renal physiology - wcvm

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Renal Physiology Job of Kidneys: maintains homeostasis, controls/maintains plasma composition, filtration, water balance, blood pressure maintenance, makes urine, excretion of metabolic wastes/foreign compounds/hormones, metabolism – converts Vit D into active form How is Kidney Disease Diagnosed? Urine sample assessment, blood sample (most important). Need blood sample to look at the composition. What is Urine? Nitrogenous waste, excess ions dissolved in water. What does this? Water in the plasma becomes the water in the urine. What does alcohol have to do with renal physiology? Alcohol is a diuretic - and changes the composition of the urine and plasma. Overall Function of the Kidney: homeostasis (maintaining composition of internal environment - ECF, blood, and plasma). Blood plasma in equilibrium with ECF - so controlling blood composition will control the composition of the ECF. Regulates electrolytes (Na/K, Cl, Ca, Mg, PO4) in blood. Controls release of ions into urine. Proper ECF (ion) helps maintain plasma volume (osmotic pressure). Regulates water balance in the body - through conservation or excretion into the urine. Maintain pH by controlling H + and HCO3 excretion into urine. Diarrhea, acidosis & dehydration: What can the kidneys do about it? Acidosis - losing lots of bicarb. Diarrhea - losing lots of water leads to dehydration. Kidneys can deal with acidosis and dehydration, but not diarrhea. Excrete metabolic waste products - filters the blood. Endogenous substances - (nitrogenous -creatinine, urea, uric acid, ammonia) Bray 1

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Page 1: Renal Physiology - WCVM

Renal Physiology

Job of Kidneys: maintains homeostasis, controls/maintains plasma composition, filtration, water balance, blood pressure maintenance, makes urine, excretion of metabolic wastes/foreign compounds/hormones, metabolism – converts Vit D into active form

How is Kidney Disease Diagnosed? Urine sample assessment, blood sample (most important). Need blood sample to look at the composition.

What is Urine? Nitrogenous waste, excess ions dissolved in water.

What does this? Water in the plasma becomes the water in the urine.

What does alcohol have to do with renal physiology? Alcohol is a diuretic - and changes the composition of the urine and plasma.

Overall Function of the Kidney: homeostasis (maintaining composition of internal environment - ECF, blood, and plasma). Blood plasma in equilibrium with ECF - so controlling blood composition will control the composition of the ECF.

Regulates electrolytes (Na/K, Cl, Ca, Mg, PO4) in blood. Controls release of ions into urine. Proper ECF (ion) helps maintain plasma volume (osmotic pressure).

Regulates water balance in the body - through conservation or excretion into the urine.

Maintain pH by controlling H+ and HCO3 excretion into urine.

Diarrhea, acidosis & dehydration: What can the kidneys do about it?

Acidosis - losing lots of bicarb.

Diarrhea - losing lots of water leads to dehydration.

Kidneys can deal with acidosis and dehydration, but not diarrhea.

Excrete metabolic waste products - filters the blood. Endogenous substances - (nitrogenous -creatinine, urea, uric acid, ammonia)

Excretion of foreign compounds from the body (Exogenous substances such as drugs and chemicals - at least the one that are water soluble - fat soluble substances are another story).

Secretes hormones: erythropoitein and renin.

Metabolic Functions: converts Vit D into active form (calcidiol —> calcitriol).

Renal Anatomy and Histology: Kidneys sit in the mid abdominal region. Left kidney sits a bit more cranially than the right kidney.

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Aorta supplies oxygenated blood. Caudal vena cava removes the filtered blood from the kidneys. Ureter leads down to the bladder. Urethra leads the urine out of the body. Retroperitoneal Structure - means behind the peritoneum (not freely floating in the abdomen -

towards the back near epaxial muscles).

Major Areas of Kidney: Cortex Medulla Capsule - fibrous Renal Fat - diagnostically important for starvation - last fat source to use by the body. Renal Pelvis - collects all the urine - drains down to the ureter. Renal Pyramids - triangle shaped. Renal artery and vein are very large - not minor vasculature. The Nephron

Focus on what goes on functionally/physiologically/metabolically/regulation. Don’t care so much about the structure.

Is the functional unit of the kidney. A kidney has millions of nephrons.

Different species have different numbers and types of nephrons.

Vascular portion - blood supply. Gets 20% of cardiac output (does vary - sympathetic stimulation - vasoconstriction - decreased

cardiac output). Direction of Blood Flow:

o Renal Arteryo Branches to Smaller Arterieso Afferent arteriole - IMPORTANTo Glomerulus – ball of leaky capillaries (filtration). 80% of the blood does not get filtered. o Efferent arterioleo Peritubular Capillaries (AKA Vasa Recta)o Renal Vein

Tubular Portion - urine collection region. Direction of Urine Flow:

o Bowmans Capsule – collect the filtrate from glomeruluso Proximal Tubuleo Loop of Henle (descending/ascending parts).

Thick and Thin Limbs: thick part of ascending limb is very important – has a big impact on water balance.

o Distal Tubuleo Collecting Duct: urine still not finished – still important physiological changes happens here.

Cortical vs. JM Nephrons

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Short Loop – in cortexLong Loop – has glomerulus in cortex region & loop of Henle extends into the medulla (some go into inner medulla some go into outer medulla).

Collecting ducts from ALL nephrons pass through the inner medulla then off to the calyx and renal pelvis.

So then what’s the point of having short loop and long loop nephrons?Long loops allow a big osmotic gradient to be established. Whereas short loop nephrons cannot

establish a large osmotic gradient. Short loop still reaps the benefit of the gradient because their collecting duct passes through the medulla.

Urine Formation:1. Filtration2. Tubular Reabsorption: gets back all the good stuff: potassium, sodium, glucose, etc. 3. Tubular Secretion: takes stuff out of peritubular capillaries.

Glomerulus Filtration

Afferent Arteriole Glomerulus Efferent Arteriole.

Macula Densa cells of the ascending loop of Henle in contact with JG cells in the afferent arteriole.

Afferent Arteriole – is muscular.

3 Parts of Glomerulus:1. Capillaries2. Basement membrane3. Bowman’s Capsule:

a. Podocyte layer (visceral layer)b. Parietal Layer

Endothelium of the capillaries are leaky. Filtrate must pass through the endothelium then basement membrane, and past the podocytes (visceral layer) and into the lumen of bowman’s capsule.

What is filtered out of the glomerulus (into tubule)?o Water (plasma)o Electrolytes (Na, K, Cl, Ca). o Small Proteins (cutoff ~ 70 kDa) anything smaller gets through filtration slits, anything bigger cannot

get through unless there is a kidney dysfunction (CLINICALLY A BIG DEAL). Looking at protein content in the urine has a high diagnostic value).

o Albumin ~69 kDa , urine:plasma ratio <1% - vast majority of albumin does not get filtered (stays in the plasma). During intense exercise some albumin can leak out.

o Hemoglobin ~68 kDa, urine:plasma ration <5% - only filtered if not bound to haptoglobin (when Hb bound to haptoglobin its way to big to get through the filtration slits). Some Hb can be seen with intravascular RBC breakdown. Large amounts of Hb can block the vasculature.

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What is NOT filtered?o Most plasma proteins (albumin,

globulins usually too large to pass through).

o Red/White blood cells and platelets (too large).

o Negatively charged compounds have more difficulty being filtered.

o Because they are repelled by negatively charged proteoglycans on the glomerulus basement membrane.

Filtration Forces

Equation: Net Filtration Pressure (how much overall pressure there is that pushes/pulls on the filtrate) = Capillary blood pressure in glomerulus – Plasma colloid osmotic pressure – Bowmans capsule hydrostatic pressure.

