DR.SREEJITH.H

KidneysKidneys are a pair of excretory organs situated on the

posterior abdominal wall, extending from upper border of T12 to L3 vertebra

Right kidney is slightly lower than the leftEach kidney is 11 cm long, 6 cm broad and 3 cm thick,

weight 150 g in males and 135 g in femalesCapsules or coverings of kidneys - Fibrous capsule, Peri-

renal fat, Renal fascia and Para-renal fatCoronal segment – cortex; medulla; renal sinus

Functions of the Kidney:nceRegulation of body fluid volume and

osmolalityRegulation of electrolyte balanceRegulation of acid-base balanceExcretion of waste products (urea,

ammonia, drugs, toxins)Production and secretion of hormonesRegulation of blood pressure

Renal cortexRenal cortex Cortical lobules - which Cortical lobules - which

form caps over the form caps over the bases of the pyramidsbases of the pyramids

Renal columns - which Renal columns - which dip in between the dip in between the pyramidspyramids

Renal medullaRenal medulla has 10 conical masses has 10 conical masses

called renal pyramids, called renal pyramids, their apices form renal their apices form renal papillaepapillae

Renal sinusRenal sinus Space that extends into kidney from hilusSpace that extends into kidney from hilus Contains branches of renal artery and renal veinContains branches of renal artery and renal vein Renal pelvis divides into 2-3 major calices and these in turn divide into 7-Renal pelvis divides into 2-3 major calices and these in turn divide into 7-

13 minor calices, each minor calyx (cup of flower) ends in an expansion 13 minor calices, each minor calyx (cup of flower) ends in an expansion which is indented by 1-3 renal papillaewhich is indented by 1-3 renal papillae

Histologically, each kidney is composed 1-3 million Histologically, each kidney is composed 1-3 million uriniferous tubules. Each consists ofuriniferous tubules. Each consists of Secretory part - which forms urine is called nephron, functional Secretory part - which forms urine is called nephron, functional

unit of kidneyunit of kidney Nephrons open in to collecting tubules. Many such tubules unite Nephrons open in to collecting tubules. Many such tubules unite

to form the ducts of Bellini which open into minor calicesto form the ducts of Bellini which open into minor calicesArterial SupplyArterial Supply One renal artery on each side arising from abdominal aorta One renal artery on each side arising from abdominal aorta At or near hilus, renal artery divides into anterior and At or near hilus, renal artery divides into anterior and

posterior branches giving rise to segmental arteriesposterior branches giving rise to segmental arteriesLymphaticsLymphatics Lateral aortic nodesLateral aortic nodesNerve SupplyNerve Supply Renal plexus (an off shoot of coeliac plexus, T10-L1)Renal plexus (an off shoot of coeliac plexus, T10-L1)

Circulation of renal blood flowCirculation of renal blood flow

Renal artery divides serially into – interlobar artery Renal artery divides serially into – interlobar artery arcuate arcuate interlobular arteries interlobular arteries afferent arterioles afferent arterioles capillary tufts of renal glomeruli into outer cortex capillary tufts of renal glomeruli into outer cortex efferent arterioles efferent arterioles in juxtamedullary zone in juxtamedullary zone arterioles become vasa recta (closely applied to loop of henle) arterioles become vasa recta (closely applied to loop of henle)Venous drainage:Venous drainage: Stelate veins Stelate veins interlobular veins interlobular veins arcuate veins arcuate veins interlobar veins interlobar veins

Two types of nephrons are presentTwo types of nephrons are present Cortical nephronsCortical nephrons with short loop of Henle with short loop of Henle Juxtamedullary nephronsJuxtamedullary nephrons with long loops of Henle with long loops of Henle

Juxtaglomerular apparatusJuxtaglomerular apparatus Macula densaMacula densa – modified portion of thick ascending limb – modified portion of thick ascending limb

which is applied to glomerulus at the vascular pole between which is applied to glomerulus at the vascular pole between the afferent and efferent arterioles containing the afferent and efferent arterioles containing chemoreceptor cells which sense tubular concentration of chemoreceptor cells which sense tubular concentration of NaClNaCl

Granular cellsGranular cells – Produce renin, which catalyses the – Produce renin, which catalyses the formation of angiotensin formation of angiotensin modulates efferent and afferent modulates efferent and afferent arterial tone and GFRarterial tone and GFR

The NephronFunctional unit of the kidney (1,000,000)Responsible for urine formation:

FiltrationSecretionReabsorption

Proximal Tubule

DistalTubule

Thin descending

Thin ascendingLoop of Henle

Thick ascending(diluting segment)

