Renal

Question 1

Describe tubuloglomerular feedback for control of GFR and NaCl deliver to the distal tubule. What is the role of the macula densa? How can tubuloglomerular feedback help prevent excessive fluid losses if there is damage to kidney proximal tubules?

Answer 1

• Feedback: increased renal arterial pressure = increased RBF and GFR = increased flow rate through proximal tubules = less time to absorb water and NaCl in proximal tubule = larger than normal volume of tubular flow into loop of Henle per unit time = macula densa senses increased flow via cilia and increased NaCl = chemical mediators (? Adenosine) released from macula = chemical mediators act on SM in afferent arteriole causing vasoconstriction, also possible inhibits release of renin = less angiotensin II = less vasoconstriction = decreased GFR - How: if proximal tubular reabsorption is reduced (d/t damage from heavy metals/drugs) there will be excessive water and NaCl delivered to the distal tubule. This feedback mechanism will cause vasoconstriction of the afferent arteriole, lowering GFR and preventing excessive fluid loss from damaged nephrons.

Question 1

Briefly describe three effects of ADH on the kidney.

Answer 1

1.) binds V2 receptors on basolateral side of collecting ducts and causes insertion of aquaporins into luminal membrane, increasing water permeability 2.) vasoconstricts pericytes surrounding descending vasa recta, decreasing blood flow and helping preserve medullary gradient 3.) increases permeability of medullary collecting ducts to urea by increasing number of urea uniporters

Question 2

Two types of nephrons:

Answer 2

• Named for location of glomeruli a.) Cortical: upper cortical zone, loops of Henle extend only to outer zone of medulla b.) Juxtamedullary: cortico-medullary junction, loops of Henle extend deep into inner medulla, has thin ascending limb

Question 2

Describe the role of the kidney in making the active form of vit D. What is the major action of the active form of vit D? What is its effect on the intestine? On the kidney? Which effect is more important?

Answer 2

• Role of kidney in production: vit D in diet is a prohormone that has to undergo two hydroxylation rxns to become active form. Starts in skin where light causes formation of vit D3. D3 is converted in liver to 25-hydroxycholecalciferol. This is converted in kidney to 1, 25-dihydroxy vit D aka calcitriol under stimulation by PTH. - Major/most important action: increase absorption of calcium and phosphate in intestine - Kidney action: stimulates renal tubule reabsorption of calcium and phosphate - Other: stimulates FGF23 secretion by osteoblasts and osteocytes, suppresses PTH synthesis in parathyroid gland

Question 3

Give the names of the two main body fluid compartments and the percentage of total body water in each. Give the names of the two main subdivisions of the ECF and the percentage of the ECF in each division.

Answer 3

• ICF: 2/3rd of total body water - ECF: 1/3rd of total body water a.) Interstitial fluid ~ 75% of ECF b.) Plasma volume ~25% of ECF c.) Transcellular fluid = CSF, pericardial fluid, synovial fluid, intraocular fluid, etc.

Question 4

Give the effect of EPO on RBC production.

Answer 4

• Increases RBC count

Question 4

Give the source of FGF 23. What is it? What are the effects of FGF23 on the kidney? What stimulates the secretion of FGF23? What are the relationships between FGF23 and PTH and calcitriol and their actions?

Answer 4

• Source: osteoblasts and osteocytes in bone - What is it: peptide hormone - Effects on kidney: decreased reabsorption of phosphate (like PTH), decreases production of calcitriol (opposite to PTH) - Stimulates secretion: elevated phosphate and calcitriol

Question 5

Give the major stimuli for EPO secretion.

Answer 5

• Anemia, hypoxia

Question 6

Describe how protein is reabsorbed in the proximal tubule

Answer 6

• Occurs in first half of proximal tubule - AAs reabsorbed via Na+-dependent secondary active transporters - smaller peptides broken down into AAs or di/tri peptides by peptidases on apical surface - larger peptides taken up by endocytosis, vessels fuse with lysosomes containing enzymes that degrade protein

Question 6

Explain why all organic acids competitively inhibit secretion of other organic acids and why all organic bases competitively inhibit secretion of all other organic bases.

Answer 6

• Organic acids and bases utilize carrier-mediated transport in the secretion process. Therefore secretion of one substance might be decreased in the presence of another that is competing for the carrier protein.

Question 7

State the two main sources of EPO production. Which organ makes the most (~90%) EPO?

Answer 7

• Main source = kidney - Other source = liver, insufficient to maintain RBC count if kidney function declines

Question 7

Identify the kidney structure that performs countercurrent exchange.

Answer 7

• Vasa recta

Question 8

Outline the RAAS system. Where is each produced?

Answer 8

• Renin: released from JG cells of kidney in response to low BP and SNS stimulation of beta-1 receptors on granular cells/renal baroreceptors - Angiotensin: released from liver. Renin degrades into angiotensin I. ACE converts angiotensin 1 into angiotensin II, which causes renal retention of salt and water, general vasoconstriction, increased SNS tone, thirst, ADH secretion and aldosterone secretion - Aldosterone: released from adrenal cortex under angiotensin II. Increased renal reabsorption of Na which raises BP

Question 9

Explain the importance of urea recirculation in the medulla of the kidney. Where is urea reabsorbed and where is it secreted?

Answer 9

• Urea is key solute involved in regulation of water excretion from kidney. - About half reabsorbed in proximal tubule through iso-osmotic reabsorption with water - Same amount reabsorbed in proximal tubule is secreted back into thin loop (descending and ascending) of Henle: this traps urea in nephron for a while before it can be excreted, this raises osmolarity of medullary interstitium. - Thick ascending loop: roughly the same amount of urea that was filtered is now found, higher concentration as less water. Impermeable to urea mostly. - Distal tubule and cortical collecting ducts impermeable to urea mostly. - Medullary collecting ducts: reabsorption of urea (exact amount dependent on concentration of ADH, which activates urea transporter) - Some of urea is excreted, depending on amount you have to begin with. • all movement of urea is down chemical concentration via uniporter, passive movement

Question 10

Describe the effect of increased plasma K on the Na/K ATPase pump on the basolateral membrane of the principal cells in the late distal tubule (second half of distal tubule) and collecting duct. What is the probable effect of aldosterone on this pump? What other effects does aldosterone have on the collecting ducts?

