Renal Flashcards
What are the parts of the nephron in order of flow of filtrate?
Glomerulus
Proximal convoluted tubule
Loop of Henle (descending, thin ascending, thick ascending)
Distal convoluted tubule
Collecting duct
What are the 2 mechanisms that create glomerular selectivity?
Size (pore slit of the diaphragm is 25-60kDa; >65kDa structures can’t make their way through the glomerulus)
Charge (negatively charged substances can’t pass through the glomerulus because all three layers carry a negative charge)
What type of collagen is found in the basement membrane of the glomerulus?
Type IV (negatively charged)
4 = floor (basement membrane)
What is normal GFR for dogs and cats?
Dogs: 3.5-4.5mL/min/kg
Cats: 2.5-3.5mL/min/kg
Amlodipine causes __ which increases glomerular filtration pressure
selective dilation of the afferent arteriole
ACE inhibitors like enalapril cause __ which decreases GFR
selective dilation of the efferent arteriole
What is the Donnan effect?
Effect where an increase in colloid osmotic pressure secondary to severe efferent arteriolar constriction causes decreased GFR
How much functional nephron mass must be lost before an azotemia develops?
75%
How is renal clearance calculated for a substance (formula)
Clearance = (Urine clearance * Urine flow rate) / (plasma concentration of substance)
What properties of a substance would make it a good estimator of GFR?
Substance that is neither reabsorbed or secreted by the tubules
Should be freely filtered
What is the gold standard for measurement of GFR?
Inulin
For an inulin clearance test, how is inulin administered?
IV
Why is inulin not used clinically?
Assay is not readily available
What are other ways to measure GFR via renal clearance besides inulin?
Creatinine clearance
What is the difference between endogenous creatinine clearance and exogenous creatinine clearance test?
Endogenous - use body’s natural creatinine as marker and measure changes over time
Exogenous - give creatinine bolus and measure urine and plasma concentrations over time
How is plasma clearance calculated for a substance (formula)?
Clearance = Dose / Area under the curve
What substances are commonly used for plasma clearance tests?
Iohexol
Radioisotopes
What is the most frequently used clinical test for measurement of GFR?
Iohexol clearance
What is a risk of iohexol clearance (more common in people)
AKI
If clearance rate of substance X is equal to clearance rate of inulin, the substance in being FILTERED/ABSORBED/SECRETED.
Filtered only
If clearance rate of substance X is less than clearance rate of inulin, the substance in being FILTERED/ABSORBED/SECRETED.
Reabsorbed
If clearance rate of substance X is greater than clearance rate of inulin, the substance in being FILTERED/ABSORBED/SECRETED.
Secreted
How much of cardiac output do kidneys receive?
25%
Through what mechanisms do the kidneys regulate arterial pressure?
Changes in extracellular fluid volume
Renin-antiogensin-aldosterone system
What makes up the juxtaglomerular apparatus?
Mesangial cells
Macula densa
Vascular baroreceptors detect what?
Changes in stretch
(Send signals to the renal sympathetic nerves)
What things can trigger RAAS?
- Vascular baroreceptors - detect decreased stretch of the afferent arteriole
- Intrarenal baroreceptors (granular JG cells) - detect decreased blood flow in the afferent arterioles
- Intrarenal NaCl detection by macula densa cells - detect drops in reabsorption to trigger RAAS
Where is the macula densa located?
Distal convoluted tubule
What is the first substance secreted by RAAS activation?
Renin
What does renin do?
Acts on angiotensinogen to convert it to angiotensin I
Angiotensinogen is produced where
Liver - it is constitutively released to make sure it’s always in circulation
After angiotensin I is produced, what happens next in RAAS pathway?
Angiotensin I travels to the lungs via the blood where angiotensin converting enzymes on the endothelial cells of the lungs convert it to angiotensin II
What are the major functions of angiotensin II in the RAAS pathway ?
Acts on the brain to drive increased thirst
Acts on arterioles to cause vasoconstriction
Stimulates adrenal gland to produce aldosterone
Aldosterone acts on the __ causing activation of __ which leads to __ of sodium and __ of potassium
Principle cells of the collecting tubule/collecting ducts
Na/K/ATPase pumps
Absorption of sodium
Excretion of potassium
Aldosterone receptor on principle cells is under the control of what drug?
