Exam # 3 Flashcards
In order for cells to survive, what must they do in regards to ECF? What is the control of this ECF/ H2O/ Na+ stores in the body?
- Cells need to maintain ECF within well defined limits.
- Gi tract will contribute to the amount of H20 in the body as well as Na+ ect. But kidneys are the main control center of water and salt maintenance.
What is the main control center of water and salt maintenance? What enables mammals to survive in variable conditions?
- kidneys are the main control center of water and salt maintenance.
- Kidneys enable mammals to survive in variable conditions.
Where is urine modified?
kidneys
What is the blood supply of the kidneys? Where does it come from?
Renal artery -> comes from the aorta
What are the functions of the kidneys?
- Filtration of blood
- Production of urine
- reabsorption of filtered substances adjusting salt and water excretion to maintain constant ECF volume and osmolality.
- Excretion of met wastes and xenobiotics
- Water/ acid-base
- production of glucose (gluconeogenesis)
- endocrine fxn
Will dialysis allow for all kidney functions to occur?
No, only allows for:
• Filtration of blood
• Production of urine
• reabsorption of filtered substances adjusting salt and water excretion to maintain constant ECF volume and osmolality.
What are some signs of kidney dysfunction in a 13 year old cat ?
- PU/PD, Vomiting (accumulation of urea/ substances that would be excreted by kidneys)
- Clinical exam: pale mm, both kidneys feel small upon palpation (decrease size with chronic disease) . Hematocrit 21% (decrease erythropoietin) , Creatinine 7.5.
- animal cannot concentrate urine
What is calcitriol?
Stimulated by PTH in response to hypocalcemia.
What is Renin?
Hormone activator, renal regulation of blood pressure, essential part of renin angiotensin aldosterone system (RAAS)
What is erythropoietin?
Hormone (glycoprotein, growth factor) essential for erythropoiesis.
How is calcitriol synthesized?
From food or the conversion of UV rays ( 7-dehydocholesterol. This is then converted to Vitamin D3 -> which is then converted by 25-hydroxylase in liver to 25(OH)-Vitamin D3 -> then 1-hydroxylase in kidney will convert 25(OH)-Vitamin D3 to 1,25(OH)20Vitamin D3 (Calcitriol)
What is a protein involved in calcium absorption that is synthesized from vitamin D?How is it synthesized/ how is calcium brought into cell and removed from cell?
• Calbindin is one of the proteins synthesized by Vitamin D
Vitamin D binds to receptor which then will go to nucleus. mRNA will leave nucleus to synthesize protein (i.e Calbindin). Calbindin will take the calcium from apical membrane and transfer it to basolateral membrane. We have calcium channels at the membrane. Stimulation of ATPase will pump calcium out into the blood.
What triggers renin?
• Renin is triggered by acute drop in plasma volume and blood pressure.
What does renin do?
• Renin is a hormone that will activate the angiotensinogen and will shorten (removing the last 4 AA) which will give you an angiotensin I.
◦ A converting enzyme (mainly found in lung) will then cut last 2 AA off, and will give you Angiotensin II. Angiotensin II has 8 AA.
What is erythropoietin? What can trigger it aside from low RBC?
- Erythropoietin is essential for new RBC formation.
- Can be triggered by high altitude.
How does erythropoietin influence RBC formation?what occurs if this synthesis does not
- Erythropoietin will go to the bone marrow and will find committed erythroid precursors which will mature and will end up making mature erythrocytes at the end.
- If that doesn’t work patients will develop anemia.
What are the main parts of the Kidney? What is the functional unit of the kidney?
Cortex and Medulla. functional unit is nephron
What can be found in the cortex? In the Medulla?
- Black line is approximate border of cortex and medulla. In the cortex you will find afferent and efferent arterioles, glomerular capillaries, peritubular capillaries, collecting ducts, ect Straight part of henlees loop is in the cortex, Straight ascending has partial in medulla and partial in the cortex.