Answer 10

• High K stimulates the Na/K ATPase pump on the basolateral surface causing K to be pumped into tubular cell and then be secreted out into the tubular fluid down concentration gradient. - Aldosterone probably also stimulates the Na/K ATPase pump causing more K to be secreted as well as more Na to be reabsorbed.

Question 11

State the normal pH of the blood. How does the pH change in a pt with acidosis or alkalosis?

Answer 11

• Normal pH = 7.4 - Acidosis = any process to lower pH, Acidemia = pH < 7.35 - Alkalosis = any process to increase pH, Alkalemia = pH > 7.45

Question 11

Describe glutamine-NH4+ buffering in severe respiratory acidosis.

Answer 11

• Used when bicarb has been reabsorbed, phosphate buffer is saturated, yet severe respiratory acidosis still exists. - In proximal tubule: Glutamine can enter the tubular cell from either the interstitium or tubular fluid and is then metabolized to 2HCo3- and 2NH4+. Bicarb is moved into interstitium as new bicarb and NH4+ is moved against Na+ (counter transport), combines with Cl- and is excreted from body. - Elsewhere in tubule (collecting duct): ammonia secreted from tubular cell combines with H+ forms NH4+, which combines with Cl- and is excreted. Bicarb generated as new from bicarb system.

Question 12

Describe what is meant by the following: a.) lumen of nephron, b.) luminal side of tubular cell, c.) apical side of tubular cell, d.) basolateral side of tubular cell

Answer 12

a.) lumen of nephron: inside of nephron b.) luminal side: side of tubular cell facing the lumen of the nephron, aka the apical side c.) apical side: see above d.) basolateral side: side of tubular cell facing the interstitial fluid containing the Na/K ATPase pump required to maintain low intracellular Na+ concentration so that Na+ moves into tubular cell down gradient

Question 13

Sketch and label parts of nephron and its associated blood vessels. Describe function with each part of the nephron: include substance/solute, transporter involved, where in proximal tubule. Which is diluting segment? Which is responsible for most isosmotic reabsorption?

Answer 13

See picture in word doc Functions: 1. Glomerulus/Bowman’s capsule: non-selective filtration of blood into Bowman’s capsule. Fluid in capsule = pre-urine filtrate 2. Proximal tubule: reabsorbs ~67% of water (isosmotic), Na+, Cl- and K+ that was filtered, practically all glucose and AAs reabsorbed, ~90% of HCO3- reabsorbed a.) Na+ reabsorption: via Na/H antiporter in both first and second halves b.) Glucose and lactate reabsorption: via Na+-dependent secondary active transporters in first half c.) AAs, small peptides and peptides: small peptides broken down into AAs or di/tri peptides by peptidases on apical surface. AAs reabsorbed via Na+-dependent secondary active transporters. Larger proteins taken up by endocytosis, vessels fuse with lysosomes containing enzymes that degrade protein. d.) Cl- reabsorption: in second half via parallel Na-H and Cl-anion antiporters on apical side and via K-Cl symporter on basolateral side e.) Water reabsorption: reabsorption of above solutes raises osmolality of interstitial fluid above that of tubule fluid. This provides driving force for passive movement of water by osmosis via aquaporins f.) Secretion of H+: via Na/H antiporter or via H-ATPase 3. Loop of Henle (thin descending limb, thin ascending limb only in juxtamedullary nephron, thick ascending limb) a.) This segment of nephron is responsible for counter current multiplication – concentration and dilution of urine b.) Thick ascending limb is the diluting segment: NaCl is pumped out of tubule, water cannot follow as this are is impermeable 4. Macula densa: specialized epithelial cells found at distal end of thick ascending loop adjacent to the glomerulus with afferent/efferent arterioles. Measures flow of fluid and rate that NaCl is being delivered to distal tubule. Releases mediators that controls vasodilation/vasoconstriction of afferent arteriole to maintain relatively constant GFR and renal blood flow despite changes in systemic arterial BP. 5. Distal tubule: a.) First part: similar to thick ascending limb of Henle; reabsorbs Na, K and Cl, but virtually impermeable to H2o and urea. Functions as diluting segment. b.) Second part (aka cortical collecting duct): 1.) principle cell with receptors for aldosterone, reabsorbs Na and secretes K; 2.) another cell type here reabsorbs K and secretes H+ 6. Collecting ducts: responsive to ADH determines if kidneys produce a concentration or dilute urine a.) Cortical portion: contains principal cells responsive to aldosterone b.) Medullary portion: urea uniporters

Question 13

Explain the effect of low urine pH on the net secretion, excretion and plasma concentration of organic acids (eg. ASA).

Answer 13

• Membranes are more permeable to compounds in proton-associated forms. When aspirin (ASA -) is secreted in acidic tubular lumen, it combines with proton (ASA-H) and leaks back into tubular cell and blood. Less of it is excreted and plasma concentration is greater than if urine were alkaline.

Question 14

State which cells produces most renin and how renin release is controlled. Which division of the ANS innervates the cells that produce renin? What is the effect of increased/decreased nervous system stimulation? What structure/part of the nephron releases chemical messengers that influence renin release?

Answer 14

• Cells: from JG cells - How: low BP (direct effect) or in response to beta-1 (SNS) receptor activation on granular cells/renal baroreceptors - ANS division: SNS - Effect increased stimulation from SNS: increase renin release = increase BP - Effect decreased stimulation from SNS: decrease renin release = decrease BP - Structure: juxtaglomerular region

Question 14

Describe the variables that are used to estimate GFR using the Cockcroft-Gault equation. How could you use the estimated GFR to help in determining dosages of drugs that are excreted in the urine?

Answer 14

• Plasma levels of creatinine, age and lean body weight - For majority of pts and for most drugs tested that did not have narrow thresholds for toxicity, there was little difference in the drug dose that would be administered using this equation. With drugs that have a narrow therapeutic index, this equation was less reliable in assessing the risk of kidney damage. According to the Natl Kidney Disease Education Program, the MDRD equation is a better for estimating GFR in adults. Depending on which equation is used, there is some disagreement in which should be used for modifying drug dosages in elderly and people with kidney disease.

Question 14

Explain what is meant by the term ineffective osmole.

