1
Q
What structure tells you you are in the cortex?
A
Glomerulus - only seen in cortex, never in medulla
2
Q
What are the two types of nephron?
A
Cortical and juxtamedullary
Juxtamedullary ahs longer loop of henle - can concentrate urine more; also has vasa recta
3
Q
How does the capillary pressure in the glomerulus compare to systemic capillary beds?
A
Higher
4
Q
What are the three componenets that make up the filtration membrane
A
Endothelium (with fenestrations), basement membrane, and podocytes
5
Q
What is the charge of hte filtration membrane?
A
Negative - cationic species of the same size are filtered more readily
6
Q
What determines the single nephron GFR?
A
kf*(Pgc - Pbs - _gc) no _ for bs (no proteins in it)
7
Q
Is GFR blood flow dependent?
A
No - dependent on hydrostatic pressure primarily (that may be altered by blood flow though)
8
Q
How do you define clearance?
A
Cx =(Ux*V)/Px
U = Urine conc
V = volume
P = plasma conc
9
Q
How do you determine GFR from clearance?
A
Inulin or creatinine
10
Q
How do oyu determien effective renal plasma flow?
A
Clearance of PAH
11
Q
How do changes in efferent and afferent tone alter renal blood flow and GFR?
A
12
Q
What is the filtration fraction?
A
GFR/RPF
Indicator of driving force for proximal reabsorption
13
Q
What are non-vascular ways to regulate GFR?
A
Contraciton/relaxation of mesangial cells - pulls on basement membrane - less filtration
Contraciton/relaxation of podocytes
14
Q
What is autoregulation of GFR and RBF?
A
Held constant by two mechanisms:
Myogenic mechanism
Tubuloglomerular feedback
15
Q
What is filtered load?
A
Px * GFR
16
Q
What is urinary excretion?
A
Ux * V
17
Q
What is fraction excreted?
A
FEx = UEx / FLx (urinary excretion/filtered load)
18
Q
How do you spill glucose (or any other substance) in to urine?
A
Overwhelm reabsorption process
19
Q
How is sodium handled in the nephron?
A
20
Q
How is sodium handled in the proximal tubule?
A
Early : sodium transport processes (coupled - to glucose, against hydrogen, etc). NO Chloride (NaCO3)
Late: Co-transporters; typically along with chloride. Paracellular (NaCl)
21
Q
How is sodium handled in the loop of Henle?
A
Na/K/2Cl transporter
Defect in this is Bartter Syndrome
22
Q
How is sodium handled in distal tubule and collecting duct?
A
Early distal tubule: water impermeable, Na cotransport with Cl
Late/collecting duct: ENaC (epithelium sodium channel); Na/K ATPase on basal side
23
Q
What cell is the target cell for aldosterone?
A
Late distal tubule and collecting duct principal cell
24
Q
How is potassium handled in the nephron?
A
25
How is potassium handled in proximal tubule and thick ascending limb?
Paracellular solvent drag
26
How is potassium handled in the distal tubule/
\_-intercalated cell: reabsorbs potassium
Principal cell : secretes potassium \*\* Where regulation occurs
27
How is potassium balance regulated?
Redistribution of K+
Renal regulation: balance between reabsorption in \_-intercalated cells and secretion in principal cells and K+ secretion down electrochemical gradient
28
How is water handled in the proximal tubule and loop of henle?
Proximal: isoosmotic reabsorption of water, sodium coupled, paracellular and transcellular
Loop: Descending is water permeable; Ascending is water impermeable; solute transport in ascending produces hypotonic fluid that is delivered to distal tubule
29
What is countercurrent multiplication?
Loop of henle functions as counter-current multiplyer
Single effect is dirving force for the system (Na, Cl and K into interstition (via Na/K/2Cl cotransport) in relative absence of water
This increases interstitial concentration and provides driving force for water movement out of descending loop
Establishes ~200 mOsm/L transverse gradient
Longitudinal gradient develops from this
30
How does water get handled in distal tubule, collecting duct?
Early distal tubule is water impermeable
Late distal tubule and colecting duct has variable water permeability depending on ADH levels
ADH:
ADH - water pores inserted into apical membrane of principal cells.
ADH - increase activity of Na/K/2Cl-cotransporter to increase the single
effect and ultimately to increase longitudinal gradient.
ADH - increases permeability of urea in inner-medullary collecting duct.
31
What are effects of ADH on the nephron/
Primary effect on late distal tubule water absorption
ADH - water pores inserted into apical membrane of principal cells.
ADH - increase activity of Na/K/2Cl-cotransporter to increase the single effect and ultimately to increase longitudinal gradient.
ADH - increases permeability of urea in inner-medullary collecting duct.
32
How is water blaance regulated?
Sodium dependent water balance
Sodium independent water transport
33
How does the kidney handle acid-base?
Bicarb and H+ absorption/secretion
34
How is bicarb handled in proximal tubule and TAL?
Reabsorbed
35
How is acid-base handled in the distal tubule and collecting duct?
Body does not allow for acidification of urine beyond a certain point (~pH of 4.5) - Transporters shut off
Work-around is NH3 -\> NH4+ (which doesn't contribute to pH)
36
What are apical Acid-Base transporters?
Na+/H+ exchanger in PT and TAL
H+-ATPase in ALL H+ secreting cells H+/K+-ATPase exchanger in alpha-intercalated cells
37
what are basolateral Acid-Base transporters?
Cl-/HCO3- countertransporter in ALL cells
1Na+/3HCO3- cotransporter in PT & TAL
Na against its concentration gradient
38
What is total body water?
~60% body weight of average build adult person
Obese people have smaller percentage, since fat contains little water
39
What are the main compartments in which total body water is distributed?
Intracellular volume (most)
Extracellular volume (interstitial, plasma, transcellular)
40
HWat is the most common extracellular cation?
Sodium (140 mEq/L)
41
What is the main determinant of plasma osmolality?
Sodium
42
What is the most common cation in plasma?
Cl
43
What is the most common intracellular cation?
Potassium
44
What is a quick and dirty way of calculating osmolality?
Serum Na \* 2
If glucose and BUN are normal
45
What are "afferent" mechanims of volume regulation/
High pressure arterial volume receptors
Intrathoracic low-pressure volume receptors
CNS receptors
Hepatic receptors
Intrarenal volume receptors (JG apparatus, etc)
46
What are the "efferent" mechanisms involved in volume regulation?
Systemic hemodynamics: sympathetic nervous system and angiotensin II
Renal Na excretion: GFR, angiotensin II, peritubular capillary forces, aldosterone, ANP, plasma Na concentration, pressure natriuresis
47
What is effective arterial volume (EAV)?
"degree of fullness" of arterial system
Clinically difficult to define
Patients with edema present with paradox of increased total body water, but decreased effective arterial volume
48
What happens to the kidneys when there is low effective arterial volume?
Low urinary volume
High urinary osmolality (high specific gravity)
Low urinary sodium concentration
High urinary urea nitrogen concentration
Low urinarea urea nitrogen content
49
How do you assess low EAV clinically?
Skin turgor, humidity of mucosas, BP, pulse, orthostatic changes
Lab: BUN, Creatinine, uric acid, BUN/Creatinine ratio
Urinary lab indices: UNa, UOsm, U/P urea, U/P creatinine, FE of Na and urea
50
What is urinary fractional excretion of substance Y
Clearance of Y/ Clearnace of creatinine
51
What are normal urinary sodium values/
Variable - no one good answer
Can be 0 to several hundreds of mEq/day in direct relation to daily sodium intake
Typically any value is normal and simply reflects intake
EXCEPT in low EAV where sodium excretion should always be decreased
52
A 43 year-old man is receiving furosemide 40 mg po qd for the past 6 months for hypertension
\_\_ His sodium intake is 150 mEq/day
\_\_ What would be the urinary sodium excretion in a 24-hour urine collection
150
53
43 y/o man with adenoma of adrenal gland leads to overproduction ov aldo. Seems to have developed 6 months ago as detected by new onset hypertension
Sodium intake is 150 mEq/day
What would urinary sodium excretion be in 24 hour collection?
150
54
What is edema? When do you see pitting edema?
Edema is increase in volume of interstitial space
Pitting requires substantial increase in volume (\>3L)
55
What are the mechanisms of edema formation?
Increase in capillary hydrostatic pressure
Decrease in plasma oncotic pressure
Decrease in interstitial hydrostatic pressure
Increase in capillary permeability
56
Does primary hyperaldosteronism produce edema?
NO - despite being salt-retaining state
57
Does SIADH produce edema?
NO - despite primary water retention
58
When do you see edema?
When cardiac output is increased
59
How do you treat edema?
Treat underlying cause
Salt restriciton
Diuretics
60
What is anasarca??
Generalized edema
Associated with 4 conditions:
1) heart failure
2) liver failure
3) renal disease (nephritic or nephrotic syndrome)
4) systemic capillary leak syndrome
61
What are the two mechanisms to change urine flow?
