Na and water renal pathology associated · use ethacrynic acid (no S) but ototoxic and liver toxic (high dose) Loop d. indications: Loop d. examples: 1.Acute pulmonary edema 1.Bumetanide

Na and water renal regulation and pathology associated Short Notes

Sunday, January 3, 2016

Na RENAL REGULATIONat PT -physiology -CA inhibitors

at Loop of Henle: -physiology -loop diuretics -Bartter syndome

at DT -physiology -Gitelman syndrome -Thiazides

at CD -physiology -K sparing diuretics -Liddle syndrome

www.askmish.comSunday, January 3, 2016

http://www.askmish.com


NA

H HCO3

BLOOD

NA

3NA

2K

LUMEN

ATP

PT physiology

GLUCOSEAA

PHOSPHATE

H2O, SOLUTES

H2CO3

CA*

CO2+H20CO2

PT CELLNa reabsorption ~ 60% in PT

1. ATP dependant Na/K pumpPRIMARY ACTIVE TRANSPORT

ubiquitous pump moves ions across the membrane against the

concentration gradient 3Na out of the cell and 2 K into

the cell

2. Na/H and Na/HCO3 pumpsSECONDARY ACTIVE TRANSPORT

uses the energy produced by Na/K ATP pump to move ions across

the membrane : Na in/ H out (antiport) and Na out/ HCO3 out

(symport)3. glucose, AA, PO4 with Na

SECONDARY ACTIVE TRANSPORTsame as 2, just gluc, AA and PO4

are totally absorbed

CO2 & H2O reabsorption

CO2 reaction w/ H2O facilitated by CA

->H2CO3->H (antiport) +HCO3 reabsorbed 90%(symport)

H2O &solutesreabsorbed by paracellular

diffusion through tight junctions less tight in PTCA*=CARBONIC ANHYDRASE

NA

CL




NA

H HCO3

NA

3NA

2K

LUMEN

CA inhibitors (CAI)

H2CO3

CA*

CO2+H20CO2

PT CELL Na reabsorption:60% PT ~ 45%w/HCO3&15% w/Cl

h-Na-emiaHCO3: Metabolic acidosis

H-Cl-emia

CA inhibitors block Na reabsorption flushing Na and

HCO3 in the urine;reabsorption of Na is increased w/

Cl compensatory.

h-K-emiah-Na-emia produced in PT

determines ALDOSTERONE in the collector duct to reabsorb Na in

exchange w/ K & H

renal stones basic urine(HCO3) produces more precipitation of oxalate and salts.

sulfa hypersensitivity based on structure (sulfonamide)

CAI indications: CAI examples:

1.Glaucoma AcetazolamideDorzolamide

DichlorphenamideMethazolamide

2.Sick mountain syndrome

AcetazolamideDorzolamide


3.Metabolic alkalosis

AcetazolamideDorzolamide


CA*=CARBONIC ANHYDRASE

ATP

NA

CL15%

45%HCO3 +

H2CO3

CA*

H2O+

XX




Loop physiology

CA, MG

NA, K NA, K

2 CL

THICK ASC.LOOP CELL(TAL)

ATP3NA

2K

NA

CL

K

+

+

+

+

+

+

+

Na reabsorption ~15-25% in TALCmain pump to reabsorb Na+ from filtrate

on apical (luminal) membrane of the thick ascending loop of Henle by SECONDARY

ACTIVE TRANSPORT. In series w/ Na/K ATP pump and Na/Cl pump on basolateral (BL) membrane.

Kgoes back into filtrate through an apical K channel creating a positive charge on the

luminal (apical) membrane

Ca, Mg repelled in the blood through paracellular tight junctions by the positive charges