Answer 14

• Effective osmole: ECF with higher osmotic pressure than ICF in cell causes water to leave cell and cell to shrink. This osmotic pressure causing osmosis between two compartments only occurs when barrier is less permeable to the solute than to water. Eg. Water more easily crosses barrier than Na. - Ineffective osmole: ECF with higher osmotic pressure than ICF in cell does not cause cell to shrink. Net osmosis of water across the barrier doesn’t occur as the solute diffuses into the cell lowering the ECF osmotic pressure and raising the ICF osmotic pressure. Eg. Occurs with urea. This occurs as the membrane is permeable to urea, so urea is considered an ineffective osmole.

Question 15

Describe the effect of angiotensin II on the following: a.) vascular SM b.) adrenal cortex c.) kidneys: efferent arteriole and proximal tubule sodium reabsorption d.) CNS: thirst center, release of ADH, sympathetic tone

Answer 15

• a.) vascular SM: contraction - b.) adrenal cortex: release of aldosterone - c.) kidneys: contraction of efferent arteriole, increased reabsorption of Na+ in the proximal tubule - d.) CNS: causes thirst leading to water intake, induces ADH release, increases sympathetic tone

Question 16

Explain why the threshold concentration for glucose is less than the transport maximum for glucose.

Answer 16

• Concept of splay - Transports maximum is not identical in all nephrons/tubules - Differs in that not all tubules have the same transport maximum. A tubule with lower than average ability to reabsorb glucose will let glucose spill into urine while other tubules have still not reached their individual transport maximum.

Question 17

Explain why the clearance of PAH is a measure of the effective renal plasma flow (ERPF).

Answer 17

• Effective renal plasma flow refers to the fact that only the plasma that goes to the nephron is useful for renal function. Some blood plasma goes to renal fat and does not have an effect on renal function directly. - PAH refers to an exogenous substance used clinically that is filtered as well as secreted, almost none is seen in renal vein. - Remember, clearance is the volume of plasma per unit time from which all substance has been removed. Therefore PAH is a good measure of ERPF.

Question 18

Describe each of the following conditions or reflexes and state when it occurs: a.) vesicoureteral reflux b.) ureterorenal reflex c.) micturition reflex d.) sympathetic storage reflex e.) somatic storage reflex (guarding or continence reflex)

Answer 18

• a.) vesicoureteral reflux: bladder contracts during urination, ureters are not totally closed permitting urine to backflow into the ureters leading to their enlargement. Can be so severe that pressure in ureters and renal pelvis can become high enough to damage them. Occurs in people with ureters’ path through bladder wall is less oblique and shorter - b.) ureterorenal reflex: Sensory afferents from affected ureter cause a reflex constriction of renal arterioles thus decreasing fluid production from kidneys. This reflex prevents excessive flow of fluid into the pelvis of the kidney with a blocked ureter. - c.) micturition reflex: when urine is flowing into bladder, stretch receptors send afferent signals via pelvic nerves to sacral segments of spinal cord. PSNS nerves carry efferent motor signal back to bladder detrusor telling it to contract thus raising pressure inside bladder. This is self-regenerating and causes cycle. Reflex fatigues and bladder relaxes. As bladder continues to fill, the reflex gets stronger and reoccurs at higher rates. - d.) sympathetic storage reflex: bladder distends and generates afferent activity travelling to spinal cord, which normally causes an efferent PSNS response in a relaxed state. This reflex refers to SNS firing from the ganglionic level to decrease PSNS inputs to bladder. - e.) somatic storage reflex: in response to sudden increase in intra-abdominal pressure such as during cough, laugh or sneeze, efferent somatic motor neurons from nucleus of Onuf are activated, which synapse onto the external sphincter.

Question 18

Describe the variables that are used to estimate GFR using the Modification of Diet in Renal Disease (MDRD) study. Just know variables that are plugged into calculator.

Answer 18

1.) Serum creatinine 2.) Age 3.) Sex 4.) Race (for adults greater than equal to 18) • appears to be more accurate for GFRs between 60 and 120 ml/min

Question 19

Define renal clearance.

Answer 19

• Volume of plasma per unit time from which all of a substance has been removed. Key here is it not measured in amount of substance, but volume of plasma. It is a theoretical concept since of course the kidney really removed some of the substance from all the plasma that was filtered in 24 hours. This term pretends that all the substance in the urine came from removing all the substance in a certain volume.? - Significance: gives information about kidney function especially when substance is only filtered.

Question 21

Describe the immediate effect on the bladder of spinal cord damage above the sacral region (ie. What is the effect of spinal shock on bladder function?)

Answer 21

• With initial injury, spinal shock (?) causes micturition to be suppressed. Bladder continues to fill until overfilled causing overflow incontinence. With time, the micturition reflex returns but the pt has no voluntary control and cannot initiate or prevent bladder emptying. Some pts can learn the reflex through stimulation of the skin in the genital region. Therefore symptoms are not immediate. Eventual dysfunction is automatic bladder, not overflow incontinence.

Question 21

Describe how chronic renal failure affects the pt’s bones.

Answer 21

• chronic renal failure = low GFR = high phosphate in plasma = elevated PTH = increased bone resorption = renal osteodystrophy

Question 22

Explain how plasma osmolality and baroreceptor signals control the release of ADH.

Answer 22

• When osmolarity of ECF is greater than ICF of hypothalamic osmoreceptors cells, which causes them to shrink. This induces release of ADH from posterior pituitary. - ECF volume sensors/baroreceptors indirectly sense intravascular pressure in low pressure areas (atria and pulmonary vasculature) and high pressure areas (carotid sinus, aortic arch). Decreased pressure/decreased blood volume stimulates release of ADH as well as triggers a thirst response (if large reduction).

Question 23

State if countercurrent exchange involves essentially passive or active transport. How does the process of countercurrent exchange allow medullary blow flow and removal of some medullary interstitial fluid without causing the washout of the concentration gradients in the renal medullary interstitium?

Answer 23

• Essentially passive transport - How: a.) Too much blood flowing through kidney medulla can wash out gradient. Preventing by: only 1-2% of efferent arteriole blood enters medullary region via vasa recta and remainder in peritubular capillaries. b.) Vasa recta runs in close proximity to descending and ascending limbs creating a counter current system. c.) Osmolarity is higher at the lower aspect of the medullary interstitium than at the higher aspect. d.) Blood osmolarity is slightly higher when blood enters the vasa recta and starts descent to deeper medulla. Water leaves capillary and NaCl / urea enter. This increases the osmolarity of the blood in the vasa recta e.) As blood starts flowing towards the cortex, blood osmolarity is higher than interstitium. Water enters capillary and NaCl / urea move passively out down concentration gradient. f.) This results in blood entering venous circulation having an osmolarity just higher than blood entering. Therefore the gradient setup by the loop of Henle is not washed out.

