REVIEW OF RENAL PHYSIOLOGY

By producing urine, kidneys contributing to the regulation of volume and chemical composition of
body fluid. this kidney function is enabled byprocessing a large amount of blood which circulates
through them. The basic processes in the kidneys during the creation of the urine are
glomerular filtration, and two selective tubular mechanism – secretion and reabsorption.
Glomerular filtration is the first step in urine formation, and it meansforming the glomerular filtrate
by separating blood cells and protein from the blood through blood urine barriers. In
general, glomerular filtration rate is dependent on hydrostatic pressure and the
oncotic pressure inside glomerular capillaries. The intensity of glomerular filtration is 180 liters/day,
and in that process entire plasma volume is filtered 60 times/day,
approximatelly.Tubular reabsorption means the transport of substances from
the tubular lumen through their wall to blood in peritubular capillaries,
while tubular secretion includes the elimination of substances from
the blood in peritubular capillaries into the tubular lumen. Numerous complex mechanisms
of transport through the cell membranes, are involved in processes in different parts of renal tubular
system
several hormonal mechanisms enable to independently control the tubular reabsorption/secretion of
almost each substance individually. Reabsorption and secretion in the proximal tubule
and Henle loop are relatively constant because the permeability of cell membrne in epithelial cells of
these area is relatively unchanged, and it does not depend on the presence of hormones. However, the
permeability of the membrane in the epithelial cells in distal tube and collecting ducts, and
consequentlyreabsorption and secretion is variable and under the influence of the hormone. That
means that distal tube and collecting ducts are the renal area which allows fine regulation of volumen
and content of body fluid. Preservation of osmolarity in plasma is almost mediated by the
hypothalamus & posterior pituitary gland (vasopressin) and Preservation of Extracellular Fluid
Volume is mediated via aldosteron (and maybe cardiac peptides). Ionic content of plasma is
mediated by influence of several hormone (parathormone, aldosteron)
Glomerulotubular balance is a regulatory mechanism that enables the adaptation of the tubular
re-absorption to the glomerular filtration dynamics. It prevents that increase in
the glomerular filtration leads to inflow of large volume of fluid in the distal tubule, which
would disrupt fine hormonal regulation of tubular transport mechanism
Afferent and efferent glomerular arterioles are the major sites of regulated vascular resistance in the
kidney. In this vascular bed, Noradrenalin, Angiotensin II, and Endothelin act as
a vasoconstrictor while Acetlcholine, NO, and PGs, are a vasodilator. Sympathetic innervation of the
afferent and efferent arterioles is the major regulator of RBF and GFR, Also, there are some
autoregulation processes (myogenic mechanism and tubuloglomerular feedback)
which serve to keep renal blood flow and glomerular filtration rate almost constant. Myogenic
Mechanism include that increased hydrostatic pressure in glomerular capillares make smoothe muscle
contraction and causes vasoconstriction while in tubuloglomerular feedback
macula densa senses increased filtered the load of NaCl and send signals to afferent arteriole
to vasoconstrict its, and in both of these mechamism thereby by normalisation of GFR)
In addition to the excretory role, kidneys secrete certain hormones (erythropoietin, renin),
and activate of vitamin D by converse it into active hormonal form (1,25 dihydroxyholecapherol).
Gravity and peristaltic contractions propel the urine along the ureter and the urinary bladder stores the
urine. Parasympathetic stimulation contracts the bladder and micturition results if the internal
and external urethral sphincters relax. The bladder filling reflexively contracts the bladder and
Internal Sphincter became mechanically open. The external sphincter is under voluntary control, and
stretch receptors in the bladder send inhibitory impulses to external sphincter but voluntary signals
from the cortex can override the reflex or allow it to take place
Renal blood flow is relatively high and inhomogeneous, with well being perfused cortex, and only
10–15% of perfusion directed to medulla. Aproximatelly, blood flow in the outer medulla is less than
50% of the cortical blood flow. Kidney medulla receives primarily blood that has previously passed
through the vascular network of the cortex, so there is less oxygen content in iT. Paradoxaly in the
epithelial cells of the thick ascending limbs, there are intensive transport substances throught
membranes that consume a significant amount of energy and this area is with the high metabolic
requirements.
Studies shown that there is a close relation between GFR, renal sodium reabsorption, and oxygen
consumption. However, an increase in renal blood flow results in a simultaneously increased tubular
sodium load due to increased GFR. Since sodium reabsorption is the major determinant of renal
oxygen consumption, increased renal blood flow besides increasing oxygen supply also increases
oxygen demand attributed to increased reabsorptive sodium load. Nearly 99% of the of filtered
sodium is reabsorbed and this is the primary energy consuming process in the kidneys. About 2/3
(60-70%) of total sodium reabsorption takes place in the proximal tubule, 25–30% in the thick
ascending limb of the loop of Henle, and less than 10% in the distal convoluted tubule and collecting
duct.
the complex mechanism which preserve osmotic gradients and enhance urinary concentration in
kidney medula, is also high energy consumining. On that reason, kidney outer medula is paradoxally
an area where there is a weaker supply of oxygen, along with increased demands for it. Like In most
other organs, an increased demand of oxygen could be associated by an increased blood flow to
increase oxygen delivery. It has been shown that renal oxygen extraction remains stable over a wide
range of renal blood flow, indicating the increased oxygen delivery by renal blood flow is directly
counteracted by increased oxygen consumption. So, increasing GFR and consequently the tubular
sodium load also increase oxygen consumption. That is the reason why the effect of various factors on
renal oxygenation is not always predictable.
The imbalance between oxygen delivery and consumption in renal medulla can frequently leading to
its hypoxia and has been recognized as an important contributor to development and progression
chronic kidney dissease. Based on recent literature, this paradoxally situation can be good position for
potential therapeutic options

