First Pass Miss Flashcards
What effect to catecholamines have on potassium homeostasis via the Beta-2 receptors? What would propranolol do?
B2 receptors promote entry of potassium into primarily skeletal muscle and liver cells -> activate Na/K ATPase
Propanolol would block this B2 receptor effect and may contribute to hyperkalemia
alpha2 agonists blocks insulin release and predisposes to hyperkalemia as well
How does insulin affect K+?
Insulin promotes entry of K+ into skeletal muscle directly by increasing the number of Na/K ATPases
Insulin stimulates Na/H exchanger in liver, bringing Na+ into the cell. Every 3 turns of this leads to 2 K+ brought into the liver cell via the Na/K ATPase
Insulin allows K+ entry into cells passively.
What effect does metabolic acidosis have on potassium homeostasis and why?
Causes hyperkalemia
- > decreased ability to run Na/H antiporter since ECF is already acidic
- > less Na+ inside the cell to run Na/K ATPase -> potassium stays outside of the cells
Is the hyperkalemic effect of metabolic acidosis worse with mineral or organic acids?
Worse with mineral acids, since the anions can’t enter the cell and must stay in the blood
Organic acids can be transported into the cell so the effect of hyperkalemia will be less dramatic. This is because organic acids entering the cell will reduce cellular pH, so Na/H antiporter can still be run to push H+ into ECV, bring Na+ in, and keep K+ balance normal.
What effect will hyperosmolarity have on blood potassium levels and why?
Hyperosmolarity - increased K+ levels
- > Osmotic drag = K+ leaves the cells with water
- > Decreased water inside cells also concentrates K+, passive movement out of cells
How is the majority of the potassium reabsorbed in the kidney?
Majority in proximal tubule
Early proximal tubule - due to solvent drag, from movement of water and sodium into cells, concentrating K+
Late proximal tubule - due to paracellular diffusion, as lumenal potential becomes positive
What is the general underlying problem of the aldosterone paradox?
High K+ levels stimulate aldosterone secretion, which preferentially leads to K+ excretion within minimal Na+ reabsorption
Angiotensin II also stimulates aldosterone secretion, which preferentially leads to Na+ reabsorption with minimal K+ excretion
What justifies the aldosterone paradox?
Angiotensin II - stimulates the WNK kinases and reabsorbs more Na+ via the NCC in the early DCT so less sodium load is delivered to late DCT / principle cells, preventing K+ losses
K+ stimulation of aldosterone - WNK kinases not affected, to K+ is lost more readily, and same amount of Na+ is reabsorbed
What is the function of the WNK kinases? What else are they stimulated by other than Angiotensin II?
They lead to removal of ROMK channels in the distal nephron -> Also stimulated by low blood potassium levels
-> make sense because we want to save potassium from excretion
What effect does pH have on K+ reabsorption and why?
Acidemia - increases K+ reabsorption, can quickly run H/K antiporter -> acidemia is associated with hyperkalemia
Alkalemia - decreases K+ reabsorption, cannot run H/K antiporter -> alkalosis is associated with hypokalemia
What endocrine abnormalities are induced by hypokalemia?
Decreased insulin secretion (already too much K+ in cells)
Increased renin with decreased aldosterone (aldosterone paradox)
-> aldosterone would waste K+
->also remember than WNK kinases are stimulated with hypokalemia -> reduce ROMK levels in collecting duct, preventing K+ wasting
What are the causes of renal K+ loss without HTN?
Vomiting Diuretics - increased Na+ load Bartter syndrome Gitelmans syndrome Renal tubular acidoses types I and II
What is pseudohyperkalemia?
- High K+ due to difficulty with venipuncture which causes local mechanical trauma and muscle K+ release.
- Serum H+ is always higher K+ than plasma K+ when measured in the lab because of clotting process leads to lysis. High WBC / platelet counts can make this effect greater
In what conditions will inadequate urinary excretion lead to hyperkalemia?
- Very late stage renal failure - GFR <20
- Effective circulatory volume depletion - K+ excretion limited by small urine volume
- Hypoaldosteronism - Type IV RTA
What are the clinical ECG manifestations of hyperkalemia? Are these more serious than hypokalemia?
Wide QRS with peaked T waves -> arrhythmias
QT intervals are shortened -> rapid repolarization
-> can cause bradycardia
Widened QRS with severe hyperkalemia can lead to loss of P waves and eventual Vfib
More serious than hypokalemia, more likely to cause emergent arrhythmia
What are the clinical muscle and endocrine manifestations of hyperkalemia?
Muscle weakness and paralysis
Endocrine - increased aldosterone and increased insulin secretion, while decreasing renin
aldosterone paradox
How does plasma osmolality relate to plasma Na concentration, conceptually?
Directly proportional. Thus, total body water content can be estimated by Na concentration, but ECF volume cannot be estimated by Na concentration (needs total body Na, a clinical assessment by physical exam or direct intravascular monitoring)
What is the formula for calculating plasma osmolality? Give the normal value?
2*Na + (glucose / 18) + (BUN / 2.8)
Na in mmol/L - because each Na is accompanied by an anion
Glucose in mg/dL
BUN in mg/dL
Normal value is around 290 mOsm / kg water
Plasma osmolality is inversely proportional to total body WATER CONTENT
What is the difference between water depletion and volume depletion? What is dehydration talking about?
Water depletion - depletion of total body water (increased Na concentration / osmolality) -> dehydration refers to this
Volume depletion - depletion of ECF volume / total body Na. Dehydration should not refer to this, but sometimes sloppily applied
What are the two cases when plasma osmolality is NOT proportional to plasma [Na]?
Pseudohyponatremia:
- Artifactual hyponatremia
- > elevated solid components lead to the same volume of blood having less plasma in it -> lower measured sodium per volume of blood drawn
- Hyperlipidemia
- Hypergammaglobulinemia (multiple myeloma - Hyperosmolal hyponatremia
- > caused by diabetes, sugar pulls water out of cells, diluting ECV
- > treated by insulin
- > Na will recover 1.6mM for every 100 mg/dL above 200 mg/dL blood sugar
What area of the brain regulates plasma osmolality? How do they relate to the BBB? how do they work? What are the osmoreceptors type?
Subfornical organ (beneath hippocampus) and organum vasculosum of lamina terminalis (OVLT)
Outside of BBB, have TRPV1 osmoreceptors and angiotensin II receptors
Other than angiotensin II, low BP, low blood volume, and high plasma osmolality, what other factors stimulate ADH release?
Other stress-related stimuli:
Nausea
Hypoxia
Hypercapnia
Pain (nociceptors)
-> keep these all in mind as causes of normal ECV hyponatremia
What effect does ADH have on the kidneys? What receptor does it bind?
Increases solute absorption via TALH (NKCC) and urea absorption by collecting duct to increase medullary osmotic gradient (greater concentrating power)
-> upregulates UT1/UT2 transporters
Binds V2 receptors. Increases Aquaporin 2 expression in collecting duct (cAMP mechanism). Aqp3 also has a minor effect.
Where is urea synthesized, filtered, reabsorbed, and secreted?
Synthesized - liver
Filtered - glomerulus, freely
Reabsorbed - inner medullary collecting duct, taken up by ascending vasa recta
Secreted - proximal straight tubule - after acquisition from ascending vasa recta
Some urea from ascending vasa recta is also transferred to adjacent descending vasa recta
What is the definition of free water clearance? How do you calculate it?