Question 24

State where ADH acts in kidney and briefly describe its role in controlling water concentration in urine

Answer 24

• Osmolarity of blood is measured by osmoreceptors in hypothalamus. - If ECF more concentrated than ICF = osmoreceptors shrink = increased ADH release from posterior pituitary = concentrated urine production - If ECF more dilute than ICF = osmoreceptors swell = decreased ADH release from posterior pituitary = dilute urine production - ADH acts on distal tubules and collecting duct in kidney to: increase H2o permeability = increases H2o reabsorption = less h2o excreted

Question 25

Explain why a person with a very high blood level of glucose will have a high urine volume (high urine excretion rate). What is osmotic diuresis?

Answer 25

• When un-reabsorbed glucose in nephron d/t transport maximum being reached and spillage into tubule, this osmotically active substance holds sodium and water leading to an increase in urine excretion. This is a process known as osmotic diuresis.

Question 27

What is meant by the term atonic bladder. What types of lesion can cause an atonic bladder? Does this type of dysfunction cause overflow incontinence?

Answer 27

• Atonic bladder = no micturition reflex as sensory signal from bladder are missing. Bladder becomes filled to capacity and then overflows a few drops at a time through the urethra. - Causes: a.) Sacral dorsal roots destroyed with spinal cord in tact. Can be d/t tabes dorsalis from tertiary syphilis b.) Crush injury to the sacral region of spinal cord. - Yes, it causes overflow incontinence.

Question 28

List the Starling forces and tell whether each would promote filtration or reabsorption at glomerular capillary.

Answer 28

• Promoting filtration: glomerular hydrostatic pressure, note: Bowman’s oncotic pressure usually 0 - Promoting reabsorption: glomerular oncotic pressure – higher on efferent arteriole end (as ultrafiltrate left behind proteins) - Net: filtration

Question 29

Define transport maximum (aka tubular maximum or maximum tubular transport capacity).

Answer 29

• Refers to the maximum rate of reabsorption of substance in kidney. - First: calculate the rate of filtration of substance = GFR x plasma concentration of substance (Px), where GFR = Ccr (clearance of creatinine) - Second: calculate the rate of excretion of substance = concentration of substance in urine (Usubstance) x urine rate flow (V) - Compare the two values: rate of filtration – rate of excretion = reabsorption. When it remains constant, that is the maximum rate.

Question 29

Explain why a high-protein diet can enable people to concentrate their urine better than people with low protein intake.

Answer 29

• People who eat high-protein diet produce more urea. As a result of more urea reabsorbed and generating a higher osmolarity in medullary interstitium, more water can be reabsorbed, resulting in more concentrated urine.

Question 30

Describe the compensatory responses to dehydration or overhydration. Include changes in plasma osmolarity, brain osmoreceptors, atrial stretch receptors, ADH secretion, water excretion and thirst.

Answer 30

• Dehydration = decreased blood volume = low volume sensed by baroreceptors in atria and large veins entering atria = less firing signal via NTS of medulla = release of ADH from posterior pituitary & increased SNS activity = ADH release via renin/ang II. Also atria decreases release in ANP = more renin/ang II = ADH release. Ang II also increases thirst. Lastly, osmoreceptors in hypothalamus shink if ECF more concentrated than ICF = increased ADH release. ADH acts on distal tubules and collecting duct in kidney to: increase H2o permeability = increases H2o reabsorption = less h2o excreted - Overhydration = opposite effects of dehydration (see above)

Question 31

Assuming creatinine production remains constant, be able to explain how changes in GFR affect serum creatinine level. If told that the creatinine serum concentration is above normal, state whether GFR is probably above or below normal.

Answer 31

• As serum creatinine level increases, GFR increases. If pt had a plasma creatinine of 1mg/100 ml their GFR would be approximately 125ml/min or 180L/day - If above normal serum creatinine, GFR would be below normal - Renal disease that caused a loss of nephrons would lead to higher than normal serum creatinine. - Normal creatinine = 0.7-1.5 mg / 100 mL dependent on muscle mass

Question 33

Briefly describe the two intrinsic renal mechanisms for autoregulation of glomerular filtration rate and renal blood flow.

Answer 33

GFR: total volume of fluid filtered from plasma into nephrons per unit time RBF: volume of blood delivered to the kidneys per unit time 1.) Myogenic mechanism: blood vessels resist stretching during increased arterial pressure d/t contraction of vascular smooth muscle. Rise in pressure in afferent arteriole met by vasoconstriction = decrease rise of glomerular hydrostatic pressure = decrease rise in GFR. Conversely, when pressure falls, reflexive vasodilation. 2.) Tubuloglomerular feedback mechanisms: increased renal arterial pressure = increased RBF and GFR = increased flow rate through proximal tubules = less time to absorb water and NaCl in proximal tubule = larger than normal volume of tubular flow into loop of Henle per unit time = macula densa senses increased flow via cilia and increased NaCl = chemical mediators (? Adenosine) released from macula = chemical mediators act on SM in afferent arteriole causing vasoconstriction, also possible inhibits release of renin = less angiotensin II = less vasoconstriction = decreased GFR

Question 35

Explain why drugs that inhibits PG synthesis can cause renal damage. Be able to recognize the common drugs that inhibit PG synthesis.

Answer 35

• Inhibitory drugs: NSAIDS (ASA, ibuprofen, naproxen) - Why: reduction of PG synthesized means that unopposed vasoconstriction occurs, which reduces blood flow to kidney leading to ischemic injury. Most RBF is to cortex, but medullary blood flow tends to be especially dependent on vasodilatory PGs. Medullary ischemic damage is often first sign of injury resulting from overdose of NSAIDS. Juxtamedullary nephrons (with long loop of Henle’s) that concentrate urine – another first sign of NSAID abuse is decreased ability to concentrate urine.

Question 36

Briefly explain why some lung CAs are associated with changes in ADH level and water balance. What is SIADH?

Answer 36

• Certain lung cell tumors secrete ADH, which is not under normal physiological controls that regulate ADH secretion from hypothalamus/posterior pituitary - SIADH = syndrome of inappropriate ADH secretion = inappropriate water retention resulting in hyponatremia with lower than nml osmolarity – true hyponatremia

Question 38

Describe the different transports mechanisms that are used for reabsorption and secretion. Describe how sodium, glucose, and water are reabsorbed. Be able to trace path from tubule lumen to capillary describing transport process used. Describe how proteins and peptides are reabsorbed.

