Physiology of kidney

Overall function

1. Homeostatic function: eg water & electrolyte balance, PH regulation and blood volume regulation 2. Excretory function: eg urea, uric acid, creatinine 3. Regulation of ABP through

a. Renin angiotensin system b. Control Na+ and water excretion c. Production of vasoactive substance as PGs and Kinin

4. Endocrinal functions eg erythropoietin (RBC production), renin (regulation of ABP) 5. Metabolic function eg: gluconeogenesis (during prolonged fasting and acidosis) , degradation of hormones as insulin

and glucagon

Renal blood flow

It is about ¼ COP, or 1200ml/min, 4 ml/1 g kidney tissue This high HBF to ensure high GFR Distribution of RBF

- 10% : supply non - functioning kidney structures as renal capsule, renal pelvis, perinephric fat - 90%: supple functioning kidney structure ( 98% cortex {4 -5ml/min/g} , 2% medulla { outer: 0.7 -1 ml/min/g ,

inner: 0.2 – 0.25ml/min/g}) Renal blood can be measure by PAH clearance

Glomeruli

These are tuft or capillaries invaginated in the Bowman’s capsule. This capsule is about 200 micron in diameter. The glomeruli act as an ultrafilter to the plasma, that allows the passage of substances having small molecular weight (electrolytes, glucose, urea, amino acids), but prevent those of colloidal size (plasma proteins) and blood cells

Glomerular membrane

It is formed of a. The endothelium of the glomerular capillaries: acts as a screen to prevent blood cells and platelets from contact with

basement membrane b. A basement membrane: act as sieve allowing retention of plasma protein main barrier c. The epithelium of Bowman’s capsule: act as laydown & maintain basement membrane, phagocytose the escaped

macromolecules

Glomerular filtration

Means the bulk flow of a solvent through a filter carrying with it the solutes that are small enough to pass through the filter or it is the volume of plasma filtered by both kidneys per unit time

Mechanism Mechanism of glomerular filtration - It is a passive ultra-filtration process of the plasma. No active transport of materials takes place in the membrane - It depends on physical forces acting to push water and dissolved solutes through a passive semipermeable

membrane

Glomerular

filtration rate (GFR)

Value: 125 ml/min, 180L/day, 60nl/min for single nephron Measured by inulin clearance Inulin clearance (Cin) = Uin x V/Pin (ml/min) Significance of high GFR: to ensure processing of plasma (3L) about 60 times/day prevent accumulation of metabolites

Factors affecting GFR

1. Hydrostatic pressure of glomerular capillaries 2. Bowman’s capsular hydrostatic pressure ( pressure GFR) 3. Oncotic pressure of plasma protein ( ) 4. Effect of RPF ( 5. Filtration coefficient (KF) : effectiveness of permeability of the barrier

Dynamic Dynamic of glomerular filtration or forces of filtration

GFR= Filtration coefficient X net filtering force

Net filtering force = ( glomerular capillary hydrostatic pressure) – ( oncotic pressure of plasma proteins in Glomerular capillaries + Bowman’s capsular hydrostatic pressure )

Net filtering force = 55mmg Hg (15mm Hg + 30 mm Hg) = 10mm Hg

NB Causes of high hydrostatic pressure of glomerular capillaries a. Afferent arteriole is a straight branch of interlobular artery b. Efferent arteriole has a relatively high resistance ( its diameter is less than the afferent arteriole) c. The glomerular capillaries are present in between the afferent and efferent arterioles d. Renal artery is short, wide and direct branch from aortic

Factors affecting GFR a. The glomerular physical forces b. Glomerular membrane filtration coefficient depends on : permeability of the glomerular membrane, its surface area

Urine formation

Process Filtration of the plasma Reabsorption Secretion

Clearance

Clearance

Concept: it is the volume of plasma cleared from certain substance excreted by kidney per unit time Unit: ml/min or L/day Calculation (C) : excretion rate / plasma concentration Excretion rate: U x V°

- U = urinary concentration - V° = urine flow rate

Significance of

clearance determination

a. If the clearance is about 125ml/min, it indicates that the substance passes through the renal tubules without change ;eg; inulin not reabsorbed nor secreted

b. It the clearance is lesser than the GFR eg; urea, it means the substance is reabsorbed

c. If the clearance is more than GFR eg; penicillin, it means that

the substance is completely secreted and synthesized by the renal tubules

d. If more than 700 eg: ammonia it means that the substance is completely secreted and synthesized by the renal tubules

e. If the clearance is 0 means it is fully reabsorbed as in glucose

Renal handling of K+ ions in the nephron

Filtered Reabsorption Secretion

Site: Malphigian corpuscle ( Bowman’s capsule, Glomeruli)

Site: 1. 80% : at proximal convoluted tubule ( absorbed passively

secondary to reabsorption of NaCl- and water) 2. 10% : at thick ALH via Na+2Cl-K+ 3. At connecting tubule and cortical collecting ducts where the

actual K+ balance occurs. Here K+ is secreted by the principle cells in amount ranging from 2%-180% of the filtered K+