Tubular Reabsorption rate are: for Water: 99%, Sodium: 99.5%, Urea: 50% and Phenol: 0%.
Odvija se By passive diffusion, By primary active transport: Sodium By secondary active
transport: Sugars and Amino Acids

Raas
Stimulates Sodium Reabsorption in distal and collecting tubules
Naturetic peptide inhibits
In absence of Aldosterone, 20mg of sodium/day may be excreted
Aldosterone can cause 99.5% retention
Excretion = Filtration - Reabsorption + Secretion
Reabsorption:and Secretion: Peritubular capillaries

Ks bubrega
Renal artery --> interlobar artery --> arcuate artery --> interlobular artery--> afferent
arteriole* --> glomerular capillaries--> efferent arteriole* --> peritubular capillaries
*serial arrangement of arterioles--important!

Renalni klirensi I protok krvi

C.O. = 5.2 L/min
RBF = 1.2 L/min (20% of cardiac output)
RPF = .66 L/min (plasma = 55% of blood); also equal to the clearance of PAH (filtered and
secreted)
GFR = Clearance of inulin or creatinine
Inulin is filtered but not secreted or reabsorbed
Creatinine clearance a slight overestimate of GFR because it is partly secreted (GFR = 0.9 X
Ccreatinine)
Filtration Fraction = GFR/RPF, normally 20%

It Is equal to the clearance of inulin and creatinine is used to calculate it

Formiranje urina
Ultrafiltration of pla
Transcellular and paracellular (lateral space) transport; latter occurs in proximal tubule due to
leaky tight junctions--> ions pass, followed by H2O
In collecting duct tight jxns are very tight and do not allow passage of water, proteins, or
solutes
Pt
Isosmotic fluid reabsorption
Reabsorbs 2/3 of filtered load of Na and water (Aquaporin 1)
Highly permeable to H2O; solvent drag of K and Ca
Understand TF/P graph

Uppert pt
Na cotransported along with bicarb, glc, amino acids, phosphate (luminal membrane)
H+ secreted as counter-transport with Na (luminal membrane)
Sodium bicarbonate is reabsorbed (basolateral membrane)
Under normal conditions, reabsorption will increase as plasma [gluc] increases
Once plasma [gluc] reaches a certain level, all glucose carriers in the PT will be saturated,
leaving some glucose behind
Tm of SGLT-2 (sodium coupled) is 200g/dl, which is exceeded in diabetics; osmotic diuresis
results

Lower pt
NaCl reabsorbed transcellularly (1/3) and paracellularly (2/3); due to transepithelial voltage
Amino Acids and Bicarbonate have been completely reabsorbed
Glucose SGLT-1 (2 Sodium coupled) transporters move glucose against higher gradient