Answer 38

1.) Endocytosis/transcytosis: - What: immunoglobulins, peptide hormones, small proteins, small amounts of large proteins - Where: reabsorbed in proximal tubule - How: a.) immunoglobulins: transcytosis from basolateral side to apical side for host defense of kidney and prevention of UTIs b.) other: enzymes on luminal/apical side that partially degrade small peptides into AAs, transported by carrier proteins (secondary active transport coupled to Na) into cell and across basolateral side (via facilitated diffusion using uniporter). Larger proteins can bind to receptors, endocytosed and degraded into constituent AAs then transported via carrier proteins across basolateral side. 2.) Reabsorption of Na: - Where: proximal tubule - How: a.) strong electrochemical gradient drives Na+ into proximal tubule cell across apical membrane via…. b.) Much through secondary active transport coupled to another solute (AAs, glucose) c.) Na-H+ antiporter d.) Na with Cl paracellularly through tight junctions e.) Once in cell, moves to interstitial fluid via Na-K ATPase 3.) Reabsorption of glucose: - Where: proximal tubule - How: a.) Apical side: secondary active transport coupled with Na down electrochemical gradient b.) Basolateral side: facilitated diffusion via glut transporters 4.) Reabsorption of water - Where: proximal tubule - How: reabsorption of solutes creates a transtubular osmotic gradient for water to move across via aquaporins 5.) Secretion mechanisms: mechanisms are same as reabsorption, secretion actively pumps substance out of interstitial fluid into tubule cell, it then flows down concentration gradient into tubular lumen via facilitated diffusion or through open channels.

Question 39

Describe phosphate buffering in respiratory acidosis.

Answer 39

• Used when bicarb buffer system has been saturated, but nephron is still secreting H+ as a result of still existent respiratory acidosis. - CO2 entering tubular cell, going through standard process to generate HCO3- (new), which is being reabsorbed into interstitial fluid, and H+ secreted into tubular fluid. H+ combines with phosphate buffer moiety in tubular lumen and is excreted.

Question 40

State which part of the nephron is responsible for countercurrent multiplication. Be able to recognize a correct description of this process.

Answer 40

• Loop of Henle - Pumping NaCl from thick ascending loop lowers the osmolality of the outflow from the loop of Henle while raising the osmolality of the interstitium. - Descending limb is permeable to water and water leaves the descending limb to move into higher osmolality interstitium. Fluid left in tubule is now hyperosmotic to plasma. - Fluid reaches the turn and enters the thin ascending limb which is impermeable to water but permeable to NaCl, which moves passively out down concentration gradient increasing osmolality of interstitium.

Question 40

State the effect of alkalosis (acute / chronic) on K. Does it cause hypokalemia or hyperkalemia?

Answer 40

• Acute metabolic alkalosis: stimulates Na/K ATPase on principal cells of late distal tubule and collecting ducts = K concentration in tubular cell increases = K secreted and excreted = hypokalemia - Chronic metabolic alkalosis: when in association with decreased ECF results in significant increase in K excretion causing hypokalemia. Why? Low volume = RAAS activation = more aldosterone = even more K secretion = more K excretion = worsened hypokalemia.

Question 41

Be able to give the effect of ethanol, morphine and nicotine on the release of ADH.

Answer 41

• Increase ADH secretion = morphine, nicotine - Decrease ADH secretion = ethanol

Question 43

Describe the effect of PTH on the kidney.

Answer 43

1.) stimulates final hydroxylation of vit D to active form calcitriol 2.) increases renal-tubular calcium reabsorption 3.) reduces proximal tubular reabsorption of phosphate, therefore increases excretion and decreasing EC phosphate concentration 4.) Effect: stimulates movement of Ca from bone into EC fluid

Question 44

Explain how/why diabetes insipidus can cause the excretion of large amounts of dilute urine. Distinguish between central and nephrogenic diabetes insipidus.

Answer 44

• Central diabetes insipidus: pts don’t make ADH possibly d/t hypothalamic lesion - Nephrogenic diabetes insipidus: pts lack either ADH receptors or type of aquaporin. - In either case, patient produces large amount of dilute urine since they cannot take advantage of the medullary interstitial gradient to remove water from the collecting ducts.

Question 45

Define term filtration fraction. How do changes in the filtration fraction affect the oncotic pressure at the efferent end of the glomerular capillaries?

Answer 45

• Definition: percent of renal plasma flow filtered at glomerulus, ie. FF = RPF/GFR, which is usually ~20% - Changes to FF: if increased = oncotic pressure at efferent end of capillary is increased above normal; if decreased = oncotic pressure at efferent end of capillary is decreased above normal. This can be d/t various clinical / pathological conditions.

Question 46

Describe ultrafiltration at the glomerulus, tubular reabsorption, and tubular secretion.

Answer 46

• Ultrafiltration: bulk flow fluid from glomerular capillaries into Bowman’s capsule under high hydrostatic pressure. Freely filtered substances (those at same concentration in plasma and filtrate) are Na, K, Cl, HCO3-, glucose, urea, AAs, peptides (eg. insulin, ADH) - Tubular reabsorption: process by which substances are reabsorbed into the blood, mainly at the proximal tubule - Secretion: process by which substances are moved into nephron (not at Bowman’s capsule) from peritubular capillaries

Question 47

Explain why creatinine clearance as a measure of GFR becomes less accurate in a renal disease pt with very low GFR. In such pt, does the creatinine clearance over estimate or underestimate the GFR?

Answer 47

• Creatinine clearance as a measure of GFR slightly overestimates as about 10-20% of what is excreted is secreted. - In pt with low GFR, secreted component is a relatively larger fraction, so GFR is severely overestimated than in pts with normal GFR.

Question 48

Explain why elevated plasma urea concentrations do not elicit ADH (aka AVP aka vasopressin) release.

Answer 48

• Urea is an ineffective osmole and doesn’t cause hypothalamic osmoreceptors to shrink thus causing the release of ADH.

Question 49

Describe the effect of increased aldosterone and increased K on the reabsorption or secretion of K in the late distal tubule (second half of distal tubule) and the collecting duct.