2 CL /NA,K

Ca

Mg

a Ca sensitive receptor on BL mb regulates NaCl intake;

its defect:Familial HYPERcalcemic

hypocalciuria

PARACELLIN-1- transmb protein in tight junction- defect: hypoMgemia &

hypercalciuria with nephrocalcinosis.TRPM6 and TRPM7 proteins are critical

for Mg reabsorption in thick asc loop cell. Defect of TRP6:

hypoMgemia & hypoCa-emia

Ca Mg

LUMEN

BLOOD

ATP




Loop diuretics

CA, MG

NA, K NA, K

2 CL

THICK ASC.LOOP CELLTAL

ATP3NA

2K

NA

CL

ATP

K

inh. Na reabsorption (25%LH) inh pump

h-Na-emia

loop diuretics inh. Na, K, 2Cl co-transporter. By acting on TAL

which handles a major fraction of Na reabsorbtion, they are very

powerful diuretics

h-K-emiametabolic alkalosis

h-Na-emia produced in PT determines ALDOSTERONE in the

collector duct to reabsorb Na in exchange w/ K & H

h-Ca-emia, h-Mg-emia Ca, Mg lost in urine - no K back to create + charge

sulfa hypersensitivity(Furosemide)

use ethacrynic acid (no S) but ototoxic and liver toxic (high dose)

Loop d. indications: Loop d. examples:1.Acute pulmonary edema 1.Bumetanide - 40x more potent

than Furosemide, less ototoxicity, less K loss (still needs K

supplements)2. Furosemid-ototoxic,H-uricemia

3. Ethacrynic acid- same as 2.4. Torsemide

2.CHF1.Bumetanide - 40x more potent

than Furosemide, less ototoxicity, less K loss (still needs K

supplements)2. Furosemid-ototoxic,H-uricemia

3. Ethacrynic acid- same as 2.4. Torsemide

3. H-Ca-emia, anion overdose

1.Bumetanide - 40x more potent than Furosemide, less ototoxicity,

less K loss (still needs K supplements)

2. Furosemid-ototoxic,H-uricemia3. Ethacrynic acid- same as 2.

4. Torsemide4. HTA, refractory edema (diuretics produce

PG renal synthesis-> vasodilation

1.Bumetanide - 40x more potent than Furosemide, less ototoxicity,

less K loss (still needs K supplements)

2. Furosemid-ototoxic,H-uricemia3. Ethacrynic acid- same as 2.

4. Torsemide

X

LUMEN




Bartter syndrome

CA, MG

NA, K NA, K

2 CL

THICK ASC.LOOP CELL(TAL)

ATP3NA

2K

NA

CL

ATP

K

LUMEN

BLOOD

X

XX

autosomal recessive disease due to a defect on any of the pumps and channel on the pic, looking “like being on furosemide all the time”

Presentation: metabolic alkalosis with hypoK-emia

Diagnostic of exclusion based on labs; genetic testing rarely done (definitive diagnostic).

Difference w/ surreptitious vomiting by high urinary Cl; difference w/surreptitios diuretic abuse by higher level of urinary Cl than diuretics, also by a urine assay for diuretics

It’s a secondary hyperaldosteronism. Difference w/ primary hyperaldosteronism by low/ normal serum Na -> normal blood pressure and high plasma renin (due to volume loss).

Treatment: NSAIDs (renal prostaglandins are produced in Bartter sd) and K sparing diuretic (spironolactone, amiloride)




Labs analysisUrinary Cl Plasma renin Plasma

ALDO Serum K Serum HCO3 Serum Na

Diuretic use

Vomiting

Bartter/Gitelman

Primary H-ALDO

Renin secr. tumor

Factitious diarrhea

/ normal

/ normal

/ normal

> 40

> 40

> 40

< 10

> 20

***

*** in diarrhea, Urinary Cl can varies, being increased in case of metabolic acidosis




DT physiology

ATP3NA

2K

CL

NA

NA

CACAPTH*

Na reabsorption ~ 5-10% in DT

main pump to reabsorb Na from filtrate on apical (luminal)

membrane of the distal tubule(DT)by SECONDARY ACTIVE

TRANSPORT.

main pump to reabsorb Ca at renal level on the BL mb in exchange w/

Na. SECONDARY ACTIVE TRANSPORT

Careabsorbed from lumen through a

channel on the apical mb under the control of PTH;