Capillary Blood Pressure (favours filtration)o Pressure “pushing” plasma into bowmans capsule.o High pressure – pushes filtrate into capsuleo Is controlled by the diameter of afferent and efferent arterioles.

o If diameter of afferent arteriole > efferent causes a backlog of blood in the glomerulus that increases capillary blood pressure in glomerulus that favours filtration.

Plasma Colloid Oncotic Pressure (opposes filtration of plasma)o Plasma proteins (albumin and globulins) are too large for filtration they kind of keep

water/plasma around them. o Osmotic force of non-filtered protein “pulls” plasma back into glomerulus from Bowman’s capsule.o Opposes capillary blood pressure.

Bowmans Capsule Hydrostatic Pressure (opposes filtration)o Is the filtrate already in Bowman’s capsule Pushes filtrate out of bowmans capsule, back into the

glomerulus. Until it moves out of the capsule new fluid can’t move in.

Net Filtration should be a positive value (favours the filtration of plasma).

Glomerular Filtration Rate

o Rate of filtrate production in the glomerulus (how much filtrate produced/time). o GFR = net filtration pressure x Kf

o Kf is a somewhat constant value, based on the leakiness of the glomerulus. It changes if mesangial cells contract.

o So increased filtration = Increased GFR

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How much filtrate is produced in your kidneys every day?

No animal can actually urinate 180 L/day – so obviously something is happening to reabsorb the filtrate.

Net Filtration pressure predominantly determines

Control of GFR

Net filtration pressure – osmotic pressure and hydrostatic pressure are NOT easily regulated!May change in some diseases like hypoalbuminea….. etc.

Glomerular capillary B.P. is altered easily by changing diameter of afferent arteriole (most important) also efferent arteriole (but less important).

We will go into depth about afferent arteriole – but not efferent arteriole – just know that efferent arteriole counteracts afferent.

Vasoconstriction of Afferent Arteriole o Decreases amount of plasma going into glomerular, less pressure and less filtration and reduced

GFR.

Vasodilation of Afferent Arterioleo More plasma enters, more capillary blood pressure, more filtration and higher GFR.

Kf (leakiness of capillary). o Determines GFR but not as easily regulated.o Mesangial cell contraction can decrease Kf.

o Sympathetic stimulationo Angiotensin II

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Increased Kf in glomerular disease (eg. Immune mediated glomerulonephritis – bunch of antibodies directed against the basement membrane of the glomerulus – the Ab are deposited in the glomerulus and scar tissue develops and becomes much leaky than it should be – plasma proteins can be filtered (not normal).

1. Autoregulation (Kidney controlling itself)o Kidneys try to maintain constant blood

flow to the glomeruluso Easiest way: change afferent arteriole

diameter.

Myogenic Mechanism – smooth muscle automatically constricts/dilates in response to changes in BP.

o If glomerular BP is high – afferent arteriole constricts and decreases flow to the glomerulus.

o If glomerular BP is low – afferent arteriole dialates and increases flow to glomerulus. o Responds within a few seconds!

Tubuloglomerular Feedback (AKA juxtoglomerular apparatus). o Macula Densa cells in the distal tubule –

detect composition (Na and Cl) of the filtrate and tubular flow rate. Lie right next to the efferent and afferent arteriole. Passes the signal on about what’s going on in the tubules to the afferent arteriole to modify how much filtration is occurring – in time it will alter what happens in the tubular portion of the nephron.

o Can release ATP and adenosine (paracrine).

o JG cells – cause afferent arteriole vasoconstriction/dilation via chemical control.

What if tubular flow/salt is too LOW?

o Low salt detected at Macula Densa cells.o Could indicate decreased GFR or renal flowo Release Less ATP/Adenosine – less stimulation of JG cellso Also release Nitric Oxide (portent vasodilator).o Result = vasodilation of afferent arteriole.

Autoregulation – keeps the renal blood flow fairly constant (even during times of hypotension = high blood pressure). At EXTREMELY high blood pressure autoregulation cannot do much. At EXTREMELY low blood pressure – autoregulation can kind of maintain renal blood flow but eventually it will just drop off. Take Bray 6

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Home: despite what is going on in the body – the body tries to maintain a constant blood flow to the kidneys. Despite big changes in systemic blood flow renal blood flow remains constant.

Question: how can non-steroidal anti-inflammatory (NSAIDs - Aspirin, advil) cause kidney damage?

Cyclooxygenase (COX) enzyme produces prostaglandins which cause aff. arteriolar vasodilation (helps maintain GFR). COX – takes lipids into inflammatory mediators (prostaglandins) is inflammatory – increases blood flow – heat, redness, swelling. NSAIDS block the COX enzymes leads to less prostaglandins.

Basal levels of prostaglandins help maintain vasodilation in the afferent arteriole. If you knock them all out (by taking whopping doses of NSAIDs) then you get less inflammatory mediators and end up with vasoconstriction in the afferent arteriole not as much filtrate is produced (decreased net filtration pressure). Can lead to acute renal failure (especially if dehydrated).

Some NSAIDs cause direct renal papillary necrosis.

Control of GFR Review 1. Autoregulation: myogenic mechanism and the juxtoglomerular apparatus.

2. Extrinsic Nervous Control (sympathetic NS – fight/flight response – a branch of the autonomic NS). a. Causes direct vasoconstriction

i. Renal artery and or afferent arterioleii. Decreased glomerular pressure = decreased GFRiii. Significant effect: renal blood flow up to 90% reduced.

b. Mesangial cells contract = decreases Kf = decreased GFRi. Less SA in the glomerulus – less opportunity for filtration.

ii. GFR = net filtration pressure x Kf if filtration rate goes down so does GFR.iii. Decreased GFR = saves water for plasma (not urine!!!)

- essential for times of decreased b.p. (eg. Hemorrhage). - maintains b.p and water balance.

Sympathetic Stimulation – afferent arteriole constriction – decreases glomerular pressure – decreases GFR – plasma kept in blood. Also causes mesangial cells to contract – lows surface area of plasma w/ filtration slits – decreases Kf – decreases GFR.

Extrinsic Neural Control of GFRWhich adrenergic receptors cause an increased cardiac output – 1

receptors on the heart = increases contractility increases SV increases HR.

Which adrenergic receptors cause vasoconstriction? 1 receptors.

BIG PICTURE: Sympathetic NS – tries to conserve fluid in the body – does this by decreasing GFR.

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Regulation of Podocyte Contraction?

Sympathetic NS causes the podocytes to contract – reduces the amount of filtration to save fluid.

Reno-Renal Reflex

Reflex response of a kidney to events occurring in same (ipsilateral) or opposite kidney (contralateral).

Requires an afferent signal (eg. Renal tubular pressure – build-up of filtrate/urine in tubule, or chemoreceptors) from one kidney can alter efferent sympathetic tone at the same kidney or the other kidney.

Eg. Left ureter blockage – black flow of filtrate back up the ureter into renal pelvis and eventually into the tubules. This would increase the tubular pressure and will inhibit sympathetic activity to the right kidney. In the right kidney the afferent arteriole would vasodilate and would increase GFR and diuresis.

Understand that the two kidneys can work in concert.

Tubular Reabsorption

Substances in the tubule came from the blood – then they are absorbed back into the blood stream.

Question: If human kidneys produce 180L of filtrate every day, why don’t we produce that much urine every day? Avg person plasma vol. (10% of the time) is only 2-4 L.