Early

LateCollecting Duct

Cortical

Medullary

FunctionsFunctions

Nephron regulatesNephron regulates Intravascular volume, osmolality, acid base balance, Intravascular volume, osmolality, acid base balance,

excrete the end product of metabolism and drugsexcrete the end product of metabolism and drugs Urine is formed by combination of glomerular Urine is formed by combination of glomerular

ultrafiltration + tubular reabsorption and secretionultrafiltration + tubular reabsorption and secretion

Nephron produces hormonesNephron produces hormones Fluid homeostasis (renin, prostaglandins, kinins)Fluid homeostasis (renin, prostaglandins, kinins) Bone metabolism (1,25-dihydroxycholecalciferol)Bone metabolism (1,25-dihydroxycholecalciferol) Hematopoiesis (erythropoietin) – produced by interstitial Hematopoiesis (erythropoietin) – produced by interstitial

cells in peritubular capillary bed (85% cells in peritubular capillary bed (85% stimulus stimulus hypoxiahypoxia

Basic Theory of Urine Formation

Filtration

Reabsorption

Secretion

Excretion

Glomerulus - Glomerulus - Five componentsFive components Capillary endotheliumCapillary endothelium – 70-100 – 70-100

nm fenestrations – restricts nm fenestrations – restricts passage of cellspassage of cells

Glomerular basement membraneGlomerular basement membrane – filters plasma proteins– filters plasma proteins

Visceral epitheliumVisceral epithelium – podocytes – podocytes with s foot processes with 25-60 with s foot processes with 25-60 nm gaps, permeability altered by nm gaps, permeability altered by contraction of foot processescontraction of foot processes

Parietal epitheliumParietal epithelium (Bowman’s (Bowman’s capsule)capsule)

MesangiumMesangium (interstitial cells) – (interstitial cells) – pericytes, structural support, pericytes, structural support, phagocytosis, restricts bld flow in phagocytosis, restricts bld flow in response to angiotensin-IIresponse to angiotensin-II

Filtr

atio

n ba

rrier

Filtr

atio

n ba

rrier

Filtration barrier - Size and charge selective

Charge: all 3 layers contain negatively charged glycoproteins restricts passage of other negatively charge proteins

Size: Molecules with radius <1.8 nm water, sodium, urea, glucose, inulin freely filtered

>3.6 nm hemoglobin and albumin not filtered

Between 1.8-3.6 cations filtered, anions not

Glomerulonephritis negatively charged glycoproteins destroyed polyanionic proteins filtered proteinuria

Glomerular Filtration Rate (GFR)Glomerular Filtration Rate (GFR) Normal GFR: in men = 125 ml/min, 10% lower in females Normal GFR: in men = 125 ml/min, 10% lower in females Depends on permeability of filtration barrierDepends on permeability of filtration barrier Difference between hydrostatic process Difference between hydrostatic process pushing fluid into pushing fluid into

Bowman’s spaceBowman’s space and and osmotic forces keeping fluid in osmotic forces keeping fluid in plasmaplasma

GFR = Kuf [(Pgc – Pbs) – (GFR = Kuf [(Pgc – Pbs) – (gc – gc – bs)bs)Pgc & Pbs = Hydrostatic pressure in glomerular capillary Pgc & Pbs = Hydrostatic pressure in glomerular capillary and basement membrane and basement membrane gc & gc & bs = plasma oncotic pressure in glomerular bs = plasma oncotic pressure in glomerular capillary and basement membranecapillary and basement membraneKuf = Ultrafiltration coefficient reflects capillary permeability Kuf = Ultrafiltration coefficient reflects capillary permeability and glomerular surface areaand glomerular surface area

Regulation of GFR

Changes in Kf (Permeability or Surface area):

Mesangial Cell Contraction or Relaxation + ANP, NO- AII, Endothelin, Norepi, Epi, ADH

A volume of plasma from which a substance is completely removed by the kidneys per unit time.

Clearance

Where UF = urine flow; Ux = urine concentration of X; Px = plasma concentration of X; Cx = clearance of X

Cx = UF Ux = Volume/Time eg. ml/min or L/day

Px

Freely Filtered Not Metabolized Not Reabsorbed Does Not Change GFRNot Secreted Not Produced

Measurement of GFR(Inulin M.W. = 5,000)

Amount Filtered = Amount Excreted

GFR · PIN = UF ·UINGFR = UF ·UIN = CIN

PIN

(Filtered Inulin = Excreted Inulin)

Excreted Inulin

Plasma Inulin(volume/time)

Reabsorption and secretion

ReabsorptionActive Transport –requires ATP

Na+, K+ ATP pumpsPassive Transport-

Na+ symporters (glucose, a.a., etc)Na+ antiporters (H+)Ion channelsOsmosis

Factors influencing ReabsorptionSaturation: Transporters can get

saturated by high concentrations of a substance - failure to resorb all of it results in its loss in the urine (eg, renal threshold for glucose is about 180mg/dl).

