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AGGIORNAMENTI
IN NEFROLOGIA CLINICA
XIII Incontro
Teramo, 11-12 ottobre 2013
Aula Convegni II Lotto
Il Trattamento dei Disturbi del
Metabolismo Minerale nell’IRC
Aspetti fisiopatologici ed epidemiologici
Sandro Mazzaferro
(Manoppello – PE)
Disturbances of Mineral
Metabolism in CRF involve … …
A possible «rule of … … …»
2
At least …
IONS
3
1. Serum Calcium
Intra- vs Extra-cellular Concentrations
Intracellular Ca++:
~10.000 fold lower!!
Ca++ = 1.10
mmol/l
Ca++ = 100 nmol/l
There must be some
mechanism that lowers
intracellular Ca++!
Cell
Blood stream
4
CaSR: its discovery has changed the status of Ca
Ca++ as
First Messenger
Ca++ = 1.10
mmol/l
Ca++ as
Second Messenger
Ca++ = 100
nmol/l
5
Smajilovic S. Br J Pharma 2011
Ca derangements in CRF
• Hypo-Calcemia and/or negative Ca
balance:
– Anxiety, Paresthesias, Cramps, Tetany, Seizures,
Abdominal pain, Congestive heart failure,
Calcifications, etc.
– High PTH, High turnover bone, Osteopenia
• Hyper-Calcemia and/or positive Ca
balance:
– Weakness, Nausea, Vomiting, Polyuria,
Polydipsia, Hypertension, Lethargy, Coma
– Low PTH, Low turnover bone, Calcifications
6
2. Serum Phosphate
Intra- vs Extra-cellular Concentrations
Intracellular P is ~50
times HIGHER
There must be some
mechanism that increases
intracellular P. (!?!)
Pi = 1.5 mmol/l
Pi = 70 mmol/l
Remember, intracellular Ca is 10.000 times LOWER!
(1.0 mmol/l vs 0.0001 mmol/l)
Blood stream
Cell
7
Pi Receptor?
No Pi Receptor identified so far.
8
Derangements of Pi in CRF
• Hypo-Phosphatemia and/or negative Pi
balance:
– Low cardiac output, Arrhytmia, Hypotension,
Astenia, Confusion, Seizures, Coma
– High insulin, Low PTH, Pseudofractures,
Osteomalacia
• Hyper-Phosphatemia and/or positive Pi
balance:
– Hypocalcemia, Hypotension, Excitability,
– High PTH, High turnover, Calcification
9
3. Serum H+
Intra- vs Extra-cellular Concentrations
H+ = 40
nmol/l
H+ = 40 nmol/l
In general intra- and extracellular H+ are quite similar
Please note that:
pH 7.30 = 50 nmol/l
pH 7.50 = 30 nmol/l
Blood stream
Cell
10
Derangements of H+ in CRF
• Acidosis and/or Acidemia:
– Fatigue, tachipnea, sleepness, confusion,
coma
– Osteopenia/Malacia
• Alkalosis and/or Alkalemia:
– Anxiety, nausea, tremor, twitching, spasm,
numbness, dizziness, coma
– Calcifications
11
At least …
HORMONES
12
1. PTH hormone & fragments
1-115
1-90
1-84
1-84
7-84
PTH fragments are produced in the cytosol,
and are influenced by Ca++ and CaSR!
Friedmann P AmJPhy-RP 2006
PTH Receptors
PTH- Type II
PTH-Type I
•Expressed in:
–
–
–
–
–
Kidney,
Osteoblasts
Smooth muscle,
Brain,
Fetal tissues,
•Binds:
– NH-term PTH (1-84);
– PTH-rP
•Expressed in:
–
–
–
–
Brain,
Endothelium
Smooth muscle,
GI tract endocrine
cells,
– sperm
•Not in Obl or kidney
•Binds:
– TIP39,
– NH-term PTH (1-84)
D’Amour P. Clin Biochem 2012
Derangements of PTH in CRF
• Hypoparathyroidism:
– Low Ca, high Pi, low AP
– Low turnover bone, Ectopic calcification
• Hyperparathyroidism:
– High Ca, high Pi, high AP
– High turnover bone, Ectopic calcification
17
2. Vitamin D Metabolites & Hormone
18
Vitamin D Receptor: expressed in almost
every tissue
19
Derangements of Vitamin D in CRF
• Hypovitaminosis D:
– HypoCa, high PTH, high AP
– Bone Resorption/Osteomalacia/Penia
– Other (pleiotropic?)
• Hypervitaminosis D:
– Hyper Ca, low-high PTH, low-high AP
– Bone mineralization, low turnover
– Ectopic Calcifications
– Other (pleiotropic?)
20
3. FGF23-Klotho
Why together?