Answer: fluid and solutes are reabsorbed from the tubular portion of the nephron. Body conserves valuable material not lose them in the urine. Have an important role in water balance. 180 L, 99% reabsorbed 1.5 L urine produced

Substance % Filtered that is normally reabsorbed into the blood

% filtered that is normally excreted in the urine

Water 99 1Sodium 99.5 0.5Glucose/AA 100 0Bicarbonate Variable VariableUrea ~50 ~50Waste Product 0 100

Don’t excrete glc/AA very wasteful. Bicarbonate variable between the acid/base balance of the body. Only half the urea is excreted why doesn’t the body just excrete it all. Water/solutes absorbed in different amounts at each region of the nephron.

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Most solutes (~99%) pass through tubule cells due to tight junctions b/w cells (transcellular). Water can sometimes pass b/w cells (paracellular) – through “leaky” junctions in some regions.

Passive simple diffusion o No energy required, substances pass through membrane (if lipophilic) or through a

transmembrane protein channel (hydrophilic) – rate of diffusion increases w/ concentration gradient and there is NO saturation.

Facilitated diffusion (passive).o Substance binds to carrier protein on membrane and changes conformation which

translocates the substance to the other side of the membrane – can become saturatedo Ions/charged molecules don’t get through the cell membranes easily. o Simple diffusion: linear increase in rate with increase in electrochemical gradient.

The higher the concentration gradient the rate of transport gets fastero Facilitated diffusion: requires specific carriers – can be saturated.

Rapid at low concentrations but at high concentrations the graph plateaus. Primary Active Transport

o Movement of substance against electrochemical gradient requires energy. ATPase pumps may be located on apical or basalateral surface of tubular cells.

Secondary Active Transport o Substance does not directly require ATP for transport. It can co-transport w/ another

molecule that itself will require an active process elsewhere. o Saturable

Pinocytosis (eg. Peptides) – for large substances

Active Transport: Sodium is the primary driver (at the basolateral surface!!)

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By pumping the sodium out (via Na/K ATPase) creates a concentration gradient that allows sodium to get into the tubular cell via a channel (diffusion) or an antiporter (Na in / H out) or a sodium cotransporter with another molecule (glc, AA, phosphate).

Reabsorption in the Proximal Tubule

Most filtered sodium (2/3) is reabsorbed here – fairly constant! (so not a major site of regulation – but can be regulated a little bit with angiotensin II and sympathetic neurons that try to increase blood volume and blood pressure).

Na+ cotransport (secondary active transport)o Glucose (SGLT), A.A, phosphate.

Passive Reabsorption (still Na+ dependent)o Chloride (electrical gradient), o Water – follows chloride!o K+ and Urea – follows water/Cl- (osmotic pull AKA solvent drag – depends on flow rates).

Calcium and phosphorus – depends on filtrate concentration and PTH. HCO3- is “absorbed” in proximal tubule

o When H+ ions secreted into lumen during acidosis. Ketone Bodies

o Mediated by a transporter mechanism?o Ketone reabsorption is saturated at high concentrations.o Waste products (e.g. creatinine) are not reabsorbed... except urea.

Big Picture: Not all getting reabsorbed at the same degree relative to water.

Flat Line 1.0 – ratio of tubular fluid to plasma. Sodium, osmolality – as sodium gets reabsorbed, water gets reabsorbed. AA/glc – getting almost completely reabsorbed – ratio is 0 because there is no AA/glc at the end of the proximal tubules.

Na+ reabsorption after Proximal Tubule Lesser amounts of sodium reabsorbed in the:

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Ascending Loop of Henle (~25%) – dependant on hormones Distal tubule (missing a bit from this sentence).

Maximum Tubular Transport Limited # of solute transporters in tubule. If tubular [solute] > transport capacity.

o Not all solute can be reabsorbed from the tubule!o Lost in urine: Volunteer Example – showing saturation of transporters at the proximal tubule.

Once saturated the substance cannot be reabsorbed (Stays in the tubule & excreted in the urine).

T = rate of tubular transport Tm = max amount of solute reabsorbed from tubule.

o Varies by individual nephron.o Some hormonal control (eg. PTH & phosphate).

PTH – has an effect on kidney – increases calcium reabsorbed and decreases phosphorus reabsorption. Tm for phosphorus goes down (kidney cannot reabsorb as much – more phos excreted in the urine).

Filtrate solute load = plasma [solute] x GFRo If plasma contains solute (glc) then the plasma [ ] of glc multiplied by GFR gives you a solute load

in the tube. (how many mg/min are transporters exposed to). Renal Threshold = max plasma [solute] producing filtrate that can still be completely reabsorbed. Eg.

Diabetes mellitus

Normal PatientPlasma glc [ ] x GFR GFR 125 ml/min5 mmol/L x (0.125 L/min)filtered load = 0.625 mmol/min (what the transporters are exposed to) – filtered load not close to Tm.

Tm = ~1.75 mmol/min (max [ ] of solute reabsorbed from tubule back into blood stream).

Diabetic PatientPlasma glc [ ] x GFR GFR 125 ml/min15 mmol/L x (0.125 L/min)filtered load = 1.87 mmol/min (what the transporters are exposed to)

A little extra bit of glc that will be excreted in the urine!

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Reabsorption in the Loop of Henle Water reabsorbed in the descending loop

¼ of the total filtered Na+ load reabsorbed in the thick ascending loop.

o Different transporter: Na+, K+, 2Cl- symporter for reabsorption

o Na transport here creates osmotic gradient in the medulla (facilitates urine concentration).

Why is the symporter clinically relevant? Diuretics – inhibits the symporter in the thick ascending limb of

the loop of henle. Sodium becomes stuck in the tubule lumen (if sodium stays, water stays too).

Na + reabsorption in the distal nephron (AKA collecting duct) 65% in proximal tubule 25% ascending loop of Henle 10% left for the distal nephron

Collecting duct: primary site of regulation of Na+ balance – under hormonal control.

Aldosterone Steroid hormone secreted from zona glomerulosa of adrenal

cortex. Lipid like – transports right across the cell membrane – into

nucleus and binds to transcription factors. Causes Na+ reabsorption in distal nephron (principal cells in

the collecting duct) – increases the gene expression of Na channels, Na/K pumps.

Released through RAAS, when blood pressure is too low (hypotension) – increases Na+ reabsorption will increase blood pressure

Reabsorption of sodium from the distal nephron can result in K excretion (may lead to hypokalemia).

RAAS System

Granular cells around the renal arterioles secrete the hormone renin in response to: ↓afferent arteriole blood pressure (i.e.,↓renal perfusion) ↓ systemic blood pressure (detected by arterial baroreceptors, results in catecholamine release,

activates β1 receptors on granular cells) ↓NaCl / ECF volume at the macula densa cells (tubular!) stimulates renin release from granular

cells. This effect is different from (but synergistic with) tubuloglomerular feedback (local control of glomerular / tubular flow rates). Note that other tissues can produce renin too, but the kidney is the 1° source.

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Renin activates angiotensinogen (precursor hormone produced by the liver) into angiotensin I (AT1). AT1 is converted to angiotensin II (AT2) by angiotensin-converting enzyme (ACE) produced primarily (though not exclusively) in the lungs.

AT2 has many different effects in the body: Stimulates secretion of aldosterone from the adrenal cortex, which stimulates Na+ reabsorption in

the distal nephron. Direct arteriolar vasoconstriction ↑ thirst and fluid intake Stimulation of ADH release Mesangial cell contraction? ↑ Na+ & Cl- reabsorption from the proximal tubule? ↑ norepinephrine release from sympathetic neurons to kidney?