- In medulla you will find peritubular capillaries collecting ducts. Thin segments of henlees loop are found in the medulla.
How many nephrons care found in the canine kidney? Feline? Cow?
Dogs: 400,000
Cats: 190,000
Cows: 4 million
Can nephrons be replaced?
no, only partially regenerated.
What are the 2 types of nephrons? Where are they found?
◦ Cortical nephrons: cortex, short loops of henlee, and are supplied by peritubular capillaries.
◦ Juxtamedullary nephrons: located near cortex/medulla junction, efferent arterioles give rise to long straight capillaries (vasa recta) that descend into renal medulla. Extremely long loops of henlee ( critical for urine concentration)
What are malphigahian bodies? what is it consisted of?
• Malpighian bodies: located in renal cortex, consists of glomerulus (capillaries) surrounded by bowmans capsule (double walled capsule)
What are the proximal tubules?
• Proximal tubule: longest part of nephron, consisting of a proximal and convoluted tubule and straight part
What is the loop of henlee?
• Loop of henlee: consists of thick descending limb ( extending into renal medulla), thin descending limb, thin ascending limb (only nephrons which have long loops( juxtamedullary nephrons)) and thick ascending limb (TAL, macula densa)
What are the distal tubules and collecting ducts?
- Distal tubule: straight and convoluted part (DCT)
- Collecting ducts: Extend through renal cortex and medulla
Where does the collecting ducts open in the renal pelvis?
Renal Papilla
What percentage of cardiac output goes to the kidneys?
20-25%
What is the path of renal blood flow?
• Abd aorta -> Renal artery -> Interlobar arteries -> arcuate artery -> interlobular arteries ( to the renal capsule) -> afferent arterioles -> glomerular capillaries -> efferent arterioles -> Peritubular capillaries/ vasa recta (no vasa recta in cortical nephrons)
What happens if O2 and energy supply are interupted in the kidneys? What is O2 used for? ATP?
◦ Active Transport Occurs in the proximal tubules, ATP is used
◦ Oxygen is needed for ETC ( aerobic metabolism)
◦ What happens if O2 and energy supply are interrupted?
‣ Infarction -> tissue damage. This will cause ischemia.
What is the consequences of renal ischemia?
- Renal ischemia causes severe histological and functional damage to the kidney.
- Interruption of o2 to tissue, and this will cause inflammatory response and increased levels of ROS. ROS are highly reactive that damage DNA, lipids and protein’s.
- Inflammatory cells infiltrate the injured tubular cells, damaged cells activate apoptotic pathways. Renal fxn becomes severely impaired.
What cells can be regenerated in the kidneys? What occurs to these cells during ischemia? What occurs after cells no longer are receiving ischemic injury?
- Tubular cells can be regenerated.
- During ischemia -> there is a loss of the brush border and carriers from basolateral membrane can be seen at the apical membrane. this is clear in staining. This causes a loss in polarity.
- Some cells will go through apoptosis, some will regenerate. Luminal obstruction will occur, but then will improve with time. ( is this AKI)
What occurs to cells during ischemia repair, and what is this dependent on?
- Some cells will be injured and loose brush border. Their will be migration and proliferation to replace and regenerate these cells.
- This depends on severity of damage and duration of ischemic injury.
What is the path of filtration of urine? How much urine is filtrated through this area? How much is excreted? What manages this?
- Filtration through glomerular capillaries into Bowmans capsule (180 L per day)
- about 1 L is actually excreted and the rest is resorbed. This is why the nephrons are so important.
- Glomerulus compact network of capillaries that retains cellular components and proteins.
Where is filtrate accumulated?
Bowmans space
What is Glomerular filtrate?
• Glomerulus produces fluid that is almost identical to plasma -> glomerular filtrate.
What determines the rate of glomerular filtration? What percentage of blood plasma flowing through kidney is filtered through glomeruli?