• FGF23 null vs Klotho null transgenic mice
21
FGF23 null vs Klotho null
FGF23-/-
Kl -/-
Serum P
High
High
1,25-D level
High
High
Serum Ca
High
High
Bone Mineralization
Defective
Defective
Ectopic
Calcification
Present
Present
Arteriosclerosis
Present
Present
Lifespan
Short
Short
Phenotype
22
FGF23 Receptors, FGF23 and Klotho
Klotho (local and circulating) is essential
for activity and selectivity of FGF23
Razzaque MS Trends in Mol Med 2006
From Kidney to Bone and viceversa
Blood
[ H +]
Klotho
[ Ca++]
[ P++]
FGF23
[1,25D]
[PTH]
Mazzaferro S. et al Arch. Biochem. Biophys. (2010)
Possible differences between the two?
25
FGF23 regulation
(Transcriptional and post-transcriptional mechanisms)
•
Systemic factors:
–
–
•
Pi ( = );
1,25D ( = )
Feed-back system!
Local factors (bone derived):
–
–
–
DMP1 deletion = increased FGF23;
Phex inactivation = increased FG23;
MEPE administration = increased FGF23
?
FGF23 synthesis
is affected
only by serum Pi and
From
Bone tonotKidney
1,25D, but also by the metabolism of other bone proteins
Blood
MEPE-ASARM
cleavage
[ 1,25D]
Klotho
DMP1
FGF23
Klotho
[ P++]
ASARM
PHEX
FGF23
Mazzaferro S. et al Arch. Biochem. Biophys. (2010)
Klotho functions outside FGF23
Organ
Activity
Effect
Kidney
NaPi2a/2c inactivation
Hypophosphatemia
Renal TRPV5/6 Activation
Ca reabsorption
Renal ROMK1 Activation
Potassium secretion
Na/K ATPase Activation
Ca homeostasis
Parathyroids Na/K ATPase Activation
PTH stimulation
Choroid
Plexus
Na/K ATPase Activation
Ca homeostasis
Sytemic
NaPi3 Reduction
Pi
Ca
K
PTH
VC
Vascular Calcification
inhibition
Ins
Insulin/IGF-1 inhibition
Insulin resistance – Anti-ageAge
Wnt suppression
Anti-age
Endothelial NO Upregulation
Endothelial dysfunction
protection
Derangements of FGF23/Klotho in CRF
S-Klotho, pg/ml
*
*
*
N
CKD 2
CKD 3
(*) p<0.005 vs Normal
CKD 4
FGF23, pg/ml
§
$
N
CKD 2
CKD 3
CKD 4
($) p<0.001 vs N
(§) p<0.006 vs N, CKD-2, CKD-3
29
Mazzaferro S et al. Soluble alpha Klotho in Chronic renal failure. ISN 2012
Low Klotho/High FGF23 Human Syndromes
• Human Klotho inactivating gene mutation
– HyperPi, HyperCa, High 1,25D, High FGF23,
Calcinosis.
• FGF23 excess related syndromes
– Primary: ADHR, ARHR, XLH, TIO
[Rickets, Osteomalacia]
– Secondary: Chronic Renal Failure
[CV disease and mortality]
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At least …
ORGANS
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1. Intestine
(Absorption, Secretion, Excretion of Ca, Pi, H)
Carriers
TRP-V5,6
Receptors
Vit. D Receptor
Hormones
1,25 D
NaPi-2a,b
PTH Receptor II
PTH
Ca Sensing Receptor FGF23/Klotho
Pi Receptor (?)
Intestinal Endocrine functions:
- several GI hormones,
- possibly a Phosphatonin
2. Kidney
(Filtration, Reabsorption, Excretion of Ca, Pi, H)
Carriers
TRP-V5,6
Receptors
Vit. D Receptor
Hormones
1,25 D
NaPi-2a,b
PTH Receptor I
PTH
Ca Sensing Receptor FGF23/Klotho
Pi Receptor (?)
Renal Endocrine functions:
- Renin, Epo, Calcitriol,
- Klotho
3. Bone
(Resorption, Deposition, Ca, Pi, H)
Carriers
TRP-V5,6
Receptors
Vit. D Receptor
Hormones
1,25 D
NaPi-2a,b
PTH Receptor I
PTH
Ca Sensing Receptor
Pi Receptor (?)
FGF23/Klotho
Bone Endocrine functions:
- FGF23
- Osteocalcin
Bone cells lineage (modern view)
Hematopoetic
stem cell
Systemic Hormones:
-PTH, 1,25D, Estrogens, etc
Cytokines:
- ILs, PGs, TGFb, etc
Runx2
Stromal cell
MRF4
Macrophage
Pre-osteoclast
Pre-osteoblast
Myocyte
OPG/RANK/
RANKL
Osteoblast
Osteoclast
Growth & Modeling
No-more inactive!