RAAS: Liver secretes Angiotensinogen. Kidney responds to decreased NaCl, ECF volume and blood pressure to secrete Renin. Renin cleaves angiotensinogen angiotensin I Angiotensin I cleaved to Angiotensin II by ACE protein. Angiotensin II – stimulates ADH production – stimulates thirst & increases fluid intake & goes to

adrenal cortex and stimulates aldosterone release. Also, stimulates vasopressin release – increase H2O reabsorption by kidney tubules & vasoconstriction (both increase BP). Also, acts on mesangial cells – causes contraction (decreases Kf) – directly causes renal Na+ & Cl- reabsorption & increases norepinephrine from sympathetic nervous system.

Aldosterone goes to the kidney and stimulates more Na reabsorption (Cl- follows passively) – conservesty NaCl that osmotically holds H2O in the ECF (H2O conserved) increases BP, ECF volume & NaCl.

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Clinical Implications: When an animal has high blood pressure or during heart failure.

ACE inhibitors: Enalapril, Benazepril, Imidapril

Angiotensin receptor blockers – blocks the AT1 receptor (angiotensin II) – results in natriuresis (sodium in urine) and less vasoconstriction (so has vasodilation) – less sodium reabsorption (natriuresis – sodium excreted in the urine).

Aldosterone receptor antagonist: Spironolactone – acts on aldosterone receptors. Even if body is releasing aldosterone it won’t have much of an effect because the receptors are blocked. Less sodium reabsorbed in the collecting duct – excreted in the urine (and H2O will follow). Does NOT mess with potassium balance.

Natriuretic Peptides – Natriuretic = sodium in urine = decreases blood pressure. ANP – atrial natriuretic peptide BNP – brain natriuretic peptide – also released from ventricles Released when arterial blood pressure is too high (too much Na and H2O).

o NP stored in granules in cardiac muscle cells.o Released when cardiomyocytes stretched by expanded plasma volume.

Natriuresis:o Direct inhibition of sodium reabsorption from the distal nephron (blocks transporters)o Decreased renin and aldosterone release = more sodium lost in the urine.

Diuresis:o Is a result of natriuresiso Inhibits ADH releaseo Glomerular Effects:

Dilate afferent arteriole, constrict efferent arteriole: Increased net filtration pressure Increased glomerular capillary blood pressure Increased GFR and urine production

Relax glomerular mesangial cells Increases Kf = Increased GFR

Natriuresis & diuresis indirectly decreases blood pressure (VERY POWERFUL). Direct Hypotensive Effects:

o Inhibit sympathetic activity to the heart (decreased cardiac output & stroke volume).o Decreases vascular resistance (decreased arteriole sympathetic tone)

BIG PICTURE: Natriuretic Peptides net effect = Antagonizes RAASPressure Diuresis

Chronically high blood pressure (high in afferent and efferent arteriole and the peritubular capillary) Peritubular capillary BP is high (even after filtration).

o Increased peritubular pressure limits water and solute reabsorption into the blood. o Eventual leak back into tubule and then excreted. o But not important in maintaining ECF volume in

the body.

Tubular Secretion Bray

Filtration – super importantReabsorption – super importantSecretion – not that important – understand the basics. 14

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Some waste products cannot be filtered at the glomerulus: Too large to pass through filtration slits Bound to proteins that are too large Negative charged, so repelled by negative charge on basement membrane

How to remove them? Secrete them into the tubule (After the glomerulus) from the peritubular capillaries.

Examples:

1) Hydrogen Ions (H+) Secreted along most of nephron

o Proximal tubule: Na+/H+ antiportero Distal tubule/Collecting duct: K+/H+ antiporter (reabsorbed K+ and secretes H+)

Solves the acidosis Useful in acidosis – to rid of hydrogen ions

2) Potassium (K+) Reabsorbed in proximal tubule automatically Variable reabsorption/secretion in distal nephron:

o Decreased BP: RAAS activation Aldosterone release to conserve Na+

K+ accidentally lost (hypokalemia) Acidosis

o In intercalated cells of the collecting duct. o Switch H+ instead of K+ in Na+/K+ pump more H+ secreted into the urineo Accidental K+ retention (hyperkalemia)

Tubular secretion/reabsorption play a big part in potassium and sodium balance!

Secretion of other drugs/toxins/metabolites: Varying degrees of transporter-substrate specificity Transporters include P-glycoprotein, Organic anion transporters are efficient at secreting foreign

compounds into the urine. Renal secretion after hepatic metabolism

o Phase I reactions in livero Phase II reactions – conjugation reactions

Hydroxylation, glucuronidation, acetylation, etc to make drugs hydrophilic (allows urinary excretion).

Inhibition of transporters: probenecido Blocks the transporters that secrete penicillin into urine. o Usually penicillin extracted and secreted from the tubule into the urine. o Keeps plasma [ ] of penicillin higher and for a lot longer – increase ½ life of penicillin.

Renal Clearance Tells us the overall effectiveness of the kidney. Bray 15

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Measure of how much PLASMA volume is cleaned/cleared of a certain solute over time.

o Measured as flow (mL/min) – can standardize to their body weight (mL/min/kg)o Not the amount of solute removed by the kidneyo Not the concentration of solute in urine.

Clearance measure the effect of urine excretion on the remaining plasma. Plasma entering the kidneys contains a certain concentration of waste products. Plasma leaving the

kidneys will contain a lower concentration of waste products, because some of the waste was filtered or secreted into the tubule and finally excreted in the urine.But how much waste was actually removed (cleared) by the kidneys?

Clearance= [solute∈urine ]∗urine flow rate / [solute∈ plasma ]

Example 1

Substance A is filtered at the glomerulus but not secreted/reabsorbed.

- renal clearance = GFR how does this happen?- GFR = 125 ml/min in a human- No reabsorption/secretion occurs- 99% of filtrate (water) is reabsorbed, but none of substance

A.- 125 ml/min x 0.99 of plasma is cleared of substance.

Examples: Inulin (fructose derived, gold standard) Creatinine (endogenously produced)

o Easy to access (may be inaccurate)o Overestimates GFR in humanso Underestimates GFR in small animalso Exogenous creatinine administration?

Iohexos Cr-EDTA others

Example 2

Substance B is filtered at the glomerulus and reabsorbed but not secreted.

- Renal clearance < GFR- Example: glucose- GFR = 125 mL/min- All glc reabsorbed in the tubules, along with 99% of the filtrate- No plasma leaving kidneys was cleared of glc.

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Example 3

Substance C is filtered at the glomerulus and secreted, but not reabsorbed

- Renal clearance > GFR- Example: para-amino-hppuric (PAH) acid (gets

completely secreted in 1 pass through the kidney), H+

- GFR = 125 mL/min- No solute is reabsorbed from tubules, so 99% of

reabsorbed filtrate is cleared of solute (125 mL/min)- Plasma in peritubular capillaries is also cleared of solute

as it is secreted into tubule. - Total Clearance = GFR + secretion

So why care about renal clearance?

Monitor renal blood flow and GFRo Progression of renal failure or vascular disease.

Drug dosing determined by clearance

Concentrating Urine

- Small volume of dark urine vs large volume of clear urine – how does this happen?- Variable reabsorption of water/ions from filtrate.

- Benefit of varying urine concentration:- Allows mammals to live in wide variety of habitats and environmental conditions.

Animals in marine environment – no fresh water to access. Animals in fresh water environment – lots of fresh water to access Animals that live in deserts – NO fresh water to access – have specialized kidneys for

these unique situation. - Water reabsorption is “passive” (OR secondary active – active sodium pumping to develop gradient)

- Depends on the osmolarity of surround ECF - Water reabsorption in the kidney depends on the osmolarity of tissue surrounding the renal tubule (the interstitial fluid, or ISF).