- Rate of glomerular filtration is dependent on the rate kidney is perfused by blood. -> called renal blood (plasma) flow.
- 20% of blood plasma flowing through kidney is filtered through glomeruli.
In this image, what is REAB, GFR, Black arrow, and Urinary excretion refering to ?
- Black arrow indicates where Drug metabolites and xenobiotics are eliminated.
- GFR is where filtration occurs -> creation of primary urine
- REAB is where reabsorption of valuable substances I.e glucose, amino acids, ect.
- Urinary excretion is where urinary excretion occurs.
What is found with by finding the difference between GFR and REAB? What % of GFR is excreted as urine? What occurs with the rest?
- Difference between GFR and REAB = Urinary excretion
- Less than 1% GFR is excreted as urine. more than 99% is resorbed.
What is glucosuria? Why does it occur?
• Glucosuria -> limit of reabsorption of glucose, so excess will end up in urine. Glucose carrier can only transport so much.
What are the components that make up the structure of the glomerulus?
- Alot of capillaries.
- Podocytes are wrapping capillaries, and are encased within bowmans capsule.
- Bowmans capsule lined with parietal epithelium.
Bowmans space is where filtrates collect.
What are the components of the filtration barrier?
- Capillary endothelial cells (fenestrated )
- Glomerular basement membrane, (no cells but many glycoproteins).
- Visceral epithelium-> podocytes
What is each layer of the glomerular basement membrane in this picture?
How can you tell what each layer is?
A.) Lamina rara interna
B.) Lamina Densa ( contains glycoproteins)
C.) Lamina Rara externa
You can tell by their density and location.
What can be found in the lamina densa? What does this cause in the glomerular capillaries?
Lamina densa is especially ritch in glycoproteins like laminins, type IV collagens, proteoglycans, ect.
The glomerular capillaries are, therefore relatively impermeable to proteins. The glomerular filtrate is essentially proten free.
What determines filterability? What substances have 100% filterability? Which do not ? What is the substance with the lowest filterability?
• Filterability is based on molecular weight and size. Water, sodium, and glucose all have 100% filterability. Myoglobin, hemoglobin, and albumin all do not have 100% and their percentages are 75%, 3%, and less than 1% respectively.
Albumin is bigger than hemaglobin, and almost completely, unable to be filtered.
• Electrolytes such as sodium and small organic compounds ( i.e glucose) are filtered freely as water.
What molecular properties does filterability rely on?
• Size -> filterability of solutes is inversely related to size -> bigger = harder to filter.
- Electrical charge -> negatively charged molecules are filtered less easily than positively charged molecules of the same molecular size
- Cationic substances are more filtered than anionic
• Plasma protein binding: this can be seen as protective mechanism for some solutes such as calcium. Some drugs will be retained in circulation for defined time period before being eliminated.
◦ All solutes bound to albumin will remain in the blood. Free solutes will be excreted.
What is the main driving forces for filtration? What are the forces opposing filtration?What is the oncotic pressure in bowmans space?
• Main driving forces for filtration is glomerular capillary hydrostatic pressure.
- The forces opposing filtration are the hydrostatic pressure in bowmans space and the oncotic pressure of the blood plasma.
- Essentially zero oncotic pressure in bowmans space.
What will occur to net filtration as we move across the glomeruli? Protein osmotic pressure ? Where is the start of glomeruli and where is considered the end?
- Protein osmotic pressure will increase as we move across glomeruli.
- Net filtration pressure will decrease as we move across the glomeruli. This occurs when the hydrostatic pressure is nearly constant
• Start is afferent arteriole, end is efferent arteriole.
Why is GFR important? What is the total volume of fluid filtered by the glomeruli into bowmans space per minute per kg?
GFR is important to analyze renal function.
total volume of fluid filtered by the glomeruli into bowmans space per minute per kg ~ 3.7 ml/min/kg
What can GFR be calculated with? What are the properties of substances?
- GFR can be calculated using indicator substances.
