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Il concetto di CKD-MBD
(Chronic Kidney Disease-
Mineral and Bone Disorder)
Maurizio Gallieni
Professore Ordinario di Nefrologia
Dipartimento di Scienze Biomediche e Cliniche
Università degli Studi di Milano

2. 2006 – Introduzione del concetto di CKD-MBD

3. 2006 – Introduzione del concetto di CKD-MBD
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 Int 2006; 69: 1945–1953

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Anomalie bioumorali del metabolismo minerale, osteodistrofia renale e malattie
cardiovascolari rappresentano i tre domini della CKD-MBD
CKD-MBD (Chronic Kidney Disease Mineral and Bone Disorder) – Definizione
Adapted from: Cozzolino M, et al. Nephrol Dial Transplant 2014;29:1815–1820

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Alterazioni specifiche della CKD-MBD che possono determinare outcome significativi e
aumento della mortalità
CKD-MBD – un disordine multifattoriale e progressivo
High Sclerostin
Low Klotho

6. Bone abnormalities in turnover,
mineralisation, volume, linear
growth or strength
Bone histology: mixed uraemic
osteodystrophy characterised by high
cellular activity with osteoclastic giant
cells in resorption lacunae, osteoid
accumulation and peri-trabecular
fibrosis*
Laboratory abnormalities of
calcium, inorganic phosphorus,
PTH or vitamin D
Thyroid gland ultrasonography
showing the right upper parathyroid
gland in a dialysis patient with
uncontrolled hyperparathyroidism
Calcification of the vasculature or
other soft tissues
Severe calcific aortic valve
stenosis revealing macroscopic
areas of ulcerative calcification
LABORATORY ABNORMALITIES BONE DISEASE CALCIFICATION
*Courtesy of Dr Gabriele Lehmann, Jena, Germany.
Adapted from: Cozzolino M, et al. Nephrol Dial Transplant 2014;29:1815–1820.
CKD-MBD – Esempi di patologie riferibili ai tre domini della CKD-MBD

7. 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.
Moe et al. Kidney Int. 2006; 69:1945-53

8. CKD-MBD – Dalle alterazioni bioumorali agli outcome

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CKD-MBD – Anomalie di laboratorio

10. Chronic
kidney disease
Phosphorus
retention
↑ FGF23
↓ Calcitriol
(1,25(OH)2D3)
Sec.HPT
↑ Serum
calcium
↑ Serum
phosphorus
↑ FGF23
↑ PTH
↓ Serum
calcium
↑ Phosphorus
excretion
in the urine
Moe S, et al. Kidney Int 2006;69:1945-1953; Goodman WG. Semin Dial 2004;17:209-216; Goodman WG, et al. Kidney Int
2008;74:276-288; Goodman WG. Med Clin N Am 2005;89:631-647; Cozzolino M, et al. Am J Nephrol 2015;42:228-236; Blaine J, et
al. Clin J Am Soc Nephrol 2014;10:1257-1272; Wolf M, et al. Clin J Am Soc Nephrol 2015;10:1875-1885
CKD-MBD – Fisiopatologia dell’iperparatiroidismo secondario

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Iperplasia delle ghiandole paratiroidi
La trasformazione nodulare si accompagna a riduzione dell’espressione dei recettori della
vitamina D (VDR) e del calcio (CaR), a una ridotta sensibilità all’azione di calcio e calcitriolo.

12. FGF23
PTH
1,25-D
Suppression
Stimulation
Phosphorus
1,25-D upregulates
expression of
FGF232
FGF23 decreases phosphorus
reabsorption in the proximal tubule
and increases net phosphorus
excretion1
Increased levels of
phosphorus stimulate
the secretion of
FGF23 from bone1
FGF23 acts as a counter-
regulatory hormone,
decreasing levels of
1,25-D1
PTH upregulates
expression of
FGF233
FGF23 may suppress
PTH secretion1
1-α-hydroxylase
24-hydroxylase
Data presented are from both animal and human studies.
1. Alon US. Eur J Pediatr 2011;170:545–554; 2. Quarles LD. J Clin Invest 2008;118:3820–3828;
3. Seiler S, et al. Kidney Int 2009;(Suppl 114):S34–S42
CKD-MBD – Il ruolo di FGF23: interazione con fosforo, PTH e vitamina D (1-25D)

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CKD-MBD. Livelli di fosforo, PTH, FGF23 e calcitriolo in diversi stadi di malattia
renale cronica, dialisi e trapianto

14. Levin A et al. Kidney Int 2007;71:31-8
CKD-MBD. I livelli di PTH si innalzano prima che siano percepibili variazioni di
calcemia e fosforemia.