- Osmotic gradient in the ECF of kidney Cortex is isotonic (300 mOsm/L) – similar to plasma Medulla progressively more hypertonic (1,200 mOsm/L in humans) – requires energy

to maintain [ ] gradient.

Loop of Henle- Descending L of H dips into hypertonic medulla

o There the osmolarity of the ECF surrounding the tubule is much higher than the filtrate in the tubule. Water osmotically pulled from tubule into the peritubular capillaries

o Urine left in tubule is more concentrate. - Ascending L of H returns to isotonic cortex

o Urine becomes hypotonic- Seems pointless – what is the benefit of this counter current flow through the L of H?

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Benefit of Counter-Current Multiplier- Establishes osmotic gradient in the medulla

o Osmotic gradient allows collecting duct to produce hypertonic concentrated urine- BUT: also allows production of hypotonic dilute urine

o Body can excrete excess water while maintaining solutes in the body.

Osmotic Gradient in Kidney – How does it happen?- Established by:

o Selective water permeability in tubuleo Selective ion transport in tubule

- But not selectively in proximal tubuleo Na actively reabsorbed (non-selective), water passively follows (non-selective) – 65% of total.o Remaining urine still isotonic (300 mOsm/L).

- Descending L of Ho Water leaves the tubule (because surrounding ECF is hypertonic), Na remains in tubule

Filtrate(urine) becomes more concentrated- Ascending L of H

o Sodium actively pumped out of tubule About 25% of total sodium reabsorption.

o Impermeable to water (stays in tubule)o Filtrate becomes hypotonic (100 mOsm/L)

Initial scene – everything is at 300 mOsm

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1. Sodium/Chloride moving out of tubule into interstitial fluid – decreases osmolarity in the ascending LOH and increases the osmolarity of the interstitial fluid. Water is pulled into the interstitial fluid & makes the descending LOH equilibriate with the interstitial fluid.

2. Stuff in ascending limb moves up and the stuff in the descending limb moves down into the turn. 3. Pumps keep pumping & maintain the gradient– NaCl moves into interstitium and decreases the

osmolarity of the ascending loop again. Water follows. 4. More filtrate added and the fluid moves through the tube. 5. Pumps keep pumping – leads to a hyperosmotic medulla! The longer the loop the bigger the

gradient. 6. Huge gradient is made – in cortex 300 mOsm – at bottom of the LOH – 1200 mOsm.

KEY THING: active sodium transport on ascending limb and passive water transport on the descending limb.

- Distal Nephrono Distal tubule & collecting duct are usually NOT permeable to water (absence of hormones).o Filtrate (urine) entering the distal nephron will be hypotonic (~100 mOsm/L)o 80% of original filtrate (180 L/day) reabsorbed before reaching the distal nephron

65% in proximal tubule (~120 L/day) 15% descending LOH (~25L/day) 20% remains (~36L/day)

How to reabsorb the rest of the water:- Make collecting duct permeable to water!- Requires vasopressing (AKA ADH or Argening

Vasopressin)o Binds to V2 receptor on collecting duct

principal cells. o 2nd messenger pathway - stimulates

vesicles to unload aquaporins (water channels) into/expressed onto the apical membrane - allows water to enter the principal cell through the apical membrane. Water leaves the principal cell via different aquaporins (ADH-independent) on the basolateral membrane, and then enters the peritubular capillary.

- Water pulled out of collecting duct (through AQP) due to osmotic gradient in medullao Remaining filtrate (urine more concentrated)

- Collecting duct is site of water regulation in the nephron proximal tubule and LOH not regulated for water reabsorption.

o Small gradient – not able to reabsorb lots of water.

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ADH/Vasopressin- Controlled by:

o Hypothalamic osmoreceptors that detect blood osmolality (not protected by blood brain barrier) – detect the “saltiness” of the plasma

o Baroreceptors (mediated by vasomotor centre) aortic arch & carotid sinus bodies.

o Angiotensin II- When is it released?

o Increased ADH if: Increased plasma osmolality and decreased BP.

A) Dilute plasma – ADH release is low.B) Once plasma osmolality increases – especially when hyperosmotic (300 mOsm) - detected by

osmoreceptors and causes ADH release from posterior pituitary. OR Hypovolemic – drop in blood pressure – want to conserve as much fluid as possible – ADH release spikes as BP drops.

C) If both plasma osmolality increases and blood pressure decreases – there is a MASSIVE spike in ADH release. - Other physiological states when urination not ideal? – eg. Sleeping.

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o Decreased ADH if: decrease in plasma osmolality & increased BP “dilute blood”o Certain chemicals – caffeine/alcohol

How does caffeine/alcohol inhibit ADH release?- Release of ADH from isolated neuro-hypophyses was reduced by ethanol. - Reduction in calcium conductivity of these membranes – calcium influx causes neurotransmitter

release (like ADH released from the hypothalamic neuron that goes into the blood stream – neurocrine).

ADH disorders

Deficiency of ADH = diabetes insipidus.- Is a lack of ADH or a lack of ADH function.- Central vs nephrogenic?

o Central – lack of production/release of ADH. o Nephrogenic – kidneys do not respond to ADH.

- Clinical signs: o Lots of peeing and lots of drinking (PUPD – polyuria & polydypsic). Glc in urine causes

polyuria. - Diagnosis:

o Urine specific gravity – low even if animal is dehydrated – animal produces lots of dilute urine. If you restrict water intake – then the kidneys should concentrate urine more and more – but with diabetes insipidus it doesn’t.

o Response to desmopressin (synthetic ADH) – start concentrating their urine – then this means they can’t produce ADH on their own – means its central.

- Treatment:o Central – supplement ADH. o Nothing – if dog is out on farm and has access to fresh water all the time. o Nephrogenic – still provide exogenous ADH – may increase urine concentration a little bit –

but more difficult to deal with and might not have much of an effect.

Urine Concentration in Humans - Hypotonic dilute urine (without ADH present).

o 100 mOsm/L – lower than the osmolality of plasma – necessary when body wants to eliminate excess water but not excess solutes. Greater urine volume produced in this situation.

- Hypertonic Urineo Concentrated up to ~1200 mOsm/L – 4x the plasma/ECF concentration – equivalent to urine

specific gravity of 1.033 (around the maximum end – when urine is very concentrated/dark).o Maximal ADH response – if body is dehydrated, need to conserve water – smaller volume of

urine is produced as a result.

Urine Concentrations in Mammals

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Pig & Beaver are species with a low maximum urinary osmolality – have a low medullary depth – meaning the medulla is not much bigger than the cortex.

Kangaroo rat is a species that produces extremely concentrated urine – has a high medullary depth – meaning the medulla is large compared to the cortex.

There is a strong relationship between the size of the medulla and the physiological result of urine concentration. In all species, the cortex osmolality is the same ~300 mOsm/L and there is a large variation in maximum medullary osmolarity.

Why is it so different among species?- Increased urine concentration is possible when larger osmotic gradient in medulla.

o If the medulla can reach 3000 mOsm/L – then the urine can become more concentrated.- But why do some species have a greater osmotic gradient?

o Species that have a larger medulla have longer Loops of Henle – the more that sodium/chloride can be pumped out of the thick ascending loop to establish the gradient.

o Longer loops of henle – more juxtamedullary nephrons Greater counter current multiplier effect as sodium pumped out of ascending loop Larger medulla:cortex ratio.

