carmine zoccali - nefroloji.org.tr ekİm... · normal (sham) uninephrectomy fibrosis (%) 5.0 2.5...
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![Page 1: Carmine Zoccali - nefroloji.org.tr EKİM... · Normal (sham) Uninephrectomy Fibrosis (%) 5.0 2.5 0.0 Martin FL, et al. Am J Physiol Regul Integr Comp Physiol. Jan 15, 2012; 302(2):](https://reader034.vdocument.in/reader034/viewer/2022042308/5ed4a5e3b5fb6d32ff7a5e9f/html5/thumbnails/1.jpg)
CKD as a systemic diseaseCarmine Zoccali
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The brain as a systems master : links with
the heart, the kidney and the bone and the
inter-organs cross-talks (Heart/vessels –
Kidney and Bone-Kidney)
Systems Physiology
The CKD phenotype as a systemic disease:
kidney dysfunction as a trigger of multi-organs
disturbances
Arthur C. Guyton
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Pressure
Natriuresis
0 10 30 1 2 4 8 16 32 1 2 4 8 16 1 2 4 8 16
Time after sudden change in Pressure
(like in acute HF)
12
9
6
3
0
sec min hours days
Arthur C. Guyton
BP deviation 80%
Residual BP deviation after
full activation of the
counter-regulatory system
11.5 %
7
! Infinite
gain
Baroreceptor,
Chemoreceptors Ischemic
CNS response
BP deviation 80%____
Residual BP deviation after
full activation of Pressure
Natriuresis 0%
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Pressure
Natriuresis
0 10 30 1 2 4 8 16 32 1 2 4 8 16 1 2 4 8 16
Time after sudden change in Pressure
12
9
6
3
0
sec min hours days
Di Bona GF Sawin L Renal nerve activity
in conscious rats during volume expansion
and depletion. Am J Physiol 1985 Jan;248(1
Pt 2):F15-23
Renal Nerve Activity
(Units)
100
80
60
40
20
0
Baseline Isotonic saline
load
- 44%
Arthur C. Guyton
Geoffrey F. Di Bona
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12
9
6
3
0
NO
1993;22:535-541
ADMANO NO
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NorepinephrineBaldock PA et al., Neuropeptide Y Knockout Mice Reveal a Central Role of
NPY in the Coordination of Bone Mass to Body Weight. PlosOne 4(12):
e8415.
Wild type NPY-/-(knock-out)
NPY receptors
OSTEOBLASTS
Neuropeptide Y
osteoblast acitivity
(alkaline phosphatase)
Representative micro-computed
tomographs of the distal femoral
metaphysis
Neural
Synapsis
Normal NPY
levelsUnmeasurable
NPY levels
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Klotho
FGF23
CC
CC(F)GF-R
FGF23
FGF23
FGF23
FGF23
FGF23
Myocardiocyte
Kl +/ -
Integrity of the
whole receptor
assembly is
needed for
renal effects
(Phosphaturia,
1,25 vit D)PO4=
Ca++
PTH
1,25 VD
FGF23
Klotho
PO4=Inhibition of the Na-
dependent phosphate
cotransporter
Faul C and Wolf M
2011;121(11):4393–4408
Mineral Metabolism
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The brain as a systems master : links with
the heart, the kidney and the bone and the
inter-organs connections (Heart/vessels –
Kidney and Bone-Kidney)
Systems Physiology
The CKD phenotype as a systemic disease:
kidney dysfunction as a trigger of multi-organs
disturbances
![Page 9: Carmine Zoccali - nefroloji.org.tr EKİM... · Normal (sham) Uninephrectomy Fibrosis (%) 5.0 2.5 0.0 Martin FL, et al. Am J Physiol Regul Integr Comp Physiol. Jan 15, 2012; 302(2):](https://reader034.vdocument.in/reader034/viewer/2022042308/5ed4a5e3b5fb6d32ff7a5e9f/html5/thumbnails/9.jpg)
restraint of central
sympathetic activity
Sympathetic fibers,
peroneal nerve
afferent
nerves
Control
subjects
Patients
with CKDWith ACE
inhibitors
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Neuropeptide YZoccali C, Mallamaci F, unpublished
(pmol/L)
3002001000
24h Proteinuria (g/day)3.0
2.5
2.0
1.5
1.0
.5
0.0
(pmol/L)
3002001000
GFR cys-creat (ml/min/1.73m2)160
140
120
100
80
60
40
20
0
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Wild NPY -/-
AJKD 2007 ;50:1001-8
NPY receptors
Neuropeptide Y
osteoblast acitivity
(alkaline phosphatase)
Brain-Bone connection
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Normal
(sham)Uninephrectomy
Fibrosis (%)
5.0
2.5
0.0
Martin FL, et al. Am J Physiol Regul
Integr Comp Physiol. Jan 15, 2012; 302(2):
R292–R299.