15. Isakova T, et al. Kidney Int 2011;79:1370–1378.
N = 3,879
Patients
(%)
CKD Stage 2
CKD Stage 3
CKD Stage 4
(mL/min/1.73 m2
)
eGFR levels:
CKD-MBD. I livelli di FGF23 si innalzano ancora prima del PTH

16. CKD-MBD. Alterazione dei lvelli di
FGF23 e PTH in diverse classi di eGFR
Isakova T, et al. Kidney Int 2011;79:1370–1378.

17. CKD-MBD. Rischio di morte di pazienti con CKD in base ai livelli di PTH, Ca e P
Analyses based on observational data. Association between markers of mineral and bone disease and
clinical outcomes was examined in 7970 patients over a median of 21 months.
Adapted from: Floege J, et al. Nephrol Dial Transplant 2011;26:1948-1955.
2.5
Relative
risk
of
all-cause
mortality
HR
(log
scale)
2
1.8
1.5
1
0
iPTH (pg/mL)
Baseline iPTH
100 200 300 400 500 600 700 800 9001000
3
2
1.8
1.5
1
0
Calcium (mmoI/L)
Baseline calcium
1.5 2 2.252.52.75 3 3.253.53.75 4
2.5
1.75
1.25
3
2
1.8
1.5
1
0.5
Phosphate (mmoI/L)
Baseline phosphate
1.25 1.5 1.75 2 2.25 2.5 2.75 3
2.5
1
0.75
1 mmol/L = 3.1 mg/dL
1 mmol/L = 4 mg/dL

18. CKD-MBD. I pazienti con PTH > 900 pg/mL hanno un rischio aumentato del 72% di
fratture, rispetto a pazienti con PTH 150-300 pg/mL
PTH (pg/mL)
(n/N pts)
RR of hip fracture (95% CI) RR of any fracture
(95% CI)
< 150 (3523/8162) 1.27 (0.78, 2.06) 1.05 (0.80, 1.38)
150–300 (2267/8162) 1.00 (Ref.) 1.00 (Ref.)
301–600 (1524/8162) 1.19 (0.63, 2.26) 1.24 (0.88, 1.76)
601–750 (295/8162) 0.33 (0.05, 2.37) 0.86 (0.41, 1.77)
751–900 (185/8162) 0.62 (0.08, 4.87) 1.03 (0.35, 3.08)
> 900 (368/8162) 1.14 (0.34, 3.80) 1.72* (1.02, 2.90)
*p < 0.05
Jadoul M, et al. Kidney Int 2006;70:1358–1366.

19. With CKD
Without CKD
CKD-MBD. Le calcificazioni arteriose e valvolari si associano ad aumento della morbilità
e mortalità cardiovascolare
Prevalence of CVD in patients with or
without CKD4
Calcification in dialysis patients
• 70% of patients have significant
coronary artery and aortic
calcification1
• 50% of patients have calcified
valves1
• 50% of cardiovascular death may
be associated with abnormal tissue
calcification in patients treated with
dialysis2
Cardiovascular mortality
69% of patients with CKD have CVD
vs 34 % of patients without CKD
1. Moe S. Kidney Int 2006;70:1535–1536; 2. Razzaque M, et al. Nephrol Dial Transplant 2005;20:2032–2035; 3. de Jager DJ, et al.
JAMA 2009;302:1782–1789; 4. US Renal Data System. Volume 1: 2016; https://www.usrds.org/2016/view/Default.aspx
• 39% of all deaths in patients on
dialysis are related to
cardiovascular mortality3
Patients
(%)
Cardiovascular disease
Any CVD
70
60
50
30
10
0
40
20
ASHD
AM
I
CHF
VHD
CVA/TIA
PAD
AFIB
SCA/VA
VTE/PE

20. With CKD
Without CKD
CKD-MBD. Dettaglio della prevalenza di malattie cardiovascolari (CVD) in
pazienti con o senza CKD
69% of patients with CKD have CVD
vs 34 % of patients without CKD
US Renal Data System. Volume 1: 2016; https://www.usrds.org/2016/view/Default.aspx
• ASHD = Atherosclerotic heart disease
• AMI = Acute myocardial infarction
• CHF = Congestive heart failure
• VHD = Valvular heart disease
• CVA = Cerebro-vascular accident
• PAD = Peripheral artery disease
• AFib = Atrial fibrillation
• SCA = Sudden cardiac arrest
• VA = Ventricular Arrhythmia
• VTE = Venous thrombo-embolism
• PE = Pulmonary edema
Patients
(%)
Cardiovascular disease
Any CVD
70
60
50
30
10
0
40
20
ASHD
AM
I
CHF
VHD
CVA/TIA
PAD
AFIB
SCA/VA
VTE/PE