Rate of flow of the filtrate: affects the time available for the transporters to reabsorb molecules.

Proximal tubule - reabsorbs 65 % of filtered Na+ as well as Cl-, Ca2+, PO4, HCO3

-. 75-90% of H20. Glucose, carbohydrates, amino acids, and small proteins are also reabsorbed here.

Loop of Henle - reabsorbs 25% of filtered Na+.

Distal tubule - reabsorbs 8% of filtered Na+. Reabsorbs HCO3-.

Collecting duct - reabsorbs the remaining 2% of Na+ only if the hormone aldosterone is present. H20 depending on hormone ADH.

SecretionProximal tubule – uric acid, bile salts,

metabolites, some drugs, some creatinineDistal tubule – Most active secretion takes

place here including organic acids, K+, H+, drugs, Tamm-Horsfall protein (main component of hyaline casts).

TubuleTubule

Proximal Tubule (PCT)Proximal Tubule (PCT)

60-75% ultrafiltrate 60-75% ultrafiltrate reabsorb isotonically in PCT reabsorb isotonically in PCT

To be reabsorbed most substances have to pass through To be reabsorbed most substances have to pass through apical side of cell membrane apical side of cell membrane basolateral cell membrane basolateral cell membrane renal interstitium renal interstitium peritubular capillaries peritubular capillaries

Carbonic anhydrase inhibitors (acetazolamide) interfere Carbonic anhydrase inhibitors (acetazolamide) interfere with Nawith Na++ reabsorption and H reabsorption and H++ secretion in PCT secretion in PCT

Pump mechanisms of tubulePump mechanisms of tubule

Sodium reabsorption in PCT (65-75% of filtered NaSodium reabsorption in PCT (65-75% of filtered Na++ load load reabsorbed)reabsorbed)

Na+ is actively transported out of PCT cells at their capillary Na+ is actively transported out of PCT cells at their capillary sides by membrane bound Nasides by membrane bound Na++ K K++ ATPase ATPase

Resulting low intracellular concentration of NaResulting low intracellular concentration of Na++

Passive movement of KPassive movement of K++ down its gradient from tubular fluid into down its gradient from tubular fluid into

epithelial cellsepithelial cells

NaNa++ reabsorption is coupled with reabsorption of other solutes reabsorption is coupled with reabsorption of other solutes and secretion of H and secretion of H+ + reabsorption of 90% of filtered HCO reabsorption of 90% of filtered HCO33 ionsions

Chloride absorption Chloride absorption passive passive follows concentration follows concentration gradient gradient transverse tight junctions between adjacent tubular transverse tight junctions between adjacent tubular epitheliumepithelium

WaterWater specialised channels composed of membrane specialised channels composed of membrane protein aquaporin-1 (apical membrane) protein aquaporin-1 (apical membrane) facilitate water facilitate water movement passively along osmotic gradientsmovement passively along osmotic gradients

Secretion :Secretion :

Cations (Cations ( Creatinine, cimetidine, quinidine,) :Creatinine, cimetidine, quinidine,) : share same share same pump mechanism and interfere in excretion of one anotherpump mechanism and interfere in excretion of one another

Anions includeAnions include Urate, ketoacids, penicillins, Urate, ketoacids, penicillins, cephalosposins, diuretics, salicyclates cephalosposins, diuretics, salicyclates and and most x-ray dyesmost x-ray dyes

FunctionsFunctionsReabsorptionReabsorption NaClNaCl WaterWater BicarbonateBicarbonate GlucoseGlucose ProteinsProteins AminoacidsAminoacids KK++, Mg, PO, Mg, PO44

++, uric acid, , uric acid, ureaurea

SecretionSecretion Organic anionsOrganic anions Organic cationsOrganic cations Ammonia productsAmmonia products

Reabsorption of solutes in PCTReabsorption of solutes in PCT

Proximal Tubule Reabsorption

Early

Late

Na+Na+

K +K +

LumenCapillary

Na+

K+

Pc

Na+Na+

K +K +

Na+

K+

Na+

Na+

Cl-

Cl-

Cl-Cl- & H2O

H2O

H2O

& H2O

Proximal Tubule Reabsorption

PROXIMAL TUBULE SUMMARY

• 2/3 of salts and water reabsorbed •All glucose and a.a. reabsorbed

•Reabsorption is isotonic:PT Osmolality is isotonic

atthe beginning & the end

CONCENTRATION & DILUTION

•permeability aspects of the Loop of Henle, DT & CD.•the importance of the high medullary interstitial osmolality.•the reabsorption of Na+, Cl-, urea and water in the Loop,

DT and CD.•changes in osmolality along the tubule and

actions of ADH on the CD.