Answer 49

• Increased aldosterone/K causes an increase in K secretion via action on Na/K ATPase pump - Reabsorption decreases

Question 51

Give proposed reason why autoregulation of GFR and RBF is useful. Can autoregulation still protect the kidney in pts with severe systemic HTN?

Answer 51

1.) many activities cause changes in BP so it is useful to uncouple this from GFR and RBF 2.) BP changes suddenly and do not want to also have changes in urinary excretion that would affect fluid and electrolyte balance 3.) Excessive BP (HTN) could cause glomerular damage - HTN can cause renal damage. Renal damage can cause HTN. This can result in bad feedback loop. So autoregulation would unlikely not be protective in this case.

Question 52

Sketch a Davenport diagram and label the x and y axis. Put in 40 PaCO2 line and show where it intercepts the line for normal pH.

Answer 52

• X-axis = pH - Y-axis = HCO3- see word doc

Question 53

Define secretion in terms of net movement of a solute.

Answer 53

• Refers to secretion of substance from the blood (peritubular capillaries) into the lumen of the nephron.

Question 54

Explain why diuretics which inhibit sodium and water reabsorption can cause the depletion of body K.

Answer 54

• Diuretics inhibit reabsorption of water at some point in nephron usually by increasing excretion of K causing hypokalemias, except aldosterone blockers, which can develop hyperkalemia. How? a.) Loop diuretics block Na/K/2Cl pumps in thick ascending loop causing higher flow of fluid through late distal tubule and collecting ducts. This causes K secretion to increase (mechanism not explained) and excretion to increase. b.) Thiazide diuretics inhibit NaCl reabsorption in early distal tubule. This inhibits water reabsorption so higher fluid to late distal tubule and collecting ducts. Again, this causes K secretion to increase (mechanism not explained) and excretion to increase. c.) Aldosterone blocker: decrease Na reabsorption, K secretion and water reabsorption. These are K excretion-sparing, cause increases in serum K.

Question 56

Give names of the autacoids/hormones which can vasodilate the afferent and efferent arterioles. Which cause vasoconstriction?

Answer 56

• Vasodilate: PGE2, PGI2, NO - Vasoconstrict: NE, Epi, endothelin, angiotensin II (preferentially vasoconstricts efferent arteriole, afferent arteriole is protected from this effect by vasodilators esp NO and PGs)

Question 57

Describe the body’s response to a sudden decrease in plasma/blood volume as a result of a hemorrhage.

Answer 57

• Hemorrhage results in following: 1.) Drop in arterial BP = a.) Increase in activity of renal sympathetic nerves (via carotid sinus and aortic arch reflexes) b.) Intrarenal receptors detect drop and combined w/ SNS activity = renin secretion 2.) Increase renal SNS = renin release (as above) and constriction of renal arteries 3.) Renin increase = RAAS system, angiotensin II = constriction of renal arteries & increase in tubular Na and water reabsorption = decrease renal excretion of Na and water = raise arterial BP 4.) Constriction of renal arteries (afferent?) = decrease in RBF and GFR = decrease in renal excretion of Na and water = raise arterial BP

Question 58

Calculate the clearance of a compound given the urine volume produced per minute, urine concentration of the compound and plasma concentration of the compound.

Answer 58

• Cx = (Vdot x Ux)/Px - Cx = clearance of X - Vdot = urine flow rate - Ux = urine concentration of X - Px = plasma concentration of X - Hint: retain units to make sure answer = ml/min - Meaning: substance with larger clearance than reference (inulin or creatinine) means secreted, smaller = reabsorbed

Question 60

Outline the pathway from angiotensinogen to angiotensin II. Where do renin and angiotensin converting enzyme (ACE) act in this pathway?

Answer 60

• Renin (released from JG cells) converts angiotensinogen (released into circulation by liver) into angiotensin I. Angiotensin I is converted into angiotensin II by ACE (endothelial cells in lungs).

Question 61

Describe the process of bicarb reabsorption. What is secreted in this process? Is it excreted? How can this process compensate for acidosis? Alkalosis?

Answer 61

1.) Compensation for acidosis - Kidney reabsorbs 100% of filtered bicarb; 90% in proximal tubule and 10% in collecting ducts - How? a.) In case of metabolic acidosis where much bicarb produced. Fluid in tubular lumen contains bicarb filtered at glomerulus. When Na+ is absorbed by tubular cell, H+ ions are actively secreted into tubular lumen. The H+ ion joins with bicarb to form H2co3, which breaks down into CO2 and H2o. CO2 diffuses into tubular cell (no carrier necessary), combines with H2o to make more H2co3 (via carbonic anhydrase) and break down into Hco3- and H+. Bicarb then moves down concentration gradient across basolateral membrane via carrier mediated diffusion. So, H+ secreted from body, but not excreted for every bicarb ion reabsorbed, the H+ is part of water now. b.) In case of respiratory acidosis when using bicarb system and all bicarb reabsorbed, but H+ still secreted. Increased CO2 in blood and interstitium diffuses into tubular cell (not filtered), combines with water and via carbonic anhydrase forms H2co3 and dissociates into HCO3- and H+. H+ secreted into tubular lumen (combines with Cl-) and HCO3- through carrier into interstitial fluid. There is limit to how much H+ can be secreted into tubular fluid, pH cannot be lowered past 4.5. c.) When bicarb system saturated, can use phosphate buffer when respiratory acidosis still exists – see next question d.) When bicarb reabsorbed, phosphate buffer saturated and severe respiratory acidosis exists, can use ammonia buffer system (glutamine-NH4+) – see next question 2.) Compensation for alkalosis - Kidney excretes bicarb - How? a.) Less CO2, less H+ secreted, so less filtered bicarb is reabsorbed from filtrate and increased excretion.

Question 62

Explain why the ICF is nearly always identical to the ECF in osmotic concentration. How does the size and osmolality of the ICF and ECF compartments change with the ingestion of pure water? With the addition of isotonic saline? With the addition of hypertonic saline?

Answer 62

• ?? why ICF is nearly identical to ECF in osmotic concentration?? - Pure water: ECF osmolality would be diluted (be decreased), ie. become hypotonic to ICF. Water would enter ICF from ECF causing cells (ICF compartment) to swell. - Isotonic saline: ECF osmolality would not change, fluid will stay in the ECF compartment and cause only that compartment to swell. - Hypertonic saline: ECF osmolality would increase, ie. become hypertonic to ICF. Water would enter ECF from ICF causing ECF compartment to swell and ICF compartment (cells) to shrink.