What about marine mammals?- No access to fresh water. - Drink sea water salinity = >1000 mOsm/L- Have special salt-secreting glands like marine birds/reptiles – but marine mammals do not have

these glands. - Most of the marine mammals have large medullary depth & long LOH – they can concentrate their

urine to a level greater than the osmolarity of seawater.- SO how do they get fresh water?

o Drink sea water – concentrate urine very effectively – excrete urine that has very high salt values – may allow them to absorb a little bit of fresh water without sodium. NOT actually done.

o Most of them produce “metabolic” water from byproducts of metabolism.

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o Fresh H20 in food.o Kidneys conserve water.

Urea Reabsorption & Recycling- Protein breakdown produces highly toxic ammonia (NH3)

o NH3 converted to less toxic form – urea – in the livero Urea is primary waste product excreted in urine.

- Only 50% of filtered urea is excreted:o Some reabsorbed from the proximal tubule

Follows water (which follows Na) Dependent on tubular flow rates

o If tubular flow rates are slower than more urea is reabsorbed? - Urea also recycled from the collecting duct:

o Reasorbed urea enters ECT into the LOH. o Urea recycling occurs only if ADH released – UT1 is ADH dependent (ADH released during

high plasma osmolality – wants to conserve water)

Max ADH response = Max water reabsorption – Urea transported out of tubule into interstitial fluid and goes through a different transporter and makes its way back into the LOH. The pink lines lining the tubule are indicative of areas where urea cannot be transported across the membrane.

Benefit of Urea Recycling- Osmotic urea makes medulla even more hypertonic. - Less osmotically active urea stuck in the tubule (collecting duct)- So, move urea out of tubule – water follows

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o Result = Increased H2O reabsorption, decreased volume of urine being produced = more concentrated urine.

Peritubular Capillary Blood Flow- Another example of counter-current flow – countercurrent “exchanger” – because it exchanges

solutes/water from the ECF into the vasculature. - Blood flows down into medulla, then flows back up towards the cortex.

Neat: High protein diet leads to more urea production & may lead to a better ability to concentrate urine.

Vasa Recta Blood Flow- Plasma equilibrates with hypertonic

ECF in medulla - solute gain, water loss.

- Plasma becomes also isotonic again in cortex – solute loss, water gain.

- Leaving nephron – plasma has regained almost all solutes & water that were filtered – BUT without disturbing the medullary ECF osmotic gradient.

- When the peritubular capillaries leave the nephron the plasma has gainged back amost all solutes/water that were originally lost in the tubule to filtration. But the medullary gradient has not been disturbed.

Unidirectional flow = medullary washoutMedullary washout:

Blood is isotonic (but hypotonic relative to the medulla) and moves into a hypertonic medulla blood would equilibrate with ECF in medulla thus removing extra solutes (salt) from the ECF when the blood leaves the medulla Thus removing osmotic gradient now urine cannot be concentrated.

If vasa recta blood flow is too fast: Less time for blood/ECF equilibration on

way back to cortex. Solutes stay in blood, leads to medullary

washout. Probably the only hypothetical issue.

Blood pressure in vasa recta is quite low & rate of blood flow is quite slow. Medullary washout doesn’t happen because there is a lot of time for equilibration.

Urine Composition Highly variable – depends on the animals physiological state/condition Yellow colour is due to urobilin

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o Bilirubin – by product of hemoglobin breakdown absorbed in intestine and incorporates into the bile Biliary secretion- converted to urobilinogen in colon GI Reabsorbed in later GI tract, oxidized to urobilin.

Red:o RBCS (hematuria) – cloudier and more turbid looking – settles when centrifuged.o Hemoglobin (hemoglobin urea) – does not settle out when centrifuged. o Myoglobin – does not settle out when centrifuged.

Odour due to components/chemicals – are species differences – can be due to concentration. Mucous (in feline urinary tract disease), RBC, WBC occasionally seen during UTIs Should be sterile (no microbes) – depends on the collection method

o Free catch urine samples – may not be sterile (does not always mean there is a UTI – the bacteria may come from the end of the urethra).

o Cystocentesis – most reliable way to see if urine is sterile. Proteinuria – may indicate glomerular or tubular damage

o Tubular damage leading to increased filtration or decreased tubular reabsorption of protein.o Drugs, toxins, infections, ischemia, etc. o Urine protein : Creatine ratio – small amounts of protein not really a big issue (eg. post

exercise) Crystalluria

o Detected in urine from many specieso Phosphate/struvite, calcium oxalate, urate, etc. o Minerals normally soluble in urine (excreted), but precipitate out if the saturation point is

exceeded. o How is urine saturation point reached?

Increased urinary [ ] of minerals Hormonal changes altering renal reabsorption of the minerals Solubility of mineral changes because pH of urine changes.

Urine pH changes will alter the solubility of minerals Urine pH influenced by diets (urinary diets) or UTIs

Precipitated minerals form kidney/bladder stones (Chronic problem) Removal by surgery Flush them out

Kidneys and Acid Base Balance

Urine pHSpecies Differences- Typically acidic – carnivores and omnivores – trying to excrete more acid- Typically alkaline – herbivores (cattle)

Metabolic Compensation:- Kidney is 3rd and last line of defence against acid-base disturbances.

o 1st = chemical bufferso 2nd = resp. compensation

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- Chemical buffers and respiratory compensation do not solve the problem. Kidneys take longer to kick in but they solve the problem by removing the excess acid and excess base and excretes them into the urine.

o Kidney is slowest to make pH corrections, but most potent Can completely correct acid-base disturbances Does not overcompensate

- Acidosis – kidney wants to excrete H+ and retain HCO3.- Alkalosis – kidney wants to retain H+ and excrete HCO3.

ACIDOSIS: H+ excretion- Small amount of H+ in tubule from filtration. - Secreted from peritubular capillary into tubule

o Proximal tubule: H+ ATPase pump, Na+/H+ antiporter In both cases protons leave tubule and enter the filtrate.

o Distal Tubule/Collecting duct (intercalated A cell): H+ ATPase pump, K+/H+ antiporterACIDOSIS: HCO3 reabsorption

- HCO3 filtered at glomerulus, trapped in tubule- Not directly reabsorbed

o Joins H+ (carbonic anhydrase) to reform CO2 & H2O CO2 & H2O diffuse into tubular cell CA in cell reforms H+ and HCO3 New HCO3 transferred to blood (Cl- exchange)

- >90% reabsorbed in proximal tubule, remainder in rest of nephron.

ALKALOSIS: Decreased H+ excretion, Increased HCO3 excretion- Filtered HCO3 not enough H+ in urine to form H2CO3

o Therefore, it cannot be reabsorbed, trapped in urine (above figure cannot happen). - Type B intercalated cell:

o Carbonic Anhydrase in cell forms H+ & HCO3 “New” H+ pumped into the blood (H+ ATPase, K+/H+ exchanger) HCO3 secreted into tubule/urine in exchange for chloride.

Limited capacity for direct H+ secretion during acidosis into urine from tubular cells (urine) because the urinary pH cannot drop to less than 4.5 in most mammals.

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- Well then how do you get rid of extra H+ ions?o Increase urine flow rate - not the best option. o Buffers in urine soak up excess H+, so that more H+ can be secreted by tubule cells (increases

the capacity of the urine to take up more hydrogen ions).

Urinary Buffers

Phosphate Buffer System- Phosphate (H2PO4) in urine is the first buffer. - When phosphate is used up, ammonia can accept H+. - Hydrogen ions go into the urine and bicarbonate goes back into the capillaries to prevent acidosis.