ADH
Solute excretion
62
What is teh effect of inreasing solute excretion/
Always induces increase in urine flow rate (regardless of ADH level)
63
What is the most common solute that causes polyuria?
Glucose - in diabetes
64
What are solutes that can cause polyuria?
Glucose (diabetes)
Non-reabsorbable solutes (mannitol, dextran, radio-opaque dyes)
Salt (increased ingestion, renal wasting)
Obstruciton of urinary tract
Releif of bostruction
Interstitial-tubular diseases
Atrial arrhythmias
65
What are causes of polyuria due to defects in urinary concentrating ability?
Make urine that is very dilute:
Diabetes insipidus (deficiency of ADH) - responds to pitressin with significant rise in urine osmolality
Hereditary nephrogenic diabetes insipidus
Psychogenic polydipsia
Others that make a urine that isn't concentrated enough:
Hypokalemia
Hypercalcemia
Lithium
Interstitial-tubular renal disease
Sickle Cell disease and trait
Protein depletion
Others (sjogren's hyperglobulinemic states, amyloidosis)
66
What is osmolality?
of dissolved particles in solution
67
What is normal osmolality?
285-290 mosm/kgH2O
Typically is ~ 2x [Na+] + [glucose] (in mmoles/L) + [urea] (mmoles/L)
But typically just 2x [Na+]
68
What are stimuli for ADH secretion?
Osmolality receptors - primary effect
Baroreceptors - secondary effect
69
What are factors that determine the amount of urine produced/concentration of urine produced?
1) fluid delivery to proximal tubule
2) fluid dilution at ascending loop of henle
3) water impermeability of collecting duct (ADH effects)
70
What is pseudohyponatremia?
Plasma sodium low, plasma osmolality normal
Due to marekd increase in plasma solids (lipids, proteins)
"True" hyponatremia is hypo-osmolar hyponatremia
71
What is "true" hyponatremia?
Hypo-osmolar hyponatremia
Needs to be hypo-osmolar in order to truly be hyponatremia
Final common pathway is an inability to produce sufficiently dilute urine
72
What is the final common cause of true hyponatremia?
Failure to produce sufficiently dilute urine
Body has capacity to produce extraordinary amount of dilute urine if everything works well. Hyponatremia means that this isn't working well
73
What occurs in hyponatremia?
Brain swelling - but brain tries to compensate by extruding sodium, potassium, water, and organic osmolytes in order to restore the balance
Can cause coma, and other effects, but dependent on speed of development, and the duration of the process
74
What are causes of hypo-osmolar hyponatremia?
Endocrine - hypothyroid, adrenocortical insufficiency (rare, needs to get severe)
Non-endocrine - changes in extracellular fluid volume, decrease in distal tubular NaCl transport, increased permeability of collecting duct, polydipsia, end stage renal disease
75
How can changes in extracellular fluid volume cause hypo-osmolar hyponatremia?
Decrease -\> requires addition of hypotonic fluid to lead to hyponatremia (e.g. cholera)
Increase -\> edematous states, severe CHF or far advanced cirrhosis)
76
How does CHF or cirrhosis cause hypo-osmolar hyponatremia?
Decreased GFR, increased NaCl and water reabsorption and inappropriately high ADH
77
What is SIADH?
Head trauma, surgery, tumors
Treatment is to restrict water
Too much ADH for whatever reason - causes increased absorption of water
78
What are some drugs that can inrease ADH effects/
SSRIs - very common
79
What happens if you rapidly correct hyponatremia?
Central Pontine Myelinolysis
Need to correct at a slower rate
80
What is hypernatremia/what are causes?
Almost always associated with water dehydration
Shoudln't develop in normal thirst mechanism and if the person has access to water
Can be caused by diabetes insipidus - routinely normonatremic
Can be casued by diabetic non-ketotic hyperglycemic coma
Correct circulatory hypovolemia first, then worry about tonicity
81
What are diuretics?
Drugs increasing rate of urine formation
Typically increase solute load adn thus the water that follows
82
How do carbonic anhydrase inhibitors work?
Decrease reabosrption of NaHCO3
Act at proximal convoluted tubule
83
How do osmotic diuretics work?
Increase solute load by being filtered but not reabsorbed
84
How do loop diuretics work?
Inhibit Na/K/2Cl symporter
Work at thick ascending limb
85
How do thiazide diuretics work?
Inhibit Na/Cl symport
Work at Distal convoluted tubule
86
How do K-sparing diuretics work?
Primary sites of action are at late distal tubule and collecting tubule
Inhibit renal epithelial Na channels
Aldosterone agonists
87
What are loop diuretics?
Furosemide, torsemide
88
What class of drug is furosemide?
loop diuretic
INhibits Na/K/2Cl transporter
Increased Na loss at thick ascending limb of henle and subsequent water loss
Decreases deposition of NaCl in renal medulla, decreasing medullary osmotic gradient
89
What are effects of loop diuretics on Mg and Ca?
K transport is important in creating + potential in the lumen, and driving Mg and Ca reabsorption paracellularly
Loop diuretics causes lumen to not be as positively charged as it shoudl be, thus there is less reabsorption of Mg and Ca -\> can cause hypomagnesemia commonly
Hypocalcemia isn't seen so commonly since Ca can be rabsorbed in the distal tubule
90
What are effects of loop diuretics outside fo teh kidney?
May cause direct or indirect effects on vasculature
Acutely increases systemic venous capacitance (prostaglandins?)
Decreases cardiac preload and may decrease pulmonary edema before diruesis occurs
91
What are adverse effects of loop diuretics?
OH DANG
(Ototoxicity, Hypokalemia, Dehydration, Allergy, Nephritis, Gout)
Volume depletion (hypotension, decreased GFR)
Hypokalemia (direct action of inhibiting Na/K/2Cl symporter; also due to increased Na+ delivery to collecting duct; also due to stimulation of RAAS) - this can cause arrhythmias in patients susceptible to it.
Metabolic alkalosis (more Na to distal nephron -\> larger negative charge in lumen -\> more H+ secretion)
Hypomagnesemia (paracellular reabsorption is decreased)
Hyponatremia (rare - more of a water issue)
**Ototoxicity** (tinnitus, loss of hearing, vertigo - typically reversible, due to ionic alterations of endolymph)
Hyperuricemia
Hyperlipidemia, hyperglycemia (maybe due to hyperkalemia)
Sulfa allergy
92
What are clinical indications for loop diuretics?
Acute pulmonary edema
Edema : CHF, Cirrhosis, Renal failure and proteinuria
Hypertension
Hypercalcemia
93
What type of drug is hydrochlorothiazide?
Thiazide diuretic
94
How does hydrochlorothiazide work?
Thiazide diuretic
Inhibits NaCl symporter in distal convoluted tubule
Amount of natriuresis and diuresis is less than with loop diuretics
Doesn't contribute to medullary gradient disruption
Causes increased calcium reabsorption (not fully understood)
95
What are common side effects of thiazide diuretics/
Volume depletion, hypotension
Hyponatremia (Na loss with no reduction in ability to reabsorb water in CD
Hypochloremia
Hypokalemia (due to increased Na delivery to collecting duct, more negative charge in lumen, more K excretion via K channel)
Metabolic alkalosis (similar to Kalemia)
Hypomagnesemia (unclear)
Hypercalcemia (may be high normal, but ture hypercalcemia is unlikely)
Hyperuricemia (diuretic and uric acid compete at OAT)
Hyperglycemia nad new onset diabetes
Sulfa allergy
96
What are clinical indications for thiazide diuretics?
Hypertension (more used for this than loop diuretics)
Edema (CHF, Cirrhosis, Renal failure and proteinuria)
Calcium nephrolithiasis (off-label) and osteoporosis (off label)
Nephrogenic diabetes insipidus (reduces urine volume by up to 50%) -unknown how
97
What are potassium sparing diuretics?
Amiloride
Triamterene
98
How do Potassium sparing diuretics work?
Inhibitors of renal epithelial Na+ channels (ENaC inhibitors)
Decrease K+, H+, Ca++, and Mg++ excretion
99
What are adverse effects of ENaC inhibitors?
Hyperkalemia
Triamterene-specific: weak folic acid antagonist (megaloblastic anemia in pts wtih cirrhosis), renal stones
100
What are indications for ENaC inhibitors (potassium sparing diuretics)?
Combination with other potassium-lowering diuretics to continue diuretic therapy while maintianing K+ levels
Liddle's syndrome: Autosomal dominant mutations in ENaC subunits (off-label)
Treatmetn of lithium-induced nephrogenic diabetes insipidus (blocks Li entry to collecting duct cells (off-label)
101
What are aldosterone antagonist potassium sparing diuretics?
Spirinolactone
Eplerenone
102
How do aldosterone antagonists work?
Competitive atnagonists at cyptoplasmic mineralocorticoid receptor
In late distal convoluted tubule and collecting duct
Increase activation and syntheis of luminal ENaC and basolateral Na/K ATP-ase
Aldosterone inhibitors similar in action to ENaC inhibitors except less rapid and depends on basal aldosterone activity
103
What are side effects of aldosterone antagonists?