Loop of HenleLoop of Henle 25-30% ultrafiltrate reaches loop of Henle25-30% ultrafiltrate reaches loop of Henle

15-20% filtered Na15-20% filtered Na++ load reabsorbed load reabsorbed Solute and water reabsorption is passive and follows Solute and water reabsorption is passive and follows

concentration and osmotic gradients concentration and osmotic gradients (except thick (except thick ascending loop)ascending loop)

Ascending thick segmentAscending thick segment Sodium reabsorption is coupled to both KSodium reabsorption is coupled to both K++ and Cl and Cl--

reabsorptionreabsorption ClCl-- in tubular fluid is rate limiting factor in tubular fluid is rate limiting factor Important site for calcium and magnesium reabsorptionImportant site for calcium and magnesium reabsorption Parathyroid hormone Parathyroid hormone calcium reabsorption at this site calcium reabsorption at this site Loop diuretics inhibit Na and Cl reabsorption in TAL Loop diuretics inhibit Na and Cl reabsorption in TAL

compete with Cl- for its binding site on carrier proteincompete with Cl- for its binding site on carrier protein

Sodium and chloride reabsorption in thick ascending loopSodium and chloride reabsorption in thick ascending loop

Countercurrent exchangeThe structure and

transport properties of the loop of Henle in the nephron create the Countercurrent multiplier effect.

A substance to be exchanged moves across a permeable barrier in the direction from greater to lesser concentration.

Image from http://en.wikipedia.org/wiki/Countercurrent_exchange

Loop of HenleGoal= make isotonic

filtrate into hypertonic urine (don’t waste H20!!)

Counter-current multiplier: Descending loop is

permeable to Na+, Cl-, H20 Ascending loop is

impermeable to H20- active NaCl transport

Creates concentration gradient in interstitium

Urine actually leaves hypotonic but CD takes adv in making hypertonic

Tubular fluid enters the distal PCT iso-osmotic with plasma (300 Tubular fluid enters the distal PCT iso-osmotic with plasma (300 mOsm/kg) mOsm/kg) (1)(1)..

Descending limb of Henle Descending limb of Henle (2)(2) water rapidly diffuses out into the water rapidly diffuses out into the increasingly hypertonic medulla and is removed by the vasa rectaincreasingly hypertonic medulla and is removed by the vasa recta

Tubular fluid becomes hypertonic, largely because of conc. of NaCl.Tubular fluid becomes hypertonic, largely because of conc. of NaCl. Urea diffuses in from the hypertonic interstitium, further increasing Urea diffuses in from the hypertonic interstitium, further increasing

tubular fluid osmolality (1200 mOsm/kg).tubular fluid osmolality (1200 mOsm/kg). Thin ascending loop of Henle Thin ascending loop of Henle (3)(3), NaCl passively diffuses into the , NaCl passively diffuses into the

interstitium along its concentration gradientinterstitium along its concentration gradient But water is trapped in the water-impermeable tubule, which But water is trapped in the water-impermeable tubule, which

progressively decreases tubular fluid osmolality.progressively decreases tubular fluid osmolality. Urea passively diffuses into the tubular fluid (urea recycling).Urea passively diffuses into the tubular fluid (urea recycling). Tubular dilution is accelerated by active reabsorption of NaCl in the Tubular dilution is accelerated by active reabsorption of NaCl in the

thick ascending loop and proximal distal tubule thick ascending loop and proximal distal tubule (4)(4)..

Fluid entering distal tubule is quite hypo-osmotic (100 mOsm/kg)Fluid entering distal tubule is quite hypo-osmotic (100 mOsm/kg) In the collecting segment In the collecting segment (5)(5), the osmolality of the tubular fluid , the osmolality of the tubular fluid

returns to that of plasma (300 mOsm/kg)returns to that of plasma (300 mOsm/kg) But contents of the proximal tubule, the solute component consists But contents of the proximal tubule, the solute component consists

largely of urea, creatinine, and other excreted compounds.largely of urea, creatinine, and other excreted compounds. Increased plasma antidiuretic hormone (ADH) renders the cortical Increased plasma antidiuretic hormone (ADH) renders the cortical

and medullary collecting ducts and medullary collecting ducts (6)(6) permeable to water, which permeable to water, which passively diffuses into the hypertonic medullary interstitium.passively diffuses into the hypertonic medullary interstitium.

Some urea diffuses out into the medulla, the maximal osmolality of Some urea diffuses out into the medulla, the maximal osmolality of concentrated urine concentrated urine (7)(7) approaches that of the hypertonic medullary approaches that of the hypertonic medullary interstitium, about 1200 mOsm/kginterstitium, about 1200 mOsm/kg

In the absence of ADH, the collecting ducts remain impermeable to In the absence of ADH, the collecting ducts remain impermeable to water, and the urine is diluted.water, and the urine is diluted.