Volume of urine per unit time that is solute free after removal of the volume of urine that is iso-osmotic plasma
Free water clearance = Urine flow rate - Osmolal clearance
Ch20 = V - Cosm
Where Cosm = (Uosm*V)/Posm
What does it mean when free water clearance is positive, negative, or 0?
If Ch20 is 0 -> urine is iso-osmotic to plasma, meaning Uosm = Posm.
If Ch20 is positive -> substract a number which is less than V, Uosm/Posm <1, urine is hypoosmotic to plasma.
If Ch20 is negative -> Uosm/Posm >1 = urine is hyperosmotic to plasma (subtract a number that is greater than V)
What is T(superscriptC)(subH20)? This relates to free water clearance.
Tubular water reabsorption
It is equal to the negative free water clearance (if free water clearance is -1.5L/day then water is being reabsorbed, and TcH20 = 1.5L/day)
How do you calculate the excess TBW for a patient who was ideally 70 kg before coming ill, and who now has a hypoosmotic plasma of 250 mOsm / kg water?
70 kg * 0.6 = 42 L = ideal TBW
M1V1 = M2V2
ideal Posm * ideal TBW = actual Posm * actual TBW
300 mOsm * 42 L = 250 mOsm * actual TBW
actual TBW = 50.4L
Actual TBW - Ideal TBW = Excess TBW
- 4L - 42 L = excess TBW = 8.4 L
- 4 L of solute free water needs to be excreted to correct the plasma osmolality
Typically you use [Na+] rather than plasma osmolality
What are the signs of ECF volume depletion and what causes this?
Loss of Na from ECF (total body Na)
Signs include low blood pressure, increased heart rate, orthostatic vital changes, dry mucous membranes, poor skin turgor
What are the acquired causes of nephrogenic diabetes insipidus?
Hypercalcemia, hypokalemia
-> impairs cAMP mechanisms, abnormal AQP2 number
Remember hypokalemia lecture mentioned impaired renal concentrating ability
Remember hypercalcemic lecture (polyuria)
What are the causes of inadequate water intake?
- Thirst deficiency - usually brain tumor in subfornical area
- Inability to obtain water (infants, unconscious, desert) - most common
- Intake of hypertonic salt without water
- ADH derangements with inadequate water intake
What are the causes of hypernatremia with low ECV?
Loss of both Na and water, but water more than sodium (hence hypernatremia)
- GI losses - diarrhea or vomiting (BEFORE you drink water to replace the water lost)
- Inability to access food or water, with loss of water and salt in sweat
- Diabetic osmotic diuresis
- Drugs that impair water and salt reabsorption (diuretics)
What is the only real cause of hypernatremia with (almost) normal ECV?
Diabetes insipidus - central or nephrogenic (sodium is absorbed fine, just can’t pull the water out of the urine at all)
Normal respiratory or dermal losses of water
-> lost water without loss of total body Na (by clinical assessment)
What are the causes of hypernatremia with high ECV?
Situations where Na is gained in excess of water
- > hypertonic breast milk / formula
- > hypertonic dialysis
- > primary hyperaldosteronism
- > iatrogenic Na bicarbonate injections (hypertonic fluids)
What is the treatment for all types of hypernatremia, and if you are low ECV vs normal or high ECV?
Treatment for all: permit acess to water, and give oral water if patient is awake / alert
Low ECV - BP is most important, give isotonic saline until BP improved, then switch to hypotonic to normalize hypernatremia
Normal / high ECV - Give D5W - basically giving pure water which is isotonic but does not raise sodium concentrations at all (ECV is already okay)
Why do disorders of urinary dilution cause their symptoms?
Plasma becomes hypoosmotic either due to decreased water loss (water retention) or a concomitant increase in solute loss / renal wasting (cannot reuptake solute)
Signs and symptoms are due to brain cell edema (water ends cells) -> skull has only 10% of space not occupied by brain tissue
How can you think of the functional solute problem differences between problems of urinary concentration and urinary dilution? How can loop diuretics contribute to both?
Urinary concentration disorder - solutes are reabsorbed okay, just can’t seem to reuptake water. Loop diuretics can make this worse by not allowing formation of medullary gradient for water reuptake
Urinary dilution disorder - solutes are not reabsorbed well, water is not being lost adequately. Diuretics make this worse by not allowing reuptake of solute (makes blood hypoosmotic by keeping urine too concentrated).
How can ADH contribute to problems with urinary dilution? What things can cause this?
Inappropriate presence of ADH leads to hyperconcentration of urine -> too much water reuptake, retention of water
Things which cause increased ADH, especially heart failure (associated with hypoxia and hypercapnia, which increases ADH), certain drugs, and SIADH
What drug is especially associated with hyponatremia?
Ecstasy - increases ADH levels + makes you ravenously thirsty
Why does congestive heart failure cause hypo-osmolality?
Normal baroreceptors become insensitive overtime to the volume overload - they stop firing, ADH release is disinhibited, exacerbating heart failure
What are some causes of low ECV hyponatremia?
Individuals lost more sodium than water, usually due to drinking water or hypotonic fluids after salt loss
GI losses
Burns: Loss of Na/water
Renal losses - osmotic diuresis, salt wasting nephritis, mineralocorticoid deficit
Hemorrhage
What are the causes of high ECV hyponatremia? Why does each of them cause this?
They have high total sodium, but VERY high TBW
Big four:
- CHF - decreased baroreceptor responsiveness
- Cirrhosis - low BP due to profound splanchnic vasodilation to increase liver blood flow + fluid loss due to oncotic changes
- Renal failure - inability of kidney to excrete water in limited function
- Nephrotic syndrome - low intravascular volume due to oncotic changes
How should you treat a patient with low ECV hyponatremia and why is this easier than high ECV hyponatremia?
low ECV hyponatremia - give isotonic saline. Na levels will normalize in body, and their baroreceptors work fine so they will lose the excess water through their kidneys
high ECV hyponatremia is bad because their baroreceptors are working badly, allowing too much ADH, or their kidneys aren’t working at all. -> kidneys will not allow them to lose water, and treating with isotonic saline would just exacerbate the problem.
Why does glucocorticoid deficiency cause normal ECV hyponatremia?
Cortisol-releasing hormone stimulates ADH release. If cortisol is not feeding back to inhibit CRH, ADH will build up.
If mineralocorticoids are normal, total body Na balance is normal in this situation
-> all normal ECV hyponatremias are caused by situations of too much ADH release when you don’t need it, or you’re just drinking too mush water
What does hypothyroidism cause in hyponatremia?
Normal ECV hyponatremia -> in patients with myxedema
What are the major causes of SIADH?
Ectopic ADH - malignancies, i.e. small cell lung cancer
Pulmonary disease - especially TB, but also asthma and other infections
(hypoxia / hypercapnia / nausea / pain induce ADH release)
CNS disorders / head trauma
(disruption of OVLT)
Certain drugs
How do demeclocycline and lithium treat SIADH?
Demeclocycline - impairs AQP2 insertion into apical membrane
Lithium - prevents cAMP formation, so AQP2 can’t be moved to the membrane
Note: Tolvaptan and Conivaptan are much better but are more dangerous
What is the risk of too rapidly correcting hyponatremia levels? What is most susceptible?
Osmotic demyelination syndrome
- > rush of fluid out of myelin sheaths into extracellular space (there was lack of osmolytes in brain to prevent cerebral edema from all this water) causes damage
- > need to give sodium back to ECF slowly to allow brain cells to generate osmolytes so fluid doesn’t leave the cells too rapidly
- > especially affects pons, can cause locked in syndrome
- > max replacement: 6 mM Na per 24 hours
What is the difference between a volatile and nonvolatile acid? Give some examples of the latter.
