Een wandeling langs het nefron /

klinische beeldenCOIG-cursusdag Water & Zout

2019

Dr. Gerald VervoortDept. of Internal medicine and Nephrology

Proximal tubule

Loop of Henle

Distal tubule

Collecting duct

Glomerulus

Filtratie

Endothelial Surface Layer (glycocalyx)

Hypothesis how endothelial sodium permeability could contribute to sodium homeostasis in the human organism.

Slit diaphragm

Tryggvason et al.

Tubulaire resorptie en secretie

Proximal tubule

Reabsorbs isosmotically ±60-70% of the filtered NaCl and H2OReabsorbs 90% of the filtered HCO3

-

Major site of ammonia production in nephronReabsorbs almost all of filtered glucose and amino acidsReabsorbs K+, phosphate, calcium, magnesium, urea, uric acidSecretes organic anions (such as urate) and cations (such as creatinine); this pathway is also used for excretion of PB-drugs and toxins

- +

basolateral (peritubular)apical (luminal)

Proximal Tubule

2K+

3Na+

ATP

ADP

Na+

Aquaporine-1H2O

- - ++

NHE3

H+

H+

Acetazolamide

H2O

HCO3-H+

CarboAnhydrase II

CO2

Na+

3HCO3-

SGLT(1)2

GlucosePhosphateAminoacidsHCO3

-

-- --

(.)gliflozine

H2O (Na+, Ca++ , Cl-, HCO3

-)Paracellular transport

- +basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

H+

Organic cation(kreatinine)

H+

Organic cation

OCT

Proximal Tubule

CimetidineTrimethoprimQuinine

-

Cimetidine Improves the Accuracy of Creatinine Clearance as an Indicator for Glomerular Filtration RateKi Chul Choi et al; 1993

GFR

- +basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

Organic anion**

Organic anion

ATP

ADP

OAT

MRP’s*

Proximal Tubule

*Multidrug resistance-associated protein** PAH, penicillins, diuretics

Probenicide

-

NaDC1

DC2-

OAT

DC2-

Proximal Tubule

*Alfa-1-MGBeta-2-MG

Imerslund-Gräsbeck syndrome

Loop of Henle

Reabsorbs 25-35% of filtered NaCl but almost no H2O

Countercurrent multiplier as NaCl reabsorbed in excess of H2O

Major site of active regulation of Mg+ excretionLoop of Henle

Tubulaire resorptie en secretie

+-

basolateralapical

2K+

3Na+

ATP

ADP

H2O

Na+

2Cl-

lisdiuretica

Cl-

ROMK

K+

K+

Na+,Ca2+, Mg2+

TALNKCC2

Loop of Henle

Defects causing Bartter’s syndrome(hypokalemia, metabolic alkalosis, hypercalciuria)

TAL

Na+,Ca2+, Mg2+

Ca2+

Ca2+

K+Na+

2Cl-

K+

Cl-

2K+

3Na+

ATP

ADP

NKCC2

ROMK CLCKB

Furosemide

K+Ba2+

+ -10 mV

basolateralapical

Barttin

CaSR

ADH, PTH?

-

-

WNK3SPAKSORLA

Countercurrent mechanism

H2O

Thiazide-diuretica(beïnvloeding verdunnend vermogen)

Lis-diuretica(beïnvloeding concentrerend vermogen)

Loop of Henle

Loop of Henle

Distal tubule Reabsorbs about 5% of filtered NaCl but almost no water

Major site, with connecting segment, of active regulation of Ca++ excretion

Tubulaire resorptie en secretie

DCT

- +Vitamin DPTHFGF23/klotho basolateralapical

2K+

3Na+

ATP

ADP

H2O

Na+

Cl-

Thiazide-diuretica

Cl-

NCCT

Ca++

Mg++

Ca++

3Na+

Ca-BP

TRPV5

ROMKK+

CLCKB

Barttin

TRPM6

Mg++?

Distale tubule

Ca++

DCT

- +

Vitamin DPTHFGF23/klotho basolateralapical

2K+

3Na+

ATP

ADP

H2O

Na+

Cl-

Thiazide

Cl-

NCCT

Ca++

Mg++

Ca++

3Na+

Ca-BP

K+

Mg++?

Defects causing Gitelman’s syndrome(hypokalemia, hypomagnesemia, hypocalciuria)

??

-

Ca++

Gain of function NCCT = Gordon’s syndrome(hypertension, hyperkalemia, metabolic acidosis) [=FHHt of pseudohypoaldosteronism type II]

- +Vitamin DPTH

basolateralapical

2K+

3Na+

ATP

ADP

H2O

Na+

Cl-

Thiazide

NCCT

Ca++

Mg++

Ca++

3Na+

Ca-BP

K+

Mg++?

Cl-

DCT

* Familiaire Hyperkalemische Hypertensie

Loop of Henle

Connecting segmentsand collecting tubule

Principle cells reabsorb Na+ and Cl - and secrete K + underinfluence of aldosteron

Intercalated cells secrete H +, reabsorb K +, and, in metabolicalkalosis, secrete HCO3

-

Reabsorb H2O in presence of antidiuretic hormone

Secrete H+ and NH3; urine pH can be reduced to as low as 4.5-5.0

Tubulaire resorptie en secretie

- +basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

AmilorideTriamterene

Aldosteron

+

SpironolactonEplerenon

ENaC

MR*

ANP-R

ANP

-

DigoxineCsA/tacrolimus

Heparin

Collecting tubule (principal cells)- -

* mineralocorticoidreceptor

- +basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

AmilorideTriamterene

Aldosteron

+

ENaC

MR*

-

Collecting tubule (principal cells)

* Mineralocorticoidreceptor** 11β-hydroxy-steroid dehydrogenase 2

Cortisol

+

11β-HSD2**

glycyrrhetinezuur

-

Liddle’s syndrome(hypertension, hypokalemia, metabolic alkalosis)

- +basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

Aldosteron

+

ENaC

MR

ANP-R

ANP

Pseudohypoaldosteronisme type 1(sodium wasting, hypovolemia, hyperkalemia)

+basolateralapical

2K+

3Na+

ATP

ADP

Na+

K+

Aldosteron

+

Spironolacton

ENaC

Aldo-R

ANP-R

ANP

-

- +

basolateralapical

vasopressine

Aquaporine 2Aquaporine 3(and -4)

V2-R

“vaptans”

Collecting tubules and ducts

-

- +

basolateralapical

Cl-

HCO3-

H+

H+

K+

ATP

ADP

ATP

ADP

H+

H2O + CO2

NH3

NH4+

Collecting tubule (intercalated cells type α)

- +

basolateralapical

Cl-

H+

HCO3

-

H2O + CO2

ATP

ADP

Collecting tubule (intercalated cells type β)

EJ Hoorn et al; JASN 2011

Aldosteron paradox

Magnesium

Calcium

PhosphateUrea cycle

Uric acid

Dr. Gerald VervoortRadboudumc Nijmegen

Thank you for your attention