Question 63

Describe what is meant by the term automatic bladder. What type of lesion can cause an automatic bladder? Do the symptoms of automatic bladder appear immediately after the lesion?

Answer 63

• Automatic bladder = micturition reflex intact, brain cannot control, facilitate or inhibit the reflex, so emptying of bladder eventually becomes automatic. - Causes: a.) spinal cord transection - With initial injury, spinal shock (?) causes micturition to be suppressed. Bladder continues to fill until overfilled causing overflow incontinence. With time, the micturition reflex returns but the pt has no voluntary control and cannot initiate or prevent bladder emptying. Some pts can learn the reflex through stimulation of the skin in the genital region. Therefore symptoms are not immediate.

Question 65

Explain why large, negatively charge molecules are less permeable to the glomerular capillary than smaller or neutral molecules.

Answer 65

• Glomerular capillaries are lined with endothelial cell layer with spaces between cells that are larger and further apart than in a “standard” capillary. Podocytes serve as another layer with pores in between them known as filtration slit, each with a closed thin membrane. - Filtration barrier is charge: endothelial cells lined with negatively charged mucopolysaccharides and also negative charges on filtration slits. Large negative molecules are repelled and are not usually filtered.

Question 66

Describe the effect of a chemical buffer when a strong acid or strong base is added to a body fluid.

Answer 66

• Strong acid: would dissociate completely so in absence of buffer, the number of free protons would equal the concentration of the acid causing large decrease in pH. With buffer system present, most of protons combine with conjugate base and there is just a small rise in number of free protons and therefore only a small change in pH. - Strong base: would dissociate completely so in absence of buffer, the number of free hydroxide ions would equal concentration of base causing a large increase in pH. With buffer system present, most hydroxide ions combine with conjugate acid and there is just a small rise in hydroxide ions and therefore only a small change in pH.

Question 67

Explain how plasma osmolality and baroreceptor signals affect thirst. How does angiotensin affect thirst?

Answer 67

• If large reduction in pressure/blood volume is detected by baroreceptors, thirst response is triggered. - Thirst is also triggered when thirst osmoreceptors shrink (water driven out) when increased osmolarity of ECF occurs. - Angiotensin II acts on brain to increase thirst.

Question 68

List nerves that innervate bladder, internal and external sphincters. State which nerve contains each of the following: the SNS input, PSNS input and voluntary motor input. Which nerve/input is the main cause of bladder contraction? Which causes constriction of the external sphincter of bladder?

Answer 68

1.) Bladder: pelvic nerves (PSNS mainly, some SNS), hypogastric nerves (SNS to blood vessels and base, trigone of bladder) 2.) Internal sphincter: hypogastric nerves (SNS) 3.) External sphincter: pudendal nerves (somatic, voluntary control)

Question 69

Briefly describe the functions of the kidney

Answer 69

1.) Regulation of water and electrolyte balance: ECF volume, plasma osmolality 2.) Regulation of arterial BP: via blood volume and RAAS 3.) Excretion of metabolic waste: urea from protein, uric acid from nucleic acid, creatinine from muscle, urobilins from heme 4.) Excretion of foreign substances 5.) Acid-Base regulation 6.) Regulation of RBC production 7.) Vit D production, final step 8.) Gluconeogenesis

Question 71

Explain why alkalinizing the urine (by ingesting bicarb) would be helpful in treating an ASA overdose.

Answer 71

• Membranes are less permeable to compounds in proton-dissociated forms. When ASA (ASA -) is secreted into alkaline tubular lumen (post bicarb ingestion), ASA predominates in ASA- form (proton-dissociated form), which means reabsorption into tubular cell and blood is decreased, more ASA is excreted and plasma concentration is lower than if urine were acidic.

Question 72

Explain why the clearance of inulin is a measure of GFR.

Answer 72

• If substance is only filtered in kidney and not reabsorbed, secreted, stored, synthesized or metabolized in kidney, the amount filtered will appear in urine at same rate it was filtered. - Clearance of this substance then would be the volume of plasma from which the that substance came per unit time. Therefore is substance is only filtred and meets above criteria, this clearance would be = GFR. - Inulin is one such substance that meets the criteria.

Question 73

Describe how the ventilation rate and thus pO2 changes with changes in pH.

Answer 73

• When pH decreases (ie. Higher H+ concentration), ventilation rate can increase to blow off CO2, thus reducing production of H2CO3 and decreasing H+ concentration and thus increasing pH. - Vice versa: increase in pH (ie. Lower H+ concentration), ventilation rate can decrease….

Question 73

Describe how the kidneys compensate for metabolic or respiratory acidosis or alkalosis.

Answer 73

• Alkalosis (respiratory / metabolic): excreting alkaline urine by placing high concentration of HCO3- into it - Acidosis (respiratory / metabolic): excreting acidic urine by reabsorbing all HCO3- that is filtered at the glomerulus and adding it to the plasma

Question 75

Calculate the filtration fraction when given GFR and ERPF.

Answer 75

• Filtration fraction = fraction of plasma delivered to kidneys that is filtered. - Equation: FF = GFR/ERPF

Question 76

Explain why the nephron segments upstream of the distal tubule do not contribute to the regulation of K balance. Hint: does the percent of filtered K reabsorbed before the distal tubule depend on the concentration of K in the plasma?

Answer 76

• Irrespective of the amount of K in the plasma (low, normal, high), roughly the same amount of K is always reabsorbed in the segments of the nephron upstream of the distal tubule (ie. In the proximal tubule and thick ascending limb). What changes depending on the plasma K is the reabsorption or secretion in the distal tubule and collecting ducts. - When K depleted (hypokalemic), K is reabsorbed in the distal tubule and collecting ducts. - When K is normal or high (hyperkalemic), K is secreted into the distal tubule and collecting ducts.

Question 77

Briefly describe the important buffer systems of the body. Where is each most useful? ECF, ICF, kidney tubules?

Answer 77

• ECF: bicarb buffer system: H2o + co2 = H2co3 = H+ + Hco3- - ICF: a.) phosphate buffer system: H3po4 = H2po4- + H+ = HPo4(2-) + H+ = PO4(3-) + H+ b.) protein buffer system: hemoglobin and plasma proteins - Kidney tubules: ammonia buffer system: glutamine = 2bicarb + 2NH4+

Question 78

Describe the effects of constricting either the afferent or efferent arteriole on RBF and GFR. How could you increase the glomerular hydrostatic pressure?

