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!