Nonvolatile - acids which cannot be evaporated.
Examples:
Sulfur-containing amino acids -> degrade to sulfuric acid
positively charged AA -> HCl
Phosphates also contribute -> phosphoric acid
negatively charged AA and organic anions -> produce bicarbonate, which buffers some of this.
Why do we need to keep making HCO3-? How does the kidney function in this?
We make about 1 mEq/kg/day of nonvolatile acids which need to be buffered by bicarbonate system.
When they are buffered, they rapidly form CO2 gas which is loss (volatile gas). This HCO3- then needs to be replaced. Kidney functions to excrete the sodium salts that are made from this conversion and replenish the HCO3- by secreting acid EXACTLY EQUAL to the nonvolatile acid produced, and reclaim filtered HCO3-.
What is total H+ secretion by the tubules equal to? (sum of other H+ secretions)?
Total H+ secretion = H+(HCO3-) + H+(NH4+) + H+(TA)
H+ total = H+ for reabsorption of bicarbonate + H+ in the form of NH4 + H+ in another titratable acid
What is the net acid secretion then / how is it calculated?
Net acid secretion = [(Excreted NH4 + Excreted TA)] - [Excreted HCO3-]
Excreted HCO3- is bicarbonate which wasn’t reabsorbed
Excretion can be calculated by the urinary concentration of the substance multiplied by the urine flow rate
What are the transporters which help reabsorb bicarbonate in the proximal tubule on both the apical and basolateral membranes?
Apical - H+-ATPase (Vacuolar), Na/H exchanger
Basolateral - 3HCO3/Na cotransporter (driven by relatively positive ECF), HCO3-/Cl- antiporter (AE1)
What is the function of the beta intercalated cell and what transporter does it have at the apical and basolateral membranes?
For secretion of bicarbonate (bases) in the lumen, rarely needed except in vegans who can have base excess. Basically a mirror image of an alpha intercalated cell.
Apical transporter - Pendrin** - functions like AE1/AE2 but not the same. HCO3- out with Cl- in.
Basolateral transporter - V-ATPase, pumps H+ out. Cl- also passively reabsorbed into blood.
What happens to NH4 in the medullary interstitium / how is it uptaken by the collecting duct?
NH3 / NH4+ is in equilibrium
It is taken up by the alpha-intercalated cell by one of two mechanisms:
1. Na/K ATPase in place of K (as in basolateral surface of TALH)
2. Rhcg channel (protein is in Rh antigen family)
Then is secreted into tubular lumen by Rhcg channel
NH3 will be again protonated by H+ secreted by alpha intercalated cell, finally resulting in a complete loss of acid.
How does systemic pH affect the action of the NH3/NH4 system?
low pH stimulates proximal tubule glutamine deamidase
(remember this and phosphate dependent glutaminase - PDG)
-> also enhanced by hypokalemia
high pH inhibits it
->also inhibited by hyperkalemia (predisposes to acidosis)
-> secrete more acid in the form of NH4+ when you need to.
How all does hypokalemia interfere with acid-base balance?
Hypokalemia - stimulates NH4+ production, increases Rhcg expression, and stimulates H+,K+ ATPase (hypokalemia will predispose to alkalosis)
What is the mechanism of increased or decreased normal (not NEW) bicarbonate reabsorption in response to alkalosis or acidosis?
Acidosis - more bicarbonate reabsorption
Alkalosis - less bicarbonate reabsorption
Mechanism - lower intracellular pH of alpha-intercalated cell favors secretion of H+ (lower cell-to-lumen gradient to push against via ATPase), and thus bicarbonate reabsorption
-> remember the collecting duct controls the pH!
What is the mechanism for contraction alkalosis?
At low blood volumes, AT2 is stimulated, which increases the number of Na/H exchangers in the proximal tubule, increasing bicarbonate reabsorption
Furthermore, aldosterone makes the collecting duct lumen more negative (favors H+ secretion) and directly alpha-intercalated V-type-ATPase -> more alkalosis
How is the compensatory fall in pCO2 for metabolic acidosis calculated?
Fall in pCO2 = 1.0 -1.3 mmHg * (fall in HCO3-)
HCO3- is assumed to be 25 mEq/L at baseline
pCO2 is assumed to be 40 mmHg at baseline
What causes an increased vs a normal plasma anion gap acidosis, conceptually?
Increased - addition or production of an acid which leaves an unmeasured anion in the blood
Normal - caused by addition of HCl (Cl- is measured in blood), or primary loss in HCO3- (excretion of HCO3- is paired with reabsorption of Cl-)
What is the urinary anion gap useful for and how is it calculated? What is a normal urine value?
Useful for the differential diagnosis of normal plasma anion gap metabolic acidosis
Based on the assumption that HCO3- and other unmeasured cations in the urine is negligible, and charges will equal out
0 = ([NH4+] + [Na+] + [K+]) - ([Cl-] + [Unmeasured anions])
Since NH4+ is difficult to measure, we can calculate the anion gap by assuming there are only four cations in the urine. Thus, we can say that
UAG = -[NH4+] = [Na+] + [K+] - [Cl-]
In normal urine, this gap is zero or slightly negative.
How do you calculate the plasma anion gap?
[Na+] - ([HCO3-] + [Cl-])
Normal = 10
How does the urinary anion gap change if the kidney is properly responding to normal plasma anion gap metabolic acidosis and why?
Normal response would be to increase renal tubule acid secretion in the collecting duct. This is done by increasing ammonia excretion. Since ammonia will be excreted as a positive cation, the Cl- in the urine will also increase to counteract this cation in the urine. This will be measured as an increase in urine chloride.
Thus, normal UAG response to metabolic acidosis is:
UAG = normal Na + Normal K+ - HIGH CL-
Urinary anion gap is VERY negative, reflecting high ammonia concentration.
-[NH4+] = UAG
If it is normal or positive in presence of normal anion gap metabolic acidosis -> distal RTA (Type I)
What is the urinary pH in Type I RTA and how does it change with plasma HCO3-? What pathophys mechanism accounts for this?
Distal renal tubular acidosis, associated with pH > 5.5 even with very low plasma [HCO3-], due to impaired ability to secrete H+ by alpha intercalated cells
- > decreased titratable acid and trapping of NH4+ -> decreased net acid secretion
- > impaired reabsorption of HCO3-, urine remains basic
What are the causes of RTA Type I?
Congenital abnormalities:
Obstruction - damages collecting duct
Hereditary mutation in H+-ATPase
Drugs:
Amphotericin B, tenofovir -> nephrotoxic, increase H+ permeability, allowing diffusion of H+ back into the cell (urine cannot be acidified)
What is RTA Type II? What will the urine characteristics be? Include pH and urinary anion gap.
RTA Type II - proximal RTA
Impaired bicarbonate reabsorption in the proximal tubule leads to increased bicarbonate loss in urine
Urine pH will still be low (<5.5) as alpha-intercalated cells are functioning properly and can secrete H+ into urine via increasing ammonia production + increased H+ secretion.
UAG will be very negative (normal response to acidosis) since cells are responding properly
What are the causes of Type II RTA?
