Le Malattie Rare : un Utile Modello Fisiopatologico

Prof. Giovambattista Capasso

Cattedra di Nefrologia

Seconda Università di Napoli

MALATTIE RAREMALATTIE RARE

Ad oggi si conoscono circa 8000 malattie rare,

che nel complesso interessano 30 milioni di

persone in Europa e circa 0.5 milione in Italia

Malattie rare = Malattie ‘orfane’

Perche studiare la malattie rare?

Motivi etici Il bene più grande della società è la SALUTE della popolazione e quello alla salute è un diritto universale

Motivi socio-economiciMigliorare la conoscenza delle malattie rare si traduce in vantaggi per lo stato di salute e la qualità della vita

Motivi scientificiLo studio di patologie rare rappresenta uno strumento utile alla comprensione di processi di fisiologia e patologia

Aim of this lecture To show whether rare diseases have been used as

models to delineate specific aspects of renal physiology and pathology

Lesson to be learnedThe study of rare disease may lead to an understanding of

common disorders

BASIS OF HYPERTENSIONBASIS OF HYPERTENSION

Essential hypertension.: contribution of enviromental factors (obesity, smoke,atherosclerosis, hormones,etc.) and predisposing inheritable factors

Serie1; 90%

Serie1; 10%

1 2

ESSENTIAL HYPERTENSION: 90%

SECONDARY HYPERTENSION: 10%

Secondary hypertension: known pathophysiological factors, among which genetic inheritable mutations

Normal Na+ handling in renal tubules

PT

TAL

CNT

CD

Na+Na+

Na+

Na+

25% OF Na+ REABSORBED

DCT5% OF Na+ REABSORBED

-

2-5%OF Na+

REABSORBED

60% OF Na+ REABSORBED

Na+ handling mediated by ENaC in ASDN cells(DCT2-CNT-CD)

Na+ K+Em=-65mV

Na+

LUMEN

INTERSTITIUM

Na+

Na+

Na+

K+ K+

K+K+

ATP-ase

ROMKENaC ENaC

DCTTAL

PT

DCT

CNT

CD

Na+

Na+

H+-ATP ase

H+

H+

H+

- - -- -INCREASED LUMEN ELECTRONEGATIVITY

Na+ 1.0 %10 d

Aldosteron~30 ng/dl

Na+ 0.01%10 d

Aldosteron~160 ng/dl

Subcellular Localization of ENaC Changes with Dietary Na+ Intake

Loffing et al. AJP 279: F252 (2000)

Liddle’s Syndrome: clinical features:

• Autosomal dominant inheritance with high penetrance

• Early onset: mostly in childhood but also in youth (10-30 years)

• Clinical signs typical of primary hyperaldosteronism:hypertension resistant to common therapies, metabolic alkalosis, hypokalemia, normal renal function, suppressedPRA and low/untreaceble plasmatic aldosterone.

•Severe cardiovascular sequelae when left untreated

• Normalization of BP with ENaC blocking agents (amiloride,triamterene) and low sodium diet.

Heterogeneous Syndrome

Liddle’s Syndrome: clinical features

Hypokalemia

Hypertension

Liddle’s Syndrome

PY m

ut

PY m

ut

PY m

ut

PY m

ut

UBIQUIT. UBIQUIT.UBIQUIT.UBIQUIT.

PROTEOSOME

-PROTEOSOMICDEGRADATION

Na+

Na+

Na+Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Increased Po

Connecting tubule profile from wild type and Liddle mice

Pradervand J Am Soc Nephrolo 2003

Hypertension resistant to conventional therapy

Hypokalemia Hyperactivation of

ENaC due to hormonal stimuli (insulin, aldosteron)

Hypertension resistant to conventional therapy

Hypokalemia Hypercativation of ENaC

due to genetic mutaion

Analogies between LS and Obesity-related hypertension

Liddle syndrome Obesity-related hypertension

DT cell

TAL cell

Cl-

Na+

3Na+

2K+

K+

K+

Na+

2Cl

recycling

Na absorption along the TAL and DT

Cl-

TAL

3Na+

2K+DT

Cl-

Tubular localization of the molecular defects

BartterBartter

GitelmanGitelman

TAL

DCT

Lumen Blood

Transport proteins involved in the pathogenesis of Bartter syndrome

NaNa++

2Cl2Cl--

KK++

3 Na3 Na++

2 K2 K++ATP

ClCl-- KK++

Type 1Type 1 XNKCCNKCC

XType 2Type 2

CaCa2+2+

MgMg2+2+

ROMKROMKClCKa/bClCKa/b

BartinBartin

X Type 3Type 3

X Type 4Type 4

CaSRCaSRX Type 5Type 5

Lumen Blood

Na+

Cl-

3 Na+

2 K+ATP

Cl-

Ca+2

X

Molecular defects in Gitelman syndrome

Ca+2

ATPATP

Polyhydramnios Prematurity Metabolic alkalosis Hypokalemia Dehydration Polyuria Polydipsia Hypercalciuria/