Vasculature: fibrosis, endothelial dysfunciton, inhibition of NO synthesis
Heart: fibrosis, LV hypertrophy, electircal excitability (arrhythmias)
Similar to ENaC inhibitors
Metabolic acidosis in cirrhotic patients
Elperenone (more selecitve mineralocorticoid activity)
Spironolactone (has antagonist activity at androgen receptors and progestoerne receptors - gyneocmastia, impotence, decreased libido, menstural irregularities)
104
What are clinical indications for aldosterone antagonists?
Spirinolactone: HTN, Edema (CHF, chrirosis -espceially with ascites, proteinuria), primary hyperaldosteronism, Decreased morbidity and mortality in Class 3 and 4 CHF and ventricular arrhythmias
Elpernonone: HTN, CHF after MI
105
What are carbonic anhydrase inhibitors?
Acetazolamide
Dorzolamide
106
How do the carbonic anhydrase inhibitors work?
Inhibits CA in proximal tubule (on luminal brush bordera nd in cyto)
Decreased HCO3 reabsorption -\> decreased Na reabsorption in proximal tubule
Effects limited bcause sodium isnt reabosrbed at proximal tubule since drug is absorbed at more distal parts of nephron
107
What are side effects of carbonic anhydrase inhibitors/
Infrequent
Hypokalemia (effect of Na delivery to collecting duct)
Metabolic acidosis (loss of bicarb and Na delivery to collecting duct)
Alkalizaiton of urine (retention of ammonia - more HCO3 to urine, therevore less H+ to urine, cuases decreased excretion of NH4 and more abosrbed NH3 -\> hepatic encephalopathy in cirrhosis); also renal stones
Sulfa allergy
108
What are clinical indications for carbonic anhydrase inhibitors?
Open angle glaucoma - ciliary body of eye secretes HCO3 from blodd into aqueous humor (dorzolamide is topical; acetazolamide is given orally)
Metabolic alkalosis - aggressive use of diuretics in volume overload states (CHF) can lead to metabolic alkalosis -\> CA inhibitor can help
109
What is an osmotic diuretic?
Mannitol
110
How do osmotic diuretics work??
Mannitol
Freely filtered and minimally reabsorbed
Increases urinary solute load, decreasing water reabsorption throughout nephron
Increases extracellular volume -\> increased renal blood flow
Washes out NaCl and urea in renal medulla (decreased water reabsorption)
Urinary excretion of everything
111
What are adverse effects of osmotic diuretics/
Extracellular fluid expansion, and fluid overlaod (Contraindicated in CHF)
Hyponatremia - increased osmotic load extracts intracellular water, diluting serum Na
Overdiuresis if you overshoot - dehydration, hypernatremia
112
What are clinical indications for osmotic diuretics?
Increase urine volume
Increased ICP - acute fulminant hepatic failure, cerebral edema is life-threatining complication
Increased intraocular pressure
113
How is mannitol administered?
IV
114
What is the role of K+ in homeostasis?
K is major intracellular cation - mostly found in cells, and only 2% is foudn in extracellular fluid
Most cells, intracellular is between 120-150 mEq/L
Extracellular K is regulated within very narrow range (only small deviations are tolerated)
115
What is high intracelluar K concentration important?
Regulation of cell volume and pH
Enzyme function
Urinary concentration
K+ concentartion gradient is important for neuromuscular excitation and contraction
116
How is K+ homeostasis governed?
3 processes:
Dietary intake
INternal K+ distribution
Excretion of K+
Adults maintain a state of zero K+ balance (In= Out)
117
Where are reservoirs for potassium buffering?
Muscle, bone, liver, RBCs
118
How does the body respond to a potassium load ingestion?
Translocation into cells, then more slowly, renal excretion
119
How do insulin and catecholamines promote K+ uptake by extrarenal tissues?
Insulin: binds receptor and hyperpolarizes cell membranes, facilitating K uptake. Activates Na/K ATPase resulting uptake of K
Catecholamiens: stimulate K+ uptake via \_2 adrenergic receptor, which generates cAMP and activates Na/K ATPase, causing influx of K in exchagne for Na
120
What factors inflence distribution of K+ between cells and exytracellular fluid?
Hormones (insulin, epinephrine, aldosterone)
Acid-Base status
Plasma tonicity
Plasma [K]
121
How is K+ eliiminated?
Potassium is freely filtered in nephron and mostly reabsorbed in early nephron (~ 90%)
Distal nephron is site of potassium secretion and determines net secretion
122
What are the effects of chronic furosemide treatment?
Na Wasting -\> Volume depletion -\> activation of RAAS, JGA hyperplasia
This leads to aldosterone secretion -\> Enhanced K+ and H+ secretion in collecting duct
Result is hypokalemai and metabolic alkalosis
123
What is Bartter Syndrome?
Normotensive, growth and mental retardation
Muscle weakness and cramps, salt craving and cosntipation; polydipsia, and polyuria
Hypokalemic, metabolic alkalosis, hyperreninemia, and hyperaldosteronism
Caused by mutations that provide same effects as loop diuretics (e.g. furosemide)
124
What is the sodium absorbing and potassium secreting cell in the distal nephron?
Principal cell
125
How are Na and K transported in the pricnipal cell fo the distal nephron?
Na absorbed through ENaC (aldo sensitive); extruded via Na/K ATPase
K passively diffuses down favorable electochemical gradient established by electrogenic Na absortion and through apial K-selective channels inot urinary space (ROMK)
126
What is the effect of a gain-of-function ENaC mutation?
Liddle's syndrome -\> enhanced Na abosrption in distal nephron, severe hypertension, HYPOkalemia, and metabolic acidosis
127
What is the effect of a loss-of-function mutation in ENaC?
Pseudohypoaldosteronism type 1
Reduced Na absorption in distal nephron (salt wasting), dehydration, hypotension, HYPERkalemia and metabolic acidosis
128
How is the magnitude of net K transport in the cortical collecting achieved/regulated?
K+ secretion by principal cells
K aborption by \_-intercalated cells
129
What factors (apart from principal cells and \_intercalated cells) influence K+ secretion int eh cortical collecting duct?
Peritubular: K+ intake, alkalosis, aldosterone, vasopressin
Luminal: flow rate, Na delivery adn absorption
130
What is teh effect of increased urine flow on potassium balance?
Increases in urinary flow rate stimulate K+ secretion in the aldosterone-sensitive distal nephron
Continuous washout of K+ secreted into urinary fluid maximizes concentration gradient to allow for sustained K+ secretion
131
A 29 y.o. male with end stage renal disease (ESRD) presents to the ER in the middle of the night complaining of weakness, having missed a routine hemodialysis treatment earlier that day. On physical examination, he appears comfortable and alert. Vital signs are stable (pulse = 88 beats/min; RR = 22 breaths/min; BP 158/113 mmHg). Serum [K+] is 8.5 mEq/L and his EKG appears as follows:
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What is the mechanism for the development of hyperkalemia in this man?\_\_
Wide QRS, elevated T waves
Decreased urinary excretion
1) Decreased flow to K+ secretory sites impairs K+ secretion
2) Impaired K+ entry into cells during uremia cuases low cell K, diminished K uptake after a K+ load, secondary to metabolic acidosis (decreassed Na/K ATPase activity)
132
What are factors that promote entry of K+ into cells?
INcrease in insulin availability
Increase in \_-adrenergic activity (administer \_-adrenergic agonists such as albuterol)
133
A 15 y.o. with Down\_\_s syndrome presents with history of vomiting x 1 wk, followed by a change in mental status. She was found unresponsive to verbal stimuli and pain and was brought to the ER where P.E. revealed: HR 100/min, BP 55/30 mmHg; wt 81 kg (baseline __ 93 kg); intermittent apnea. Multiple central lines were placed and NS boluses given. The patient coded several times, requiring defibrillation x 6 and repeated doses of epinephrine.
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What happened?
Diabetic ketoacidosis with severe dehydration (shock)
Presented with hyperkalemia due to decreased excretion and shift of K+ out of cells
134
What factors shift K+ out of cells and into ECF?
```
Metabolic acidosis
Insulin deficiency (diabetes)
```
Hyperosmolality
\_-adrenergic blcokade
severe exercise or tissue catabolism
135
What is the role of calcium in the body
Acts as second messenger for intracellular processes
Maintians membrane potential
Critical for epithelial cell adhesion
136
What is the role of phosphorus in the body
Critical for ATP, cAMP
137
What is the role of magnesium in the bodoy?
Cofactor for multiple cellular porcesses
138
Where is calcium and phosphate located in the body?
99% of calcium in bone
1% in serum (half of that is free, half is complexed)
85% of phosphate in bone, 14% intracellular, 1% in extracellular volume
139
How is calcium and phosphate balacne maintained in the body/ how is it different from Na and K?