Spironolactone
What is the MOA of spironolactone
Blocks aldosterone receptor of the principle cells of the collecting tubule/collecting ducts
What is the MOA of amiloride?
Potassium sparing diuretic - inhibits sodium channels on the luminal membrane of principle cells of the collecting tubule/collecting ducts
What is responsible for RAAS inhibition?
Atrial natriuretic peptide (ANP)
Where is ANP produced and what is the stimulus for production?
Secreted by cardiac atrial muscle fibers
Release is stimulated by distention of the atria (plasma volume expansion)
What are the effects of ANP?
- Inhibit release of renin from kidney
- Inhibits actions of angiotensin II (aka decreased aldosterone secretion)
- Inhibits sodium reabsorption (from the decreased in aldosterone; natriuresis and diuresis)
- Vasodilation (to decrease blood pressure)
- Increases GFR (to try and further decrease sodium and excess water levels; increased GFR also leads to decreased renin production)
What percentage of glucose is filtered through the glomerulus?
100%
What part of the nephron reabsorbs all glucose and by what?
Proximal tubule by sodium glucose co-transporters (SGLT)
There is SGLT 1 and SGLT2
Where are sodium glucose co-transporters located on proximal tubular cells?
Brush border
Approximately 90% of the filtered glucose is reabsorbed by __ in the __ part of the proximal tubule.
SGLT2
early (S1) part of the proximal tubule
Glucose is brought into the interstitial fluid from what receptors and in what part of the proximal tubule are they located?
GLUT2 - located in S1
GLUT 1 - located in S3
What is the renal threshold of glucose in a dog?
Dog: 180-220
Higher in cats
Other than glucose, what is reabsorbed in the proximal tubule?
All amino acids
65% of Na and H2O (water is passive, follows sodium)
40-50% of urea
80% of bicarbonate
80-85% calcium
80-95% phosphorus
65-90% of citrate (metabolized to bicarb)
**If you’re asked where something is reabsorbed, the PCT is a good guess!
Where is the majority of calcium reabsorbed? Is it passive or active?
Proximal tubule - 65%
Both passive and active
In what three areas of the nephron is calcium reabsorbed?
Proximal tubule - 65%
Thick ascending limb of loop of Henle (this is passive) - 25-30%
Distal convoluted tubule and collecting tubules - 4-9%
Where does PTH act in the nephron?
Distally - thick ascending limb of loop of Henle and distal convoluted tubule and collecting tubules
Hyperphosphatemia is most often due to
Decreased GFR
Where in the nephron is phosphate reabsorbed?
Proximal tubule - 75-80%
Distal convoluted tubule - 10%
Loop of Henle and Collecting tubules - <1%
How does PTH influence phosphorus balance by the kidneys?
PTH decreases transport maximum for phosphate by renal tubules, leading to more phosphate loss in urine
Where in the nephron is the majority of magnesium reabsorbed?
LOOP OF HENLE - 65% (mostly from thick ascending limb)
Some is reabsorbed by proximal tubule and distal convoluted tubule and collecting ducts, but less than loop of Henle
Definition of osmolarity
Number of osmoles per liter of solution (plasma)
Affected by volume and temperature
Definition of osmolality
Number of osmoles per kilogram of solvent
NOT affected by volume and temperature
What is the equation for calculating plasma osmolality?
Osmolality (calculated) = 2 x (Na + K) + (Glucose / 18) + (BUN / 2.8)
What is the normal urine osmolality in dogs and cats?
Dog: 300mOsm/kg
Cat: 310mOsm/kg
= ISOSTHENURIA
What is needed to concentrate urine?
- Functional nephron - need at least 1/3 nephron mass to concentrate urine
- Medullary gradient
- Antidiuretic hormone (ADH)/Vasopressin
- ADH response at level of the kidney - mediated by V2 receptors
What osmolality does filtrate have when entering nephron?
300mOsm
Why does osmolality of filtrate not change in the proximal convoluted tubule?
Because of absorption of electrolytes but also b/c of absorption of water –> no net change here, happens further down (distally) in nephron
As you progress down the medullary gradient, what happens to water? What structure allows this?
