Prof. Giovambattista CapassoFattori di rischio legati al paziente L’età avanzata Disidratazione...
Transcript of Prof. Giovambattista CapassoFattori di rischio legati al paziente L’età avanzata Disidratazione...
Prof. Giovambattista Capasso
Roma,28 Novembre 2019
RENAL AGING
Eoin D. O’Sullivan, et al.JASN February 2017
TUBULOPATIE SECONDARIE
TUBULOPATIE GENETICHE TARDO ONSET
S. Gitelman S.Liddle
FARMACI
MALATTIE SISTEMICHE
TUBULOPATIE NELL’ANZIANO
Tubulopatie secondarie a FARMACI
• Chemioterapici• Antibiotici• Antivirali• Diuretici
Tossicità intrinseca del farmaco
Fattori di rischio legati al paziente
L’età avanzata
Disidratazione
Ricoveri nelle terapia intensiva
Condizioni che riducano il volume
plasmatico circolante (sindrome
nefrosica, cirrosi ecc.)
Insufficienza renale acuta o cronica
Sepsi, diabete e scompenso cardiaco
Neoplasie
Capolongo G. et alManuale di Nefrologia.
Garibotto et al
PCT
DCT
CD
•FARMACI : CHEMIOTERAPICI
• Cisplatino• Carboplatino• Ifosfamide• Streptozocina
• Tenofovir• Adefovir• Cidofovir• Foscarnet
ANTIVIRALI
ANTIBIOTICI• tetracicline• Rifampicina
• MALATTIE SISTEMICHE
AMILOIDOSI
MIELOMA
LINFOMA
FANCONI-LIKE
Bicarbonaturia
Glicosuria
Iperfosfaturia
AmminoaciduriaIpouricemia
Ipopotassemia
SINDROME DI FANCONI
HPO4--
Na+
Lumen
Na+
H+
Glucosio
Apical membrane
NaPi IIaNaPi IIc
SGLT2
Na+
NHE3
Na+
a.a.
80%
15%
~0%
BICARBONATE REABSORPTION ALONG THE NEPHRON
4%
1%
It is generally part of the Fanconi syndrome that is a generalized proximal disorder:
Can also be secondary to:TetracyclineIfosfamideMercury, poisons
Or to:Multiple myeloma
Or can be an isolated formInheritedAcetazolamide(AC II deficit)
Type 2 Renal Tubular Acidosis (proximal)
Bicarbonate load test
Plasma bicarbonate (mmol/l)
0
3
6
9
12
15
18
0 5 10 15 20 25 30
PCT
DCT
CD
Art. afferenteArt. efferente
Macula densa
TAL
Lume tubulare Sangue
Na+
K+
Na+
Glu
GLUT2
SGLT2
Na+
Na+Na+
Na+
Na+Na+
GLU
GLUGLU
GLU GLUGLU
X
Na+
GLU
GLICOSURIA
3 Na+ 1 HPO42-
HPO42-
IIa
2 Na+ 1 HPO42-
IIc
apical
basolateral
NaPi-IIa and NaPi-IIc
• NaPi-IIa knock-out: Pi uptake into BBMV reduced by 70%
maximally upregulated NaPi-IIc
• NaPi-IIc knock-out: no phenotype with regard to phosphate handlingno upregulation of NaPi-IIa
Expressed before
weaning age
Latest findings in phosphate homeostasisDominique Prié, et al.,
KIDNEY INTERNATIONAL (2009)
CISPLATINO
TRATTAMENTO: diuresi forzataIdratazioneSupplemento di potassio e magnesio
parenterale
Talora insorge Sindrome di Fanconi ( fatale!!)
Amifostina efficace nella prevenzione, ma uso limitato dall’insorgenza della sindrome di Stevens-Johnson.
Perazella, CJASN 2012
IFOSFAMIDE
Anushree C. Shirali and Mark A. Perazella,
National Kidney Foundation 2014
TENOFOVIR
J. Tourret et al. JASN October 2013
TDF entra nelle cellule epiteliali tubulari attraverso
i recettori hOAT1 and hOAT3 ed è escreto nel lume
attraverso MRP2 and MRP4.
• INIBISCE LA DNA POLIMERASI MITOCONDRIALE
• ↓ sintesi delle proteine della catena respiratoria
e anomalie morfologiche dei mitocondri.