Counter current multiplierCounter current multiplier

Counter current exchange by vasa rectaCounter current exchange by vasa recta

Distal tubuleDistal tubule Very tight junctions between tubular cells Very tight junctions between tubular cells

relatively impermeable to water and Narelatively impermeable to water and Na++

5% of filtered Na5% of filtered Na++ load load reabsorbed reabsorbed Major site of parathyroid hormone and vit D Major site of parathyroid hormone and vit D

mediated calcium reabsorptionmediated calcium reabsorption The late distal segment (collecting segment)The late distal segment (collecting segment)

Hormone mediated CaHormone mediated Ca++ reabsorption reabsorption Aldosterone mediated NaAldosterone mediated Na++ reabsorption reabsorption

Collecting tubuleCollecting tubule

5-7% of filtered Na5-7% of filtered Na++ load is reabsorbed load is reabsorbedCortical collecting tubule – two types of Cortical collecting tubule – two types of cells:cells:

Principal cells Principal cells secrete K secrete K++ aldosterone aldosterone mediated Namediated Na++ reabsorption reabsorptionIntercalated cells Intercalated cells acid base regulation acid base regulation

Secretion of hydrogen and reabsorption of bicarbonate Secretion of hydrogen and reabsorption of bicarbonate and potassium in cortical collecting tubuleand potassium in cortical collecting tubule

AldosteroneAldosterone

Enhances NaEnhances Na++ K K++ ATPase activity by ATPase activity by number of open Na number of open Na++ & K& K++ channels in luminal membrane channels in luminal membrane

Enhances HEnhances H++ secreting ATPase on the luminal border od secreting ATPase on the luminal border od intercalated cellsintercalated cells

Because principal cells reabsorb NaBecause principal cells reabsorb Na++ via an electrogenic via an electrogenic pumppump Either ClEither Cl-- must be reabsorbed must be reabsorbed KK++ must be secreted to maintain electroneutrality must be secreted to maintain electroneutrality

intracellular Kintracellular K++ favours K favours K++ secretion secretion

K+ sparing diureticsK+ sparing diuretics

CompetitiveCompetitive Spironolactone – aldosterone receptor antagonistSpironolactone – aldosterone receptor antagonist Inhibits aldosterone mediated sodium reabsorption and Inhibits aldosterone mediated sodium reabsorption and

potassium secretion in collecting tubulepotassium secretion in collecting tubule

Non-competitiveNon-competitive Triamterene and amiloride inhibits sodium reabsorption and Triamterene and amiloride inhibits sodium reabsorption and

potassium secretion by decreasing number of open potassium secretion by decreasing number of open channels in luminal membrane of collecting tubulechannels in luminal membrane of collecting tubule

Medullary collecting tubuleMedullary collecting tubule Site of actiion of ADH or AVP (arginine vasopressin) Site of actiion of ADH or AVP (arginine vasopressin)

activates adenylate cyclase activates adenylate cyclase Dehydration Dehydration ADH secretion ADH secretion luminal membrane luminal membrane

becomes permeable to water becomes permeable to water water is osmotically drawn water is osmotically drawn out of tubular fluid passing through the medulla out of tubular fluid passing through the medulla concentrated urine (upto 1400 mos)concentrated urine (upto 1400 mos)

Adequate hydration – suppressed ADH secretion Adequate hydration – suppressed ADH secretion fluid in fluid in collecting tubule passes through medulla unchanged and collecting tubule passes through medulla unchanged and remains hypotonic (100-200 msom/l)remains hypotonic (100-200 msom/l)

Hydrogen ion secreted are excreted in the form of titrable Hydrogen ion secreted are excreted in the form of titrable acids (phosphates) and ammonium ionsacids (phosphates) and ammonium ions