Fanconi syndrome - proximal tubule transporters don’t work at all, leading to loss of all types of things in urine
-> caused by drugs like ifosfamide, cisplatin, tenofovir, expired tetracyclines
Carbonic anhydrase inhibitors - i.e. acetazolamide
Cystinosis
What will a mutation in AE1 cause?
Anion exchanger mutation on basolateral surface of alpha-intercalated cell (and proximal tubule, but failed distal acidification takes precedence)
-> Type I RTA
What is the pathogenesis of Type IV RTA?
Hypoaldosteronism leads to hyperkalemia
Hyperkalemia causes impaired NH4+ generation by proximal tubule -> impaired excretion of acid
-> hyperkalemic renal tubular acidosis
What is the definition of increased anion gap and what are the causes of increased anion gap metabolic acidosis?
Increased: Anion gap >12 mEq/L
MUDPILES M: Methanol, METFORMIN U: Uremia D: Diabetic ketoacidosis / ketoacidosis in general P: Paracetamol - acetaminophen I: Isoniazid, Iron tablets L: Lactic acidosis E: Ethylene glycol S: Salicylates
What are the non-renal loss of HCO3- causes which induce a hyperchloremic (normal anion gap) metabolic acidosis?
Diarrhea - Rich in HCO3- and K+. Kidney will compensate well with acid secretion and K+ reabsorption.
Small bowel or pancreatic drainage - loss of HCO3- secretions
Ureterosigmoidostomy / malfunctioning ileal loop
What is dilutional hyperchloremic acidosis? Where does this appear in the mnemonic for normal anion gap metabolic acidosis?
Rapid ECF expansion via NaCl will dilute out the current concentration of HCO3-, making the body relatively acidic
HARDASS Hyperalimentation Addison disease (hypoaldosteronism -> hyperkalemia -> acidosis) Renal tubular acidosis Diarrhea Acetazolamide Spironolactone - Type IV RTA Saline infusion
What are situations where “HCl” could be added to induce hyperchloremic acidosis?
Parenteral nutrition - formulas contain excess cations -> arginine-Cl or lysine-Cl -> chloride rises and arginine / lysine are acid cations which need to be buffered
Eating HCl or NH4Cl -> ammonium chloride used to be used as a diet pill
Why does increased HCO3- worsen alkalosis?
Increased HCO3- delivery to collecting duct -> non-reabsorbable anion -> secrete more K+ -> hypokalemia -> alkalosis due to stimulation of NH4+ production
What is the formula for respiratory compensation of metabolic alkalosis? What is the limitation?
rise in pCO2 (hypoventilation) - limitation of hypoventilation is hypoxemia
Rise in pCO2 = 0.5 to 1.0 * rise in [HCO3-]
What is the differential diagnosis of metabolic alkalosis based off of?
Based on urine [Cl-] -> low concentration of Cl- implies that bicarbonate is being reabsorbed largely because there is a deficit in Cl- to run Na/Cl- cotransporter -> HCO3- transporter goes in its place. -> kidney is focusing on ECF depletion, its #1 priority
What are the two categories of metabolic alkalosis?
- Saline responsive: Urinary [Cl-] < 20 mEq/L
- > ECF depletion is the issue - Saline unresponsive: Urinary [Cl-] > 20 mEq/L
- > ECF is normal or expanded
What are two common causes of saline responsive metabolic alkalosis?
Diuretics (must stop using them, urine will start reabsorbing chloride again, will be saline responsive. Otherwise saline unresponsive), especially loop diuretics -> volume depletion, loss of chloride and sodium(NKCC)
Vomiting -> HCl loss, volume depletion
How can hypercapnia predispose to alkalosis? Is it saline responsive?
Long period of respiratory acidosis -> kidney stimulates HCO3- reabsorption
-> once intubated, HCO3- remains high, takes a couple days to correct
Yes it is saline responsive -> you want new chloride to be able to take the place of Cl- for reabsorption
What are the two usual broad causes of saline unresponsive metabolic alkalosis?
Excess mineralocorticoids -> K+ wasting, with increased acid secretion to reabsorb K+. Cl- will be high because we are volume overloaded so we are not holding onto chloride
Severe K+ depletion -> same reason as above, + more ammoniagenesis in PCT
What are the syndromes associated with excess mineralocorticoids leading to saline unresponsive metabolic alkalosis?
Primary hyperaldosteronism
Cushing’s disease / syndrome - enough cortisol can overcome 11b-hydroxysteroid DH
Licorice ingestion - blockade of 11b-hydroxysteroid-DH
Why does non-hyperparathyroid hypercalcemia cause metabolic alkalosis?
When bone is broken down, calcium carbonate is released. This is normally stimulated by PTH, whhich also signals to excrete bicarbonate in urine to prevent alkalosis.
If PTH is not accompanying the hypercalcemia, the release of bone bicarbonate will not accompany bicarbonate excretion -> alkalosis.
What is the acute and chronic kidney compensation formula for changes in [HCO3-] with respiratory acidosis? What’s the max?
Acute: 1 mEq/L per 10 mmHg rise
Chronic: 3.5 mEq/L per 10 mmHg rise
Cannot rise above 35 mEq/L with compensation alone
What is the acute and chronic kidney compensation formula for changes in [HCO3-] with respiratory alkalosis? What’s the min for each?
Acute: 2 mEq/L per 10 mmHg fall, but not less than 18
Chronic: 5 mEq/L per 10 mmHg fall, but not less than 14
What is the system for approaching acid-base imbalances?
- Look at pH -> acidemia or alkalemia?
- Look at the directional change in HCO3- and pCO2 -> metabolic or respiratory issue? -> evaluate bicarbonate first
- Look at the amount of compensation -> if not appropriate, mixed disorder
- What is the underlying cause? -> calculate anion gap.
Look at urinary chloride if metabolic alkalosis
Calculate urinary anion gap if normal anion gap metabolic acidosis
Why is acetazolamide not the most effective diuretic, other than the distal sodium reabsorption issue?
Only 30% of filtered Na is reabsorbed by bicarbonate, most is reabsorbed as NaCl
Hyperchloremic metabolic acidosis causes physical properties of CA to change so it’s not so easily inhibited
Fall in serum HCO3 also results in decreased filtered load and thus decreased diuresis
What are the metabolic effects of acetazolamide and what type of urine / osmolyte imbalances will it cause?
Normal anion gap hyperchloremic metabolic acidosis -> by blocking bicarbonate reabsorption, NaCl reabsorption is favored, and base is lost.
Urine - becomes alkalinized, due to high concentration of bicarbonate
Electrolytes: causes hypokalemia due to increased distal convoluted tubule ENaC absorption to compensate (think of banana on ground next to red #2 car) -> for so much more sodium reaching distal tubule
Other than rare use in glaucoma (methazolamide), what are the primary clinical indications of acetazolamide? What will be made worse by this?
Cystinuria and hyperuricemia -> cystine and uric acid are more soluble in alkaline urine
Calcium phosphate stones will be made worse by this -> less soluble in higher pH
Treatment of metabolic alkalosis in edematous states (fluid overload, good to correct this)
Altitude sickness -> corrects respiratory alkalosis caused by hyperventilation
What effect do loop diuretics have on gout?
Acutely - increased uric acid excretion due to increased flow rate
Chronically - volume contraction results in increased uric acid reabsorption in proximal tubule -> worsens gout
-> reason why we have to give furosemide with saline if we are treated gout or hypercalcemia
What are the edematous states which loop diuretics are useful in treating?