Only partially absorbed in the gut - that amount is regulated by hormonal milieu
Na and K are fully absorbed
140
What are regulators of Ca/Phosphate?
Organs: kidneys, liver, bone, intestine, parathyroid, skin
Hormones: Vit. D, PTH, Calcitonin
Goal is to maintain serum Ca and P and total body Ca and P balance
141
How do adults maintain calcium balance?
Between ingestion, interplay with bone, and excretion through kidney
142
Are children in calcium balance?
No, typically ingest more than they excrete (deposit in growing bones)
143
What is calcitriol?
1,25 vitamin D
Receptors in : GI, liver, kdiney, heart, Skeletal, Fibroblasts, Parathyroid and others
Increases Ca (active transoprt) and phosphate absorption from gut
Suprresses PTH secretion and 1\_-hydroxylase in PT of kidney
Regulates bone remodeling, secondary ability to induce osteoblast/osteoclast differntiation
144
What is parathyroid hormoen?
Increases 1\_-hydroxylase in kidney
Increase Ca absorption by kidney
Decrease phosphate absorption by kidney (ie.e enhacned phosphate excretion via effects on proximal tubule, downregulates Na-Pi cotransporter)
Increases Ca resorption from bone
145
What is Calcitonin?
Inhibits osteoclast function (decreased Ca resorption from bone)
Promotes renal excretion of Ca, Phos, Na, K, and Mg
Role in normal Ca/Phos homeostasis is not well udnerstood
146
What factors augment PTH secretion?
Hypocalcemia (direct)
Hyperphosphatemia (direct and indirect via inhibition of 1\_-hydroxylase)
Low calcitriol levels
Polymorphisms of Ca sensing receptor on Parathyroid glands
147
What factors inhibit PTH secretion?
Hypercalcemia (direct)
Hypophosphatemia (direct adn indirect via 1\_-hydroxylase)
High calcitrol levels
Hypermagnesemia
Estrogens (lower set poitn for PTH secretion)
Aluminum
148
How is parathyroid hormone regulated?
Phosphate is a modulator (high levels -\> decrease Vit.D receptor -\> upregulates PTH)
149
What are factors that stimluate calcitriol production?
High levels of PTH (direct via 1\_-hydroxylase)
Hypophosphatemia (direct)
Hypocalcemia (indirect via PTH)
150
What are factors that inhibit calcitriol production?
Low levels of PTH (directly via 1\_-hydroxylase)
Hyperphosphatemia (directly)
Hypercalcemia (indirectly via PTH)
Anticonvulsants block action of calcitrol on bone/gut
151
What is the effects of PTH in the short term and long term?
Short term - direct increased bone Ca resorption (acts in minutes to increase plasma calcium)
Long term - increases kidney 1\_-hydroxylase, whcih increases plasma 1,25 (OH)D , which increases Ca absorption in gut which increases plasma calcium
152
How is calcium transported in kidney?
50-60% filtered load absorbe din PT (passive and active Na dependent mechanisms)
Thick ascending limb of lop of henle (active)
DCT (active)
Collecting duct (active)
PTH acts at DCT and CD level to regulate ca absorption
NOrmally 97% is reabsorbed
**Generally speaking, Ca follows Na**
153
How is calcium transport regulated in teh Gut?
Absorption by the gut is dependent on quantity of Ca complexed to phosphate, fatty acids, adn phytates which remains unavailable
2 mechanisms: Vitamin D dependent active transport and passive diffusion
154
What are characteristics of the diffisional and active transport of calcium in the gut?
Active transoprt is limited
155
What are clinical features of hypercalcemia?
Neurologic: confusion, coma, lethargy, emotional lability, depression, hypotonia
GI: anorexia, vomiting, constipation, peptic ulceration, acute pancreatitis, visceral calcification
CV: HTN, arrhythmia, sensitivity to digoxin
Renal: Polyuria (nephrogenic DI), polydipsia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired GFR
Other: soft tissue calcification, red eye syndrome, pseudogout, pruritis
156
What are causes of hypercalcemia?
Common: Primary hyperparathyroidism, neoplasia (PTHrp), Vitamin D toxicity, thiazide diuretics, art factual (hyperproteinemia)
Others
157
How do you treat hypercalcemia?
Restore extracellular fluid volume (saline)
Loop diuretics (inhibit Ca reabsorption at loop of henle (first ensure patient volume is expanded)
Calcitonin - peak effect within 4-6 hours -augments Na and Ca urinary excretion and inhibits osteoclastic activity
Bisphosphonates - inhibit osteoclastic acitivty
Corticosteroids - inhibits calcitriol production
158
WHat are clinical features of hypocalcemia?
Neuro: Nueromuscular irritability (parasthesia, tetany), convulsions, intracranial calcification, papilloedema
Eyes: cataracts
CV: prolonged QT, Resistance to digoxin, Torsades do POintes
159
What are causes of hypocalcemia?
Progressive renal failure
Acute renal failure
Hypoparathyroidism
Vitamin D deficiency
160
What are GI causes of hypophosphatemia?
Decreased intake (artificial feeding, associated witha ntacids)
Phosphate binding agents (Al/Mg agents)
Vitamin D deficiency (decreased intake/absorption/hydroxylation)
Malabsorption of P or Vit D
Glucocoritcoid excess
UGI losses
161
What are renal causes of hypophosphatemia?
Fanconi syndrome - related to toxic substances sucha s Pb, Hg, Cd, aminoglycosides
Primary hyperparathyroidism or PTHrp-lowish P with hypercalcemia (increased intestinal absorption of P, increased P excretion, osteotitis fibrosis
Kidney transplant
Alcoholism
162
What are causes of hyperphosphatemia?
ARF/CRF - decreased urinary excretion of phosphate
Hypoparathyroidism
Acromegaly
Increased intake
Shift of phosphate to ECV
Vitamin D intoxication
Familial syndromes
163
How do you treat hypophosphatemia?
Hyperalimentation
PO intake
Renal losses - phosphate and vitamin D supplementation
164
What is secondary hyperparathyroidism?
Complication of renal disease
Elevated PTH in response to secondary event
Specifically - related to loss of GFR in renal disease
165
How does secondary hyperparathyroidism occur?
Early renal disease (CrCl 60-80) : GFR falls, 1,25VitD production by 1\_-hydroxylase falls; 1,25VitD is typically involved in feedback inhibition of PTH, so increased PTH; Increase in serum PTH helps enhance enzyme activity to maintain 1,25VitD levels in serum
Late renal disease (CrCl 15-35): PTH continues to rise as GFR falls since 1,25VitD concentrations fall (frank loss of 1\_-hydroxylase; Unable to maintain 1,25VitD levels by enzyme induction, and phosphorus is unable to be excreted, so PTH secretion is further enhanced
166
What must you first correct before you correct hypocalcemia and hypokalemia?
Hypomagnesemia (if present)
167
Hypercalcemia and hypophosphatemia -\> elevated calcium is causeing constipation and depression , more likely than not
Order PTH hormone, 1,25VitD levels, adn 25VitD levels
PTH elevated, 1,25VitD normal (or high normal), 25VitD is normal
Primary disorder is primary hyperparathyroidism
PTH acts to increase serum calcium by increaseing calcium absorption by bone and kidney, activating 1\_-hydroxylase (elevates 1,25VitD). PTH also enhances urinary phosphorous xcretion, leading to hypophosphatemia. No elevated 1,25VitD since there is feedback inhibition of 1\_-hydroxylase
168
Renal failure leads to inability to make 1,25VitD; Low levels increase PTH
Secondary Hyperparathyroidism
Renal failure leads to inability to make 1,25VitD. The tonic inhibition of 1,25VitD increases PTH. This helps maintain serum calcium and increase urinary phosphorus excretion
169
How is pCO2 related to pH?
Indirectly
pCO2 \* 0.03 = [H2CO3] typically - this goes into henderson-hasselbach equation
170
What are sources of acid production?
Carbohydrate metabolism
Fat and Phospholipid Metabolism
Protein Metabolism
171
What are the two classes of acid?
Carbonic acid - H2CO3 - from CO2
Noncarbonic acid - Ammonium, phosphate, and sulfuric acid -\> primarily from proteins (eliminated in 2 steps: 1 - combines with bicarb and intracellular buffers, 2- excreted by kidney)
172
How do the kidneys handle bicarbonate?
Highly efficient
Bicarb is reclaimed at the proximal tubule (no new bicarb is formed by H+ secretion in proximal tubule)
Bicarb is regenerated at the collecting duct (and late distal tubule)
173
How is bicarb handled by the proximal tubule?
Recliamed
No new bicarb is formed by H+ secretion in proximal tubule
174
How is bicarb handled in the collecting duct (late distal tubule)?
\_-Intercalated cells
Bicarb is regenerated (to the blood side)
175
What is the etiology of respiratory acidosis?
