La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di Nefrologia Seconda Università di Napoli.

Presentazioni simili


Presentazione sul tema: "Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di Nefrologia Seconda Università di Napoli."— Transcript della presentazione:

1 Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di Nefrologia Seconda Università di Napoli

2 MALATTIE 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’

3 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

4 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

5 BASIS OF HYPERTENSION Essential hypertension.: contribution of enviromental factors (obesity, smoke,atherosclerosis, hormones,etc.) and predisposing inheritable factors ESSENTIAL HYPERTENSION: 90% SECONDARY HYPERTENSION: 10% Secondary hypertension: known pathophysiological factors, among which genetic inheritable mutations

6 Normal Na + handling in renal tubules PT TAL CNT CD Na + 25% OF Na + REABSORBED DCT 5% OF Na + REABSORBED - 2-5% OF Na + REABSORBED 60% OF Na + REABSORBED

7

8 Na + handling mediated by ENaC in ASDN cells (DCT2-CNT-CD) Na + K+K+ Em=-65mV Na + LUMEN INTERSTITIUM Na + K+K+ K+K+ K+K+ K+K+ ATP- ase ROMK ENaC DCT TAL PT DCT CNT CD Na + H + - ATP ase H+H+ H+H+ H+H INCREASED LUMEN ELECTRONEGATIVITY

9 Na % 10 d Aldosteron ~30 ng/dl Na % 10 d Aldosteron ~160 ng/dl Subcellular Localization of ENaC Changes with Dietary Na + Intake Loffing et al. AJP 279: F252 (2000)

10 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, 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. Heterogeneous Syndrome

11 Liddle’s Syndrome: clinical features Hypokalemia Hypertension

12 Liddle’s Syndrome PY mut UBIQUIT. PROTEOSOME - PROTEOSOMIC DEGRADATION Na + Increased Po

13 Connecting tubule profile from wild type and Liddle mice Pradervand J Am Soc Nephrolo 2003

14 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

15 DT cell TAL cell Cl- Na + 3Na + 2K + K+K+ K+K+ Na + 2Cl recycling Na absorption along the TAL and DT Cl - TAL 3Na + 2K + DT Cl -

16 Tubular localization of the molecular defects Bartter Gitelman TAL DCT

17 LumenBlood Transport proteins involved in the pathogenesis of Bartter syndrome Na + Na + 2Cl - K+K+K+K+ 3 Na + 2 K + ATP Cl - Cl - K+ K+ K+ K+ Type 1 XNKCC X Type 2 Ca 2+ Mg 2+ ROMK ClCKa/b Bartin X Type 3 X Type 4 CaSR X Type 5

18 Lumen Blood Na + Cl - 3 Na + 2 K + ATP Cl - Ca +2 X Molecular defects in Gitelman syndrome Ca +2 ATP Calbindin 28KD

19  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

20 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

21 History of FHH Paver & Pauline described the first case of 15-year-old Australian boy affected by hyperkalemia with hypertension and normal renal function Arnold & Healy restudied the same patient; they measured plasma renin and aldosterone that were found to be low 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 de Wardener included Gordon’s syndrome with Liddle’s and Bartter’s syndrome in the disorders resulting from congenital defects of tubular function Wilson et al. demonstrated the mutations in WNK kinases

22 Two syndromes with ‘mirror’ features Hypokalemia Metabolic Alcalosis Hypocalciuria Hypereninemia Hypotension/Normal blood pressure Hyperkalemia Metabolic Acidosis Hypercalciuria Hyporeninemia Hypertension Gitelman syndrome Gordon syndrome

23 Effects of WNK4 on NCCT expression in Xenopus oocytes Wilson FH et al. PNAS 2003 Uninjected NCCT WNK4 + NCCT

24 Effects of WNK1 and WNK4 on NCC mediated 22 Na uptake in Xenopus oocytes H2OH2OH2OH2OWNK1NCC NCC + WNK Na Uptake (% of NCCT alone) 5 6 WNK4 NCC + WNK4 WNK1+WNK4 Yang et al. - J Clin Invest 2003 cRNA cRNA + HCTZ

25 NCCT WNK4 (Kinase - Dead) NCCT WNK4 (WT) NCCT WNK4 (Q562E) P< 1x10 -9 NS Effects of WNK4 NCCT mediated 22Na flux in Xenopus oocytes Wilson FH et al PNAS Na Uptake (% of NCCT alone)

26 WNK : a “molecular switch” that controls renal excretion of Na + and K +WNK4 Baseline Normal Aldosterone Hyperkaliemia High Aldosterone Hypovolemia High AldosteroneWNK4Blood Lumen Cl - Na+ Cl - Na+ K+ WNK4 Cl - Na+ K+

27 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


Scaricare ppt "Le Malattie Rare : un Utile Modello Fisiopatologico Prof. Giovambattista Capasso Cattedra di Nefrologia Seconda Università di Napoli."

Presentazioni simili


Annunci Google