Ammonia Buffer System:

Proximal Tubule:- Glutaminase (prox tubule) splits glutamine (A.A) into NH3 and glutamate- Glutamate dehydrogenase splits glutamate into NH4+ and alpha-ketoglutarate- Alpha-ketoglutarate metabolism will use up excess H+ and results in ammonia production which can

act as a buffer. - Alpha ketoglutarate:

o can be oxidized in the TCA cycle to produce energy.o used as a substrate in gluconeogenesis glucose.

Both of the above pathways (TCA/gluconeogenesis) use up H+ and help to solve the acidosis.

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Breaking up glutamine directly uses up hydrogen ions to solve acidosis and produces more ammonia to help buffer

Collecting Duct:- NH3 uncharged so it diffuses/secreted into the tubular lumen- If ammonia is in the lumen w/ acidic urine, then binds with H+ to form NH4+

o Now trapped in the urine (tubular lumen) because it is a charged molecule.

Ammonia production is upregulated during severe/chronic acidosis – increases capacity for urinary H+ excretion. Allows the kidney to keep excreting the H+ to deal with the acidosis.

So, who is better at fixing acidosis and potassium disturbances – the kidney or the veterinarian?- The dumbest kidney is still smarter than the smartest veterinarian. We think we are doing good

with fluid infusion, alkalotic solutions but the kidney is the best at its job. - All we must do is make sure the animal is hydrated then let the kidney do its job.

Acid-Base Problems

Classifying clinical acid-base conditions:- 1st: Look at the overall blood pH – is it acidosis or alkalosis?- 2nd: Is it the bicarb (metabolic) or the PCO2 (respiratory) which is the primary problem? - 3rd: Is the other system compensating for the acid-base problem.

Q1. Dog is vomiting off and on for 2 days.- Blood pH = 7.53 Alkalotic Normal = 7.4- pCO2 = 46 mmHg High-end of Normal Normal = 40 mmHg- HCO3-= 37 mEq/L High Normal = 24 mEq/L

A: Compensated Metabolic Alkalosis (compensation through lungs)

Q2. Arterial blood sample from anesthetised horse. - Caused by depression of respiratory centre in the brain.

- Blood pH = 7.20 Acidosis- PCO2 = 67 mmHg High contributes to acidosis- HCO3- = 26 mEq/L

A: Respiratory acidosis, no (significant) metabolic compensation.

Q3. Scouring Calf- Blood pH = 7.16 Acidosis- PCO2 = 29 mmHg Low trying to solve- HCO3- = 11 mEq/L Low contributes to the acidosis

A: Metabolic Acidosis, with respiratory compensation. - Calf likely hyperventilating to blow off CO2.

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Q4. Student freaking out before final exam- Blood pH = 7.51 Alkalosis- PCO2 = 26 mmHg Low respiratory alkalosis- HCO3- = 25 mEq/L Normal not compensating

A: Respiratory Alkalosis, no metabolic compensation.

Q5. Cat with blood glucose of 13.5 mmol/L- Blood pH = 7.12 Acidosis- PCO2 = 25 mmHg High contributes to acidosis- HCO3- = 14 mEq/L

Metabolic Acidosis, with compensatory respiratory alkalosis. Likely a ketoacidosis

Micturition Reflex

Parasympathetic stimulates contractionSympathetic stops contraction and keeps urine in the bladder.

Sympathetic innervation comes from the lumbar vertebrae. Out comes the hypogastric nerve which innervates the detrusor muscle via beta receptors.

Pelvic nerve is parasympathetic and causes the contraction of the detrusor muscle. It is opposed by the hypogastric nerve which stimulates beta muscle which inhibits the detrusor muscle from contracting. Alpha branches help to block the pelvic nerve. Alpha branches also go to the internal urethral sphincter

Pudendal nerve is somatic and comes from the sacral vertebrae and innervates the external urethral sphincter (which is striated muscle) and allows the human to have voluntary control over urination.

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The bladder is innervated by both the autonomic (sympathetic and parasympathetic) and somatic (voluntary) nervous systems (see Figure 48-1):

Parasympathetic: facilitates micturition! Pelvic nerve originates from sacral spinal cord (S1 - S3) Stimulates contraction of detrusor smooth muscle

(expels urine)

Sympathetic: opposes micturition! Hypogastric nerve originates from lumbar spinal cord (L1 - L4) Inhibitions contraction of detrusor muscle(β-

adrenergic receptors) Simulates contraction of trigone region/internal urethral sphincter(α- adrenergic receptors)

Somatic: can facilitate or oppose micturition (voluntarily inactive or active) Pudendal nerve originates from sacral spinal cord (S1 - S3) Stimulates contraction of striated muscle of

external urethral sphincter

Micturition reflex: See neuro notes Stretch receptors in bladder wall detect urine fill, afferent signals sent to spinal cord and brain. CNS can voluntarily stimulate or oppose micturition

What affects the urethral sphincter tone? Alpha-1 Antagonist (Prazosin) inhibits urethral spasms causes a drop in blood pressure (gotta be careful

when using it. Estrogens Alpha-1 Agonists (Propalin)

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Avian/Reptile Kidneys Excreting ammonia vs urea vs uric acid. Energy required ammonia is the cheapest (formed by protein breakdown/muscle metabolism), urea takes

a lot of energy (takes a lot of ATP to form urea from ammonia), uric acid is even more energy intensive (~3-4x more energy required to make uric acid compared to urea).

Toxicity uric acid is the least toxic, urea is toxic, and ammonia is the most toxic (bovine bonkers). Water Loss ammonia needs a lot of dilution to be excreted, urea is osmotically active & requires less water

to excrete compared to ammonia – but there MUST be some water excreted with it, uric acid has poor solubility so it can be excreted without water following it.

Specifics of Uric Acid- Primary mechanism of N excretion in birds, most reptiles, some insects, and amphibians.

o Production in mammals too (gout). - Secreted into tubule by organic ion transporters- Little solubility, so precipitates out- Not osmotically active, so less water loss- Can damage tubule, so covered in albumin (urate balls)

o One of the reasons that avian urine is higher in protein than mammalian urine.

Ureter brings urine into the cloaca urodaeum. Some leaves right away, but some mixes with the feces in the coprodaeum and distal colon (allows these structures to try to reabsorb some of the fluid). The stuff excreted is a mixture of urine and feces.

Renal Portal System- Found in birds/reptiles- Venous blood from caudal region flow to peritubular capillaries in the kidneys- Joins filtered blood from the efferent arteriole- Leaves through renal vein (as usual)- Impact on drug administration?

o If you give an injection in the tail end a crocodile let’s say, it goes into the peritubular capillaries and may be secreted before it gets back into the caudal vena cava before it gets back to the heart.

Renal Diseases

Large kidney functional reserve capacity. - Both good and bad – why?

Renal dysfunction can result in different clinical signs:- Severity of kidney disease - Time course of kidney disease (acute vs chronic)

o Ie. Antifreeze (ethylene glycol) toxicity vs CRF

- Specific location of kidney damageo But “functional nephron hypothesis” – If any

one portion of nephron is irreversible damage then the whole nephron is “shot”.

- Animals environment, diet, etc. o Eg. Lack of ADH

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Loss of Renal Reserve- bout 50 % of the nephrons – loses reserve capacity – NO overt clinical signs.- Loss of 2/3 of nephrons – loss of concentrating ability. - Loss of 75% of nephrons – azotemia- >75% of nephrons – death.