Hypoventilation = decreaed respiratory rate
INcreases PaCO2, which increases H+ levels, adn decreases pH
Seen in neuromuscular disorder, chest wall deformity, iatrogenic (opioid OD)
176
What are clinical causes of respiratory acidosis?
Neuromuscular disorder
Chest wall deformity
Iatrogenic: Opioid OD
177
What is the etiology of respiratory alkalosis?
Hyperventilation - increased respiratory rate
Decreased PaCO2 = decreased H+ and increased pH
Clinically seen in:
Anxiety/panic attack
Hypoxia (Pulm. Emoblism)
Pain (acute MI)
Cirrhosis (ascites restricting ventilation)
Pregnancy
178
When do you clinically see respiratory Alkalosis?
Anxiety/panic attack
Hypoxia (Pulm. Emoblism)
Pain (acute MI)
Cirrhosis (ascites restricting ventilation)
Pregnancy
179
What are clinical causes of metabolic acidosis?
Overproduction of organic acids
Intoxication of acids or agents metabolized to acids
Underescretion of normal acid load
Bicarb wasting or bicarb underproduciton
Dilutional metabolic acidosis
180
What are labs in metabolic acidosis?
increased H+ causes low pH, low HCO3 and low pCO2 (respiratory compensation = hyperventilate)
181
What is the respiratory compensation for metabolic acidosis?
Hyperventilate = decrease pCO2
182
What ionic disturbance do you see in metabolic acidosis?
Hyperkalemia
Largest positively charged ion in cell is K
High H+ extracellular shifts the balance of H/Na antiporter, which affects Na/K ATPase activity
183
What is anion gap?
Serum is typically electrically neutral
AG is the differnce between unmeasured anions and cations
AG = Na - (Cl + HCO3)
Normally 12 mEq/L; if increased, signifies presence of additional anions
184
What is a normal anion gap?
~12
185
What are unmeasured anions that contribute to the anion gap?
Protein
PO4-
SO4-
Organic acids
186
What is lactic acidosis?
Anion is lactate
Caused by :
Type A = tissue hypoperfusion/hypoxia (circulatory shock, strenuous exercise or seizures, hypoxemia)
Type B = Liver failure, alcoholism, congenital enzyme deficiency, malignancy, mitochondrial disease, meds (HAART, metformin)
187
Where does lactic acid come from?
Derived from metabolism of pyruvic acid
Increased produciton during impaired tissue oxygenation (increased anaerobic metabolism)
188
How do you treat lactic acidosis?
Treat underlying cause (most common is shock, so IV fluids, Abx if septic, vasopressors)
189
What is ketoacidosis?
Anion is ketones (actoacetate, acetone, \_-hydroxybutyrate)
Caused by: alcohol, starvation, diabetes (DKA in type I adn associated with high Anion Gap)
190
What is Salicylic Acidosis?
Anion - Salycilate
Aspirin is Acetyl-salicyclic acid
Causes concomitant metabolic acidosis and respiratory alkalosis (mixed acid-base disorder)
Symptoms: tinnitus, hearing impairment and dizziness; decreased vision, headache; N/V; Bleeding; fever - uncoupling of oxidative phosphorylation
191
What do you see in aspirin overdose?
Acid base derangements:
Respiratory alkalosis - stimulation of respiratory center in medulla
Metabolic acidosis: from salicylic acid and from uncoupling of oxidative phosphorylation resulting in lactic acid
Respiratory acidosis: late stage of intoxication results in depression of respiration and from decerased mental status
In severe cases, you can see cerebral edema (can be coma), acute respiratory distress syndrome (ARDS), renal failure, death
192
How do you treat salicylate intoxication?
Alkalinize urin with bicarb intravenously to trap ions (ion trapping)
193
What is a mnemonic for remembering causes of high anion gap metabolic acidosis?
MUDPILES
Methanol
Uremia
Diabetic Ketoacidosis
Paraldehyde
Iron, isoniazid
Lactic acidosis
Ethylene glycol
Salicylates
194
What is an osmolar gap?
(measured Posm) - (calculated Posm)
Calculated Posm = 2(Na) + Glucose/18 + BUN/2.8
Normal osmolar gap is 6 +/- 4
195
What is a normal osmolar gap?
6 +/- 4
196
how do you calculate plasma osmolarity?
Posm = 2\*Na + Glucose/18 + BUN/2.8
197
What intoxicants can produce an osmolar gap?
Methanol
Ethanol
Ethylene Glycol
Isopropyl Alcohol
Ehtanol is not an acid and doesn't increase anion gap, but can develop alcoholic ketoacidosis
Isopropyl alcohol causes mild metabolic acidosis, but does not increase anion gap
198
What do you see in methanol intoxication clinically?
Osmolar gap metabolic acidosis and high anion gap
Anion is formate and lactate
Can cause retinal injury with optic disc hyperemia and edema -\> permanent blindness
199
What do you see in ethylene glycol intoxication?
High anion gap metabllic acidosis with osmolar gap
Anion is glycolate, lactate, and oxalate
Can get calcium oxalate crystals that can precipitate in tubules and cause acute renal failure (acute kidney injury)
200
What is ethylene glycol?
Antifreeze - can pick up on urine with a woods lamp
201
How do you treat metahnol or ethylene glycol intoxication?
Treat with fomepizole (competitive antagonist of alcohol dehydrogenase - blcoks metabolism and therefore production of toxic metabolites)
Can use ethanol IV infusion - alcohol dehydrogenase used to metabolize large amounts of ethanol, so less enzyme available to metabolize methanol or ethylene glycol
202
What can help you distinguish from a simple or mixed acid base disorder in metabolic acidosis?
Winter's Formula
ONLY IN METABOLIC ACIDOSIS
Calculates expected PaCO2 given normal respiratory compensation in setting of gapped metabolic acidosis
expected PaCO2 = 1.5\*[HCO3-] + 8 +/- 2
203
What does a lower than expected PaCO2 (lower than that calculated from winter's formula) signify?
Secondary respiratory alkalosis
204
What does a higher than expected PaCO2 (higher than that calculated from winter's formula) signify?
Secondary respiratory acidosis
205
What does a large anion gap and a normal pH indicate?
Suspect a mixed acid-base disorder
Metabolic acidosis + lower/higher than expected PaCO2 from Winter's formula
206
What is non-gapped metabolic acidosis?
Hyperchloremic metabolic acidosis"
Unlike anion gap metabolic acidosis, Cl- rises as HCO3- falls (resulting in unchanged AG)
Caused by HCO3 wasting (or underproduction): Diarrhea with associated hypokalemia; renal tubular acidosis
207
What can cause a non-gapped metabolic acidosis?
GI: diarrhea (usually associated with hypokalemia)
Renal: Renal tubular acidosis (potassium varies)
208
What is a urinary anion gap?
Helps differentiate GI bicarb loss from renal wasting
UAG = (Na + K) - Cl
H+ secreted in distal tubule is buffered by ammonia and excretd as ammonium
NH4 is accompanied by Cl anion to maintain electroneutrality
Acidosis from GI cause: kidneys clear acid load by excreting more H as NH4 and urine Cl rises; UAG will be negative
If acidosis from renal cause: kidneys unable to excrete H+, urine Cl doesn't rise and UAG is positive
209
What does a positive UAG tell you?
Non-gapped metabolic acidosis is renal in cause (renal tubular acidosis)
Kidneys unable to excrete H+ and urine Cl doesn't rise
UAG = (Na + K) - Cl
210
What does a negative UAG tell you?
Non-gapped metabolic acidosis is likely from GI (diarrhea) causes
Kidneys clear acid load by exreting more H+ ad NH4 in urine and Cl in urine rises
UAG = (Na + K) - Cl
211
What is RTA type I?
Renal tubular acidosis
"Classic" type
Distal tubular defect in H+ secretion (non gapped metabolic acidosis)
NH+ excretion reduced (+ UAG)
Cannot acidify urine (pH \> 5.5)
Typically Hypokalemic
Seen with nephrolithiasis - acidosis increases serum calciuma nd decreases citrate in urine - predisposing to stone formation
212
What can cause type I RTA?
Sjogren's Syndrom
Lupus
Amphotericin B
TOluene
Lithium
Hereditary
Sickle cell
213
How do oyu treat Type I RTA?
Alkali (bicarb, citrate), potassium
214
What is RTA type II?
Proximal tubular defect in bicarb reabsorption (non-gapped metabolic acidosis)
Bicarb threshold - able to aacidify urine when bicarb reaches 15-20 mEq/L because distal nephron acidifies
Can be part of Fanconi's Syndrome (generalized defect in proximal tubular transport with decreasd reabsorption of glucose, phosphate, uric acid, and small amino acids)
Tx with alkali, potassium, phosphorus
215
How do you treat RTA type II?
Alkali, potassium, phosphorus
216
Where is the defect in RTA type I?
Distal tubule (defect in H+ secretion)
Causes non-gapped metabolic acidosis)
217
Where is the defect in RTA type II?
Proximal tubule bicarb reabsorption
Causes non-gapped metabolic acidosis
218
What is RTA type IV?