Properties of Substances:
- Must be freely filterable
- Their filtered amount must not change due to reabsorption or secretion in the tubule.
- They must not be metabolized in the kidney
- They must not alter renal function
What are some candidates for GFR calculation?
Inulin, and Creatine
How do we find GFR via inulin concentration?
GFR = Urine excretion rate * inulin (concentration) in urine/ inulin (concentration) in plasma.
Why is inulin less used in calculations for GFR?
Because measurement of creatinine clearance does not require intravenous infusion into the patient, this method is much more widely used than inulin clearance for estimating GFR clinically .
What is creatinine? What is it used for? What does an increase in plasma creatinine indicate?
- Creatinine is a by product of muscle metabolism. In dogs it is not secreted by tubular system. In some other species up to 10% is secreted)
- In clinical practice, serum creatinine level is also useful to assess renal function.
- If creatinine in plasma is elevated -> GFR is reduced
How do you calculate BSA (Body Surface Area)?
How do you calculate GFR when using creatinine?
GFR = Volume urine * urine creatinine / plasma creatinine
Divide answer by BCS to get ml/min/m2
-> unit: ml/min or ml/min/m2
What is the calculation for RPF?
GFR = Volume urine * urine PAH/ plasma PAH -> unit ml/min
- Divide answer by body surface area to get ml/min/m2
What is the calculation for RBF?
RBF = RPF / (1-hct) -> ml/min
Divide answer by Body surface area to get ml/min/m2
How is fractional filtration calculated?
FF = (GFR/RPf )x 100 -> %
You can use the GFR and RPF that has been divided by BSA to calculate the answer without having to divide it by BSA.
What is GFR measured by?
GFR is measured by the clearance of a free filterable substance that is neither reabsorbed nor secreted by the renal tubules (= inulin or creatinine)
What is the Renal Plasma blood flow?
Renal plasma flow (RPF, the volume of plasma delivered to the kidneys) is measured uring PAH (= para-aminohippuric acid) which is filtered and (in contrast to creatinine/inulin) additionally secreted by the renal tubules. The formula is exactly the same as for GFR but with PAH concentration instead of creatinine concentration
What is Renal Blood Flow?
Renal blood flow, RBF, the amount of blood delivered to the kidneys, is calculated from the measured RPF and the hematocrit
What is the Filtration Fraction, or fractional filtration?
Filtration fraction or fractional filtration, FF, the fraction of the renal plasma flow that is filtered across the glomerular capillaries, is calculated dividing GFR by RPF
How is GFR kept within the physiologic range? What can cause changes to the pressure of glomerular capillaries and peritubular capillaries?
• GFR is kept within physio range by renal modulation of systemic blood pressure and intravascular volume, as well as intrinsic control of renal blood flow.
What is the window which autoregulatory effects cqan normalize the GFR and R?BD?
- Autoregulatory window btwn 80-180 mmHg : short term changes in systemic blood within this range will only minimally alter GFR and RBF
- Variation above will cause issues with urine production, ect.
What are the responses that regulate blood flow?
- ) Myogenic reflex ( Bayliss effect)
- ) Tubulo glomerular feedback
- ) Renin Angiotensin Aldosterone System
What is the Myogenic reflex set off by? What is its mechanism of action?
The Myogenic reflex detects changes in glomerular perfusion. This occurs as a local effect because of increased tension of arteriolar wall, which causes depolarization of vascular smooth muscle cells. Calcium will then enter the cell and cause contraction of muscle cell and constriction of afferent arteriole. When arteriole blood pressure falls a dialation of the affterent arteriole occurs
Like closing water supply when too much water is coming out.
What is the mechanism of the tubuloglomerular feedback?
This detects changes in tubule fluid delivery. Part of tubule in close contact with glomerulus and this detects changes in tubule fluid delivery.
• Renin is synthesized in cells located in the wall of the afferent arteriole (juxtaglomerular cells) and used locally. They are in close contact with macuala densa.
