1 / 27

Le Malattie Rare : un Utile Modello Fisiopatologico

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,

karan
Download Presentation

Le Malattie Rare : un Utile Modello Fisiopatologico

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. MALATTIE RARE Malattie rare = Malattie ‘orfane’ Ad oggi si conoscono circa 8000 malattie rare, che nel complesso interessano 30 milioni di personein Europa e circa 0.5 milione in Italia

  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 Lessontobelearned The studyof rare diseasemayleadtoanunderstandingof common disorders

  5. BASIS OF HYPERTENSION SECONDARY HYPERTENSION: 10% 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

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

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

  8. Na+ 0.01% 10 d Na+ 1.0 % 10 d Aldosteron ~30 ng/dl Aldosteron ~160 ng/dl Subcellular Localization of ENaC Changes with Dietary Na+ Intake Loffing et al. AJP 279: F252 (2000)

  9. 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.

  10. Hypertension Liddle’s Syndrome: clinical features Hypokalemia

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

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

  13. 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 • Hypertensionresistanttoconventionaltherapy • Hypokalemia • HyperactivationofENaC due tohormonalstimuli (insulin, aldosteron)

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

  15. Tubular localization of the molecular defects Gitelman DCT TAL Bartter

  16. Na+ X Transport proteins involved in the pathogenesisof Bartter syndrome 2Cl- 3 Na+ X K+ Type 1 ATP 2 K+ Type 5 X Type 2 Cl- K+ X Type 4 NKCC CaSR X Type 3 ClCKa/b ROMK Bartin Ca2+ Mg2+ Lumen Blood

  17. Na+ 3 Na+ ATP 2 K+ Cl- Cl- Ca+2 Ca+2 Molecular defects in Gitelman syndrome X ATP Lumen Blood

  18. Bartter’s syndrome Gitelman’s syndrome • 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

  19. 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

  20. 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

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

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

  23. Effects of WNK1 and WNK4 on NCC mediated 22Na uptake in Xenopus oocytes 6 cRNA 5 cRNA + HCTZ 4 Uptake (% of NCCT alone) 3 2 Na 1 22 0 NCC + WNK1+ WNK4 NCC + WNK4 NCC + WNK1 H2O NCC WNK1 WNK4 Yang et al. - J ClinInvest 2003

  24. Effects of WNK4 NCCT mediated 22Na flux in Xenopus oocytes NS 140 NS P< 1x10-9 120 100 Uptake (% of NCCT alone) 80 60 40 Na 22 20 0 NCCT WNK4 (Kinase - Dead) NCCT WNK4 (WT) NCCT WNK4 (Q562E) NCCT Wilson FH et al PNAS 2003

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

  26. 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

More Related