Distal tubular defect in H+ secretion due to aldosterone deficiency or resistance (and resultant hyperkalemia)
Decreaed aldo causes decreased Na reabsorption, decreases electronegativity of lumen, which decreaes secretion of H+ and K+
Causes hyperkalemia
219
What can cause RTA type IV?
Diabetic nephropathy
Interstitial nephritis
Sickle cell disease
Obstructive nephropathy
Meds: cyclosporine, spironolactone, ACE inhibitors
220
How do you treat RTA type IV?
Kayexelate, Lasix, bicarb (and remove offending agent if possible)
221
Where is the defect in RTA type IV?
Distal tubule defect in H+ secetion due to aldosterone deficiency or resistance
Causes non-gapped metabolic acidosis
222
What is metabolic alkalosis?
Primary increases in serum bicarb concentration
Manifests as mental status changes, low seizure threshold, tetany, cardiac arrhythmias
Associated with Hypokalemia (shifted intracellularly)
Associated wiht hypocalcemia (shifts ionized calcium onto albumin (increases bound, inactie form)
223
How can you generate metabolic alkalosis?
Acid loss : extra-renal acid loss (vomiting, gastric drainage) or renal acid loss (primary increase in distal sodium delivery or mineralocorticoid activity)
Gain of base: massive blood transfusions (Citrate), TPN (acetate), Milk-alkali syndrome
224
How do you maintaine metabolic acidosis?
Decreased HCO3 excretoin despite elevated bicarb levels
Due to: volume depletion (increased sodium avidity, increased proximal HCO3 reabsorption and increased distal acid excretion from \_-intercalated cells); or due to hypokalemia
225
How do you help reverse metabolic alkalosis
Return volume
Give potassium
226
What are the two categories of metabolic acidosis?
Hypovolemic - acid loss driven by secondary hyperaldosteronism (hypovolemic, metabolic alkalosis, hypokalmeic): chloride sensitive, caused by Gi loss, diuretics, genetic syndromes; Tx with volume repletion
Euvolemic/hyperovlemic - chloride insensitive; use BP to further determine cause
227
What are hypertensive eu/hypervolemic metabolic acidosis causes?
Renal artery stenosis (high renin, high aldo)
Primary hyperaldosteronism (low renin, high aldo)
Cushing syndrome
Liddle's Syndrome (Mutated ENaC, constantly open)
Syndrome of Apparent Mineralocorticoid excess (AME)
228
What are normotensive eu/hypervolemic metabolic acidosis causes?
Exogenous consumption of bicarb in face of decreased renal excretion (NaHCO3, CaCO3,baking soda, tums)
Milk-alkali syndrome - triad of hypercalcemia, metabolic alkalosis, renal insufficiency - caused by consumption of large amounts of calcium and absorbable alkali
229
What is the general approach of acid-base disturbances?
1) Check pH: acidemia or alkalemia?
2) Check HCO3- or PaCO2: Respiratory or Metabolic
3) Check anion gap: Gapped or non-gapped metabolic acidosis
4) If gapped, check Winter's formula: normal respiratory compensation or secondary disturance
5) If non-gapped metabolic acidosis, check urine anion gap: renal or extra-renal cause
230
What is sildenafil?
phosphodiesterase 5 inhibitor
INcreasing halflife of cGMP produced in response to nitric oxide
Enhances vasodilatory effects of NO
231
When is sildenafil indicated?
Erectile dysfunction (viagra)
Pulmonary hypertension (revatio)
232
What are side effects of sildenafil?
Headache
Nasal congestion
Visual disturbance (blue vision) - PDE5 also present in retina
Reports of abrupt hearing and vision loss
Most side effects due to vasodilatory activity
233
What are contraindications for sildenafil use?
Concurrent use of nitrates in any form
COncurrent use of HIV protease inhibitors
Hypersensativity to sildenafil
234
What is the basis for the contraindication of concurrent use of sildenafil and nitrates?
PDE inhibitor shunts cGMP to smooth muscle relaxation pathway in smooth muscle
Nitrates exacerbate this -\> will cause cardiac and other muscle relaxation
235
What is tamsulosin?
Alpha 1 antagonist
Used to improve urin flow rate since it leads to relaxation of smooth muscle of the prostate, prostatic urethra, and neck of the bladder
236
When is tamsulosin indicated?
BPH
237
What are adverse effects of tamsulosin?
Dizziness, orthostatic hypotension (\_1 blocker)
238
When is tamsulosin contraindicated/precautions?
Contranidicated in hypersensitivity
Precaution with CYP inhibitors, be aware of side effects
239
What is vasopressin (AVP, ADH)?
Antidiuretic hormone
Source in paraventricular and supraoptic nuclei of hypothalamus that project to posterior pituitary
240
What are the ADH receptors?
V2 receptor: Kidney collecting duct luminal epithelium; works by cAMP (Gs) to absorb free water adn concentrate urine
V1 receptor: Cardiac muscel and smooth muscle of vasculature; works by phospholipase C (Gq); causes vasoconstriction
241
What is the effects of vasopressin on its receptors?
242
How does V2 receptor activation cause resorption of water?
Aquaporin upregulation and insertion into apical membrane
243
What controls vasopressin release?
Osmotic stimuli is initial and quick control
Volume stimuli is later and causes bigger releases of ADH
244
In a patient who is hyponatremic (hypoosmotic), say Na of 110 (normal ~ 140), but is also hypovolemic (severe hypotension), what will ADH levels be?
High! baroreceptors win out
245
What is desmopressin (DDAVP)?
Synthetic ADH with increased selectivity at V2 receptor
Used in DI, hemophilia, primary nocturnal enuresis
246
When do you use vasopressin?
For V1 mediated effects of ADH - vascular vasoconstriction (can also use Epi, Norepi, Dobutamine)
247
When do you use desmopressin?
V2 mediated effects
Diabetes insipidus (central) - not effective in nephrogenic
Hemophelia A or von Willebrand's Disease when factor VIII levels are \> 5%
Primary nocturnal enuresis
248
What is unique about desmopressin pharmacokinetics?
VERY low bioavailability ([F] \< 0.01) - but still produces effects
249
\_\_ A 35 year old woman comes to see you in the office on her lunch break, and is happy to tell you she started her new job as a nurse in the hospital. She has no complaints, except that she urinates frequently. No dysuria. She states she usually drinks a lot of water, but recently has decreased her fluid intake because no one is allowed to have fluids to drink at the nurse\_\_s station.
\_\_ Past Medical History: Migraines
\_\_ Medications: Ibuprofen
\_\_ Labs:
\_\_ Na 154 mEq/L Cl 95 mEq/L BUN 20 mg/dL Glucose 75 mg/dL
\_\_ K 4.0 mEq/L Bicarb 24 mEq/L Cr 0.9 mg/dL
\_\_ Urine Na 50 mEq/L, Urine Osm 200 mOsm/L
Diabetes Insipidus - give desmopressin
250
An 85 year old man with hypertension, DM, and chronic kidney disease is admitted for cough and weight loss. 3 days ago, his outpatient doctor placed him on clarithromycin for empiric treatment for pneumonia. While in-hospital, after a battery of tests, he is diagnosed with small cell lung carcinoma. You are helping him and his family cope with this diagnosis. And in the meantime, his lab tests come back.
\_\_ Na 117 mEq/L Cl 95 mEq/L BUN 40 mg/dL
\_\_ Glucose 120 mg/dL
\_\_ K 4.0 mEq/L Bicarb 24 mEq/L Cr 3.0 mg/dL
\_\_ Cr Cl 21 ml/min
\_\_ Urine Na 80 mEq/L, Urine Osm 650 mOsm/kg
SIADH
Pt is euvolemic - urine sodium is high
Urine osmolarity (650) is higher than plasma (234) - too much activity of ADH
251
How do you treat hyponatremia in SIADH?
Start with water restriction
252
What are vaptans?
Vasopressin receptor antagonists
253
What is conivaptan?
V1 and V2 antagonist
254
When is conivaptan indicated?
SIADH - short term treatment
255
What are adverse effects of conivaptan?
V1 and V2 antagonist -\> so can casue hypokalemia due to polyuria
Infusion site reactions
Can cause hypernatremia (overshoot)
Constipation/diarrhea
256
When is conivaptan contraindicated?
CYP inhibitor use
Hypovolemic hyponatremia - need to rehydrate so you need ADH to reabsorb water
Anuria - if can't make urine, won't have an effect
257
What is demeclocycline?
Old drug used for SIADH (antibiotic - tetracycline)
Thought to work because it inhibits the synthesis of a protein receptor in the distal renal tubule/collecting tubule that is needed for ADH\_\_s action.
Adverse effects - nephrogenic Diabetes Insipidus
258
How do you want to collect a urine sample?
Obtain mid-stream, clean cath sample
To avoid cellular or microbial contamination
259
what does a 24 hour urine collection help identify? What is it used for?