Lining cell
+ Remodeling = mineral metabolism
Osteocyte
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Organic Matrix
- Non Collagenous Proteins (11%)
1. GAGs:
- Proteoglycans, Hyaluronan;
2. Glycoproteins:
- ON, SIBLINGs (OPN; BSP; DMP1; SPP1; MEPE), OPG,
SOST, RDG contaning proteins, Thrombospondin
bone protein contribute to
3. Non-collagenous
Γ-Carboxylic Acid containing:
- MGP,Ca
OCand Pi fluxes from and into bone
4. Other Proteins:
- Growth factors (BMPs, FGFs), Enzymes (AP, TRAP, PHEX,
MMPs), Absorbed from circulation (Albumin, Fetuin)
36
Normal
FGF23
DMP1
MEPE
CKD
Stage -2
La disfunzione della «ghiandola osso» inizia
già nelle fasi precoci della CKD
A possible «rule of … … …»
IONS
HORMONES
ORGANS
Systemic (CV)
involvement
or CKD-MBD
39
Targets for Mineral Metabolism Control in CRF
PTH
H
Ca
1,25D
P
FGF23/
Klotho
Available drugs for CKD-MBD
1. Phosphate binders
2. Vitamin D and analogs
3. Calcimimetics
(again … … … )
41
Epidemiologic aspects
(in Dialysis)
Aim of the study:
To evaluate
- Drug prescription policy,
- Biochemical control of SH,
with new available drugs (from
2006 to 2008)
1. Drug Prescription policy:
(a.) PTH inhibitors
Calcitriol p.o.
Paricalcitol i.v.
Calcitriol i.v.
Cinacalcet p.o.
Any Vitamin D from
50.8% to 58.2% (p<.001)
~2ug/w
~3.5ug/w
~45mg/d
1. Drug Prescription policy:
(b.) Phosphate Binders
Changes in P binders prescription policy
Any
Ca Carbonate Sevelamer
Aluminum
Ca Acetate
Average doses of P binders
Ca Acetate
Ca Carbonate
Sevelamer
Aluminum
~2g/day
~2g/day
~4g/day
~2g/day
2. Biochemical control of SH
Mean (SD) Values of PTH, Ca, and P During the Survey.
PTH,
pg/mL
Ca,
mg/dL
P,
mg/dL
Baseline Month 6
310.3
287.8
(292.4)
(252.2)
9.1
9.0
(0.8)
(1.0)
5.0
4.9
(1.4)
(1.3)
Month
12
Month
18
P
value
286.4
(248.1)
279.5
(250.1)
0.0002
9.0
(0.7)
9.0
(0.7)
0.383
5.0
(1.3)
5.0
(1.4)
0.085
Ca=calcium, P=phosphate, PTH=parathyroid hormone.
Patients at target (K/DOQI)?
Ca
P
PTH
All three
Conclusions
• CKD-MBD = complex metabolic
derangement of renal failure, with
significant systemic involvement and
morbidity/mortality.
• Its therapeutic management is rather
difficult, even with new drugs,
• The «rule of 3» seems cute, but
insufficient to help manage it properly
52
EVOLVE: Study Design
Screening
Phase
Up to 30 Days
Titration
Phase
Follow up Phase
(Visits Q8 Wks)
(Visits Q2
Wks)
Placebo plus standard of care(n = 1,900)
Event-driven study that concludes when
approximately 1,882 subjects have
experienced a primary composite event
Cinacalcet plus standard of care (n = 1,900)
Trial Population
• Hemodialysis
• iPTH  300 pg/mL
• Ca  8.4 mg/dL
Day 1
Week 20
Week 52
• Ca x P  45 mg2/dL2
Enrollment = ~ 1.5 years
Adapted from: Chertow GM, et al. Clin J Am Soc Nephrol. 2007;2:898-905.
All patients could receive
vitamin D sterols and phosphate
binders, as necessary, at the
discretion of the physician.
Follow-up period = ~ 2.5 years
Primary Composite Endpoint (ITT) not met:
Non-significant* 7% Reduction in the Risk of Death or Nonfatal
Cardiovascular Events in Patients with SHPT
Kaplan-Meier plot of the time to the primary composite endpoint (death, myocardial infarction,
hospitalization for unstable angina, heart failure, or peripheral vascular event) in EVOLVE™.
Proportion Event-free
1.0
Placebo
Cinacalcet
0.9
0.8
0.7
0.6
0.5
Hazard ratio, 0.93 (95% CI, 0.85, 1.02)
Log-rank test, P = 0.11*
0.4
0.0
0
4
8
12
16
20
1804
1842
28
32
36
40
44
48
52
56
60
996
1051
940
989
650
679
404
399
114
113
Time (months)
Subjects at risk:
1935
1948
24
1693
1739
1579
1638
1476
1556
1384
1472
1312
1384
1224
1303
1160
1230
1109 1053
1177 1115
* The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis
Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624
CKD-MBD Working Group ERA-EDTA
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