• High concentration of NaCl in macula densa will lead to depolarization of cells and release of ATP basolaterally. This will then lead to suppression of renin release from JGC. Messangial cells will contract, and there will be increased resistance of afferent arteriole. Reduced GFR is the overall consequence.
What is the job of TGF? How does the nephron adjust the GFR? Where is sodium and chloride reabsorbed?
- TGF mechanism prevents a flow rate that would exceed the transport capacity of the tubular system.
- The nephron will adjust the GFR to the reabsorption capacity of solutes. Macula densa is where sodium and chloride are reabsorbed.
If an increase in sodium or chloride is sensed what will occur?
If an increase in sodium or chloride is sensed, it indicates an increased GFR so the response is to close the afferent arteriole so that they don’t loose as much Na and Cl
• RAAS -> systemic response.
What causes the kidneys to release renine? What is the pathway of Renin to angiotensin II?
• Kidney releases renin in response to decrease in arterial pressure. Renin will convert angiotensinogen ( which comes from liver) to angiotensin I in plasma. Angiotensin I will be converted ( by ACE) to angiotensin II in the capillaries of the lungs. Angiotensin II has many effects in the body.
What are the effects of Angiotensin II on the body?
◦ Increased thirst( which leads to increased fluid intake) , increased ADH (which leads to increased renal absorption of H2O), increased arteriolar contraction (which leads to increased TPR), increased aldosterone ( which leads to increased renal absorption of Na+)
◦ In peritubular capillaries : decreased hydrostatic pressure, increased protein osmotic pressure. ( which leads to increased renal reabsorption of H2O and salt)
◦ All of these changes drive arterial blood pressure towards normal
What are the vasodilatory agents?
- NO - Produced by Nitric Oxide Synthase
- PGE2- Produced by Coxygenase (COX-2)
What is the role of NO and PGE2?
◦ These both modulate messangial cell constriction to prevent an excessive reduction in single nephron GFR (fxn as break)
What can occur with prolonged use od NSAIDS?
◦ Prolonged use of NSAIDs can lead to renal failure. (Related to blockage of COX-2 (which is responsible for the creation of many important prostaglandins)
What are the constricting factors?
- Constricting factors: Endothelin, TXA2, ANG2
- a- adrenergic stimulation
Critical thinking: What happens to the GFR if …
↑ RBF →
↑ Systemic pressure →
↑ afferent arteriole tone →
↑ efferent arteriole tone (slight) →
↑ ↑ efferent arteriole tone (strong) →
↑ hydrostatic pressure of Bowman‘s capsule (PBC) →
↑ RBF → ↑ GFR
↑ Systemic pressure → ↑ GFR
↑ afferent arteriole tone → ↓ GFR
↑ efferent arteriole tone (slight) → ↑ GFR
↑ ↑ efferent arteriole tone (strong) → ↓ GFR
↑ hydrostatic pressure of Bowman‘s capsule (PBC) → ↓ GFR
What is primary urine?
• primary urine, filtrate that accumulates in the capsular space between glomerulus and bowmans capsule. Same concentration of NaCl and glucose as plasma.
What is tubule fluid?
• Tubular fluid ( primary urine inside tubular system) passes through tubular system and is continuously modified by tubular reabsorption. This will become final urine at the end.
What is the fractional excretion rate? What is the calculation for it?
• Fractional excretion rate: net rate of reabsorption and secretion of a filtered substance and indicator of fxn integrity of renal tubules.
• FEx = (Urine concentration of X /Plasma concentration of x) / (Ucreat/ Pcreat) * 100
◦ this will give you percentage of filtered x that is excreted
What is the function of the glomerulus?
Glomerulus: Filters the blood (Solutes, water, Urea, Creatinine) = primary urine
What is the function of the proximal tubule?