Site: cortical portion of collecting duct Mechanism: occurs secondary to Na+ reabsorption, which help increase of the electrochemical gradient for K+ secretion high K+ concentration inside the cell and –ve lumen( -45mvolt) Factors affecting K+ secretion

a. Plasma K+ : increase K+ concentration increase K+ secretion

b. Tubular flow rate: increase tubular flow rate increase K+ secretion

c. Acid base status : acidosis decrease secretion , alkalosis increase secretion

d. Aldosterone

Renal handling of water

PCT Loop of Henle Distal tubules and collecting ducts

65-70% of GFR is reabsorbed by osmosis secondary to reabsorption of solute

Routes of water reabsorption a. Transcellular b. Paracellular

DLH: 15% of the filtered load of water is reabsorbed passively by osmosis Not controlled by ADH

Early distal tubules is hardly permeable to water Late distal tubules and collecting duct are permeable to water in the presence of ADH reabsorb about 10% of filtered load of water

ALH: totally impermeable to water

Ion reabsorption in Proximal tubule

Na reabsorption

General

1. Reabsorb about 67% of the filtered load of Na+ with the same percentage of water 2. In early PT, Na+, water, glucose, HCO3-, amino acids and organic anions as lactate, pyruvate, and

phosphate all are absorbed secondary to Na+ 3. In the late PT: Na+ is absorbed with Cl- mainly

At basolateral membrane

1. Na+ is actively pumped out of cell to peritubular space by the electrogenic Na+K+ATPase enzyme (primary active transport)

2. In PT, Na+ reabsorption is the major forces for solutes & water reabsorption

At apical luminal border

Transcellular pathway Paracellular pathway

Carrier mediated a. Carrier-mediated electrogenic transport:

Na+glucose co transport & Na+ -amino acid co transport or symport. The accompanying Cl- is reabsorbed through paracellular space from leaky tight junction

b. Carrier – mediated electroneutral transport:

i. Symport with anions Cl-, phosphate, sulphate, lactate by a specific carrier for each one

ii. Antiport with H+ essential for HCO3 reabsorption

Bulk flow or solvent drag The slight increase in peritubular osmolarity ( by 3-5 mosmol/L) in late segment of PT cause dragging of water from lumen to paracellular space taking with it NaCl-

Channel mediated Through special chanel at apical border. In this condition, the accompanying Cl- is reabsorbed either through special Cl- parallel channel or through the paracellular space

Cl- derived Na+ reabsorption a. The preferential reabsorption of HCO3-

in early segment than Cl- increase Cl- concentration from 105meg/L at start of early segment to 132 meq/L at start of late segment

b. This facilitates passive diffusion of Cl- according to concentration gradient from lumen to paracellular and Na+ follows it

Glucose reabsorption

Apical border of PT Basolateral side

Glucose combine with specific transporter, together with Na+ then glucose is actively absorbed by secondary active transport utilizing the energy stored in Na+ due to basolateral Na+K+ATPase

Once glucose is liberated from the apical transporter in the cytoplasm, it diffuses to paracellular space by facilitated diffusion utilizing basolateral transporter called GLUT1,2 (glucose transporter)

Amino acid reabsorption

As glutamate and glycine: are absorbed with Na+ (symport) and pass through the basolateral side by facilitated diffusion

Plasma proteins reabsorption

Ions reabsorption in Loop of Henle

Na+ reabsorption

Descending Loop of Henle

Is impermeable to Na but highly permeable to water

Thin Ascending Loop of Henle (ALH)

Na+ is passively absorbed due to presence of gradient between Na+ inside (high) and outside (low) thin ALH

Thick Ascending Loop of Henle

Na+ is actively absorbed 25% by a common transporter for Na+K+2cl-. This transporter is inhibited by the loop diuretics as frusemide and edecrine.

Ions reabsorption in Distal tubules and Collecting duct

Na+ reabsorption

Early distal tubules 4% of filtered Na+ is reabsorbed Na+ is reabsorbed by a common carrier with Cl- . This carrier is inhibited by Thiazide diuretic As the ALH, the wall of this segment is impermeable to water, and the fluid leaving it is more hypotonic, thus the thick ALH and early

distal tubules are called the diluting tubule

Late distal tubule Principle cell Intercalated cell

Principle cell

1. Reabsorb Na+ via apical epithelial Na+ channel (blocked by amiloride diuretics) then it is actively pumped to through the basolateral side to the interstitium by Na+K+ ATPase.