300

300

300300

300

300

1200 1200 1200

900 900 900

400 400 400500 500 500600 600 600700 700 700800 800 800

1100 1100 11001000 1000 1000

300

300

300300

300

300

1200

Low permeability to solutes

High permeability to water

H2O

H2O

1200 1200 1200

Thin descending limb of the loop of Henle

300

300

300300

300

300

1200

permeable to solutes

H2O

H2OThin ascending limb of the loop of Henle low permeability to H2O

NaClUrea

300

300

300300

300

300

12001200 1200 1200

Na+

K+

2 Cl-

Na+

K+

2 Cl-

150

Thick Ascending limb of the loop of Henle (TAL)Diluting segment

impermeable to H2O

Special carriers co-transport ions from tubule to interstitium

Na+

K+

2 Cl-

Na+

K+

2 Cl-

300

300

300 300

300

12001200 1200 1200

Na+

K+

2 Cl-

Na+

K+

2 Cl-

150Distal Tubule

Na+

K+

2 Cl-

Na+

K+

2 Cl-

Impermeable to H2OSpecial carriers co-transport ions from tubule to interstitium

60Na ClNa Cl

300

300

300 300

300

12001200 1200 1200

Na+

K+

2 Cl-

Na+

K+

2 Cl-

150

Na+

K+

2 Cl-

Na+

K+

2 Cl-

60Na ClNa Cl

Cortical Collecting Duct

120

0

H2O

H2O

H2O

H2O

Medullary Collecting Duct

Variable permeability to H2ORegulated by Antidiuretic Hormone(ADH)

Renal Regulation of Special SubstancesUrea, Glucose, Phosphate, Sulfate, Water, Sodium, Potassium & Calcium

John R. DietzPhysiology & BiophysicsUniversity of South Florida

College of Medicine

Renal Regulation of Special Substances(Urea, Glucose, Phosphate & Sulfate)

•How urea is reabsorbed.•Principles of secondary active transport and how it applies to

carrier mediated secretion and reabsorption.•Transport maximum and how it is calculated.•Renal handling of glucose in diabetes.

Reabsorption of Urea

50% of FilteredUrea Reabsorbed

4

5

30

100

500

60

0

600

Tubular Concentrations of Urea are in mmoles/L

MaximalADH

H2O

H2O

H2O

H2O

Reabsorption of Glucosein the Proximal Tubule

LumenBasal Membrane

Na+

K+

Glucose

Glucose

Na+SGLT1

GLUT2

Glu

Sodium Powered Secondary Active Transport

Na+Na+

LumenCell Membrane

Stanley J. Nazian, Ph..D.,

This slide was stolenwithout remorse from

Na+

Na+

Na+

Na+

Na+

Glu

Reabsorption of Glucosein the Proximal Tubule

LumenCapillary

Na+

K+

Glucose

Glucose

Na+SGLT1

GLUT2

Facilitated DiffusionInterstitium

CellMembrane

Glu

GluGlu

GluGlu

GluGlu

Secondary Active Transport

Henderson-Hasselbalch Equation:

pH = pK + log HCO3-

CO2

pH =

  H+ exchanged for Na+

H+ ATPase

H+ - K+ ATPase

Various Mechanisms of H+ Secretion

H+

H+

H+

H+

H+

H+

H+

H+

H+

CO2 + H2O

H2CO3

HCO3- + H+

HCO3-

Cl-

HCO3-

Na+

Na+

H+

ATPaseH+

C.A.

Blood Cell Lumen

ATPaseH+

K+

Renal Transport of HCO3- & H+

CO2 + H2O

H2CO3

HCO3- + H+

Bicarbonate Reabsorption

C.A.

Filtered

H2CO3

CO2 + H2O

C.A.

Primarily in Proximal Tubule - 0 % of Acid Excretion

Blood Cell Lumen

HCO3-

Na+ Na+HCO3-Na+

H+ H+

CO2 + H2O

H2CO3

HCO3- + H+

Bicarbonate Reabsorption

C.A.

Filtered

H2CO3

CO2 + H2O

C.A.

Primarily in Proximal Tubule - 0 % of Acid Excretion

Blood Cell Lumen

HCO3-

Na+ Na+HCO3-Na+

H+ H+

CO2 + H2O

H2CO3

HCO3- + H+

Titratable Acid Excretion

C.A.Na+

Filtered

H+ + HPO42-

Primarily in Distal Tubule & CD - 33 % of Acid Excretion

Na+ + H2PO4-

or H SO4-

+ HPO42-

or SO42-

H+

Blood Cell Lumen

HCO3-

Cl-

ATPase

CO2 + H2O

H2CO3

HCO3- + H+

Ammonium Excretion

C.A.

H+ + NH3

Primarily in Distal Tubule & CD - 66 % of Acid Excretion

NH4+

H+

NH3 produced in the cortex from glutamine

NH3 NH3

[H+] is 1000 X greater in the lumen than the cell

HCO3-

Cl-

ATPase

H+ Secretion in the Nephron

Factors that Stimulate H+ Secretion

• AcidosisMetabolic or Respiratory

• Hypokalemia• Aldosterone

Regulation of H+ Excretion

CO2 + H2O

H2CO3

HCO3- + H+

HCO3-

Na+

H+

C.A.

