The emerging connection between

calcium-regulatory hormones and

inflammation

Alberto Ortiz, MD, PhD

IIS-Fundacion Jimenez Diaz

Madrid, Spain

1.Inflammatory biomarkers are

associated with mortality in CKD

2. CKD-MBD biomarkers are associated

with mortality in CKD

Is there a connection?

What is the connection?

How can we exploit the connection theraputically?

Emerging connection?

Calciphylaxis is a condition of hvpersensitivity in which, during a "critical period"

a) after sensitization by a systemic calcifying factor (e.g. vitamin-D compounds, PTH, …),

b) treatment with certain challengers (e.g. metallic salts, Fe-Dex, egg white) causes an

c) acute, local calcification followed by inflammation and sclerosis.

Calcium content rat aortic ring

Calcitriol 10-8 M

Paricalcitol 10-8 M

P P + TNF

?

10-10 M

Direct anti-inflammatory effect of VDR activation on

cultured podocytes

Vitamin D receptor activation has anti-

inflammatory effects

How are calcitriol levels regulated?

Kuro-o M. Korean Journal of Internal Medicine. 2011

FGF23 and Klotho in kidney tubular cells

Phosphaturia

FGF23

Fibroblast growth factor 23 and Inflammation in CKD

Mendoza et al. Clin J Am Soc Nephrol. 2012 Jul;7(7):1155-62

CRIC CKD stages 2–4, n=3612, age 21–74

FGF23 quartile

Odds ratio for

severe

inflammmation

Kuro-o M. Korean Journal of Internal Medicine. 2011

Membrane Klotho in kidney tubular cells

Kuro-o M. Korean Journal of Internal Medicine. 2011

Soluble Klotho in kidney tubular cells

Klotho functions

1. Phosphaturia (FGF23-dependent and

independent actions)

2. Other (Glycosidase activity)

1. Anti-oxidant

2. Anti-inflammatory

3. Anti-fibrosis

4. Interferes with insulin/IGF-1

signaling...

Klotho -/-

WT mice

Klotho

overexpressing

mice Klotho -/-

Mutation of the mouse klotho gene leads to a syndrome resembling ageing

Kuro-o M. Nature. 1997

High serum

phosphate

John GB et al. AJKD 2011

Early decrease in Klotho and increase in

FGF23 in human CKD Decreased in CKD stage 1

The problem: loss of renal parenchyma Normal kidney

ESRD

Atrophy: cell death

Fibrosis

Inflammation

Moreno et al. JASN 2011

Decreased kidney Klotho expression during

experimental AKI

Persistent Kidney

Klotho

mRNA

Macrophage

s

How to treat Klotho deficiency in kidney

injury?

May we decrease

inflammnation to preserve

Klotho expression?

Canonical

Upregulates chemokines and

others

JASN 2010

IB siRNA = NFB activation

NFB activation promotes Klotho dowregulation

Moreno et al. JASN 2011

Canonical

Parthenolide

(PTN)

= NFB inhibition

Cytokine-induced Klotho downregulation in renal tubular cells is NFkB-

dependent

Moreno et al. JASN 2011

NFB inhibition prevents Klotho dowregulation

TWEAK promotes NFkB-dependent kidney Klotho downregulation in

healthy mice

Moreno et al. JASN 2011

NFB inhibition prevents Klotho dowregulation in vivo

Upregulates chemokines and

others

Downregulates Klotho

Canonical

borderline high (Pi-BH; 2 mmol/L -glycerophosphate) and high (Pi-H, 5 mmol/L -glycerophosphate) phosphate in vitro culture conditions

Circulation. 2012;125:2243-2255

VSMC

Take home message

• There is an increasingly recognized link between inflammation and CKD-MBD

• Inflammation may favor CKD-MBD and CKD-MBD may favor inflammation

• Inflammation down regulates Klotho in kidney and vessels

• This offers the possibility for therapeutic intervention

Collaborators and sponsors

• IIS-Fundación Jiménez Díaz/Universidad Autónoma de Madrid

– Ana Belén Sanz, M. Dolores Sánchez Niño, Juan Moreno, M Concepción Izquierdo, Alvaro Ucero, Alberto Benito

– Marta Ruiz Ortega, Jesus Egido, Luis Blanco-Colio

• H La Paz: Rafael Selgas

• H Cordoba: Rafael Ramirez

• H Central Asturias. Carlos Lopez Larrea, Belén Suarez alvarez

• University of Michigan: Matthias Kretzler

• Biogen Idec: Linda Burkly, Aniela Jakubowski

Sponsors

•Comunidad Autonoma de Madrid

•Instituto de Salud Carlos III (ISCIII-FIS)

•European Union

•Sociedad Española de Nefrología