Diffuses out of filtrate
Facilitated by aquaporin 1 channels (AQP-1)
This is PASSIVE process
As you move up the thin ascending loop of Henle in the medulla, is it more permeable to solute or water?
Solute
Why do we require active transport of NaCl in the thick ascending loop of Henle?
It lies in the cortex and there is no concentration gradient to drive diffusion
What diuretic acts in thick ascending loop of Henle?
Loop diuretics
Tubular filtrate entering the distal convoluted tubule is HYPO/ISOS/HYPERsthenuric?
HYPOSTHENURIC
How is the medullary gradient maintained?
Maintained by 2 major solutes:
Sodium
Urea
Sodium reabsorption in the proximal convoluted tubule is upregulated by what?
Angiotensin II
Sodium reabsorption in the collecting ducts is regulated by what?
Aldosterone and ANP
Urea reabsorption in the proximal tubule is facilitated by what transporter?
UT-A1
Urea secretion into the thin loop of Henle is facilitated by what transporter?
UT-A2
Urea reabsorption into the collecting duct is facilitated by what transporter?
UT-A3
(Also UT-A1)
What hormone regulates urea reabsorption and what transporters does it act on?
Vasopressin/ADH
UT-A1 and UT-A3 - these are upregulated which increases urea in interstitium and increases concentration ability
What should a normal BUN to creat ratio be?
<30
If BUN to creat ratio is >30 (ie BUN > creat), what are your ddx?
Pre-renal azotemia
GI bleeding
High protein diet
Muscle wasting in CKD
Vasopressin (ADH) is produced where?
Supraoptic nuclei of the hypothalamus
**Remember it is NOT PRODUCED in the posterior pituiatary, it’s STORED there
What stimulates secretion of ADH/vasopressin?
- Increased plasma osmolality –> regulated by osmoreceptors in the anterior hypothalamus (outside BBB)
- Decreased arterial pressure/blood volume –> regulated by baroreceptors of the carotid arteries and aortic arch
Other stimuli:
- Nausea/vomiting
- Drugs (increase ADH = nicotine, morphine, cyclophosphamide; decrease ADH = clonidine, haloperidol)
What are the types of vasopressin receptors and where do they act?
V2 receptors - found in collecting ducts and lead to increase in aquaporin 2 channels; also found in endothelial cells (cause release of factor VII and vWF) and vascular smooth muscle (cause vasodilation)
V1A - vascular smooth muscle –> causes vasoconstriction; also in the hepatocytes (stimulate glycogenolysis), brain and spinal cord (act as neurotransmitter), and platelets (cause thrombosis)
V3 (V1B) receptor - found in anterior pituitary and promote ACTH secretion from anterior pituitary; also in the adrenal medulla which promotes release of catecholamines
Vasopressin/ADH binding V2 receptors on cells of the distal tubules, collecting tubules, and collecting ducts leads to what downstream effects?
ATP converted to cAMP
cAMP activates protein kinase A
Protein kinase A causes protein phosphorylation which frees up aquaporin 2 channels that go to tubular lumen side and insert themselves –> increased water resorption and concentrates urine
What aquaporins act independent of ADH?
AQP-3 and AQP-4
What diuretics act in thick ascending loop of Henle?
Loop diuretics
What is the MOA of loop diuretics?
Act on Na-2Cl-K channels to decrease reabsorption of Na, Mg, K+
Will decrease water retention
What kind of diuretic is furosemide?
Loop diuretic
What diuretics act in the distal convoluted tubule?
Thiazide diuretics
What is the MOA of thiazide diuretics?
Inhibit Na-CL cotransporter –> more sodium and water excretion
What are examples of thiazide diuretics?
Chlorothiazide
Hydrochlorothiazide
Trichlormethiazide
Where do aldosterone receptor antagonist diuretics work?
Distal convoluted tubule
What is an example of an aldosterone receptor antagonist diuretic?
Spironolactone
In animals, what is the major source of vitamin D and what form is it primary in?
Diet
Vit D3/cholecalciferol
What two organs are key for vitamin D activation?
Liver
Kidneys
On what position does the liver hydroxylate vitamin D3?
25th position
What enzyme in the kidneys hydroxylates vitamin D3 and at what position?