• Deficit di ATP
• ↓assorbimento ioni e piccole molecole
• SINDROME DI FANCONI
• Attivazione caspasipathway
• Apoptosi cellule epiteliali
• NECROSI TUBULARE ACUTA
AMILOIDOSI
MIELOMA
LINFOMA
MALATTIE SISTEMICHE
PCT DCT
CD
ANTIBIOTICI• Gentamicina• Capreomicina
S.BARTTER-LIKE
Lumen Blood
Transport proteins involved in the TAL
Na+
2Cl-
K+
3 Na+
2 K+ATP
Cl-K+
Type 1 XNKCC
XType 2
Ca2+
Mg2+
ROMKClCKa/b
Bartin
X Type 3
X Type 4
CaSRX Type 5
• Hypokalemia• Metabolic alkalosis• Hyperreninemia• Hyperplasia juxtaglomerular
apparatus• Normal magnesemia• Increased urinary calcium
excretion • Vascular hyporeactivity• Polyuria• Polydipsia
• DIURETICI DELL’ANSA: FUROSEMIDE E TORASEMIDE
SINDROME DI BARTTER
PCT DCT
CD
ANTIBIOTICI• Amminoglicosidi• Cisplatino• Patologie
Autoimmuni( s. Sjogren)
S.GITELMAN-LIKE
• Hypokalemia
• Metabolic alkalosis
• Low urinary calcium excretion
• Hypomagnesemia with urinary magnesium wasting
• DIURETICI TIAZIDICI
Na+
Cl-
3Na+
2K+
ATPXCa++
ATP
Calbindin 28KD
Calbindin 28KD
Calbindin 28KD
Calbindin 28KD
Calbindin 28KD
SINDROME DI GITELMAN
PCT
DCT
CD
• S. Sjogren• Epatite autoimmune• Cirrosi biliare
primitiva• LES• Artrite reumatoide
MALATTIE AUTOIMMUNI
FARMACI
• Ifosfamide• Amfotericina B• foscarnet• Carbonato di Litio• Ibuprofene
• m. wilson• Sarcoidosi
MALATTIE SISTEMICHE
ACIDOSI TUBULARE DISTALE TIPO I
The clinical assessment was first described by Lightwood in 1935 and later by Butler et al. in 1936 and is characterized of:
Metabolic acidosisHypokalemiaNephrocalcinosisRickets
Primary Autosomal dominant Autosomal recessive
Secondary Autoimmune disorders (es. Sjogren) Drugs/toxins (es. Amphotericin) Nephrocalcinosis Other systemic diseases Pregnancy
-intercalated cell deafness
HCO3-/Cl-
H+-ATPase
H+/K+
DISTAL RENAL TUBULAR ACIDOSIS (TYPE 1)
Acidification along the nephronp
H r
ed
ucti
on
of
tub
ula
r fl
uid
( p
H u
nit
)
2.0
1.6
1.2
0.8
0.4
0.0
2.0
1.6
1.2
0.8
0.4
0.0
%PCT lenght
0 20 40 60 80 100 0 50 100 0 50 100
%DCT lenght %CD lenght
Profile of tubular fluid pH at basal conditions
pH
re
du
cti
on
of
tub
ula
r fl
uid
( p
H u
nit
)
Background: Inability of kidneys to produce a urine pH lower then 5.3 in presence of spontaneous or induced metabolic acidosis and with a normal GFR
Fludrocortisone/furosemide test
Walsh et al.
1mg + 40 mg
Diagnosis
Ammonium chloride challengeWrong and Davies 100 mg/kg + water ……emetic!
4
5
6
7
0 1 2 3 4 5 6
Distal RTA
Normal
Time (h)
Uri
ne p
HNH4Cl load test
Description of combined effects of frusemide and fludrocortisone
NKCC2X
HCO3-
+H+
ROMK
-intercalated cell
ENaC
H+ Cl-
Na+
Principal cell
K+
H+
ATPasiHCO3
-/Cl-
Na+/K+
ATPase
H+/K+
Na+
TAL DCT
CD
Urine
Frusemide
Compared effects on urine pH of NH4Cl load vs frusemide/fludrocortisone administration
Walsh SB et al Kidney Int. 2007
Uri
ne p
H
4
5
6
7
8
1 54320 6 7 84
5
6
7
8
1 54320 6 7 8
Uri
ne p
H
Time (h)
4
5
6
7
8
1 54320 6 7 8
Time (h)
4
5
6
7
8
1 54320 6 7 8
NH4Cl test
Control group
Distal RTA group
Furosemide/Fludrocortisone
Control group
Distal RTA group
Amfotericina B Acidosi tubulare distale
R. Zietse et al. Nat. Rev. Nephrol. 2009
1. Amfotericina B può creare pori nella membrana cellulare
2. Si verifica retrodiffusione di H+
3. ↓escrezione urinaria di H+
Altre tubulopatieda amfotericina B:
• S. Fanconi
• Perdita di magnesio e potassio con le urine
• Necrosi tubulare acuta
Prevenzione nefrotossicità
• Infusione di soluzione salina pree post
• Utilizzo di formulazioni lipidiche
(liposomiale-AmBisome®; dispersione colloidale-Amphotec®; vettori lipidici-Abelcet®)
• Evitare associazione con farmaci nefrotossici
BASIS 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
DCT
5% 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)
•Late onset : rare cases in the Elderly.
• 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
Liddle’s Syndrome: clinical features
Hypokalemia
Hypertension
Liddle’s Syndrome
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 resistantto conventional therapy
Hypokalemia
Hyperactivation of ENaCdue to hormonal stimuli(insulin, aldosteron)
Analogies between LS and Obesity-relatedhypertension
Hypertension resistant toconventional therapy
Hypokalemia
Hypercativation of ENaCdue to genetic mutaion
Liddle syndromeObesity-related
hypertension
Marker di danno tubulare
eGFR ?
Esame delle urine e concentrazione elettroliti urinari
(sodio, potassio, calcio, fosforo, magnesio, ac. Urico)
Proteinuria 24h
beta2-microglobulina
Proteomica e metabolomica urinaria
Biomarcatori (NHE3, NaPI2, NKCC, NCC, AQP2)
Misure generali
1. valutare la funzione renale prima di iniziare la terapia
2. regolare il dosaggio del farmaco
3. evitare la combinazione di più farmaci nefrotossici
4. riconoscere eventuali fattori di rischio legati alla condizione del
paziente e correggerli
5. assicurare un’adeguata idratazione prima e nel corso della terapia
6. utilizzare, quando possibile, antibiotici meno nefrotossici
7. monitorare la funzione renale durante la terapia.
Geriatra = diagnosi precoce anomalie elettrolitiche
Nefrologo= diagnosi precoce tubulopatia
Tubulopatie acquisite:
• Reversibili
• Fatali
GRAZIE DELL’ATTENZIONE!