To measure CrCl (GFR) and accurately quantify proteinuria
Normal volume is ~1-2 liters
Man 20-25 Cr/kg/day
Woman 10-15 Cr/kg/day
260
What does a 4 liter urine sample with 3 gm of Cr likely signify?
Overcollection
261
What does urine typically look like?
Clear, light yellow in color
262
What does dilute urine potentially indicate?
Diabetes insipidus, psychogenic polydipsia
263
What does darker urine potentially indicate?
More concentrated - dehydration
264
What does cloudy, turbid urine indicate?
Leukocytes, possibly
Bacteria, UTI
265
What does sweet/fruity urine indicate?
Ketosis, Diabetes Mellitus
266
What does musty urine indicate?
Phenylketonuria (PKU)
267
What does maple syrupy urine indicate?
Maple Syrup disease
268
What does red/orange/brown urine indicate?
Hematuria (RBCs, GI, vasculitis, Nephritis, infection, cancer, nephrolithiasis)
Hemoglobinuria (hemolysis)
Myoglobinuria (rhabdomyolisis)
Meds (rifampin)
Food dyes (beets)
Metabolites (bilirubin, porphyrins)
269
How do you differentiate between hematuria and hemoglobinuria/myoglobinuria?
Hematuria = red sediment (+ RBCs), and CLEAR supernatant
Hemoglobinuria/Myoglobinuria = red superanatant (+hemoglobin/myoglobin)
270
What does blood on dipstick but no RBCs suggest?
Rhabdomyolysis/hemolysis
271
What is the specific gravity of urine?
Ratio of fluid's weight to the weight of equal volume of distilled water
Range = 1.003 to 1.030 (dilute to concentrated)
272
What is a good surrogate of urine osmolarity?
Specific gravity
273
What is isosthenuria?
Kidneys can't concnetrate urine
Urine osm = plasma osm (typically SG = 1.010
274
What is urinary pH?
4.5-7.8, typically
275
What can cause alkaline urine?
UTI with urea-splitting bacteria (Proteus mirabilis, klebsiella)
Bacterial urease breaks down urea to ammonia, and hydrolyzes to ammonium and hydroxide and lowers free H+; raising pH
---
Type I RTA patient cannot properly acidify urine (metabolic acidosis + alkaline urine)
276
What stones does acidic urine favor the formation of?
Uric acid
277
What stones does alkali urine promote the formation of?
Calcium phosphate
Struvite
278
What is leukocyte esterase?
Esterases released from lysed granulocytes - indicates presence of WBCs in urine
279
What is nitrite?
Produced when gram-negative bacteria convert nitrate (typically in urine) to nitrite
Signifies presence of bacteria in urine
False negative: UTI 2ndary to bacteria that do not produce nitrite (enterococcus), or urine not rentained in bladder long enough
280
How can you diagnose UTI with urinalysis?
Leukocyte estearse (LE) and Nitrate
Urine culture to confirm diagnosis and guide abx choice
281
What is urine glucose helpful in screening for?
Diabetes (prior to fingersticks, was typically used)
Gulcosuria typically reflects high serum glucose
Hyperglycemia overcomes renal threshold for reabsorption
Rarely indicative of impaired glucose reabsorption and decreased renal threshold for excretion (Fanconi's Syndrome)
282
What do urine ketones indicate?
Ketones are acetoacetate, acetone; \_-hydroxybutyrate is NOT detected
Detected via nitroprusside reaction on reagent strip
Ketones suggest fasting state or starvation, alcoholic ketoacidosis, or diabetic ketoacidosis
283
What proteins do urinalysis dipsticks typically detect?
Negatively charged (i.e. albumin)
Unable to detect positively charged (i.e. light chaines in multiple myeloma)
Useful for diabetic nephropathy but poor test for cast nephropathy
284
What is a sulfosalicylic acid precipitation test?
Used to quantify total protein concentration (albumin and light chains)
SSA added, measure turbidity (increased proteinuria, increased turbidity); compare to standards
Significant proteinuria on 24 hr collection with negative dipstick = light chains
285
What is healthy protein urine output?
30-130 mg/day
286
What are ranges of urine protein adn what do they indicate?
Normal = 30-130 mg/day
Overt proteinuria = 300-500 mg/day
Nephrotic-range proteinuria = 3.5gm/day
287
What is the lower limit of urine dipstick protein detection?
20mg/dL (300 mg per day if 1.5 L produced)
288
What are formed elements that you may see on urinaysis?
cells
Casts
crystals
microorganisms
289
What are casts?
Cylindrical bodies formed ind istla tubules and/or collecting ducts
Tamm-Horsfall protein (THP) - secreted by thick ascending limb of Loop of Henle, can form a cast matrix that precipitates cells in the urinary space
290
Urinalysis, what is this?
Squamous epithelial cell - contamination
291
What is this, urine:
Renal tubular cell
Larger than WBC, shed in renal tubular damage (ATN)
292
What do dysmorphic RBCs indicate on urine?
problem at glomerulus
293
What is pyuria?
WBCs in blood
294
What is this?
Hyaline cast - nonspecific, nonpathologic cast of mucoprotein (THP) only
Seen in normal
295
What is this?
Finely granular cast - no big deal
296
What is this?
Coarsely granular cast - NBD
297
What is this?
"muddy brown" granular cast
Pathognomonic for ATN
298
What is this?
WBC cast - present in pyelonephritis and interstitial nephritis
299
What is this?
Broad waxy casts
Formed in dialted, atrophic tubules
Suggestive of chronic kidney disease
300
What is this?
Fatty cast - seen in nephrotic syndrome
301
What is this?
Calcium oxalate crystals
Oxalate crystals + metabolic acidosis = ethylene glycol ingestion
302
What is this?
Magnesium ammonium phosphate (STruvite) crystals
Seen during infection with urea-splitting organisms in alkaline urine
303
What do you see ?
Rhombus shape, form in acidic urine - treat stones by alkalinizing urine, decrease uric acid production)
In setting of acute renal failure after chemo suggests tumor lysis syndrome
304
What is this?
Cystine crystals
Seen in cystinuria
Inherited disorder in which renal tubular absorption of cystine is reduced
305
What is this?
Sulfonamide crystals
306
What is this?
Indinavir crystals
Protease inhibitor used in treatment of HIV; may cause ARF if patients not well hydrated
307
What is the scale of proteinuria (trace, 1+, 2+, 3+, 4+)?
Trace = 5 to 20 mg/dL
1+ = 30 mg/dL
2+ = 100 mg/dL
3+ = 300 mg/dL
4+ = \> 2000 mg/dL
308
What is the classic presentation of nephrotic syndrome?
Proteinuria (\> 3-3.5 grams/24 hours) - necessary
Hypoalbuminemia
Hyperlipidemia
Edema
Primary protein lost is albumin
309
What does this glomerular basement membrane show?
Diffuse foot process effacement
Podocyte damage -\> disease
310
What is the normal glomerular filtration barrier charge?
Negative
Lost in disease (nephrotic syndrome)
311
What are the consequences of nephrotic syndrome?
Proteinuria, hypoalbuminemial, low serum Ig, low coag factors
312
Why do we see the complications in nephrotic syndrome?
313
What are complications of nephrotic syndrome?
Infections due to low serum Ig
Edema/ascites, and increased hepatic synthesis due to hypoalbuminemia
Hypercoagulability due to decreased coag factors
314
What are causes of nephrotic syndrome?
315
What is Minimal Change Disease?
Puffy, periorbital edema, looks like michelin man
"Nil" disease
Looks normal under light microscope
Diffuse foot process effacement
316
What is the most common cause of nephrotic syndromein children?
Minimal change disease
317
What is the cause of minimal change disease?
Unknown - immune mediated
Negative immunofluorescence
Steroid responseive
Sometimes follows febrile disease
Alterations in lymphocyte populations
318
What is Membranous Nephropathy?
Most common cause of nephrotic syndrome
319
What do you see here?
Membranous nephropathy
320
What is the most common cause of nephrotic syndrome in adults?
Membranous nephropathy
321
What are causes of membranous nephropathy?
INfections (hep B, syphilis)
Malignancy (solid tumors)
Autoimmune disease (lupus)
Meds (gold, penicillamine)
322
What is FSGS?
Focal Segmental Glomerulosclerosis
323
What is focal segmental glomerulosclerosis?
Increasingly common cause of nephrotic syndrome - most common in blacks
Multifactorial:
Hyperfiltration (remnant kidney, obesity)
Infections (HIV, parvo B19)
Meds (bisphosphonates, IFN)
Genetic
324
What is the most common cause of nephrotic syndrome in blacks?
Focal Segmental Glomerulosclerosis
325
What are Familial Nephrotic Syndromes?
Nephrin and Podocin (NPHS1 and NPHS2 respectively) mutations
Produce nephrotic syndromes
326
What is diabetic nephropathy?
LEading cause of end stage renal disease - but doesn't often produce nephrotic syndrome
327
What do we see here?