21. CKD-MBD. Omeostasi del fosforo
Komaba. Kidney Int 2016; 90: 753–763

22. CKD-MBD. L’importanza del fosforo
Kidney Int 1972; 2: 147-151

23. The effects of proportional reduction in
phosphate intake in a representative dog
with experimental decrease in GFR.
CKD-MBD. L’importanza del fosforo
Slatopolsky et al. Kidney Int 1972; 2: 147-151

24. “Controlling phosphate load remains the
primary goal in the treatment of CKD.”
Clin JASN 2016;11:1088–1100
CKD-MBD. Sebbene i livelli di fosforo si innalzino in una fase tardiva della
malattia renale cronica, il ruolo della ritenzione di fosforo è fondamentale nella
patogenesi della CKD-MBD

25. Phosphate homeostasis: A complex crosstalk between the kidney,
parathyroid gland, bone, and intestine
Ritter CS. Clin JASN 2016;11:1088–1100
Note: «RETENTION», not «Hyperphosphatemia»
Red lines indicate inhibition
Blue lines indicate stimulation

26. Ritter CS. Clin JASN 2016;11:1088–1100
Phosphate reabsorption in the kidney via NaPi-2a/c cotransporters, absorption in
the gut via NaPi-2b cotransporter, and resorption from the bone contribute to the
retention of phosphate (black dashed lines)

27. Ritter CS. Clin JASN 2016;11:1088–1100
Phosphate retention increases levels of the parathyroid hormone (PTH) and
fibroblast growth factor 23 (FGF23) hormones (black solid lines), both of which
inhibit phosphate reabsorption in the kidney by decreasing expression of NaPi-
2a/c, resulting in phosphaturia.

28. Ritter CS. Clin JASN 2016;11:1088–1100
The increase in FGF23 decreases phosphate absorption in the gut by inhibiting
NaPi-2b expression and suppressing circulating calcitriol, which in turn, will inhibit
intestinal absorption of phosphate.

29. Ritter CS. Clin JASN 2016;11:1088–1100
A negative feedback loop exists between PTH and FGF23; PTH increases FGF23
(both directly and indirectly via calcitriol), whereas FGF23 inhibits PTH.
High calcitriol levels inhibit PTH and stimulate FGF23, whereas low calcitriol levels
stimulate PTH.

30. Ritter CS. Clin JASN 2016;11:1088–1100
In sintesi: nella CKD la ritenzione di P si associa ad una riduzione dei livelli di
calcitriolo ed un aumento dei livelli di FGF23 e PTH,

31. Livelli di fosfatemia vs. eGFR
Mean serum phosphate levels as a function of creatinine clearance
Grey area: Highest P quintile
Grey area: Lowest P quintile
Kestenbaum, J Am Soc Nephrol 16: 520-528, 2005

32. • Phosphate excess has been well recognized as a critical factor in the
pathogenesis of mineral and bone disorders associated with chronic kidney
disease, but recent investigations have also uncovered toxic effects of
phosphate on the cardiovascular system and the aging process.
• Compelling evidence also suggests that increased FGF23 and PTH levels in
response to a positive phosphate balance contribute to adverse clinical
outcomes.
• Given the potential toxicity of excess phosphate, the general population may
also be viewed as a target for phosphate management.
Kidney International (2016) 90, 753–763

33. Meccanismi compensatori che mantengono il bilancio del P fino alle fasi medio-
avanzate della CKD
Komaba. Kidney Int 2016; 90: 753–763

34. CKD-MBD. Rappresentazione schematica della tossicità del fosforo
Komaba. Kidney Int 2016; 90: 753–763

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CKD-MBD. Linee guida KDIGO 2017: osso

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CKD-MBD. L’osteodistrofia renale e la classificazione TMV
Moe et al. Kidney Int 2006; 69: 1945–1953

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CKD-MBD. La biopsia ossea
• The numerous biochemical alterations observed in CKD, namely the reduced
natural and active vitamin D metabolites, hypocalcemia, hyperphosphatemia,
high parathyroid hormone (PTH), high fibroblast growth factor 23 (FGF23), high
sclerostin, and low klotho, independently or in concert affect bone metabolism
and ultimately bone quality and quantity.
• However, alone or combined, these circulating biomarkers are poor predictor of
the type of bone disease in CKD.
• To establish a firm diagnosis of the type of bone disease in CKD the qualitative
and quantitative histomorphometric evaluation of a bone biopsy still remains
the gold standard.