1-alpha-hydroxylase
First position
What are PTH’s effects on the kidneys?
Increase calcium reabsorption
Increase phosphorus excretion
Upregulates activity of 1-alpha-hydroxylase
How does the kidney make erythropoietin?
When hypoxic, hypoxic-inducible factor 1alpha (HIF-1alpha) translocates to nucleus and upregulates production of
How does the kidney make erythropoietin?
When hypoxic, hypoxic-inducible factor 1alpha (HIF-1alpha) translocates to nucleus and upregulates production of EPO gene
HIF-1alpha is inactivated and degraded by prolyl hydroylase which is stabilized in the presence of oxygen
Where is the majority of bicarbonate reabsorbed?
Proximal convoluded tubule
Some reabsorbed in cortical collecting ducts under influence of aldosterone
What cells does aldosterone act on in the collecting ducts to stimulate bicarbonate reabsorption?
Type A intercalated cells
What is the difference between type I and type II renal tubular acidosis?
Type I - distal renal tubular acidosis = inability to secrete H+ by intercalated cells
Type II - proximal renal tubular acidosis = inability to reabsorb bicarb
What is the main mechanism through which GFR decreases?
Decreased glomerular hydrostatic pressure
This can be from decreased arterial pressure (systemic hypotension), constriction of afferent arterioles (leading to decreases in renal blood flow), severe constriction of efferent arterioles (Donna effect), or decreased filtration coefficient (typically from chronic hypertension leading to thickening of the glomerular basement membrane, or nephron loss)
What three mechanisms decrease GFR?
- Decreased glomerular hydrostatic pressure
- Increased hydrostatic pressure in Bowman’s capsule (usually secondary to something else, think ureteral obstruction)
- Increased glomerular capillary on optic pressure - 2 mechanisms
- Increased arterial oncotic pressure
- Decreased fraction of plasma filtered by the glomerular capillaries (filtration fraction) - plasma proteins remain in capillary longer than they should and exert higher oncotic force
What are the three components of the glomerular filtration barrier?
- Endothelium - negatively charged, contains numerous pores (fenestrae) that are not spanned by diapraghms
- Glomerular basement membrane - made of collagen and proteoglycan fibrillae
- Pseudopod layer (podocytes) - foot processes separated by slit pores
Where do carbonic anydrase inhibitors work?
Proximal convoluted tubule
Example: acetazolamide
MOA of carbonic anhydrase inhibitors
Cause an accumulation of carbonic acid by preventing its breakdown. The result is lower blood pH (i.e., more acidic), given the increased carbonic acid, which has a reversible reaction into bicarbonate and a hydrogen ion
Carbonic anhydrase is found in the proximal tubule of the nephron and red blood cells. It works to reabsorb sodium, bicarbonate, and chloride. Once acetazolamide inhibits carbonic anhydrase, sodium, bicarbonate, and chloride get excreted rather than reabsorbed; this also leads to the excretion of excess water. The clinical result is a decrease in blood pressure, decreased intracranial pressure, and decreased intraocular pressure. Bicarbonate excretion also increases the acidity of the blood
How much bicarbonate is reabosrbed in the proximal convoluted tubule?
80-90%
What percentage of amino acids are reabsorbed in the PCT?
99%
Through what 2 processes do the renal tubules regulate acid/base homeostasis?
- Reabsorption of bicarbonate in the proximal tubule
- Excretion of H+ in the distal tubule
Renal tubular acidosis causes what acid base disturbance?
Hyperchloremic metabolic acidosis
What urine pH is expected with Type I (distal) renal tubular acidosis?
pH >6.0
How is type I (distal) renal tubular acidosis diagnosed?
Failure to acidify urine with ammonium chloride challenge test
What drug can cause nephrotoxicosis that can lead to type II (proximal) renal tubular acidosis?
Gentamicin
How is type II (proximal) renal tubular acidosis diagnosed?
Increased oral bicarbonate fractional excretion after normalizing serum bicarbonate
How is type II renal tubular acidosis treated?
Potassium citrate
What electrolyte abnormalities (urine or serum) might you see in renal tubular acidosis?