Kimmelsteil-Wilson Nodules + increased goo in mesangium
Diabetic Nephropathy
328
What is amyloid nephropathy?
Rare disease that commonly causes nephrotic syndrome
Congo Red Stain
329
What is this?
Amyloid Nephropathy
330
How do you treat nephrotic syndrome?
Remove/Treat underlying cause (tumor, Hep B, weight loss, ARVs)
Reduce proteinuria (antihypertensives, ACEi/ARB)
Immunosuppression therapy
Treat complications (diuretics, anticoag, statins, antibiotics)
331
Why do we give immunosuppression for membranous nephropathy/
Immune complex disease
Spontaneous remission
May respond
332
Why do we give immunosuppression for Minimal Change disease?
No immune complexes, genetic basis and may follow febrile illness
Typically responds well to steroids though
333
What is the rationale for immunosuppression in FSGS?
Focal Segmental Glomerulosclerosis
No immune complexes, minimal inflation; recurs after transplant; has infectious and genetic causes
Generally less responsive
334
What is the commonality of all nephrotic syndrome diseases?
Abnormalities in the glomerular filtration barrier
Podocyte injury is the common thread
335
What is nephritis?
Inflammation of the kidney
336
What is glomerulonephritis?
Inflammation fo the glomeruli
337
What is Nephritic syndrome?
Constellation of:
Hematuria (typically with RBC casts)
Proteinuria (leaky filter)
Renal Failure (decreased GFR, increased serum creatinine
338
What are differences between Nephrotic and Nephritic syndrome?
Nephrotic -\> damaged filtration barrier that leaks protein but not RBCs
Nephritic -\> Hematuria including RBC casts and/or dysmorphic RBC in urine (larger hole in filter)
Nephritic needs hematuria for diagnosis
339
What is hematuria?
RBCs may enter urine anywhere from glomerulus to tip of urethra
Need to evaluate fam hx, coexisting illnesses, systemic inflammatory disease, renal failure, and other clinical contexts
340
What are soem major renal problems associated with hematuria?
GLomerulonephritis
Thin basement membrane disease
Alport syndrome (hereditary nephritis)
Polycystic kidney disease)
RCC
Interstitial nephritis
Renal vein thrombosis
341
What do you see here?
RBC cast -\> glomerulonephritis until proven otherwise
342
What do you see here?
Dysmorphic RBCs, -\> Glomerulonephritis until proven otherwise
343
What are clues that can indicate glomerulonephritis?
Hematuria (microscopic)
RBC casts
Proteinuria (\> 1g/day, may or may not be in nephrotic range)
Progressive renal failure
Hypertension
Peripheral edema
344
What are the classifications of glomerulonephritis
Antibody mediated - Ab against target in blood vessel
Immune complex deposition - deposition of immune complexes in vessel wall, resulting in immune attack
Pauci-immune - no immune complexes by immunofluorescence, but still inflammatory
345
30year-oldwhitemale
\_\_ Presents with fatigue, mild flank pain and edema
\_\_ Recent mild bloody sputum
\_\_ Exam remarkable for mild edema
\_\_ Labs remarkable for anemia, creatinine = 6.0 (normal ~1.0)
\_\_ Urinalysis with many RBC casts
Acute renal failure with RBC casts -\> rapidly progressive glomerulonephritis
346
What is anit-GBM disease?
Anti glomerular basememnt membrane disease
Antibodies (IgG) against basement membrane \_3 chain of type IV collagen
Ab-mediated neutrophil attack on BM
347
What is extracappillary or crescentic glomerulonephritis?
Anti-glomerular basememnt membrane disease
Diagnosed with fluorescent microscopy
IgG antibodies against basement membrane
348
What is Goodpasture's Disease?
Constellation of alveolar hemorrhage, glomerulonephritis, and anti-GBM antibodies
349
10 yo female well until 2 weeks ago when she developed strep throat
\_\_ Treated for 2 weeks with penicillin with good clinical response
\_\_ Now presents with \_\_coca cola\_\_ colored urine, creatinine 2.5 (normal\<1), hypertension, moderate peripheral edema
\_\_ 24 hour urine with 2g protein
\_\_ UA with many dysmorphic RBC\_\_s, RBC casts
\_\_ Renal US with echogenic, mildly enlarged kidneys
Post-streptococcal Glomerulonephritis
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350
What do we see here?
Post-Streptococcal Glomerulonephritis
Endocapillary glomerulonpehritis - many cells, but within capillaries
351
What do you see on immunofluorescence in post-strept glomerulonephritis?
Granular deposits - unlikely to be antibody to basement membrane
352
What do we see here?
Granular deposits in the glomreulus
Likely from post-strpet glomerulonephrtitis
353
What do we see here?
Electron densities under podocytes - Ab-Ag complex deposition in basement membrane
354
What is post-strpetococcal glomerulonephritis?
COmmonly in children
2 weeks after pharyngitis caused by Group A \_-hemolytic streptococcus (~3 weeks after skin infections)
Diagnosis clinically
Caused by deposition of antiodies in basement bmembrane, passively; Either immune complex or direct deposition
Supportive treatment, typically resolves
355
35 yo Asian male first told he had blood in the urine 6 years ago (no gross hematuria)
\_\_ Creatinine 1.4mg/dL (1.3 a year ago)
\_\_ Has mild hypertension, microscopic hematuria with rbc casts
\_\_ 24 hour urine with 2.5g of protein (normal \<150mg)
\_\_ Other workup unremarkable
Chronic glomerulonephritis
356
What do you see here?
Increased cellularity and matrix in mesangial regions
IgA nephropathy
Diagnosed with immunofluorescence
357
What is IgA nephropathy?
Most common form of glomerulonephritis worldwide
More common in Asians, uncommon in Africans
Passive deposition of IgA in mesangium
358
What do we see here?
Membranoproliferative glomerulonephritis
Thickened basement membranes and expansion of mesangial regions
359
32 yo woman with history of injection drug use
\_\_ Creatinine now 2.0 (was 1.0 a year ago, 1.5 6 months ago)
\_\_ Has microscopic hematuria with RBC casts, palpable purpura on exam
\_\_ 24 hour protein with 1.5g protein
\_\_ Other labs:
\_\_ Hepatitis C positive
\_\_ low serum complement (suggests consumption by immune complexes
Membranoproliferative glomerulonephritis
360
What is membranoproliferative glomerulonephritis?
Deposition of immune complexes in basement membrane
Most often due to Hep C infection
Slowly progressive - Treatment focused on treating underlying viral infection
Detectable cryoglobulines and immune complexes wiht HCV viral proteins
See granular complement deposition on inmmunofluorescence
361
25 yo woman without previous PMH or family history with recent onset of polyarthritis, anemia. Now with peripheral edema, creatinine 2.8, microscopic hematuria (with RBC casts) and 4g protein excretion/day
\_\_ RBC casts in urine
Rapidly porgresive glomerulonephritis until proven otherwise
362
What do we see here?
SLE diffuse proliferative glomerulonephritis
Thickened basement membranes and extra cells occluidng capillary loops
363
What is lupus nephritis?
4 forms
1) mesangial - immune deposits in mesangium only (benign)
2) focal proliferative GN - \< 50% involved (good prognosis)
3) diffuse proliferative GN - \>50% involved; most common in SLE, (poor prognosis)
4) Membranous glomerulopathy - No inflammation, Ig deposits and thickened BM; Nephrotic syndrome, not nephritic
364
What are immune complex mediated glomerulonephritis?
Post strept (post infectious)
IgA nephropathy/ HSP
Cryoglobulinemic vasculitis (hep C associated)
Lupus nephritis
365
What do we see here?
Crescentic glomerulonephritis
Pauci-immune (no immune deposits)
Seen in :
\_\_ Anti-GBM disease
\_\_\_\_ Lupus nephritis
\_\_ GPA/Wegener\_\_s granulomatosis
\_\_ Microscopic polyangiitis
\_\_ Isolated pauci- immune glomerulonephritis
366
What are common diseases characterized by pauci-immune GN?
Granulomatosis with polyangiitis (Wegener's granulomatosis)
Microscopic polyangiitis
Isolated pauci-immune glomerulonephritis
367
What is Granulomatosis with polyangiitis (GPA) or Wegener's Granulomatosis?
Small vessel vasculitis - necrotizing granulmomatous inflammation
Most commonly involved in Upper resp. tract, lungs, kidneys, and other organs
Positive cANCA and anti proteinase 3
368
What is c-ANCA seen in?
Granulomatous respiratory tract disease (GPA/Wegener's Granulomatosis)
369
What is p-ANCA seen in?
Isolated pauci-glomerulonephritis of kidneys
370
What is autosomal dominant polycysitic kidney disease?
Most common monogenetic disease in humans inherited autosomally
Most are asymptomatic until late, presents with:
abdominal distension duet o massively enlarged kidneys
Renal failure
pain, hematuria due to cyst rupture
small percentage develop intracranial arterial aneurysims
cysts in liver and/or pancreas
Renal
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