiogram can be
used to detect the presence or absence of valvular calcification,
as reasonable alternatives to computed tomography-based
imaging (2C).
3.3.2: We suggest that patients with CKD G3a–G5D with known
vascular or valvular calcification be considered at highest
cardiovascular risk (2A).
It is reasonable to use this information to guide the management
of CKD-MBD (Not Graded).

Renal Transplantation:
CKD-MBD Guidelines

 Chronic kidney disease-mineral and bone disorder
(CKD-MBD) patients have a huge morbidity and
mortality.
 Only relatively minor progress in therapeutic
strategies has been made in the past decades.
 This is at least partially due to a lack of predictive
diagnostic tools allowing personalized treatment of
CKD-MBD patients
 Without precise diagnostic tools a personalized
therapy is not possible. This, however, was part of the
success story in oncology.

 However, there is hope; Researchers highlighted key
recommendations in areas of controversy or conjecture in the
management of (CKD-MBD) in a recent synopsis of the
(KDIGO) 2017 .
 The original update, published in Kidney International (2017;7(Suppl 1):1-
59), resulted in 15 revised recommendations based on evidence of
varying strengths accumulated since the 2009 KDIGO guidelines
 They described the recent progress in the diagnosis of
disturbances of the PTH, calcium & phosphate & metabolism
in patients with CKD plus the currently available imaging
modalities to Dx. different subcategories of CKD-MBD.
 These new tools may have the potential of allowing
personalized therapy for the treatment of CKD-MBD and
hence improving outcome.

CKD-MBD Management
Controlling Ca, Pi, PTH, Vitamin D, FGF23
To Prevent
MBD
MVD
Morbidity & Mortality

Study of Cardiovascular Calcifications among Regular Hemodialysis Patients with
and Without Chronic Hepatitis C Virus Infection
Abdel-hady Hassan*, Reda S.B*, Walaa F.**, Ehab A A.*, Ashraf G D* and Dina M A*.
Internal Medicine* and Cardiology** Departments, Faculty of Medicine, Menofiya University Hospitals,
Egypt. ( in press.)

Thank you for your attention
Phramongkutklao Hospital and
College of Medicine

Elias MR et al., Current Osteoporosis report. October 2018

Prof.said khamis ckd mbd 1 2019

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