CKD as a systemic diseaseCarmine Zoccali

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

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%

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

12

9

6

3

0

NO

1993;22:535-541

ADMANO NO

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

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

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

restraint of central

sympathetic activity

Sympathetic fibers,

peroneal nerve

afferent

nerves

Control

subjects

Patients

with CKDWith ACE

inhibitors

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

Wild NPY -/-

AJKD 2007 ;50:1001-8

NPY receptors

Neuropeptide Y

osteoblast acitivity

(alkaline phosphatase)

Brain-Bone connection

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

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

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

Klotho

CC

CC(F)GF-R

FGF23 ADMA

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.

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.

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;

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

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.