Blood Cell Lumen

ATPase

Renal Responses to a Metabolic Acidosis

• Decreased filtered bicarbonate• Increased H+ secretion• Increased NH3 production

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+

H+ H+

Increased Renal Acid Secretion in Acidosis

Hormones Produced by the KidneyRenin:

Released from juxtaglomerular apparatus when low blood flow or low Na+. Renin leads to production of angiotensin II, which in turn ultimately leads to retention of salt and water.

Erythropoietin: Stimulates red blood cell development in bone

marrow. Will increase when blood oxygen low and anemia (low hemoglobin).

Vitamin D3: Enzyme converts Vit D to active form

1,25(OH)2VitD. Involved in calcium homeostasis.

Renin-Angiotensin systemRegulation of Blood Pressure and Sodium Output

The American Heritage® Dictionary of the English Language

Stimulation of Renin Secretion

Blood pressure activates renal vascular receptor (baroreceptor) and renin. Blood pressure also GFR and delivery of Cl- to

Macula Densa in the distal tubule which renin.

Blood pressure causes a reflex activation of renal sympathetic nerves which renin.

JuxtaglomerularApparatus

Renin-Angiotensin-Aldosterone System

Blood Pressure

Renin (Kidney)

Angiotensin I

Angiotensin II

Angiotensinogen (Liver)

Angiotensin Converting Enzyme (ACE)

Aldosterone

Na+ Reabsorption

FF ADH & Thirst (water reabsorption)

Vasoconstriction

Renin, Angiotensin, Aldosterone:

Regulation of Salt/Water Balance

Renin/AII and Regulation of GFRGFR = Kf(PGC - PBS - COPGC)

• “flight or fright”

sympathetic tone

• afferent arteriolar constriction (divert cardiac output to other organs)

PGC

GFR and renal blood flow

Renin/AII and Regulation of GFRGFR = Kf(PGC - PBS - COPGC)

•Low BP sensed in afferent arteriole or low Na in distal tubule

•renin released

•renin converts angiotensinogen to Angiotensin I

•ACE converts AI to AII

•efferent > afferent arteriolar constriction

PGC GFR (this is AUTOREGULATION of GFR)

PGC

constricts

AldosteroneSecreted by the adrenal glands in

response to angiotensin II or high potassium

Acts in distal nephron to increase resorption of Na+ and Cl- and the secretion of K+ and H+

NaCl resorption causes passive retention of H2O

Anti-Diuretic Hormone (ADH)Osmoreceptors in the brain (hypothalamus)

sense Na+ concentration of blood.High Na+ (blood is highly concentrated)

stimulates posterior pituitary to secrete ADH.ADH upregulates water channels on the

collecting ducts of the nephrons in the kidneys.

This leads to increased water resorption and decrease in Na concentration by dilution

Summary of ADH Actions on the Kidneys

• Increases permeability of entire Collecting Duct to Water.• Increases permeability of Medullary CD to Urea.• Decreases Vasa Recta blood flow.• Increases expression of the Na/K/2Cl transporter in the TAL.

RENAL BLOOD FLOW (RBF)

NORMAL = 1200-1300ml/min. (both kidneys) = 20-25% of C. O.

RENAL PLASMA FLOW (RPF) = RBF (1-hematocrit) = 600-700 ml/min. (both kidneys)

FILTRATION FRACTION (FF) = GFR/RPF = 125ml/min/650 ml/min = 20 %

Regulation of Blood Flow (review of CV)Clearance (again?)

John R. Dietz, Ph.D.Molecular Pharmacology & PhysiologyUniversity of South FloridaCollege of Medicine

Distribution of Blood Flow

Cortex - 1000 ml/min (75%)Outer Medulla - 240 ml/min (20%)Inner Medulla - 60 ml/min (5%)

Renal autoregulationRenal autoregulation Enables the kidney to maintain solute and water regulation Enables the kidney to maintain solute and water regulation

independently of fluctuations in arterial blood pressureindependently of fluctuations in arterial blood pressure Kidney maintains a constant renal blood flow and GFR Kidney maintains a constant renal blood flow and GFR

through renal arterial range of 80-180 mmHgthrough renal arterial range of 80-180 mmHg

• Blood Pressure

• Intrinsic: autoregulation

1. Myogenic2. Tubuloglomerular feedback

prostaglandins

• Extrinsic:nerves

hormones

Control of Renal Blood Flow

Afferent and efferent control mechanism (myogenic)Afferent and efferent control mechanism (myogenic)Renal vascular resistanceRenal vascular resistance

Mediated by variable resistance of afferent arteriolesMediated by variable resistance of afferent arterioles

mean arterial pressuremean arterial pressure

renal vascular resistancerenal vascular resistance

(( tone, dilatation of afferent arterioles) tone, dilatation of afferent arterioles)