Pulmonary edema, edema in patients with renal failure (also induce increased RBF by inducing COX), nephrotic syndrome, heart failure
What is the relative potency of mannitol vs loop diuretics?
Lower sodium excretion, but highest peak urine flow of all diuretics -> greatest risk for dehydration
It increases free water clearance
Mechanism of action: Increases vasa recta blood flow, reducing medullary interstitial gradient
What are the three most important indications of mannitol?
- Cerebral edema
- Prevention of dialysis disequilibrium syndrome (rapid removal of osmolytes from plasma causes cerebral edema)
- Intoxications - enhances urinary excretion of toxins / drugs
What is the diuretic braking effect and how can this be prevented?
Prolonged diuretic use results in a plateau in weight loss and return to previous value, due to increased stimulus for Na retention and less natriuretic response to drug.
Prevented by dietary sodium restriction in conjunction with diuretic use, as well as more frequent / prolonged dosing.
What will the effect of decreasing pH have on the calcium levels and why? Wat about alkalosis?
Decreasing pH in bood will making H+ ions displace Ca+2 from albumin, causing symptoms of hypercalcemia WITHOUT an increase in total calcium concentration
Opposite will occur in alkalosis -> symptoms of hypocalcemia
Both may have same total calcium concentration, but hypo versus hypercalcemia
What are three inhibitors of PTH?
Calcitriol
Hypomagnesia - important because hypomagnesia is a cause of hypocalcemia, and can be treated with Mg+2 supplements
Hypercalcemia
What is the net effect of calcitriol on calcium and phosphate levels, and what stimulates its release?
Increases blood calcium and phosphate levels
Release is stimulated by hypophosphatemia and PTH
What effect does calcitonin have on bone, kidney, and intestines? Read this closely!
Bone - stops osteoclasts -> decreased bone breakdown, increased bone formation, losing calcium and phosphate
Minor effects:
Kidney - DECREASES urinary calcium excretion (no hormone increases it, only calcium sensing receptors), increases phosphate excretion
Intestine - INCREASES calcium and phosphate reabsorption
Where in the nephron is the majority of calcium reabsorbed, and by what primary route? How will a diuretic affect this?
Proximal convoluted tubule
Mostly paracellularly via solvent drag, with a small amount transcellularly (absorbed via NCX in exchange for three sodium)
Diuretics decrease calcium reabsorption by failing to concentrate calcium in the proximal tubule, inhibiting its paracellular reabsorption
-> much better if hypercalcemic
How is calcium reabsorbed in the thick ascending loop of Henle and how will diuretics affect this?
50% via the transcellular route and 50% paracellular
NKCC pulls in K+, which can be leaked back out thru K+ transporter (ROMK). This generates the positive intraluminal potential which pushes paracellular calcium reabsorption. This K+ channel is blocked by the Ca+2-sensing receptor.
Diuretics block this K+ mechanism and decrease calcium reabsorption
How is calcium reabsorbed in the distal convoluted tubule (DCT, that is, NOT collecting duct)? What controls this?
Entirely through the transcellular route, via apical TRPV5 channels and basolateral Ca+2-ATPase and NCX.
TRPV5 channels are upregulated by PTH and calcitriol (remember it stimulates Ca+2 reabsorption). NCX also upregulated by PTH
What are the two ways malignancies can cause hypercalcemia?
- Local osteolytic hypercalcemia - tumor cells invade bone and produce cytokines stimulating osteoclastic bone resorption
- Humoral hypercalcemia - produce circulating PTHrP, or other cytokines
What is PTHrP and will it be detected easily? What cancers is it associated with?
Parathyroid hormone-related peptide - NOT detected by normal PTH immunoassay
Associated with sQuamous cell cancers of lung, head, and neck (Q is next to P in the alphabet), as well as renal, bladder, breast, and ovarian cancers.
Think Q + urinary tract + BRCA
How does vitamin D toxicity cause hypercalcemia (what mechanisms?) and who is it typically seen in?
Due to increased Ca+2 mobilization from bone as well as increased calcium absorption in GI tract (hard to overdo it in kidney)
Seen in patients treated with vitamin D: Renal failure (given vitamin D to combat chronically high PTH levels), and hypoparathyroidism (given vitamin D to increase Ca+2 levels)
Why does hypercalcemia cause polyuria and increased Na+ excretion?
Ca+2 sensing receptor will inhibit the K+ channel in the TALH, which slows NKCC as well -> inhibits sodium reabsorption.
This destroys osmotic gradient of medulla -> cannot concentrate urine as well.
Also inhibits adenylate cyclase activity in collecting duct -> less ADH = nephrogenic diabetes insipidus
What usually causes hyperparathyrodism?
Usually parathyroid adenoma or hyperplasia.
Less commonly due to parathyroid carcinoma.
Can also rarely occur in the setting of multiple endocrine neoplasia
How do you correct total serum calcium levels to see if a patient is actually hypocalcemic in the setting of hypoalbuminemia?
Add 0.8 mg/dL for every 1 mg/dL decrease in serum albumin below 4 mg/dL
What are causes of vitamin D deficiency and hence hypocalcemia?
- Decreased ingestion
- Decreased absorption - partial gastrectomy or intestinal bypass
- Deficiency of sunlight
- Deficiency of 25-D3, severe liver disease or anticonvulsant use (CYP inducers)
- Deficiency of calcitriol - advanced renal failure, hypoparathyroidism
What are the general features of hypocalcemia?
Neuromuscular irritability and tetany
-> can lead to lethargy, seizures, larnygospasm, and heart failure
Trousseau’s sign - carpal SPASM when BP cuff is inflated above systolic pressure for three minutes
Chvostek’s sign - TWITCHING of facial muscles when nerve is tapped at parotid gland -> think Chvostek = cheek
What is the definition of abnormal proteinuria and what can urine dipstick detect?
> 150 mg/day in urine
Dipstick can detect >250 mg/day.
Not sensitive for lower proteinuria
What is renal glycosuria?
Condition where proximal convoluted tubules cannot reabsorb as much glucose as the average person, so glucose becomes positive in urine even with normal blood sugar levels
How many renal tubular epithelial cells can be seen per HPF? What are the three types? What do they look like?
0-2/HPF again, like RBCs and WBCs
- Renal tubular epithelial cells
- >Slightly larger than WBC with large, round nucleus which is very prominent. They will also be slightly less granular than WBCs. - Transitional epithelial cells
- >Round or pear-shaped cells, appear 2-4 times larger than WBCs. They are larger and tend to appear in groups. - Squamous epithelial cells
- > Large cytoplasm sheets with small central nuclei
What urinalysis finding is pathognomonic of nephrotic syndrome and how does it appear under the microscope?
Oval fat body -> renal tubular epithelial cells with fat droplets in their cytoplasm, due to fat secretion through glomerulus
Polarized light shows “Maltese Cross” pattern of cholesterol and cholesterol ester
When are WBC casts seen?
When the interstitium around the tubules is inflamed. Casts are usually formed by PMNs.
-> interstitial nephritis or pyelonephritis
What are the two types of granular casts and which one indicates acute tubular necrosis?
- Finely granular casts - aggregations of proteins and cellular debris, non-specific renal injury
- Coarsely granular casts - “Muddy brown” - very dark colored, indicative of acute tubular necrosis.
How do waxy casts appear and why? What disease process do they indicate?
Appear as “broad” casts which are similar in appearance to hyaline casts, but borders are more determinable
- > may be due to degeneration of granular casts
- > appear “broad” because of dilation or hypertrophy of tubules
Seen in advanced chronic kidney disease / renal failure
What causes formation of calcium oxalate crystals usually, and how do they appear?