Answer 78

1.) Afferent: decreases both RBF and GFR 2.) Efferent: decreases RBF, but increases GFR as hydrostatic pressure increases with backed up fluid

Question 79

Compare the compositions of the ICF with the ECF. What are the main cations and anions for each? State the main difference between the interstitial fluid and the intravascular portion (plasma) of the ECF compartment. Why do they differ?

Answer 79

1.) ICF: high protein, K and phosphate; low Na and Cl 2.) ECF: high Na, Cl and bicarb; low K a.) Similar for both plasma and interstitial fluid, difference = higher concentration of protein in plasma than interstitial fluid

Question 81

Given the following Davenport diagram, label where a pt would be if in: a.) uncompensated respiratory alkalosis b.) partially compensated respiratory alkalosis c.) uncompensated respiratory acidosis d.) partially compensated respiratory acidosis e.) uncompensated metabolic acidosis f.) partially compensated metabolic acidosis g.) uncompensated metabolic alkalosis h.) partially compensated metabolic alkalosis Also, list conditions that would cause them to be in each.

Answer 81

see word doc Answers: a.) C. Hyperventilation d/t panic attack, short-term high altitude b.) D. Mechanical ventilation, kidney excretes bicarb to correct c.) A. Hypoventilation d/t airway obstruction, depression of respiratory center by opiates/sedatives d.) B. Longer duration of opiate overdose, kidney reabsorbs more/makes bicarb to correct e.) G. Diarrhea, DKA f.) E. Kidney excretes bicarb to correct, hyperventilation at lungs g.) H. Drinking bicarb (alkaseltzer, baking soda), NG suction to remove stomach acid (eg. for ileus), vomiting h.) F. Kidney reabsorbs bicarb to correct, hypoventilation at lungs

Question 82

Describe the alterations in blood pressure, sympathetic tone, renin secretion, angiotensin II production, and ANP production that occur when excess NaCl ingestion occurs in a salt sensitive individual.

Answer 82

• Ingestion of Na in salt senstivie individual causes the following effects: a.) Na+ in ECF causes water to leave ICF and expand ECF = raise in BP b.) Raise in BP = decrease in activity of renal sympathetic nerves = decrease in renin c.) Decrease renin = less angiotensin II (ultimately) = less aldosterone, less vasoconstriction, less sodium reabsorption in proximal tubule, less thirst d.) Decrease aldosterone = decreased sodium reabsorption in collecting duct (and distal tubule?) e.) Plasma volume increase = atrial stretch = ANP secretion = inhibition of renin release, inhibition of angiotensin II action on reabsorption of sodium, inhibition of sodium reabsorption in collecting duct f.) Increased osmolality = brain osmoreceptors shrink = thirst activation and release of ADH g.) ADH release = more water reabsorbed from collecting ducts = further expansion of ECF with decrease in osmolality = decrease in ADH as osmoreceptors swell h.) Thirst = consumption of water * initial rise in BP, followed by mechanisms to bring pressure back to pre-salt ingestion level

Question 84

Explain why an excretion rate that exceeds the filtration rate for a compound means that the compound was secreted.

Answer 84

• If the rate at which something was excreting exceeds that at which it was filtered, then something downstream of where filtration was occurring is causing the rate to exceed filtration. This means that the substance must not only be leaving through filtration, but also through secretion.

Question 85

Describe the effect of hyperkalemia on aldosterone secretion.

Answer 85

• High K causes aldosterone to be secreted from the adrenal cortex directly, not via RAAS system.

Question 86

Identify the portions of the loop of Henle that: a. reabsorb sodium and chloride b. are permeable to water c. are impermeable to water

Answer 86

• a.) thick ascending limb uses secondary active transport to move Na and Cl out via a Na, K, 2Cl co-transporter – therefore this is called the diluting segment of nephron, thin ascending limb is permeable and NaCl reabsorbed here too - b.) thin descending limb is permeable to water - c.) thin and thick ascending limbs are impermeable to water

Question 87

Define the following terms: a.) respiratory acidosis b.) respiratory alkalosis c.) metabolic acidosis d.) metabolic alkalosis e.) acidemia f.) alkalemia

Answer 87

• a.) respiratory acidosis: hypoventilation resulting in lowering pH - b.) respiratory alkalosis: hyperventilation resulting in raising pH - c.) metabolic acidosis: non-respiratory process resulting in lowering pH - d.) metabolic alkalosis: non-respiratory process resulting in raising pH - e.) acidemia: pH below 7.35 - f.) alkalemia: pH above 7.45

Question 88

Describe the effect of ADH (vasopressin) concentration on the cortical collecting ducts and the medullary collecting ducts. Which area of the nephron can develop the highest osmolarity in the presence of ADH?

Answer 88

• Both responsive to ADH causing insertion of aquaporins into membranes. Interstitial fluid osmolarity is highest in medullary cortical duct region, so urine can be concentrated to much higher amount than in cortical duct region where interstitial fluid osmolarity is lower.

Question 89

Explain why the clearance of creatinine is a reasonable estimate of GFR and why measuring it is easier than measuring the clearance of inulin.

Answer 89

• Creatinine is used clinically to measure GFR since it is much more convenient than using inulin (requires IV infusion, catheterization, several hours in office). It is a by-product of muscle catabolism and released into systemic circulation at fairly consistent rate. No IV, no catheter. Pt can just collect urine over 24 hour period at home. - Small amount of creatinine is secreted so using it results in slight over-estimation of GFR.

Question 90

Calculate the ERPF when given the plasma and urinary concentrations of PAH and the rate of urine production.

Answer 90

• Equation for effective renal plasma flow: Cpah = (Upah x Vdot) / Ppah - Cpah = clearance of PAH in ml/min – aka ERPF - Upah = urine concentration of PAH - Vdot = volume of urine collected per minute - Ppah = plasma concentration of PAH

Question 91

Describe the possible cause and symptoms associated with uninhibited neurogenic bladder.

Answer 91

• Cause: partial damage in spinal cord or brain stem that interrupts most of descending inhibitory signals, leaving descending facilitory signals intact - Symptoms: small amount of urine in bladder elicits an uncontrollable micturition reflex, so pt arrives in office with frequent and relatively uncontrolled micturition.