Changes in the
activity of 103 genes
in the TGFβ and
apoptosis pathways
Stage 1-2 CKD model…. Unchanged renin,
aldosterone and BP….
... Well beyond the Sympathetic
System, renal function loss has
unsuspected adverse effects on
the heart
1.51.00.50.0-0.5-1.0
120
100
80
60
40
20
LVMI(g/m2.7)
ADMA (lg10 mol/L)
Zoccali C et al. Kidney International 2002;62:339-45.
21:444, 2010
12
9
6
3
0
ADMALVH
NO myocardial growth
restraint
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Mihout, F et al., J Pathol 223:37, 2011
Uninephrectomized
mice
continous infusion of
ADMA by mini-pumps
TGF
12
9
6
3
0
ADMALVH
NO myocardial growth
restraint
Fully preventable by
reducing ADMA levels
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1.0
0.75
0.50
0.25
ESRD risk Death risk
0 10 20 30 0 10 20 30 months
ADMA < 0.76 µM/L
ADMA >= 0.76 µM/L
HR 2.20 (95% CI 1.20, 4.04)
Ravani P, Tripepi G, Malberti F, Testa F, Mallamaci F, Zoccali. JASN 16: 2449, 2005
Few today doubt that high ADMA is a
relevant cardiovascular and renal risk
factor but numerous attempts at
advancing drugs stimulating ADMA
degradation in CKD patients have
failed to enter phase 1-2 studies.
12
9
6
3
0
ADMA
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Klotho
CC
CC(F)GF-R
FGF23 ADMA
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r= - 0.48
P<0.001
r= - 0.21
P<0.001
Competitive Interaction
P =0.001
P for effect modification=0.009
100806040200
3.5
3.0
2.5
2.0
1.5
1.0
0.5
eGFR (ml/min/1.73m2)
lg10 pg/mL
100806040200
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
eGFR (ml/min/1.73m2)
(µMol/L)
ADMA
FGF23
HR (20 pg/ml)
0.450.30 0.60 0.75 0.90 1.05 1.20
1.24
1.20
1.16
1.12
1.08
1.04
1.00
0.96
0.92
0.88
ADMA (µMol/L)
FGF23
HR (20 pg/ml FGF-23)
0.450.30 0.60 0.75 0.90 1.05 1.20
1.24
1.20
1.16
1.12
1.08
1.04
1.00
0.96
0.92
0.88
ADMA (µMol/L)
FGF23
Southern Italy cohort, n=756, Tripepi G, Mallamaci F Zoccali C JASN 2015
MMKD Central-Northern European cohort,
n=176 Florian Kronenberg (Fliser, Ritz)
A quintessential example of the
systemic , widespread nature of the
risk phenotype of CKD.
FGF23, a bone factor and
ADMA, an endothelium
substance, interact in CKD
progression.
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Renin
Blood Volume nor. or
Salt intake
Cardio Vascular
Disease
Blood Volume
Salt intake Continuous
fluids loss
Survival
Death
….a «reductionist -Cartesian- approach»
deliberately adopted for clarity and communication….
..BUT EFFECTS ARE «CONTEXT DEPENDENT»
..a methodological critique and self-
critique…..
Exactly the same happens
with ADMA, which may be
life saving in the setting of
septic shock.
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1° day of observation
n…day of observation
we explore connections with the reductionist
approach and identify syndromes that do
not exists
Kidney International Supplements (2011) 1, 2–5;
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Metabolomics and Metebonomics move the
risk profile of CKD from mono-dimensionality to
multi-dimensionality.
HPLC- mass spectrometry
and NMR Spectroscopy
Understanding the complexity will allow
precise individual risk profiling and treatment
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Summary and Conclusions
Inter-organs connections and integration during growth, adult life and
aging is the most complex biological process in living organisms
Until now this process has been mainly investigated with a reductionist
approach.
CKD profoundly perturbs inter-organs relationships. We currently identify
pseudo-syndromes. We have just a glimpse into this complex scenario.
A mature technology for a system-analysis approach to physiology and
pathophysiology exists. A novel approach based on this technology has
already started to form a new basis for clinical research and clinical
epidemiology.