Ethylene glycol ingestion
Crystals appear “envelope-shaped” -> i think they look like origami game
Also associated with veganism, Crohn’s disease, and hypocitraturia
How do uric acid crystal appear?
Rhomboid or diamond-shaped
-> also appear slightly brown from taking up pigment
How do triple phosphate / struvite / ammonia magnesium phosphate crystals appear? What condition do they appear in?
Coffin lid shaped (three strikes and you’re out and in a coffin)
Appear in conditions of increased urine pH, especially UTI’s with urease + organisms (urea -> ammonia).
What is a lobe vs a lobule of the kidney?
Lobe - a grossly apparent medullary pyramid with its associated cortex, separated by cortical columns
Lobule - group of nephrons draining into a common collecting duct
What are the three layers of the glomerular basement membrane by TEM?
Lamina rara interna - electron-lucent peripheral layer near capillary endothelial side
Lamina densa - Thick, electron-dense central layer (formed by fused basemenet membranes of endothelial cells and podocytes)
Lamina rara externa - electron-lucent peripheral layer near podocyte foot processes
Where do slightly anionic molecules, neutral molecules, and cationic molecules end up in the glomerulus?
Slightly anionic - subendothelial, between inner GBM and endothelial cells -> repelled by GBM so they can’t get through.
Neutral molecules - in mesangial network (i.e. immunoglobulins in IgA nephropathy)
Cationic molecules - subepithelial -> between outer GBM and podocytes
What are anti-GBM antibodies directed against? What is their DIF staining pattern? What type of glomerular disease do they cause?
noncollagenous domain of type IV collagen (NC1)
Staining pattern - fixed and regular, causing a diffuse, linear staining pattern
Usually cause rapidly progressive glomerulonephritis (RPGN)
What happens when resident glomerular cells are injured in FSGS?
- Endothelial injury -> activation of coagulation cascade
- Damage to podocytes -> effacement and proteinuria. Also decreases support for glomerular capillaries -> pressure imbalances and segmental capillary asymmetries
- Proliferation of mesangial cells and infiltration by monocytes and macrophages leads to increased production of growth factors and synthesis of ECM -> “sclerosis”
How is sclerosis different than hyalinosis and fibrosis?
Sclerosis - Deposition of extracellular matrix, primarily collagen (vs hyalinosis, which is deposition of plasma proteins)
Fibrosis - deposition of extracellular matrix by fibroblasts (vs sclerosis, where the ECM is made by mesangial cells)
What does proteinuria and decreased blood flow through efferent arteriole lead to? How does this correlate to renal function?
Leads to tubular ischemia and injury / activation of tubular cells
-> production of proinflammatory cytokines / growth factors and interstitial inflammation / fibrosis
End result: Tubulointerstitial fibrosis, correlates better decreased renal function than the extent of glomerular damage
What causes primary membranous glomerulonephropathy? What will EM show?
Antibodies to phospholipase A2 receptor, a podocyte antigen
- > autoimmune disease
- > subepithelial, most common primary nephrotic syndrome in Caucasian adults
- > “spike and dome” on EM
What are the causes of secondary membranous glomerulonephropathy?
- Medications - NSAIDs, penicillamine, captopril
- Infections - HBV, HCV, syphilis
- Malignancies - solid tumors put new Ags in circulation
- SLE - this is the nephrotic presentation of SLE
What is the pathogenesis of MCD?
Most common cause of nephrotic syndrome in children
Usually a primary disease, but may begin secondary to another immune disease, commonly Hodgkin’s lymphoma.
Insult is due to cytokine production -> damage podocytes -> massive proteinuria, mostly albumin.
What is primary FSGS caused by, and what will happen to the glomeruli / ECM?
Idiopathic
- > it is like really bad MCD, caused by a circulating pathogenic factor
- > damage to podocytes -> leakage of plasma proteins = hyalinosis
- > hyalinosis -> increased ECM production = sclerosis
Patchy hyalinosis and sclerosis can be seen.
What disorders and comorbidities are associated with causing secondary FSGS?
- Glomerular hyperfiltration - due to a significant loss in functional nephrons, as described before
- Heroin abuse
- HIV infection - think of dz association with African American men
- Sickle cell disease
Inherited: Apoprotein L1 allele, podocyte (slit diaphragm protein)
What will the HIV-associated variant of FSGS show on light microscopy and what is this variant called? Give what the glomeruli and tubules will show.
Collapsing variant of FSGS
LM:
Glomerular pathology - retraction of glomerular tuft (collapsing) with proliferation and enlargement of podocytes, typical FSGS pathology elsewhere
Tubular pathology - focal cystic dilatation of tubular cells (HIV can infect tubular cells)with intraluminal proteinaceous material and surrounding fibrosis / inflammation
What is seen on EM for PSGN and how does this differ from nephrotic syndrome in appearance?
Large, subepithelial deposits (below podocytes, like membranous glomerulonephropathy), which are LARGER and more interspersed, like humps (vs MGN where they are closer together and smaller).
What is MPGN, Type I caused by if it is primary or seconday? Where do things deposit?
Primary - idiopathic
Secondary - associated with HBV or HCV, or SLE
Subendothelial immune complex deposits
What is MPGN type II also called, and what causes it? What will happen to serum complement levels?
Dense-deposit disease -> development of an auto-antibody called C3 nephritic factor
-> IgG antibody stabilizes C3 convertase of alternative pathway (C3bBb) for persistent complement activation and decreased C3 levels
What does LM show for MPGN, both Types I and II?
Both show a “tram-track” or “split” appearance with PAS stain (stains only the glycoproteins in the basement membrane) -> GBM is split through the middle by mesangial cell processes
Glomerulus is hypercellular and proliferative, also appears somewhat lobulated (semidiscretely divided)
What does IF show for Type III RPGN?
No staining for IgG or C3 -> immune negative = pauciimmune
What is the pathogenesis of Berger disease? Include the type of cell which is most damaged.
Susceptible individuals increase IgA synthesis following infection (or with celiac disease or decreased IgA clearance in hepatobiliary diseases)
- > increased polymeric IgA
- > deposition in mesangium of glomeruli
- > activation of ALTERNATIVE complement pathway with primary mesangial injury
What are the clinical manifestations of Alport syndrome?
Can’t see, can’t pee, can’t hear a bee
- Renal disease - hematuria with RBC casts, which progressively worsens to chronic kidney disease
- Sensorineural hearing loss (involves BM of ear)
- Ocular involvement - retinal flecks, anterior lenticonus (weird lens shape)
X-linked mutation in Type IV collagen
What does LM and DIF (what are we looking for?) show for Alport syndrome?
LM - Interstitial foam cells with progressive sclerosis of glomeruli, interstitium, and vasculature
DIF - Absence of normal GBM staining using antibodies against collagen alpha-chain
EM - Basketweave appearance - interspersed breaking apart of lamina densa
What are the six classes of renal pathology associated with SLE? Which one is most common presenting type?
Class I - minimal mesangial lupus glomerulonephritis
Class II - mesangial proliferative lupus glomerulonephritis
Class III - focal proliferative lupus glomerulonephritis
*Class IV - diffuse proliferative glomerulonephritis - most common presenting type
Class V - membranous lupus glomerulonephritis
Class VI - advanced sclerosing lupus glomerulonephritis
What does DIF show for glomerulonephritis of lupus?