Hypercalciuria
Hyperphosphaturia
Hypokalemia - mild with proximal/type II, mild to severe with distal/type I
What type of renal tubular acidosis requires more bicarbonate administration?
Type II/proximal
Is the anion gap high or normal with renal tubular acidosis?
Normal due to hyperchloremia
What are the criteria for nephrotic syndrome?
Proteinuria
Hypoalbuminemia
High cholesterol
Ascites
Nephrotic syndrome is sometimes seen in what disease?
Lyme nephritis
What histopath finding would you expect with Lyme-associated renal failure?
Membranoproliferative glomerulonephritis
Which part of the renal tubule is affected in gentamicin toxicity?
Proximal tubular epithelial cells (same with other aminoglycosides)
Which antibiotics are toxic to the vestibular region?
Streptomycin
To Brady in
Gentamicin
Which aminoglycosides are toxic to the cochlear region?
Amikacin
Neomycin
Kanamycin
What facilitates glucose transport in the proximal tubules?
- Sodium-glucose cotransporters
- Passive glucose transporters
Sodium-glucose cotransporters are located where on the proximal tubular cells?
Brush border
Is ATP needed for sodium-glucose cotransporters?
NO - they carry glucose into the cell cytoplasm against a concentration gradient, but the uphill transport of glucose is coupled with downhill movement of Na+ along its gradient so no ATP is needed
Where are passive glucose transporters located on proximal tubular cells?
Basolateral membrane
Do GLUT1 and GLUT2 facilitate active or passive transport?
Passive
Which sodium-glucose cotransporter filters most of the glucose and where is it located?
SGT2 - reabsorbs 90% of filtered glucose in early part of proximal tubule (S1 segment)
Located in S1 segment
Where is GLUT2 located within the proximal tubule?
S1 segment
Where is GLUT1 located within the proximal tubule?
S3 segment
What glucose transporters are insulin dependent?
GLUT 4
(GLUT 1-3 are insulin independent)
Where are GLUT4 transporters located?
Skeletal muscle
Adipose tissue
Heart
Where are GLUT3 transporters located?
Brain
Neurons
Sperm
Where are GLUT2 transporters located?
Liver
Pancreas
Small intestine
Where are GLUT1 transporters located?
Blood
Blood-brain barrier
Heart (lesser extent)
What drives PU/PD in CKD patients (4 mechanisms)
- Osmotic dieresis in remnant nephrons due to increased solute load or decreased tubular resorption (of NaCl, bicarbonate, etc)
- Pressure dieresis due to increased flow rate per surviving nephron and increased BP
- Nephrogenic diabetes insipidus (acquired) —> tubular insensitivity to ADH
- Medullary washout due to altered medullary blood flow or decreased NaCl resorption in the ascending limb (fractional Na reabsorption decreases as GFR falls, causing decreased solute concentration in the medulla)
What electrolyte abnormalities would you see with nephrogenic diabetes insipidus?
Hypernatremia
Hypercalcemia
Hypokalemia
What breeds are predisposed to ammonium biurate crystalluria in the absence of hepatobiliary disease?
English Bulldog
Dalmatian
A dog was recently treated for a UTI and discontinued antibiotics 10 days ago, but now has a recurrent UTI. He as culture negative while on antibiotics. What term is used to describe this scenario?
Relapse
UTI treatment failure is defined as
Failure to eradicate bacteriuria during treatment and failure to prevent relapse
UTI relapse is defined as
Return of infection due to the same microorganism which is often drug resistant. It is defined as recurrence of bacteriuria with the same organism within three weeks of completing treatment, which during treatment rendered the urine sterile. Implies failure to eradicate the infection.
Recurrence of UTIs is defined as
3 or more episodes of a UTI in a 12 month period
A false negative protein in urine on dipstick could be caused by what type of proteins?
Bence Jones proteins - these are not detectable by dipstick b/c that only picks up albumin, not globulins
A Dalmatian on allopurinol would also have what in his urine?
Xanthine
Can you dissolve struvite stones in a cat if the urine osmolality is high?
No
Struvite stones are __ on x-rays and typically seen in __ urine pH
Radiopaque
Alkaline urine
Struvite stones in dogs are typically associated with what types of bacteria?
