Le Malattie Rare : un Utile
Modello Fisiopatologico
Prof. Giovambattista Capasso
Cattedra di Nefrologia
Seconda Università di Napoli
MALATTIE RARE
Malattie rare = Malattie ‘orfane’
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
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-economici
Migliorare la conoscenza delle malattie rare si traduce in vantaggi per
lo stato di salute e la qualità della vita
Motivi scientifici
Lo 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 learned
The study of rare disease may lead to an understanding of
common disorders
BASIS OF HYPERTENSION
SECONDARY HYPERTENSION: 10%
Serie1; 10%
1
Serie1; 90%
ESSENTIAL HYPERTENSION: 90%
Essential hypertension.: contribution of enviromental factors
(obesity, smoke,atherosclerosis, hormones,etc.)
and predisposing inheritable factors
Secondary hypertension: known pathophysiological factors,
among which genetic inheritable mutations
2
Normal Na+ handling in renal tubules
DCT
5% OF Na+ REABSORBED
CNT
-
PT
2-5%
OF Na+
REABSORBED
Na+
Na+ + Na+
Na
CD
60% OF Na+ REABSORBED
25% OF Na+ REABSORBED
TAL
Na+ handling mediated by ENaC in ASDN cells
(DCT2-CNT-CD)
- - --
LUMEN
Na+
Na+
CNT
INCREASED LUMEN ELECTRONEGATIVITY
ENaC
DCT
ENaC
ROMK
H+ATP ase
CD
H+
H+
H+
Na+
PT
TAL
DCT
Em=-65mV
Na+
Na+
Na+
Na+
INTERSTITIUM
ATPase
K+
K+
K+
K+
K+
Subcellular Localization of ENaC
Changes with Dietary Na+ Intake
Na+ 1.0 %
10 d
Aldosteron
~30 ng/dl
Na+ 0.01%
10 d
Aldosteron
~160 ng/dl
Loffing et al. AJP 279: F252 (2000)
Liddle’s Syndrome: clinical features:
Heterogeneous Syndrome
• 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, suppressed
PRA and low/untreaceble plasmatic aldosterone.
•Severe cardiovascular sequelae when left untreated
• Normalization of BP with ENaC blocking agents (amiloride,
triamterene) and low sodium diet.
Liddle’s Syndrome: clinical features
Hypokalemia
Hypertension
Liddle’s Syndrome
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+Na+
Increased Po
UBIQUIT.
PROTEOSOMIC
DEGRADATION
UBIQUIT.
-
PROTEOSOME
UBIQUIT.
UBIQUIT.
Connecting tubule profile from wild type
and Liddle mice
Pradervand J Am Soc Nephrolo 2003
Analogies between LS and Obesity-related
hypertension
Liddle syndrome
 Hypertension resistant to
conventional therapy
 Hypokalemia
 Hypercativation of ENaC
due to genetic mutaion
Obesity-related
hypertension
 Hypertension resistant to
conventional therapy
 Hypokalemia
 Hyperactivation of ENaC
due to hormonal stimuli
(insulin, aldosteron)
Na absorption along the TAL and DT
3Na+
Na+
DT
2K+
DT cell
Cl-
Cl-
TAL
3Na+
Na+
2Cl
K+
recycling
K+
2K+
TAL cell
Cl-
Tubular localization of the molecular defects
DCT
TAL
Bartter
Gitelman
Transport proteins involved in the pathogenesis
of Bartter syndrome
Na+
Type 1
2Cl-
K+
Type 2
X
X
NKCC
ROMK
Ca2+
2
K+
ATP
X
CaSR
K+
Cl-
X
X
ClCKa/b
Bartin
3 Na+
Type 5
Type 3
Type 4
Mg2+
Lumen
Blood
Molecular defects in Gitelman syndrome
Na+
Cl-
X
2 K+
Calbindin
28KD
Calbindin
28KD
Ca+2
Ca+2
Calbindin
28KD
ATP
3 Na+
ATP
Calbindin
28KD
Calbindin
28KD
Cl-
Lumen
Blood
Bartter’s syndrome









Polyhydramnios
Prematurity
Metabolic alkalosis
Hypokalemia
Dehydration
Polyuria
Polydipsia
Hypercalciuria/nephrocalcinosi
Orthostatic hypotension
Gitelman’s syndrome






Hypokalemia
Metabolic alkalosis
Hypomagnesemia with
urinary magnesium wasting
Low urinary calcium
excretion
Childhood
Orthostatic hypotension
Familiar Hyperkaliemia and Hypertension (FHH)
(Pseudohypoaldosteronism type II or Gordon Syndrome)
FHH is an autosomal dominant disorder
characterized by:
 Hyperkalemia with hypertension
 Normal GFR
 Low renin
 Hypercalciuria
 High 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
Gitelman syndrome
 Hypokalemia
 Metabolic Alcalosis
 Hypocalciuria
 Hypereninemia
 Hypotension/Normal
blood pressure
Gordon syndrome
 Hyperkalemia
 Metabolic Acidosis
 Hypercalciuria
 Hyporeninemia
 Hypertension
Effects of WNK4 on NCCT
expression in Xenopus oocytes
Uninjected
NCCT
WNK4 + NCCT
Wilson FH et al. PNAS 2003
Effects of WNK1 and WNK4 on NCC mediated
uptake in Xenopus oocytes
22Na
22
Na Uptake (% of NCCT alone)
6
cRNA
5
cRNA + HCTZ
4
3
2
1
0
H2 O
Yang et al. - J Clin Invest 2003
NCC
WNK1
WNK4
NCC +
WNK1
NCC +
WNK4
NCC +
WNK1+
WNK4
Effects of WNK4 NCCT mediated 22Na flux in
Xenopus oocytes
NS
22
Na Uptake (% of NCCT alone)
140
NS
P< 1x10-9
120
100
80
60
40
20
0
NCCT
NCCT
WNK4
(WT)
NCCT
WNK4
(Kinase - Dead)
NCCT
WNK4
(Q562E)
Wilson FH et al
PNAS 2003
WNK : a “molecular switch” that
controls renal excretion of Na+ and K+
K+
K+
K+
K+
K+
K+
K+
Blood
K+
K+
WNK4
WNK4
Lumen
WNK4
Cl-
Cl-
Cl-
Cl-
Cl-
Na+
Na+
Baseline
Normal Aldosterone
Na+
Hypovolemia
High Aldosterone
Na+
Na+
Hyperkaliemia
High Aldosterone
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