Granular appearance with lumpy-bumpy deposition of immune complexes in mesangium and glomerular capillary walls (intramembranous)
Where will the immune complexes deposit via TEM in Class III, IV, and V lupus glomerulonephritis?
Mesangium first +/-:
III & IV - proliferative picture -> subendothelial deposits
V - membranous picture -> subepithelial deposits
Give the causes of ATN/ATI within the nephrotoxic category.
Exogenous: aminoglycosides**, heavy metals like lead, cisplatin, ethylene glycol, radiocontrast agents.
Endogenous: myoglobinuria (crush injury), hemoglobinuria, monoclonal light chains (Bence-Jones protein), urate
What are the typical causes of acute tubulointerstitial nephritis (ATIN)?
Drug reaction - penicillins, sulfa drugs (TMP/SMX, thiazide/loop diuretics, NSAIDs, proton pump inhibitors)
Systemic infections - i.e. mycoplasma
What is reflux or obstructive nephropathy?
Reflux nephropathy - damage caused by prolonged vesicoureteral reflux -> recurrent acute pyelonephritis infections
Obstructive nephropathy - chronic urinary tract obstruction leads to urine buildup and damage (i.e. due to kidney stones, BPH, or cervical carcinoma)
What do urinalysis, dipstick, and culture show for bacterial cystitis?
urinalysis - >10 WBC/hpf, with urine often cloudy
dipstick - leukocyte esterase and nitrite positive (bacterial)
Culture - >100,000 CFU / mL
What are the possible structural underlying causes of vesicoureteral reflux?
- Deficiency in longitudinal muscle of the ureter which causes ureter to enter bladder without sufficient tunneling -> does not close during detrussor contraction
- Congenital para-ureteral diverticulum -> dilatation disallows bladder contraction
- Inflammation of bladder wall, making it stiff.
How will chronic pyelonephritis appear microscopically?
Tubules contain eosinophilic casts resembling thyroid tissue -> thyroidization of tubules.
Everything else will be scarred and fibrosed -> glomerulosclerosis and interstitial fibrosis, with tubular atrophy (obviously)
What is the pathogenesis of diabetic nephropathy? What will happen to GFR?
Nonenzymatic glycosylation of the glomerular basement membrane as well as arterioles, predominantly the efferent arteriole. Leads to hyaline arteriolosclerosis of vessels and sclerosis of mesangium (ECM expands due to actions of TGFbeta)
-> increases GFR initially, followed by decrease in GFR later in the disease
What light microscopic changes of the glomeruli accompanies diabetic nephropathy?
Diffuse and nodular glomerulosclerosis
- > GBM thickening
- > Exaggerated mesangial expansion, with characteristic nodules (Kimmelstiel-Wilson nodules)
What does amyloid deposition in the glomerulus resemble under the microscope and how do you differentiate from this?
Looks like amorphous hyaline material depositing in the mesangium, just like diabetes
Differentiated via clinical picture and Congo red stain, (or immunofluoresence to kappa/lamda light chains or SAA protein)
How does myeloma cast nephropathy appear under light microscope?
Due to reaction between AL amyloid and Bence Jones protein
Tubules within the cortex / medulla have expanded, large, pink casts with cracked or fractured appearance
-> can often have swirling / lamelled character like psammoma bodies
What is the pathogenesis of HUS?
Shigatoxin damages endothelial cells in kidney -> swelling + detachment of endothelial cells -> decrease in capillary luminal area with deposition of platelets and fibrin
Leads to microangiopathic hemolytic anemia, thrombocytopenia, and renal symptoms
-> most common cause of ARF in infants and young children
How can TTP be acquired and what are the symptoms?
Acquired via auto-antibody to ADAMTS13 which is a vWF metalloprotease
Fever, thrombocytopenia, microangiopathic hemolytic anemia, renal symptoms, and neurologic symptoms-> headaches, seizures, confusion, hemiparesis
Where do the cysts arise from in ADPKD vs ARPKD?
ADPKD - can arise from any duct (cuboidal epithelium)
-> remember this one is also associated with mitral valve prolapse
ARPKD - arise from collecting duct**
What are the clinical manifestations of ARPKD and what is the function of the missing protein? When does it present?
Missing protein - another nonmotile cilia - polyDUCTin
Presents in infancy, often prenatally
- > congenital hepatic fibrosis leading to portal hypertension
- > renal failure and hypertension
What are some causes of thrombotic microangiopathies which are not TTP/HUS?
- SLE - anticardiolipin Abs
- Malignant hypertension - barotrauma
- Drugs - cyclosporine, tacrolimus (calcineurin inhibitors)
- Radiation, pre-eclampsia, other causes of endothelial damage
What are the inherited causes of Fanconi’s syndrome?
- Cystinosis
- Wilson’s disease
- Tyrosinemia
- Glycogen storage diseases
-> thought to be due to defective energy metabolism
What are the acquired causes of Fanconi’s syndrome?
Lead poisoning
Multiple myeloma
Ingestion of expired tetracyclines
Tenofovir
What renal condition is usually unilateral but when bilateral may be easily confused with autosomal recessive polycystic kidney disease? How is it inherited? What is the pathogenesis?
Multicystic dysplastic kidney
- > it is actually a non-inherited congenital abnormality
- > usually unilateral
- > Ureteric bud fails to induce differentiation of metanephric mesenchyme
- > will be cartilage and no reniform architecture preserved
What are the most common causes of calcium stones?
- Conditions of high calcium:
- Idiopathic hypercalcemia
- Hypercalciuria with hypercalcemia (bone disease, sarcoidosis, hyper-PTH) - Conditions associated with high oxalate:
- Crohn’s disease -> small bowel damage increases oxalate resorption
- vegetarians -> diet rich in oxalates
What type of kidney stones is ammonium magnesium phosphate known for forming?
Staghorn caliculi -> occupy a large part of the renal pelvis
May also occur in cystinuria
What is a renal papillary adenoma / where is it located and how does it look under the microscope?
Benign tumor of renal tubular epithelium invariably located in the renal cortex (also called renal cortical adenoma)
Appears as cytologically bland epithelial cells composed of branching papillary structures
Incidental finding <5mm in size
What cells are an oncocytoma comprised of? Is it benign or malignant?
Comprised of oncocytes - renal collecting duct intercalated epithelial cells which stain very eosinophilically due to abundant mitochondria and lack of perinuclear clearing
It is a benign tumor
What are the three most common types of RCC? Which have the best prognosis?
- Clear cell RCC
- Papillary RCC
- Chromophobe RCC
Papillary / chromophobe better prognosis than clear cell
Arise from proximal tubule, associated with Birt-Hogg-Dube
What is the function of VHL / how do things go awry?
Tumor suppressor gene which inhibits hypoxia inducible factor
-> defect leads to increased transcription of HIF -> increased transcription of VEGF and PDGF
What are the most common benign / malignant tumors associated with von Hippel Lindau?
Hemangioblastomas - especially cerebellum
Pheochromocytomas
Bilateral renal cell carcinomas, happening at younger ages
What inherited genetic disorder is associated with development of papillary RCC? What gene product has gone awry?
hereditary papillary renal cell carcinoma (HPRCC)
Autosomal dominant, due to mutation in a tyrosine kinase of MET proto-oncogene on chromosome 7
-> chromosome 7 associated with papillary tumors
-> differentiate from hereditary leiomyomatosis RCC from lack of cutaneous smooth muscle tumors
What is Birt-Hogg-Dube syndrome associated with?