Myogenic responseMyogenic response

Renal blood flow and GFR maintainedRenal blood flow and GFR maintained

Vice versa, afferent arterioles constrict in response to Vice versa, afferent arterioles constrict in response to MAP MAP

GFP = 60 mmHg (N), i.e. 60% of MAP

Afferent and efferent control mechanism (myogenic)Afferent and efferent control mechanism (myogenic)

Tubuloglomerular feedbackTubuloglomerular feedback

GFRGFR

delivery of NaCl to distal tubuledelivery of NaCl to distal tubule

Cl- sensed by macular Densa cellsCl- sensed by macular Densa cells

Release of renin (from afferent arterioles)Release of renin (from afferent arterioles)

AngiotensinAngiotensin

Arteriolar constrictionArteriolar constriction GFR and RBFGFR and RBF

Normally, a balance is present between systems promoting Normally, a balance is present between systems promoting renal vasoconstriction and sodium retention versus systems renal vasoconstriction and sodium retention versus systems promoting renal vasodilation and sodium excretion.promoting renal vasodilation and sodium excretion.

Surgical stress, ischemia, and sepsis tip the balance in favor of Surgical stress, ischemia, and sepsis tip the balance in favor of vasoconstriction and sodium retention.vasoconstriction and sodium retention.

On the other hand, hypervolemia (or induction of atrial stretch) On the other hand, hypervolemia (or induction of atrial stretch) tips the balance in favor of vasodilation and sodium excretion.tips the balance in favor of vasodilation and sodium excretion.

Hormonal RegulationHormonal Regulation

Epinephrine & norepinephrineEpinephrine & norepinephrine

Afferent arterial tone (directly & preferentially)Afferent arterial tone (directly & preferentially)

Marked Marked in GFR prevented indirectly by release of renin and in GFR prevented indirectly by release of renin and angiotensin-IIangiotensin-II

Renin angiotensin and Atrial natriuretic peptide (ANP)Renin angiotensin and Atrial natriuretic peptide (ANP) Hypotension or hypovolemia Hypotension or hypovolemia renin renin afferent arteriole afferent arteriole

angiotensin II angiotensin II release of aldosterone from the adrenal cortex release of aldosterone from the adrenal cortex Volume reexpansion causes atrial distention Volume reexpansion causes atrial distention release of ANP release of ANP ANP inhibits the release of renin, renin's action on ANP inhibits the release of renin, renin's action on

angiotensinogen to form angiotensin II, angiotensin-induced angiotensinogen to form angiotensin II, angiotensin-induced vasoconstriction, stimulation of aldosterone secretion by vasoconstriction, stimulation of aldosterone secretion by angiotensin II, and action of aldosterone on collecting ductangiotensin II, and action of aldosterone on collecting duct

ProstaglandinsProstaglandins

Systemic hypotension and renal ischemiaSystemic hypotension and renal ischemia

Angiotensin induced prostaglandin synthesis (PGDAngiotensin induced prostaglandin synthesis (PGD22, PGE, PGE22 & PGI & PGI22))

Vasodilation (protective mechanism)Vasodilation (protective mechanism)

Neuronal RegulationSympathetic outflow from spinal cord

Celiac & renal plexus

1 receptors sodium reabsorption in

PCT

2 receptors Na+ reabsorption and

water excretion

Dopamine dilates afferent and Dopamine dilates afferent and efferent arterioles efferent arterioles

(via D1 receptor activation) (via D1 receptor activation)

Low dose dopamine partially Low dose dopamine partially reverses norepinephrine induced reverses norepinephrine induced

renal vasoconstrictionrenal vasoconstriction

Dopamine Dopamine PCT Na PCT Na++ reabsorption reabsorption

Autoregulation impaired inAutoregulation impaired in

Severe sepsisSevere sepsis

ARFARF

During cardiopulmonary bypassDuring cardiopulmonary bypass

Autoregulation is not abolished by most anaesthetic agentsAutoregulation is not abolished by most anaesthetic agents

ReferencesReferences

Miller’s Anaesthesia, 6th ed. Functional anatomy and renal Miller’s Anaesthesia, 6th ed. Functional anatomy and renal physiology.physiology.

Wylie and Churchill Davidson’s. Functional anatomy and renal Wylie and Churchill Davidson’s. Functional anatomy and renal physiology, 7th ed.physiology, 7th ed.

Barash Clinical Anaesthesia, Functional anatomy and renal Barash Clinical Anaesthesia, Functional anatomy and renal physiology, 5th ed.physiology, 5th ed.

Morgan. Clinical Anaesthesiology, 4Morgan. Clinical Anaesthesiology, 4 thth ed. ed.

Ganong WF. Review of Medical Physiology, 20Ganong WF. Review of Medical Physiology, 20 thth ed. ed.