Thick asc
Reabsorbs 1/4 of filtered Na
Has the Na-K-2Cl cotransporter
Inhibited by Furosemide (loop diuretic)
Impermeable to water; tubular osmolarity decreases (“diluting segment”)--> separation of
movement of water and solute
Lumen becomes positively charged, causing paracellular transport of Na, K, Ca, and Mg
Early Distal Tubule/Collecting Duct
Also impermeable to water (like TAL)
Continues the dilution of urine; the “cortical diluting segment”
Reabsorption of Na/Cl (cotransporter)
Inhibited by Thiazide diuretics
Thiazide diuretics unique in that they increase Ca++ reabsorption (Loop diuretics increase
Ca++ excretion by diminishing NaK2Cl + lumen effect)

Late Distal Tubule/Collecting Duct: fine tuning

Principal cells--reabsorb Na, H2O, and secrete K+
Impermeable to water, except in presence of ADH (Vasopressin)
ADH causes water channels to relocate to apical cell membrane (AQUAPORIN 2)
Na (transcellularly) and Cl (paracellularly) are reabsorbed
Aldosterone causes an increase in Na absorption and increases K secretion
Spironolactone (K-sparing) blocks aldosterone; other K-sparing diuretics (Triamterene,
Amiloride) act directly on the Na channel, independent of aldosterone
Intercalated cells--secrete H+ through primary active transport
exchange H+ out of cell for K+ into cell; K+ reabsorption
possess carbonic anhydrase activity for bicarb reabsorption

Konc urina
Countercurrent Multiplication--creation of osmotic gradient
Loop of Henle
Generates a urine that is concentrated as high as 600 mosm/L
Urea recycling
Medullary Collecting Duct
Needed to increase the osmolar gradient from 600 to 1200 mosm/L
Kidneys use urea to do osmotic work when in state of antidiuresis
Countercurrent exchange--vasa recta maintains the medullary insterstitial osmotic gradient
set up by the countercurrent multiplier

Raas Stimulates Sodium Reabsorption in distal and collecting tubules but Naturetic peptide
inhibits that. In absence of Aldosterone, 20mg of sodium/day may be excretedAldosterone
can cause 99.5% retention

Glucose and Amino Acids are reabsorbed by secondary active transport. They are actively
transported across the apical cell membranes of the epithelial cells. Their active transport
depends on the sodium gradient across this membrane All other steps are passive

Tubular Secretion: Protons (acid/base balance), Potassium and Organic ions

Reabsorption in Proximal Tubule (Summary)

Glucose and Amino Acids
67% of Filtered Sodium
Other Electrolytes
65% of Filtered Water
50% of Filtered Urea
All Filtered Potassium

Secretion in Proximal Tubule (Summary)

Variable Proton secretion for acid/base regulation
Organic Ion secretion

Reabsorption in Distal Tubule (Summary)

Variable Sodium controlled by Aldosterone
Chloride follows passively
Variable water controlled by vasopressin

Secretion in Distal Tubule (Summary)

Variable Proton for acid/base regulation
Variable Potassium controlled by aldosterone

Sabirni kanal
Variable water reabsorption controlled by vasopressin
Variable Proton secretion for acid/base balance

REGULATION OF URINE CONCENTRATION

Medullary countercurrent system
Osmotic gradient established by long loops of Henle
Descending limb
Highly permeable to water
No active sodium transport
Ascending limb
Actively pumps sodium out of tubule to surrounding interstitial flui
Impermeable to water
Vasopressin

Renal failure
Hroni~na bubre`na insuficijencija je progredijentno I ireverzibilno oste}enje svih bubre`nih
funkcija, koje se u terminalnom stadiju o~ituje u hipervolemiji, sa pojavom edema,
hipernatremiji (rije|e hiponatremiji) I uremiji te Metaboli~ka acidoza zbog nemogu}nosti
izlu~ivanja jona vodonika. Sa napredovanjem acidoze, iz kostiju se oslobadjaju alkalne soli -
kalcijumov karbonat I fosfat, {to remeti koncentraciju kalcijumovih jona u plazmi. Poreme}aj
acidobazne ravnote`e u pravcu acidoze pra}eno je porastom koncentracije jona kalijuma.
Poreme}aj u ravnote`I kalcijuma se javlja i zbog naru{ene endokrine funkcije bubrega, tj.
nedostatka aktivnog oblika vitamina D3, kao I zbog deponovanja fosfata u tkivima u obliku
kalcijum fosfata.
Smanjeno lu~enje eritropoetina dovodi do anemije, koja se pogor{ava pojavom hemolize
zbog toksi~nog efekta uremijskih toksina na Na-K pumpu membrane eritrocita.
Acute: Sudden onset, rapid reduction in urine output - usually reversible
Chronic: Progressive, not reversible
Up to 75% function can be lost before it is noticeable