Autosomal dominant tumor suppressor loss
- Fibrofolliculomas -> fibroblast tumors of hair follicles with skin tags
- Pneumothoraces - due to development of pulmonary blebs / cysts
- Increased risk for RCCs (especially chromophobe), oncocytomas
How does a clear cell renal carcinoma appear grossly?
Large tumors which are most often golden-yellow due to high lipid content
Tumors are often cystic, with frequent necrosis
-> metastases to lung and bone
What is an angiomyolipoma? How does it present if acute?
Hamartoma with “Triphasic” morphology - blood vessels, smooth muscle, fat
How does the presentation of angiomyolipoma differ between sporadic and genetic/hereditary-predisposed individuals?
Sporadic - usually solitary lesion -> usually presents with hemorrhage
Hereditary - happens in Tuberous sclerosis (disease of hamartomas) -> usually multiple and bilateral, which is why it causes renal failure
What are the three syndromes associated with Wilms tumor? What gene is awry in each?
- WAGR syndrome - WT1
- Denys-Drash syndrome - WT1
- Beckwith-Wiedemann syndrome - WT2 (2nd rate because it is due to an imprinting problem)
What are the important risk factors for transitional cell bladder cancer? What will be seen?
Pee SAC
Phenacetin - discontinued NSAID
Smoking
Aniline dyes
Cyclophosphamide
Fibrovascular core with urothelium on ouside
What is the staging system for bladder cancer?
Stage 1 - Invasion of submucosa, but not muscle layers
Stage 2 - Invasion of muscularis propria
Stage 3 - Invasion of peribladder tissues
Stage 4 - Invasion of adjacent structures (i.e. prostate, cervix)
What is the most common bladder tumor in kids?
Rhabdomyosarcoma - an embryonic small blue cell tumor
Gelatinous polyploid masses called “sarcoma botryoides” -> botryoides means grape-like
What are the GFR criteria for RIF of the RIFLE criteria?
Risk - Serum creatinine is 1.5x, or GFR decreases by 25%
Injury - Serum creatinine is 2x or GFR decrease by 50%
Failure - Serum creatinine is 3x
or GFR decrease by 75%.
What is the definition of Loss or ESKD?
Loss - persistent ARF –> complete loss of kidney function for >4 weeks
ESKD - >3 months of ARF = CKD endstage, dialysis required
Is post-renal azotemia common, and who tends to get it?
No - because it required bilateral obstruction to produce azotemia
Newborns - congenital anomalies
Older males - BPH
Females - pelvic malignancy
Why does renal ischemia or toxic injury lead to intrarenal vasoconstriction, worsening ischemia?
Ischemia -> sublethal endothelial injury
Injury to endothelial cells causes increased endothelin release (potent vasoconstrictor) and reduced nitric acid production (vasodilator)
- > this is intended to cause thrombosis and repair of injury, but just worsens existing ischemia
- > thrombosis and procoagulation also causes congestion inducing hypoxia
What happens to urine production, electrolytes, and nitrogenous substances during the recovery period of ARF?
Polyuria -> BUN and serum creatinine fall as GFR recovers
Risk of hypokalemia from overexcretion
At what threshold should hyperkalemia be treated and how should it be done?
> 5.3 mEq/L
Treat bicarbonate when it falls below 15 mEq/L
At what threshold should hyperkalemia be treated and how should it be done?
> 5.3 mEq/L
Calcium gluconate for membrane stabilization, sodium bicarbonate (correct acidosis), B-agonists, hypertonic glucose with insulin, Keyexalate (resin), dialysis -> all from potassium lecture
What are the indications for dialysis in ARF?
- Fluid overload which is refractory to diuretics
- Persistent hyperkalemia
- Severe metabolic acidosis refractory to treatment, especially methanol / ethylene glycol poisoning
- Uremic symptoms, and automatically if BUN>100.
- GI bleeding
How is FENa calculated?
(Urinary / Plasma [Sodium]) / (Urinary / Plasma [Creatinine]) * 100%
Normal: <1% Na excreted -> creatinine excretion approximates GFR
How is FENa calculated?
(Urinary / Plasma [Sodium]) / (Urinary / Plasma [Creatinine]) * 100%
Normal: <1% Na excreted -> creatinine excretion approximates GFR
What are the six possible markers of kidney damage that would define CKD (other than GFR reduction)?
- Albuminuria: >30 mg/day or >30 mg/g creatinine
- Urine sediment abnormalities - RBC casts, WBC casts, oval fat bodies
- Electrolyte or other abnormalities caused by tubular disorders - i.e. RTA, Fanconi, nephrogenic DI
- Pathological abnormalities by kidney biopsy
- Imaging abnormalities (CT, ultrasound, etc)
- History of kidney transplant
What is the Cockcroft-Gault equation for estimating GFR based on creatinine?
Ccr = (140-age)(body wt in kg) / (72 * serum creatinine in mg/dL) * 0.85 if female
0.85 in females because women are less muscular for the same body weight -> less creatinine should be being produced
What drugs can influence GFR calculation and why?
Cimetidine and trimethoprim
-> block tubular secretion of creatinine, raising serum creatinine levels -> causes an artificial fall in calculated GFR even though it hasn’t changed
What are the consequences of the increased intraglomerular pressure and hyperfiltration in the remaining functional nephrons?
This maintains the GFR initially, but leads to capillary wall stretching, which promotes mechanical injury to endothelial cells, mesangial cells, and podocytes
Endothelial damage - localized microthrombi organizing to thrombosis
Mesangial cells - inflammatory cytokines, progressive fibrosis of glomeruli
Podocytes - albuminuria, and loss of podocytes favors fixation of glomerular tuft to parietal layer of bowman’s capsule.
How does CKD affect sodium balance?
Inability to adapt to acute changes in sodium loss or increase sodium loading
- > Generally Na+/H20 retention
- > will also not be able to stop secreting a base level of sodium in diarrhea (unable to adapt)
What are some conditions which may cause hyperkalemia even if GFR is high?
- Diabetes - hyporeninemic hypoaldosteronism
- Renal diseases affecting distal nephron (sickle cell, obstructive nephropathy)
- Acidosis
- Hemolysis
- Increased intake
- K+ sparing diuretics and NSAIDs
- Oliguria / volume depletion
-> all should be avoided in CKD
What happens to the calcium sensing receptors in CKD?
They are reduced in number and thus become less sensitive
-> higher serum Ca+2 levels are needed to suppress PTH, so PTH rises
How can extraskeletal calcification be an active process?
Elevated phosphorus (as well as elevated urea and other products) leads to upregulation of osteoblast production of a specific core binding factor Cbfa1
- > vascular smooth muscle cells are made into osteoblast-like cells
- > new osteoblast like cells produce bone matrix and lead to calcification
What are the late stages of neuromuscular complications in CKD?
Neuromuscular irritability, with cramps, twitching, asterixis (flapping), myoclonus, seizures, and coma
Stage 4 - sensory > motor peripheral neuropathy
What happens to glucose metabolism in CKD and why? Will patients need more or less insulin as GFR drops?
Insulin resistance -> due to accumulation of uremic toxins
Decreased insulin degradation - insuulin normally taken up by PCT cells and degraded
-> when GFR declines, insuline half-life is prolonged
In ESKD, less insulin is needed due to longer halflife
What does CKD do to growth in children?
Increased resistance to growth hormone -> growth retardation in children
Women have abortions, men have low testosterone and oligospermia