PTH->Gs receptor-> AMPc -> phosphorilates Ca++ channel->

opens

CL /NA

CA /NA

LUMEN BASOLATERAL MB

DISTAL TUBULE CELL




Thiazides

ATP3NA

2K

CL

NA

NA

CACAPTH*

X Na reabsorption: 5-10% DT inhibit pump

h-Na-emia

Thiazides, most commonly used diuretics inh. Na/Cl cotransporter in the

DT. Here only 5% of filtered Na is reabsorbed, these diuretics are less efficient than loop d. in producing

diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy

most therapeutic needs requiring a diuretic.

h-K-emiametabolic alkalosis

h-Na-emia produced in DT determines ALDOSTERONE in the collector duct to

reabsorb Na in exchange w/ K & H

H-glycemiaH-lipemia* (except Indapamide)

vasodilation

Thiazides open K channels on:-vasculature: relaxation->vasodilation- beta pancreatic cells: block INSULIN

release-> H-glycemia. Low insulin mobilizes fat-> H-lipemia

H-Ca-emia Thiazides stimulates Na/Ca pump

sulfa hypersensitivity based on structure (S compound)

Hyperuricemia

Indications: Examples:

Nephr.Diab.Ins.

HydrochlorothiazideChlorthalidoneClorothiazideIndapamideMetolazone

HTN


CHF

HydrochlorothiazideChlorthalidoneClorothiazideIndapamideMetolazonenephrolitiasis


DISTAL TUBULE CELL

LUMEN




Gitelman syndrome

3NA

2K

CL

NA

NA

CACA

Xsimilar to Bartter in presentation:

autosomal recessive

secondary hyperaldosteronism with hypokalemia and metabolic alkalosis

difference w/ Bartter is the site of the defect and urine Ca: Gitelman is a defect on DT, the Na/Cl co-transporter and urine Ca is low (usually).

is like being on thiazide diuretic all the time

DISTAL TUBULE CELL

PTH*

ATP

LUMEN BASOLATERAL MB




Bartter vs Gitelman Bartter sd.

(like being on LOOP diuretic all the time)

Gitelman sd.(like being on

THIAZIDES all the time)genetic aut recessive aut recessive

sign POLYURIA, POLYHYDRAMNIOS POLYURIA

LABS h-K-emiametab.alkalosis

h-K-emiamet.alkalosis

Urinary Ca or urine Ca/creatinine

Ca-URIA normal->high Ca-uria low

Pathophysiology

NaCl& water is lost in urine by defects on Na,K,2Cl cotransporter or other pumps on TALH-> activates

Ren,Ang,ALDO system

NaCl and water is lost in urine by defect on Na,Cl pump on DT ->

activates Ren,Ang,ALDO system

Tx NSAIDs and K sp.diuretics K sp diuretics, ACEI




CD physiologyPARIETAL CELL

NA

K, H

3NA

2K

NA

K

CO2+H20CA*

INTERCALATED CELL

H2CO3H

ATP

HCO3

LUMEN

ADHH2O

Na reabsorption ~ 1-2% in CD

~ 1-2% Na from filtrate is reabsorbed through Na/K,H exchanger. It reabsorbes Na and

secretes K&H. ALDOSTERONE through Zn fingers regulates the expression of this pump

based on Na conc. If Na conc is low ->hyperALDO->increased Na reabsorption in

exchange w/ K&H.

Na, K on apical membrane, Na is reabsorbed and K secreted through 2 un-gated channels.

NA/K,HALDOSTERONE

H2O,HCO3 reabsorption

H2O ADH stimulates Gs coupled receptor(V2)

->prot kinase A-> phoshorilates water channels(aquaporin)-> open-> H2O diffusion.Li uncouples the receptor-> Neph. Diab.Ins.

Amiloride directly recouples them.

HCO3produced by CA from CO2 and H2O.

Reabsorbed 10% in CD while H is secreted.




K sparing diureticsPARIETAL CELL

NA

K, H

3NA

2K

NA

K

CO2+H20CA*

INTERCALATED CELL

H2CO3H

ATP

ALDOSTERONE

HCO3

LUMEN

ADHH20

XX

Aldosterone receptor antagonistsAldosterone receptor antagonists

Spironolactone EplerenoneBoth block the effect of Aldosterone on receptors located on Na/K,H exchanger (so aldosterone must be present in order for them to have

effect). This causes more Na to pass into the CD and less K,H to be lost in the urine and this is why they are called K sparing d.