Renin - released from juxtaglomerular apparatus (JGA) activate RAA system which
Regulates Body fluid volume, plasma Na+ & K+. Aldosteron Regulates plasma Na+, K+ &
body fluid volume is Released in response to plasma K+ - 0.1 mM plasma Na+ -
minor, concentration maintained by osmoregulation ECF volume - via renin-angiotensin. it
Acts on Distal tubule Collecting duct Causes reabsorption Na+ reabsorption
H2O secretion K+ & H+. Coordinate regulation with renin-angiotensin system Neto
efekat plasma Na+ plasma K+ ECF volume

Faktori koji uticu na dinamiku glomerularne filtracije

Promjene u krvotoku bubrega
Promjene u hidrostatskom pritisku kapilara glomerula
- promjene u sistemskom krvnom pritisku
- konstrikcija aferentnih i eferentnih arteriola
Promjene hidrostatskog pritiska u Baumenovoj cauri
- obstrukcija uretera
- edem bubrega unutar renalne kapsule
Promjene u koncentraciji proteina plazme (Dehidracija, hipoproteinemija)

Regulacija glomerularne filtracije

Autoregulacija glomerularne filtracije
Diureza usled pritiska / uticaj arterijskog pritiska
Simpaticka stimulacija
Hormonska stimulacija
- noradrenalin
- angiotenzin II
- prostaglandini
- NO, endotelini
Miogena teorija

pritisak u peritubularnom intersticiju zavisi od pritisaka u peritubularnim kapilarima

SMANJENJE PERITUBULARNE KAPILARNE REAPSORPCIJE: Smanjenje
koloidoonkotskog pritiska perituularnih kapilara, /POP/, porast kapilarnog pritiska /PKP/ –
dolazi do povecanja hidrostatskog pritiska intersticijuma – smanjenja
koloidoosmotskog pritiska intersticijuma zbog razblazivanja - smanjenja
reapsorpcije vode iz tubula u intersticijum - voda sa elektrolitima se vraca
u tubul
POVECANJE PERITUBULARNE KAPILARNE REAPSORPCIJE: Povecanje
koloidoonkotskog pritiska peritubularnih kapilara, /POP/, smanjenje kapilarnog pritiska
/PKP/ u peritubularnim kapilarima – dolazi do smanjenja hidrostatskog pritiska intersticijuma
– povecanja koloidoosmotskog pritiska intersticijuma /koncentracija supstanci/ - povecanja
reapsorpcije vode iz tubula u intersticijum / osmoza/ i povlacenja rastvorenih supstanci / vuca
rastvaraca/. Sile koje povecavaju peritubularnu kapilarnu reapsorpciju povecavaju i
reapsorpciju iz tubula u intersticijum. Sile koje smanjuju peritubularnu kapilarnu reapsorpciju
smanjuju i reapsorpciju iz tubula u intersticijum

Principi reapsorpcije i sekrecije u tubulima

ENERGIJA ZA TRANSPORT
- KONCENTRACIONI GRADIJENT
- ELEKTRICNI GRADIJENT
- AKTIVNI TRANSPORT
NACIN TRANSPORTA
- DIFUZIJA
- OLAKSANA DIFUZIJA / SEKUNDARNI AKTIVNI TRANSPORT
- OSMOZA
Za supstance koje se aktivno transportuju:
- opterecenje plazme
- opterecenje tubula
- transportni maksimum

SUPSTANCE ZA KOJE NE POSTOJI TRANSPORTNI MAKSIMUM:transportuju se

difuzijom na osnovu gradijenta I njihov transport zavisi od vremena zadrzavanja tecnosti u
tubulima gradijent / vrijeme