Proximal Tubule: Reabsorbs most filtered solutes eg. glucose, amino acids, peptides, proteins, Na+, K+, Cl-, HCO3- Ca ++, Mg++ Reabsorbs water Excretion of waste and xenobiotics
What is the function of the thin limbs of henlees loop?
Maintain medullary hypertonicity, reabsorbs water, Na+, Cl-
What is the function of the thick ascending limb?
Reabsorbs Na+, K+, Cl- Dilutes tubule fluid and maintain medullary hypertonicity
What is the function of the distal convoluted tubules?
Reabsorbs Na+, Cl-, Ca ++, Mg++ Conecting segments regulate acid, HCO-, ammonia, Ca ++, Na+, K+, and water excretion
What is the function of the collecting ducts?
Collecting ducts: Regulates acid, HCO-, ammonia, Na+, K+, and water excretion/reabsorption = final urine
What are the components of the proximal tubule?
PT cells are polarized (apical and
basolateral membrane)
- Brush borders (microvilli)
- Tight junctions
What structures are present on the apical membrane of proximal tubule cells? The basolateral membrane? What is found below the basement membrane?
Apical membrane has brush borders (on picture, BB)
Basolateral membrane has infoldings (micropedici ‚tiny feet‘)
Don‘t forget the peritubular capillaries below the basement membrane
What are the mechanisms that move tubule fluid back into the blood?
Transcellular pathway
and
Paracellular pathway
What is the transcellular pathway?
Transcellular pathway: largely by carrier-mediated transport substances cross
the apical membrane, cytoplasm, and basolateral plasma membrane into the
interstitial fluid
From interstitial fluid -> to the peritubular capillaries
What is the paracellular pathway?
Paracellular pathway: tubule fluids pass through the epithelium accross the tight junctions (passive difussion or solvent drag). Substances enter the lateral
intercellular space and the interstitial fluid
From interstitial fluid -> peritubular capillaries
What are the transport mehanisms in the proximal tubules ? What is each driven/ fueled by?
- Primary active transport: Fueled directly by ATP consumption, e.g., Na+, K+- ATPase (located basolaterally)
- Secondary active transport: Driven by the electrochemical gradient produced by the primary active transporter, e.g., SGLT
- Tertiary active transport: The carrier is driven by the gradient generated by a
secondary active transporter, e.g., peptide, H+ cotransporter
Why is urinalysis ideal to run in a clinic setting for patients with potential kidney issues?
Urine analysis is a simple and cheap test that provides you with valuable information
Before begining any microscopic analysis what should you do?
A physical examination
A macroscopic analysis using fresh urine (within 30 min after collection). Use your senses and observe for clarity/turbidity, color, etc
You may use urine stripes
Refractometer to analyze specific gravity
Microscopic analysis (look for sediments)
You may use some special reagents for protein analysis
How do Specific Gravity and Osmolality differ? Do they correlate?
SG and osmolality correlate as well but remember SG of the urine varies depending on the type of solute present whereas osmolality depends on the amount of osmotically active particles regardless of their size
How are low molecular weight proteins reabsorbed in the proximal tubules? What is needed to have this occur?
Low-molecular-weight proteins (filtered insulin, glucagon, PTH, etc) are reabsorbed by a completely different mechanism, called „receptor-mediated endocytosis“
This process needs the presence of receptors in the plasma membrane of PT cells (megalin and cubilin)
After endocytosis ther is fusion with lysosomes and degradation of proteins into amino acids
What allows for the reabsorption of glucose? What is the difference between the two glucose transporters?
Reabsorption of glucose is achieved by sodium-dependent transporter (Sodium- glucose transporter, SGLT)
There are two different sodium-dependent glucose transporters: -A low-affinity one located in the pars convoluta (SGLT2) -And a high-affinity one in the pars recta (SGLT1)
Saturation can occur! (Michaelis-Menten kinetics)
What mTAL relevant transport system is inhibited by furosemide?
NKCC is inhibited by furosemide, a commonly used diuretic