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CKD-MBD. La biopsia ossea
The bone histomorphometric nomenclature system describes four types of bone
disease in CKD:
• Osteitis fibrosa or high bone turnover
• Adynamic bone disease
• Osteomalacia
• Mixed lesions associating high bone turnover and osteomalacia,
This classification of CKD bone diseases is mainly based on three parameters:
• Bone formation rate after tetracyclin double labeling
• Bone volume
• Amount of unmineralized osteoid surface (mineralization abnormalities)

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CKD-MBD. La biopsia ossea: aspetti istomorfometrici dell'osteodistrofia renale

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CKD-MBD. La biopsia ossea: aspetti istomorfometrici dell'osteodistrofia renale
In secondary hyperparathyroidism with severe
osteitis fibrosa, the excess of PTH leads to
marrow fibrosis, expansion of osteoid surfaces,
woven osteoid, increased number and activity
of osteoblasts, numerous osteoclasts and
resorptive surfaces. Tetracycline labels cover
the majority of the bone mineralization surfaces
and a larger space between the double-labeled
staining indicating accelerated bone formation.
No mineralization defect is observed.
In adynamic bone disease there is no
tetracycline labeling along the bone surface.
There a very low number of osteoblast and
osteoclast cells. Low bone turnover is
represented by the absence of differentiation of
the double-tetracycline labeling.

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CKD-MBD. La biopsia ossea: aspetti istomorfometrici dell'osteodistrofia renale
Patients with an increased amount of
unmineralized osteoid surfaces, low number
of osteoblast and osteoclast cells, and a
decreased bone formation rate are classified
as having osteomalacia. Similar to adynamic
bone, tetracycline double labeling shows the
absence or a light diffusion of tetracycline
labeling.

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CKD-MBD. La classificazione TMV basata sull’istomorfometria ossea
Moe et al. Kidney Int 2006; 69: 1945–1953
The TMV classification system more precisely describes the range
of pathologic abnormalities that can occur in patients with CKD.
Each axis represents one of the descriptors in the TMV
classification: turnover (from low to high), mineralization (from
normal to abnormal), and bone volume (from low to high).
• The red bar (OM, osteomalacia) is currently described as low-
turnover bone with abnormal mineralization. The bone
volume may be low to medium, depending on the severity and
duration of the process and other factors that affect bone.
• The green bar (AD, adynamic bone disease) is described as
low-turnover bone with normal mineralization, and the bone
volume in this example is at the lower end of the spectrum,
but other patients with normal mineralization and low
turnover will have normal bone volume.
• The yellow bar (mild HPT-related bone disease) and purple bar
(OF, osteitis fibrosa or advanced HPT-related bone disease)
represent a range of abnormalities along a continuum of
medium to high turnover, and any bone volume depending on
the duration of the disease process.
• The blue bar (MUO, mixed uremic osteodystrophy) is variably
defined internationally. In the present graph, it is depicted as
high-turnover, normal bone volume, with abnormal
mineralization.

43. È bene trattare l’osteoporosi nei pazienti con CKD?
Conclusion: Effects of osteoporosis medications on BMD,
fracture risk, and safety among patients with CKD are not
clearly established.
Study supported by KDIGO (Kidney Disease: Improving Global Outcomes)
2017;166:649-658

44. Obiettivi terapeutici e potenziali esiti clinici nella CKD-MBD
• Riduzione dell’assorbimento dietetico
di fosforo, del sovraccarico di fosforo
e della fosfatemia
• Controllo PTH
• Rallentamento progressione CKD, riduzione
della massa ventricolare sin; riduzione
eventi CV, riduzione mortalità.
• Riduzione eventi CV, riduzione anomalie del
rimaneggiamento osseo e fratture
• Riduzione FGF23 ??
• Evitare sovraccarico di calcio e
ipercalcemia
• Trattamento delle alterazioni ossee
quantitative e qualitative ??
• Riduzione eventi CV, riduzione mortalità
• Riduzione calcificazioni vascolari ed eventi
CV
• Riduzione delle fratture?