BUN & GFR- Normal levels of blood urea nitrogen or creatinine - when there is a loss of 25% of nephron function- Mild increase in BUN/creatinine – when there is about 50% loss of nephron function- EXPONENTIAL INCREASE- Huge increase in BUN/creatinine - when 90% of nephron function is lose

Possible adverse effects caused by kidney disease/renal failure:

1. Decreased ability to concentrate urine. - Damage to proximal tubule or L of H cells:

o Soluble transport dysfunction?o Loss of osmotic gradient?

- Decrease in functional nephrons: increased volume of filtrate produced per nephron.- Compensatory polyuria.

o Results in polydipsia to compensate for polyuria.

2. Decreased waste removal from the plasma Decreased GFR = less filtration of urea & creatinine.

- Decreased clearance of urea & creatinine.- Increased plasma urea and creatinine

Azotemia and Uremia – ulcers (oral cavity), vomiting/nausea, depression (CNS disruption).

Types of Azotemia- Prerenal: dehydration or hypovolemia

o Decreased GFR due to decreased renal perfusion (because of decreased blood pressure) Decreased in urea/creatinine being filtered = more stays in the blood. Filtered urea: slow filtration because GFR slow = more time for urea to be reabsorbed

in proximal tubule (solvent drag – Na moves, water follows, urea follows water). o Leakiness of GFR – changes over time – may change with sympathetic stimulation – not as

big of a factor for determining GFR. o Should resolve when underlying problem fixed (hydration status and blood pressure

problem) = improves GFR & blood flow to kidney.- Renal: kidney dysfunction

o Decreased GFR due to nephron damage Decreased urea/creatinine filtered = more urea/creatinine in blood

o Doesn’t resolve (easily) Therapies: Almost NONE – kidney transplant needed.

Dialysis

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Try to increase blood pressure (net capillary pressure) which would increase GFR doesn’t work!

Benazopril (fortacor) – for renal failure (for cats w/ protein in urine), may prolong lifespan.

- Post Renal: blockage o Back up of urine.o Increases urea/creatinine – reabsorbed back into the blood streamo Should resolve if blockage is fixed.

Then waste products can be released = urea/creatinine decreases

How do differentiate b/w types of azotemia?- Is it before, during, or after the kidney?- Check for dehydration – skin tent, eyeballs (not easy on Sharpay’s)- PCV – increased hematocrit (ratio of RBCs to plasma is high – possibly due to dehydration). - Urine Test – specific gravity

o If pre-renal azotemia: due to dehydration, urine will be very concentrated (high USG) – urine in small volumes.

o If renal azotemia: due to kidney disease, urine will be poorly concentrated (isosthenuric). o If post-renal azotemia: enlarged bladder, lack of micturition (they strain to urinate, but

can’t).

3. Anemia - Decreased erythropoietin production = RBC number drops = anemia

4. Metabolic Acidosis - Decreased hydrogen ion secretion or bicarb reabsorption.

5. Hyperkalemia - Reduced GFR (not filtered from blood) – less K filtration – builds up in blood stream.- Compensation for metabolic acidosis (turn on K+/H+ antiporters in intercalated cells)- Urine obstruction:

o Reduced secretion of distal nephron?o Reabsorption from “stagnant” urine (K+ reabsorbed in the bladder).

6. Other Electrolyte Disturbances - Decreased reabsorption of Na+, Cl-, Ca++/P

o Proximal tubule (primary location of electrolyte reabsorption)- Decreased activation of Vitamin D

o Decreased Ca++ absorption from gut. - So what is the impact on the kidney?

o Increased PTH secreted to increase blood Cao But increased bone reabsorption causes increased blood phosphate

(hyperphosphatemia). o Reduced GFR (b/c of kidney disease) = decreased phosphate filtration/excretion =

phosphate stays elevated in the blood stream.

7. Protein Loss - Damaged glomerulus = increased leakiness

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o Increases protein in filtrate = further tubular damage.

o Leads to proteinuria (protein in urine) and possibly hypoproteinemia (prognostic value).

Dialysis

Artificial filtering of the blood.

- Hemodialysis: used in humans, blood pumped out of patient, then equilibrates with isotonic solution (needs right about of PO2, PCO2, right temperature, right amount of glucose – is deficient in waste products thus waste products are pulled into the dialysis solution). Utilizes counter current flow!

- Excess urea, creatinine, K, H, etc, from plasma diffuses into the dialysis solution.

- Cleaned blood then pumped back in.

- Peritoneal Dialysis (used in Vet Med) - Not counter current!- Isotonic solution pumped into abdomen (same

properties as the fluid used in hemodialysis)- Equilibrates with plasma across peritoneal membrane- Fluid (including diffused waste products) removed

from abdomen. - Peritoneal fluid cannot have higher concentration

than blood because it only is through passive diffusion.

Urinary Tract Infections- Huge deal in clinical practice- Urine is usually sterile (no bacteria) – once urine passes through urethra then bacteria may

contaminate it. Thus, if you collect when the animal urinates then the animal may have bacteria in urine. Should be sterile when urine collected via a cystotentesis.

- BUT: bacterial infections can occur throughout urinary tracto Cystitis (bladder – more common)o Pyelonephritis (kidney)o Origin: ascending urethra (from urethra into bladder), haematogenous (spread from

bloodstream).- Clinical Signs: RBC/WBC in urine, dysuria, stranguria (painful urination)- Causes: bacteria (E coli, Staph, leptospirosis), fungal infections (rare).

Urinary Tract Blockage- Numerous causes:

o Uroliths (crystals that have formed in stones)o Tumors

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o Mucous FLUTD (feline lower urinary tract disease) – crystals, sludgy urine, etc. - “Plug up” the urinary tract (usually urethra) so urine not excreted- Lead to hyperkalemia (cannot excrete K)- Male ruminants (longer urethra) have high prevalence: on pastures w/ high silicon, decreased Mg

forages.- “Blocked” cats (signalment: male, castrated, cat) – VERY common in practice unfortunately

Bladder Rupture- Secondary to urethral blockage (blocked cats, or feedlot steer “water bellies”), or HBC (hit by car). - Urine leaks from bladder into abdomen

o Urea/K higher in urine than plasmao Diffuse into peritoneal vasculature (revers peritoneal dialysis: how it gets back into blood

stream)- Hyperkalemia, uremia, metabolic acidosis

o Hyperkalemia – effects cardiac muscle contractility changes the ECG (messes up Phase 2 and repolarization phase– increases length of the plateau phase (elongates cardiac cycle) stops the heart).

Autoimmune Kidney Disease

Immune Mediated Glomerulonephritis: antibodies attack glomerulus- Inflammation and scarring of glomerulus

o Makes rest of nephron non-function- Arterial blood shunted to other nephrons

o Increased glomerular pressure, increases work load, perpetuates damage.

Toxins Affecting Kidneys- Metals: lead, mercury, cadmium- Certain antibiotics (aminoglycosides)- Foods: grapes/raisins/currants- Mechanism: proximal tubular cell damage

o Affinity for tubular specific transporters o Binding to apical brush border & subsequent transport into the cello Activation by renal cytochrome P450 enzymeso ROS damage to mitochondriao Ischemia due to vasoactive change

- Anti-Inflammatories: NSAIDS, ibuprofen, diclofenaco Vascular (PGE inhibition) and/or other toxicity.

- Ethylene Glycol (antifreeze) poisoningo Not directly toxic, but metabolism by alcohol dehydrogenase produces glycolate/oxalate.o Treatment: 4-MP, ethanol (vodka)o Alcohol dH – use vodka to competitively inhibit ethylene glycol. Ethanol would saturate

alcohol dehydrogenase – animal urinates out ethylene glycol before it was metabolized to its harmful form.

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