Both block the effect of Aldosterone on receptors located on Na/K,H exchanger (so aldosterone must be present in order for them to have

effect). This causes more Na to pass into the CD and less K,H to be lost in the urine and this is why they are called K sparing d.

Androgen receptor antagonists -

Indications:1. HYPERALDOSTERONISM

2. FEMALE HIRSUTISM3. adjunct to diuretics that make

K wasting

Indications:1. HYPERALDOSTERONISM

3. adjunct to diuretics that makeK wasting

Na ch.blockers:Amiloride,Triamterenedirectly inhibit Na channels associated w/ Aldosterone sensitive pump

and therefore have similar effects on K and H ions as ALDO antagonists. Also weak diuretics.

ADH stim Gs coupled V2 receptor-> prot kinase A phosphorilates water channel->open. Li uncouple Gs and receptor -> NDI.

Amiloride, Triamterene directly recouple themIndications:

1.adjunct to K wasting diuretics2. Nephrogenic diabetes insipidus Lithium induced




Liddle syndromePARIETAL CELL

NA

K, H

3NA

2K

NA

K

CO2+H20CA*

INTERCALATED CELL

H2CO3H

ATP

ALDOSTERONE

HCO3

LUMEN

ADHH20

Liddle sd.(PseudoHYPER

aldosteronism)

Conn sd.(Primary HYPERaldosteronism)

appears children any age

sign HTN HTN

LABS h-K-emiametab.alkalosis

h-K-emiamet.alkalosis

Aldosterone level

normal/low high

Due to:aut.dominant,

overactivity of Na ch-> Na reabs

adrenal tumor (adenoma) or

adrenal hyperplasia

Tx Na channel inhibitors

ALDO receptor inhibitors




WATER REGULATION

Water balance

Water in the body (compartments)

Water renal regulation




Water balanceICF 28L

METABOLISM: NUTRIENTS + O2 ->CO2 + H2O

LUNG

SKIN

EVAPORATION900ML/DAY

FOOD AND DRINK2200 ML/DAY

ECF 14LPLASMA 3.5L

URINE1500ML/DAY

FECES100ML/DAY

RENAL

GI TRACT

Regulatinghormone Stimulation Result

ADHECF osmotic

pressure (osmR)

ECBV -> vol R

ECF osmotic pressure

Blood volume

Aldosterone ECBV -> RAA+ECF K+

Blood volumeECF K+

ADULT: 2500 ML/70KG =36 ML/KGBABY: 1200 ML/5KG = 240 ML/KG




Water in the body compartments

Water percentage decreases as the body ages: newborn ~80%-> adult 60%-> elderly 50%

Water passes freely through membranes and spaces driven by tonicity of compartment. Its distribution depends on the body compartment:

ICF: 40% ECF: 20% (5% IVF and 15% ISF)




Water renal regulationAll water reabsorption in the kidney is passive.

Water moves in response to osmotic gradients that are directly/indirectly due to the reabsorption of solute, particularly Na. There are no water pumps in the body.

GFR (180 l/day)

65% reabsorbed in the PT

15% reabsorbed in loop of Henle (thin descending limb)

20% of filtrate enters DT from which:

8% reabsorbed in CD (with no ADH)

>19% reabsorbed in CD (with maximal ADH)

left in urine 12% (-ADH) or 1% (maximal ADH) meaning 22L/day at 30-60 mOsm/L or 500 mL at 1200 mOsm/day

anaesthesiamcq.com: Summary of Renal Water Handling




Bibliography

Harrison’s: Principles of Internal Medicine, 2009, Nephrology

Lionel Raymon, PhD: Pharmacology, Kaplan 2007

Wikipedia

Richard Klabunde, PhD: Diuretics, http://cvpharmacology.com


http://cvphysiology.com






Documents

Na and water renal pathology associated · use ethacrynic acid (no S) but ototoxic and liver toxic (high dose) Loop d. indications: Loop d. examples: 1.Acute pulmonary edema 1.Bumetanide