nephrocalcinosi Orthostatic hypotension

Hypokalemia Metabolic alkalosis Hypomagnesemia with

urinary magnesium wasting

Low urinary calcium excretion

Childhood Orthostatic hypotension

Gitelman’s syndromeBartter’s syndrome

Familiar Hyperkaliemia and Hypertension (FHH) (Pseudohypoaldosteronism type II or Gordon Syndrome)

FHH is an autosomal dominant disordercharacterized by:

Hyperkalemia with hypertensionNormal GFRLow reninHypercalciuriaHigh response to thiazide diuretics

Severe FHH clinical features are :

Muscular weakness Hyperchloremic metabolic acidosis Short stature Intelligence below average

History of FHH

1964 - Paver & Pauline described the first case of 15-year-old Australian boy affected by hyperkalemia with hypertension and normal renal function

1969 - Arnold & Healy restudied the same patient; they measured plasma renin and aldosterone that were found to be low

1970 - Gordon et al. reported the case of 10-year-old Australian girl who presented with short stature, hypertension and hyperkalemia. Plasma renin activity was undetectable, aldosterone secretion was low-normal

1973 - de Wardener included Gordon’s syndrome with Liddle’s and Bartter’s syndrome in the disorders resulting from congenital defects of tubular function

2001 - Wilson et al. demonstrated the mutations in WNK kinases

Two syndromes with ‘mirror’ features

HypokalemiaMetabolic AlcalosisHypocalciuriaHypereninemiaHypotension/Normal

blood pressure

HyperkalemiaMetabolic AcidosisHypercalciuriaHyporeninemiaHypertension

Gitelman syndrome Gordon syndrome

Effects of WNK4 on NCCT expression in Xenopus oocytes

Wilson FH et al. PNAS 2003Wilson FH et al. PNAS 2003

Uninjected NCCT WNK4 + NCCT

Effects of WNK1 and WNK4 on NCC mediated 22Na uptake in Xenopus oocytes

HH22OO WNK1WNK1NCCNCC NCC +NCC +WNK1WNK1

00

11

22

33

44

22

22 N

aN

a Up

take (

% o

f N

CC

T a

lon

e)

Up

take (

% o

f N

CC

T a

lon

e)

55

66

WNK4WNK4 NCC +NCC +WNK4WNK4

NCC +NCC +WNK1+WNK1+WNK4WNK4Yang et al. - J Clin Invest 2003Yang et al. - J Clin Invest 2003

cRNAcRNA

cRNA + cRNA + HCTZHCTZ

NCCT NCCTWNK4

(Kinase - Dead)

NCCTWNK4(WT)

NCCTWNK4

(Q562E)

P< 1x10-9

NS

NS

Effects of WNK4 NCCT mediated 22Na flux in Xenopus oocytes

Wilson FH et alWilson FH et alPNAS 2003PNAS 2003

0

20

40

60

80

100

120

140

22 N

a Up

take (

% o

f N

CC

T a

lon

e)

WNK : a “molecular switch” that controls renal excretion of Na+ and

K+

BaselineNormal Aldosterone

HyperkaliemiaHigh Aldosterone

HypovolemiaHigh Aldosterone

WNK4WNK4

Blo

od

Blo

od

Lum

en

Lum

en

Cl-

Na+

Cl- Cl-

Na+Na+

K+

K+

K+K+

K+K+

WNK4WNK4

Cl- Cl-

Na+Na+

K+

K+

K+

CONCLUSIONI

• Lo studio delle malattie rare è utile alla comprensione di aspetti di fisiologia e fisiopatologia

• L’osservazione clinica di patologie rare ha contribuito alla caratterizzazione della funzione renale nell’equilibrio idro-elettrolitico e nel controllo della BP

• I Meccanismi fisiopatologici alla base di malattie rare spesso sono condivisi da disordini comuni, pertanto la loro conoscenza può fornire il razionale per lo sviluppo di strategie terapeutiche per altre patologie