Urease-producing bacteria (Staph, Proteus, Klebsiella, Corynebacterium, Enterococcus, Mycoplasma)
Usually found in sterile urine in cats
How are struvite stones treated?
Diets that ACIDIFY urine and are low in Mg
Antibiotics in dogs
Urate stones are __ on radiographs and occur in __ urine pH
Radiolucent
Acidic urine pH
Urate stones are associated with what conditions
Hepatic dysfunction - PSS
Metabolic defect - occurs in Dalmatians and English Bulldogs
What is the etiology for urate stone formation in Dalmatians?
Autosomal recessive defect in purine metabolism
Purine —> hypoxanthine —xanthine oxidase—> xanthine —xanthine oxidase—> uric acid —uricase—> allantoin
Conversion of uric acid to allantoin occurs via the intracellular hepatic enzyme uricase
Dalmatians cannot transport uric acid into hepatocytes and reabsorb less uric acid in the proximal tubules than other dogs
How are urate stones treated?
Hills u/d diet - low protein (decreases ammonia) and low in purines (decreases uric acid) - NOT ACIDIFYING
Allopurinol - inhibits xanthine oxidase - this may predispose to forming xanthine uroliths - CONTRAINDICATED IN RENAL FAILURE
Urine alkalization with potassium citrate PRN
Dissolution of urate stones is possible in DOGS/CATS but not possible in DOGS/CATS
Possible in dogs
Not possible in cats
True/false: Cystine stones are found only in cats
FALSE - only in dogs
Cystine stones are __ on radiographs and occur in __ urine pH
Radiolucent
Acidic urine pH
What breeds are predisposed to cystine stone formation?
Dachshund
English Bulldog
Newfoundland
Labs
What is the etiology of cystine stone formation in predisposed breeds?
Sex-linked or autosomal recessive genetic defect in proximal tubular reabsorption of cystine —> increased amount of cystine in urine
How are cystine stones treated?
Dissolution is possible
Thiola [N-(2-mercaptopropionyl)-glycine or 2-MPG] - forms stable complex cystine that is more soluble than cystine alone
Diet: low methionine, reduced protein, Na-restricted, urine alkalinizing, high moisture, calculolytic
Urine alkalinizer (potassium citrate) if diet alone doesn’t work
Calcium oxalate stones are __ on radiographs
Radiopaque
Calcium oxalate stones are more common in what breeds?
Small breed dogs like Schanuzer, Shih tzu, Pomeranian, Yorkie, Maltese, Keeshond
Can calcium oxalate stones be dissolved?
NO - diet is aimed at decreasing recurrence
How are calcium oxalate stones treated
Diet: Non-acidifying high-moisture diet without excessive protein, Ca, oxalate, and Na; adequate phosphorus to avoid renal activation of Vit D - diet can decrease recurrence but will not dissolve
Alkalinizing urine - potassium citrate
Per ACVIM consensus statement:
- Urocystoliths associated with clinical signs should be removed by minimally invasive procedures
- Nonclinical urocystoliths unlikely to cause urinary obstruction do not require removal
- Nonclinical urocystoliths likely to cause urinary obstruction should be removed by minimally invasive procedures
With what stone types do you want an ALKALINIZING diet
Urate
Cystine
Calcium oxalate
With what stone types do you want an ACIDIFYING diet
Struvite
How is glomerulonephritis diagnosed on histopathology?
Cortex biopsy (biopsy of the medulla is not necessary and is associated with increased risk of hemorrhage, infarction, and fibrosis)
Why is acidosis seen in severe/end stage CKD?
Decline in excretion of H+ and decreased filtration of titratable acids such as phosphate and sulfate compounds
This results in an increased anion gap
What are consequences of chronic acidosis w/CKD
Negative calcium balance and bone demineralization
Negative potassium balance
Decreased cardiac output, arterial pressure, hepatic, and renal blood flow (due to peripheral arterial vasodilation and central venoconstriction)
Promotes re-entry arrhythmias and reduced threshold for ventricular fibrillation
Accelerates proteolysis (increases activity of muscle branched-chain keto acid dehydrogenase, the rate limiting enzyme in branched-chain acid catabolism)
What are predisposing causes of UTIs in older cats?
Diabetes mellitus
CKD
Hyperthyroidism