2. Reabsorb water (under control of ADH) 3. Secrete K+ due to high content of K+ influx by

Na+K+ATPase and also K+ naturally high concentration in cell

4. Na+ reabsorption and K+ secretion is influenced by aldosterone

5. About 2% of the filtered Na+ is influenced by aldosterone hormone in the principle cell

Intercalated cell For secretion of H+ by either H+ATPase or K+H+ATPase that secretes H+ and reabsorb K+

Proteinuria

Definition It is the appearance of protein in urine particularly the albumin

Causes Pre--renal Renal Post – renal Physiological

Presence of abnormal proteins of low molecular weight as Bence Jones proteins which cross the glomerular membrane easily

As in Nephrotic syndrome ( lost negative charges from filtering membrane )

Presence of proteins in the urinary tract (ureter, urinary bladder) as pus of inflammation

Handling water

Mechanism As in page 2

Control of water balance

1. Water input: thirst 2. Water output: concentration and dilution of urine by kidney

Countercurrent multiple system

Definition It is the system in which the inflow runs parallel to , close to and in counter direction to the outflow

Requirement

1. Active transport (NaCl reabsorption ) process by thick ALH a. It is resposnsible for horizontal gradient in osmolarity between ALH and surrounding

interstitium, at any level by about 200 mosmol/L. This helps the absorption of water from DLH b. The impermeability to water cause delivery of diluted fluid to the distal tubules & collecting

ducts. In the presence of ADH, water is absorbed without urea in the connecting tubules, CCD, and outer MCD increase urea concentration in inner MCD urea is reabsorbed into medullary interstitium increasing its osmolarity (shift of horizontal to vertical gradient)

c. The high inner medullary osmolarity induced by urea, cause water reabsorption from DLH d. This makes concentrated fluid at the bend of loop of Henle helps passive diffusion of NaCl

from thin ALH to the medullary interstitium, futher increasing its osmolarity.

2. Different water and solutes permeability of the Loop of Henle 3. Counter – current flow of fluid in DLH, ALH,CD

a. The DLH is being permeable only to water allows water reabsorption by the surrounding hyperosmolarity of the fluid flowing in DLH

b. Thin ALH being permeable only to solutes, allows NaCl- reabsorption passively into medullary interstitium

c. This features of the loop of Henle together with the counter – current flow in the loop of Henle shift the horizontal gradient into vertical one

4. Water reabsorption from late distal tubule and cortical collecting duct a. About 2/3 of water delivered to connecting tubules and CCD is reabsorbed (about 10ml from

15ml). This makes the hypotonic fluid from loop of Henle isotonic in the cortex. So, little fluid is delivered to medulla increasing urea concentration diffusion of urea to medullary interstitium increasing medullary osmolarity. Accordingly, medullary washout will occur if excess fluid is delivered to it due to absence of water reabsorption in connecting tubule and CCD as in absence of ADH

5. Osmotic equilibrating device of the medullary CD a. To help reabsorption of urea & solutes from collecting duct to medullary interstituium, so

increasing deep medullary osmolarity

Role of ADH

i. Stimulation of co-transport of Na+K+Cl- at thick ALH ii. It decreases medullary blood flow maintenance of medullary gradient iii. It increases water permeability of connecting tubule and CCD iv. It increases water permeability of medullary CD urea concentration is increased help

urea reabsorption from inner medullary collecting duct v. It increases urea permeability in PCD so it will diffuse to the medulla increasing its osmolarity

Thirst

Stimuli

1- Hyperosmolarity:. 2- Decreased blood volume. 3- Angiotensin ll. 4- Dryness of the mouth.

Diuretics and diuresis

Definition Diuresis: increased urine flow Diuretic: substance that increased urine volume

Physiological bases of

mechanism of Diuretics

Type Site of Action Mechanism Example

Water Diuresis CT and CDs It decrease ADH production decreased water permeability in late CT and CD

decreased facultative water reabsorption

Ingestion of large amount of water

Osmotic Diuresis

PT, DLH; CDs Decrease water & salt reabsorption decreased obligatory and facultative water

reabsorption.

Ingestion of non absorbable solutes as mannitol and

excess glucose

Carbonic anhydrase enzyme

inhibitors

PCT Inhibit the brush border CAE failure of H+ secretion and NaHCO3 reabsorption.

Diamox

Loop diuretics Thick ALH Block Na+-K+-2Cl transporter Frusemide

Thiazide diuretics

Early DCT Inhibit Na+-Cl-

transporter Thiazide

Amiloride Principal cell in CDs

Block specific Na+

channels Amiloride

Aldosterone antagonist

Principal cell in CDs

Compete with aldosterone for its receptor Aldactone

ADH antagonist

Principal cells of CD

Compete for ADH for its receptors

Nb

Diuretics: Amiloride and Aldactone prevent K+ loss in urine so, they are called K+ -sparing diuretics while the other usually cause K+ loss in urine and so, they are called K+ - loosing diuretics. Mechanism: Diuretics acting on PCT, thick ALH, early DCT increase delivery of more Na+ to late DT and CDs increase K+ secretion and excretion, so called K+ - loosing diuretics. Diuretics blocking the special Na+ channel of the principal cells or those antagonizing aldosterone prevent K+ secretion, so called K+ - sparing diuretics.